Opinion statement
Recognizing that systemic inflammation is a major contributor to the increased risk of cardiovascular disease (CVD), including stroke, in rheumatoid arthritis (RA) serves as the basis for prevention strategies for cerebrovascular disease in RA. In addition to traditional cardiovascular risk factors, recognize that RA may be an independent risk factor for cerebrovascular accident (CVA). The risk of CVD should be assessed in each patient with RA, utilizing modified risk score calculators. Careful monitoring and control of systemic inflammation should be undertaken in conjunction with assessing each patient’s CVD risk, acknowledging the benefits and risks of specific RA-directed therapies. Emphasis should be given to early and aggressive control of inflammation in RA patients, particularly those with seropositivity, increased inflammatory markers, long disease duration (>10 years), and/or extra-articular manifestations. In RA patients requiring glucocorticoid therapy, attempts should be made to use or wean to the minimal effective dose (preferably less than 7.5 mg/day). It should be recognized that both disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate, and tumor necrosis factor (TNF)-alpha inhibitors partially mitigate the risk of CVD. In patients with inadequate control of inflammation with DMARDs, consideration should be given to switch to anti-TNF agents earlier in the disease process. Modifiable risk factors should be addressed as per guidelines for the general population. Active RA may be considered as a risk equivalent to diabetes mellitus when applying these guidelines. With regard to lipid management and use of statin therapy, further studies are required given the apparent “lipid paradox” in RA. Use of aspirin for primary prevention in RA has not been well studied; however, when aspirin is used for secondary prevention, one should recognize that concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) may decrease the antiplatelet effect. Given the cardiovascular risk associated with NSAIDs, the lowest possible dose for the shortest time should be used.
Similar content being viewed by others
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008;59:1690–7.
Peters MJ, Symmons DP, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010;69:325–31.
Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107:1303–7.
de Groot L, Posthumus MD, Kallenberg CG, Bijl M. Risk factors and early detection of atherosclerosis in rheumatoid arthritis. Eur J Clin Invest. 2010;40:835–42.
Gullick NJ, Scott DL. Co-morbidities in established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2011;25:469–83.
Meune C, Touze E, Trinquart L, Allanore Y. High risk of clinical cardiovascular events in rheumatoid arthritis: levels of associations of myocardial infarction and stroke through a systematic review and meta-analysis. Arch Cardiovasc Dis. 2010;103:252–61.
Liang KP, Liang KV, Matteson EL, McClelland RL, Christianson TJ, Turesson C. Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extraarticular disease manifestations. Arthritis Rheum. 2006;54:642–8.
Bacani AK, Gabriel SE, et al. Noncardiac vascular disease in rheumatoid arthritis. Arthritis Rheum. 2012;64:53–61.
Liou T-H, Huang S-w, et al. Risk of stroke in patients with rheumatism: a nationwide longitudinal population-based study. Sci Rep. 2014;4:5110. doi:10.1038/srep05110.
Sodergren A, Stegmayr B, et al. Increased incidence of stroke and impaired prognosis after stroke among patient with seropositive rheumatoid arthritis. Clin Exp Rheumatol. 2009;27:641–4.
Semb AG et al. Lipids, myocardial infarction and ischemic stroke in patients with rheumatoid arthritis in the Apolipoprotein-Related Mortality Risk (AMORIS) Study. Ann Rheum Dis. 2010;69:1996–2001. doi:10.1136/ard.2009.126128.
Solomon DH, Kremer J, Curtis JR, et al. Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity. Ann Rheum Dis. 2010;69:1920–5.
Peters MJ, van Halm VP, Voskuyl AE, et al. Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum. 2009;61:1571.
Goodson NJ, Wiles NJ, et al. Mortality in early inflammatory polyarthritis: cardiovascular mortality is increased in seropositive patients. Arthritis Rheum. 2002;46:2010–9.
Bili A, Tang X, Pranesh S, et al. TNF-alpha inhibitor use and decreased risk for incident coronary events in rheumatoid arthritis patients. Arthritis Care Res 2013.
Solomon DH, Curtis JR, Saag KG, et al. Cardiovascular risk in rheumatoid arthritis: comparing TNF-alpha blockade with nonbiologic DMARDs. Am J Med. 2013;126:730.e9–730.e17. A large retrospective study comparing TNF inhibitors with non-biologic DMARDs in reducing risk for CV end points in patients with rheumatoid arthritis. This study serves as a good reference point when choosing RA therapy to control inflammation and also emphasizes the role of TNF in promoting atherosclerosis in RA.
van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE. Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther. 2006;8:R151.
Myasoedova E, Crowson CS, Kremers HM, 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. 2011;70:482–7.
Hallenbeck JM. Inflammatory reactions at the blood-endothelial interface in acute stroke. Adv Neurol. 1996;71:281–97.
Del Zoppo GJ. TIAs and the pathology of cerebral ischemia. Neurology. 2004;62(8 Suppl 6):S15–9.
Becker KJ. Targeting the central nervous system inflammatory response in ischemic stroke. Curr Opin Neurol. 2001;14:349–53.
Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375:132–40.
Libby P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am J Med. 2008;121 Suppl 1:S21–31.
Miller AM, McInnes IB. Cytokines as therapeutic targets to reduce cardiovascular risk in chronic inflammation. Curr Pharm Des. 2011;17:1–8.
Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–95.
Curb JD, Abbott RD, Rodriguez BL, Sakkinen P, Popper JS, Yano K, et al. C-reactive protein and the future risk of thromboembolic stroke in healthy men. Circulation. 2003;107:2016–20.
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557–65.
Hallenbeck JM. The many faces of tumor necrosis factor in stroke. Nat Med. 2002;8:1363–8.
Schultz O, Oberhauser F, Saech J, et al. Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS One. 2010;5:e14328.
Chung CP, Oeser A, Solus JF, et al. Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms. Arthritis Rheum. 2008;58:2105–12.
Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24:987–1003.
Wilson PW, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–47. 13–14; EULAR.
Luqmani R, Hennell S, Estrach C, Basher D, Birrell F, Bosworth A, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of rheumatoid arthritis (after the first 2 years). Rheumatology (Oxford). 2009;48:436–9. BSR.
Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Torp-Pedersen C, et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis. 2011;70:929–34.
Crowson CS, Gabriel SE. Towards improving cardiovascular risk management in patients with rheumatoid arthritis: the need for accurate risk assessment. Ann Rheum Dis. 2011;70:719–21. 26; A.
Gomez-Vaquero C, Robustillo M, Narvaez J, et al. Assessment of cardiovascular risk in rheumatoid arthritis: impact of the new EULAR recommendations on the score cardiovascular risk index. Clin Rheumatol. 2012;31:35–9. A study of 200 patients with RA, in whom the application of the EULAR recommendations for assessing CV risk was studied, particularly the use of modified risk score which showed an association with increased ischemic CV events.
Kremers H, Nicola PJ, et al. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2005;52(3):722–32.
National Institute for Health and Clinical Excellence. Rheumatoid arthritis: the management of rheumatoid arthritis in adults 2009. URL: http://www.nice.org.uk/nicemedia/live/12131/43327/43327.pdf.
Scottish Intercollegiate Guidelines Network. Management of early rheumatoid arthritis. URL: http://www.sign.ac.uk/guidelines/fulltext/123/index.html.
Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625–39.
The Royal Australian College of General Practitioners. Clinical guideline for the diagnosis and management of early rheumatoid arthritis. 2009. URL: http://www.racgp.org.au/download/documents/Guidelines/Musculoskeletal/racgp_ra_guideline.pdf.
Tornero Molina J, Sanmarti Sala R, Rodriquez Valverde V, et al. Update of the Consensus Statement of the Spanish Society of Rheumatology on the management of biologic therapies in rheumatoid arthritis. Rheumatol Clin. 2010;6:23–36.
Hannawi S, Haluska B, Marwick TH, et al. Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation. Arthritis Res Ther. 2007;9:R116.
Wong M, Toh L, Wilson A, et al. Reduced arterial elasticity in rheumatoid arthritis and the relationship to vascular disease risk factors and inflammation. Arthritis Rheum. 2003;48:81–9.
Hall FC, Dalbeth N. Disease modification and cardiovascular risk reduction. Two sides of the same coin? Rheumatology (Oxford). 2005;44:1473.
Choi HK, Hernan MA, Seeger JD, et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359:1173.
Georgiadis AN, Voulgari PV, et al. Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum. 2008;38:13.
Reiss AB, Carsons SE, Anwar K, et al. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum. 2008;58:3675.
van Ede AE, Laan RFJM, Blom HJ, et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford). 2002;41:658–65.
Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244–79.
Stagakis I, Bertsias G, Karvounaris S, et al. Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance. Arthritis Res Ther. 2012;14:R141.
Wijbrandts CA, van Leuven SI, Boom HD, et al. Sustained changes in lipid profile and macrophage migration inhibitory factor levels after anti-tumour necrosis factor therapy in rheumatoid arthritis. Ann Rheum Dis. 2009;68:1316–21.
Sattar N, Crompton P, Cherry L, et al. Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: a double-blind, placebo-controlled study. Arthritis Rheum. 2007;56:831–9.
Greenberg JD, Kremer JM, Curtis JR, et al. Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70:576–82.
Popa C, Netea MG, Radstake T, et al. Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis. Ann Rheum Dis. 2005;64:303–5.
Jacobsson LT, Turesson C, Gulfe A, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular event in patients with rheumatoid arthritis. J Rheumatol. 2005;32:1213.
Dixon WG, Watson KD, Lunt M, 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. 2007;56:2905–12.
Westlake SL, Colebatch AN, Baird J, et al. Tumour necrosis factor antagonists and the risk of cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology. 2011;50:518–31.
Greenberg JD, Kremer JM, Curtis JR, et al. Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70:576–82. doi:10.1136/ard.2010.129916.
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. 2009;68:460–9.
Robertson J, Peters MJ, McInnes IB, Sattar N. Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm. Nat Rev Rheumatol. 2013;9:513–23. Detailed review discussing the “lipid paradox” in inflammatory arthritis and the impact of DMARDs and biologics on the lipoprotein measures.
Daien CI, Duny Y, Barnetche T, et al. Effect of TNF inhibitors on lipid profile in rheumatoid arthritis: a systematic review with meta-analysis. Ann Rheum Dis. 2012;71:862–8.
Saiki O, Takao R, Naruse Y, et al. Infliximab but not methotrexate induces extra-high levels of VLDL-triglyceride in patients with rheumatoid arthritis. J Rheumatol. 2007;34:1997–2004.
Sociedad Espanola de Reumatologia. Guias de practica clinica finalizadas:guia de manejo de la gota. 2011. URL: http://www.ser.es/practicaClinica/Guias_practica_clinica/Guias_finalizadas.php. (20; E).
Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160–236. doi:10.1161/STR.0000000000000024.
McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double blind, randomized placebo-controlled trial. Lancet. 2004;363:2015.
Rollefstad S, Ikdahl E, Hisdal J, Olsen IC, Holme I, Hammer HB, Smerud KT, Kitas GD, Pedersen TR, Kvien TK, Semb AG. Rosuvastatin induced carotid plaque regression in patients with inflammatory joint diseases: the RORA-AS study. Arthritis Rheumatol. 2015 Mar 16. This most recent study shows the effects of lipid lowering with rosuvastatin on carotid atherosclerotic plaque regression in patients with inflammatory joint disease and may serve as a benchmark for future studies with statins and CV end points in rheumatoid arthritis
Ridker PM, Solomon DH. Should patient with rheumatoid arthritis receive statin therapy? Arthritis Rheum. 2009;60:1205.
Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med. 2004;141:764.
Da Silva JAP, Jacobs JWG, Kirwan JR, et al. Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis. 2006;65:285–93.
Dessein PH, Joffe BI, Stanwix AE, et al. Glucocorticoids and insulin sensitivity in rheumatoid arthritis. J Rheumatol. 2004;31:867–74.
Panoulas VF, Douglas KMJ, Stavropoulos-Kalinoglou A, et al. Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis. Rheumatology (Oxford). 2008;47:72–5.
Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med. 2004;141:764–70.
Hallgren R, Berne C. Glucose intolerance in patients with chronic inflammatory diseases is normalized by glucocorticoids. Acta Med Scand. 1983;213:351–5.
Boers M, Nurmohamed MT, Doelman CJA, et al. Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62:842–5.
van Everdingen AA, Jacobs JW, van Reesema DR S, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med. 2002;136:1–12. doi:10.7326/0003-4819-136-1-200201010-00006.
Davis 3rd JM, Maradit Kremers H, Crowson CS, Nicola PJ, Ballman KV, Therneau TM, et al. Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 2007;56(3):820–30.
Bolten WW. Problem of the atherothrombotic potential of non-steroidal anti-inflammatory drugs. Ann Rheum Dis. 2006;65:7–13.
Garner SE, Fidan DD, Frankish RR, et al. Rofecoxib for rheumatoid arthritis. Cochrane Database Syst Rev. 2005;1:CD003685.
Goodson NJ, Brookhart AM, Symmons DP, et al. 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. 2009;68:367272.
Scheiman JM, Fendrick AM. Practical approaches to minimizing gastrointestinal and cardiovascular safety concerns with COX-2 inhibitors and NSAIDs. Arthritis Res Ther. 2005;7 Suppl 4:S23–9.
Panoulas VF, Metsios GS, Pace AV, et al. Hypertension in rheumatoid arthritis. Rheumatology. 2008;47:1286–98.
Rozman B, Praprotnik S, Logar D, Tomsic M, Hojnik M, et al. Leflunomide and hypertension. Ann Rheum Dis. 2002;61:567–9.
Tikiz C, Utuk O, Pirildar T, et al. Effects of angiotensin-converting enzyme inhibition and statin treatment on inflammatory markers and endothelial functions in patients with longterm rheumatoid arthritis. J Rheumatol. 2005;32:2095–101.
Flammer AJ, Sudano I, Hermann F, et al. Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis. Circulation. 2008;117:2262–9.
Dagenais NJ, Jamali F. Protective effects of angiotensin II interruption: evidence for antiinflammatory actions. Pharmacotherapy. 2005;25:1213–29.
Martin MF, Surrall KE, McKenna F, et al. Captopril: a new treatment for rheumatoid arthritis? Lancet. 1984;1:1325–8.
Kremers HM, Crowson CS, Therneau TM, Roger VL, Gabriel SE. High ten-year risk of cardiovascular disease in newly diagnosed rheumatoid arthritis patients: a population-based cohort study. Arthritis Rheum. 2008;58(8):2268–74. doi:10.1002/art.23650.
Brady SR, de Courten B, Reid CM, Cicuttini FM, de Courten MP, Liew D. The role of traditional cardiovascular risk factors among patients with rheumatoid arthritis. J Rheumatol. 2009;36(1):34–40. doi:10.3899/jrheum.080404.
Manfredsdottir VF, Vikingsdottir T, Jonsson T, et al. The effects of tobacco smoking and rheumatoid factor sero-positivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology. 2006;45:734–40.
Compliance with Ethics Guidelines
Conflict of Interest
Namrata Dhillon and Kimberly Liang declare no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by the authors.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is part of the Topical Collection on Cerebrovascular Disorders
Rights and permissions
About this article
Cite this article
Dhillon, N., Liang, K. Prevention of Stroke in Rheumatoid Arthritis. Curr Treat Options Neurol 17, 31 (2015). https://doi.org/10.1007/s11940-015-0356-3
Published:
DOI: https://doi.org/10.1007/s11940-015-0356-3