Review Article | Published:

Microvascular endothelial dysfunction in rheumatoid arthritis

Nature Reviews Rheumatology (2018) | Download Citation


The systemic autoimmune disease rheumatoid arthritis (RA) is characterized by increased cardiovascular mortality and morbidity and is an independent cardiovascular risk factor. Cardiovascular diseases (CVDs) result from accelerated atherogenesis, which is a consequence of endothelial dysfunction in the early stages of the disease. Endothelial dysfunction is a functional and reversible alteration of endothelial cells and leads to a shift in the properties of the endothelium towards reduced vasodilation, a pro-inflammatory state, and proliferative and prothrombotic properties. In RA, endothelial dysfunction can occur in the large vessels (such as the conduit arteries) and in the small vessels of the microvasculature, which supply oxygen and nutrients to the tissue and control inflammation, repair and fluid exchange with the surrounding tissues. Growing evidence suggests that microvascular endothelial dysfunction contributes to CVD development, as it precedes and predicts the development of conduit artery atherosclerosis and associated risk factors. As such, numerous studies have investigated microvascular endothelial dysfunction in RA, including its link with disease activity, disease duration and inflammation, the effect of treatments on endothelial function, and possible circulating biomarkers of microvascular endothelial dysfunction. Such findings could have important implications in the cardiovascular risk management of patients with RA.

Key points

  • Microvascular endothelial dysfunction is an early and/or seminal event in the development of cardiovascular diseases and associated organ damage and is also present in patients with rheumatoid arthritis (RA).

  • Microvascular endothelial dysfunction does not correlate with disease activity, disease duration, levels of C-reactive protein or the erythrocyte sedimentation rate.

  • Antirheumatic drugs and other therapies can be used to treat microvascular endothelial dysfunction, but the effects of these therapies differ.

  • Achieving remission in RA does not guarantee the normalization of microvascular endothelial function.

  • Semiautomated methods for the measurement of microvascular endothelial dysfunction exist; therefore, the concept of endothelial-guided therapies in RA deserves attention.

  • The predictive value of microvascular endothelial dysfunction for cardiovascular events needs to be demonstrated in future studies.

  • Subscribe to Nature Reviews Rheumatology for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Giles, J. T. Cardiovascular disease in rheumatoid arthritis: current perspectives on assessing and mitigating risk in clinical practice. Best Pract. Res. Clin. Rheumatol. 29, 597–613 (2015).

  2. 2.

    López-Mejías, R. et al. Cardiovascular risk assessment in patients with rheumatoid arthritis: The relevance of clinical, genetic and serological markers. Autoimmun. Rev. 15, 1013–1030 (2016).

  3. 3.

    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).

  4. 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. 5.

    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).

  6. 6.

    Holmqvist, M. E. et al. Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006. J. Intern. Med. 268, 578–585 (2010).

  7. 7.

    Kaplan, M. J. Cardiovascular complications of rheumatoid arthritis: assessment, prevention, and treatment. Rheum. Dis. Clin. North Am. 36, 405–426 (2010).

  8. 8.

    van den Hoek, J. et al. Mortality in patients with rheumatoid arthritis: a 15-year prospective cohort study. Rheumatol. Int. 37, 487–493 (2017).

  9. 9.

    Prati, C., Demougeot, C., Guillot, X., Godfrin-Valnet, M. & Wendling, D. Endothelial dysfunction in joint disease. Joint Bone Spine 81, 386–391 (2014).

  10. 10.

    Daiber, A. et al. Targeting vascular (endothelial) dysfunction. Br. J. Pharmacol. 174, 1591–1619 (2016).

  11. 11.

    Gutterman, D. D. et al. The human microcirculation: regulation of flow and beyond. Circ. Res. 118, 157–172 (2016).

  12. 12.

    Moroni, L., Selmi, C., Angelini, C. & Meroni, P. L. Evaluation of endothelial function by flow-mediated dilation: a comprehensive review in rheumatic disease. Arch. Immunol. Ther. Exp. 65, 463–475 (2017).

  13. 13.

    Kotani, K., Miyamoto, M. & Ando, H. The effect of treatments for rheumatoid arthritis on endothelial dysfunction evaluated by flow-mediated vasodilation in patients with rheumatoid arthritis. Curr. Vasc. Pharmacol. 15, 10–18 (2017).

  14. 14.

    Gonzalez-Gay, M. A., Gonzalez-Juanatey, C., Vazquez-Rodriguez, T. R., Martin, J. & Llorca, J. Endothelial dysfunction, carotid intima-media thickness, and accelerated atherosclerosis in rheumatoid arthritis. Semin. Arthritis Rheum. 38, 67–70 (2008).

  15. 15.

    Haller, H. Endothelial function. General considerations. Drugs 53 (Suppl. 1), 1–10 (1997).

  16. 16.

    Kimura, K. et al. Diversity and variability of smooth muscle phenotypes of renal arterioles as revealed by myosin isoform expression. Kidney Int. 48, 372–382 (1995).

  17. 17.

    Napoli, C. et al. Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis. Proc. Natl Acad. Sci. USA 99, 1689–1694 (2002).

  18. 18.

    Takahashi, M., Ishida, T., Traub, O., Corson, M. A. & Berk, B. C. Mechanotransduction in endothelial cells: temporal signaling events in response to shear stress. J. Vasc. Res. 34, 212–219 (1997).

  19. 19.

    Triggle, C. R. & Ding, H. The endothelium in compliance and resistance vessels. Front. Biosci. Sch. Ed. 3, 730–744 (2011).

  20. 20.

    Matsuzawa, Y. & Lerman, A. Endothelial dysfunction and coronary artery disease: assessment, prognosis, and treatment. Coron. Artery Dis. 25, 713–724 (2014).

  21. 21.

    Liao, J. K. Linking endothelial dysfunction with endothelial cell activation. J. Clin. Invest. 123, 540–541 (2013).

  22. 22.

    Linder, L., Kiowski, W., Bühler, F. R. & Lüscher, T. F. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation 81, 1762–1767 (1990).

  23. 23.

    Panza, J. A., Quyyumi, A. A., Brush, J. E. & Epstein, S. E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N. Engl. J. Med. 323, 22–27 (1990).

  24. 24.

    Treasure, C. B. et al. Epicardial coronary artery responses to acetylcholine are impaired in hypertensive patients. Circ. Res. 71, 776–781 (1992).

  25. 25.

    Calver, A., Collier, J. & Vallance, P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-ependent diabetes. J. Clin. Invest. 90, 2548–2554 (1992).

  26. 26.

    Cosentino, F. et al. High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation 107, 1017–1023 (2003).

  27. 27.

    Mäkimattila, S. et al. Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus. Circulation 94, 1276–1282 (1996).

  28. 28.

    Steinberg, H. O. et al. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J. Clin. Invest. 97, 2601–2610 (1996).

  29. 29.

    Casino, P. R., Kilcoyne, C. M., Quyyumi, A. A., Hoeg, J. M. & Panza, J. A. The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients. Circulation 88, 2541–2547 (1993).

  30. 30.

    Spieker, L. E. et al. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation 105, 1399–1402 (2002).

  31. 31.

    Hamburg, N. M. et al. Relation of brachial and digital measures of vascular function in the community: the Framingham heart study. Hypertension 57, 390–396 (2011).

  32. 32.

    Sitia, S. et al. From endothelial dysfunction to atherosclerosis. Autoimmun. Rev. 9, 830–834 (2010).

  33. 33.

    Kieda, C. Heterogeneity of endothelial cells — role in vessel specialization and cooperation in vasculogenic mimicry. Postepy Biochem. 59, 372–378 (2013).

  34. 34.

    Geiger, M., Stone, A., Mason, S. N., Oldham, K. T. & Guice, K. S. Differential nitric oxide production by microvascular and macrovascular endothelial cells. Am. J. Physiol. 273, L275–L281 (1997).

  35. 35.

    Gerritsen, M. E., Niedbala, M. J., Szczepanski, A. & Carley, W. W. Cytokine activation of human macro- and microvessel-derived endothelial cells. Blood Cells 19, 325–339 (1993).

  36. 36.

    Sumagin, R. & Sarelius, I. H. Emerging understanding of roles for arterioles in inflammation. Microcirculation 20, 679–692 (2013).

  37. 37.

    Aird, W. C. Phenotypic heterogeneity of the endothelium. I. Structure, function, and mechanisms. Circ. Res. 100, 158–173 (2007).

  38. 38.

    Stokes, K. Y. & Granger, D. N. The microcirculation: a motor for the systemic inflammatory response and large vessel disease induced by hypercholesterolaemia? J. Physiol. 562, 647–653 (2005).

  39. 39.

    Anderson, T. J. et al. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation 123, 163–169 (2011).

  40. 40.

    Lind, L., Berglund, L., Larsson, A. & Sundström, J. Endothelial function in resistance and conduit arteries and 5-year risk of cardiovascular disease. Circulation 123, 1545–1551 (2011).

  41. 41.

    Reis, S. E. et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am. Heart J. 141, 735–741 (2001).

  42. 42.

    von Mering, G. O. et al. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 109, 722–725 (2004).

  43. 43.

    Flammer, A. J. et al. The assessment of endothelial function: from research into clinical practice. Circulation 126, 753–767 (2012).

  44. 44.

    Vizzardi, E. et al. Noninvasive assessment of endothelial function: the classic methods and the new peripheral arterial tonometry. J. Investig. Med. 62, 856–864 (2014).

  45. 45.

    Lockhart, C. J., Hamilton, P. K., Quinn, C. E. & McVeigh, G. E. End-organ dysfunction and cardiovascular outcomes: the role of the microcirculation. Clin. Sci. 116, 175–190 (2009).

  46. 46.

    Chantler, P. D. & Frisbee, J. C. Arterial function in cardio-metabolic diseases: from the microcirculation to the large conduits. Prog. Cardiovasc. Dis. 57, 489–496 (2015).

  47. 47.

    Anderson, T. J. & Phillips, S. A. Assessment and prognosis of peripheral artery measures of vascular function. Prog. Cardiovasc. Dis. 57, 497–509 (2015).

  48. 48.

    Lekakis, J. et al. Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation. Eur. J. Cardiovasc. Prev. Rehabil. 18, 775–789 (2011).

  49. 49.

    Bourdarias, J. P. Coronary reserve: concept and physiological variations. Eur. Heart J. 16 (Suppl. 1), 2–6 (1995).

  50. 50.

    Al Mheid, I. et al. Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans. J. Am. Coll. Cardiol. 58, 186–192 (2011).

  51. 51.

    Rammos, C. et al. Macrophage migration inhibitory factor is associated with vascular dysfunction in patients with end-stage renal disease. Int. J. Cardiol. 168, 5249–5256 (2013).

  52. 52.

    Secrest, A. M., Prince, C. T., Costacou, T., Miller, R. G. & Orchard, T. J. Predictors of and survival after incident stroke in type 1 diabetes. Diab. Vasc. Dis. Res. 10, 3–10 (2013).

  53. 53.

    Gonzalez-Juanatey, C. et al. HLA-DRB1 status affects endothelial function in treated patients with rheumatoid arthritis. Am. J. Med. 114, 647–652 (2003).

  54. 54.

    Bergholm, R. et al. Impaired responsiveness to NO in newly diagnosed patients with rheumatoid arthritis. Arterioscler. Thromb. Vasc. Biol. 22, 1637–1641 (2002).

  55. 55.

    Palomino-Morales, R. et al. A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis. Arthritis Res. Ther. 12, R71 (2010).

  56. 56.

    Palomino-Morales, R. et al. Interleukin-6 gene -174 promoter polymorphism is associated with endothelial dysfunction but not with disease susceptibility in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 27, 964–970 (2009).

  57. 57.

    Liang, K. P. et al. Autoantibodies and the risk of cardiovascular events. J. Rheumatol. 36, 2462–2469 (2009).

  58. 58.

    Marder, W. et al. Interleukin 17 as a novel predictor of vascular function in rheumatoid arthritis. Ann. Rheum. Dis. 70, 1550–1555 (2011).

  59. 59.

    Amaya-Amaya, J. et al. Novel risk factors for cardiovascular disease in rheumatoid arthritis. Immunol. Res. 56, 267–286 (2013).

  60. 60.

    Fenton, S. A. M. et al. Sitting time is negatively related to microvascular endothelium-dependent function in rheumatoid arthritis. Microvasc. Res. 117, 57–60 (2018).

  61. 61.

    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).

  62. 62.

    Arosio, E. et al. Forearm haemodynamics, arterial stiffness and microcirculatory reactivity in rheumatoid arthritis. J. Hypertens. 25, 1273–1278 (2007).

  63. 63.

    Sandoo, A. et al. Lack of association between asymmetric dimethylarginine and in vivo microvascular and macrovascular endothelial function in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 30, 388–396 (2012).

  64. 64.

    Sandoo, A., Kitas, G. D., Carroll, D. & Veldhuijzen van Zanten, J. J. C. S. The role of inflammation and cardiovascular disease risk on microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional and longitudinal study. Arthritis Res. Ther. 14, R117 (2012).

  65. 65.

    Sandoo, A. et al. Classical cardiovascular disease risk factors associate with vascular function and morphology in rheumatoid arthritis: a six-year prospective study. Arthritis Res. Ther. 15, R203 (2013).

  66. 66.

    Sandoo, A., Carroll, D., Metsios, G. S., Kitas, G. D. & Veldhuijzen van Zanten, J. J. The association between microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res. Ther. 13, R99 (2011).

  67. 67.

    Faccini, A., Kaski, J. C. & Camici, P. G. Coronary microvascular dysfunction in chronic inflammatory rheumatoid diseases. Eur. Heart J. 37, 1799–1806 (2016).

  68. 68.

    Klimek, E. et al. Alterations in skin microvascular function in patients with rheumatoid arthritis and ankylosing spondylitis. Clin. Hemorheol. Microcirc. 65, 77–91 (2017).

  69. 69.

    Turiel, M. et al. Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control study of early rheumatoid arthritis patients. Rheumatology 48, 834–839 (2009).

  70. 70.

    Foster, W., Lip, G. Y. H., Raza, K., Carruthers, D. & Blann, A. D. An observational study of endothelial function in early arthritis. Eur. J. Clin. Invest. 42, 510–516 (2012).

  71. 71.

    van Eijk, I. C., Serné, E. H., Dijkmans, B. A. C., Smulders, Y. & Nurmohamed, M. Microvascular function is preserved in newly diagnosed rheumatoid arthritis and low systemic inflammatory activity. Clin. Rheumatol. 30, 1113–1118 (2011).

  72. 72.

    Verhoeven, F. et al. Glucocorticoids improve endothelial function in rheumatoid arthritis: a study in rats with adjuvant-induced arthritis. Clin. Exp. Immunol. 188, 208–218 (2017).

  73. 73.

    Verhoeven, F. et al. Diclofenac but not celecoxib improves endothelial function in rheumatoid arthritis: a study in adjuvant-induced arthritis. Atherosclerosis 266, 136–144 (2017).

  74. 74.

    Yki-Jarvinen, H., Bergholm, R. & Leirisalo-Repo, M. Increased inflammatory activity parallels increased basal nitric oxide production and blunted response to nitric oxide in vivo in rheumatoid arthritis. Ann. Rheum. Dis. 62, 630–634 (2003).

  75. 75.

    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).

  76. 76.

    Mäki-Petäjä, K. M. et al. Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction. Int. J. Cardiol. 129, 399–405 (2008).

  77. 77.

    Alomari, M. A. et al. Vascular function and handgrip strength in rheumatoid arthritis patients. ScientificWorldJournal 2012, 580863 (2012).

  78. 78.

    Ciftci, O. et al. Impaired coronary microvascular function and increased intima-media thickness in rheumatoid arthritis. Atherosclerosis 198, 332–337 (2008).

  79. 79.

    Recio-Mayoral, A. et al. Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease. Eur. Heart J. 30, 1837–1843 (2009).

  80. 80.

    Kakuta, K. et al. Chronic inflammatory disease is an independent risk factor for coronary flow velocity reserve impairment unrelated to the processes of coronary artery calcium deposition. J. Am. Soc. Echocardiogr. 29, 173–180 (2016).

  81. 81.

    Ikonomidis, I. et al. Increased benefit of interleukin 1 inhibition on vascular function, myocardial deformation, and twisting in patients with coronary artery disease and coexisting rheumatoid arthritis. Circ. Cardiovasc. Imag. 7, 619–628 (2014).

  82. 82.

    Anyfanti, P. et al. Subendocardial viability ratio in patients with rheumatoid arthritis: comparison with healthy controls and identification of prognostic factors. Clin. Rheumatol. 36, 1229–1236 (2017).

  83. 83.

    Foster, W., Carruthers, D., Lip, G. Y. H. & Blann, A. D. Inflammation and microvascular and macrovascular endothelial dysfunction in rheumatoid arthritis: effect of treatment. J. Rheumatol. 37, 711–716 (2010).

  84. 84.

    Provan, S. A. et al. Remission is the goal for cardiovascular risk management in patients with rheumatoid arthritis: a cross-sectional comparative study. Ann. Rheum. Dis. 70, 812–817 (2011).

  85. 85.

    Santos, M. J. et al. Early vascular alterations in SLE and RA patients — a step towards understanding the associated cardiovascular risk. PLoS ONE 7, e44668 (2012).

  86. 86.

    Pieringer, H., Stuby, U., Pohanka, E. & Biesenbach, G. Augmentation index in patients with rheumatoid arthritis and ankylosing spondylitis treated with infliximab. Clin. Rheumatol. 29, 723–727 (2010).

  87. 87.

    Pieringer, H. et al. Heart rate, ejection duration and subendocardial viability ratio in patients with rheumatoid arthritis as compared to controls. Int. J. Rheum. Dis. 17, 39–43 (2014).

  88. 88.

    Heffernan, K. S., Karas, R. H., Patvardhan, E. A., Jafri, H. & Kuvin, J. T. Peripheral arterial tonometry for risk stratification in men with coronary artery disease. Clin. Cardiol. 33, 94–98 (2010).

  89. 89.

    Dimitroulas, T., Sandoo, A., Hodson, J., Smith, J. P. & Kitas, G. D. In vivo microvascular and macrovascular endothelial function is not associated with circulating dimethylarginines in patients with rheumatoid arthritis: a prospective analysis of the DRACCO cohort. Scand. J. Clin. Lab. Invest. 76, 331–337 (2016).

  90. 90.

    Galarraga, B., Khan, F., Kumar, P., Pullar, T. & Belch, J. J. F. C-reactive protein: the underlying cause of microvascular dysfunction in rheumatoid arthritis. Rheumatology 47, 1780–1784 (2008).

  91. 91.

    Galarraga, B., Belch, J. J. F., Pullar, T., Ogston, S. & Khan, F. Clinical improvement in rheumatoid arthritis is associated with healthier microvascular function in patients who respond to antirheumatic therapy. J. Rheumatol. 37, 521–528 (2010).

  92. 92.

    Shrivastava, A. K., Singh, H. V., Raizada, A. & Singh, S. K. C-Reactive protein, inflammation and coronary heart disease. Egypt. Heart J. 67, 89–97 (2015).

  93. 93.

    Datta, D., Ferrell, W. R., Sturrock, R. D., Jadhav, S. T. & Sattar, N. Inflammatory suppression rapidly attenuates microvascular dysfunction in rheumatoid arthritis. Atherosclerosis 192, 391–395 (2007).

  94. 94.

    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).

  95. 95.

    Toutouzas, K. et al. Myocardial ischaemia without obstructive coronary artery disease in rheumatoid arthritis: hypothesis-generating insights from a cross-sectional study. Rheumatology 52, 76–80 (2013).

  96. 96.

    Dimitroulas, T., Hodson, J., Sandoo, A., Smith, J. & Kitas, G. D. Endothelial injury in rheumatoid arthritis: a crosstalk between dimethylarginines and systemic inflammation. Arthritis Res. Ther. 19, 32 (2017).

  97. 97.

    Komai, N., Morita, Y., Sakuta, T., Kuwabara, A. & Kashihara, N. Anti-tumor necrosis factor therapy increases serum adiponectin levels with the improvement of endothelial dysfunction in patients with rheumatoid arthritis. Mod. Rheumatol. 17, 385–390 (2007).

  98. 98.

    Rongen, G. A. et al. Vasodilator function worsens after cessation of tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis only if a flare occurs. Clin. Rheumatol. 37, 909–916 (2018).

  99. 99.

    Hjeltnes, G. et al. Relations of serum COMP to cardiovascular risk factors and endothelial function in patients with rheumatoid arthritis treated with methotrexate and TNF-α inhibitors. J. Rheumatol. 39, 1341–1347 (2012).

  100. 100.

    Hjeltnes, G. et al. Serum levels of lipoprotein(a) and E-selectin are reduced in rheumatoid arthritis patients treated with methotrexate or methotrexate in combination with TNF-α-inhibitor. Clin. Exp. Rheumatol. 31, 415–421 (2013).

  101. 101.

    Sandoo, A. & Kitas, G. D. The impact of abatacept treatment on the vasculature in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 33, 589 (2015).

  102. 102.

    Ruiz-Limón, P. et al. Tocilizumab improves the proatherothrombotic profile of rheumatoid arthritis patients modulating endothelial dysfunction, NETosis, and inflammation. Transl Res. 183, 87–103 (2017).

  103. 103.

    Petersons, C. J. et al. Low dose prednisolone and insulin sensitivity differentially affect arterial stiffness and endothelial function: An open interventional and cross-sectional study. Atherosclerosis 258, 34–39 (2017).

  104. 104.

    Radhakutty, A. et al. Effect of acute and chronic glucocorticoid therapy on insulin sensitivity and postprandial vascular function. Clin. Endocrinol. 84, 501–508 (2016).

  105. 105.

    Verhoeven, F., Prati, C., Maguin-Gaté, K., Wendling, D. & Demougeot, C. Glucocorticoids and endothelial function in inflammatory diseases: focus on rheumatoid arthritis. Arthritis Res. Ther. 18, 258 (2016).

  106. 106.

    Marder, W. et al. The peroxisome proliferator activated receptor-γ pioglitazone improves vascular function and decreases disease activity in patients with rheumatoid arthritis. J. Am. Heart Assoc. 2, e000441 (2013).

  107. 107.

    Ormseth, M. J. et al. Reversing vascular dysfunction in rheumatoid arthritis: improved augmentation index but not endothelial function with peroxisome proliferator–activated receptor γ agonist therapy. Arthritis Rheumatol. 66, 2331–2338 (2014).

  108. 108.

    Tam, L.-S. et al. Effects of rosuvastatin on subclinical atherosclerosis and arterial stiffness in rheumatoid arthritis: a randomized controlled pilot trial. Scand. J. Rheumatol. 40, 411–421 (2011).

  109. 109.

    Arts, E. E. A. et al. Statins inhibit the antirheumatic effects of rituximab in rheumatoid arthritis: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Ann. Rheum. Dis. 70, 877–878 (2011).

  110. 110.

    Crowson, C. S. et al. Rheumatoid arthritis and cardiovascular disease. Am. Heart J. 166, 622–628.e1 (2013).

  111. 111.

    Metsios, G. S. et al. Individualised exercise improves endothelial function in patients with rheumatoid arthritis. Ann. Rheum. Dis. 73, 748–751 (2014).

  112. 112.

    Sandoo, A., van Zanten, J. J., Toms, T. E., Carroll, D. & Kitas, G. D. Anti-TNFα therapy transiently improves high density lipoprotein cholesterol levels and microvascular endothelial function in patients with rheumatoid arthritis: a pilot study. BMC Musculoskelet. Disord. 13, 127 (2012).

  113. 113.

    Gonzalez-Juanatey, C. et al. Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody. Arthritis Rheum. 51, 447–450 (2004).

  114. 114.

    Bernelot Moens, S. J. et al. Unexpected arterial wall and cellular inflammation in patients with rheumatoid arthritis in remission using biological therapy: a cross-sectional study. Arthritis Res. Ther. 18, 115 (2016).

  115. 115.

    Turiel, M. et al. Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis. Cardiovasc. Ther. 28, e53–64 (2010).

  116. 116.

    Ranganathan, P. et al. Vitamin D deficiency, interleukin 17, and vascular function in rheumatoid arthritis. J. Rheumatol. 40, 1529–1534 (2013).

  117. 117.

    Nordestgaard, B. G. et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur. Heart J. 31, 2844–2853 (2010).

  118. 118.

    Fleck, C., Schweitzer, F., Karge, E., Busch, M. & Stein, G. Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in patients with chronic kidney diseases. Clin. Chim. Acta 336, 1–12 (2003).

  119. 119.

    Zsuga, J. et al. Dimethylarginines at the crossroad of insulin resistance and atherosclerosis. Metabolism 56, 394–399 (2007).

  120. 120.

    Kiechl, S. et al. Asymmetric and symmetric dimethylarginines are of similar predictive value for cardiovascular risk in the general population. Atherosclerosis 205, 261–265 (2009).

  121. 121.

    Mangiacapra, F. et al. Relationship of asymmetric dimethylarginine (ADMA) with extent and functional severity of coronary atherosclerosis. Int. J. Cardiol. 220, 629–633 (2016).

  122. 122.

    Vitiello, L. et al. Microvascular inflammation in atherosclerosis. IJC Metab. Endocr. 3, 1–7 (2014).

  123. 123.

    Hjeltnes, G. et al. Anti-CCP and RF IgM: predictors of impaired endothelial function in rheumatoid arthritis patients. Scand. J. Rheumatol. 40, 422–427 (2011).

  124. 124.

    Totoson, P., Maguin-Gaté, K., Prati, C., Wendling, D. & Demougeot, C. Mechanisms of endothelial dysfunction in rheumatoid arthritis: lessons from animal studies. Arthritis Res. Ther. 16, 202 (2014).

  125. 125.

    Dooley, L. M. et al. Endothelial dysfunction in an ovine model of collagen-induced arthritis. J. Vasc. Res. 51, 90–101 (2014).

  126. 126.

    Dooley, L. M. et al. Effect of mesenchymal precursor cells on the systemic inflammatory response and endothelial dysfunction in an ovine model of collagen-induced arthritis. PLoS ONE 10, e0124144 (2015).

  127. 127.

    Totoson, P. et al. Microvascular abnormalities in adjuvant-induced arthritis: relationship to macrovascular endothelial function and markers of endothelial activation. Arthritis Rheumatol. 67, 1203–1213 (2015).

  128. 128.

    Agca, R. et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann. Rheum. Dis. 76, 17–28 (2017).

  129. 129.

    Gómez-Vaquero, C. et al. SCORE and REGICOR function charts underestimate the cardiovascular risk in Spanish patients with rheumatoid arthritis. Arthritis Res. Ther. 15, R91 (2013).

  130. 130.

    Arts, E. E. A. et al. Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms. Ann. Rheum. Dis. 75, 674–680 (2016).

  131. 131.

    Kalaria, R. N. Cerebrovascular disease and mechanisms of cognitive impairment: evidence from clinicopathological studies in humans. Stroke 43, 2526–2534 (2012).

  132. 132.

    Oláh, C. et al. Assessment of intracranial vessels in association with carotid atherosclerosis and brain vascular lesions in rheumatoid arthritis. Arthritis Res. Ther. 19, 213 (2017).

  133. 133.

    Rodriguez-Rodriguez, L. et al. Rheumatoid arthritis: genetic variants as biomarkers of cardiovascular disease. Curr. Pharm. Des. 21, 182–201 (2015).

Download references

Author information


  1. PEPITE EA4267, FHU INCREASE, Universitaire Bourgogne Franche-Comté, UFR Santé, F-25000, Besançon, France

    • Romain Bordy
    • , Perle Totoson
    • , Clément Prati
    •  & Céline Demougeot
  2. Service de Rhumatologie, Centre Hospitalier Régional et Universitaire de Besançon, F-25000, Besançon, France

    • Clément Prati
    •  & Daniel Wendling
  3. INSERM UMR1093 CAPS, Universitaire Bourgogne Franche-Comté, UFR des Sciences de Santé, F-21000, Dijon, France

    • Christine Marie
  4. EA 4266, Universitaire Bourgogne Franche-Comté, UFR Santé, F-25000, Besançon, France

    • Daniel Wendling


  1. Search for Romain Bordy in:

  2. Search for Perle Totoson in:

  3. Search for Clément Prati in:

  4. Search for Christine Marie in:

  5. Search for Daniel Wendling in:

  6. Search for Céline Demougeot in:


C.D. and R.B. researched data for the article and wrote the article. C.D. provided substantial contribution to the discussion of its content. All authors reviewed and/or edited the article before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Céline Demougeot.

Supplementary information



A disorder of lipoprotein metabolism characterized by a spectrum of quantitative and qualitative changes in lipids and lipoproteins.

Framingham risk score

An algorithm used to estimate the 10-year risk of developing coronary heart disease on the basis of age, sex, cholesterol levels, blood pressure (and whether the individual is being treated for hypertension), diabetes and smoking status.

Pulsatile pressure

The difference between the systolic and diastolic blood pressure (also called pulse pressure), which is governed by the relationship between ventricular ejection and the viscoelastic properties of the large arteries (arterial stiffness).

Reactive hyperaemia

A transient increase in blood flow that occurs following a brief period of ischaemia (for example, arterial occlusion).

Myocardial ischaemia

A restriction in blood supply to the myocardium resulting from reduced blood flow in the coronary arteries. This restriction leads to an imbalance between myocardial oxygen supply and demand, causing cardiac dysfunction, myocardial infarction, arrhythmias and sudden death.

About this article

Publication history



Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.