Neovascularization in the rheumatoid synovium plays an important role in the propagation of rheumatoid synovitis because the emigration of mononuclear cells and the growth of pannus are critically dependent on the development of small blood vessels. Inhibition of local vascular endothelial cell (EC) proliferation, which is essential for growth of these vessels, therefore, would have the potential to suppress rheumatoid inflammation. We investigated the effects of methotrexate (MTX), low doses of which are commonly administered to rheumatoid arthritis patients, on DNA synthesis by human umbilical vein EC in vitro and on rabbit corneal neovascularization in vivo. MTX inhibited both basal and EC growth factor-stimulated tritiated deoxyuridine (3H-UdR) incorporation into EC in a dose-dependent manner. Significant inhibition was observed at a concentration of 5 X 10-9M, which is that attained in the serum of treated patients. Neovascularization in vivo was also suppressed by low-dose intramuscular injections. These results suggest that MTX has an antiangiogenic effect, and may suppress rheumatoid inflammation through the reduction of synovial small blood vessels responsible for mononuclear cell infiltration and proliferation of synovial tissue.

To investigate the effects of D-penicillamine (B-Pen) on

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As mononuclear cell infiltration and growth of pannus critically depend on synovial neovascularization in rheumatoid arthritis (RA), inhibition of the synovial blood vessels would have the potential to reduce rheumatoid inflammation. In this investigation, we studied the effect of gold sodium thiomalate (GST) and auranofin (AUR) on neovascularization in vivo by using a micropocket technique. Both GST and AUR suppressed rabbit corneal neovascularization in a dose-dependent fashion. Significant inhibition was observed by 3 mg/kg GST and 1 mg/kg AUR injected intravenously every other day. These injections maintained serum gold concentrations at the level of 2-5 micrograms/ml and less than 2 micrograms/ml in GST- and AUR-injected rabbits, respectively. These are concentrations attained in the serum or synovium of rheumatoid patients treated by gold compounds. Similar inhibition was observed by both intramuscular administration of GST and oral administration of AUR. In contrast, no inhibition was observed when non-steroidal anti-inflammatory drugs (NSAIDs; 20 mg/kg acetylsalicylic acid, 10 mg/kg ibuprofen and 10 mg/kg indomethacin) were injected intravenously on a daily basis. These results suggested that gold compounds have an antiangiogenic effect in vivo. The inhibition of neovascularization by gold compounds suggested that they may suppress rheumatoid synovitis by reducing the number of small blood vessels required for mononuclear cell infiltration and synovial tissue proliferation.

Abstract--As a part of the rheumatoid synovial tissue reaction, proliferating synovial cells penetrate the cartilage in the forro of a pannus, and cartilage destruction takes place in the zone between the cells and cartilage. The cellular origin of rheumatoid pannus has been debated by many investigators, and ir is accepted that fibroblast proliferation, endothelial cell proliferation and monocyte chemotaxis ate probably involved. It has been observed that fibroblasts in the pannus share properties of the fibroblasts and chondrocytes. Mast cell activation is frequently associated with proinflammatory cytokine and metalloprotease expression, suggesting ah important role for the mast cell in mediating matrix degradation. The mechanism of interaction of polymorphonuclear leukocytes with immune complexes trapped in rheumatoid cartilage resembles that associated with phenomenon of frustrated phagocytosis. Increased levels of IL-1 in the rheumatoid joint may play ah important role in joint destruction by stimulation of pannus formation through induction of synovial cell attachment to the articular surface. Synovial cell attachment to cartilage may be the initial step in pannus formation. We have recently shown that the increased expression of VLA-5 and ICAM-I at the cartilage-pannus junction may result from the interaction of synovial mononuclear cells with matrix proteins. Therefore, we have raised the possibility that VLA-5 may facilitate the growth of pannus by virtue of its ability to react with fibronectin with resulting proliferation of the synoviocytes of the pannus. Further study will be needed in order to understand the precise mechanism of cartilage erosion and pannus formation in the various arthritic disorders.