New insights to the mechanisms underlying atherosclerosis in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory circumstance, which has been associated with increased risk of cardiovascular disease (CVD). Although RA management has been promoted, mortality rate due to CVD remains remarkable. Approximately, 50% of premature death cases in RA are attributable to CVD. RA patients develop atherosclerosis in a greater amount than the general population. Moreover, atherosclerotic lesions develop rapidly in RA patients and might be more susceptible to rupture. The inflammatory condition of RA, such as cytokines, abnormally activated immune cells, play a role in the initiation, perpetuation and exacerbation of atherosclerosis. RA and CVD have genetic and environmental contributing risk factors in common, implying to potential coincidence of both disorders. Accelerated atherosclerosis in RA is attributed to inflammation, which carries its role out both through modulation of traditional risk factors and direct effect on the vessel wall. Hence, anti‐inflammatory medications in RA like tumor necrosis factor blockers might have a beneficial effect on preventing cardiovascular development. Increasing age, smoking, hypertension, male gender, hypercholesterolemia and diabetes are enumerated as traditional CVD risk factors. Hopefully, further understanding of the cardiovascular risk factors by perceiving the disease conditions behind CVD, will improve management of cardiovascular risks in patients with RA.     

Cardiovascular Disease in Systemic Lupus Erythematosus: The Role of Traditional and Lupus Related Risk Factors

Atherosclerosis is a chronic inflammatory disorder characterized by immune cell activation, inflammation driven plaque formation and subsequent destabilization. In other disorders of an inflammatory nature, the chronic inflammatory state per se has been linked to acceleration of the atherosclerotic process which is underlined by an increased incidence of cardiovascular disease (CVD) in disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and antiphopholipid (Hughes) syndrome (APS). SLE is an autoimmune disease that may affect any organ. Premature coronary heart disease has emerged as a major cause of morbidity and mortality in SLE. In addition to mortality, cardiovascular morbidity is also markedly increased in these patients, compared with the general population. The increased cardiovascular risk can be explained only partially by an increased prevalence of classical risk factors for cardiovascular disease; it also appears to be related to inflammation. Inflammation is increasingly being considered central to the pathogenesis of atherosclerosis and an important risk factor for vascular disease. Recent epidemiologic and pathogenesis studies have suggested a great deal in common between the pathogenesis of prototypic autoimmune disease such as SLE and that of atherosclerosis.We will review traditional risk factors for CVD in SLE. We will also discuss the role of inflammation in atherosclerosis, as well as possible treatment strategies in these patients.Key Words: Cardiovascular disease, systemic lupus erythematosus, atherosclerosis.     

Cardiovascular risk in rheumatoid arthritis: How to lower the risk?

Patients with rheumatoid arthritis (RA) carry an excess risk for cardiovascular disease, which is comparable to the risk in patients with type 2 diabetes mellitus. The mechanisms involved are partly related to traditional cardiovascular risk factors, disease-associated inflammation and undertreatment of traditional cardiovascular disease (CVD) risk factors. Since atherosclerosis is an inflammatory disease, the auto-immune mediated inflammation observed in RA patients contributes to increased endothelial dysfunction, oxidative stress and activation and vascular migration of leukocytes. This concept is underscored by the CVD risk reduction that is seen by anti-inflammatory disease modifying anti-rheumatic drugs such as methotrexate and TNFα inhibitors. The evidence for underdiagnosis and undertreatment of traditional CVD risk factors in RA strengthens the potential benefit of structured CVD risk management in these patients. Current cardiovascular guidelines recommend screening and treatment of CVD risk factors in RA patients, without well defined treatment targets. At present, there is a lack of scientific evidence to establish treatment targets for CVD risk factors in RA. Therefore, expanding research regarding screening and treatment of traditional CVD risk factors in RA patients is needed.     

Cardiovascular disease in patients with rheumatoid arthritis

The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) is 1.5–2-fold higher than age- and sex-matched individuals from the general population. This excess risk is attributed to the systemic chronic inflammation which is a hallmark of RA. Challenges to optimizing CV risk management in RA include the need for improved methods to predict CV risk, and defining the target risk factor(s) to reduce CV risk. Lessons learned from RA studies can also inform CV risk prevention in the general population, where inflammation also has an important role in the pathogenesis of atherosclerosis.     

Relations between autoantibodies against oxidized low-density lipoprotein, inflammation, subclinical atherosclerosis, and cardiovascular disease in rheumatoid arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is associated with an unexplained increased cardiovascular risk. Autoantibodies recognizing oxidized low-density lipoprotein (oxLDL-ab) are associated with atherosclerosis in the general population and have been reported in several autoimmune diseases. We investigated relations between oxLDL-ab, inflammation, subclinical atherosclerosis, and cardiovascular disease (CVD) in patients with RA. METHODS: In a nested case-control study, serum concentrations of oxLDL-ab were measured in 140 RA patients. Ultrasound examination of the carotid artery [i.e., carotid intima-media thickness (CIMT)] was performed in a third of these patients. Correlations were calculated for oxLDL-ab, C-reactive protein (CRP), and high-density lipoprotein (HDL) cholesterol. Regression analyses were used to examine associations between oxLDL-ab and prevalent CVD, and oxLDL-ab and CIMT. RESULTS: OxLDL-ab were positively correlated with CRP (r = 0.33, p < 0.001) and negatively correlated with HDL cholesterol (r = -0.28, p = 0.001). An indication for interaction was found (p = 0.09), suggesting that inflammation modifies the relation between HDL cholesterol and oxLDL-ab. OxLDL-ab were independently associated with intimal thickening, but not associated with prevalent CVD. CONCLUSION: OxLDL-ab were strongly related with the degree of inflammation and may predispose to a higher risk for CVD, as they were independently associated with subclinical atherosclerosis in patients with RA.     

类风湿关节炎心血管病变的研究进展

类风湿关节炎(RA)是临床中常见的自身免疫性疾病,其病因和发病机制复杂多样,具有较高的致残率和死亡率。除了经常引起关节肿胀、压痛外,心脏受累是RA常见的关节外表现,且与RA患者的预后密切相关。与普通人群相比,RA患者发生心血管疾病(CVD)的风险明显升高,从而会进一步增加患者的死亡风险。除了传统的心血管危险因素,如高血压、高脂血症、吸烟、肥胖、糖尿病、慢性肾脏病等外,一些非传统心血管危险因素如炎症、免疫、抗风湿药物的使用等被发现在RA患者的CVD发病中起重要作用。本文对RA患者合并心脏损害的相关临床表现及危险因素等展开综述,旨在为此类患者的诊断和治疗提供一定理论帮助。     

Triggers of Cardiovascular Diseases in Rheumatoid Arthritis

The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) is higher than that in patients without RA, and it is even higher than that in patients with diabetes. Autoimmune-mediated inflammation is observed in patients with RA, resulting in endothelial dysfunction, oxidative stress and activation, and vascular migration of white blood cells. Traditionally, RA-associated CVD was assumed to be mediated by disease-related inflammation, resulting in atherosclerosis (AS). However, this concept has been challenged because treatment with anti-rheumatic drugs, such as methotrexate or proinflammatory cytokine antagonists, such as tumor necrosis factor-alpha (TNF-α) inhibitors, did not reduce the risk of CVD in patients with RA. Current cardiovascular guidelines recommend screening and treatment of CVD risk factors in patients with RA but without clear biomarkers and treatment goals. There is no scientific basis for establishing therapeutic targets for cardiovascular risk factors in RA. Numerous studies have shown that the mechanism of early cardiac dysfunction in patients with RA may occur prior to AS. Therefore, it is crucial to explore the related mechanisms to prevent early cardiac dysfunction in patients with RA.     

Therapy Insight: managing cardiovascular risk in patients with rheumatoid arthritis

Chronic low-grade inflammation was recognized during the past decade as an important risk factor for the development of atherosclerosis and, more recently, for the development of heart failure. Patients with rheumatoid arthritis (RA) are at increased risk of morbidity and mortality from ischemic cardiovascular events and heart failure. Epidemiologic and clinical studies indicate that RA is an independent risk factor for cardiovascular disease, which suggests that chronic exposure to high levels of inflammatory mediators contributes to this enhanced risk. The relative contribution of conventional risk factors to the acceleration of cardiovascular disease does not seem to be increased in patients with RA compared with control populations. Nonetheless, some preclinical laboratory measures of risk factors (e.g. insulin sensitivity) are adversely modulated in the context of the highly inflammatory rheumatoid microenvironment. Discerning the net effect of RA therapies on cardiovascular disease is also challenging because, theoretically, their biologic effects could either promote or attenuate atherosclerosis and ventricular dysfunction; however, available data suggest a beneficial effect on cardiovascular morbidity and mortality in patients with RA. This review provides an overview of the potential influence of RA and its treatment on the development and progression of cardiovascular disease, and outlines some preliminary recommendations for prevention and management of this complication in patients with RA.     

Diabetes mellitus and insulin resistance in patients with rheumatoid arthritis: risk reduction in a chronic inflammatory disease

Objective

To perform a systematic literature review of the potential association among molecular markers of inflammation, alterations in body composition, and insulin resistance (IR), a precursor to type 2 diabetes mellitus (DM), in rheumatoid arthritis (RA) patients. To determine the impact of tumor necrosis factor α (TNFα) as a pivotal proinflammatory cytokine in the pathophysiology of type 2 DM and RA, and the effect of antirheumatic drugs on glycemic control.

Methods

We performed a search of PubMed to identify articles on IR and body habitus in patients with RA.

Results

Patients with RA had characteristics placing them at high risk for IR and type 2 DM. The incidence and prevalence of type 2 DM in RA was not clearly increased compared with the general population; however, studies suggested that patients with RA are likely to have IR and have increased risk of cardiovascular disease (CVD). The prevalence of type 2 DM and IR could be estimated from reports of risk factors for CVD in RA patients. The TNFα antagonists provided rapid and effective control of RA‐related inflammation. Evidence indicated that extended use of TNFα antagonists in RA may provide the additional benefit of improving insulin sensitivity. These treatment‐related changes may contribute to an overall reduction in the risk of type 2 DM and CVD in RA patients.

Conclusion

Controlling inflammation may improve insulin sensitivity and subsequently reduce the risk of developing type 2 DM in RA patients. This may also reduce the risk of CVD in this high‐risk group. Future studies are required to elucidate the relationships between inflammation, body composition, IR, TNFα antagonist use, and the risk of developing type 2 DM in RA patients.     

Atherosclerosis in patients with autoimmune disorders

Recent findings indicate that presence of activated immune competent cells and inflammation are typical of atherosclerosis, the main cause of cardiovascular disease (CVD). The risk of CVD is very high in a prototypic autoimmune disease, systemic lupus erythematosus (SLE), and is also raised in other autoimmune diseases such as rheumatoid arthritis. Autoimmunity-related CVD and atherosclerosis are important clinical problems. They may also shed light on interactions between immune reactions and atherosclerosis development and manifestations, not least in women, who have a much higher risk of autoimmune disease than men. In general, a combination of traditional and nontraditional risk factors, including dyslipidemia (and to a varying degree, hypertension, diabetes, and smoking), inflammation, antiphospholipid antibodies (aPLs), and lipid oxidation, contribute to CVD in autoimmune diseases. Premature atherosclerosis is likely to be a major underlying mechanism, although distinctive features, if any, of autoimmunity-related atherosclerosis compared with "normal" atherosclerosis are not clear. One interesting possibility is that factors such as inflammation, neoepitopes on endothelial cells, or aPLs make atherosclerotic lesions in autoimmune disease more prone to rupture than in "normal" atherosclerosis. Some cases of autoimmunity-related CVD may be more related to thrombosis than atherosclerosis. Whether premature atherosclerosis is a general feature of autoimmune diseases such as SLE or only affects a subgroup of patients whereas others do not have an increased risk remains to be demonstrated. Treatment of patients with autoimmune disease should also include CVD aspects and be focused on traditional risk factors as well as on disease-related factors. Hopefully novel therapeutic principles will be developed that target the causes of the inflammation present in atherosclerotic lesions.     

类风湿关节炎治疗药物对心血管病变影响的研究进展

类风湿关节炎(RA)是一种常见的慢性自身免疫性疾病,各个系统都可受累。RA患者患心血管系统疾病(CVD)的风险要明显高于一般人群,其危险因素包括常见的心血管病变危险因素,如肥胖、高血压、糖尿病及吸烟等,同时亦与RA的慢性炎症、抗风湿药物的应用有关。众多研究表明,抗风湿药物的应用可提高疾病缓解率,但有些药物可能会增加CVD的风险,还有一些不改变或者可降低CVD风险。本文主要综述了治疗RA常用药物对CVD风险的影响,以期为临床用药提供参考。     

Epidemiology of vascular disease in renal failure.

Cardiovascular disease (CVD) is the leading cause of death in the general population and a major cause of morbidity and mortality chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. The high prevalence of CVD in incident dialysis populations suggests that CVD begins during or before the stage of chronic renal insufficiency. While traditional risk factors observed in the general population may play a role in the progression of CVD in CKD and ESRD patients, the presence of several nontraditional factors related to the extent of uremia seems to be the more significant feature of CVD in this patient population. Recently, there have been significant advances in our understanding of how inflammation contributes to the pathogenesis of atherosclerosis and myocardial infarction. The fact that chronic inflammation and CVD are highly prevalent in ESRD patients, it is probable that chronic inflammation may be a causative factor for accelerated atherosclerosis observed in CKD and ESRD patients. Given the extent of the problem, efforts to lower the mortality rate among ESRD patients will require new approaches to reduce and/or prevent cardiovascular morbidity and mortality.     

Cardiovascular Disease Risk in Young People with Type 1 Diabetes

Cardiovascular disease (CVD) is the most frequent cause of death in people with type 1 diabetes (T1D), despite modern advances in glycemic control and CVD risk factor modification. CVD risk identification is essential in this high-risk population, yet remains poorly understood. This review discusses the risk factors for CVD in young people with T1D, including hyperglycemia, traditional CVD risk factors (dyslipidemia, smoking, physical activity, hypertension), as well as novel risk factors such as insulin resistance, inflammation, and hypoglycemia. We present evidence that adverse changes in cardiovascular function, arterial compliance, and atherosclerosis are present even during adolescence in people with T1D, highlighting the need for earlier intervention. The methods for investigating cardiovascular risk are discussed and reviewed. Finally, we discuss the observational studies and clinical trials which have thus far attempted to elucidate the best targets for early intervention in order to reduce the burden of CVD in people with T1D.     

Systemic lupus erythematosus and cardiovascular disease

The prognosis in systemic lupus erythematosus (SLE) has improved due to better treatment and care, but cardiovascular disease (CVD) still remains an important clinical problem, since the risk of CVD in SLE is much higher than among controls. Atherosclerosis is the main cause of CVD in the general population, and in SLE, increased atherosclerosis, especially the prevalence of atherosclerotic plaques, has been demonstrated. Atherosclerosis is an inflammatory condition, where immunity plays an important role. Interestingly, oxidized low-density lipoprotein, defective clearance of dead cells, and inflammation, with a pro-inflammatory T-cell profile are characteristics of both atherosclerosis and SLE. In addition to atherosclerosis as an underlying cause of CVD in SLE, there are also other non–mutually exclusive mechanisms, and the most important of these are antiphospholipid antibodies (aPL) leading to the antiphospholipid antibody syndrome with both arterial and venous thrombosis. aPL can cause direct pro-inflammatory and prothrombotic effects on endothelial and other cells and also interfere with the coagulation, for example, by inhibiting annexin A5 from its antithrombotic and protective effects. Antibodies against phosphorylcholine (anti-PC) and other small lipid-related epitopes, sometimes called natural antibodies, are negatively associated with CVD and atherosclerosis in SLE. Taken together, a combination of traditional risk factors such as hypertension and dyslipidemia, and nontraditional ones, especially aPL, inflammation, and low anti-PC are implicated in the increased risk of CVD in SLE. Close monitoring of both traditional risk factors and nontraditional ones, including treatment of disease manifestations, not lest renal disease in SLE, is warranted.     

Rheumatoid Arthritis Pharmacotherapies: Do They Have Anti-Atherosclerotic Activity?

Rheumatoid arthritis (RA) is associated with a heightened risk of cardiovascular disease (CVD) events, presumably related to a greater burden of atherosclerosis, as well as atherosclerotic plaques that tend to be inflamed and rupture prone. Many of the inflammatory pathways underlying the pathobiology of RA are also recognized contributors to atherosclerosis. Immunomodulation is the mainstay for RA therapy, and a variety of biologic and non-biologic pharmacotherapies are used either singly or in combination to control articular and systemic inflammation and prevent joint destruction. Almost all of these agents have theoretical potential to favorably affect atherogenesis and atherothrombosis, but mechanisms by which they exert effects have been incompletely studied, to date. However, whether clinical control of RA disease activity is associated with a reduction in CVD events regardless of agent used or whether the potency of anti-atherogenic effects varies between disease-modifying anti-rheumatic drugs (DMARDs) is an area of current interest in RA research. More broadly, RA immunotherapies are currently being tested in high-CVD-risk patients in proof-of-concept clinical trials that could alter the paradigm for CVD treatment and prevention in the general population. In this review, we will summarize the current evidence ascribing atheroprotective effects to RA pharmacotherapies.     

Antibodies against oxidized low-density lipoprotein are associated with subclinical atherosclerosis in recent-onset rheumatoid arthritis

Rheumatoid arthritis (RA) patients have increased mortality largely as a result of cardiovascular diseases (CVD) that cannot be explained by traditional risk factors, suggesting that systemic inflammation may accelerate atherosclerosis. We investigated the presence of subclinical atherosclerosis in early RA (<12 months) and the possible association of RA-related risk factors. Forty patients with early RA and 40 controls matched for age, sex, and traditional risk factors for CVD were selected. Carotid US examination, assay of lipogram, C-reactive protein (CRP), and oxidized low-density lipoprotein antibodies (OxLDL-ab) were done. RA patients had significantly higher carotid intima-media thickness (cIMT) values and more plaque than the control (P < 0.001 and P = 0.0122, respectively). CRP and OxLDL-ab were significantly higher in RA patients than controls. Traditional risk factors and RA-related risk factors (disease duration, DAS-28, duration of treatment with steroids, erythrocyte sedimentation rate, and CRP) as well as OxLDL and cIMT were significantly higher in RA with plaques compared to those without plaques. Regression analysis identified the age of patients, CRP, and OxLDL-ab as an independent risk factor associated with the presence of atherosclerosis. Conclusion: there is increased prevalence of carotid plaques in patients with recent-onset RA compared to matched controls. The accelerated atherosclerosis is predicted by age, CRP, and oxLDL-ab. The association of plaques with elevated CRP and OxLDL-ab support the hypothesis that chronic systemic autoimmune inflammatory process is probably a driving force for premature atherosclerosis.     

Clustering of cardiovascular risk factors in rheumatoid arthritis: the rationale for using statins

Atherosclerosis may be more prevalent and more extensive in individuals with rheumatoid arthritis (RA) compared with the general population. Despite the fact that traditional and novel cardiovascular disease (CVD) risk factors are clinically important in these patients, it seems that inflammation--a key feature of RA--plays a crucial role in atherogenesis. Reducing the CVD burden in patients with RA is a more complex process than in the general population, mostly due to inadequate inflammation suppression as well as multiple concomitant drug therapy. Furthermore, there is no current consensus on whether RA patients should be treated as individuals at high-risk for vascular events. Statins have proved their efficacy in reducing CVD events in the general population. Despite the fact that they are not specifically indicated in RA, there is evidence supporting a beneficial effect on CVD risk factors as well as disease activity and progression. The present review considers the traditional and novel as well as the RA-specific CVD risk factors. The current evidence supporting the use of statins in this patient population is also discussed.     

Rheumatoid arthritis and cardiovascular disease

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease affecting approximately 1% of the adult general population. Cardiovascular disease is recognized as the leading cause of death in RA patients, accounting for nearly 40% of their mortality. Patients with RA are at a twofold increased risk for myocardial infarction and stroke, with risk increasing to nearly threefold in patients who have had the disease for 10 years or more. Congestive heart failure appears to be a greater contributor to excess mortality than ischemia. This increased cardiovascular disease risk in RA patients seems to be independent of traditional cardiovascular risk factors. Pathogenic mechanisms include pro-oxidative dyslipidemia, insulin resistance, prothrombotic state, hyperhomocysteinemia, and immune mechanisms such as T-cell activation that subsequently lead to endothelial dysfunction, a decrease in endothelial progenitor cells, and arterial stiffness, which are the congeners of accelerated atherosclerosis observed in RA patients. This paper discusses pathogenic mechanisms, effects of methotrexate, tumor necrosis factor antagonists, steroids, and statins, with a perspective on therapy.     

Atherosclerosis and inflammation: insights from rheumatoid arthritis

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. Presented as Medicine Grand Rounds at the University of Alberta. This review was supported by grants (HL04012 and HL67964) from the National Institutes of Health.