The Riddle of Cardiovascular Disease in RA

Feb 24, 2014

Cardiovascular risk is known to be increased among patients with rheumatoid arthritis (RA), but the interplay between inflammatory and cardiovascular causes and the possible role of medications muddle the picture. No wonder, perhaps, that rheumatologists have difficulty managing this risk. Here, some guidance from experts on the question.

It’s well-established that rheumatoid arthritis patients have a 2- to 3-fold increased risk for cardiovascular disease (CVD) and heart attacks compared to the general population.1,2  What’s not well-established poses a chicken-and-egg riddle for rheumatologists: Which came first, the RA or the risk?

If and when that riddle is solved, what then might be the best way to treat CVD in RA patients?  When it comes to cardiovascular disease and RA, little seems to be straightforward.

RA patients often have a higher prevalence of classic risk factors for CVD, notably smoking, hypertension, obesity, insulin resistance, and elevated cholesterol.3 At the same time, CVD risk can be impacted by medications commonly used to treat RA, such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and some disease-modifying antirheumatic drugs (DMARDs).4

The European League Against Rheumatism 2010 CVD guidelines5 note that “the increased risk appears to be due to both an increased prevalence of traditional risk factors and the inflammatory burden.”

While RA principally affects the joints, systemic inflammation can affect other organs -- including the heart and blood vessels6,7  – and the risk increases with RA severity.8 There’s also a genetic component.

Despite this knowledge, recent research suggests that CVD risk factors and symptoms are recognized less often and managed less well by rheumatologists than by general practitioners.9 This may be partly because GPs typically screen for and manage risk factors such as hypertension and diabetes.

A small Canadian study just published online in Clinical Rheumatology compared RA patients with matched controls and reported that elevated cardiovascular risk due to traditional risk factors is “not unique to RA patients” -- even though twice as many of the RA patients had a history of coronary artery disease (13% versus 5%).10

The authors said that the burden of CVD screening by rheumatology clinics “could be considerable,” and concluded that rheumatologists should manage inflammatory disease while other “health care services should be improved to insure the optimal management of traditional CV risk factors for all rheumatology patients.”

However, many rheumatologists contend that RA does carry some unique cardiac risks that need further exploration and possibly treatment by rheumatology.

The Role of Inflammation

Current thinking is that phenomena such as body-wide inflammation, elevated levels of inflammatory cytokines, and immune dysregulation (which are common in other rheumatic diseases such as systemic lupus erythematosus as well as RA), play a role in accelerated atherosclerotic CVD.1,2 Elevated biomarkers of inflammation in autoimmune diseases like RA are known to be present long before signs and symptoms become evident, and risk may escalate even before diagnosis.

Elevated C-reactive protein (CRP), a marker of systemic inflammation, is considered an independent risk factor for coronary heart disease.11 CRP is also factored into the disease activity in the 28-joint CRP score (DAS28-CRP).

RA patients frequently have CRP levels considered high for general inflammation. However, their risk is also increased by elevated high-sensitivity CRP (hs-CRP), which has a lower cut-off (above 3mg/L for hsCRP vs.8 mg/L for CRP) and is not part of routine CVD screening in RA, notes Kimberly P. Liang MD of the Department of Medicine and Division of Rheumatology and Clinical Immunology at the University of Pittsburgh.

“Many of us who are studying CVD risk in RA do suspect that the elevation of markers of inflammation, including CRP and erythrocyte sedimentation rate (ESR), contribute to the higher CVD risk. This also supports the finding of higher disease activity in RA being associated with CVD risk,” said Liang in an interview. She is author of a commentary on CVD risk in RA published online in the December 2013 Journal of Rheumatology,

Another marker, high-sensitivity cardiac troponin T (HS-cTnT), is typically associated with heart attacks and cardiac damage. French researchers recently found that HS-cTnT and CRP are both increased in patients with RA independent of CV risk factors. These findings “support the link between myocardial injury/dysfunction and inflammation,” they suggest.6

Higher Risk, Poorer Prediction

RA patients have an overall 60% higher risk of cardiovascular events such as heart attacks and stroke, but the risk can vary with age, the presence of other CVD risk factors, and disease activity.

The risk of cardiovascular events is “probably increased even before diagnosis,” wrote Danish researchers in the December 2013 Annals of the Rheumatic Diseases. “Screening may underestimate the absolute risk of cardiovascular death in 10 years, because increased disease activity, genetic dispositions to CVD, obesity and lack of exercise will further affect the patient’s risk.”4

There has also been a lack of rigorous screening and prevention studies in RA, Liang points out. This may be due partly to the inadequacy of some CVD risk assessment and stratification tools.

For example, a 2013 study from Spain suggests RA patients with ischemic heart disease and heart attacks missed the high-risk cut-off in the Systematic Coronary Risk Evaluation (SCORE) system modified by EULAR recommendations.12

The SCORE system is based on classic risk factors including the ratio of total cholesterol (TC) to high-density lipoprotein cholesterol (HDL), smoking, blood pressure, age, and gender. For RA patients, EULAR says scores should be multiplied by 1.5 when disease duration is longer than 10 years, extra-articular manifestations are seen, and/or tests are positive for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCPs).5

The use of the TC-HDL ratio may be especially applicable in the SCORE system since, as with CRP, elevated LDL cholesterol alone may not always be a straightforward indicator of risk, suggests Naveed Sattar PhD, a professor of metabolic medicine at the University of Glasgow Cardiovascular Research Centre.

A recent study co-authored by Sattar and colleagues in the journal Nature Rheumatology Reviews notes that “evidence, although limited, suggests that lower cholesterol levels, in the context of very high levels of inflammation, can be associated with increased risk of cardiovascular disease in RA.”13

“While LDL does rise with some biologics, it may do so in conjunction with reduction in inflammation parameters," Sattar said in an interview. “When inflammation declines, lipids generally rise and vice versa, so the net effect on CVD is not easy to determine based on these ‘surrogate’ risk factors.”

The 2010 EULAR guidelines acknowledge the CVD-related risk of inflammation in RA, but do not mention traditional and biological DMARDs. EULAR prefers traditional treatments for CVD -- cholesterol-lowering statins and anti-hypertensives –- for their possible anti-inflammatory effects, along with smoking cessation.5

The group also recommends the lowest possible dose of corticosteroids and is cautious about most NSAIDs (including Coxibs), due to their adverse cardiovascular effects.5

Will DMARDs Dampen Risk?

A number of studies presented at the 2013 American College of Rheumatology (ACR) annual meeting found a modest reduction in CVD risk for biologics and traditional DMARDs.

Among them:

A two-year prospective cohort study from Canada, conducted among 228 patients, suggested a downward trend in 10-year CV event risk in RA patients treated with biologic DMARDs, possibly due to the drugs’ favorable effect on cholesterol and inflammation. 15

A large retrospective study from Sweden of almost 31,000 RA patients found that anti-TNF-α drugs slightly reduced – but did not abolish -- the risk of acute coronary syndromes (ACS), such as heart attacks or unstable angina. The risk of ACS was 27% lower for RA patients on TNF-α inhibitors compared with those who had never taken the drugs.15

Also, a study by British researchers looking at the rate of heart attacks in 14,258 RA patients from 2001 to 2008 concluded those using biologics to manage their inflammation had a lower risk of heart attacks than patients using traditional DMARDs, but found little difference in the severity of the attacks.16

More recently, a study by Sattar and colleagues in the Annals of the Rheumatic Diseases looked at the effects on cholesterol of a newer drug, the interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ). When compared with placebo, TCZ induced elevations in “bad” LDL while at the same time altering the composition of “good” HDL particles “towards an anti-inflammatory effect.”17

While TCZ favorably modified vascular risk surrogates like HDL, notes Sattar, since some RA patients with very severe disease may have greater heart risk at lower cholesterol levels, the overall effect of such changes in CVD risk is yet to be determined. “Clinical end-point trials are perhaps the only way to definitively work out net vascular effects, although cardiovascular event rates over time can give some indication,” he adds

“Keeping disease activity down likely reduces risk,” Sattar concludes. “Certainly, the more active the disease and the longer one has it, the more excess the CVD risk.”  There is also an important role for modifying traditional risk factors (i.e. smoking, cholesterol, blood pressure) in those at elevated CVD risk.

A 2014 systematic review of 13 studies concluded that the “balance of evidence suggests that TNF-α antagonists may have a beneficial effect… It remains unknown whether this effect is specific to TNF-α antagonists or relates to better control of inflammation irrespective of the disease modification strategy by which this is achieved.”18

Regardless of the treatment, the review concludes that “It is very important that the patient’s disease activity is treated to target at the same time as we are trying to reduce the patient’s (cardiovascular) risk.”

From a rheumatologist’s standpoint, the “treat-to-target” approach for biological and DMARD agents still refers to the disease activity level, says  Liang. 

“It is unlikely that the risks of intensifying these therapies would be outweighed by the CV risk benefits, in the absence of clinical indications for doing so (i.e., ongoing RA disease activity),” she told Rheumatology Network.  “We still need further research in targeted CV risk prevention strategies in the RA population, so that additional evidence-based guidelines can be developed in terms of how best to manage these patients’ risk.”

References:

1.      Ajeganova S, Andersson MLE, FrostegÃ¥rd J, Hafström I. Disease Factors in Early Rheumatoid Arthritis Are Associated with Differential Risks for Cardiovascular Events and Mortality Depending on Age at Onset: A 10-year Observational Cohort Study. J Rheum (2013) 40:1958-1966. doi: 10.3899/jrheum.130365.
2.      Liang KP. Editorial: Cardiovascular Risk in Rheumatoid Arthritis (RA): Does It Matter If RA Is Diagnosed in Early or Late Age?J. Rheum. (2013) 40:1945-1947.doi:10.3899/jrheum.131109.
3.      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 Research & Therapy  (2013) 15:R203. doi:10.1186/ar4396 [e-pub 2 Dec 2013].
4.      Primdahl J, Clausen J, Hørslev-Petersen K. Results from systematic screening for cardiovascular risk in outpatients with rheumatoid arthritis in accordance with the EULAR recommendations.Ann Rheum Dis. (2013) [Published Online First:July 12, 2013] doi:10.1136/annrheumdis-2013-203682
5.      Peters MJL, Symmons DPM, 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) 69:325–331. doi:10.1136/ard.2009.113696.
6.      Avouac J, Meune C, Chenevier-Gobeaux C, et al., Inflammation and Disease Activity are Associated with High Circulating Cardiac Markers in Rheumatoid Arthritis Independently of Traditional Cardiovascular Risk Factors. J Rheumatol. (2013) Dec 15. [Epub ahead of print].
7.      Arts EE, Fransen J, den Broeder AA, et al. The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients. Ann Rheum Dis. (2014) Jan 23. doi: 10.1136/annrheumdis-2013-204531. [Epub ahead of print].
8.      Kuller LH, Mackey RH, Walitt BT, et al., Determinants of Mortality among Postmenopausal Women Who Report Rheumatoid Arthritis in the Women’s Health Initiative. Arthritis & Rheumatism, Accepted article, (2013). DOI 10.1002/art.38268.
9.      Desai SS, Myles JD, Kaplan MJ, Suboptimal cardiovascular risk factor identification and management in patients with rheumatoid arthritis: a cohort analysis.Arthritis Research & Therapy (2012) 14:R270.
10.      Luck Y, Baron M, Bardakjian S, et al., The role of rheumatologists vis-à-vis assessment of traditional cardiovascular risk factors in rheumatoid arthritis. Clin Rheumatol. (2014) Feb 15. [Epub ahead of print] DOI 10: 1007/s1006-014-2522-5.
11.      Buckley DI, Fu R, Freeman M, et al., C-Reactive Protein as a Risk Factor for Coronary Heart Disease: A Systematic Review and Meta-analyses for the U.S. Preventive Services Task Force.Ann Intern Med. (2009) 151:483-495.
12.      Rosales-Alexander JL, Salvatierra J, Llorca J, et al., Cardiovascular risk assessment in rheumatoid arthritis: impact of the EULAR recommendations on a national calibrated score risk index. Clin Exp Rheumatol. (2014) Jan 3. [Epub ahead of print].
13.      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) Advance online publication December 2013. doi:10.1038/nrheum.2013.91.
14.      Khraishi M, Aslanov R. Effect Of Biologic Disease Modifiers On Cardiovascular Risk Of Patients With Rheumatoid Arthritis – 2 Years Prospective Cohort Study. ACR Abstract: #382, October 27, 2013.
15.      Ljung L, Askling J, Solbritt M, and the ARTIS Study Group2, et al., Tumour Necrosis Factor Inhibitors and The Risk Of Acute Coronary Syndrome In Rheumatoid Arthritis – a National Cohort Study. ACR Abstract # 804, October 29, 2013.
16.      Low ASL, Hyrich KL, Lunt M, et al., Incidence and Severity Of Myocardial Infarction In Subjects Receiving Anti Tumour Necrosis Factor Drugs For Rheumatoid Arthritis: Results From Linking the British Society For Rheumatology Biologics Register For Rheumatoid Arthritis and Myocardial Ischaemia National Audit Project. ACR Abstract #: 803, October 29, 2013.
17.      McInnes IB, Thompson L, Giles JT, et al., Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann Rheum Dis (2013) doi:10.1136/annrheumdis-2013-204345 [Online first December 24, 2013].
18.      Tam LS, Kitas GD, González-Gay MA. Can suppression of inflammation by anti-TNF prevent progression of subclinical atherosclerosis in inflammatory arthritis?Rheumatology (Oxford). (2014) doi: 10.1093/rheumatology/ket454 [e-pub Feb 5 14].

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