The Role of TNFα in the Pathogenesis of Rheumatoid Synovitis
© Current Science Ltd 2000
Published: 15 November 1999
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 . Circulating lymphocyte count is increased in a dose-dependent manner. Further studies have shown a reduction in chemokine expression . 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 . 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 .
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 .
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.
- Maini RN, Taylor PC: Anti-cytokine therapy for rheumatoid arthritis in the clinic. Annu Rev Med. 1999,Google Scholar
- Maini RN, Elliott MJ, Brennan FM, et al: Monoclonal anti-TNFα antibody as a probe of pathogenesis and therapy of rheumatoid disease. Immunol Rev. 1995, 144: 195-223.PubMedView ArticleGoogle Scholar
- Charles P, Elliott MJ, Davis D, et al: Regulation of cytokines, cytokine inhibitors and acute phase proteins following anti-TNFα therapy in rheumatoid arthritis. J Immunol. 1999, 163: 1521-1528.PubMedGoogle Scholar
- Tak PP, Taylor PC, Breedveld FC, et al: Decrease in cellularity and expression of adhesion molecules by anti-TNFα monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1996, 39: 1077-1081.PubMedView ArticleGoogle Scholar
- Paleolog EM, Hunt M, Elliott MJ, Feldmann M, Maini RN, Woody JN: Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor α antibody in rheumatoid arthritis. Arthritis Rheum. 1996, 39: 1082-1091.PubMedView ArticleGoogle Scholar
- Taylor PC, Peters AM, Paleolog E, et al: TNFalpha blockade in patients with rheumatoid arthritis reduces chemokines and leukocyte traffic to joints. Arthritis Rheum. 1999, 42: 448-54. 10.1002/1529-0131(199904)42:3<448::AID-ANR9>3.0.CO;2-8.PubMedView ArticleGoogle Scholar
- Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN: Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor α and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. 1998, 41: 1258-1265. 10.1002/1529-0131(199807)41:7<1258::AID-ART17>3.0.CO;2-1.PubMedView ArticleGoogle Scholar
- Brennan FM, Browne KA, Green PA, Jaspar J-M, Maini RN, Feldmann M: Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-α (cA2) therapy. Br J Rheumatol . 1997, 36: 643-650. 10.1093/rheumatology/36.6.643.PubMedView ArticleGoogle Scholar