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  • Review Article
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Role for TNF in atherosclerosis? Lessons from autoimmune disease

Abstract

Inflammatory pathways have been implicated in the initiation and progression of cardiovascular diseases. Accelerated atherosclerosis has been described in patients with chronic inflammatory diseases, particularly rheumatoid arthritis, disproportionate to individuals' detectable traditional vascular risk factors. This finding suggests that other pathways associated with inflammation might account for increased vascular risk in such diseases. Highly specific biologic agents can precisely block the activity of cytokines generated during inflammatory cascades; the effects of these inflammatory moieties on vascular physiology and overall risk of cardiovascular events has been directly evaluated. This Review summarizes key epidemiologic, physiologic and model data, which together suggest that tumor necrosis factor, a pivotal cytokine in the inflammatory cascade, is directly involved in vascular pathophysiology and that its inhibition might confer an overall advantage to the recipient. Moreover, such data obtained in chronic inflammatory diseases likely have relevance to primary atherosclerosis.

Key Points

  • A variety of chronic inflammatory disorders confer increased risk of cardiovascular disease and attendant early mortality

  • Tumor necrosis factor (TNF) is a key cytokine that mediates effector pathways in both inflammatory disease target tissues and in atherosclerotic vessels

  • Clinical TNF blockade for treating inflammatory arthritis modulates vascular risk factors, generally in a beneficial direction, but there is a need for further data

  • Epidemiologic data suggest that TNF blockade, and inflammatory suppression in general, might have beneficial effects on vascular outcomes in patients with inflammatory arthritis; however, definitive data are lacking

  • Current data do not support the use of TNF antagonists as the primary intervention for the treatment or prevention of cardiovascular disease

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Figure 1: TNF remains on the cell membrane as a functional membrane protein, or is solubilized via the action of a membrane-bound cleaving enzyme (TACE).
Figure 2: TNF might cause atherosclerosis through actions on leukocytes, endothelial cells and adipocytes.
Figure 3: Effects of TNF blockade on systemic inflammation, surrogate vascular and metabolic markers and CVD events.

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References

  1. McInnes, I. B. & Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Immunol. 7, 429–442 (2007).

    Article  CAS  Google Scholar 

  2. Feldmann, M., Brennan, F. M. & Maini, R. N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996).

    Article  CAS  Google Scholar 

  3. Zhang, H. et al. Role of TNF-alpha in vascular dysfunction. Clin. Sci. (Lond.). 116, 219–230 (2009).

    Article  CAS  Google Scholar 

  4. Grisar, J. et al. Endothelial progenitor cells in active rheumatoid arthritis: effects of tumournecrosis factor and glucocorticoid therapy. Ann. Rheum. Dis. 66, 1284–1288 (2007).

    Article  CAS  Google Scholar 

  5. Quinn, K., Henriques, M., Parker, T., Slutsky, A. S. & Zhang, H. Human neutrophil peptides: a novel potential mediator of inflammatory cardiovascular diseases. Am. J. Physiol. Heart Circ. Physiol. 295, H1817–H1824 (2008).

    Article  CAS  Google Scholar 

  6. Zhao, S. P. & Dong, S. Z. Effect of tumor necrosis factor alpha on cholesterol efflux in adipocytes. Clin. Chim. Acta 389, 67–71 (2008).

    Article  CAS  Google Scholar 

  7. Nguyen, M. T. et al. JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J. Biol. Chem. 280, 35361–35371 (2005).

    Article  CAS  Google Scholar 

  8. Van Doornum, S., McColl, G. & Wicks, I. P. Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis? Arthritis Rheum. 46, 862–873 (2002).

    Article  CAS  Google Scholar 

  9. Capell, H., McCarey, D., Madhok, R. & Hampson, R. “5D” Outcome in 52 patients with rheumatoid arthritis surviving 20 years after initial disease modifying antirheumatic drug therapy. J. Rheumatol. 29, 2099–2105 (2002).

    CAS  PubMed  Google Scholar 

  10. Wallberg-Jonsson, S., Ohman, M. L. & Dahlqvist, S. R. Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden. J. Rheumatol. 24, 445–451 (1997).

    CAS  PubMed  Google Scholar 

  11. del Rincón, I. D., Williams, K., Stern, M. P., Freeman, G. L. & Escalante, A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 44, 2737–2745 (2001).

    Article  Google Scholar 

  12. Gonzalez-Gay, M. A. et al. HLA-DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis. Arthritis Rheum. 57, 125–132 (2007).

    Article  CAS  Google Scholar 

  13. Sattar, N., McCarey, D. W., Capell, H. & McInnes, I. B. Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 108, 2957–2963 (2003).

    Article  Google Scholar 

  14. Aviña-Zubieta, J. A. et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 59, 1690–1697 (2008).

    Article  Google Scholar 

  15. Hannawi, S., Haluska, B., Marwick, T. H. & Thomas, R. Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation. Arthritis Res. Ther. 9, R116 (2007).

    Article  Google Scholar 

  16. Hahn, B. H., Grossman, J., Ansell, B. J., Skaggs, B. J. & McMahon, M. Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res. Ther. 10, 213 (2008).

    Article  Google Scholar 

  17. Cheng, X. et al. The Th17/Treg imbalance in patients with acute coronary syndrome. Clin. Immunol. 127, 89–97 (2008).

    Article  CAS  Google Scholar 

  18. Pasceri, V. & Yeh, E. T. A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation 100, 2124–2126 (1999).

    Article  CAS  Google Scholar 

  19. Feldmann, M., Brennan, F. M. & Maini, R. N. Rheumatoid arthritis. Cell 85, 307–310 (1996).

    Article  CAS  Google Scholar 

  20. Brennan, F. M., Chantry, D., Jackson, A., Maini, R. & Feldmann, M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2, 244–247 (1989).

    Article  CAS  Google Scholar 

  21. Keffer, J. et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991).

    Article  CAS  Google Scholar 

  22. Williams, R. O., Feldmann, M. & Maini, R. N. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl Acad. Sci. USA 89, 9784–9788 (1992).

    Article  CAS  Google Scholar 

  23. Maini, R. et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354, 1932–1939 (1999).

    Article  CAS  Google Scholar 

  24. Feldmann, M. & Maini, R. N. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu. Rev. Immunol. 19, 163–196 (2001).

    Article  CAS  Google Scholar 

  25. Bathon, J. M. et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N. Engl. J. Med. 343, 1586–1593 (2000).

    Article  CAS  Google Scholar 

  26. Weinblatt, M. E. et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 48, 35–45 (2003).

    Article  CAS  Google Scholar 

  27. Hänsel, S., Lässig, G., Pistrosch, F. & Passauer, J. Endothelial dysfunction in young patients with long-term rheumatoid arthritis and low disease activity. Atherosclerosis 170, 177–180 (2003).

    Article  Google Scholar 

  28. Booth, A. D. et al. Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation. Circulation 109, 1718–1723 (2004).

    Article  CAS  Google Scholar 

  29. Gonzalez-Juanatey, C. et al. Endothelial dysfunction in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis Rheum. 57, 287–293 (2007).

    Article  CAS  Google Scholar 

  30. Hürlimann, D. et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 106, 2184–2187 (2002).

    Article  Google Scholar 

  31. Irace, C. et al. Effect of anti TNFalpha therapy on arterial diameter and wall shear stress and HDL cholesterol. Atherosclerosis 177, 113–118 (2004).

    Article  CAS  Google Scholar 

  32. Laurent, S. et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 37, 1236–1241 (2001).

    Article  CAS  Google Scholar 

  33. Wilkinson, I. B. et al. Pulse-wave analysis: clinical evaluation of a noninvasive, widely applicable method for assessing endothelial function. Arterioscler. Thromb. Vasc. Biol. 22, 147–152 (2002).

    Article  CAS  Google Scholar 

  34. Weber, T. et al. Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation 109, 184–189 (2004).

    Article  Google Scholar 

  35. Mäki-Petäjä, K. M. et al. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy. Circulation 114, 1185–1192 (2006).

    Article  Google Scholar 

  36. Avalos, I. et al. Increased augmentation index in rheumatoid arthritis and its relationship to coronary artery atherosclerosis. J. Rheumatol. 34, 2388–2394 (2007).

    PubMed  Google Scholar 

  37. Van Doornum, S., McColl, G. & Wicks, I. P. Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis. Rheumatology (Oxford) 44, 1428–1432 (2005).

    Article  CAS  Google Scholar 

  38. Van Doornum, S., McColl, G. & Wicks, I. P. Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis. Ann. Rheum. Dis. 63, 1571–1575 (2004).

    Article  CAS  Google Scholar 

  39. Jonsson, S. W. et al. Increased prevalence of atherosclerosis in patients with medium term rheumatoid arthritis. J. Rheumatol. 28, 2597–2602 (2001).

    CAS  PubMed  Google Scholar 

  40. Gonzalez-Juanatey, C. et al. High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis Rheum. 57, 1074–1780 (2007).

    Article  Google Scholar 

  41. Gonzalez-Juanatey, C., Llorca, J., Garcia-Porrua, C., Martin, J. & Gonzalez-Gay, M. A. Effect of anti-tumor necrosis factor alpha therapy on the progression of subclinical atherosclerosis in severe rheumatoid arthritis. Arthritis Rheum. 55, 150–153 (2006).

    Article  CAS  Google Scholar 

  42. Del Porto, F. et al. Response to anti-tumour necrosis factor alpha blockade is associated with reduction of carotid intima–media thickness in patients with active rheumatoid arthritis. Rheumatology (Oxford) 46, 1111–1115 (2007).

    Google Scholar 

  43. Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L. & Spiegelman, B. M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Invest. 95, 2409–2415 (1995).

    Article  CAS  Google Scholar 

  44. Dandona, P. et al. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J. Clin. Endocrinol. Metab. 83, 2907–2910 (1998).

    CAS  PubMed  Google Scholar 

  45. Gonzalez-Gay, M. A. et al. Influence of anti-TNF-alpha infliximab therapy on adhesion molecules associated with atherogenesis in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 24, 373–379 (2006).

    CAS  PubMed  Google Scholar 

  46. Yazdani-Biuki, B. et al. Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti-TNF-alpha antibody infliximab. Eur. J. Clin. Invest. 34, 641–642 (2004).

    Article  CAS  Google Scholar 

  47. Kiortsis, D. N., Mavridis, A. K., Vasakos, S., Nikas, S. N. & Drosos, A. A. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann. Rheum. Dis. 64, 765–766 (2005).

    Article  CAS  Google Scholar 

  48. Sarwar, N., Sattar, N., Gudnason, V. & Danesh, J. Circulating concentrations of insulin markers and coronary heart disease: a quantitative review of 19 Western prospective studies. Eur. Heart J. 28, 2491–2497 (2007).

    Article  Google Scholar 

  49. British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, Stroke Association. JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 91 (Suppl. 5), v1–v52 (2005).

  50. Allanore, Y., Kahan, A., Sellam, J., Ekindjian, O. G. & Borderie, D. Effects of repeated infliximab therapy on serum lipid profile in patients with refractory rheumatoid arthritis. Clin. Chim. Acta 365, 143–148 (2006).

    Article  CAS  Google Scholar 

  51. Vis, M. et al. Short term effects of infliximab on the lipid profile in patients with rheumatoid arthritis. J. Rheumatol. 32, 252–255 (2005).

    CAS  PubMed  Google Scholar 

  52. Popa, C. et al. Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis. Ann. Rheum. Dis. 64, 303–305 (2005).

    Article  CAS  Google Scholar 

  53. Sattar, N. et al. Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: a double-blind, placebo-controlled study. Arthritis Rheum. 56, 831–839 (2007).

    Article  CAS  Google Scholar 

  54. Peters, M. J. et al. Changes in lipid profile during infliximab and corticosteroid treatment in rheumatoid arthritis. Ann. Rheum. Dis. 66, 958–961 (2007).

    Article  CAS  Google Scholar 

  55. Popa, C. et al. Modulation of lipoprotein plasma concentrations during long-term anti-TNF therapy in patients with active rheumatoid arthritis. Ann. Rheum. Dis. 66, 1503–1507 (2007).

    Article  CAS  Google Scholar 

  56. Rossner, S. & Lofmark, C. Dyslipoproteinaemia in patients with active, chronic polyarthritis. A study on serum lipoproteins and triglyceride clearance (intravenous fat tolerance test). Atherosclerosis 28, 41–52 (1977).

    Article  CAS  Google Scholar 

  57. Vermont, C. L. et al. Serum lipids and disease severity in children with severe meningococcal sepsis. Crit. Care Med. 33, 1610–1615 (2005).

    Article  CAS  Google Scholar 

  58. Alexopoulos, C. G., Pournaras, S., Vaslamatzis, M., Avgerinos, A. & Raptis, S. Changes in serum lipids and lipoproteins in cancer patients during chemotherapy. Cancer Chemother. Pharmacol. 30, 412–416 (1992).

    Article  CAS  Google Scholar 

  59. Akgun, S., Ertel, N. H., Mosenthal, A. & Oser, W. Postsurgical reduction of serum lipoproteins: interleukin-6 and the acute-phase response. J. Lab. Clin. Med. 131, 103–108 (1998).

    Article  CAS  Google Scholar 

  60. Popa, C. et al. Anti-inflammatory therapy with TNFα inhibitors improves HDL-cholesterol anti-oxidative capacity in rheumatoid arthritis patients. Ann. Rheum. Dis. doi:10.1136/ard.2008.092171 (2008).

  61. Jick, S. S., Choi, H., Li, L., McInnes, I. B. & Sattar, N. Hyperlipidaemia, statin use and the risk of developing rheumatoid arthritis. Ann. Rheum. Dis. 68, 546–551 (2008).

    Article  Google Scholar 

  62. Listing, J. et al. Does tumor necrosis factor alpha inhibition promote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum. 58, 667–677 (2008).

    Article  CAS  Google Scholar 

  63. Jacobsson, L. T. et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J. Rheumatol. 32, 1213–1218 (2005).

    CAS  PubMed  Google Scholar 

  64. Dixon, W. G. et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 56, 2905–2912 (2007).

    Article  CAS  Google Scholar 

  65. Dixon, W. G. et al. Rates of myocardial infarction and cerebrovascular accident are reduced in patients with rheumatoid arthritis treated with anti-TNF therapy compared to those treated with traditional DMARDS: results from the BSR biologics register. Ann. Rheum. Dis. 65 (Suppl. II), 109 (2006).

    Google Scholar 

  66. Mann, D. L. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ. Res. 91, 988–998 (2002).

    Article  CAS  Google Scholar 

  67. Levine, B., Kalman, J., Mayer, L., Fillit, H. M. & Packer, M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N. Engl. J. Med. 323, 236–241 (1990).

    Article  CAS  Google Scholar 

  68. Chung, E. S. et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107, 3133–3140 (2003).

    Article  CAS  Google Scholar 

  69. Mann, D. L. et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109, 1594–1602 (2004).

    Article  CAS  Google Scholar 

  70. Kwon, H. J., Coté, T. R., Cuffe, M. S., Kramer, J. M. & Braun, M. M. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann. Intern. Med. 138, 807–811 (2003).

    Article  Google Scholar 

  71. Nicola, P. J. et al. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum. 52, 412–420 (2005).

    Article  Google Scholar 

  72. Smolen, J. S. et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371, 987–997 (2008).

    Article  CAS  Google Scholar 

  73. Choy, E. & Sattar, N. Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann. Rheum. Dis. 68, 460–469 (2009).

    Article  CAS  Google Scholar 

  74. Gonzalez-Juanatey, C. et al. Short-term improvement of endothelial function in rituximab-treated rheumatoid arthritis patients refractory to tumor necrosis factor alpha blocker therapy. Arthritis Rheum. 59, 1821–1824 (2008).

    Article  CAS  Google Scholar 

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Correspondence to Iain B. McInnes.

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G. E. McKellar has received speaker fees from Abbott. D. W. McCarey has served on an advisory board for Wyeth, and has received speaker fees and conference funding from Wyeth and Abbott. N. Sattar has consulted on TNF blockers for Abbott, consulted for Roche, and received speakers fees from both companies. I. B. McInnes consulted on TNF blockers for, and received unrestricted research grant support from, Schering, Wyeth and Abbott.

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McKellar, G., McCarey, D., Sattar, N. et al. Role for TNF in atherosclerosis? Lessons from autoimmune disease. Nat Rev Cardiol 6, 410–417 (2009). https://doi.org/10.1038/nrcardio.2009.57

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