TNF-alpha blockade induces a reversible but transient effect on endothelial dysfunction in patients with long-standing severe rheumatoid arthritis (original) (raw)

Abstract

Considerable evidence indicates that patients with rheumatoid arthritis (RA) are at greater risk of developing atherosclerosis and cardiovascular disease. Recent studies support the predictive ability of endothelial function measures for subsequent atherosclerotic events. We have investigated the effects of infliximab, a chimeric monoclonal anti-tumor necrosis factor (TNF) antibody, on endothelial vasodilation, measured by brachial ultrasonography and on the levels of inflammatory biomarkers and adhesion molecules in ten consecutive patients with severe long-standing RA, despite methotrexate therapy, during the loading phase of infliximab therapy. Flow-mediated dilation (FMD) in RA patients at baseline was significantly impaired compared with healthy controls (7.71 ± 2.78% vs 14.91 ± 6.41%; p = 0.008) and improved significantly after infliximab infusion (12.63 ± 1.63% vs 7.71 ± 2.78%; p = 0.005). At baseline, a statistically significant correlation between C-reactive protein levels and FMD was found (r = −0.69, p = 0.026). However, this improvement was transitory, as FMD values returned to baseline values before each infliximab infusion at weeks 2, 6 and 14. There were no significant differences in baseline brachial artery diameter between visits, although at each time, the diameter was increased. According to European League Against Rheumatism response criteria, all ten patients were good responders. No significant differences were observed in intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, vascular endothelial growth factor and E-selectin plasma levels before and after each infusions. This study demonstrates that endothelial dysfunction is a reversible phenomenon in RA. The addition of anti-TNFα treatment reduces inflammatory symptoms in patients with severe RA. The improvement of endothelial function during the loading phase of therapy is transitory, suggesting an enhanced and persistent TNF-α generation within the arterial wall.

Loading...

Loading Preview

Sorry, preview is currently unavailable. You can download the paper by clicking the button above.

References (26)

  1. Van Doornum S, McColl G, Wicks IP et al (2002) Accelerated atherosclerosis. An extraarticular feature of rheumatoid arthritis. Arthritis Rheum 46:862-873
  2. Ferraccioli GF, Gremese E (2004) Autoantibodies and thrombophilia in RA: TNFalpha and TNFalpha blockers. Ann Rheum Dis 63: 613-615
  3. Kvien TK (2004) Epidemiology and burden of illness of rheumatoid arthritis. Pharmacoeconomics 22(S2):1-12
  4. Symmons DP, Jones MA, Scott DL et al (1998) Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 25:1072-1077
  5. Pasceri V, Yeh ET (1999) A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation 100:2124-2126
  6. Bacon PA, Stevens RJ, Carruthers DM et al (2002) Accelerated atherogenesis in autoimmune rheumatic diseases. Autoimmun Rev 1:338-347
  7. Pradhan AD, Rifai N, Ridker PM (2002) Soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and the development of symptomatic peripheral arterial disease in men. Circulation 106:820-825
  8. Hurlimann D, Forster A, Noll G et al (2002) Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 106:2184-2187
  9. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A et al (2004) Transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor α antibody. Arthritis Rheum 51:447-450
  10. Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315-324
  11. Van Gestel AM, Prevoo ML, Van't Hof MA et al (1996) Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League against Rheuma- tism Criteria. Arthritis Rheum 39:34-40
  12. Coretti MC, Anderson TJ, Benjamin EJ, International Brachial Artery Reactivity Task Force et al (2002) Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 16: 257-265
  13. Del Rincon I, Freeman GL, Haas RW et al (2005) A Relative contribution of cardiovascular risk factors and rheumatoid arthritis clinical manifestations to atherosclerosis. Arthritis Rheum 52:3413-3423
  14. Wang P, Ba ZF, Chaudry IH (1994) Administration of tumor necrosis factorα in vivo depresses endothelium dependent relaxation. Am J Physiol 266:2535-2541
  15. Young JL, Libby P, Schonbeck U (2002) Cytokines in the pathogenesis of atherosclerosis. Thromb Haemost 88:554-567
  16. Ross R (1999) Atherosclerosis-an inflammatory disease. N Engl J Med 340:115-126
  17. Hunt BJ (2000) The endothelium in atherogenesis. Lupus 9:189-193
  18. Lundman P, Eriksson MJ, Stuhlinger M et al (2001) Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine. J Am Coll Cardiol 38:111-116
  19. Al Suwaidi J, Higano ST, Holmes DR et al (2001) Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries. J Am Coll Cardiol 37:1523-1528
  20. Arcaro G, Cretti A Balzano S et al (2002) Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation 105:576-582
  21. Clarkson P, Celermajer DS, Donald AE et al (1996) Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J Am Coll Cardiol 28:573-579
  22. Kuvin JT, Patel AR, Sliney KA et al (2001) Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. J Am Coll Cardiol 38:1843-1849
  23. Anderson TJ, Uehata A, Gerhard MD et al (1995) Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 26:1235
  24. Irace C, Mancuso G, Fiaschi E et al (2004) Effect of anti TNFα therapy on arterial diameter and wall shear stress and HDL cholesterol. Atherosclerosis 177:113-118
  25. Vaudo G, Marchesi S, Gerli R et al (2004) Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity. Ann Rheum Dis 63:31-35
  26. Gonzalez-Juanatey C, Llorca J, Sanchez Andrade A et al (2006) Short-term adalimumab therapy improves endothelial function in