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Rheumatoid arthritis (RA) is an inflammatory disease associated with intense angiogenesis and vascular expression of integrin [small alpha, Greek]v[small beta, Greek]3.Intra-articular administration of a cyclic peptide antagonist of integrin [small alpha, Greek]v[small beta, Greek]3 to rabbits with antigen-induced arthritis early in disease resulted in inhibition of synovial angiogenesis and reduced synovial cell infiltrate, pannus formation, and cartilage erosions. These effects were not associated with lymphopenia or impairment of leukocyte function. Furthermore, when administered in chronic, preexisting disease, the [small alpha, Greek]v[small beta, Greek]3 antagonist effectively diminished arthritis severity and was associated with a quantitative increase in apoptosis of the angiogenic blood vessels. Therefore, angiogenesis appears to be a central factor in the initiation and persistence of arthritic disease, and antagonists of integrin [small alpha, Greek]v[small beta, Greek]3 may represent a novel therapeutic strategy for RA.J.Clin. Invest. 103:47-54 (1999).