Atherosclerosis and inflammation: insights from rheumatoid arthritis
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- Chung, C.P., Avalos, I., Raggi, P. et al. Clin Rheumatol (2007) 26: 1228. doi:10.1007/s10067-007-0548-7
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Cardiovascular disease is a major health care problem and the most common cause of death among individuals from developed nations. Our understanding of atherosclerosis has evolved from a passive process resulting in narrowing of the lumen and consequent myocardial ischemia to a dynamic process that involves inflammation. The study of atherosclerosis in patients with chronic inflammation, such as rheumatoid arthritis (RA), will provide insights into the relationship between inflammation and atherosclerosis. We review the relationship between atherosclerosis and inflammation within the context of RA, providing evidence that patients with RA have increased cardiovascular morbidity and mortality and accelerated coronary and extra-coronary atherosclerosis. In addition, traditional and novel cardiovascular risk factors are discussed. Finally, actions that a rheumatologist can take to better control this cardiovascular morbidity are suggested. These can be summarized as follows: (1) careful assessment and treatment of cardiovascular risk, (2) better control of inflammation, and (3) individual risk–benefit evaluation of need for cyclo-oxygenase-2 inhibitors, nonsteroidal anti-inflammatory drugs, and high doses of corticosteroids.
Cardiovascular disease is a major health care problem and over the last century has remained the most common cause of death among individuals from developed nations. Recent statistics indicate that more than 900,000 deaths per year in the USA are attributed to cardiovascular causes, accounting for 1 of every 2.7 deaths and a cost of more than 400 billion US dollars .
Our understanding of atherosclerosis has changed over time. The initial perception that this was a passive process resulting from the accumulation of lipid in the artery wall with narrowing of the lumen and consequent myocardial ischemia, has changed. We now recognize that atherosclerosis is a dynamic process that involves inflammation at all stages—from the early stages of wall damage to rupture of an unstable plaque.
Many large studies in different populations have shown that markers of inflammation such as C-reactive protein (CRP) are associated with atherosclerosis and cardiovascular outcomes [2–4]. It is unclear if the low-grade inflammation detected in such population studies is the result of subclinical atherosclerosis or if it is directly implicated in the pathogenesis of vascular disease. The study of atherosclerosis in populations with chronic inflammation could provide insights into the relationship between inflammation and atherosclerosis.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by increased cardiovascular morbidity and mortality , and in this article, we review the relationship between atherosclerosis and inflammation within the context of RA.
Overall and cardiovascular mortality are increased in patients with RA
For many years, it has been recognized that patients with RA die prematurely , and although the frequency of cardiovascular death varied among different studies, most have concluded that it was the most common cause of death. This is important because RA affects a relatively young population comprised predominantly of women. The proportion of deaths attributed to cardiovascular causes range from 39 to 50% [7–12]. RA can affect the heart in several ways.
Cardiac involvement in RA
The heart is one of the organs involved in extra-articular manifestations of RA. A classic and common manifestation is pericarditis, but uncommon conditions, such as myocarditis, atrioventricular block, valvular disease, vasculitis, nodules, and amyloidosis, can also occur. However, epidemiologic and clinical studies indicate that the increased cardiovascular mortality is not due to these manifestations of RA but rather due to coronary atherosclerosis, and that this is the most clinically important cardiac condition associated with RA.
Myocardial infarction in RA
Epidemiologic data indicate that patients with RA are at an increased risk of myocardial infarction (MI). A long-term prospective cohort study involving more than 114,000 women showed that those with RA had twice the risk of MI after adjustment for multiple confounders, and that this risk was three times higher in those with disease of more than 10 years duration . Other studies have also shown an increased risk of MI in patients with RA. In 236 consecutive patients with RA and more than 4,600 control subjects from the same community, RA increased the risk of MI more than five times . In addition, a population-based study found that patients with RA already had a threefold increased risk of MI in the 2 years preceding the diagnosis of RA. The association was statistically independent of cardiovascular risk factors, suggesting that this risk may be present even before RA is recognized .
MI is a late complication of atherosclerosis, and the ability to measure atherosclerosis noninvasively before an event has occurred allows the study of predisposing factors and the identification of individuals at particular risk. Two widely used techniques are the measurement of coronary artery calcification by electron bean computer tomography (EBCT) and carotid intima-media thickness by ultrasound.
Coronary artery atherosclerosis in RA
Several cross-sectional studies have reported that patients with RA have increased carotid intima-media thickness (IMT) [18–20]. A prospective follow-up study that included 62 patients with RA and 63 control subjects confirmed this observation, and follow-up scans showed that the annual standardized rate of progression of IMT was higher in patients with RA and correlated significantly with CRP concentrations and ESR . Another recent ultrasound study of 98 patients with RA and 98 control subjects matched for age, sex, and race found that the risk of having carotid artery plaque was three times higher in patients with RA, and this remained significant after adjustment for traditional cardiovascular risk factors such as age, smoking, and hypertension. Age and current smoking were independently associated with carotid plaque .
Traditional cardiovascular risk factors
Several risk factors that contribute to increased cardiovascular risk in the general population have also been implicated in patients with RA . These include age, male sex, dyslipidemia, diabetes, family history of coronary disease, impaired renal function, and the metabolic syndrome. Individual cardiovascular risk factors have limited predictive ability and interact with each other—this has given rise to composite cardiovascular risk scores.
Another composite of cardiovascular risk factors, the metabolic syndrome, is of particular interest, as it can be modified. The metabolic syndrome is a composite of central obesity, dyslipidemia, hypertension, and either hyperglycemia or insulin resistance. The concept of impaired glucose handling in association with RA is not new; Svenson, in the early 1980s, described increased fasting insulin concentrations that were reversed by control of inflammation . However, the role of insulin resistance and the metabolic syndrome in atherosclerosis in patients with RA was not known. Recently, we have shown that the prevalence of the WHO-defined metabolic syndrome, which includes insulin resistance, is markedly increased in patients with RA and that this association is independent of body mass index—raising the concept of an inflammation-driven metabolic syndrome . Furthermore, other investigators have shown that the metabolic syndrome is associated with increased carotid artery intima-media thickness in RA .
Inflammation-related risk factors
Several markers of current or cumulative inflammation, such as CRP, ESR, interleukin-6, and CD4-CD28 cells, swollen and tender joint counts, presence of rheumatoid factor, deformities and presence of extra-articular disease, as well as medications used to treat RA, have been associated with an increased risk of atherosclerosis . The weight of the evidence suggests that the inflammation induced by RA plays a role in accelerated atherosclerosis; however, the mechanisms by which this occurs are poorly understood and are the subject of ongoing research.
What can a rheumatologist do?
Assess and treat cardiovascular risk factors
Measurement and interpretation of risk as well as interventions to properly modify the risk are generally accepted as physician responsibilities; however, several problems in the pathway weaken the translation of what is known into what is done in clinical practice, including the assessment of cardiovascular risk . This also appears to be a problem in rheumatology. A study in patients with lupus showed that almost one in three patients had never had a cholesterol measurement and that treatment of cardiovascular risk factors was achieved in only 58% . Such information suggests that there is room for improvement in the assessment of cardiovascular risk in patients with rheumatic diseases. Current guidelines suggest periodic assessment of cardiovascular risk in healthy people and appropriate interventions based on the findings [24, 32]. Smoking, hypertension, and increased lipids are cardiovascular risk factors often present among patients with RA , suggesting the need for assessments and intervention. The risk assessment and treatment guidelines in use were developed for the general population, not specifically for patients with RA. Nevertheless, in the absence of specific data, it seems reasonable to ensure that patients with RA have, at a minimum, the level of care considered optimal for the general population.
Lipid-lowering agents such as statins may also provide a novel approach to improve control of inflammation. A randomized trial of 116 patients with RA, with 58 patients receiving atorvastatin 40 mg per day and 58 patients receiving placebo in addition to their regular therapy, showed interesting results. The primary endpoint was change in the 28 joint-based disease activity score (DAS28). Patients receiving atorvastatin not only improved their lipid profile, but interestingly, they also achieved a significant response in disease activity measured by DAS28, CRP, and number of swollen joints .
Use potentially harmful drugs with caution
Conclusions regarding the association between corticosteroids and atherosclerosis differ due to differences in study design , but there appears to be a relationship between higher doses of corticosteroids and poorer cardiovascular outcomes. A population-based study evaluated the effect of low, intermediate, and high doses of prednisone (>7.5 mg/day) on a composite outcome that included hospitalizations with the primary diagnoses of MI, angina, angioplasty, coronary revascularization, strokes, transient ischemic attack, congestive heart failure, or cardiovascular death. The results showed a dose-dependent trend for increased risk, with a fivefold increased risk in patients with inflammatory arthritis receiving the highest dose . Concordant with these data, another study that evaluated 647 patients with RA, estimated the association of corticosteroid exposure with three outcomes: carotid plaque, carotid obstruction, and lower limb peripheral arteries compressibility . Patients with a cumulative corticosteroid dose of approximately 16 g or more had a significant increase in the risk of having carotid plaque and atherosclerosis of the peripheral arteries. This association was not seen in patients who received doses of 6 g or less. An explanation for the association between exposure to corticosteroids and adverse cardiovascular outcomes that is difficult to exclude in retrospective studies is that patients with more severe disease are more likely to be exposed to higher doses of corticosteroids; however, the results of this study remained significant after adjustment for several variables including tender and swollen joints and ESR .
Other drugs, such as selective (coxibs) and perhaps some nonselective cyclo-oxygenase-2 inhibitors, increase the risk of MI through mechanisms that remain unclear. They can also increase blood pressure. Thus, their use in RA should not be routine but based on individual assessment of risks and benefits .
Studies of several disease-modifying anti-rheumatic drugs (DMARDs) and cardiovascular outcomes suggest that controlling inflammation may have beneficial cardiovascular effects. A longitudinal study evaluated the effect of methotrexate in 1,240 patients with RA from a single clinic and found a significant decrease in the number of cardiovascular deaths, an association that remained after adjustment for sex, age, RF, year, duration of disease, smoking, education, HAQ, joint counts, ESR, prednisone, and a number of other DMARDs . In a nested case-control study of patients with RA using claims-based databases, 558 cases of MI were matched for age, sex, and race with 5,580 controls. The adjusted relative risk of MI was significantly lower for those patients who were treated with methotrexate, leflunomide, and other DMARDs .
Patients with RA have increased cardiovascular morbidity and mortality.
Atherosclerosis is an inflammatory condition.
Patients with RA have accelerated coronary and extra-coronary atherosclerosis.
Better control of inflammation, individual risk–benefit evaluation of need for coxibs, nonsteroidal anti-inflammatory drugs (NSAIDs), and high doses of corticosteroids and the assessment and treatment of cardiovascular risk factors may decrease the adverse consequences of accelerated atherosclerosis in this patient population.