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Atherosclerosis in rheumatoid arthritis: is it all about inflammation?

Key Points

  • The prevalence and rate of progression of atherosclerosis is increased in rheumatoid arthritis (RA), and atherosclerotic plaques in patients with RA might have a rupture-prone phenotype

  • Atherosclerosis is a chronic inflammatory condition, and similarities exist in the cellular processes and cytokines involved in both atherosclerosis and rheumatoid synovitis

  • Cardiovascular disease (CVD) and RA share genetic and environmental risk factors, including polymorphisms in genes within the HLA region, smoking and obesity

  • The prevalence of some traditional CVD risk factors is increased in patients with RA, but traditional risk-prediction models perform poorly in this population

  • Chronic inflammation is closely linked with atherosclerosis in RA; burden of inflammation is associated with clinical and subclinical CVD, and PET can reveal arterial inflammation in patients with active RA

  • Although treatments for RA seem to have beneficial effects on cardiovascular event rates, mortality remains increased and further work is required to better estimate and treat cardiovascular risk in RA

Abstract

Rheumatoid arthritis (RA) has long been associated with increased cardiovascular risk, but despite substantial improvements in disease management, mortality remains high. Atherosclerosis is more prevalent in RA than in the general population, and atherosclerotic lesions progress at a faster rate and might be more prone to rupture, causing clinical events. Cells and cytokines implicated in RA pathogenesis are also involved in the development and progression of atherosclerosis, which is generally recognized as an inflammatory condition. The two diseases also share genetic and environmental risk factors, which suggests that patients who develop RA might also be predisposed to developing cardiovascular disease. In RA, inflammation and atherosclerosis are closely linked. Inflammation mediates its effects on atherosclerosis both through modulation of traditional risk factors and by directly affecting the vessel wall. Treatments such as TNF inhibitors might have a beneficial effect on cardiovascular risk. However, whether this benefit is attributable to effective control of inflammation or whether targeting specific cytokines, implicated in atherosclerosis, provides additional risk reduction is unclear. Further knowledge of the predictors of cardiovascular risk, the effects of early control of inflammation and of drug-specific effects are likely to improve the recognition and management of cardiovascular risk in patients with RA.

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Figure 1: Important pathological features common to both atherosclerotic plaque and the inflamed rheumatoid synovium.
Figure 2: Development of an atherosclerotic plaque.

References

  1. 1

    Maradit-Kremers, H. et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 52, 402–411 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Sololmon, D. H. et al. Patterns of cardiovascular risk in rheumatoid arthritis. Ann. Rheum. Dis. 65, 1608–1612 (2006).

    Article  Google Scholar 

  3. 3

    del Rincon, I., 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  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Libby, P. Inflammation in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 32, 2045–2051 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Rothwell, P. M. et al. Reanalysis of the final results of the european carotid surgery trial. Stroke 34, 514–523 (2003).

    Article  CAS  Google Scholar 

  7. 7

    Everett, B. M. et al. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am. Heart J. 166, 199–207 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Anderson, T. J. Assessment and treatment of endothelial dysfunction in humans. J. Am. Coll. Cardiol. 34, 631–638 (1999).

    Article  CAS  Google Scholar 

  10. 10

    Skaug, E. A., Madssen, E., Aspenes, S. T., Wisloff, U. & Ellingsen, O. Cardiovascular risk factors have larger impact on endothelial function in self-reported healthy women than men in the HUNT3 fitness study. PLoS ONE 9, e101371 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Chia, S. et al. Intra-arterial tumor necrosis factor α impairs endothelium-dependent vasodilatation and stimulates local tissue plasminogen activator release in humans. Arter. Thromb. Vasc. Biol. 23, 695–701 (2003).

    Article  CAS  Google Scholar 

  12. 12

    Legein, B., Temmerman, L., Biessen, E. & Lutgens, E. Inflammation and immune system interactions in atherosclerosis. Cell. Mol. Life Sci. 70, 3847–3869 (2013).

    Article  CAS  Google Scholar 

  13. 13

    Hansson, G. K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685–1695 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Sakakura, K. et al. Pathophysiology of atherosclerosis plaque progression. Heart Lung Circ. 22, 399–411 (2013).

    Article  Google Scholar 

  15. 15

    Sukhova, G. K. et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation 99, 2503–2509 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Sun, J. et al. Sustained acceleration in carotid atherosclerotic plaque progression with intraplaque hemorrhage: a long-term time course study. JACC Cardiovasc. Imaging 5, 798–804 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Redgrave, J. N. E., Lovett, J. K., Gallagher, P. J. & Rothwell, P. M. Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms. Circulation 113, 2320–2328 (2006).

    Article  CAS  Google Scholar 

  18. 18

    Kaptoge, S. et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur. Heart J. 35, 578–589 (2014).

    Article  CAS  Google Scholar 

  19. 19

    IL6R Genetics Consortium Emerging Risk Factors Collaboration. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 379, 1205–1213 (2012).

  20. 20

    Kerwin, W. S. et al. Inflammation in carotid atherosclerotic plaque: a dynamic contrast-enhanced MR imaging study. Radiology 241, 459–468 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Davies, J. R. et al. Identification of culprit lesions after transient ischemic attack by combined 18F fluorodeoxyglucose positron-emission tomography and high-resolution magnetic resonance imaging. Stroke 36, 2642–2647 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Sandoo, A., Veldhuijzen van Zanten, J. J. C. S., Metsios, G. S., Carroll, D. & Kitas, G. D. Vascular function and morphology in rheumatoid arthritis: a systematic review. Rheumatology (Oxford) 50, 2125–2139 (2011).

    Article  Google Scholar 

  23. 23

    Nagata-Sakurai, M. et al. Inflammation and bone resorption as independent factors of accelerated arterial wall thickening in patients with rheumatoid arthritis. Arthritis Rheum. 48, 3061–3067 (2003).

    Article  Google Scholar 

  24. 24

    Giles, J. T. et al. Longitudinal predictors of progression of carotid atherosclerosis in rheumatoid arthritis. Arthritis Rheum. 63, 3216–3225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Semb, A. G. et al. Carotid plaque characteristics and disease activity in rheumatoid arthritis. J. Rheumatol. 40, 359–368 (2013).

    Article  CAS  Google Scholar 

  26. 26

    Aubry, M. C. et al. Differences in atherosclerotic coronary heart disease between subjects with and without rheumatoid arthritis. J. Rheumatol. 34, 937–942 (2007).

    CAS  Google Scholar 

  27. 27

    van den Oever, I. A. M. et al. Rheumatoid arthritis is associated with systemic inflammation in coronary vessels [abstract]. Arthritis Rheum. 65 (Suppl. 10), 386 (2013).

    Google Scholar 

  28. 28

    Karpouzas, G. A. et al. Prevalence, extent and composition of coronary plaque in patients with srheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Ann. Rheum. Dis. 73, 1797–1804 (2014).

    Article  Google Scholar 

  29. 29

    Goodson, N., Marks, J., Lunt, M. & Symmons, D. Cardiovascular admissions and mortality in an inception cohort of patients with rheumatoid arthritis with onset in the 1980s and 1990s. Ann. Rheum. Dis. 64, 1595–1601 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Gabriel, S. E. et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 48, 54–58 (2003).

    Article  Google Scholar 

  31. 31

    Barton, A. & Worthington, J. Genetic susceptibility to rheumatoid arthritis: an emerging picture. Arthritis Care Res. 61, 1441–1446 (2009).

    Article  CAS  Google Scholar 

  32. 32

    Roberts, R. & Stewart, A. F. R. Genes and coronary artery disease: where are we? J. Am. Coll. Cardiol. 60, 1715–1721 (2012).

    Article  CAS  Google Scholar 

  33. 33

    Stahl, E. A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Farrall, M. et al. Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome 17. PLoS Genet. 2, e72 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Torkamani, A., Topol, E. J. & Schork, N. J. Pathway analysis of seven common diseases assessed by genome-wide association. Genomics 92, 265–272 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Karczewski, K. J. et al. Systematic functional regulatory assessment of disease-associated variants. Proc. Natl Acad. Sci. USA 110, 9607–9612 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Bowes, J. & Barton, A. Recent advances in the genetics of RA susceptibility. Rheumatology (Oxford) 47, 399–402 (2008).

    Article  CAS  Google Scholar 

  38. 38

    Paakkanen, R. et al. Proinflammatory HLA-DRB1*01-haplotype predisposes to ST-elevation myocardial infarction. Atherosclerosis 221, 461–466 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Shimane, K. et al. A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population. Ann. Rheum. Dis. 68, 377–383 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Fries, J. F. et al. HLA-DRB1 genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: frequency, severity, and treatment bias. Arthritis Rheum. 46, 2320–2329 (2002).

    Article  CAS  Google Scholar 

  41. 41

    Swanberg, M. et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat. Genet. 37, 486–494 (2005).

    Article  CAS  Google Scholar 

  42. 42

    Nolan, D. et al. Genome-wide linkage analysis of cardiovascular disease biomarkers in a large, multigenerational family. PLoS ONE 8, e71779 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Sarwar, N. et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 379, 1205–1213 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Ikonomidis, I., Lekakis, J., Vamvakou, G., Andreotti, F. & Nihoyannopoulos, P. Cigarette smoking is associated with increased circulating proinflammatory and procoagulant markers in patients with chronic coronary artery disease: effects of aspirin treatment. Am. Heart J. 149, 832–839 (2005).

    Article  CAS  Google Scholar 

  45. 45

    Chen, Y., Dawes, P. T., Packham, J. C. & Mattey, D. L. Interaction between smoking and polymorphism in the promoter region of the VEGFA gene is associated with ischemic heart disease and myocardial infarction in rheumatoid arthritis. J. Rheumatol. 38, 802–809 (2011).

    Article  CAS  Google Scholar 

  46. 46

    Lahiri, M. et al. Using lifestyle factors to identify individuals at higher risk of inflammatory polyarthritis (results from the European Prospective Investigation of Cancer-Norfolk and the Norfolk Arthritis Register (the EPIC-2-NOAR Study). Ann. Rheum. Dis. 73, 219–226 (2014).

    Article  Google Scholar 

  47. 47

    Mikuls, T. R. et al. Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis Rheumatol. 66, 1090–1100 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Mikuls, T. R. et al. Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis. Arthritis Rheum. 64, 3522–3530 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Bahekar, A. A., Singh, S., Saha, S., Molnar, J. & Arora, R. The prevalence and incidence of coronary heart disease is significantly increased in periodontitis: a meta-analysis. Am. Heart J. 154, 830–837 (2007).

    Article  Google Scholar 

  50. 50

    Edwards, C. J. et al. The autoantibody rheumatoid factor may be an independent risk factor for ischaemic heart disease in men. Heart 93, 1263–1267 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Cambridge, G., Acharya, J., Cooper, J. A., Edwards, J. C. & Humphries, S. E. Antibodies to citrullinated peptides and risk of coronary heart disease. Atherosclerosis 228, 243–246 (2013).

    Article  CAS  Google Scholar 

  52. 52

    Gonzalez, A. et al. Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients? Ann. Rheum. Dis. 67, 64–69 (2008).

    Article  CAS  Google Scholar 

  53. 53

    Arts, E. E. A. et al. Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis. Ann. Rheum. Dis. 74, 668–674 (2015).

    Article  CAS  Google Scholar 

  54. 54

    Boyer, J. F., Gourraud, P. A., Cantagrel, A., Davignon, J. L. & Constantin, A. Traditional cardiovascular risk factors in rheumatoid arthritis: a meta-analysis. Joint Bone Spine 78, 179–183 (2011).

    Article  Google Scholar 

  55. 55

    Montagna, G. L. et al. Insulin resistance is an independent risk factor for atherosclerosis in rheumatoid arthritis. Diabet. Vasc. Dis. Res. 4, 130–135 (2007).

    Article  Google Scholar 

  56. 56

    Mirjafari, H. et al. Seropositivity is associated with insulin resistance in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register (NOAR): an observational study. Arthritis Res. Ther. 13, R159 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Dessein, P. H., Joffe, B. I. Insulin resistance and impaired beta cell function in rheumatoid arthritis. Arthritis Rheum. 54, 2765–2775 (2006).

    Article  CAS  Google Scholar 

  58. 58

    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 

  59. 59

    Stavropoulos-Kalinoglou, A. et al. Anti-tumour necrosis factor α therapy improves insulin sensitivity in normal-weight but not in obese patients with rheumatoid arthritis. Arthritis Res. Ther. 14, R160 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Popa, C. et al. Circulating leptin and adiponectin concentrations during tumor necrosis factor blockade in patients with active rheumatoid arthritis. J. Rheumatol. 36, 724–730 (2009).

    Article  CAS  Google Scholar 

  61. 61

    Derdemezis, C. S. et al. Effects of a 6-month infliximab treatment on plasma levels of leptin and adiponectin in patients with rheumatoid arthritis. Fundam. Clin. Pharmacol. 23, 595–600 (2009).

    Article  CAS  Google Scholar 

  62. 62

    Targonska-Stepniak, B., Dryglewska, M. & Majdan, M. Adiponectin and leptin serum concentrations in patients with rheumatoid arthritis. Rheumatol. Int. 30, 731–737 (2010).

    Article  CAS  Google Scholar 

  63. 63

    Santos, M. J., Vinagre, F., Canas da Silva, J., Gil, V. & Fonseca, J. E. Body composition phenotypes in systemic lupus erythematosus and rheumatoid arthritis: a comparative study of Caucasian female patients. Clin. Exp. Rheumatol. 29, 470–476 (2011).

    CAS  Google Scholar 

  64. 64

    Giles, J. T. et al. Abdominal adiposity in rheumatoid arthritis: association with cardiometabolic risk factors and disease characteristics. Arthritis Rheum. 62, 3173–3182 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Kremers, H. M., Nicola, P. J., Crowson, C. S., Ballman, K. V. & Gabriel, S. E. Prognostic importance of low body mass index in relation to cardiovascular mortality in rheumatoid arthritis. Arthritis Rheum. 50, 3450–3457 (2004).

    Article  Google Scholar 

  66. 66

    Zhang, J. et al. The risk of metabolic syndrome in patients with rheumatoid arthritis: a meta-analysis of observational studies. PLoS ONE 8, e78151 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Toms, T. E. et al. Statin use in rheumatoid arthritis in relation to actual cardiovascular risk: evidence for substantial undertreatment of lipid-associated cardiovascular risk? Ann. Rheum. Dis. 69, 683–688 (2010).

    Article  CAS  Google Scholar 

  68. 68

    Hahn, B. H., Grossman, J., Chen, W. & McMahon, M. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J. Autoimmun. 28, 69–75 (2007).

    Article  CAS  Google Scholar 

  69. 69

    Georgiadis, A. et al. Atherogenic lipid profile is a feature characteristic of patients with early rheumatoid arthritis: effect of early treatment—a prospective, controlled study. Arthritis Res. Ther. 8, R82 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    McMahon, M. et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 54, 2541–2549 (2006).

    Article  CAS  Google Scholar 

  71. 71

    Charles-Schoeman, C. et al. Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis. Ann. Rheum. Dis. 71, 1157–1162 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Myasoedova, E. et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann. Rheum. Dis. 70, 482–487 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Robertson, J., Peters, M. J., McInnes, I. B. & Sattar, N. Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm. Nat. Rev. Rheumatol. 9, 513–523 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Navarro-Millan, I. et al. Changes in lipoproteins associated with methotrexate therapy or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial. Arthritis Rheum. 65, 1430–1438 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Papadopoulos, N. G. et al. Does cigarette smoking influence disease expression, activity and severity in early rheumatoid arthritis patients? Clin. Exp. Rheumatol. 23, 861–866 (2014).

    Google Scholar 

  76. 76

    Hyrich, K. L., Watson, K. D., Silman, A. J. & Symmons, D. P. M. Predictors of response to anti-TNFα therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 45, 1558–1565 (2006).

    Article  CAS  Google Scholar 

  77. 77

    Panoulas, V. F. et al. Hypertension in rheumatoid arthritis. Rheumatology (Oxford) 47, 1286–1298 (2008).

    Article  CAS  Google Scholar 

  78. 78

    Mattey, D. L. et al. Association of DRB1 shared epitope genotypes with early mortality in rheumatoid arthritis: results of eighteen years of followup from the early rheumatoid arthritis study. Arthritis Rheum. 56, 1408–1416 (2007).

    Article  CAS  Google Scholar 

  79. 79

    Farragher, T. M. et al. Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis. Arthritis Rheum. 58, 359–369 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Gorman, J. D. et al. Impact of shared epitope genotype and ethnicity on erosive disease: a meta-analysis of 3,240 rheumatoid arthritis patients. Arthritis Rheum. 50, 400–412 (2004).

    Article  Google Scholar 

  81. 81

    Thomson, W. et al. Quantifying the exact role of HLA–DRB1 alleles in susceptibility to inflammatory polyarthritis: results from a large, population-based study. Arthritis Rheum. 42, 757–762 (1999).

    Article  CAS  Google Scholar 

  82. 82

    Weyand, C. M., Xie, C. & Goronzy, J. J. Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis. J. Clin. Invest. 89, 2033–2039 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Farragher, T. M. et al. Association of a rheumatoid arthritis susceptibility variant at the CCL21 locus with premature mortality in inflammatory polyarthritis patients. Arthritis Care Res. 62, 676–682 (2010).

    Article  Google Scholar 

  84. 84

    Rodriguez-Rodriguez, L. et al. Genetic markers of cardiovascular disease in rheumatoid arthritis. Mediators Inflamm. 2012, 574817 (2012).

    PubMed  PubMed Central  Google Scholar 

  85. 85

    Wolfe, F. et al. The mortality of rheumatoid arthritis. Arthritis Rheum. 37, 481–494 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Naz, S. M., Farragher, T. M., Bunn, D. K., Symmons, D. P. & Bruce, I. N. The influence of age at symptom onset and length of followup on mortality in patients with recent-onset inflammatory polyarthritis. Arthritis Rheum. 58, 985–989 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Turesson, C., McClelland, R. L., Christianson, T. J. H. & Matteson, E. L. Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis. Ann. Rheum. Dis. 66, 70–75 (2007).

    Article  CAS  Google Scholar 

  88. 88

    Jacobsson, L. T. H. et al. Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians. Arthritis Rheum. 44, 1170–1176 (2001).

    Article  CAS  Google Scholar 

  89. 89

    Wallberg-Jonsson, S., Johansson, H., Ohman, M. L. & Rantapaa-Dahlqvist, S. Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis. A retrospective cohort study from disease onset. J. Rheumatol. 26, 2562–2571 (1999).

    CAS  PubMed  Google Scholar 

  90. 90

    Goodson, N. J. et al. Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year followup study of a primary care-based inception cohort. Arthritis Rheum. 52, 2293–2299 (2005).

    Article  CAS  Google Scholar 

  91. 91

    Rose, S. et al. A comparison of vascular inflammation in psoriasis, rheumatoid arthritis and healthy subjects by FDG-PET/CT: a pilot study. Am. J. Cardiovasc. Dis. 3, 273–278 (2013).

    PubMed  PubMed Central  Google Scholar 

  92. 92

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

    Article  CAS  Google Scholar 

  93. 93

    Tahara, N. et al. Vascular inflammation evaluated by 18F-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome. J. Am. Coll. Cardiol. 49, 1533–1539 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Rominger, A. et al. 18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease. J. Nuclear Med. 50, 1611–1620 (2009).

    Article  Google Scholar 

  95. 95

    Protogerou, A. et al. Arterial hypertension assessed “out-of-office” in a contemporary cohort of rheumatoid arthritis patients free of cardiovascular disease is characterized by high prevalence, low awareness, poor control and increased vascular damage-associated “white coat” phenomenon. Arthritis Res. Ther. 15, R142 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Peters, M. J. et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann. Rheum. Dis. 69, 325–331 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    JBS3 Board. Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart 100 (Suppl. 2), ii1–ii67 (2014).

  98. 98

    ATACC-RA Consortium. A TransAtlantic Cardiovascular risk Calculator for Rheumatoid Arthritis [online], (2015).

  99. 99

    Myasoedova, E., Gabriel, S. E., Green, A. B., Matteson, E. L. & Crowson, C. S. Impact of statin use on lipid levels in statin-naive patients with rheumatoid arthritis versus non-rheumatoid arthritis subjects: results from a population-based study. Arthritis Care Res. 65, 1592–1599 (2013).

    Article  CAS  Google Scholar 

  100. 100

    Semb, A. G., Holme, I., Kvien, T. K. & Pedersen, T. R. Intensive lipid lowering in patients with rheumatoid arthritis and previous myocardial infarction: an explorative analysis from the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) trial. Rheumatology (Oxford) 50, 324–329 (2011).

    Article  CAS  Google Scholar 

  101. 101

    Semb, A. G. et al. Effect of intensive lipid-lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease. Arthritis Rheum. 64, 2836–2846 (2012).

    Article  CAS  Google Scholar 

  102. 102

    Ridker, P. M. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med. 359, 2195–2207 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Tahara, N. et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J. Am. Coll. Cardiol. 48, 1825–1831 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Dadoun, S. et al. Mortality in rheumatoid arthritis over the last fifty years: systematic review and meta-analysis. Joint Bone Spine 80, 29–33 (2013).

    Article  Google Scholar 

  105. 105

    Brown, A. K. et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum. 54, 3761–3773 (2006).

    Article  CAS  Google Scholar 

  106. 106

    Ridker, P. M., Rifai, N., Rose, L., Buring, J. E. & Cook, N. R. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N. Engl. J. Med. 347, 1557–1565 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Micha, R. et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am. J. Cardiol. 108, 1362–1370 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Westlake, S. L. et al. The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology (Oxford) 49, 295–307 (2010).

    Article  CAS  Google Scholar 

  109. 109

    Avina-Zubieta, J. A. et al. Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: a population-based study. Rheumatology (Oxford) 52, 68–75 (2013).

    Article  CAS  Google Scholar 

  110. 110

    del Rincon, I., Battafarano, D. F., Restrepo, J. F., Erikson, J. M. & Escalante, A. Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol. 66, 264–272 (2014).

    Article  CAS  Google Scholar 

  111. 111

    Sihvonen, S. et al. Mortality in patients with rheumatoid arthritis treated with low-dose oral glucocorticoids. A population-based cohort study. J. Rheumatol. 33, 1740–1746 (2006).

    CAS  PubMed  Google Scholar 

  112. 112

    Davis, J. M. et al. Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 56, 820–830 (2007).

    Article  CAS  Google Scholar 

  113. 113

    Barnabe, C., Martin, B. J. & Ghali, W. A. Systematic review and meta-analysis: anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res. 63, 522–529 (2011).

    Article  CAS  Google Scholar 

  114. 114

    Westlake, S. L. et al. Tumour necrosis factor antagonists and the risk of cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology (Oxford) 50, 518–531 (2011).

    Article  CAS  Google Scholar 

  115. 115

    Hyrich, K. L., Watson, K. D., Lunt, M. & Symmons, D. P. M. Changes in disease characteristics and response rates among patients in the United Kingdom starting anti-tumour necrosis factor therapy for rheumatoid arthritis between 2001 and 2008. Rheumatology (Oxford) 50, 117-23 (2011).

    Article  CAS  Google Scholar 

  116. 116

    Lunt, M., Watson, K. D., Dixon, W. G., Symmons, D. P. & Hyrich, K. L. No evidence of association between anti-tumor necrosis factor treatment and mortality in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 62, 3145–3153 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Low, A. et al. Comparison of the occurrence and severity of myocardial infarction in subjects with rheumatoid arthritis receiving tumour necrosis factor inhibitors or standard non-biologic disease modifying antirheumatic drugs: results from a linkage between the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis and the Myocardial Ischaemia National Audit Project. Rheumatology (Oxford) 53 (Suppl. 1), i34–i35 (2014).

    Article  Google Scholar 

  118. 118

    van Vollenhoven, R. F. et al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann. Rheum. Dis. 72, 1496–1502 (2013).

    Article  CAS  Google Scholar 

  119. 119

    Listing, J. et al. Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNF α inhibitors and rituximab. Ann. Rheum. Dis. 74, 415–421 (2015).

    Article  CAS  Google Scholar 

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Acknowledgements

I.N.B. is a National Institute for Health Research (NIHR) Senior Investigator and is supported by Arthritis Research UK, the Manchester Academic Health Science Centre, the NIHR Manchester Musculoskeletal Biomedical Research Unit, the NIHR Manchester Wellcome Trust Clinical Research Facility and the Manchester Biomedical Research Centre. S.S. acknowledges funding from the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (grant number G1000417/94909) in partnership with ICON, GlaxoSmithKline, AstraZeneca and the Medical Evaluation Unit, and is also supported by the NIHR Manchester Musculoskeletal Biomedical Research Unit. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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Both authors contributed to researching data for the article, discussing the content, writing the article and review and/or editing of the manuscript before submission.

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Correspondence to Ian N. Bruce.

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I.N.B. declares that he has received consultancy and/or speaker's fees from GSK, Pfizer, Medimmune, Merck Serono and UCB. S.S. declares no competing interests.

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Skeoch, S., Bruce, I. Atherosclerosis in rheumatoid arthritis: is it all about inflammation?. Nat Rev Rheumatol 11, 390–400 (2015). https://doi.org/10.1038/nrrheum.2015.40

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