Cardiovascular Complications of Rheumatoid Arthritis: Assessment, Prevention, and Treatment




Morbidity and mortality rates are higher in individuals with rheumatoid arthritis (RA) than in the general population. Ischemic heart disease and heart failure now represent one of the most common causes of death in RA. Indeed, RA appears to represent an independent risk factor for ischemic heart disease, similar to diabetes mellitus. However, no clear guidelines with regard to cardiovascular disease diagnosis and prevention in RA have been developed. This review highlights recent investigations on the assessment, prevention, and treatment of cardiovascular disease in RA.


The impact of cardiovascular disease in the prognosis of patients with rheumatoid arthritis


Rheumatoid arthritis (RA), a chronic inflammatory disease that affects approximately 1% of the general population, is associated with increased mortality and reduced life expectancy, with standardized mortality rates ranging from 1.28 to 3.0. Despite remarkable improvements in RA treatment, there is evidence indicating that the mortality gap between patients with this disease and the general population is not closing. When patients in the Rochester RA cohort were grouped by the decade of disease incidence when they first met American College of Rheumatology criteria, no significant differences in survival were observed over four decades. Because the control population showed decreases in mortality rate, these observations support the notion that the mortality gap between patients with RA and healthy controls is actually widening, particularly in patients who are seropositive for the rheumatoid factor (RF).


This increase in mortality in RA is predominantly caused by accelerated coronary artery and cerebrovascular atherosclerosis, and to other cardiovascular (CV) complications, including heart failure. Indeed, cardiovascular disease (CVD)-associated mortality risk is increased in men and women with seropositive RA. A recent meta-analysis indicated that the risk for CVD-associated death could be as much as 50% higher among patients with RA compared with controls, with the risk for ischemic heart disease and cerebrovascular diseases being elevated to a similar degree. RA is an independent risk factor for multi-vessel coronary artery disease. The enhanced vascular risk is not restricted to individuals with established RA, because increased mortality in patients who are positive for the RF and have early inflammatory polyarthritis has been reported.


In men and women with RA with disease onset in the 1980s and 1990s, CVD mortality was significantly increased (standardized mortality rates of 1.36 and 1.93, respectively). However, standardized admission rates for CV complications were not raised in these patients, suggesting either that vascular disease in RA has a higher case fatality than in the general population or that it often goes unrecognized before the fatal event. Patients with RA also have substantially increased 30-day mortality from all causes and from CVD following a first acute vascular event, and more frequent recurrent ischemic events after acute coronary syndrome. RA extra-articular manifestations, usually related to uncontrolled inflammation, are also associated with increased CV mortality, suggesting that processes intrinsic to RA pathogenesis play important roles in CV damage and its clinical consequences.


CVD does not only impact mortality in RA but also leads to significant morbidity. CV events occur approximately a decade earlier in RA than in controls and patients with RA are twice as likely to suffer a myocardial infarction with the increased relative risk for CV events being concentrated in younger patients with RA and individuals without known prior CV events. However, in a population of male United States’ veterans older than 50 years, RA has also been associated with a higher risk for major adverse CV events, particularly in patients with increased disease activity independent of traditional risk factors.


Patients with prolonged arthritis have more atherosclerosis than patients of the same age with more recent disease onset, suggesting that atherogenesis accelerates after the onset of RA. The odds ratio for the likelihood of having more severe coronary artery calcification in established RA has been determined at 3.42, after adjusting for traditional CV risk factors. Further, an increased prevalence of severe subclinical atherosclerotic findings in long-term treated patients who have RA without clinical evidence of atherosclerotic disease has been reported. However, even patients with early RA show evidence of increased subclinical atherosclerosis, as assessed by carotid plaque, carotid intima media thickness, and coronary calcification. Patients with RA also exhibit significantly increased arterial stiffness and young to middle-aged patients who have RA with low disease activity and free from traditional CV risk factors and overt CVD have altered endothelial reactivity.


In many ways, CVD in RA shares similarities with CVD in diabetes mellitus (DM). Preclinical atherosclerosis and the risk for CVD appears to be of equal frequency and severity in RA and DM of similar duration. Compared with non-diabetic controls, patients who are non-diabetic with RA and those with type 2 DM have comparable hazard ratios for CVD: 2.16 (95% CI 1.28–3.63, P = .004) and 2.04 (95% CI 1.12–3.67, P = .019), respectively. Further, similar to what occurs in DM, patients with RA are less likely to report symptoms of angina and more likely to experience unrecognized myocardial infarction and sudden cardiac death. However, despite the increased risk for vascular events, strategies to prevent CVD are similar among women with and those without RA.


Patients with RA are also at significantly higher risk for congestive heart failure (CHF) compared with those without the disease. CHF risk precedes the diagnosis of RA and cannot be explained by an increased incidence of traditional CV risk factors. RA is associated with increased left ventricular mass, which is independently related to disease duration, whereas systolic function is typically preserved. Abnormalities of transmitral and pulmonary venous flow have been proposed as markers of altered diastolic function in patients who have long-standing RA with normal systolic function. The clinical presentation and the outcome of CHF differ significantly between RA and control individuals. In the former, CHF presentation may be more subtle but mortality from this complication is significantly higher. Even after adjusting for CV risk factors and ischemic heart disease, patients with RA have almost twice the risk for developing CHF than patients without arthritis. Again, this increase has been seen primarily in patients who are seropositive for the RF. In addition, patients with RA are at increased risk for death in the period immediately after CHF develops and this risk remains elevated for 6 months.


Previous studies have suggested that traditional CV risk factors do not fully account for the increased propensity to vascular complications in RA and that immune dysregulation, inflammation, and metabolic disturbances observed in RA could play an important role in accelerated atherogenesis and mortality. Indeed, histologic examination of coronary arteries in RA has revealed less atherosclerosis but greater evidence of inflammation and instability.




Pathogenic mechanisms involved in premature cardiovascular disease in patients with rheumatoid arthritis


Over the past few years, striking similarities in the inflammatory and immunologic responses in atherosclerosis and RA have been described. Although chronic inflammation can promote endothelial cell activation and vascular dysfunction, which leads to decreased blood vessel compliance and atheroma formation, the reasons for the dramatic increase in atherosclerotic disease in RA are not totally understood and appear to be fairly complex ( Fig. 1 ). It appears that variables that increase CV mortality in RA are present very early during the natural history of the disease, because patients with new onset RF positive inflammatory arthritis exhibit evidence of abnormal endothelial function, which is considered a good predictor of future development of atherosclerosis. RF as an independent risk factor for ischemic heart disease in the general population has been suggested by some studies. Indeed, RF has been associated with increased all-cause mortality and CV mortality after adjustment for traditional risk factors, even among subjects without joint symptoms. Further, preliminary evidence indicates that patients with RA who are positive for anti-cyclic citrullinated peptide antibodies (Abs) (anti-CCP) have higher subclinical atherosclerosis than those who are not. A recent study indicated that anti-CCP Abs in RA are independently associated with the development of ischemic heart disease (odds ratio[OR] 2.8; 95% CI 1.19–6.56; P = .009). The precise role that autoantibodies (autoAbs) play in premature CVD in RA, however, remains to be determined.




Fig. 1


Putative mechanisms leading to endothelial dysfunction and vascular damage in RA.


Traditional Cardiovascular Risk Factors


RA is associated with traditional and nontraditional CV risk factors. Therefore, assessments based only on traditional risk factors are insufficient to capture the extent of CV risk in RA. A higher Framingham risk score is independently associated to coronary calcification in RA. Age and hypertension correlate with increased CV risk RA, but so do factors associated with inflammation, including neutrophil count and radiographic score. It also appears that physically inactive patients with RA have significantly worse CVD risk profile compared with those who are physically active. Although smoking is associated with RF and anti-CCP Abs production and is now recognized as an independent risk factor for RA development, it does not appear to predict CV events or cardiac-associated mortality in seropositive patients with inflammatory arthritis. However, the prevalence and severity of coronary calcification in established RA has been linked in part to tobacco use. Indeed, a personal history of ischemic heart disease, smoking, hypertension, and diabetes mellitus has been found to contribute to CV death in RA.


A proatherogenic lipid profile has been reported in patients with RA. Beyond the abnormalities in plasma lipids, increased levels of small, dense LDL are common in patients who are drug-naïve with early RA. The role that these particles may play in the atherogenic process in this disease is still unclear. AutoAbs recognizing oxidized LDL are associated with atherosclerosis in the general population. These antibodies are present in RA and correlate with inflammation but their role in CVD in RA remains to be determined. Serum lipoprotein A is significantly increased and high-density lipoprotein cholesterol (HDL) significantly decreased in women with RA. In addition, HDL function is abnormal in RA, because this molecule is unable to protect LDL from oxidation and is therefore considered proinflammatory. Proinflammatory HDLs can contribute to oxidative damage and have been reported in approximately 20% of patients with RA. Further, a recent study indicates that proinflammatory HDL in RA is associated with active disease and an altered protein cargo. A recent study suggests that total cholesterol and LDL levels significantly decrease within 5 years before the diagnosis of RA. The mechanisms and significance of these findings remains to be determined.


Insulin Resistance, Body Weight, Homocysteine, and Thyroid Function


Other metabolic abnormalities that predispose to vascular disease in the general population (microalbuminuria, insulin resistance, and increased homocysteine) are prevalent in RA. Insulin resistance is an important risk factor for CVD, and tumor necrosis factor (TNF)-α and other proinflammatory molecules directly affect insulin sensitivity. Factors that lead to increased systemic oxidative stress and proinflammatory cytokine overexpression may therefore promote insulin resistance. RA is associated with a higher prevalence of the metabolic syndrome than control subjects, which was present in about a third of patients with early disease and in 42% of patients with long-standing disease. Patients with RA have evidence of impaired glucose handling, which is secondary to peripheral insulin resistance mediated by the inflammatory response. Further, patients who have RA with carotid plaque have higher insulin resistance. The precise role that corticosteroids play in insulin resistance development in RA remains to be determined. Insulin resistance has been shown to improve with the use of disease-modifying antirheumatic drugs (DMARDs) and biologics in RA. Increased trunk fat has been significantly and independently associated with increased arterial stiffness in patients who are postmenopausal with RA.


High homocysteine levels have been linked to atherothrombosis in RA. A potential role of thyroid function in the development of subclinical atherosclerosis in this disease has also been proposed, because hypothyroidism in RA is an independent association with carotid plaque and this is enhanced in patients who also have other traditional CV risk factors or neutrophilia.


Family History


A parental history of death from CVD is associated with a 70% increase in risk for fatal CVD in RA and an increase in 10-year mortality from CVD from 5% to 10% in men and from 2% to 4% in women aged 50 to 67 years.


Genetic Influences


Functional polymorphisms that relate to major histocompatibility complex (MHC) expression are associated with increased susceptibility to RA, myocardial infarction, and multiple sclerosis. A −168A → G polymorphism in the type III promoter of the MHC class II transactivator (MHC2TA) has been associated with increased susceptibility to these three diseases and with lower expression of MHC2TA after leukocyte stimulation with interferon-γ. These polymorphisms may result in differential MHC molecule expression and could potentially be associated with susceptibility to common complex diseases with inflammatory components. Shared epitope alleles ( HLA DRB1 genotype), particularly compound heterozygotes, are associated with death from all causes and from CVD, independently of autoAb status in RA. However, the combination of shared epitope, smoking, and anti-CCP antibodies is associated with a higher risk for premature death in patients with inflammatory polyarthritis and RA. Other studies have also linked the shared epitope to ischemic heart disease in RA. The exact mechanisms by which the presence of the shared epitope may enhance premature vascular damage in RA remain to be determined.


A recent study suggests that the IL-6-174C-allele may associate with CVD in RA and possibly exerts its effect via increased inflammation. Patients with RA who carry the TNF-α-1031 T/C polymorphism have smaller LDL particles that have greater affinity for extracellular matrix and higher susceptibility for oxidation. Other genetic polymorphisms that have been proposed to be associated to the development of CVD in RA include plasminogen activator inhibitor I (PAI-1) and coagulation factor XIII. Polymorphisms in TNF receptor type II are associated with hypertension in Scandinavian subjects with RA. In another recent Scandinavian study, no increased occurrence of CVD before the onset of RA was detected. The authors then concluded that shared risk factors or susceptibilities for RA and CVD likely contributed less than RA-related factors to the increased occurrence of vascular complications in this disease.


The Role of Inflammation in Cardiovascular Disease in Rheumatoid Arthritis


Recent evidence indicates that there is a close temporal correlation between inflammation and morphologic features of rapidly progressive carotid atherosclerosis, which suggests that elevations in inflammatory biomarkers might help in predicting the presence of atherosclerosis. Markers of systemic inflammation confer a statistically significant additional risk for CV death among patients with RA, even after controlling for traditional CV risk factors and comorbidities. Increased levels of proinflammatory mediators, including TNF; interleukin-6 (IL-6); interleukin-17 (IL-17); and others, could be detrimental to the endothelium and myocardium and promote insulin resistance. Levels of these cytokines are increased in RA. The C-reactive protein (CRP) concentration at baseline is an important predictor of subsequent death from CVD in patients with new onset inflammatory polyarthritis, and is independent of other factors of disease severity. High levels of CRP also correlate with carotid intima media thickness. High sensitivity CRP and lower glomerular filtration rate have been independently predictive of endothelial dysfunction in RA. Higher erythrocyte sedimentation rate, small and large joint swelling, rheumatoid nodules, vasculitis and rheumatoid lung have been independently associated with increased risk for CV death. In a recent study comparing subjects with RA and controls, TNF-α and IL-6 were significantly associated with the severity of coronary artery calcification in RA, independent of Framingham risk score. Enhanced arterial stiffness in RA correlates with CRP and IL-6 levels. Similarly, in those subjects experiencing new onset CHF, the proportion of subjects with high sedimentation rate was greatest in the 6 months preceding the diagnosis of cardiac dysfunction. This finding indicates that an enhanced inflammatory process may promote the development of heart dysfunction in inflammatory arthritis The magnitude and chronicity of the inflammatory response, as measured by circulating levels of inflammatory markers, correlates with carotid atherosclerosis development in RA. Levels of adhesion molecules linked to vascular damage, including soluble vascular cell adhesion molecule-1 (VCAM-1); intercellular adhesion molecule-1; and endothelial–leukocyte adhesion molecule, were higher in RA. VCAM-1 levels have been associated with carotid atherosclerosis in RA.


Although the exact role of IL-17 in premature vascular damage in RA remains to be determined, recent work indicates that this cytokine may play a role in atherosclerosis development in murine models of vascular disease and elevated circulating levels of IL-17 have been reported in patients with acute coronary syndromes. IL-17 is produced concomitantly with IFN-γ by coronary artery-infiltrating T cells and these cytokines act synergistically to induce proinflammatory responses in vascular smooth muscle cells. IL-17 accelerates myocardial fibrosis in animal models of heart injury. However, there is recent evidence that IL-17 may also play a regulatory role in atherosclerosis and future studies should determine whether this cytokine plays a pivotal role in vascular damage in RA.


T Cells


An expanded population of CD4 + CD28 T cells has been demonstrated in the peripheral blood of patients with RA, and clonal expansion of a similar T-cell subset has been reported in the blood and atherosclerotic plaques of patients with unstable angina. These cells can injure the endothelium and cause vascular damage. Patients who have RA with persistent CD4 + CD28 expansion have presented with increased preclinical atherosclerotic changes, including endothelial dysfunction and carotid atherosclerosis, compared with those without expansion. TNF-α induces downregulation of the CD28 molecule in CD4 + T cells, suggesting a pathogenic mechanism for the development of these cells. Treatment with anti-TNF agents has been found to downregulate this cell subset in patients with RA and in patients with unstable angina and no RA. The precise role that these cells play in the development of acute coronary events in RA requires further investigation.


Abnormalities in Vasculogenesis


An adequate balance between endothelium destruction and regeneration is needed to maintain vascular health. Endothelial progenitor cells (EPCs) are present in the circulation of patients with different forms of vascular damage and are released from the bone marrow during acute vascular injury. EPCs appear to be crucial in normal revascularization after endothelium damage occurs. Furthermore, reduced EPC numbers and abnormal EPC function correlate with increased incidence of atherosclerosis, impaired vasculogenesis after ischemia, and future CV events. Recent reports suggest that EPC numbers are decreased in the systemic circulation of patients with active RA and that their functions are impaired. Potentially, this phenomenon could contribute to atherosclerosis but further studies correlating abnormal EPCs with functional markers of endothelial dysfunction in RA are needed. Endothelial dysfunction in patients who have RA with low-grade inflammation was associated with decreased EPC numbers and low-grade dysfunction of these cells. A single dose of infliximab significantly increases EPC numbers and improves their functional properties in RA. Others have proposed that asymmetric dimethylarginine, a major endogenous inhibitor of nitric oxide synthase associated with atherosclerosis risk in the general population, may contribute to EPC depletion in RA via depressed NO-dependent mobilization or survival of these cells.


EPCs can contribute to synovial neovascularization in RA. Proinflammatory cytokines upregulate vascular endothelial growth factor, which increases synovial EPCs and is essential to the pro-angiogenic process. The discrepancy observed between decreased angiogenic responses in RA peripheral blood and enhanced angiogenesis at the level of the synovium has not been clarified but may be related to differences in EPC homing, perhaps driven by the proinflammatory milieu of the joint.




Pathogenic mechanisms involved in premature cardiovascular disease in patients with rheumatoid arthritis


Over the past few years, striking similarities in the inflammatory and immunologic responses in atherosclerosis and RA have been described. Although chronic inflammation can promote endothelial cell activation and vascular dysfunction, which leads to decreased blood vessel compliance and atheroma formation, the reasons for the dramatic increase in atherosclerotic disease in RA are not totally understood and appear to be fairly complex ( Fig. 1 ). It appears that variables that increase CV mortality in RA are present very early during the natural history of the disease, because patients with new onset RF positive inflammatory arthritis exhibit evidence of abnormal endothelial function, which is considered a good predictor of future development of atherosclerosis. RF as an independent risk factor for ischemic heart disease in the general population has been suggested by some studies. Indeed, RF has been associated with increased all-cause mortality and CV mortality after adjustment for traditional risk factors, even among subjects without joint symptoms. Further, preliminary evidence indicates that patients with RA who are positive for anti-cyclic citrullinated peptide antibodies (Abs) (anti-CCP) have higher subclinical atherosclerosis than those who are not. A recent study indicated that anti-CCP Abs in RA are independently associated with the development of ischemic heart disease (odds ratio[OR] 2.8; 95% CI 1.19–6.56; P = .009). The precise role that autoantibodies (autoAbs) play in premature CVD in RA, however, remains to be determined.




Fig. 1


Putative mechanisms leading to endothelial dysfunction and vascular damage in RA.


Traditional Cardiovascular Risk Factors


RA is associated with traditional and nontraditional CV risk factors. Therefore, assessments based only on traditional risk factors are insufficient to capture the extent of CV risk in RA. A higher Framingham risk score is independently associated to coronary calcification in RA. Age and hypertension correlate with increased CV risk RA, but so do factors associated with inflammation, including neutrophil count and radiographic score. It also appears that physically inactive patients with RA have significantly worse CVD risk profile compared with those who are physically active. Although smoking is associated with RF and anti-CCP Abs production and is now recognized as an independent risk factor for RA development, it does not appear to predict CV events or cardiac-associated mortality in seropositive patients with inflammatory arthritis. However, the prevalence and severity of coronary calcification in established RA has been linked in part to tobacco use. Indeed, a personal history of ischemic heart disease, smoking, hypertension, and diabetes mellitus has been found to contribute to CV death in RA.


A proatherogenic lipid profile has been reported in patients with RA. Beyond the abnormalities in plasma lipids, increased levels of small, dense LDL are common in patients who are drug-naïve with early RA. The role that these particles may play in the atherogenic process in this disease is still unclear. AutoAbs recognizing oxidized LDL are associated with atherosclerosis in the general population. These antibodies are present in RA and correlate with inflammation but their role in CVD in RA remains to be determined. Serum lipoprotein A is significantly increased and high-density lipoprotein cholesterol (HDL) significantly decreased in women with RA. In addition, HDL function is abnormal in RA, because this molecule is unable to protect LDL from oxidation and is therefore considered proinflammatory. Proinflammatory HDLs can contribute to oxidative damage and have been reported in approximately 20% of patients with RA. Further, a recent study indicates that proinflammatory HDL in RA is associated with active disease and an altered protein cargo. A recent study suggests that total cholesterol and LDL levels significantly decrease within 5 years before the diagnosis of RA. The mechanisms and significance of these findings remains to be determined.


Insulin Resistance, Body Weight, Homocysteine, and Thyroid Function


Other metabolic abnormalities that predispose to vascular disease in the general population (microalbuminuria, insulin resistance, and increased homocysteine) are prevalent in RA. Insulin resistance is an important risk factor for CVD, and tumor necrosis factor (TNF)-α and other proinflammatory molecules directly affect insulin sensitivity. Factors that lead to increased systemic oxidative stress and proinflammatory cytokine overexpression may therefore promote insulin resistance. RA is associated with a higher prevalence of the metabolic syndrome than control subjects, which was present in about a third of patients with early disease and in 42% of patients with long-standing disease. Patients with RA have evidence of impaired glucose handling, which is secondary to peripheral insulin resistance mediated by the inflammatory response. Further, patients who have RA with carotid plaque have higher insulin resistance. The precise role that corticosteroids play in insulin resistance development in RA remains to be determined. Insulin resistance has been shown to improve with the use of disease-modifying antirheumatic drugs (DMARDs) and biologics in RA. Increased trunk fat has been significantly and independently associated with increased arterial stiffness in patients who are postmenopausal with RA.


High homocysteine levels have been linked to atherothrombosis in RA. A potential role of thyroid function in the development of subclinical atherosclerosis in this disease has also been proposed, because hypothyroidism in RA is an independent association with carotid plaque and this is enhanced in patients who also have other traditional CV risk factors or neutrophilia.


Family History


A parental history of death from CVD is associated with a 70% increase in risk for fatal CVD in RA and an increase in 10-year mortality from CVD from 5% to 10% in men and from 2% to 4% in women aged 50 to 67 years.


Genetic Influences


Functional polymorphisms that relate to major histocompatibility complex (MHC) expression are associated with increased susceptibility to RA, myocardial infarction, and multiple sclerosis. A −168A → G polymorphism in the type III promoter of the MHC class II transactivator (MHC2TA) has been associated with increased susceptibility to these three diseases and with lower expression of MHC2TA after leukocyte stimulation with interferon-γ. These polymorphisms may result in differential MHC molecule expression and could potentially be associated with susceptibility to common complex diseases with inflammatory components. Shared epitope alleles ( HLA DRB1 genotype), particularly compound heterozygotes, are associated with death from all causes and from CVD, independently of autoAb status in RA. However, the combination of shared epitope, smoking, and anti-CCP antibodies is associated with a higher risk for premature death in patients with inflammatory polyarthritis and RA. Other studies have also linked the shared epitope to ischemic heart disease in RA. The exact mechanisms by which the presence of the shared epitope may enhance premature vascular damage in RA remain to be determined.


A recent study suggests that the IL-6-174C-allele may associate with CVD in RA and possibly exerts its effect via increased inflammation. Patients with RA who carry the TNF-α-1031 T/C polymorphism have smaller LDL particles that have greater affinity for extracellular matrix and higher susceptibility for oxidation. Other genetic polymorphisms that have been proposed to be associated to the development of CVD in RA include plasminogen activator inhibitor I (PAI-1) and coagulation factor XIII. Polymorphisms in TNF receptor type II are associated with hypertension in Scandinavian subjects with RA. In another recent Scandinavian study, no increased occurrence of CVD before the onset of RA was detected. The authors then concluded that shared risk factors or susceptibilities for RA and CVD likely contributed less than RA-related factors to the increased occurrence of vascular complications in this disease.


The Role of Inflammation in Cardiovascular Disease in Rheumatoid Arthritis


Recent evidence indicates that there is a close temporal correlation between inflammation and morphologic features of rapidly progressive carotid atherosclerosis, which suggests that elevations in inflammatory biomarkers might help in predicting the presence of atherosclerosis. Markers of systemic inflammation confer a statistically significant additional risk for CV death among patients with RA, even after controlling for traditional CV risk factors and comorbidities. Increased levels of proinflammatory mediators, including TNF; interleukin-6 (IL-6); interleukin-17 (IL-17); and others, could be detrimental to the endothelium and myocardium and promote insulin resistance. Levels of these cytokines are increased in RA. The C-reactive protein (CRP) concentration at baseline is an important predictor of subsequent death from CVD in patients with new onset inflammatory polyarthritis, and is independent of other factors of disease severity. High levels of CRP also correlate with carotid intima media thickness. High sensitivity CRP and lower glomerular filtration rate have been independently predictive of endothelial dysfunction in RA. Higher erythrocyte sedimentation rate, small and large joint swelling, rheumatoid nodules, vasculitis and rheumatoid lung have been independently associated with increased risk for CV death. In a recent study comparing subjects with RA and controls, TNF-α and IL-6 were significantly associated with the severity of coronary artery calcification in RA, independent of Framingham risk score. Enhanced arterial stiffness in RA correlates with CRP and IL-6 levels. Similarly, in those subjects experiencing new onset CHF, the proportion of subjects with high sedimentation rate was greatest in the 6 months preceding the diagnosis of cardiac dysfunction. This finding indicates that an enhanced inflammatory process may promote the development of heart dysfunction in inflammatory arthritis The magnitude and chronicity of the inflammatory response, as measured by circulating levels of inflammatory markers, correlates with carotid atherosclerosis development in RA. Levels of adhesion molecules linked to vascular damage, including soluble vascular cell adhesion molecule-1 (VCAM-1); intercellular adhesion molecule-1; and endothelial–leukocyte adhesion molecule, were higher in RA. VCAM-1 levels have been associated with carotid atherosclerosis in RA.


Although the exact role of IL-17 in premature vascular damage in RA remains to be determined, recent work indicates that this cytokine may play a role in atherosclerosis development in murine models of vascular disease and elevated circulating levels of IL-17 have been reported in patients with acute coronary syndromes. IL-17 is produced concomitantly with IFN-γ by coronary artery-infiltrating T cells and these cytokines act synergistically to induce proinflammatory responses in vascular smooth muscle cells. IL-17 accelerates myocardial fibrosis in animal models of heart injury. However, there is recent evidence that IL-17 may also play a regulatory role in atherosclerosis and future studies should determine whether this cytokine plays a pivotal role in vascular damage in RA.


T Cells


An expanded population of CD4 + CD28 T cells has been demonstrated in the peripheral blood of patients with RA, and clonal expansion of a similar T-cell subset has been reported in the blood and atherosclerotic plaques of patients with unstable angina. These cells can injure the endothelium and cause vascular damage. Patients who have RA with persistent CD4 + CD28 expansion have presented with increased preclinical atherosclerotic changes, including endothelial dysfunction and carotid atherosclerosis, compared with those without expansion. TNF-α induces downregulation of the CD28 molecule in CD4 + T cells, suggesting a pathogenic mechanism for the development of these cells. Treatment with anti-TNF agents has been found to downregulate this cell subset in patients with RA and in patients with unstable angina and no RA. The precise role that these cells play in the development of acute coronary events in RA requires further investigation.


Abnormalities in Vasculogenesis


An adequate balance between endothelium destruction and regeneration is needed to maintain vascular health. Endothelial progenitor cells (EPCs) are present in the circulation of patients with different forms of vascular damage and are released from the bone marrow during acute vascular injury. EPCs appear to be crucial in normal revascularization after endothelium damage occurs. Furthermore, reduced EPC numbers and abnormal EPC function correlate with increased incidence of atherosclerosis, impaired vasculogenesis after ischemia, and future CV events. Recent reports suggest that EPC numbers are decreased in the systemic circulation of patients with active RA and that their functions are impaired. Potentially, this phenomenon could contribute to atherosclerosis but further studies correlating abnormal EPCs with functional markers of endothelial dysfunction in RA are needed. Endothelial dysfunction in patients who have RA with low-grade inflammation was associated with decreased EPC numbers and low-grade dysfunction of these cells. A single dose of infliximab significantly increases EPC numbers and improves their functional properties in RA. Others have proposed that asymmetric dimethylarginine, a major endogenous inhibitor of nitric oxide synthase associated with atherosclerosis risk in the general population, may contribute to EPC depletion in RA via depressed NO-dependent mobilization or survival of these cells.


EPCs can contribute to synovial neovascularization in RA. Proinflammatory cytokines upregulate vascular endothelial growth factor, which increases synovial EPCs and is essential to the pro-angiogenic process. The discrepancy observed between decreased angiogenic responses in RA peripheral blood and enhanced angiogenesis at the level of the synovium has not been clarified but may be related to differences in EPC homing, perhaps driven by the proinflammatory milieu of the joint.




Effect of rheumatoid arthritis treatment on cardiovascular disease risk


The lack of a unifying explanation for accelerated CVD in RA is reflected by the confusion that still exists regarding possible preventive measures aimed at decreasing atherogenic risk. There is still considerable uncertainty on how to manage patients with RA effectively to reduce their risk for future CV events, because some of the medications used to treat RA might have dual effects on risk for CV morbidity. This risk is exemplified by the use of corticosteroids, which on one hand may decrease CV complications in RA by decreasing inflammation but on the other hand increase it by promoting pro-atherosclerotic lipid profiles, hypertension, and insulin resistance. Methotrexate can promote hyperhomocysteinemia (usually corrected by folic acid supplementation) and cause endothelial damage. However, long-term follow-up of patients with RA has suggested that methotrexate significantly reduces overall and CV mortality. Furthermore, use of DMARDs is associated with reductions in risk for hospitalization for congestive heart failure in RA. The author will now discuss the role that various medications may play in CV risk or prevention in RA.


Nonsteroidal Antiinflammatory Drugs and Cardiovascular Complications in Rheumatoid Arthritis


Current and new users of all classes of non-aspirin nonsteroidal antiinflammatory drugs (NSAIDS), including patients with RA, have an elevated relative risk estimate for myocardial infarction. Several patient characteristics increase the risk for CV events among users of some NSAIDS, including increased age, hypertension, previous myocardial infarction and CVD, chronic renal disease, chronic obstructive pulmonary disease, and RA. This finding indicates that patients who have RA with various comorbidities and advanced age may be particularly prone to developed CV complications while on specific NSAIDS. However, a large case-control analysis found that the risk for first-time myocardial infarction is increased for several weeks after the cessation of NSAID therapy, an effect that is more pronounced in patients with RA or lupus and in individuals who discontinue NSAID therapy after previous long-term use. These findings suggest that NSAIDs might have a role in suppressing the risk for myocardial infarction in patients with RA and other inflammatory conditions and that, ideally, abrupt discontinuation of NSAIDS in these populations should be avoided.


Role of Corticosteroids in Cardiovascular Disease in Rheumatoid Arthritis


Corticosteroids can induce hypertension, insulin resistance, and disturbances in blood lipids; they induce obesity and may enhance hypercoagulability. As mentioned earlier, whether glucocorticoids promote accelerated atherogenesis in RA is still a matter of debate. In one study, subjects exposed to glucocorticoids had higher incidence of carotid plaque and arterial incompressibility, independent of CV risk factors and RA clinical manifestations. A Scandinavian study reported that treatment with low-dose prednisolone did not influence endothelial function or carotid intima media thickness in RA, although it promoted higher levels of total cholesterol. An increased risk for CV events with high cumulative exposure to corticosteroids has been found in patients with RA who are seropositive for RF, but not on the patients who are seronegative. However, in patients who have RA with a history of ischemic heart disease, use of corticosteroids attenuated the risk for CV death.


Disease-Modifying Antirheumatic Drugs


A recent study indicated that prolonged exposure to various DMARDS, including methotrexate, leflunomide, and sulfasalazine, was associated with a reduction of CV risk in RA, and similar trends were observed with corticosteroid use. Further supporting a beneficial effect of methotrexate treatment in CVD prevention, this drug reduced the incidence of vascular disease in veterans with psoriasis or RA. Low to moderate cumulative doses appeared to be more beneficial than higher doses. In addition, a combination of methotrexate and folic acid led to a further reduction in the incidence of CVD, suggesting that the latter did not decrease the efficacy of methotrexate. Furthermore, methotrexate use was associated with a significantly lower risk for CV events in patients with RA compared with patients who had never used DMARDs (OR 0.16). Methotrexate use has also been associated with a decreased incidence of the metabolic syndrome, whereas corticosteroids or other DMARDS did not show a protective effect. Adding additional DMARDS, such as sulfasalazine and hydroxychloroquine, appears to provide additional CV protection. In a Canadian study, DMARD use was associated with a reduction in myocardial infarction risk in patients with RA, whereas corticosteroids showed an increased risk and coxibs did not change risk. In a recent cross-sectional analysis, drugs used to treat RA did not have major adverse effects on CV risk factors and use of antimalarials was actually associated with beneficial lipid profiles and lower blood pressure. As a potential antiatherogenic mechanism of methotrexate (MTX), Reiss and colleagues have shown that through adenosine A2A receptor activation, MTX promotes reverse cholesterol transport and limits foam cell formation in macrophages.


Anti-tumor Necrosis Factor Therapy


The effects of TNF-α blockers on CVD in RA are complex because these drugs may promote CHF and decrease heart compliance while controlling inflammation and decreasing risk for plaque formation. Infliximab can improve endothelial function in RA after 12 weeks of therapy, and anti-TNF therapy also reduces aortic stiffness to a level comparable to that of healthy individuals by 4 and 12 weeks of treatment. Prolonged effects on endothelial function (18 months of therapy) were recently reported with infliximab and adalimumab. It appears that the risk to develop first CV events in RA is lower in patients treated with TNF blockers. However, prospective, long-term, longitudinal studies are required to evaluate the precise role of anti-TNF therapy in atherosclerosis prevention. Anti-TNF therapy can also improve other risk factors for accelerated atherosclerosis, including promoting a decrease in insulin resistance, CRP, IL-6 and CD4 + CD28 T cells, and an increase in HDL. However, it appears that at least some of the beneficial effects of anti-TNF agents on endothelial function are not sustained, have not been reported in all studies, and are not seen in all patient populations (eg, in the case of patients with diabetes treated with etanercept). In one study, although an initial improvement in RA endothelial function was observed with infliximab, values returned to baseline 4 weeks after the infusion in subjects followed for 1 year. Another report found that, although infliximab induces a transient increase in flow-mediated dilatation (FMD), the drug also induces vasoconstriction and increases in wall shear stress. There is also evidence that biologics may induce elevations in blood lipids with a deleterious shift in the atherogenic index in RA. It is possible that the various TNF antagonists have different effects on endothelial and smooth muscle cells and on vascular function. Animal studies suggest a negative influence of TNF-α inhibitors on collateral artery growth, and this observation deserves further investigation into the potential role of this therapy in decreasing alternative mechanisms of cardiac perfusion in individuals with impaired coronary circulation.


Previous studies in the general population have shown that short-term TNF-α antagonism with infliximab does not improve and high doses (10 mg/kg) adversely affect the clinical condition of patients with moderate-to-severe chronic heart failure. Despite contraindication to the use of these agents in patients with moderate-severe heart failure, epidemiologic studies in RA have not consistently substantiated this association. In fact, a recent German study has concluded that inhibition of TNF that effectively reduces inflammatory activity in RA is more likely to be beneficial than harmful with regards to CHF risk, especially when not combined with corticosteroids of coxibs. Similarly, a recent study indicates that blocking TNF in patients who have RA without evident heart failure decreases N-terminal pro-brain natriuretic peptide pointing at no treatment-induced deterioration in cardiac function, and a potential CV risk benefit. However, TNF-inhibitors may increase the risk for first hospitalization and exacerbation of CHF in elderly patients with RA. A recent study indicates that, when compared with patients who have RA receiving MTX monotherapy, those receiving biologic immunosuppressive agents had no changes in the risk for experiencing a CV event, whereas use of oral glucocorticoids and other cytotoxic immunosuppressive agents (leflunomide, azathioprine) was associated with significant increases in the risk for CV events.


Rituximab and Other Biologics


Preliminary data from various groups suggests that rituximab infusions exert early and sustained favorable effects on endothelial dysfunction and plasma lipids. The role of abatacept and anakinra in CV prevention in RA remains to be determined, although there is some preliminary evidence that chronic inhibition of IL-1 actions with anakinra improves left ventricle deformation in parallel with endothelial function and nitro-oxidative stress in RA.

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Cardiovascular Complications of Rheumatoid Arthritis: Assessment, Prevention, and Treatment

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