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The Role of TNFα in the Pathogenesis of Rheumatoid Synovitis
Arthritis Research & Therapyvolume 1, Article number: S46 (1999)
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In this presentation we summarise the insights that have been gained into the role of TNFα in the pathophysiology of rheumatoid synovitis from observations in patients receiving infliximab (Remicade™), an anti-TNFα specific, neutralising, monoclonal antibody [1,2,3].
Serial synovial biopsies and serum samples before and after anti-TNF therapy show a reduction in the density of infiltrating lymphocytes and macrophages associated with a reduction in the expression of adhesion molecules E-selectin, ICAM-1 and VCAM-1 [4]. Circulating lymphocyte count is increased in a dose-dependent manner. Further studies have shown a reduction in chemokine expression [5]. Taken together these data have suggested that anti-TNF therapy alters leukocyte trafficking patterns with a net reduction in immune and inflammatory cell mass in the synovium.
Direct evidence of reduced retention of indium111-labelled polymorphonuclear cells in RA joints has recently been obtained following infliximab therapy [6]. This is likely to be due to effects on cell margination and migration but may also reflect a reduction in angiogenesis, a conclusion supported by the finding of a reduction in circulating VEGF concentrations and vessel density in serial synovial biopsies [7].
Neoangiogenesis not only increases delivery of inflammatory cells to the joint, but plays a part in cartilage and bone destruction in RA. It is not yet known whether anti-TNF treatment prevents structural damage but reduced serum levels of complexed (inactive) MMP-1 and MMP-3 are observed in treated patients [8].
Clinical trials have demonstrated that ~ 30% of patients do not appear to respond to anti-TNF therapy. Clearly other molecular mechanisms are involved in this sub-population. In the majority of RA patients, however, TNFα plays a key role in the expression of synovitis. The need for continuing therapy to control disease expression implies that other, as yet unidentified, factors are involved in maintaining the chronicity of disease.
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Keywords
- Infliximab
- Synovitis
- Vessel Density
- Infiltrate Lymphocyte
- Cell Margination
