Skip to main content
Home
Latest news
Browse topics
Lupus Rheumatoid arthritis Spondyloarthropathies COVID-19 Browse all topics
In focus
Bimekizumab: Dual IL-17A/IL-17F inhibition in SpA Anifrolumab for the treatment of SLE JAK inhibitor safety: Weighing up the data and understanding the risks Rituximab and rheumatology practice in the COVID-19 era Safety snapshot: Upadacitinib in patients with PsA Repurposing rheumatology drugs for COVID-19 Telemedicine in rheumatology: COVID-19 and beyond Managing PsA in resource-limited settings
Conferences
ACR Convergence 2022 EULAR 2022 Congress
About us
Medicine Matters Rheumatology
EXTENDED SEARCH
Top

18-08-2015 | Comorbidities | Article

Cardiovascular comorbidity in rheumatic diseases

Authors: Michael T. Nurmohamed, Maaike Heslinga, George Kitas, Andrew J Murphy

Login to get access

Abstract

Patients with rheumatoid arthritis (RA) and other inflammatory joint diseases (IJDs) have an increased risk of premature death compared with the general population, mainly because of the risk of cardiovascular disease, which is similar in patients with RA and in those with diabetes mellitus. Pathogenic mechanisms and clinical expression of cardiovascular comorbidities vary greatly between different rheumatic diseases, but atherosclerosis seems to be associated with all IJDs. Traditional risk factors such as age, gender, dyslipidaemia, hypertension, smoking, obesity and diabetes mellitus, together with inflammation, are the main contributors to the increased cardiovascular risk in patients with IJDs. Although cardiovascular risk assessment should be part of routine care in such patients, no disease-specific models are currently available for this purpose. The main pillars of cardiovascular risk reduction are pharmacological and nonpharmacological management of cardiovascular risk factors, as well as tight control of disease activity.

Nat Rev Rheumatol 2015; 11: 693–704. doi:10.1038/nrrheum.2015.112

Compared with the general population, patients with rheumatic diseases are at increased risk of developing several comorbid conditions, of which cardiovascular comorbidities are the most common and have the greatest effect on mortality.1 The epidemiology and pathogenesis of cardiovascular comorbidities in inflammatory joint diseases (IJDs) are particularly well-studied for rheumatoid arthritis (RA), but have also been investigated for rheumatic diseases such as ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE). Growing awareness of this increased cardiovascular risk has led to several efforts to unravel the underlying mechanisms, especially in RA. The elevated risk is only partly explained by increased prevalence of traditional cardiovascular risk factors such as age, gender, dyslipidaemia, hypertension, smoking, obesity and diabetes mellitus; systemic inflammation, genetic factors and treatment effects might also have important roles (Figure 1). Pathogenic mechanisms and clinical expression of cardiovascular comorbidities vary greatly between different rheumatic diseases, but atherosclerosis seems to be a shared factor in all IJDs. However, not all cardiovascular comorbidity and mortality can be attributed to atherosclerosis: nonischaemic heart failure (HF), microvascular dysfunction, cardiac autonomic neuropathy and arrhythmias are emerging as major contributors to the cardiovascular burden, and medications to treat the rheumatic disease can influence cardiovascular risk positively or negatively. Some cardiac manifestations show a degree of disease specificity—conduction disturbances and aortic insufficiency, for example, are associated with AS.2

Literature
  1. Avina-Zubieta, J. A., Thomas, J., Sadatsafavi, M., Lehman, A. J. & Lacaille, D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann. Rheum. Dis. 71, 1524–1529 (2012).
  2. Nurmohamed, M. T., van der Horst-Bruinsma, I. & Maksymowych, W. P. Cardiovascular and cerebrovascular diseases in ankylosing spondylitis: current insights. Curr. Rheumatol. Rep. 14, 415–421 (2012).
  3. Gabriel, S. E. et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 48, 54–58 (2003).
  4. van Halm, V. P. et al. Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE Investigation. Ann. Rheum. Dis. 68, 1395–1400 (2009).
  5. Lindhardsen, J. et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann. Rheum. Dis. 70, 929–934 (2011).
  6. Myasoedova, E. & Gabriel, S. E. Cardiovascular disease in rheumatoid arthritis: a step forward. Curr. Opin. Rheumatol. 22, 342–347 (2010).
  7. Solomon, D. H. et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 107, 1303–1307 (2003).
  8. Turesson, C., Jarenros, A. & Jacobsson, L. Increased incidence of cardiovascular disease in patients with rheumatoid arthritis: results from a community based study. Ann. Rheum. Dis. 63, 952–955 (2004).
  9. Levy, L., Fautrel, B., Barnetche, T. & Schaeverbeke, T. Incidence and risk of fatal myocardial infarction and stroke events in rheumatoid arthritis patients. A systematic review of the literature. Clin. Exp. Rheumatol. 26, 673–679 (2008).
  10. 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).
  11. Markusse, I. M. et al. Mortality in a large cohort of patients with early rheumatoid arthritis that were treated-to-target for 10 years [abstract 817]. Arthritis Rheumatol. 66, S359 (2014).
  12. Widdifield, J. et al. Trends in excess mortality among patients with rheumatoid arthritis in Ontario, Canada. Arthritis Care Res. (Hoboken) http://dx.doi.org/10.1002/acr.22553.
  13. Kitas, G., Banks, M. J. & Bacon, P. A. Cardiac involvement in rheumatoid disease. Clin. Med. 1, 18–21 (2001).
  14. Mavrogeni, S. et al. Myocardial inflammation in autoimmune diseases: investigation by cardiovascular magnetic resonance and endomyocardial biopsy. Inflamm. Allergy Drug Targets 8, 390–397 (2009).
  15. Aydemir, M. et al. Cardiac autonomic profile in rheumatoid arthritis and systemic lupus erythematosus. Lupus 19, 255–261 (2010).
  16. Adlan, A. M., Lip, G. Y., Paton, J. F., Kitas, G. D. & Fisher, J. P. Autonomic function and rheumatoid arthritis—a systematic review. Semin. Arthritis Rheum. 44, 283–304 (2014).
  17. Peters, M. J., van der Horst-Bruinsma, I. E., Dijkmans, B. A. & Nurmohamed, M. T. Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis. Semin. Arthritis Rheum. 34, 585–592 (2004).
  18. Papagoras, C., Voulgari, P. V. & Drosos, A. A. Atherosclerosis and cardiovascular disease in the spondyloarthritides, particularly ankylosing spondylitis and psoriatic arthritis. Clin. Exp. Rheumatol. 31, 612–620 (2013).
  19. Mathieu, S., Pereira, B. & Soubrier, M. Cardiovascular events in ankylosing spondylitis: an updated meta-analysis. Semin. Arthritis Rheum. 44, 551–555 (2015).
  20. Horreau, C. et al. Cardiovascular morbidity and mortality in psoriasis and psoriatic arthritis: a systematic literature review. J. Eur. Acad. Dermatol. Venereol. 27 (Suppl. 3), 12–29 (2013).
  21. Palazzi, C., Salvarani, C., D'Angelo, S. & Olivieri, I. Aortitis and periaortitis in ankylosing spondylitis. Joint Bone Spine 78, 451–455 (2011).
  22. Urowitz, M. B. et al. The bimodal mortality pattern of systemic lupus erythematosus. Am. J. Med. 60, 221–225 (1976).
  23. Manzi, S. et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am. J. Epidemiol. 145, 408–415 (1997).
  24. Frostegård, J. Systemic lupus erythematosus and cardiovascular disease. Lupus 17, 364–367 (2008).
  25. Gustafsson, J. T. & Svenungsson, E. Definitions of and contributions to cardiovascular disease in systemic lupus erythematosus. Autoimmunity 47, 67–76 (2014).
  26. Narshi, C. B., Giles, I. P. & Rahman, A. The endothelium: an interface between autoimmunity and atherosclerosis in systemic lupus erythematosus? Lupus 20, 5–13 (2011).
  27. Li, J. et al. Interferon-α priming promotes lipid uptake and macrophage-derived foam cell formation: a novel link between interferon-α and atherosclerosis in lupus. Arthritis Rheum. 63, 492–502 (2011).
  28. Bichile, T. & Petri, M. Prevention and management of co-morbidities in SLE. Presse Med. 43, e187–e195 (2014).
  29. 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).
  30. Semb, A. G. et al. Lipids, myocardial infarction and ischaemic stroke in patients with rheumatoid arthritis in the Apolipoprotein-related Mortality RISk (AMORIS) Study. Ann. Rheum. Dis. 69, 1996–2001 (2010).
  31. Kavanaugh, A. Dyslipoproteinaemia in a subset of patients with rheumatoid arthritis. Ann. Rheum. Dis. 53, 551–552 (1994).
  32. 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).
  33. 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).
  34. Vermont, C. L. et al. Serum lipids and disease severity in children with severe meningococcal sepsis. Crit. Care Med. 33, 1610–1615 (2005).
  35. 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).
  36. Innala, L. et al. Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study. Arthritis Res. Ther. 13, R131 (2011).
  37. Toms, T. E. et al. Are lipid ratios less susceptible to change with systemic inflammation than individual lipid components in patients with rheumatoid arthritis? Angiology 62, 167–175 (2011).
  38. Toms, T. E. et al. Rheumatoid arthritis susceptibility genes associate with lipid levels in patients with rheumatoid arthritis. Ann. Rheum. Dis. 70, 1025–1032 (2011).
  39. Charles-Schoeman, C. et al. Potential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib. Arthritis Rheumatol. 67, 616–625 (2015).
  40. 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).
  41. Rollefstad, S. et al. Treatment to lipid targets in patients with inflammatory joint diseases in a preventive cardio-rheuma clinic. Ann. Rheum. Dis. 72, 1968–1974 (2013).
  42. Solomon, A., Norton, G. R., Woodiwiss, A. J. & Dessein, P. H. Obesity and carotid atherosclerosis in African black and Cauian women with established rheumatoid arthritis: a cross-sectional study. Arthritis Res. Ther. 14, R67 (2012).
  43. 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).
  44. Summers, G. D., Metsios, G. S., Stavropoulos-Kalinoglou, A. & Kitas, G. D. Rheumatoid cachexia and cardiovascular disease. Nat. Rev. Rheumatol. 6, 445–451 (2010).
  45. Metsios, G. S. et al. Association of physical inactivity with increased cardiovascular risk in patients with rheumatoid arthritis. Eur. J. Cardiovasc. Prev. Rehabil. 16, 188–194 (2009).
  46. Stavropoulos-Kalinoglou, A. et al. Individualised aerobic and resistance exercise training improves cardiorespiratory fitness and reduces cardiovascular risk in patients with rheumatoid arthritis. Ann. Rheum. Dis. 72, 1819–1825 (2013).
  47. Metsios, G. S. et al. Individualised exercise improves endothelial function in patients with rheumatoid arthritis. Ann. Rheum. Dis. 73, 748–751 (2014).
  48. Wadley, A. J. et al. Three months of moderate-intensity exercise reduced plasma 3-nitrotyrosine in rheumatoid arthritis patients. Eur. J. Appl. Physiol. 114, 1483–1492 (2014).
  49. Chung, C. P. et al. Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms. Arthritis Rheum. 58, 2105–2112 (2008).
  50. Giles, J. T. et al. Insulin resistance in rheumatoid arthritis: disease-related indicators and associations with the presence and progression of subclinical atherosclerosis. Arthritis Rheumatol. 67, 626–636 (2015).
  51. Dessein, P. H., Joffe, B. I. & Stanwix, A. E. Inflammation, insulin resistance, and aberrant lipid metabolism as cardiovascular risk factors in rheumatoid arthritis. J. Rheumatol. 30, 1403–1405 (2003).
  52. van den Oever, I. A., van Sijl, A. M. & Nurmohamed, M. T. Management of cardiovascular risk in patients with rheumatoid arthritis: evidence and expert opinion. Ther. Adv. Musculoskelet. Dis. 5, 166–181 (2013).
  53. 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).
  54. Solomon, D. H. et al. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA 305, 2525–2531 (2011).
  55. Stolt, P. et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based e-control study, using incident es. Ann. Rheum. Dis. 62, 835–841 (2003).
  56. Wolfe, F. The effect of smoking on clinical, laboratory, and radiographic status in rheumatoid arthritis. J. Rheumatol. 27, 630–637 (2000).
  57. Klareskog, L., Malmstrom, V., Lundberg, K., Padyukov, L. & Alfredsson, L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin. Immunol. 23, 92–98 (2011).
  58. Hyrich, K. L., Watson, K. D., Silman, A. J. & Symmons, D. P. Predictors of response to anti-TNF-α therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 45, 1558–1565 (2006).
  59. Abhishek, A., Butt, S., Gadsby, K., Zhang, W. & Deighton, C. M. Anti-TNF-α agents are less effective for the treatment of rheumatoid arthritis in current smokers. J. Clin. Rheumatol. 16, 15–18 (2010).
  60. Stavropoulos-Kalinoglou, A. et al. Cigarette smoking associates with body weight and muscle mass of patients with rheumatoid arthritis: a cross-sectional, observational study. Arthritis Res. Ther. 10, R59 (2008).
  61. Panoulas, V. F. et al. Hypertension in rheumatoid arthritis. Rheumatology (Oxford) 47, 1286–1298 (2008).
  62. 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).
  63. Protogerou, A. D. 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).
  64. Dougados, M. et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann. Rheum. Dis. 73, 62–68 (2014).
  65. Panoulas, V. F. et al. Galectin-2 (LGALS2) 3279C/T polymorphism may be independently associated with diastolic blood pressure in patients with rheumatoid arthritis. Clin. Exp. Hypertens. 31, 93–104 (2009).
  66. Panoulas, V. F. et al. Polymorphisms of the endothelin-1 gene associate with hypertension in patients with rheumatoid arthritis. Endothelium 15, 203–212 (2008).
  67. Panoulas, V. F. et al. Transforming growth factor-β1 869T/C, but not interleukin-6 -174G/C, polymorphism associates with hypertension in rheumatoid arthritis. Rheumatology (Oxford) 48, 113–118 (2009).
  68. Wong, M. et al. Reduced arterial elasticity in rheumatoid arthritis and the relationship to vascular disease risk factors and inflammation. Arthritis Rheum. 48, 81–89 (2003).
  69. Klarenbeek, N. B. et al. Blood pressure changes in patients with recent-onset rheumatoid arthritis treated with four different treatment strategies: a post hoc analysis from the BeSt trial. Ann. Rheum. Dis. 69, 1342–1345 (2010).
  70. Sandoo, A. et al. Anti-TNFα therapy may lead to blood pressure reductions through improved endothelium-dependent microvascular function in patients with rheumatoid arthritis. J. Hum. Hypertens. 25, 699–702 (2011).
  71. Panoulas, V. F. et al. Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis. Rheumatology (Oxford) 46, 1477–1482 (2007). 
  72. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288, 2015–2022 (2002).
  73. Morgan, S. L., Baggott, J. E., Lee, J. Y. & Alarcón, G. S. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J. Rheumatol. 25, 441–446 (1998).
  74. van Ede, A. E. et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford) 41, 658–665 (2002).
  75. Martí-Carvajal, A. J., Solà, I. & Lathyris, D. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD006612. http://dx.doi.org/10.1002/14651858.CD006612.pub4.
  76. Palomino-Morales, R. et al. A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis. Arthritis Res. Ther. 12, R71 (2010).
  77. Ichiki, T. Thyroid hormone and atherosclerosis. Vascul. Pharmacol. 52, 151–156 (2010). 
  78. Raterman, H. G. et al. Increased progression of carotid intima media thickness in thyroid peroxidase antibodies-positive rheumatoid arthritis patients. Eur. J. Endocrinol. 169, 751–757 (2013).
  79. 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).
  80. Gonzalez-Juanatey, C. et al. HLA-DRB1 status affects endothelial function in treated patients with rheumatoid arthritis. Am. J. Med. 114, 647–652 (2003).
  81. Rodríguez-Rodríguez, L. et al. TNFA -308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis 216, 125–130 (2011).
  82. Rodriguez-Rodriguez, L. et al. CCR5Δ32 variant and cardiovascular disease in patients with rheumatoid arthritis: a cohort study. Arthritis Res. Ther. 13, R133 (2011).
  83. López-Mejías, R. et al. NFKB1–94ATTG ins/del polymorphism (rs28362491) is associated with cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis 224, 426–429 (2012).
  84. Toms, T. E. et al. Apolipoprotein E gene polymorphisms are strong predictors of inflammation and dyslipidemia in rheumatoid arthritis. J. Rheumatol. 39, 218–225 (2012).
  85. Toms, T. E., Symmons, D. P. & Kitas, G. D. Dyslipidaemia in rheumatoid arthritis: the role of inflammation, drugs, lifestyle and genetic factors. Curr. Vasc. Pharmacol. 8, 301–326 (2010).
  86. Dimitroulas, T. et al. Relationship between dimethylarginine dimethylaminohydrolase gene variants and asymmetric dimethylarginine in patients with rheumatoid arthritis. Atherosclerosis 237, 38–44 (2014).
  87. Kaptoge, S. et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 375, 132–140 (2010). Liang, K. P. et al.
  88. Autoantibodies and the risk of cardiovascular events. J. Rheumatol. 36, 2462–2469 (2009).
  89. Kremers, H. M., Crowson, C. S., Therneau, T. M., Roger, V. L. & Gabriel, S. E. High ten-year risk of cardiovascular disease in newly diagnosed rheumatoid arthritis patients: a population-based cohort study. Arthritis Rheum. 58, 2268–2274 (2008).
  90. Maradit-Kremers, H. et al. Raised erythrocyte sedimentation rate signals heart failure in patients with rheumatoid arthritis. Ann. Rheum. Dis. 66, 76–80 (2007).
  91. Rho, Y. H. et al. Inflammatory mediators and premature coronary atherosclerosis in rheumatoid arthritis. Arthritis Rheum. 61, 1580–1585 (2009).
  92. Dessein, P. H. et al. Traditional and nontraditional cardiovascular risk factors are associated with atherosclerosis in rheumatoid arthritis. J. Rheumatol. 32, 435–442 (2005).
  93. 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).
  94. Libby, P., Ridker, P. M. & Maseri, A. Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002).
  95. Lerman, A. & Zeiher, A. M. Endothelial function: cardiac events. Circulation 111, 363–368 (2005).
  96. Anderson, T. J. et al. Close relation of endothelial function in the human coronary and peripheral circulations. J. Am. Coll. Cardiol. 26, 1235–1241 (1995).
  97. Sandoo, A., Veldhuijzen van Zanten, J. J., Metsios, G. S., Carroll, D. & Kitas, G. D. Vascular function and morphology in rheumatoid arthritis: a systematic review. Rheumatology (Oxford) 50, 2125–2139 (2011).
  98. Karpouzas, G. A. et al. Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Ann. Rheum. Dis. 73, 1797–1804 (2014).
  99. Semb, A. G. et al. Carotid plaque characteristics and disease activity in rheumatoid arthritis. J. Rheumatol. 40, 359–368 (2013).
  100. Douglas, K. M. et al. Excess recurrent cardiac events in rheumatoid arthritis patients with acute coronary syndrome. Ann. Rheum. Dis. 65, 348–353 (2006).
  101. Aubry, M. C. et al. Differences in atherosclerotic coronary heart disease between subjects with and without rheumatoid arthritis. J. Rheumatol. 34, 937–942 (2007).
  102. Zöller, B., Li, X., Sundquist, J. & Sundquist, K. Autoimmune diseases and venous thromboembolism: a review of the literature. Am. J. Cardiovasc. Dis. 2, 171–183 (2012).
  103. Gasparyan, A. Y., Ayvazyan, L., Mikhailidis, D. P. & Kitas, G. D. Mean platelet volume: a link between thrombosis and inflammation? Curr. Pharm. Des. 17, 47–58 (2011).
  104. Gasparyan, A. Y., Stavropoulos-Kalinoglou, A., Mikhailidis, D. P., Douglas, K. M. & Kitas, G. D. Platelet function in rheumatoid arthritis: arthritic and cardiovascular implications. Rheumatol. Int. 31, 153–164 (2011).
  105. Chung, W. S. et al. Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Ann. Rheum. Dis. 73, 1774–1780 (2014).
  106. Bengtsson, A., Zöller, B., de Frutos, P. G., Dahlbäck, B. & Sturfelt, G. Factor V:Q506 mutation and anticardiolipin antibodies in systemic lupus erythematosus. Lupus 5, 598–601 (1996).
  107. Pahor, A. et al. Antiphospholipid antibodies as a possible risk factor for atherosclerosis in patients with rheumatoid arthritis. Immunobiology 211, 689–694 (2006).
  108. Mavrogeni, S., Dimitroulas, T., Sfikakis, P. P. & Kitas, G. D. Heart involvement in rheumatoid arthritis: multimodality imaging and the emerging role of cardiac magnetic resonance. Semin. Arthritis Rheum. 43, 314–324 (2013).
  109. Mavrogeni, S. et al. Myocarditis as a precipitating factor for heart failure: evaluation and 1-year follow-up using cardiovascular magnetic resonance and endomyocardial biopsy. Eur. J. Heart Fail. 13, 830–837 (2011).
  110. Mavrogeni, S., Dimitroulas, T. & Kitas, G. D. Multimodality imaging and the emerging role of cardiac magnetic resonance in autoimmune myocarditis. Autoimmun. Rev. 12, 305–312 (2012).
  111. Yndestad, A. et al. Role of inflammation in the progression of heart failure. Curr. Cardiol. Rep. 9, 236–241 (2007).
  112. Gonzalez-Juanatey, C. et al. Echocardiographic and Doppler findings in long-term treated rheumatoid arthritis patients without clinically evident cardiovascular disease. Semin. Arthritis Rheum. 33, 231–238 (2004).
  113. Davis, J. M. 3rd et al. The presentation and outcome of heart failure in patients with rheumatoid arthritis differs from that in the general population. Arthritis Rheum. 58, 2603–2611 (2008).
  114. Bell, C. & Rowe, I. F. The recognition and assessment of cardiovascular risk in people with rheumatoid arthritis in primary care: a questionnaire-based study of general practitioners. Musculoskeletal Care 9, 69–74 (2011).
  115. Ikdahl, E. et al. EULAR task force recommendations on annual cardiovascular risk assessment for patients with rheumatoid arthritis: an audit of the success of implementation in a rheumatology outpatient clinic. Biomed. Res. Int. 2015, 515280 (2015).
  116. D'Agostino, R. B. Sr et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 117, 743–753 (2008).
  117. Ridker, P. M., Paynter, N. P., Rifai, N., Gaziano, J. M. & Cook, N. R. C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men. Circulation 118, 2243–2251 (2008).
  118. Ridker, P. M., Buring, J. E., Rifai, N. & Cook, N. R. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 297, 611–619 (2007).
  119. Hippisley-Cox, J. et al. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ 336, 1475–1482 (2008).
  120. Conroy, R. M. et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur. Heart J. 24, 987–1003 (2003). 
  121. 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).
  122. Perk, J. et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012): the fifth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Int. J. Behav. Med. 19, 403–488 (2012).
  123. Arts, E. E. 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).
  124. Arts, E. E. et al. Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2014-206879.
  125. Stone, N. J. et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129, S1–S45 (2014).
  126. Kawai, V. K. et al. The ability of the 2013 American College of Cardiology/American Heart Association cardiovascular risk score to identify rheumatoid arthritis patients with high coronary artery calcification scores. Arthritis Rheumatol. 67, 381–385 (2015).
  127. Tournadre, A. et al. Application of the European Society of Cardiology, Adult Treatment Panel III and American College of Cardiology/American Heart Association guidelines for cardiovascular risk management in a French cohort of rheumatoid arthritis. Int. J. Cardiol. 183, 149–154 (2015).
  128. 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).
  129. Gonzalez-Juanatey, C. et al. Increased prevalence of severe subclinical atherosclerotic findings in long-term treated rheumatoid arthritis patients without clinically evident atherosclerotic disease. Medicine (Baltimore) 82, 407–413 (2003).
  130. Gonzalez-Juanatey, C., Llorca, J., Martin, J. & Gonzalez-Gay, M. A. Carotid intima-media thickness predicts the development of cardiovascular events in patients with rheumatoid arthritis. Semin. Arthritis Rheum. 38, 366–371 (2009).
  131. Corrales, A. et al. Carotid ultrasound is useful for the cardiovascular risk stratification of patients with rheumatoid arthritis: results of a population-based study. Ann. Rheum. Dis. 73, 722–727 (2014).
  132. Eder, L., Chandran, V. & Gladman, D. D. The Framingham Risk Score underestimates the extent of subclinical atherosclerosis in patients with psoriatic disease. Ann. Rheum. Dis. 73, 1990–1996 (2014).
  133. López-Mejías, R. et al. Osteoprotegerin concentrations relate independently to established cardiovascular disease in rheumatoid arthritis. J. Rheumatol. 42, 39–45 (2015).
  134. Dessein, P. H. et al. Independent relationship of osteoprotegerin concentrations with endothelial activation and carotid atherosclerosis in patients with severe rheumatoid arthritis. J. Rheumatol. 41, 429–436 (2014).
  135. López-Mejías, R. et al. Angiopoietin-2 serum levels correlate with severity, early onset and cardiovascular disease in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 31, 761–766 (2013).
  136. Dimitroulas, T. et al. B-type natriuretic peptide in rheumatic diseases: a cardiac biomarker or a sophisticated acute phase reactant? Autoimmun. Rev. 11, 837–843 (2012).
  137. Panoulas, V. F. et al. Serum uric acid is independently associated with hypertension in patients with rheumatoid arthritis. J. Hum. Hypertens. 22, 177–182 (2008).
  138. Daoussis, D. et al. Uric acid is a strong independent predictor of renal dysfunction in patients with rheumatoid arthritis. Arthritis Res. Ther. 11, R116 (2009).
  139. Panoulas, V. F. et al. Association of serum uric acid with cardiovascular disease in rheumatoid arthritis. Rheumatology (Oxford) 46, 1466–1470 (2007).
  140. Daoussis, D. & Kitas, G. D. Uric acid and cardiovascular risk in rheumatoid arthritis. Rheumatology (Oxford) 50, 1354–1355 (2011).
  141. Daoussis, D. et al. Microalbuminuria in rheumatoid arthritis in the post penicillamine/gold era: association with hypertension, but not therapy or inflammation. Clin. Rheumatol. 30, 477–484 (2011).
  142. Gasparyan, A. Y., Stavropoulos-Kalinoglou, A., Toms, T. E., Douglas, K. M. & Kitas, G. D. Association of mean platelet volume with hypertension in rheumatoid arthritis. Inflamm. Allergy Drug Targets 9, 45–50 (2010).
  143. Sandoo, A. et al. Cumulative inflammation associates with asymmetric dimethylarginine in rheumatoid arthritis: a 6 year follow-up study. Rheumatology (Oxford) 54, 1145–1152 (2015).
  144. Dimitroulas, T., Sandoo, A. & Kitas, G. D. Asymmetric dimethylarginine as a surrogate marker of endothelial dysfunction and cardiovascular risk in patients with systemic rheumatic diseases. Int. J. Mol. Sci. 13, 12315–12335 (2012).
  145. Wloch, A., Wieczorek-Surdacka, E., Sulicka-Grodzicka, J., Kruszelnicka, O. & Surdacki, A. Asymmetric dimethylarginine reflects cumulative inflammatory burden in rheumatoid arthritis. Rheumatology (Oxford) 54, 1135–1136 (2015).
  146. Blankenberg, S. et al. Contribution of 30 biomarkers to 10-year cardiovascular risk estimation in 2 population cohorts: the MONICA, risk, genetics, archiving, and monograph (MORGAM) biomarker project. Circulation 121, 2388–2397 (2010).
  147. Ford, E. S. et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N. Engl. J. Med. 356, 2388–2398 (2007).
  148. McCarey, D. W. et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 363, 2015–2021 (2004).
  149. Moodley, I. Review of the cardiovascular safety of COXIBs compared to NSAIDS. Cardiovasc. J. Afr. 19, 102–107 (2008).
  150. Solomon, D. H. et al. Subgroup analyses to determine cardiovascular risk associated with nonsteroidal antiinflammatory drugs and coxibs in specific patient groups. Arthritis Rheum. 59, 1097–1104 (2008).
  151. Roubille, C. et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann. Rheum. Dis. 74, 480–489 (2015).
  152. del Rincón, 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).
  153. Ridker, P. M. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J. Thromb. Haemost. 7 (Suppl. 1), 332–339 (2009).
  154. Greenberg, J. D. et al. Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis. Ann. Rheum. Dis. 70, 576–582 (2011).
  155. van Sijl, A. M. et al. The effect of TNF-α blocking therapy on lipid levels in rheumatoid arthritis: a meta-analysis. Semin. Arthritis Rheumatol. 41, 393–400 (2011).
  156. Souto, A. et al. Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials: a systematic review and meta-analysis. Arthritis Rheumatol. 67, 117–127 (2015).
  157. Glund, S. & Krook, A. Role of interleukin-6 signalling in glucose and lipid metabolism. Acta Physiol. (Oxf.) 192, 37–48 (2008).
Image Credits