Patients with rheumatoid arthritis (RA) are at high risk of developing cardiovascular disease (CVD). Inflammation has a pivotal role in the pathogenesis of CVD. RA is an inflammatory joint disease and, compared with the general population, patients with RA have approximately double the risk of atherosclerotic CVD, stroke, heart failure and atrial fibrillation. Although this high risk of CVD has been known for decades, patients with RA receive poorer primary and secondary CVD preventive care than other high-risk patients, and an unmet need exists for improved CVD preventive measures for patients with RA. This Review summarizes the evidence for atherosclerotic CVD in patients with RA and provides a contemporary analysis of what is known and what needs to be further clarified about recommendations for CVD prevention in patients with RA compared with the general population. The management of traditional CVD risk factors, including blood pressure, lipids, diabetes mellitus and lifestyle-related risk factors, as well as the effects of inflammation and the use of antirheumatic medication on CVD risk and risk management in patients with RA are discussed. The main aim is to provide a roadmap of atherosclerotic CVD risk management and prevention for patients with RA.
Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease (CVD) compared with the general population.
The improvement of CVD risk prevention in patients with RA is an unmet need.
CVD risk calculators developed for use in the general population inaccurately predict CVD in patients with RA, but the addition of RA-specific risk factors does not improve CVD risk prediction
The use of ultrasonography of the carotid arteries improves CVD risk classification in patients with RA by identifying atherosclerotic plaques.
CVD risk prevention in patients with RA closely follows the recommendations for the general population; however, clinicians should be aware of some specific drug–drug interactions in this patient population.
Inflammation and antirheumatic medication use in patients with RA does not affect the doses of statins or antihypertensive medications required for attainment of recommended lipid or blood pressure goals.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Prevalence and influence of hypouricemia on cardiovascular diseases in patients with rheumatoid arthritis
European Journal of Medical Research Open Access 21 November 2022
Effect of biological disease-modifying antirheumatic drugs on body composition in patients with rheumatoid arthritis: a systematic review and meta-analysis
Advances in Rheumatology Open Access 23 May 2022
Cardiovascular disease risk calculators to reflect the subclinical atherosclerosis of coronary artery in rheumatoid arthritis: a pilot study
BMC Rheumatology Open Access 30 August 2021
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Helmick, C. G. et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 58, 15–25 (2008).
Gabriel, S. E. The epidemiology of rheumatoid arthritis. Rheum. Dis. Clin. North. Am. 27, 269–281 (2001).
Myasoedova, E., Crowson, C. S., Kremers, H. M., Therneau, T. M. & Gabriel, S. E. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955–2007. Arthritis Rheum. 62, 1576–1582 (2010).
Roth, G. A. et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J. Am. Coll. Cardiol. 70, 1–25 (2017).
Lillegraven, S., van der Heijde, D., Uhlig, T., Kvien, T. K. & Haavardsholm, E. A. What is the clinical relevance of erosions and joint space narrowing in RA? Nat. Rev. Rheumatol. 8, 117–120 (2012).
Scott, D. L., Wolfe, F. & Huizinga, T. W. Rheumatoid arthritis. Lancet 376, 1094–1108 (2010).
Crowson, C. S. et al. Rheumatoid arthritis and cardiovascular disease. Am. Heart J. 166, 622–628 (2013).
Kalogeropoulos, A. et al. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J. Am. Coll. Cardiol. 55, 2129–2137 (2010).
Mach, F. et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur. Heart J. 41, 111–188 (2020).
Grundy, S. M. et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation 139, e1082–e1143 (2019).
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).
Avina-Zubieta, J. A. et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 59, 1690–1697 (2008).
Goodson, N. J. et al. Mortality in early inflammatory polyarthritis: cardiovascular mortality is increased in seropositive patients. Arthritis Rheum. 46, 2010–2019 (2002).
Radovits, B. J. et al. Excess mortality emerges after 10 years in an inception cohort of early rheumatoid arthritis. Arthritis Care Res. 62, 362–370 (2010).
Myasoedova, E. et al. Decreased cardiovascular mortality in patients with incident rheumatoid arthritis (RA) in recent years: dawn of a new era in cardiovascular disease in RA? J. Rheumatol. 44, 732–739 (2017).
Kerola, A. M. et al. No increased cardiovascular mortality among early rheumatoid arthritis patients: a nationwide register study in 2000–2008. Clin. Exp. Rheumatol. 33, 391–398 (2015).
Holmqvist, M., Ljung, L. & Askling, J. Acute coronary syndrome in new-onset rheumatoid arthritis: a population-based nationwide cohort study of time trends in risks and excess risks. Ann. Rheum. Dis. 76, 1642–1647 (2017).
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).
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).
McCoy, S. S. et al. Long-term outcomes and treatment after myocardial infarction in patients with rheumatoid arthritis. J. Rheumatol. 40, 605–610 (2013).
Ungprasert, P., Srivali, N. & Kittanamongkolchai, W. Risk of incident atrial fibrillation in patients with rheumatoid arthritis: a systematic review and meta-analysis. Int. J. Rheum. Dis. 20, 434–441 (2017).
Wiseman, S. J., Ralston, S. H. & Wardlaw, J. M. Cerebrovascular disease in rheumatic diseases: a systematic review and meta-analysis. Stroke 47, 943–950 (2016).
Lindhardsen, J. et al. Initiation and adherence to secondary prevention pharmacotherapy after myocardial infarction in patients with rheumatoid arthritis: a nationwide cohort study. Ann. Rheum. Dis. 71, 1496–1501 (2012).
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).
Chen, Y. R. et al. Rheumatoid arthritis significantly increased recurrence risk after ischemic stroke/transient ischemic attack. J. Neurol. 265, 1810–1818 (2018).
Wolfe, F. & Michaud, K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. Am. J. Med. 116, 305–311 (2004).
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).
Mantel, A., Holmqvist, M., Andersson, D. C., Lund, L. H. & Askling, J. Association between rheumatoid arthritis and risk of ischemic and nonischemic heart failure. J. Am. Coll. Cardiol. 69, 1275–1285 (2017).
Logstrup, B. B. et al. Development of heart failure in patients with rheumatoid arthritis: a Danish population-based study. Eur. J. Clin. Invest. 48, e12915 (2018).
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).
Davis, J. M. III 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).
Liang, K. P. et al. Increased prevalence of diastolic dysfunction in rheumatoid arthritis. Ann. Rheum. Dis. 69, 1665–1670 (2010).
Piepoli, M. F. et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts): developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur. J. Prev. Cardiol. 23, NP1–NP96 (2016).
Damen, J. A. et al. Prediction models for cardiovascular disease risk in the general population: systematic review. BMJ 353, i2416 (2016).
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).
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).
Rollefstad, S. et al. in Handbook of Cardiovascular Disease Management in Rheumatoid Arthritis. Ch. 4 (ed. Semb, A. G.) 53–71 (Springer, 2017).
Cooney, M. T. et al. Cardiovascular risk estimation in older persons: SCORE O.P. Eur. J. Prev. Cardiol. 23, 1093–1103 (2016).
Goff, D. C. Jr. et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J. Am. Coll. Cardiol. 63, 2935–2959 (2014).
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).
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).
Hippisley-Cox, J. et al. Derivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: prospective open cohort study. BMJ 335, 136 (2007).
Hippisley-Cox, J. et al. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ 336, 1475–1482 (2008).
Hippisley-Cox, J., Coupland, C. & Brindle, P. Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study. BMJ 357, j2099 (2017).
Crowson, C. S. et al. Challenges of developing a cardiovascular risk calculator for patients with rheumatoid arthritis. PLoS One. 12, e0174656 (2017).
Solomon, D. H. et al. Derivation and internal validation of an expanded cardiovascular risk prediction score for rheumatoid arthritis: a consortium of rheumatology researchers of North America Registry Study. Arthritis Rheumatol. 67, 1995–2003 (2015).
Crowson, C. S. et al. Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries. Rheumatology 56, 1102–1110 (2017).
Wahlin, B. et al. Performance of the expanded cardiovascular risk prediction score for rheumatoid arthritis is not superior to the ACC/AHA risk calculator. J. Rheumatol. 46, 130–137 (2019).
Crowson, C. S., Matteson, E. L., Roger, V. L., Therneau, T. M. & Gabriel, S. E. Usefulness of risk scores to estimate the risk of cardiovascular disease in patients with rheumatoid arthritis. Am. J. Cardiol. 110, 420–424 (2012).
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 (2014).
Alemao, E. et al. Comparison of cardiovascular risk algorithms in patients with vs without rheumatoid arthritis and the role of C-reactive protein in predicting cardiovascular outcomes in rheumatoid arthritis. Rheumatology 56, 777–786 (2017).
Schieir, O., Tosevski, C., Glazier, R. H., Hogg-Johnson, S. & Badley, E. M. Incident myocardial infarction associated with major types of arthritis in the general population: a systematic review and meta-analysis. Ann. Rheum. Dis. 76, 1396–1404 (2017).
Arts, E. E. et al. Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms. Ann. Rheum. Dis. 75, 674–680 (2016).
Ljung, L. et al. Performance of the expanded cardiovascular risk prediction score for rheumatoid arthritis in a geographically distant national register-based cohort: an external validation. RMD Open 4, e000771 (2018).
O’Leary, D. H. et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N. Engl. J. Med. 340, 14–22 (1999).
Khanna, N. N. et al. Rheumatoid arthritis: atherosclerosis imaging and cardiovascular risk assessment using machine and deep learning-based tissue characterization. Curr. Atheroscler. Rep. 21, 7 (2019).
Den Ruijter, H. M. et al. Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis. JAMA 308, 796–803 (2012).
O’Leary, D. H. & Bots, M. L. Imaging of atherosclerosis: carotid intima-media thickness. Eur. Heart J. 31, 1682–1689 (2010).
Touboul, P. J. et al. Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th Watching the Risk Symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovasc. Dis. 34, 290–296 (2012).
Semb, A. G., Ikdahl, E., Hisdal, J., Olsen, I. C. & Rollefstad, S. Exploring cardiovascular disease risk evaluation in patients with inflammatory joint diseases. Int. J. Cardiol. 223, 331–336 (2016).
Svanteson, M. et al. Associations between coronary and carotid artery atherosclerosis in patients with inflammatory joint diseases. RMD Open 3, e000544 (2017).
Ajeganova, S., de Faire, U., Jogestrand, T., Frostegard, J. & Hafstrom, I. Carotid atherosclerosis, disease measures, oxidized low-density lipoproteins, and atheroprotective natural antibodies for cardiovascular disease in early rheumatoid arthritis — an inception cohort study. J. Rheumatol. 39, 1146–1154 (2012).
Evans, M. R. et al. Carotid atherosclerosis predicts incident acute coronary syndromes in rheumatoid arthritis. Arthritis Rheum. 63, 1211–1220 (2011).
Rollefstad, S. et al. Rosuvastatin-induced carotid plaque regression in patients with inflammatory joint diseases: the Rosuvastatin in Rheumatoid Arthritis, Ankylosing Spondylitis and other inflammatory joint diseases study. Arthritis Rheumatol. 67, 1718–1728 (2015).
Rollefstad, S. et al. Association of chest pain and risk of cardiovascular disease with coronary atherosclerosis in patients with inflammatory joint diseases. Front. Med. 2, 80 (2015).
Budoff, M. J. et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J. Am. Coll. Cardiol. 52, 1724–1732 (2008).
van Velzen, J. E. et al. Diagnostic performance of non-invasive multidetector computed tomography coronary angiography to detect coronary artery disease using different endpoints: detection of significant stenosis vs. detection of atherosclerosis. Eur. Heart J. 32, 637–645 (2011).
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).
Haberl, R. et al. Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1,764 patients. J. Am. Coll. Cardiol. 37, 451–457 (2001).
Hecht, H. S. & Superko, H. R. Electron beam tomography and National Cholesterol Education Program guidelines in asymptomatic women. J. Am. Coll. Cardiol. 37, 1506–1511 (2001).
van Werkhoven, J. M. et al. Multislice computed tomography coronary angiography for risk stratification in patients with an intermediate pretest likelihood. Heart 95, 1607–1611 (2009).
Gepner, A. D. et al. Comparison of carotid plaque score and coronary artery calcium score for predicting cardiovascular disease events: the multi-ethnic study of atherosclerosis. J. Am. Heart Assoc. 6, e005179 (2017).
Mortensen, M. B. et al. A simple disease-guided approach to personalize ACC/AHA-recommended statin allocation in elderly people: the BioImage study. J. Am. Coll. Cardiol. 68, 881–891 (2016).
Semb, A. G. et al. Cardiovascular disease assessment in rheumatoid arthritis: a guide to translating knowledge of cardiovascular risk into clinical practice. Ann. Rheum. Dis. 73, 1284–1288 (2014).
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).
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).
Monk, H. L., Muller, S., Mallen, C. D. & Hider, S. L. Cardiovascular screening in rheumatoid arthritis: a cross-sectional primary care database study. BMC Fam. Pract. 14, 150 (2013).
Ikdahl, E. et al. Feasibility of cardiovascular disease risk assessments in rheumatology outpatient clinics: experiences from the nationwide NOCAR project. RMD Open 4, e000737 (2018).
Crowson, C. S. et al. Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis. Ann. Rheum. Dis. 77, 48–54 (2018).
Baghdadi, L. R., Woodman, R. J., Shanahan, E. M. & Mangoni, A. A. The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis. PLoS One 10, e0117952 (2015).
Wibetoe, G. et al. Cardiovascular disease risk profiles in inflammatory joint disease entities. Arthritis Res. Ther. 19, 153 (2017).
Williams, B. et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur. Heart J. 39, 3021–3104 (2018).
Whelton, P. K. et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J. Am. Coll. Cardiol. 71, e127–e248 (2018).
Mills, K. T. et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation 134, 441–450 (2016).
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).
Jafri, K., Bartels, C. M., Shin, D., Gelfand, J. M. & Ogdie, A. Incidence and management of cardiovascular risk factors in psoriatic arthritis and rheumatoid arthritis: a population-based study. Arthritis Care Res. 69, 51–57 (2017).
O’Driscoll, N., Kennedy, N., Amjum, S., Fraser, A. & Hannigan, A. Comparing cardiovascular risk factors, disease and treatment in participants with rheumatoid arthritis and without arthritis in a population based study. Ir. Med. J. 110, 562 (2017).
Panoulas, V. F. et al. Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis. Rheumatology 46, 1477–1482 (2007).
Scott, I. C., Ibrahim, F., Johnson, D., Scott, D. L. & Kingsley, G. H. Current limitations in the management of cardiovascular risk in rheumatoid arthritis. Clin. Exp. Rheumatol. 30, 228–232 (2012).
An, J. et al. Traditional cardiovascular disease risk factor management in rheumatoid arthritis compared to matched nonrheumatoid arthritis in a US managed care setting. Arthritis Care Res. 68, 629–637 (2016).
Ikdahl, E. et al. Guideline recommended treatment to targets of cardiovascular risk is inadequate in patients with inflammatory joint diseases. Int. J. Cardiol. 274, 311–318 (2019).
Wright, J. T. Jr., Whelton, P. K. & Reboussin, D. M. A randomized trial of intensive versus standard blood-pressure control. N. Engl. J. Med. 374, 2294 (2016).
Fulcher, J. et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 385, 1397–1405 (2015).
Liao, K. P., Liu, J., Lu, B., Solomon, D. H. & Kim, S. C. Association between lipid levels and major adverse cardiovascular events in rheumatoid arthritis compared to non-rheumatoid arthritis patients. Arthritis Rheumatol. 67, 2004–2010 (2015).
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).
Choy, E., Ganeshalingam, K., Semb, A. G., Szekanecz, Z. & Nurmohamed, M. Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology 53, 2143–2154 (2014).
Carroll, M. D., Fryar, C. D. & Nguyen, D. T. Total and high-density lipoprotein cholesterol in adults: United States, 2015–2016. NCHS Data Brief. 290, 1–8 (2017).
Kitas, G. D. et al. A multicenter, randomized, placebo-controlled trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheumatol. 71, 1437–1449 (2019).
Mihaylova, B. et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380, 581–590 (2012).
Baigent, C. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376, 1670–1681 (2010).
Huang, C. Y. et al. Effect of statin therapy on the prevention of new-onset acute coronary syndrome in patients with rheumatoid arthritis. Int. J. Cardiol. 253, 1–6 (2018).
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).
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).
Rollefstad, S. et al. Systemic inflammation in patients with inflammatory joint diseases does not influence statin dose needed to obtain LDL cholesterol goal in cardiovascular prevention. Ann. Rheum. Dis. 74, 1544–1550 (2015).
Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet 393, 407–415 (2019).
Finegold, J. A., Manisty, C. H., Goldacre, B., Barron, A. J. & Francis, D. P. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. Eur. J. Prev. Cardiol. 21, 464–474 (2014).
Gupta, A. et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet 389, 2473–2481 (2017).
Giugliano, R. P. et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 390, 1962–1971 (2017).
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).
Schmitt, C., Kuhn, B., Zhang, X., Kivitz, A. J. & Grange, S. Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin. Pharmacol. Ther. 89, 735–740 (2011).
Phan, B. A., Dayspring, T. D. & Toth, P. P. Ezetimibe therapy: mechanism of action and clinical update. Vasc. Health Risk Manag. 8, 415–427 (2012).
Davidson, M. H. et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J. Am. Coll. Cardiol. 40, 2125–2134 (2002).
Cannon, C. P. et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).
Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1722 (2017).
Schwartz, G. G. et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N. Engl. J. Med. 379, 2097–2107 (2018).
Giugliano, R. P., Sabatine, M. S. & Ott, B. R. Cognitive function in a randomized trial of evolocumab. N. Engl. J. Med. 377, 1997 (2017).
Sarwar, N. et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 western prospective studies. Circulation 115, 450–458 (2007).
Miller, M. et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J. Am. Coll. Cardiol. 51, 724–730 (2008).
Reiner, Z. Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: a clinical update. Nutr. Metab. Cardiovasc. Dis. 23, 799–807 (2013).
Harris, W. S. et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J. Cardiovasc. Risk 4, 385–391 (1997).
Boden, W. E. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365, 2255–2267 (2011).
Chapman, M. J., Redfern, J. S., McGovern, M. E. & Giral, P. Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol. Ther. 126, 314–345 (2010).
Graham, D. J. et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 292, 2585–2590 (2004).
Barter, P. et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N. Engl. J. Med. 357, 1301–1310 (2007).
Nissen, S. E. et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290, 2292–2300 (2003).
Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012).
Nicholls, S. J. CETP-inhibition and HDL-cholesterol: a story of CV risk or CV benefit, or both. Clin. Pharmacol. Ther. 104, 297–300 (2018).
Ference, B. A. et al. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA 318, 947–956 (2017).
Voight, B. F. et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 380, 572–580 (2012).
Tsimikas, S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J. Am. Coll. Cardiol. 69, 692–711 (2017).
Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).
Kamstrup, P. R., Tybjaerg-Hansen, A., Steffensen, R. & Nordestgaard, B. G. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301, 2331–2339 (2009).
Nordestgaard, B. G. et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur. Heart J. 31, 2844–2853 (2010).
Erqou, S. et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302, 412–423 (2009).
O’Donoghue, M. L. et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 139, 1483–1492 (2019).
Chen, L., Magliano, D. J. & Zimmet, P. Z. The worldwide epidemiology of type 2 diabetes mellitus — present and future perspectives. Nat. Rev. Endocrinol. 8, 228–236 (2011).
American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. Diabetes Care 41, S13–S27 (2018).
Chung, C. P. et al. Prevalence of traditional modifiable cardiovascular risk factors in patients with rheumatoid arthritis: comparison with control subjects from the multi-ethnic study of atherosclerosis. Semin. Arthritis Rheum. 41, 535–544 (2012).
Castaneda, S. et al. Cardiovascular morbidity and associated risk factors in Spanish patients with chronic inflammatory rheumatic diseases attending rheumatology clinics: baseline data of the CARMA project. Semin. Arthritis Rheum. 44, 618–626 (2015).
Ruscitti, P. et al. Prevalence of type 2 diabetes and impaired fasting glucose in patients affected by rheumatoid arthritis: results from a cross-sectional study. Medicine 96, e7896 (2017).
Beagley, J., Guariguata, L., Weil, C. & Motala, A. A. Global estimates of undiagnosed diabetes in adults. Diabetes Res. Clin. Pract. 103, 150–160 (2014).
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).
Cosentino, F. et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur. Heart J. 41, 255–323 (2020).
Besseling, J., Kastelein, J. J., Defesche, J. C., Hutten, B. A. & Hovingh, G. K. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA 313, 1029–1036 (2015).
Libby, P., Ridker, P. M. & Hansson, G. K. Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol. 54, 2129–2138 (2009).
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).
Ridker, P. M. et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N. Engl. J. Med. 344, 1959–1965 (2001).
Ridker, P. M. et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) investigators. Circulation 98, 839–844 (1998).
Ridker, P. M., Glynn, R. J. & Hennekens, C. H. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 97, 2007–2011 (1998).
Mason, J. C. & Libby, P. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur. Heart J. 36, 482–489c (2015).
Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).
Ridker, P. M. et al. Low-dose methotrexate for the prevention of atherosclerotic events. N. Engl. J. Med. 380, 752–762 (2019).
World Health Organization. Global health risks: mortality and burden of disease attributable to selected major risks. WHO Health Statistics and Information Systems http://www.who.int/healthinfo/global_burden_disease/GlobalHealthRisks_report_full.pdf (2009).
Belbasis, L., Dosis, V. & Evangelou, E. Elucidating the environmental risk factors for rheumatic diseases: an umbrella review of meta-analyses. Int. J. Rheum. Dis. 21, 1514–1524 (2018).
Joseph, R. M., Movahedi, M., Dixon, W. G. & Symmons, D. P. Smoking-related mortality in patients with early rheumatoid arthritis: a retrospective cohort study using the clinical practice research datalink. Arthritis Care Res. 68, 1598–1606 (2016).
Gianfrancesco, M. A. et al. Smoking is associated with higher disease activity in rheumatoid arthritis: a longitudinal study controlling for time-varying covariates. J. Rheumatol. 46, 370–375 (2019).
Roelsgaard, I. K. et al. Smoking cessation is associated with lower disease activity and predicts cardiovascular risk reduction in rheumatoid arthritis patients. Rheumatology https://doi.org/10.1093/rheumatology/kez557 (2019).
Roelsgaard, I. K. et al. The effect of an intensive smoking cessation intervention on disease activity in patients with rheumatoid arthritis: study protocol for a randomised controlled trial. Trials 18, 570 (2017).
Joseph, R. M., Movahedi, M., Dixon, W. G. & Symmons, D. P. Risks of smoking and benefits of smoking cessation on hospitalisations for cardiovascular events and respiratory infection in patients with rheumatoid arthritis: a retrospective cohort study using the clinical practice research datalink. RMD Open 3, e000506 (2017).
Naranjo, A. et al. Smoking cessation advice by rheumatologists: results of an international survey. Rheumatology 53, 1825–1829 (2014).
National Health Service. Smoking and rheumatoid arthritis: how to deliver brief smoking advice. National Rheumatoid Arthritis Society https://www.nras.org.uk/data/files/For%20professionals/Smoking%20and%20RA/RA%20Smoking%20Brief%20advice%20leaflet1.pdf (2012).
Naranjo, A. et al. Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study. Arthritis Res. Ther. 10, R30 (2008).
Wolfe, F. & Michaud, K. Effect of body mass index on mortality and clinical status in rheumatoid arthritis. Arthritis Care Res. 64, 1471–1479 (2012).
Escalante, A., Haas, R. W. & del Rincón, I. Paradoxical effect of body mass index on survival in rheumatoid arthritis: role of comorbidity and systemic inflammation. Arch. Intern. Med. 165, 1624–1629 (2005).
Stavropoulos-Kalinoglou, A. et al. Associations of obesity with modifiable risk factors for the development of cardiovascular disease in patients with rheumatoid arthritis. Ann. Rheum. Dis. 68, 242–245 (2009).
Elkan, A. C., Hakansson, N., Frostegard, J., Cederholm, T. & Hafstrom, I. Rheumatoid cachexia is associated with dyslipidemia and low levels of atheroprotective natural antibodies against phosphorylcholine but not with dietary fat in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res. Ther. 11, R37 (2009).
McKellar, G. et al. A pilot study of a Mediterranean-type diet intervention in female patients with rheumatoid arthritis living in areas of social deprivation in Glasgow. Ann. Rheum. Dis. 66, 1239–1243 (2007).
Eckel, R. H. et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J. Am. Coll. Cardiol. 63, 2960–2984 (2014).
Fagerhoi, M. G., Rollefstad, S., Olsen, S. U. & Semb, A. G. The effect of brief versus individually tailored dietary advice on change in diet, lipids and blood pressure in patients with inflammatory joint disease. Food Nutr. Res. 62, 1512 (2018).
Brady, S. R. et al. The role of traditional cardiovascular risk factors among patients with rheumatoid arthritis. J. Rheumatol. 36, 34–40 (2009).
Veldhuijzen van Zanten, J. J. et al. Perceived barriers, facilitators and benefits for regular physical activity and exercise in patients with rheumatoid arthritis: a review of the literature. Sports Med. 45, 1401–1412 (2015).
Rausch Osthoff, A. K. et al. 2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis. Ann. Rheum. Dis. 77, 1251–1260 (2018).
Hammam, N., Ezeugwu, V. E., Rumsey, D. G., Manns, P. J. & Pritchard-Wiart, L. Physical activity, sedentary behavior, and long-term cardiovascular risk in individuals with rheumatoid arthritis. Phys. Sportsmed. 47, 463–470 (2019).
Byram, K. W. et al. Exercise is associated with increased small HDL particle concentration and decreased vascular stiffness in rheumatoid arthritis. J. Clin. Rheumatol. 24, 417–421 (2018).
Metsios, G. S., Stavropoulos-Kalinoglou, A. & Kitas, G. D. The role of exercise in the management of rheumatoid arthritis. Expert. Rev. Clin. Immunol. 11, 1121–1130 (2015).
Goodson, N. J., Brookhart, A. M., Symmons, D. P., Silman, A. J. & Solomon, D. H. Non-steroidal anti-inflammatory drug use does not appear to be associated with increased cardiovascular mortality in patients with inflammatory polyarthritis: results from a primary care based inception cohort of patients. Ann. Rheum. Dis. 68, 367–372 (2009).
Davis, J. M. III et al. Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 56, 820–830 (2007).
Wilson, J. C. et al. Incidence and risk of glucocorticoid-associated adverse effects in patients with rheumatoid arthritis. Arthritis Care Res. 71, 498–511 (2019).
Rempenault, C. et al. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Ann. Rheum. Dis. 77, 98–103 (2018).
Lee, J. L. et al. Biologics and cardiovascular events in inflammatory arthritis: a prospective national cohort study. Arthritis Res. Ther. 20, 171 (2018).
Tam, L. S., Tomlinson, B., Chu, T. T., Li, T. K. & Li, E. K. Impact of TNF inhibition on insulin resistance and lipids levels in patients with rheumatoid arthritis. Clin. Rheumatol. 26, 1495–1498 (2007).
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 50, 518–531 (2011).
Dixon, W. G. et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 56, 2905–2912 (2007).
Singh, S. et al. Comparative risk of cardiovascular events with biologic and synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res. 72, 561–576 (2020).
Baniaamam, M., Paulus, W. J., Blanken, A. B. & Nurmohamed, M. T. The effect of biological DMARDs on the risk of congestive heart failure in rheumatoid arthritis: a systematic review. Expert. Opin. Biol. Ther. 18, 585–594 (2018).
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).
Taylor, P. C. Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis. Rheumatology 58, i17–i26 (2019).
Harigai, M. Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis. Rheumatology 58, i34–i42 (2019).
Charles-Schoeman, C. et al. Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor. Semin. Arthritis Rheum. 46, 261–271 (2016).
European Medicines Agency. Increased risk of blood clots in lungs and death with higher dose of Xeljanz (tofacitinib) for rheumatoid arthritis. EMA News https://www.ema.europa.eu/en/news/increased-risk-blood-clots-lungs-death-higher-dose-xeljanz-tofacitinib-rheumatoid-arthritis (2019).
Qiu, C. et al. Baricitinib induces LDL-C and HDL-C increases in rheumatoid arthritis: a meta-analysis of randomized controlled trials. Lipids Health Dis. 18, 54 (2019).
Taylor, P. C. et al. Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies. Ann. Rheum. Dis. 77, 988–995 (2018).
Xie, W. et al. Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann. Rheum. Dis. 78, 1048–1054 (2019).
The work of the authors has been supported by grants from the South Eastern Regional Health Authorities of Norway (2013064 to A.G.S. and 2016063 to S.R.).
The authors declare no competing interests.
Peer review information
Nature Reviews Rheumatology thanks M. Nurmohamed and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Diastolic dysfunction
A stiffening of the ventricles that restricts the ability of the heart to fill with blood between beats.
- Heart failure with preserved ejection fraction
A form of heart failure in which the ejection fraction — the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the left ventricle is maximally filled — is normal, defined as greater than 50%.
- Atrial fibrillation
An irregular, rapid heart rate that occurs when the atria beat out of rhythm with the ventricles, which can cause symptoms including heart palpitations, fatigue and shortness of breath.
- Coronary angiography
Radiography performed with contrast agent in the coronary arteries.
- Coronary artery stenosis
Narrowing of the arteries that supply blood to the heart muscle.
About this article
Cite this article
Semb, A.G., Ikdahl, E., Wibetoe, G. et al. Atherosclerotic cardiovascular disease prevention in rheumatoid arthritis. Nat Rev Rheumatol 16, 361–379 (2020). https://doi.org/10.1038/s41584-020-0428-y
This article is cited by
Effect of biological disease-modifying antirheumatic drugs on body composition in patients with rheumatoid arthritis: a systematic review and meta-analysis
Advances in Rheumatology (2022)
Prevalence and influence of hypouricemia on cardiovascular diseases in patients with rheumatoid arthritis
European Journal of Medical Research (2022)
The comparison of cardiovascular disease risk prediction scores and evaluation of subclinical atherosclerosis in rheumatoid arthritis: a cross-sectional study
Clinical Rheumatology (2022)
Cardiovascular disease risk calculators to reflect the subclinical atherosclerosis of coronary artery in rheumatoid arthritis: a pilot study
BMC Rheumatology (2021)
Cardiovascular risk comorbidities in rheumatoid arthritis patients and the use of anti-rheumatic drugs: a cross-sectional real-life study
Advances in Rheumatology (2021)