It is widely accepted that certain chronic diseases, such as type 2 diabetes mellitus and chronic kidney disease, are associated with an increased cardiovascular (CV) risk.^1,2 In recent years the CV impact of rheumatoid arthritis (RA) has come to the forefront of international attention. 

The concept of RA as a non-traditional CV risk factor evolved following observations of high CV morbidity and mortality in this group.^3,4 Meta-analysis suggests that there is a 50% increase in CV deaths in those with RA compared to the general population.⁵ 

There are conflicting reports regarding the prevalence of traditional CV risk factors in patients with RA. Some suggest that rates of diabetes, hypertension and dyslipidaemia are no different than in the general population.⁶ Others suggest that the metabolic syndrome is seen more frequently in patients with RA.⁷

Also, for a multitude of reasons, patients with RA tend to exercise less than recommended.⁸ However, the excess CV risk is not fully explained by the presence of traditional risk factors.⁹ It is thought that a number of other clinical, genetic and pharmacological factors interact in this patient population leading to the increased propensity for CV disease. 

Clinical factors

Atherosclerosis is a complex, dynamic, fibro-proliferative condition. The role of chronic inflammation in the pathogenesis is well established¹⁰ and several inflammatory biomarkers, including high sensitivity C-reactive protein, consistently correlate with atherosclerotic burden.¹¹

Modified macrophages (foam cells) and numerous pro-inflammatory cytokines exert a multitude of atherogenic effects. In the setting of chronic RA, there is an abundance of such inflammatory cytokines. 

It is unclear whether the CV risk is increased prior to the development of clinically active arthritis or if it develops as a function of the disease severity and duration. A small Swedish study examined this issue using preclinical markers for CV disease.¹²

Although serum markers of endothelial activation were elevated in patients with very early RA when compared with controls, carotid intimal medial thickness and endothelial dependent flow-mediated dilation were no different, and instead correlated with traditional CV risk factors. At 18-month follow-up, however, intimal medial thickness had progressed in the RA patients but not the controls.¹² A prospective Swedish registry, published by the same group, examined hard clinical outcomes in patients with early RA.¹³

CV morbidity and mortality in the first five years was associated with the traditional CV risk factors but also the cumulative disease activity score during the first six months post-diagnosis.¹³ 

Although early disease activity therefore appears to be important in predicting risk, disease duration also correlates with CV risk; those patients with longer duration of disease have increased risk.¹⁴ 

Other variables that have been found to be predictive of CV risk include seropositivity¹⁵ (rheumatoid factor and anti-cyclic citrullinated peptide) and severe extra-articular manifestations.¹⁶

Genetic factors

Rheumatoid arthritis and atherosclerosis are both complex disease processes with polygenic origins.^17,18 Multiple genes have been studied in an attempt to quantify their contribution to the development of preclinical and clinical atherosclerosis in patients with RA. The HLA-DRB1 gene is one such candidate gene. 

Specific alleles confer high CV risk in this patient group, particularly in the sub-population of patients who smoke and have anti-CCP positivity.¹⁹ Certain gene mutations in the LTA gene (which codes for TNF-α) and the promoter region of the TNF-α gene have an association with higher CV event rates in RA.^20,21 Certain cytokine, chemokine, adipocytokine and other genes have been studied, with varying degrees of association reported.²² 

Pharmacological factors

The therapeutic approach to RA typically involves non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, various disease-modifying anti-rheumatic drugs (DMARDs) and biological agents such as anti-TNF-α agents. Each of these has been shown to modify the CV-risk profile of the patient. 

The CV side-effects of non-selective NSAIDs and selective COX-2 inhibitors are well described.^23,24 Their pro-thrombotic side-effects have been reported in patients with and without RA.²⁴ 

There is also a growing body of evidence to suggest that concomitant administration of some NSAIDs with aspirin may impair the anti-platelet effects of aspirin and therefore reduce its cardio-protective effects.²⁵ 

The European League against Rheumatism (EULAR) recommends caution in prescribing NSAIDs and COX-2 inhibitors in patients with RA, especially in those with other CV risk factors or documented CV disease.²⁶ There is controversy regarding the effects of corticosteroids on CV risk in RA. 

Their anti-inflammatory properties may help dissipate the inflammatory, atherogenic milieu.²⁷ On the other hand, side-effects include hypertension, central obesity and impaired glucose handling; all of which predispose to CV disease.²⁸

In the absence of clear-cut data, EULAR recommendations are conservative; the lowest dose of corticosteroids, used for the shortest time possible, is recommended.²⁶

Methotrexate (MTX), alone or in combination with biologic therapy, is the most commonly prescribed DMARD in RA. Meta-analysis of 18 observational studies suggests that there is decreased CV morbidity and mortality in MTX-treated patients.²⁹

It is postulated that this is due to the suppression of systemic inflammation and therefore the progression of atherosclerosis.²⁹

The effect of TNF-α inhibitors has also been examined in observational studies. Patients with good clinical response to the TNF-α inhibitors appear to enjoy a decreased CV risk.³⁰ Again, this is thought to be due to the suppression of systemic inflammation.³¹

Predicting risk

Standard tools for prediction of CV risk do not take these non-traditional variables into account and can therefore underestimate the CV risk.³² The Framingham and SCORE models are widely used internationally.^33,34 EULAR recommends that the CV risk estimate derived from the above models is multiplied by 1.5 in patients with RA and two of the following: seropositivity, severe extra-articular manifestations, disease duration > 10 years.²⁶ 

Management of CV risk

Attention must be focused on reducing CV risk in patients with RA. A number of recommendations have been made by EULAR.²⁶ Given the heightened CV risk in smokers in the general population, EULAR recommends that rheumatologists actively pursue smoking cessation with all patients.²⁶

EULAR recommends that other CV risk factors, such as hypertension and dyslipidaemia, be managed to the targets laid out in local guidelines. Commonly used thresholds are a systolic blood pressure of 140mmHg and a LDL-cholesterol level of 2.5mmol/l.²⁶

In terms of specific agents, there are no intervention trials to guide choices. Statins and ACE inhibitors have certain favourable effects on endothelial function and inflammation and so are preferred by EULAR.²⁶

Indeed, atorvastatin has been shown to improve lipid profile as well as disease activity scores in a randomised controlled trial.³⁵

The effects of statins on lipid profile and CV risk appear similar in patients with and without RA.³⁶ Of course, the usual precautions and monitoring should be routinely undertaken with these drugs. 

There is a growing body of evidence to suggest that CV risk is increased in patients with other inflammatory polyarthritides.^37,38

We eagerly await randomised controlled trials to guide CV risk factor management in RA and other chronic connective tissue diseases. 

In the meantime, heightened CV awareness in all RA patients is imperative.²⁶

References

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