Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects 0.2–2.0% of the Brazilian population,1–3 mainly women, with peak incidence between the ages of 30 and 50 years.4 In recent years, studies have shown that the life expectancy of patients with RA is 5–10 years less than in the general population, due to their greater risk for cardiovascular disease (2–5 times higher than in the general population).2,3,5,6 Patients with RA thus have an equivalent absolute cardiovascular risk to those without RA who are 5–10 years older.6–8 Although the increased relative risk (RR) of cardiovascular events is more marked in younger patients with RA, older patients have more events in absolute terms, mainly due to premature development of coronary artery disease (CAD).2 A prospective cohort study in the US of 609 patients with RA with a mean follow-up of 14 years found greater risk of death in RA patients with RA than in those without RA of the same age and gender (Fig. 1) and a higher incidence of cardiovascular events (RR=1.6; p<0.001).8

Figure 1.

Survival in individuals with rheumatoid arthritis compared to expected survival in the general population (adapted from Ref. 8).

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In this review we summarize recent publications on the pathophysiology of atherosclerosis in patients with RA, examining the contribution of classical risk factors and inflammatory mechanisms that are specific to RA. We also analyze recent clinical studies on the occurrence of cardiovascular events in RA and discuss strategies for risk stratification and treatment of CAD in patients with RA.

There is growing evidence from controlled clinical trials that patients with RA present more extensive atherosclerosis and coronary calcification than those without. This suggests that their higher incidence of cardiovascular events reflects greater and earlier atherosclerotic activity.9 Based on calcium scores, these patients have earlier and greater calcification of the aorta, carotid arteries and coronary arteries than controls.6 This increased calcification is more marked in males and younger age-groups, and more extensive calcification is associated with more severe RA.10

RA is considered an independent risk factor for intima-media thickening of the common carotid and femoral arteries, which correlates with the severity and chronicity of the disease.3,11 The reasons for this premature and more severe atherosclerosis have been the subject of considerable research. It is now accepted that the chronic inflammation found in RA plays an important part in the genesis and development of atherosclerotic plaques.10 Chronic inflammation, with elevated levels of circulating cytokines and autoantibodies, can destabilize atherosclerotic plaques and increase the risk of rupture. The substrate of CD4 and CD8 T lymphocytes found in unstable plaques is also seen in bone erosions in RA and in vasculitis. In addition, granzyme B, a product of macrophages involved in remodeling the extracellular matrix, is observed in large quantities in the synovia of patients with RA and in areas with ruptured atherosclerotic plaques, supporting the idea that systemic inflammation increases the risk of cardiovascular events.2

Other molecules known to be relevant to the pathophysiology of RA are also associated with atherosclerosis, including matrix metalloproteinases, proteolytic enzymes involved in joint destruction as well as in destabilization and rupture of vulnerable plaques. Similarly, elevated levels of coagulation factors and inflammatory cytokines such as fibrinogen, tissue factor, von Willebrand factor, plasminogen activator inhibitor, C-reactive protein (CRP), interferon-gamma, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta are found in both RA and CAD.5,11–13 Another molecule found at high concentrations in patients with RA is nitric oxide, which is produced by endothelial cells and is partly responsible for apoptosis and regulation of T lymphocytes in atherosclerotic plaques.12

Endothelial function is crucial to the development of atherosclerotic plaques.12 The endothelium plays an important role in regulating vascular tone, platelet activity and thrombogenesis. Endothelial dysfunction is one of the first stages in the development of atherosclerotic plaques, and can be triggered by systemic inflammatory states such as RA, mainly due to elevated levels of circulating cytokines. Some studies have indirectly shown endothelial dysfunction in RA, as individuals with RA present less endothelium-dependent vasodilation than those without.12

Besides the atherogenic effects of chronic systemic inflammation, classical risk factors such as smoking, hypertension, diabetes and dyslipidemia also contribute to the genesis of atherosclerosis in patients with RA.14 Various studies have examined their prevalence and contribution to the genesis of cardiovascular disease in RA patients. No significant differences were found in the prevalence of hypertension, diabetes, dyslipidemia or obesity between individuals with and without RA in the initial stages of the disease; only smoking was more prevalent in patients with RA, which puts them at greater cardiovascular risk even before the appearance of inflammatory disease.6,11,12,15

Over the course of the disease, the prevalence of some risk factors changes, as patients with RA begin to present significantly less risk of developing hyperlipidemia and lower body mass index (BMI) than the general population.6,7 Little is known concerning the prevalence and type of dyslipidemia in these patients, different studies showing conflicting results. Some authors have found lower HDL cholesterol and higher LDL cholesterol in patients with RA11,16 compared to individuals without CAD or RA, but others have reported reduced total, LDL and HDL cholesterol and increased triglycerides, correlating directly with systemic inflammatory activity.2,11 In support of the latter finding, there is evidence that lipid profile has a paradoxical relationship with cardiovascular risk in patients with RA, with total and LDL cholesterol levels falling sharply in the three to five years preceding the onset of RA. Lower total and LDL cholesterol would thus indicate greater cardiovascular risk in these patients due to the presumed greater inflammatory activity associated with the disease. Furthermore, some studies have observed higher serum levels of lipoprotein(a), which may also be associated with greater risk, although this has not been proved.11,12

Unlike in the general population, a low BMI (<20kg/m2) in individuals with RA is linked to significant risk for cardiovascular death. As low BMI in patients with RA may indicate greater systemic inflammatory activity, this finding supports the importance of inflammation in these patients’ cardiovascular risk.6,7 Functional limitations due to bone lesions arising from the disease also tend to make individuals with RA more sedentary, which will also increase their cardiovascular risk.12

An important additional risk factor in patients with RA is increased insulin resistance and metabolic syndrome, which are directly related to carotid intima-media thickening and high coronary calcium score.2 Increased insulin resistance is related to dysfunction of pancreatic beta cells due to chronic inflammation.11 TNF-α is another important mediator in this process through its inhibition of glucose uptake in skeletal muscle.11

Curiously, although the prevalence of classical risk factors in patients with RA is similar to the general population, their impact is decidedly less: the risk of cardiovascular events related to such factors is considerably lower. This is probably because the cardiovascular risk arising from the presence of systemic inflammation in RA is so high that it dilutes the effect of other risk factors.2,6,7 The Framingham risk score, widely used in clinical practice, has been validated in patients with RA, and should be used in conjunction with noninvasive imaging studies, since a high Framingham risk score is a strong predictor of coronary calcification in patients with RA.9,16

As pointed out above, chronic pro-inflammatory factors contribute to the development of atherosclerotic plaques in patients with RA (Table 1). In recent years attempts have been made to quantify such markers in order to predict cardiovascular risk in this population.6 Of these, erythrocyte sedimentation rate (ESR)>40mm/h, involvement of small and medium joints, bone erosions, rheumatoid nodules, vasculitis and rheumatoid pulmonary disease have been associated with greater risk of death.2,6–8,17,18

One extensively researched marker is rheumatoid factor (RF). In several studies high RF levels have been directly related to greater risk for death and combined endpoints including myocardial infarction (MI), heart failure (HF) and peripheral vascular disease.6,19 Gabriel7 showed that the RR of cardiovascular death in women with RA and negative RF was 1.59 (95% CI: 1.14–2.15) compared with 2.10 (95% CI: 1.73–2.51) in those with positive RF. In men, the results showed a similar trend, with RR of 1.59 (95% CI: 1.19–2.09) for positive RF and 0.81 (95% CI: 0.41–1.46) for negative RF. Some authors have suggested that even in the absence of RA, individuals with positive RF are at greater risk for cardiovascular events.19

Similar results have been found in patients with RA with antinuclear factor (ANF), which is also associated with greater risk for cardiovascular events.7,19

High levels of CRP, which is central to the pathophysiology of atherosclerosis, have also been shown to increase cardiovascular risk in patients with RA. In women, multivariate analysis has demonstrated that adjusting for serum CRP eliminates the relation between coronary calcification and RA, once again highlighting the importance of inflammatory activity as a risk marker in this disease.2,5,6,11

Besides ESR, RF, ANF and CPR, other markers associated with cardiovascular events include IL-6, soluble type 1 intercellular adhesion molecule, amyloid A, and fibrinogen.11,12 The importance of IL-6 as a mediator of cardiovascular events is indicated by the fact that adjusting for serum levels of this interleukin weakens the relation between coronary calcification and RA.20

Patients with RA have a high risk of acute coronary syndromes. A study based on the Rochester project,15 which followed 603 patients with RA, showed that in the two years before the appearance of RA these patients were more likely to suffer MI (odds ratio [OR] 3.17, 95% CI: 1.16–8.68) and silent ischemia (OR 5.86, 95% CI: 1.29–26.64) than gender- and age-matched controls.2,3,7,15,16,21 After diagnosis the higher risk for silent ischemia persisted (OR 2.13, 95% CI: 1.13–4.03), as well as for sudden death (OR 1.94, 95% CI: 1.05–3.55) (Fig. 2).3,7,15,21

Figure 2.

Cumulative incidence of silent ischemia, angina and sudden death in patients with rheumatoid arthritis compared to controls (adapted from Ref. 15).

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The longer the duration of the disease, the greater the risk of coronary events, particularly more than 10 years after diagnosis.16 This may be explained by increased production of pro- and anti-inflammatory cytokines in individuals with RA, which alters their perception of pain.7,15 It may also be linked to their reduced mobility due to joint disease, which prevents them from taking strenuous exercise that would trigger angina, or failure by the physician or the patient to give due weight to anginal pain, attributing it to the musculoskeletal effects of RA.7,11

Unlike all in vivo anatomical studies, an autopsy study found no differences in extent and degree of coronary stenosis between those with and without RA. Unexpectedly, fewer individuals with RA had three-vessel disease than those without (32% vs. 61%; p<0.018), and they tended to have less severe atherosclerotic disease.22 However, greater inflammatory activity was observed in atherosclerotic plaques in the circumflex and anterior descending coronary arteries, 48% of those in the anterior descending artery being classified as vulnerable, compared to only 22% in those without RA (p=0.018).7,22 Once again, this study suggests that the etiology of CAD in patients with RA is mainly related to inflammation.7,22 It should be stressed that this autopsy study is the only one aimed specifically at analyzing atherosclerosis in RA, and its sample size was small, which limits generalization of its results.

Rheumatoid arthritis should be considered an independent risk factor for coronary artery disease. There have been considerable advances in recent years in our knowledge of autoimmune diseases and cardiovascular risk. However, much of the evidence concerning cardiovascular disease in patients with RA comes from observational studies, and further research is needed. Particular strategies for risk stratification and treatment are required for these patients and new guidelines should be issued based on current evidence. In general, appropriate control of systemic inflammation is the principal factor in reducing risk for coronary events and should always be the goal.

The authors have no conflicts of interest to declare.