Mitigating Risk of Cardiovascular Disease in Rheumatoid Arthritis
Mechanisms of CVD Development in RA
Growing evidence implicates chronic inflammation in the development of atherosclerosis and premature heart disease in patients with systemic autoimmune conditions such as RA.<sup>1-7</sup> Post-mortem and imaging studies suggest that although patients with RA have plaque levels similar to the general population, persistent arterial inflammation leaves the plaque unstable and vulnerable to rupture.<sup>1</sup> Inflammation also causes endothelial dysfunction, which promotes atherosclerosis formation and damage to the vascular wall. This damage contributes to carotid intima-media thickening (cIMT). Studies have observed endothelial dysfunction in patients with newly diagnosed or longstanding RA.<sup>7</sup> Genetic factors also contribute to CV risk in RA.<sup>7</sup> The <i>HLA-DRB1*04</i> shared epitope alleles are thought to enhance the risk of CVD mortality and morbidity, possibly through promotion of endothelial dysfunction and development of carotid plaques. Genetic variants in the TNF family have also been linked to CVD in RA.<sup>7</sup> <i>Photo credit: Living Art Enterprises, LLC / Science Source</i>
Epidemiology of Heart Disease in RA
Rheumatoid arthritis (RA) is an independent risk factor for CVD. Patients with RA are twice as likely as the general population to develop CAD or congestive heart failure (CHF).<sup>4</sup> To calculate excess risks of morbidity and mortality due to CVD, Juan Aviña-Zubieta, MD, and colleagues conducted 2 meta-analyses.<sup>5,6</sup> The first included 24 observational studies and found patients with RA were 50% more likely to die of CVD than the general population, 59% more likely to die of ischemic heart disease, and 52% more likely to die of a cerebrovascular accident (CVA).<sup>5</sup> The second meta-analysis included 14 observational studies and found a 48% increased risk of incident CVD (fatal and nonfatal myocardial infarction [MI], CVA, or CHF), a 68% increased risk of incident MI, and a 41% increased risk of incident CVA.<sup>6</sup> The risk of CVD appears to correlate with RA severity. The magnitude of excess CV risk in RA is on par with the excess risk associated with type 2 diabetes.<sup>10</sup>
Role of Classic CVD Risk factors in CVD Development in RA
Classic risk factors for CVD, such as hypertension, type 2 diabetes, smoking, hypercholesterolemia, and obesity increase the risk of cardiovascular mortality or morbidity patients with RA.<sup>8</sup> Some evidence suggests RA inflammation and genetic factors act synergistically with classic risk factors to enhance development of atherosclerosis.<sup>1,7</sup> Other data point to classic CV risk factors as having a greater effect on CV risk than inflammation.<sup>9</sup> A prospective study that followed 201 RA patients for 6 years found baseline hypertension, dyslipidemia, and insulin resistance were better long-term predictors of worse microvascular endothelial function than systemic disease-related inflammation.
Treatment of Established CVD Risk Factors in RA
Treatment selection is important for patients with RA who have established risk factors for CVD. Limited data from studies that have examined the relationship between RA treatment and CVD suggest non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids increase the risk of some cardiovascular events (CVEs), whereas disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) inhibitors and methotrexate decrease the risk of CVEs. <sup>3 </sup> The reduction in CVEs associated with DMARD use may result from decreased systemic inflammation. More data from randomized controlled studies are needed to determine the degree of cardiovascular benefit patients with RA receive from different DMARDs and how it should factor into treatment decisions. <sup>3 </sup>
Guidelines for CV Risk Assessment in RA
Despite a clear link between RA and CVD, many RA practice guidelines—including the 2015 ACR guidelines—do not address screening for CV risk.<sup>10,11</sup> The European League Against Rheumatism (EULAR) offers the only dedicated guideline for CV risk management in RA.<sup>12</sup> EULAR recommends performing a CV risk assessment at least once every 5 years or after treatment changes. Variables are the same as those used for the general population and featured in common tools for estimating 10-year CVE risk, such as Framingham or Systematic Coronary Risk Evaluation (SCORE). They include gender, age, smoking status, blood pressure, lipid levels, and diabetes. Few CV risk models specific to RA are available.<sup>12</sup> If the risk calculator does not factor in RA, EULAR suggests multiplying risk by 1.5. Another approach is to increase the patient’s age by 15 years. Carotid ultrasonography to identify plaques and cIMT values and biomarker tests could help identify high-risk RA patients not captured by risk models.<sup>7</sup>
Management of CV Risk in Patients With RA
Despite RA patients’ increased CV risk, they are less likely to receive proper CV care.<sup>3,4</sup> This may be partly because patients with RA see many physicians, including PCPs, who may lack knowledge of CV risk in RA.<sup>3</sup> The “lipid paradox” and lack of knowledge about RA-related CV risk may lead PCPs to underestimate patients’ risk.<sup>4,13,14</sup> Data show some RA patients with significantly elevated inflammatory markers paradoxically have lower cholesterol levels.<sup>13</sup> EULAR cautions rheumatologists against assuming the PCP is monitoring CV health and to instead take responsibility for ensuring patients’ CV risk is managed appropriately.<sup>12</sup> Reducing patients’ CV risk begins with optimal control of inflammation.<sup>12</sup> One study found patients with high disease activity and high C-reactive protein levels in the 2 years after RA diagnosis had twice as many CVEs.<sup>15</sup> Patients with modifiable risk factors should be advised to make lifestyle changes.<sup>12</sup> Pharmacological treatment should be used per national CVD guidelines.
Effects of RA Pharmacotherapy on CVD Risk
Several studies have reported significant reductions in CVD risk in patients with RA treated with conventional synthetic DMARDs or TNF inhibitors.<sup>12</sup> Long-term use is associated with further declines in CVD risk, supporting the hypothesis that controlling inflammation reduces CV risk in patients with RA. A recent meta-analysis of clinical trials compared CV outcomes of CVE, MI, stroke, major adverse cardiac events, and congestive heart failure between different classes of anti-rheumatic drugs. Data showed TNF inhibitors significantly reduced the risk of CVE, MI, stroke, and major cardiac events but had a neutral effect on CHF.<sup>3</sup> Methotrexate reduced the risk of CVE and MI and had no significant effect on stroke, major adverse cardiac events, or CHF. Nonsteroidal anti-inflammatory drugs significantly increased the risk of CVE and stroke and had a neutral effect on MI, CHF, and major adverse cardiac events. Corticosteroids significantly increased the risk of all CV outcomes assessed.<sup>3</sup> <i>Image Credit: Scott Camazine / Science Source</i>
Are There Differences in Cardiovascular Risk Between Various NSAIDs?
PRECISION is the largest randomized controlled trial to compare CV safety between NSAIDs commonly used to treat arthritis.<sup>16</sup> The 10-year trial enrolled 24,081 patients with osteoarthritis or RA who had a history of CVEs or elevated CV risk and assigned them to daily celecoxib, ibuprofen, or naproxen. The primary outcome was a composite of CV death, nonfatal MI, and nonfatal stroke. Overall, there was no significant difference in the CV outcome between NSAIDs. However, ibuprofen was associated with a significantly greater risk of nonfatal MI than naproxen and a significantly greater risk of hospitalization for hypertension than celecoxib. Also, hypertension occurred more often with ibuprofen than with celecoxib or naproxen. The celecoxib dose was limited to 200 mg, and authors noted studies have associated 400 to 800 mg doses with a higher risk of CVE. Overall, the findings show the 3 NSAIDs are relatively safe in patients with osteoarthritis or RA who have CV risk factors.<sup>16</sup>
Benefits of Patient Education on Mitigating CVD Risk in RA
Patients are often unaware of their increased CV risk related to RA. One study found 95% of patients with RA stratified as having a high risk of CVD underestimated their risk.<sup>17</sup> Data show patients with RA are less likely to report angina symptoms, which increases their chances of an unrecognized MI or sudden cardiac death and decreases their likelihood of getting a needed coronary artery bypass graft.<sup>18</sup> Some studies have shown interventions to educate RA patients about their risk of CVD have the potential to increase screening for CV risk by PCPs and treatment.<sup>19,20</sup> Results from other studies have been less positive. One trial found although educational interventions improved patients’ understanding of their CV risk and prompted intentions to make lifestyle changes, patients did not carry through with their stated intentions.<sup>21</sup> Nevertheless, patients should be made aware of all important aspects of their disease.
Slideshow Take-Home Messages
•Inflammation related to RA increased patients’ risk of CV morbidity and mortality. •Classic CV risk factors also contribute to CV risk in RA patients. •Often, patients with RA are not screened for CV risk or CV risk is underestimated. •Rheumatologists must ensure their patients’ CV risk is managed appropriately. •Patients should be screened routinely for CV risk and counseled to make lifestyle changes that reduce risk. •Controlling inflammation is essential for reducing CV risk. •CV risk should be considered when prescribing anti-rheumatic treatment. •Synthetic and biologic DMARDs are associated with better CV outcomes than NSAIDs or corticosteroids. •Modifiable CV risk factors such as hypertension or hypercholesterolemia should be managed in line with national guidelines. •Educating patients and PCPs about the increased risk of CVD in RA could improve screening and management. •Educating patients could also improve their ability to recognize CV symptoms and receive lifesaving care.
Patients with rheumatoid arthritis (RA) have an increased risk of developing cardiovascular disease (CVD) and CVD-related mortality compared with the general population. The excess cardiovascular risk in RA is due partly to the inflammatory process, which contributes to coronary abnormalities, and partly due to the presence of traditional risk factors for CVD, such as diabetes mellitus, smoking, obesity, and hypertension.1,2 Despite the growing recognition of CVD as a common complication of RA, many rheumatologists do not aggressively manage CV risk in patients with rheumatic disease.1,2 In addition, few practice guidelines advise rheumatologists with concrete algorithms for treatment.
Cardiovascular risk in RA continues to be a major research interest. At the 2016 ACR/ARHP Annual Meeting in November, numerous abstracts were presented on the relationship between CVD and RA. The accumulated evidence supports the need to increase awareness CV risk in RA among rheumatologists and primary care providers (PCPs).
- Mason JC, Libby P. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J. 2015;36:482-489c.
- Desai SS, Myles JD, Kaplan MJ. Suboptimal cardiovascular risk factor identification and management in patients with rheumatoid arthritis: a cohort analysis. Arthritis Res Ther. 2012;14:R270.
- Roubille C, Richer V, Starnino T, 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. 2015;74:480-489.
- Crowson CS, Liao KP, Davis III, JM, et al. Rheumatoid arthritis and cardiovascular disease. Am Heart J. 2013;166:622-628.
- Aviña-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;59:1690-1697.
- Aviña-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2012;71:1524-1529.
- López-Mejías, Castañeda S, González-Juanatey C, et al. Cardiovascular risk assessment in patients with rheumatoid arthritis: the relevance of clinical, genetic and serological markers. Autoimmun Rev. 2016;15:1013-1030.
- Baghdadi LR, Woodman RJ, Shanahan EM, Mangoni AA. The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis. PLoS One. 2015;17:10:e0117952.
- Sandoo A, Chanchlani N, Hodson J, et al. Classical cardiovascular disease risk factors associate with vascular function and morphology in rheumatoid arthritis: a six-year prospective study. Arthritis Res Ther. 2013;15:R203.
- Barber CE, Smith A, Esdaile JM, et al. Best practices for cardiovascular disease prevention in rheumatoid arthritis: a systematic review of guideline recommendations and quality indicators. Arthritis Care Res (Hoboken). 2015;67:169-179.
- Singh JA, Saag KG, Bridges Jr SL, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2016;68:1-26.
- Agca R, Heslinga SC, Rollefstad S, 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. 2016 Oct 3. [Epub ahead of print]
- 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;70:482-487.
- Reddy S, Meng X, Hitchon C. Exploring the link between RA disease activity, lipid levels, and cardiovascular disease in an early inflammatory arthritis cohort [abstract]. Arthritis Rheumatol. 2015;67(suppl 10).
- Rydell E, Book C, Nilsson J, et al. High disease activity over time and persistent inflammation are associated with increased risk of cardiovascular disease in patients with early rheumatoid arthritis [abstract]. Arthritis Rheumatol. 2015;67(suppl 10).
- Nissen SE< Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016 Nov 13. [Epub ahead of print]
- Boo S, Froelicher ES, Yun JH, Kim YW, Jung JY, Suh CH. Perceived and actual risk of cardiovascular disease in patients with rheumatoid arthritis in Korea: a cross-sectional study. Medicine (Baltimore). 2016;95:e5117.
- Maradit-Kremers H, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 2005;52:402-411.
- Ambrose NL, O'Connell P, Kearns G. Limiting cardiovascular risk in Irish rheumatoid arthritis patients. Ir J Med Sci. 2009;178:53-55.
- Jolly M, Steinig E, Walt L, et al. Web-based PILOT intervention study to improve cardiovascular risk knowledge among rheumatoid arthritis patients [abstract]. Arthritis Rheumatol. 2016;68(suppl 10).
- John H, Hale ED, Treharne GJ, Kitas GD, Caroll D. A randomized controlled trial of a cognitive behavioural patient education intervention vs a traditional information leaflet to address the cardiovascular aspects of rheumatoid disease. Rheumatology (Oxford). 2013
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