Risk factors for cardiovascular disease in rheumatoid arthritis
The reasons for the increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) have not been determined. The presence of traditional CVD risk factors such as abnormal lipid metabolism, hypertension, obesity, and smoking cannot fully explain the higher incidence of CVD events in this population . Novel risk factors such as systemic inflammation and autoimmune activation have been identified as important players in the development of premature atherosclerosis. In fact, epidemiological evidence suggests that inflammation correlates with cardiovascular events and confers a statistically significant increased risk for CVD deaths in patients with RA . Clinical and serological features of severe, uncontrolled RA such as high inflammatory markers, rheumatoid factor positivity, large joint swelling, and extra-articular involvement are highly significant predictors of cardiovascular outcome and mortality . Such observations underline the complex interrelations between traditional, novel, and disease-related risk factors all of which contribute to heightened CVD risk in patients with RA .
In this chapter we focus on hypertension, lipid profile, and insulin resistance/diabetes as contributors to the increased CVD risk in RA and discuss the impact of systemic inflammation and disease activity on CVD complications in this population.
Traditional cardiovascular risk factors in patients with rheumatoid arthritis
Conventional CVD risk factors are strong predictors of CVD events and outcomes in the general population, but their impact on CVD morbidity and mortality in RA remains only partly understood. RA patients tend to have a different profile of risk factors compared with the general population, which is associated with higher frequency of smoking, unfavorable total cholesterol/HDL ratio, hypertension, and insulin resistance . However, studies examining the distribution of classic CVD risk factors amongst RA and non-RA individuals provide somewhat contradictory results. Reports from different groups [5,6] have demonstrated that the incidence of many of the traditional CVD risk factors is similar between RA and non-RA subjects, while others have found increased prevalence of – unrecognized and/or undertreated - hypertension, high lipid levels, and diabetes mellitus within RA populations [7–9]. Even if classic CVD risk factors are equally or only slightly more prevalent in RA, there are notable differences in the way they influence CVD outcomes with some of the risk factors displaying paradoxical effects and associations . For example low body mass index (BMI) is associated with increased CVD risk among RA patients but not in non-RA individuals, because low BMI in RA may reflect body composition changes due to increased disease activity. It has been suggested that classical CVD risk factors operate differently in RA patients and the general population as systemic inflammation modulates the adverse effects of such risk factors on vasculature. This concurs with published data suggesting that the relative impact of several traditional risk factors on CVD was less in RA subjects compared with those who do not have RA . Other studies have shown that the importance of the traditional risk factors regarding risk of CVD morbidity in patients with RA has been shown to be comparable to what is reported for the general population. A meta-analysis revealed that traditional risk factors independently increase the risk of CVD morbidity in RA; hypertension (relative risk [RR] 2.24, 95% confidence interval [CI] 1.42, 3.06), hypercholesterolemia (RR 1.73, 95% CI 1.03, 2.44), diabetes mellitus (RR 1.94, 95% CI 1.58, 2.30), smoking (RR1.50, 95% CI 1.15, 1.84), and obesity (RR 1.16, 95% CI 1.03, 1.29). In addition, recent findings indicate that classic CVD risk factors are better predictors of abnormal vascular function and morphology than current and/or cumulative inflammatory load in RA [13,14], underscoring their important role in the initiation of vascular injury and highlighting the need for CVD prevention and management strategies in this population.
Hypertension is an important modifiable risk factor for the development of CVD in the general population  and the risk of CVD morbidity can be reduced with a modest reduction in blood pressure (3–5 mmHg). There are contradictory reports regarding whether hypertension is more common in RA compared with the general population (Table 3.1) [16–19]. However in a recent study Chung et al  found that undiagnosed hypertension was more common in RA patients compared with controls. According to a systematic review the prevalence of hypertension in RA patients lies between 52% and 73%; the wide range of reported incidence can be attributed to differences in study populations assessed, varied sample sizes, and the definition of hypertension used . High blood pressure appears to be a major player in increasing CVD risk in RA as it associates with subclinical atherosclerosis  and has been characterized as one of the most important independent predictors of CVD events with relative risk ranging from between 1.49 to 4.3 [22,23]. Despite the growing appreciation regarding the important role of hypertension in the increased CVD risk amongst patients with RA, high blood pressure still remains underdiagnosed and poorly controlled within this population [16, 24]. Thus, it is not surprising that unrecognized and untreated hypertension is associated with more frequent and severe target organ damage in RA .
A multitude of interrelated factors may be contributing to the high prevalence of hypertension in RA patients, including physical inactivity . RA itself can also be a risk factor for the development of hypertension through various mechanisms (Figure 3.1). Systemic inflammation affects nitric oxide production leading to endothelial dysfunction, vasoconstriction, and vascular damage promoting atherosclerosis and hypertension . In addition, chronic inflammation results in arterial stiffness as RA patients demonstrate reduced small- and large-artery elasticity and greater systemic vascular resistance compared with age- and sex-matched controls , which may subsequently lead to higher values of central blood pressure. In the general population, it has been shown to be an association between chronic-low grade inflammation – assessed by high sensitivity CRP–and hypertension , which has not been confirmed in RA . This unresolved issue remains to be addressed in prospective studies.
Disease modifying anti-rheumatic medications (DMARDs) and other drugs used for the management of RA can also induce high blood pressure. Non-steroidal anti-inflammatory drugs (NSAIDs) leflunomide and cyclosporine have significant hypertensive effects and prescription of these medications, particularly in patients with hypertension, should be decided cautiously and preferably after ensuring the 24-hour average blood pressure is achieved by use of blood pressure surveillance systems. Corticosteroids may also contribute to the development of hypertension. However, it remains unknown whether the higher prevalence of hypertension documented in patients receiving a medium dose of prednisolone (≤7.5 mg/day) is attributable to the medication itself or can be explained on the basis of higher inflammatory burden observed in patients requiring regular treatment with steroids .
The relationship between lipids and risk of CVD in RA patients is complex. In the general population, a nearly linear relationship between cholesterol and risk of CVD is well-established. Although, increased lipid levels have been shown to be common and affect between 55% and 65% of RA patients in one UK cohort , patients with RA generally have lower lipid levels compared with non-RA persons. It may be that the lipid/CVD risk curve is U-shaped, because low lipid levels in RA also confer high CVD risk; this has been termed the lipid paradox. Despite lower lipid levels in RA patients compared with non-RA subjects in the AMORIS study, RA patients had a higher risk of both myocardial infarction and ischemic stroke compared with non-RA subjects . The increased risk of CVD at low lipid levels may be confounded by inflammation, considering a reported significant interaction between low density lipoprotein cholesterol (LDL-c) and erythrocyte sedimentation rate (ESR) . Acute or chronic high-grade inflammation results in the suppression of total cholesterol with a proportionately greater suppression of high-density lipoprotein cholesterol (HDL-c), which yields an increased and unfavorable total cholesterol:HDL-c ratio. This may better reflect the actual risk of CVD in RA patients than use of the individual lipid parameters .
Retrospective studies have reported abnormal lipoprotein patterns even 10 years prior to the onset of RA  suggesting that lower lipid levels may render people more susceptible to development of RA. It remains unknown whether these changes in lipids are associated with the pro-inflammatory state present many years before the clinical manifestations of RA or with the genetic background. Toms et al  reported an association between RA susceptibility genes and low lipid levels in RA patients. These findings have later been confirmed by Liao and colleagues reporting that RA risk alleles were also found to be linked to lower LDL-c .
In the general population HDL-c takes part in reverse cholesterol transport of LDL-c from the periphery atherosclerotic plaque) to the liver. HDL-c also entails anti-inflammatory and other anti-atherosclerotic properties. It has been shown that increasing levels of HDL-c have a cardioprotective effect. Although, data indicate that the cardioprotective effect of HDL-c is also U-shaped because both high  and low  HDL-levels do not confer a benefit against CVD events. Furthermore, the functional properties of HDL-c have been shown to be influenced by inflammation and the interactions between systemic inflammation and abnormal lipid metabolism are complex. Inflammatory mediators and cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), act in adipose tissue, liver, and skeletal muscle to promote changes in lipid metabolism (Figure 3.2). The level of HDL-c has been shown to be related to IL-6  while other acute phase proteins such as serum amyloid A and phospholipase A2 have been reported to cause structural and functional changes of HDL-c, altering its anti-atherogenic functions . Systemic inflammation may influence HDL-c properties and composition by various mechanisms, converting it to a more pro-oxidant molecule .
Antirheumatic medication such as biologic DMARDs (bDMARDs), dampening inflammation, may also restore the HDL functions . Adding to this complexity, the fact that conventional and bDMARDs as well as lifestyle factors such as physical inactivity and obesity also affect lipid levels and function; it is clear that further research is required to investigate this interplay.
Insulin resistance and diabetes
RA shares numerous pathophysiological processes with the metabolic syndrome, such as high blood pressure, obesity, low HDL-c, and high triglyceride levels . Insulin resistance is one of the main components of the metabolic syndrome and it is an important contributor to the CVD risk. The chronic low-grade inflammation present in the metabolic syndrome and the multiple pleiotropic effects of adipokines on the vasculature has been implicated in the pathogenesis of vascular injury in RA patients . It is now well-recognized and accepted that the magnitude of CVD risk in RA is comparable to that of diabetes mellitus [46,47]. In patients with RA also having diabetes, the risk of CVD is nearly doubled compared with RA patients without diabetes .
The impact of rheumatoid arthritis disease activity and severity on cardiovascular comorbidity
Electrophysiological and structural function of the heart has been shown to be affected by disease activity (Table 3.2). Autonomic heart dysfunction and echocardiographic indices of left ventricular remodeling have been shown to correlate with disease severity in cross-sectional studies [48–50]. In addition, several lines of evidence suggest a link between accelerated atherosclerosis and disease activity. For example, inflammatory markers such as ESR and CRP have been associated with morphological markers of subclinical atherosclerosis [51,52]. Carotid atherosclerotic plaque vulnerability has been shown to be associated with moderate/high disease activity in RA patients compared with patients in remission and non-RA subjects . Subclinical disease activity and age >55 years of age were described as the sole predictors of coronary artery plaque vulnerability in RA patients , confirming previous reports underlying the higher probability of acute CVD events in patients with severe, uncontrolled disease. However, this evidence is mainly based on a single-point determination of RA activity measure, which obviously does not precisely reflect the magnitude of the inflammatory response over time. Patients with longer periods of severe disease are more likely to develop CVD complications possibly due to the effect of accumulated inflammatory burden on the vasculature [55,56].
In this regard, Myasoedova et al described the association of RA disease flare and higher cumulative burden of RA severity with CVD occurrence, using population-based longitudinal data . Similar observations were made in a large cohort of almost 25,000 patients after a median follow-up period of 2.7 years, in whom lower disease activity was accompanied by a trend towards reduced risk of CVD events . In contrast, disease duration does not appear to have the same effect on CVD risk  and such findings underscore the importance of tight, sustained control of systemic inflammation not only for the improvement of functional status but also for the reduction of CVD risk.
The role of inflammation in the development of cardiovascular disease manifestations of rheumatoid arthritis
The role of systemic inflammation as an additional contributor to the excess CVD risk in RA, is increasingly appreciated. Levels of CRP and ESR have been linked with heightened CVD morbidity in both the general population  and RA individulas even after adjusting for traditional CVD risk factors . Inflammatory processes in the rheumatoid synovium and atherosclerotic plaques are remarkably similar, suggesting that the intensity of vascular inflammation is an important factor to the development of accelerated atherosclerosis in RA. Although the exact mechanism by which rheumatic inflammation and atherosclerosis influence each other remains to be determined, growing evidence supports the notion that pro-inflammatory cytokines such as TNF-alpha and IL-6 disrupt endothelial hemostasis leading to vascular dysfunction – an early step in atherogenesis . The impaired vascular function and morphology in RA patients lacks a clear association with systemic inflammatory burden . In addition, systemic inflammation contributes to abnormal fibrinolytic activity and enhances prothrombotic propensity in RA patients , playing a crucial role in thrombus formation. In conclusion, chronic high-grade systemic inflammation precipitates adverse effects of traditional CVD risk factors on the vascular wall, underlining the complexity of the links between RA-related factors and impairment of endothelial function (Figure 3.3) .
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