BioMed Research International Volume 2014 (2014), Article ID 367359, 31 pages
Review Article
Cardiovascular Involvement in Autoimmune Diseases
1Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 11001000 Bogotá, Colombia
2Mederi, Hospital Universitario Mayor, Calle 24 No. 29-45, 11001000 Bogotá, Colombia
2Mederi, Hospital Universitario Mayor, Calle 24 No. 29-45, 11001000 Bogotá, Colombia
Received 23 March 2014; Accepted 1 May 2014; Published 22 July 2014
Academic Editor: Miguel A. González-Gay
Copyright © 2014 Jenny Amaya-Amaya et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Autoimmune diseases (AD) represent a broad spectrum of chronic conditions that may afflict specific target organs or multiple systems with a significant burden on quality of life. These conditions have common mechanisms including genetic and epigenetics factors, gender disparity, environmental triggers, pathophysiological abnormalities, and certain subphenotypes. Atherosclerosis (AT) was once considered to be a degenerative disease that was an inevitable consequence of aging. However, research in the last three decades has shown that AT is not degenerative or inevitable. It is an autoimmune-inflammatory disease associated with infectious and inflammatory factors characterized by lipoprotein metabolism alteration that leads to immune system activation with the consequent proliferation of smooth muscle cells, narrowing arteries, and atheroma formation. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and progression of AT. Several risk factors, known as classic risk factors, have been described. Interestingly, the excessive cardiovascular events observed in patients with ADs are not fully explained by these factors. Several novel risk factors contribute to the development of premature vascular damage. In this review, we discuss our current understanding of how traditional and nontraditional risk factors contribute to pathogenesis of CVD in AD.
1. Introduction
Autoimmune diseases (ADs) represent a broad spectrum of chronic conditions that may afflict specific target organs or multiple systems with a significant burden on quality of life. These conditions have common mechanisms including genetic and epigenetic factors, gender disparity, environmental triggers, pathophysiological abnormalities, and certain subphenotypes which are represented by the autoimmune tautology [1–3]. Atherosclerosis (AT) was once considered to be a degenerative disease that was an inevitable consequence of aging. However, research in the last three decades has shown that AT is not degenerative or inevitable. It is an autoimmune-inflammatory disease associated with infectious and inflammatory factors characterized by lipoprotein metabolism alteration that leads to immune system activation with the consequent proliferation of smooth muscle cells, narrowing arteries, and atheroma formation [4]. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and progression of atheromatous lesions [5].
In recent years, many reports have focused on the immunological background of AT, and there is no longer any doubt that it shares several autoimmune pathways [6, 7]. Therefore, it is not surprising to find an accelerated AT in quite a lot of ADs. Several risk factors, known as classic risk factors, have been described since the Framingham heart study. Over time, these lead to endothelial dysfunction, subclinical AT, and cardiovascular (CV) events [8–12]. Interestingly, the excessive CV events observed in patients with ADs are not fully explained by these factors. Several novel risk factors contribute to the development of premature vascular damage. Sarmiento-Monroy et al. [13], based on a model of rheumatoid arthritis (RA), proposed a classification for nontraditional risk factors in ADs, which divided them into genetic determinants, AD-related, and miscellaneous [14, 15]. Therefore, a complex interaction between traditional and disease-specific traits leads to a premature AT process in autoimmunity. All of these pathways may possibly converge into a shared proatherogenic phenotype [16]. While ADs are characterized by a high degree of cardiovascular disease (CVD), there are several subphenotypes such as arterial hypertension (HTN); coronary artery disease (CAD): angina, ischemic heart disease (IHD), and myocardial infarction (MI); congestive heart failure (CHF); peripheral vascular disease (PVD); left ventricular diastolic dysfunction (LVDD); cerebrovascular disease (cerebrovascular accidents (CVAs); transient ischemic attacks (TIAs)); thrombosis: deep vein thrombosis (DVT), pulmonary embolism (PE); and subclinical AT.
In this paper, we discuss our current understanding of how traditional and nontraditional risk factors contribute to pathogenesis of CVD in ADs. It has become evident over the last few years that some ADs are characterized by common pathogenic mechanisms and high rates of morbidity and mortality that are mainly CVD-related. The increased CV mortality in the 3 rheumatic disorders studied the most (i.e., RA, systemic lupus erythematosus (SLE), and antiphospholipid syndrome (APS)) appears to be caused by vascular damage secondary to accelerated AT. However, the burden of CV involvement in other ADs (Sjögren’s syndrome (SS) and systemic sclerosis (SSc)) appears to be lower and it is characterized by specific risk factors in addition to those shared with the general population.
2. Methods
Studies were identified via a MEDLINE search using the following medical subject heading (MeSH) terms: “Arthritis, Rheumatoid” OR “Lupus Erythematosus, Systemic” OR “Antiphospholipid Syndrome” OR “Sjögren’s Syndrome” OR “Scleroderma, Systemic” AND “Cardiovascular Diseases.” Each group was cross-referenced with the following MeSH terms/keywords: “risk factors,” “traditional risk factors,” “classic risk factors,” “nontraditional risk factors,” and “novel risk factors.” Each term was counted for the greatest number of results. Limits regarding language (i.e., English), age (i.e., adults), and humans were taken into account. Assessment for inclusion of studies was done independently by two blinded reviewers (JAA-LMS). Disagreements between them were resolved by consensus using predefined eligibility criteria, from inception up to February 2014.
2.1. Study Selection, Data Extraction, and Quality Assessment
Abstracts and full-text articles were reviewed in search of eligible studies. A study was included if (a) the abstract was available, (b) it contained original data, (c) it used accepted classification criteria for each AD, (d) it measured CV risk factors, and (e) it examined clinical endpoints. Articles were excluded from the analysis if they dealt with juvenile pathologies or were done on animal models. Studies were also excluded if they were reviews or case reports, if they discussed topics not related to CVD in AD, if they did not meet the inclusion criteria, if they had insufficient data, or if they had results that showed lack of statistical significance. Likewise, the two blinded reviewers (JAA, LMS) looked for duplicates, excluded them, and organized selected articles. Only novel and classic risk factors [14, 15] with statistical significance were included.
3. Results
There were 6,324 articles identified in PubMed. Of these, 5,800 were identified as duplicates, lacking data or significant statistical associations. A total of 524 full-text articles were assessed for eligibility. Only 322 articles were included for methodological analysis. Finally, 168 articles that had interpretable data and fulfilled the eligibility criteria were included. Several traditional cardiovascular risk factors such as dyslipidemia, hyperhomocysteinemia, smoking, and T2DM had been reported. Many studies were associated with nontraditional risk factors such as genetic markers, autoantibodies, duration of the diseases, markers of chronic inflammation, polyautoimmunity, and familial autoimmunity. These factors and their associations are depicted in Tables 1, 2, 3, 4, and 5 and in Figures 1 and 2.
Table 1: Traditional and nontraditional risk factors
associated with CVD and RA.
associated with CVD and RA.
Table 2: Traditional and nontraditional risk factors
associated with CVD and SLE.
associated with CVD and SLE.
Table 3: Traditional and nontraditional risk factors
associated with CVD and APS.
associated with CVD and APS.
Table 4: Traditional and nontraditional risk factors
associated with CVD and SS.
associated with CVD and SS.
Table 5: Traditional and nontraditional risk factors
associated with CVD and SSc.
associated with CVD and SSc.
Figure 1: Traditional and nontraditional risk factors for cardiovascular disease in rheumatoid arthritis. AD: autoimmune disease; CVD: cardiovascular disease; IMT: intima-media thickness; RA: rheumatoid arthritis; RF: rheumatoid factor. includes a broad spectrum of subphenotypes: stroke/transient ischemic attack, coronary artery disease, myocardial infarction, angina, congestive heart failure, arrhythmias, ventricular diastolic dysfunction, hypertension, pulmonary embolism, deep vein thrombosis, and peripheral arterial/venous disease. Mainly HLA-DRB10404 shared epitope alleles. The presence of any diagnosed AD in first-degree relatives of proband. The presence of two concomitant AD in a single patient on the basis of international criteria. Rheumatoid factor, anti-cyclic citrullinated peptides antibodies, anti-oxidized low-density lipoprotein, anticardiolipins, anti-phosphorylcholine, anti-modified citrullinated vimentin, anti-apolipoprotein A-1, and anti-cytokeratin 18 antibodies. High levels of c-reactive protein and erythrocyte sedimentation rate. Methotrexate, leflunomide, and nonsteroidal anti-inflammatory drugs. Patients (females and males) with RA working on household duties. von Willebrand factor, plasminogen activator inhibitor-1, and tissue plasminogen activator. Hypothyroidism, periodontal disease, and other markers such as mannose-binding lectin, serum pentraxin 3, osteopontin, osteoprotegerin, and seric uric acid.
Figure 2: Traditional and autoimmune-related mechanisms of cardiovascular disease in systemic lupus erythematosus and antiphospholipid syndrome. A complex interaction between traditional and disease-specific traits leads to premature atherosclerosis process. Several risk factors (left) have been described since the Framingham heart study, known as classic risk factors, which over time conduce to endothelial dysfunction, subclinical atherosclerosis, and CV event manifest. In the autoimmune setting (right), several novel risk factors contribute to development of premature vascular damage. This damage is represented by impaired endothelial function and early increase of intima-media thickness, which are surrogates of the accelerated atherosclerosis process. These associations are even more pronounced in this case of polyautoimmunity (SLE and APS in the same individual), where risk factors have additive effects and atherosclerosis develops earlier. The cornerstone of management of CV risk includes an aggressive treatment of disease activity, the continuous monitoring and treatment of modifiable CV risk factors, and the use of other medications in order to diminish the CV burden. ACE-I: angiotensin-converting enzyme inhibitors; AMs: antimalarials; APS: antiphospholipid syndrome; AT-II blockers: angiotensin II receptor blockers; Auto-Ab: autoantibodies; AZA: azathioprine; CIC: circulating immune complex; CYC: cyclophosphamide; CVD: cardiovascular disease; HDL: high-density lipoprotein; HRT: hormone replacement therapy; IR: insulin resistance; MetS: metabolic syndrome; MMF: mycophenolate mofetil; oxLDL/β2GPI complex: oxidized low-density lipoprotein/2 glycoprotein I; SLE: systemic lupus erythematosus; T2DM: type 2 diabetes mellitus.
3.1. Rheumatoid Arthritis
A broad spectrum of subphenotypes and mortality due to CVD, including stroke, HTN, IHD, intima-media thickness (IMT), CAD, MI, PVD, thrombosis, and LVDD were described in RA, and the general prevalence range is 30%–50% [17–26]. Table 1 shows the main traditional and nontraditional risk factors associated with CVD in RA, and Figure 1 exemplifies these associations.
3.2. Systemic Lupus Erythematosus
CVD is at least doubled among SLE patients compared to other populations and mortality is also increased [27]. CVD burden in SLE includes carotid plaques, MI, angina, CHF, stroke, IMT, PVD, pericarditis, and others discussed below [16, 28–35]. Table 2 shows traditional and nontraditional risk factors associated with CVD in SLE.
3.3. Antiphospholipid Syndrome
The prevalence of CVD ranges from 1.7 to 6%, and it could increase up to 14% in patients with antiphospholipid antibodies (APLA). On the other hand, the prevalence of CVD in asymptomatic AT reaches 15% compared to 9% in SLE patients and 3% in normal controls [36, 37]. In the Euro-Phospholipid cohort, MI was the presenting manifestation in 2.8% of the patients, and it appeared during the evolution of the disease in 5.5% of the cohort [38]. Cardiac manifestations may be found in up to 40%, but significant morbidity appears in only 4–6% of these patients. Most of these manifestations are explicable on the basis of thrombotic lesions either in the coronary circulation or on the valves [39]. Table 3 shows the main traditional and nontraditional risk factors associated with CVD in APS.
3.4. Sjögren’s Syndrome
CV events occurred in 5–7.7% with stroke, MI, CVA, DVT, and arrhythmias [40–44] being the most frequent. Furthermore, tricuspid regurgitation, injured mitral and aortic valves, pulmonary hypertension, and increased left ventricular mass have also been reported [45]. Table 4 shows the main traditional and nontraditional risk factors associated with CVD in SS.
3.5. Systemic Sclerosis
A broad spectrum of subphenotypes and mortality due to CVD have been described. Mortality in patients with SSc caused by CVD is between 20 and 30% and, despite being similar to the general population, it occurs a decade earlier (11). CV symptoms are found in 10% of the SSc patients while asymptomatic patients with coronary artery calcification (CAC) accounted for approximately 33.3% in diffuse SSc and 40% in limited SSc [46–54]. However, Doppler results have shown that 64% of the patients have carotid stenosis, compared to 35% of the control patients [55]. Arrythmias, coronary spasm, MI, PVD, CVA, CAD, LVDD, and myocardial fibrosis [46, 52, 54, 56–60] are also defined. Table 5 shows the main traditional and nontraditional risk factors associated with CVD in SSc.
4. Discussion
This review adds further evidence about high frequency of CVD in patients with ADs and their traditional (i.e., dyslipidemia, abnormal BMI, and male) and nontraditional risk factors (i.e., steroids, household duties, and autoantibodies) [14, 15]. It also highlights the impact on public health and the need to develop new strategies in prediction, prevention, and treatment. Through the review, several factors and outcomes related to CVD were also identified.
4.1. Physiopathology of Atherosclerosis in AD
AT is a multifactorial, chronic, and inflammatory disease that had been traditionally viewed as a lipid-based disorder affecting the vessel walls. Nowadays, this theory has been modified, and it is known that all arms of the immune system take part in atheroma formation. The increased understanding of the mechanisms promoting vascular damage has recently led to a sharper focus on proinflammatory pathways, which appear to play a key role in the development and propagation of the disease. Thus, some of the mechanisms that drive atherosclerotic plaque formation, and therefore CVD, are shared with several ADs although each disease may have particular immunological aberrations that provide specific proatherogenic pathways [5–7, 16, 24, 61–68]. This process is characterized by the accumulation of lipid particles, immune cells, autoantibodies, autoantigens, and the multiple production of inflammatory cytokines such as tumor necrosis factor-α (e.g.,TNF-α). All these components lead to a gradual thickening of the intima layer, thus causing a decrease in elasticity, narrowing of the arterial lumen, reduction of blood flow, plaque rupture, and, finally, the CV event [69, 70]. The systemic inflammatory response that characterizes AT also involves acute-phase reactants such as erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) [71–75].
Endothelial dysfunction is the first step leading to AT and has been associated with both traditional and nontraditional risk factors related to several ADs. Other factors involved are high concentrations of angiotensin II, increased smooth muscle hypertrophy, peripheral resistance, and oxidation of low-density lipoprotein cholesterol (LDL) as well as elevated plasma homocysteine concentrations and genetic alterations [76–78]. Thus, the different forms of injury increase endothelium adhesiveness for leukocytes or platelets as well as endothelium permeability with the expression of multiple vascular cell adhesion molecules (VCAM), intercellular adhesion molecules-1 (ICAM-1), selectins, and chemokines [4, 79, 80]. In addition to their differentiation, macrophages (Mϕ) are associated with upregulation of toll-like receptors, which enhances a cascade of Mϕ activation and release of vasoactive molecules such as nitric oxide (NO), reactive oxygen, endothelins, and proteolytic enzymes. All of them lead to the plaque destabilization and the increased risk for rupture [4, 79, 81–83].
T cells, predominantly lymphocyte T helper 1 (Th1), are also recruited to the subendothelial space. Th1 cells dominate over lymphocyte T helper 2 (Th2) as well as their anti-inflammatory mediators (i.e., IL-4, -5, and -10). This kind of reaction is greater in several ADs with a high production of TNF-α, IL-2, IL-6, IL-17, and so forth, which, in combination, activates T cells even more and favors smooth muscle cell migration, proliferation, and foam cell formation [16, 61, 84, 85]. Furthermore, activated Mϕ express human leukocyte antigen (HLA) II that allows them to present antigens to T lymphocytes. Smooth muscle cells from the lesions also have class II HLA molecules on their surfaces and can also present antigens to T cells such as ox-LDL and heat shock proteins (HSP) 60/65 [4, 61]. The immune regulatory molecule CD40 ligand and its receptor CD40 are expressed by Mϕ, T cells, endothelium, and smooth muscle. Both are upregulated in lesions of AT and thus provide further evidence of immune activation [5, 86]. As ox-LDL is a macromolecule with many potential autoantigens, it is possible that antioxidized low-density lipoprotein antibodies (anti-oxLDL) represent a family of autoantibodies against different autoantigens involved in CVD. Thus, the clinical impact of these autoantibodies might vary. However, there are reports showing that elevated anti-oxLDL titers have been detected in patients with early-onset PVD, severe carotid AT, CHF, CAD, MI, and death [87, 88]. This suggests a proatherogenic role for these autoantibodies and supports a key role for them in the progression of AT [87,89, 90].
Beta-2 glycoprotein-1 (β2GPI) is considered to be an autoantigen in APS. Moreover, it is abundantly expressed within the subendothelial regions and in the intima-media layers at the border of atherosclerotic plaque. Both IgM and IgG anti-β2GPI levels are elevated in patients with AT and other inflammatory conditions [91]. β2GPI is the actual autoantigen for most anticardiolipin antibodies (ACLA), a group of antibodies with procoagulant activity. The association between APLA, AT, and thrombosis can also be seen outside the setting of autoimmunity. Thus, ACLA promote AT by attracting monocytes into the vessel wall and inducing monocyte adherence to endothelial cells. All of this is mediated by adhesion molecules such as ICAM-1, VCAM-1, and E-selectin [7, 92]. The APLA should be considered more than an AT marker since they can enhance AT and are proatherogenic [93, 94]. Likewise, serum from patients with CVD shows a high prevalence of antibodies against HSP60, which mediate lysis of stressed endothelial cells [91, 95, 96].
4.2. Rheumatoid Arthritis
In addition to diarthrodial joints, RA can damage virtually any organ thus leading to potential extra-articular manifestations (EAMs). CVD is considered an EAM and represents the major predictor of poor prognosis and the main cause of death in this population [13, 17, 97, 98]. There is evidence that vascular damage accrual begins prior to the diagnosis of RA and accelerates as the disease progresses. RA patients present with endothelial dysfunction and increased subclinical AT compared to age-matched controls [99–101]. Endothelial function, assessed by brachial artery flow-mediated vasodilation, also worsens with disease duration [102]. The CV mortality is higher in RA and life expectancy of patients with RA is three to ten years less than that of the general population [103, 104]. CVD is known to appear earlier and 3.6 times more frequently than in the general population [70, 98, 105]. Thus, CVD is the leading cause of death for RA patients around the world [106, 107]. Currently, IHD secondary to AT is the most prevalent cause of death associated with CVD in RA patients [108]. Almost all mortality studies have been done on populations of European origin, and there is limited information on other ethnic groups. A meta-analysis of 24 RA mortality studies, published between 1970 and 2005, reported a weighted combined all-cause standardized mortality ratio (meta-SMR) of 1.50 with similar increases in mortality risk apparent from the ratios for IHD (meta-SMR 1.59) and for CVA (meta-SMR 1.52) [109]. RA patients with CVD frequently experience “silent” IHD with no symptoms before a sudden cardiac death. Indeed, sudden cardiac deaths are almost twice as common in patients with RA as in the general population [110]. According to the above, the Rochester Epidemiology Project [100] showed that patients with RA had a greater risk of MI than controls of equivalent age and sex. Recently, Sarmiento-Monroy et al. [13] did a systematic literature review of CVD in the Latin American (LA) population. A wide range of prevalence for CVD has been reported (13.8–80.6%) for this population. The highest prevalence was indicated in Puerto Rican patients (55.9%) by Santiago-Casas et al. [111], while for Brazil [112, 113], Colombia [14, 97, 114, 115], and Argentina [116, 117], a similar prevalence was reported (47.4, 35.1, and 30.5%, resp.). However, the mortality in RA patients has been poorly evaluated in this population. Acosta et al. [118] demonstrated a mortality rate of 5.2% in a six-year follow-up. For both, the most frequent cause of death was CVD in 44.7% and 22.2% of the cases, respectively. Table 1 and Figure 1 give a summary of the main findings related to traditional and nontraditional CVD risk factors in RA patients. In the Colombian population, Amaya-Amaya et al. [14] found that the traditional risk factors including male gender, hypercholesterolemia, and an abnormal body mass index (BMI) were associated with CVD. Nevertheless, the increased prevalence of CV events in RA is not fully explained by these classic risk factors. Both nontraditional RA risk factors and traditional risk factors act together to develop CVD (Figure 1).
Regarding CV risk screening and management, strategies have been developed for the general population and are based on CV risk score calculators such as the Framingham score and the Systematic Coronary Risk Evaluation (SCORE) model, but the accuracy of these models has not been adequately evaluated in inflammatory arthritis [119]. Recent studies have shown that the SCORE underestimates the actual cardiovascular risk of patients with RA. In this regard, a study showed a high frequency of carotid plaques in the group of individuals included in the category of moderate risk according to SCORE risk charts [120]. The major strategy is to develop healthy life styles as a way to maintain control of classical risk factors. Statins can effectively lower total cholesterol in RA patients and significantly improve the rates of CV-related and all-cause mortality when used for primary prevention of vascular events [121, 122]. Similarly, ACE inhibitors and angiotensin II blockers may also have a favorable effect on inflammatory markers and endothelial function in RA [123, 124]. Regarding novel risk factors, it is necessary to establish an adequate management of the disease [19]. The main goal of the treatment should be to reduce the disease activity, and, therefore, decrease the CV burden [124]. Both conventional [125] and biological disease modifying antirheumatic drugs (DMARDs) are used for this purpose. Some studies have shown greater disease control with nonconventional DMARDs such as anti-TNF agents, which lower CRP and IL-6 levels, increase HDL levels, and improve endothelial function [126–129]. Effective treatment may also result in improved physical activity which subsequently leads to a decreased risk of hypertension, obesity, and diabetes, all important determinants of CV disease [127]. The antimalarial (AMs) drugs have been associated with a better CV outcome, enhanced glycemic control, improved lipid profiles, a decreased thrombosis risk, and a reduced probability of developing T2DM in patients with RA [127, 130, 131]. The glucocorticoids (GC) should be used prudently to minimize CV risk secondary to their effects on metabolic parameters and blood pressure. Altogether, there is no clear evidence that low doses of GC contribute significantly to an enhanced CV risk in inflammatory arthritis in contrast to high doses. GCs rapidly and effectively suppress inflammation in RA and their use might be justified for short-term treatment, for example, for “bridging therapy” in the period between initiation and response to DMARD treatment, although the debate does not appear to be settled yet. Therefore, a conservative approach was chosen in which the use of the lowest dose for the shortest period possible was recommended [19, 124, 125, 132]. Reports indicate that anti-TNF is independently associated with a lower CV risk due to the fact that it reduces CV events in young patients by improving the lipid profile, insulin resistance, endothelial function, and aortic compliance and decreasing progression rates of subclinical AT [124, 133–138]. Other biological therapy also produces the same effect. A good example of that was the improvement of endothelial function following rituximab therapy in patients with RA that had been refractory to anti-TNF-alpha drugs [139, 140]. Finally, data about other biologics are conflicting and preliminary; as such, randomized, controlled studies are needed to identify their CV risk reduction role [69, 70].
4.3. Systemic Lupus Erythematosus
SLE occurs most often in young women of child-bearing age, the same population that is at the highest relative risk of subclinical AT [141, 142]. Classically, there is a bimodal mortality pattern among SLE patients with an early peak in the first 3 years after diagnosis due to active disease, infections, and nephritis and a second peak with deaths occurring 4–20 years after SLE diagnosis due to CVD as described by Urowitz et al. [143]. Although the overall mortality rate for SLE patients has improved over the past 30 years, mortality due to CVD (i.e., 3–25%) has remained the same [144–146]. There is strong epidemiologic evidence that CVD risk among SLE patients compared to the general population is at least doubled [27]. Carotid plaque is prevalent in 21% of SLE patients under age 35 and in up to 100% of those over age 65 [147]. The increased risk of MI and angina among SLE patients has been well characterized in a number of population-based studies [146, 148–152]. Bengtsson et al. [152] further corroborated these results in their population-based Swedish study where they demonstrated that the risk of CVA and/or MI in the total SLE population was 1.27-fold higher than that in the general population, but among women with SLE aged 40–49, it was 8-fold higher over the 7-year follow-up period. Several research groups have reported prevalence rates in SLE cohorts. In the Systemic Lupus International Collaborating Clinics-Registry for Atherosclerosis (SLICC-RAS) cohort, there were 8 cases of PVD among 1,249 patients during a 2-year period [153]. In the Lupus in Minorities: Nature versus Nurture study (LUMINA), 5.3% of 637 patients developed PVD over a mean follow-up of 4.4 years [154]. In a recent meta-analysis, Schoenfeld et al. [27] showed that epidemiological data strongly support the hypothesis that SLE patients are at an elevated relative risk of CVD. The variability regarding the relative importance of risk factors for CVD among SLE patients in past epidemiological studies is likely due, in part, to different design methods and different patient and comparison groups. Independent predictive risk factors (from multivariate analysis) for CV events have been assessed in five large prospective cohorts of patients with SLE, including the Baltimore [155], Pittsburg [149], LUMINA [32], Toronto [156], and SLICC-RAS [153] cohorts. The main results are discussed in Table 2 and Figure 2. Diverse SLE cohorts have shown the influence of advanced age, dyslipidemia, obesity, HTN, and hyperhomocysteinemia as classical risk factors for CVD in the lupus population [27,157–159]. There is strong epidemiological evidence that traditional CVD risk factors also elevate CVD risk among SLE patients (Figure 2). Amaya-Amaya et al. [160] recently added further evidence of the high frequency of CVD in 310 consecutive patients with SLE (36.5%). Their findings on traditional risk factors (i.e., dyslipidemia, smoking), plus the confirmation that coffee consumption is another risk factor, showed that, in combination, they contribute to this complication in the LA population. It is well known that while traditional CVD risk factors are undoubtedly important in increasing the CVD risk among SLE patients, these do not fully account for the elevated risk of CVD in this population. Esdaile et al. [161] evaluated risk factors for CAD in two Canadian lupus cohorts by means of the Framingham multiple logistic regression model and found a high risk of developing CAD after removing the influence of these risk factors. Therefore, SLE-associated factors play an important role in the premature AT process characteristic of those patients [70, 162–166]. Hence, there is an increasing interest in identifying novel risk factors that might explain the development of accelerated AT in these populations. The proposal has been made that SLE be managed the same way that T2DM is—as a “CVD equivalent”—with lower lipid goals, more aggressive aspirin use, and potentially more aggressive monitoring [167, 168].
Recent studies have started to address the question of whether traditional treatment regimens may prevent or slow AT in SLE patients [142]. There are several new mechanisms of action described for AMs, many of which have beneficial effects in the management of CV risk in patients with SLE [131, 169]. There is evidence that AM drugs reduce LDL levels, elevate HDL, and, when taken concomitantly with steroids, can reduce TC [170]. In addition, beneficial effects of HCQ on thrombosis formation have also been described [171–174]. Ruiz-Irastorza et al. [175, 176] found that HCQ use conferred a 50–60% decrease in the risk of CVD. Otherwise, the recent randomized controlled Lupus Atherosclerosis Prevention Study by Petri et al. [28] suggests that atorvastatin did not in fact slow progression of subclinical AT in 200 SLE patients over 2 years. However, in other studies, it has been demonstrated that statins do reduce CD40 levels in vivo and in vitro and, therefore, interfere with CD40-CD40 ligand interactions in both SLE and AT [177]. As inflammation is one of the targets of therapy in SLE, several other immunosuppressant drugs and biological therapies currently employed in SLE could also be considered such as potential new antiatherogenic agents [178, 179].
4.4. Antiphospholipid Syndrome
The APS is a prothrombotic state that can affect both the venous and arterial circulations. The deep veins of the lower limbs and cerebral arterial circulation are the most common sites of venous and arterial thrombosis, respectively [180]. The heterogeneity of APS clinical manifestations is likely linked to the varied effects that APLA can induce on endothelial cells [181]. Thrombotic events are the clinical hallmark of APS, occurring in venous and arterial circulations with a high recurrence rate of arterial involvement. They can be expressed as carotid disease, CVA, CAD, and PVD due to thrombus formation or AT [182–188]. Further, other cardiac manifestations may include irregular thickening of the valve leaflets due to deposition of immune complexes that may lead to vegetation and valve dysfunction, which are frequent and may be a significant risk factor for stroke [189–192]. Table 3 and Figure 2 show the main traditional and nontraditional risk factors associated with APS and CVD. Early diagnosis of APS through examination of the heart and aggressive control of all traditional risk factors through lifestyle modifications and pharmacotherapy, probably anti-inflammatory treatment, and close follow-up of APS patients may help to minimize CV risk in these individuals [189, 193]. The APS coagulopathy in these patients requires careful and judicious use of appropriate antiaggregant and anticoagulant therapy [39]. Specifically targeted therapies that exert anti-inflammatory or immunomodulatory effects become important therapeutic tools in APS. In order to achieve beneficial effects, these drugs should primarily antagonize the pathogenic effects of APLA. Moreover, these treatments should also control atheroma, which is one of the major causes of CV mortality in this pathology [177]. For instance, AM drugs may exert evident antiatherogenic properties [168, 194]. Statins also have pleiotropic characteristics, which include antiatherosclerotic (i.e., preventing endothelial dysfunction), anti-inflammatory (i.e., reducing CRP levels), antioxidant, immunomodulatory, and antithrombotic effects [195–200]. Likewise, aspirin has been used in primary and secondary prevention in APS patients particularly for its inhibitory effects on platelet aggregation [201, 202]. In addition to their anticoagulant effects, unfractionated heparins and low molecular weight heparins also have anti-inflammatory properties. Thus, heparins may represent another anti-inflammatory therapeutic tool even though the mechanisms of action responsible for their anti-inflammatory effects are not yet fully understood [203]. Recent improvements in the understanding of the pathogenic mechanisms have led to the identification of novel potential targets and therapies that might be used as new potential immunomodulatory approaches in APS and CVD such as B-cell targeted therapies, complement inhibition, inhibition of costimulation, intracellular pathway inhibition, and anticytokine therapies [204].
4.5. Sjögren’s Syndrome
This is an autoimmune epithelitis that affects the exocrine glands with a functional impairment that usually presents as persistent dryness of the eyes and mouth [205, 206]. Its clinical spectrum extends from an autoimmune exocrinopathy to a systemic involvement with vasculitis and diverse extraglandular systemic manifestations (40–50%). This includes CVD although with lower prevalence as mentioned above [207, 208]. Chronic systemic inflammation is a risk factor for developing AT, however, and contrary to what is expected, the prevalence of CVD associated with AT is not appreciably increased in patients with SS. This probably is characterized by chronic but milder inflammation as Ramos-Casals et al. showed [205]. In fact, Akyel et al. [209] found endothelial dysfunction in SS patients although their carotid IMT was comparable to the healthy control group. It should be noted that the CV risk in patients with SS is rising as a result of the population affected by the disease (i.e., postmenopausal women) [43, 210]. Vaudo et al. [211] found a high rate of subclinical AT due to changes in the carotid arterial wall studied/seen by femoral and carotid ultrasonography. All these findings (i.e., Table 4) suggest that a functional impairment of the arterial wall may sustain early phases of atherosclerotic damage in SS. A combined effect of disease-related chronic inflammatory and immunological factors appears to support dysfunction of endothelium and vascular smooth muscle cells, respectively. Table 4 contains the most frequent traditional and nontraditional risk factors related to CVD and SS. The management of CVD in SS patients must be directed toward rigorous intervention of modifiable risk factors as well as nontraditional risk factors, warranting a routine evaluation of autoantibodies and other SS-related factors. Pérez-De-Lis et al. [210] found a protective role of AMs in CVD and SS patients since these drugs show an association with a lower frequency of HTN, T2DM, and dyslipidemia. So, in the future, it will be necessary to analyze the incidence of CVD and the role of the different risk factors listed in Table 4prospectively for the development of such complications.
4.6. Systemic Sclerosis
There are two major disease presentations: the microvascular and macrovascular involvement. The vasculopathy of SSc typically affects the small arteries and capillaries (i.e., microvascular occlusive disease with vasospasm and intimal proliferation) while macrovascular disease has been demonstrated by carotid ultrasonography, ankle brachial blood pressure index, and peripheral angiography [48, 50, 52] due to fibrosis, thickening, and chronic proliferation of the intimal layer as well as transmural lymphocytic infiltrate without evidence of atherosclerotic plaque [48, 53]. However, recently, the evidence has demonstrated increased atherosclerosis, including CAC, higher prevalence of subclinical CAD, and higher carotid IMT [46, 212]. Patchy fibrosis is the most important feature in the myocardium, especially when it is localized in subendocardial regions. This fibrosis usually accompanies LVDD [59, 60], but it is symptomatic in 10% of the cases [213]. There have been reported MI or myocardial perfusion defects with coronary arteries which suggests that the etiology of infarction may be due to microvascular disease rather than coronary AT although we must recognize that the latter is higher in patients with SSc [214, 215]. Patients with SSc have a reduced coronary flow reserve [216, 217], which is associated with higher coronary events [218, 219]. Other authors have reported ectasia, spasm, and coronary artery stenosis [56, 57]. Arrhythmias and conduction disturbances are characteristic of cardiac involvement in SSc as hypertrophy and heart failure contractility [58, 60] have been reported. Ultrasonography evaluation is also used to evaluate the carotid arteries and has been proven to be a useful marker for the assessment of subclinical AT and a strong predictor of subsequent MI and CVA [77, 216,220]. In addition, once SSc has been diagnosed and established, attention to treatment of the vascular component is critical. While the traditional approach has been solely to use vasodilator therapy, new investigations are underway to develop novel therapies, to prevent further vascular injury, and to stimulate vascular repair. Some of the current treatment approaches include the following: prostacyclin analogs, endothelin antagonists, phosphodiesterase inhibitors, immunosuppressive therapy, and tyrosine kinase inhibitors [221].
4.7. Spondyloarthropathies
Since spondyloarthropathies are also chronic autoimmune-autoinflammatory diseases associated with accelerated atherosclerosis, the patients with spondyloarthropathies also have a higher risk of cardiovascular disease than the general population. Ankylosing spondylitis has been associated with increased mortality rate compared to the general population, which is, in great part, the result of cardiovascular complications. Also, subclinical atherosclerosis, manifested by the presence of endothelial dysfunction and increased carotid intima-media wall thickness and carotid plaques, has been observed in patients with psoriatic arthritis and ankylosing spondylitis. In patients with ankylosing spondylitis, TNF-alpha blockade was associated with improvement of insulin resistance, markers of metabolic syndrome, and biomarkers of endothelial dysfunction [222–232].
5. Conclusions
AT and ADs share several mechanisms. The excessive CV events observed in patients with ADs are not fully explained by classic risk factors. Several novel risk factors contribute to development of premature vascular damage. Therefore, a complex interaction between traditional and disease-specific traits converges into a shared proatherogenic phenotype in this population. Until additional research and disease-specific risk prediction tools are available, current evidence supports aggressive treatment of disease activity and careful screening for and management of modifiable traditional risk factors in patients with ADs. The finding and understanding of complex interactions between predisposing factors (i.e., genetic, environmental factors, and ADs per se) will allow us to better describe and assess the broad spectrum of CV subphenotypes in ADs and their treatments.
Conflict of Interests
The authors have indicated that they have no conflict of interests regarding the content of this paper.
Acknowledgments
The authors thank their colleagues at the Center for Autoimmune Diseases Research (CREA), for fruitful discussions. This work was supported by the School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
References
[1] J.-M. Anaya, A. Rojas-Villarraga, and M. Garc´ıa-Carrasco, “The
autoimmune tautology: from polyautoimmunity and familial
autoimmunity to the autoimmune genes,” Autoimmune Diseases,
vol. 2012, Article ID 297193, 2 pages, 2012. [2] J. M. Anaya, J. Castiblanco, A. Rojas-Villarraga et al., “The multiple autoimmune syndromes. A clue for the autoimmune tautology,” Clinical Reviews in Allergy and Immunology, vol. 43, no. 3, pp. 256–264, 2012.
[3] J-M. Anaya, “The diagnosis and clinical significance of polyautoimmunity,” Autoimmunity Reviews, vol. 13, no. 4-5, pp. 423– 426, 2014.
[4] G. K. Hansson, I. Kriszbacher, M. Koppan, and J. B ´ odis, ´ “Inflammation, atherosclerosis, and coronary artery disease,” The New England Journal of Medicine, vol. 352, pp. 1685–1695, 2005.
[5] C. Blasi, “The autoimmune origin of atherosclerosis,” Atherosclerosis, vol. 201, no. 1, pp. 17–32, 2008.
[6] R. R. S. Packard, A. H. Lichtman, and P. Libby, “Innate and adaptive immunity in atherosclerosis,” Seminars in Immunopathology, vol. 31, no. 1, pp. 5–22, 2009.
[7] L. J. Jara, G. Medina, O. Vera-Lastra, and M.-C. Amigo, “Accelerated atherosclerosis, immune response and autoimmune rheumatic diseases,” Autoimmunity Reviews, vol. 5, no. 3, pp. 195–201, 2006.
[8] C. Gonzalez-Juanatey, J. Llorca, J. Martin, and M. A. GonzalezGay, “Carotid intima-media thickness predicts the development of cardiovascular events in patients with rheumatoid arthritis,” Seminars in Arthritis and Rheumatism, vol. 38, no. 5, pp. 366– 371, 2009.
[9] H. M. M. S. Ahmed, M. Youssef, and Y. M. Mosaad, “Antibodies against oxidized low-density lipoprotein are associated with subclinical atherosclerosis in recent-onset rheumatoid arthritis,” Clinical Rheumatology, vol. 29, no. 11, pp. 1237–1243, 2010.
[10] A. Karrar, W. Sequeira, and J. A. Block, “Coronary artery disease in systemic lupus erythematosus: a review of the literature,” Seminars in Arthritis and Rheumatism, vol. 30, no. 6, pp. 436– 443, 2001.
[11] J. J. Belch, S. McSwiggan, and C. Lau, “Macrovascular disease in systemic sclerosis: the tip of an iceberg?” Rheumatology, vol. 47, supplement 5, pp. v16–v17, 2008.
[12] R. Gerli, G. Vaudo, E. B. Bocci et al., “Functional impairment of the arterial wall in primary Sjogren’s syndrome: Combined ¨ action of immunologic and inflammatory factors,” Arthritis Care and Research, vol. 62, no. 5, pp. 712–718, 2010.
[13] J. C. Sarmiento-Monroy, J. Amaya-Amaya, JS. Espinosa-Serna, C. Herrera-D´ıaz, J. M. Anaya, and A. Rojas-Villarraga, “Cardiovascular disease in rheumatoid arthritis: a systematic literature review in latin america,” Arthritis, vol. 2012, Article ID 371909, 17 pages, 2012.
[14] J. Amaya-Amaya, J. C. Sarmiento-Monroy, R. Mantilla, R. Pineda-Tamayo, A. Rojas-Villarraga, and J. M. Anaya, “Novel risk factors for cardiovascular disease in rheumatoid arthritis,” Immunologic Research, vol. 56, no. 2-3, pp. 267–286, 2013.
[15] J. Amaya-Amaya, J. C. Sarmiento-Monroy, J. Caro-Moreno et al., “Cardiovascular disease in latin American patients with systemic lupus erythematosus: a cross-sectional study and a systematic review,” Autoimmune Diseases, vol. 2013, Article ID 794383, 20 pages, 2013.
[16] J. M. Kahlenberg and M. J. Kaplan, “Mechanisms of premature atherosclerosis in rheumatoid arthritis and lupus,” Annual Review of Medicine, vol. 64, pp. 249–263, 2013.
[17] A. Sandoo, J. J. C. S. Veldhuijzen van Zanten, G. S. Metsios, D. Carroll, and G. D. Kitas, “Vascular function and morphology in rheumatoid arthritis: a systematic review.,” Rheumatology, vol. 50, no. 11, pp. 2125–2139, 2011.
[18] S. Corrao, S. Messina, G. Pistone, L. Calvo, R. Scaglione, and G. Licata, “Heart involvement in Rheumatoid Arthritis: Systematic review and meta-analysis,” International Journal of Cardiology, vol. 167, no. 5, pp. 2031–2038, 2013.
[19] C. S. Crowson, K. P. Liao, J. M. Davis III et al., “Rheumatoid arthritis and cardiovascular disease,” American Heart Journal, vol. 166, no. 4, pp. 622.e1–628.e1, 2013.
[20] E. A. R. Khan, L. K. Stamp, J. L. O’Donnell, and P. T. Chapman, “Cardiovascular morbidity in rheumatoid arthritis patients in North Canterbury, New Zealand 1999–2008,” International Journal of Rheumatic Diseases, vol. 16, no. 1, pp. 19–23, 2013.
[21] M. Holmqvist, E. Gransmark, ¨ A. Mantel et al., “Occurrence and ¨ relative risk of stroke in incident and prevalent contemporary rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 72, no. 4, pp. 541–546, 2013.
[22] K. Yiu, M. Mok, S. Wang et al., “Prognostic role of coronary calcification in patients with rheumatoid arthritis and systemic lupus erythematosus,” Clinical and Experimental Rheumatology, vol. 30, no. 3, pp. 345–350, 2012.
[23] C. D. Popa, E. Arts, J. Fransen, and P. L. C. M. van Riel, “Atherogenic index and high-density lipoprotein cholesterol as cardiovascular risk determinants in rheumatoid arthritis: the impact of therapy with biologicals,” Mediators of Inflammation, vol. 2012, Article ID 785946, 9 pages, 2012.
[24] A. Solomon, G. R. Norton, A. J. Woodiwiss, and P. H. Dessein, “Obesity and carotid atherosclerosis in African black and Caucasian women with established rheumatoid arthritis: a crosssectional study,” Arthritis Research and Therapy, vol. 14, no. 2, article R67, 2012.
[25] H. G. Raterman, H. Levels, A. E. Voskuyl, W. F. Lems, B. A. Dijkmans, and M. T. Nurmohamed, “HDL protein composition alters from proatherogenic into less atherogenic and proinflammatory in rheumatoid arthritis patients responding to rituximab,” Annals of the Rheumatic Diseases, vol. 72, no. 4, pp. 560–565, 2013.
[26] A. M. van Sijl, K. van den Hurk, M. J. L. Peters et al., “Different type of carotid arterial wall remodeling in rheumatoid arthritis compared with healthy subjects: a case-control study,” The Journal of Rheumatology, vol. 39, no. 12, pp. 2261–2266, 2012.
[27] S. R. Schoenfeld, S. Kasturi, and K. H. Costenbader, “The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review,” Seminars in Arthritis and Rheumatism, vol. 43, no. 1, pp. 77–95, 2013.
[28] M. A. Petri, A. N. Kiani, W. Post, L. Christopher-Stine, and L. S. Magder, “Lupus atherosclerosis prevention study (LAPS),” Annals of the Rheumatic Diseases, vol. 70, no. 5, pp. 760–765, 2011.
[29] L. S. Magder and M. Petri, “Incidence of and risk factors for adverse cardiovascular events among patients with systemic lupus erythematosus,” The American Journal of Epidemiology, vol. 176, no. 8, pp. 708–719, 2012.
[30] A. N. Kiani, J. Vogel-Claussen, L. S. Magder, and M. Petri, “Noncalcified coronary plaque in systemic lupus erythematosus,” Journal of Rheumatology, vol. 37, no. 3, pp. 579–584, 2010. 18 BioMed Research International
[31] L. V. Scalzi, C. S. Hollenbeak, and L. Wang, “Racial disparities in age at time of cardiovascular events and cardiovascular-related death in patients with systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 62, no. 9, pp. 2767–2775, 2010.
[32] S. M. A. Toloza, A. G. Uribe, G. McGwin Jr. et al., “Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXIII. Baseline predictors of vascular events,” Arthritis and Rheumatism, vol. 50, no. 12, pp. 3947–3957, 2004.
[33] Z. Touma, D. D. Gladman, D. Ibanez, and M. B. Urowitz, “Ability ˜ of non-fasting and fasting triglycerides to predict coronary artery disease in lupus patients,” Rheumatology, vol. 51, no. 3, Article ID ker339, pp. 528–534, 2012.
[34] C. W. L. Chin, C.-Y. Chin, M. X. R. Ng et al., “Endothelial function is associated with myocardial diastolic function in women with systemic lupus erythematosus,” Rheumatology International. In press.
[35] T. A. Gheita, H. A. Raafat, S. Sayed, H. El-Fishawy, M. M. Nasrallah, and E. Abdel-Rasheed, “Metabolic syndrome and insulin resistance comorbidity in systemic lupus erythematosus—effect on carotid intima-media thickness,” Zeitschrift fur Rheumatologie, vol. 72, pp. 172–177, 2013.
[36] P. G. Vlachoyiannopoulos and M. Samarkos, “Peripheral vascular disease in antiphospholipid syndrome,” Thrombosis Research, vol. 114, no. 5-6, pp. 509–519, 2004.
[37] S. Bucciarelli, R. Cervera, G. Espinosa, J. A. Gomez-Puerta, ´ M. Ramos-Casals, and J. Font, “Mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors,” Autoimmunity Reviews, vol. 6, no. 2, pp. 72–75, 2006. [38] R. Cervera, J. Piette, J. Font et al., “Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients,” Arthritis and Rheumatism, vol. 46, no. 4, pp. 1019–1027, 2002. [39] R. Cervera, “Coronary and valvular syndromes and antiphospholipid antibodies,” Thrombosis Research, vol. 114, no. 5-6, pp. 501–507, 2004. [40] H-J. Haga, E. M. Jacobsen, and E. Peen, “Incidence of thromboembolic events in patients with primary Sjogren’s syndrome,” ¨ Scandinavian Journal of Rheumatology, vol. 37, no. 2, pp. 127– 129, 2008. [41] S. G. Pasoto, H. P. Chakkour, R. R. Natalino et al., “Lupus anticoagulant: a marker for stroke and venous thrombosis in primary Sjogren’s syndrome,” ¨ Clinical Rheumatology, vol. 31, no. 9, pp. 1331–1338, 2012. [42] M. Ramos-Casals, P. Brito-Zeron, A. Sis ´ o, A. Vargas, E. Ros, ´ and A. Bove, “High prevalence of serum metabolic alterations in primary Sjogren’s syndrome: influence on clinical and immuno- ¨ logical expression,” Journal of Rheumatology, vol. 34, pp. 754– 761, 2007. [43] B. M. Lodde, V. Sankar, M. R. Kok, R. A. Leakan, P. P. Tak, and S. R. Pillemer, “Adult heart block is associated with disease activity in primary Sjogren’s syndrome,” ¨ Scandinavian Journal of Rheumatology, vol. 34, no. 5, pp. 383–386, 2005. [44] J. Kang and H. Lin, “Comorbidities in patients with primary Sjogren’s syndrome: a registry-based case-control study,” ¨ Journal of Rheumatology, vol. 37, no. 6, pp. 1188–1194, 2010. [45] V. A. Vassiliou, I. Moyssakis, K. A. Boki, and H. M. Moutsopoulos, “Is the heart affected in primary Sjogren’s syndrome? An ¨ echocardiographic study,” Clinical and Experimental Rheumatology, vol. 26, no. 1, pp. 109–112, 2008. [46] S. Guiducci, R. Giacomelli, and M. M. Cerinic, “Vascular complications of scleroderma,” Autoimmunity Reviews, vol. 6, no. 8, pp. 520–523, 2007. [47] S. Guiducci, O. Distler, J. H. Distler, and M. Matucci-Cerinic, “Mechanisms of vascular damage in SSc—implications for vascular treatment strategies,” Rheumatology, vol. 47, supplement 5, pp. v18–v20, 2008. [48] U. Nussinovitch and Y. Shoenfeld, “Atherosclerosis and macrovascular involvement in systemic sclerosis: myth or reality,” Autoimmunity Reviews, vol. 10, no. 5, pp. 259–266, 2011. [49] M. Y. Mok, C. S. Lau, S. S. H. Chiu et al., “Systemic sclerosis is an independent risk factor for increased coronary artery calcium deposition,” Arthritis and Rheumatism, vol. 63, no. 5, pp. 1387– 1395, 2011. [50] M. Turiel, L. Gianturco, C. Ricci et al., “Silent cardiovascular involvement in patients with diffuse systemic sclerosis: a controlled cross-sectional study,” Arthritis Care and Research, vol. 65, no. 2, pp. 274–280, 2013. [51] L. Chung, O. Distler, L. Hummers, E. Krishnan, and V. Steen, “Vascular disease in systemic sclerosis,” International Journal of Rheumatology, vol. 2010, Article ID 714172, 2 pages, 2010. [52] C.-H. Chiang, C.-J. Liu, C.-C. Huang et al., “Systemic sclerosis and risk of ischaemic stroke: a nationwide cohort study,” Rheumatology, vol. 52, no. 1, Article ID kes352, pp. 161–165, 2013. [53] M. E. Hettema, D. Zhang, K. de Leeuw et al., “Early atherosclerosis in systemic sclerosis and its relation to disease or traditional risk factors,” Arthritis Research & Therapy, vol. 10, no. 2, article R49, 2008. [54] S.-Y. Chu, Y.-J. Chen, C.-J. Liu et al., “Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study,” The American Journal of Medicine, vol. 126, pp. 982–988, 2013. [55] M. Ho, D. Veale, C. Eastmond, G. Nuki, and J. Belch, “Macrovascular disease and systemic sclerosis,” Annals of the Rheumatic Diseases, vol. 59, no. 1, pp. 39–43, 2000. [56] E. Tarek, A. E. Yasser, and T. Gheita, “Coronary angiographic findings in asymptomatic systemic sclerosis,” Clinical Rheumatology, vol. 25, no. 4, pp. 487–490, 2006. [57] W. Grassi, P. D. Medico, F. Izzo, and C. Cervini, “Microvascular involvement in systemic sclerosis: capillaroscopic findings,” Seminars in Arthritis and Rheumatism, vol. 30, no. 6, pp. 397– 402, 2001. [58] Y. Allanore, C. Meune, and A. Kahan, “Systemic sclerosis and cardiac dysfunction: evolving concepts and diagnostic methodologies,” Current Opinion in Rheumatology, vol. 20, no. 6, pp. 697–702, 2008. [59] A. D’Andrea, S. Stisi, P. Caso et al., “Associations between left ventricular myocardial involvement and endothelial dysfunction in systemic sclerosis: noninvasive assessment in asymptomatic patients,” Echocardiography, vol. 24, no. 6, pp. 587–597, 2007. [60] A. Kahan, G. Coghlan, and V. McLaughlin, “Cardiac complications of systemic sclerosis,” Rheumatology, vol. 48, supplement 3, pp. iii45–iii48, 2009. [61] F. K. Swirski and M. Nahrendorf, “Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure,” Science, vol. 339, no. 6116, pp. 161–166, 2013. [62] M. Scotece, J. Conde, R. Gomez et al., “Role of adipokines ´ in atherosclerosis: interferences with cardiovascular complications in rheumatic diseases,” Mediators Inflamm, vol. 2012, Article ID 125458, 14 pages, 2012. [63] E. Profumo, M. Di Franco, B. Buttari et al., “Biomarkers of subclinical atherosclerosis in patients with autoimmune disorders,” Mediators of Inflammation, vol. 2012, Article ID 503942, 8 pages, 2012. BioMed Research International 19 [64] N. S. Wade and A. S. Major, “The problem of accelerated atherosclerosis in systemic lupus erythematosus: insights into a complex co-morbidity,” Thrombosis and Haemostasis, vol. 106, no. 5, pp. 849–857, 2011. [65] G. Wick, M. Knoflach, and Q. Xu, “Autoimmune and inflammatory mechanisms in atherosclerosis,” Annual Review of Immunology, vol. 22, pp. 361–403, 2004. [66] E. Matsuura, “Atherosclerosis and autoimmunity.,” Clinical Reviews in Allergy & Immunology, vol. 37, no. 1, pp. 1–3, 2009. [67] I. del Rincon, D. H. O’Leary, G. L. Freeman, and A. Escalante, ´ “Acceleration of atherosclerosis during the course of rheumatoid arthritis,” Atherosclerosis, vol. 195, no. 2, pp. 354–360, 2007. [68] P. A. Gordon, J. George, M. A. Khamashta, D. Harats, G. Hughes, and Y. Shoenfeld, “Atherosclerosis and autoimmunity,” Lupus, vol. 10, no. 4, pp. 249–252, 2001. [69] Y. Sherer and Y. Shoenfeld, “Mechanisms of disease: atherosclerosis in autoimmune diseases,” Nature Clinical Practice Rheumatology, vol. 2, no. 2, pp. 99–106, 2006. [70] J. Frostegard, “Atherosclerosis in patients with autoimmune ˚ disorders,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, pp. 1776–1785, 2005. [71] M. Nikpour, P. J. Harvey, D. Ibanez, D. D. Gladman, and M. B. Urowitz, “High-sensitivity C-reactive protein as a marker of cardiovascular risk in systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 64, no. 9, pp. 3052–3053, 2012. [72] S. G. O’Neill, D. A. Isenberg, and A. Rahman, “Could antibodies to C-reactive protein link inflammation and cardiovascular disease in patients with systemic lupus erythematosus?” Annals of the Rheumatic Diseases, vol. 66, no. 8, pp. 989–991, 2007. [73] B. Galarraga, F. Khan, P. Kumar, T. Pullar, and J. J. F. Belch, “C-reactive protein: the underlying cause of microvascular dysfunction in rheumatoid arthritis,” Rheumatology, vol. 47, no. 12, pp. 1780–1784, 2008. [74] K. Maksimowicz-McKinnon, L. S. Magder, and M. Petri, “Predictors of carotid atherosclerosis in systemic lupus erythematosus,” Journal of Rheumatology, vol. 33, no. 12, pp. 2458–2463, 2006. [75] M. A. Gonzalez-Gay, C. Gonzalez-Juanatey, A. Pineiro, C. ˜ Garcia-Porrua, A. Testa, and J. Llorca, “High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis,” The Journal of Rheumatology, vol. 32, no. 7, pp. 1219–1223, 2005. [76] A. Mart´ınez-Berriotxoa, G. Ruiz-Irastorza, M. V. Egurbide, M. Rueda, and C. Aguirre, “Homocysteine, antiphospholipid antibodies and risk of thrombosis in patients with systemic lupus erythematosus,” Lupus, vol. 13, no. 12, pp. 927–933, 2004. [77] F. Bartoli, C. Angotti, C. Fatini et al., “Angiotensin-converting enzyme I/D polymorphism and macrovascular disease in systemic sclerosis,” Rheumatology, vol. 46, no. 5, pp. 772–775, 2007. [78] L. Rodr´ıguez-Rodr´ıguez, R. Lopez-Mej ´ ´ıas, M. Garc´ıaBermudez, C. Gonz ´ alez-Juanatey, M. A. Gonz ´ alez-Gay, ´ and J. Mart´ın, “Genetic markers of cardiovascular disease in rheumatoid arthritis,” Mediators of Inflammation, vol. 2012, Article ID 574817, 14 pages, 2012. [79] S.-H. Kim, C.-K. Lee, E. Y. Lee et al., “Serum oxidized lowdensity lipoproteins in rheumatoid arthritis,” Rheumatology International, vol. 24, no. 4, pp. 230–233, 2004. [80] R. Lopez-Mej ´ ´ıas, F. Genre, C. Gonzalez-Juanatey, and M. A. ´ Gonzalez-Gay, “Autoantibodies and biomarkers of endothelial ´ cell activation in atherosclerosis,” Vasa, vol. 43, no. 2, pp. 83–85, 2014. [81] S. Sayols-Baixeras, C. Llu´ıs-Ganella, G. Lucas, and R. Elosua, “Pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants,” The Application of Clinical Genetics, vol. 7, pp. 15–32, 2014. [82] R. Ross, “Atherosclerosis—an inflammatory disease,” The New England Journal of Medicine, vol. 340, no. 2, pp. 115–126, 1999. [83] C. Lopez-Pedrera, C. P ´ erez-S ´ anchez, M. Ramos-Casals, M. ´ Santos-Gonzalez, A. Rodriguez-Ariza, and M. Jose Cuadrado, ´ “Cardiovascular risk in systemic autoimmune diseases: epigenetic mechanisms of immune regulatory functions,” Clinical and Developmental Immunology, vol. 2012, Article ID 974648, 10 pages, 2012. [84] M. Ferenc´ık, V. Stvrtinova, and I. Hul ´ ´ın, “Defects in regulation of local immune responses resulting in atherosclerosis,” Clinical and Developmental Immunology, vol. 12, pp. 225–234, 2005. [85] E. E. Emeson, M. Shen, C. G. H. Bell, and A. Qureshi, “Inhibition of atherosclerosis in CD4 T-cell-ablated and nude (nu/nu) C57BL/6 hyperlipidemic mice,” The American Journal of Pathology, vol. 149, no. 2, pp. 675–685, 1996. [86] M. Garc´ıa-Bermudez, C. Gonz ´ alez-Juanatey, R. L ´ opez-Mej ´ ´ıas et al., “Study of association of CD40-CD154 gene polymorphisms with disease susceptibility and cardiovascular risk in Spanish rheumatoid arthritis patients,” PLoS ONE, vol. 7, p. e49214, 2012. [87] Y. Sherer, A. Tenenbaum, S. Praprotnik et al., “Coronary artery disease but not coronary calcification is associated with elevated levels of cardiolipin, beta-2-glycoprotein-I, and oxidized LDL antibodies,” Cardiology, vol. 95, no. 1, pp. 20–24, 2001. [88] T. Inoue, T. Uchida, H. Kamishirado, K. Takayanagi, and S. Morooka, “Antibody against oxidized low density lipoprotein may predict progression or regression of atherosclerotic coronary artery disease,” Journal of the American College of Cardiology, vol. 37, no. 7, pp. 1871–1876, 2001. [89] A. O. Santos, F. A. H. Fonseca, S. M. Fischer, C. M. C. Monteiro, S. A. B. Brandao, and R. M. S. P ˜ ovoa, “High circulating autoan- ´ tibodies against human oxidized low-density lipoprotein are related to stable and lower titers to unstable clinical situation,” Clinica Chimica Acta, vol. 406, pp. 113–118, 2009. [90] J. Che, G. Li, W. Wang et al., “Serum autoantibodies against human oxidized low-density lipoproteins are inversely associated with severity of coronary stenotic lesions calculated by Gensini score,” Cardiology Journal, vol. 18, no. 4, pp. 364–370, 2011. [91] E. Matsuura, K. Kobayashi, K. Inoue, L. R. Lopez, and Y. Shoenfeld, “Oxidized LDL/𝛽2-glycoprotein I complexes: New aspects in atherosclerosis,” Lupus, vol. 14, no. 9, pp. 736–741, 2005. [92] A. Gurlek, C. Ozd ¨ ol, G. Pamir, I. Dinc ¨ ¸er, H. Tutkak, and D. Oral, “Association between anticardiolipin antibodies and recurrent cardiac events in patients with acute coronary syndrome,” International Heart Journal, vol. 46, pp. 631–638, 2005. [93] B. Nowak, M. Szmyrka-Kaczmarek, A. Durazinska et al., ´ “Anti-Ox-LDL antibodies and anti-Ox-LDL-B2GPI antibodies in patients with systemic lupus erythematosus,” Advances in Clinical and Experimental Medicine, vol. 21, no. 3, pp. 331–335, 2012. [94] E. Cucurull, L. R. Espinoza, E. Mendez, J. F. Molina, J. Ordi-Ros, and A. E. Gharavi, “Anticardiolipin and anti-𝛽2glycoproteinI antibodies in patients with systemic lupus erythematosus: comparison between Colombians and Spaniards,” Lupus, vol. 8, no. 2, pp. 134–141, 1999. [95] M. Dieude, J. A. Correa, C. Neville et al., “Association of ´ autoantibodies to heat-shock protein 60 with arterial vascular 20 BioMed Research International events in patients with antiphospholipid antibodies,” Arthritis and Rheumatism, vol. 63, no. 8, pp. 2416–2424, 2011. [96] H. Zinger, Y. Sherer, and Y. Shoenfeld, “Atherosclerosis in autoimmune rheumatic diseases-mechanisms and clinical findings,”Clinical Reviews in Allergy & Immunology, vol. 37, no. 1, pp. 20–28, 2009. [97] A. Rojas-Villarraga, O. Ortega-Hernandez, L. F. Gomez et al., “Risk factors associated with different stages of atherosclerosis in Colombian patients with rheumatoid arthritis,” Seminars in Arthritis and Rheumatism, vol. 38, no. 2, pp. 71–82, 2008. [98] A. N. DeMaria, “Relative risk of cardiovascular events in patients with rheumatoid arthritis,” The American Journal of Cardiology, vol. 89, no. 6, pp. 33D–38D, 2002. [99] S. Hannawi, B. Haluska, T. H. Marwick, and R. Thomas, “Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation,” Arthritis Research and Therapy, vol. 9, article R116, 2007. [100] D. P. M. Symmons and S. E. Gabriel, “Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE,” Nature Reviews Rheumatology, vol. 7, no. 7, pp. 399–408, 2011. [101] C. Gonzalez-Juanatey, J. Llorca, A. Testa, J. Revuelta, C. Garcia-Porrua, and M. A. Gonzalez-Gay, “Increased prevalence of severe subclinical atherosclerotic findings in long-term treated rheumatoid arthritis patients without clinically evident atherosclerotic disease,” Medicine, vol. 82, no. 6, pp. 407–413, 2003. [102] C. Gonzalez-Juanatey, J. Llorca, and M. A. Gonz ´ alez-Gay, “Cor- ´ relation between endothelial function and carotid atherosclerosis in rheumatoid arthritis patients with long-standing disease,” Arthritis Research & Therapy, vol. 13, no. 3, article R101, 2011. [103] V. R. da Cunha, C. V. Brenol, J. C. T. Brenol, and R. M. Xavier, “Rheumatoid arthritis and metabolic syndrome,” Revista Brasileira de Reumatologia, vol. 51, no. 3, pp. 260–268, 2011. [104] M. Cisternas, M. A. Gutierrez, J. Klaassen, A. M. Acosta, and S. ´ Jacobelli, “Cardiovascular risk factors in Chilean patients with rheumatoid arthritis,” Journal of Rheumatology, vol. 29, no. 8, pp. 1619–1622, 2002. [105] P. Sarzi-Puttini, F. Atzeni, R. Gerli et al., “Cardiac involvement in systemic rheumatic diseases: an update,” Autoimmunity Reviews, vol. 9, no. 12, pp. 849–852, 2010. [106] M. Chan, “Global status report on noncommunicable diseases,” World Heal Organ, 2010. [107] D. Yach, C. Hawkes, C. L. Gould, and K. J. Hofman, “The global burden of chronic diseases: overcoming impediments to prevention and control,” The Journal of the American Medical Association, vol. 291, no. 21, pp. 2616–2622, 2004. [108] D. H. Solomon, E. W. Karlson, E. B. Rimm et al., “Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis,” Circulation, vol. 107, no. 9, pp. 1303–1307, 2003. [109] J. A. Avina-Zubieta, H. K. Choi, M. Sadatsafavi, M. Etminan, J. ˜ M. Esdaile, and D. Lacaille, “Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies,” Arthritis Care and Research, vol. 59, no. 12, pp. 1690–1697, 2008. [110] H. Maradit-Kremers, C. S. Crowson, P. J. Nicola et al., “Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study,” Arthritis and Rheumatism, vol. 52, no. 2, pp. 402–411, 2005. [111] Y. Santiago-Casas, T. Gonzalez-Rivera, L. Castro-Santana, G. R´ıos, and V. Rodr´ıguez, “Impact of age on clinical manifestations and outcome in Puerto Ricans with rheumatoid arthritis,” Ethnicity & Disease, vol. 20, no. 1, supplement 1, pp. S1–S195, 2010. [112] I. Pereira, I. Laurindo, R. Burlingame et al., “Auto-antibodies do not influence development of atherosclerotic plaques in rheumatoid arthritis,” Joint Bone Spine, vol. 75, no. 4, pp. 416– 421, 2008. [113] V. R. da Cunha, C. V. Brenol, J. C. T. Brenol et al., “Metabolic syndrome prevalence is increased in rheumatoid arthritis patients and is associated with disease activity,” Scandinavian Journal of Rheumatology, vol. 41, no. 3, pp. 186–191, 2012. [114] R. Pineda-Tamayo, G. Arcila, P. Restrepo, and J. M. Anaya, “Impact of cardiovascular illness on hospitalization costs in patients with rheumatoid arthritis,” Biomedica, vol. 24, no. 4, pp. 366–374, 2004. [115] O. D. Ortega-Hernandez, R. Pineda-Tamayo, A. L. Pardo, A. Rojas-Villarraga, and J. M. Anaya, “Cardiovascular disease is associated with extra-articular manifestations in patients with rheumatoid arthritis,” Clinical Rheumatology, vol. 28, no. 7, pp. 767–775, 2009. [116] M. Larroude and A. Romanowicz, “Artritis reumatoidea y aterosclerosis,” Revista Argentina de Reumatolog´ıa, vol. 14, pp. 16–24, 2003. [117] C. Lascano, P. Alba, C. Gobbi et al., “Disfuncion diast ´ olica ´ ventricular izquierda en la artritis reumatoidea,” Revista de la Facultad de Ciencias Medicas, vol. 66, pp. 58–65, 2009. [118] R. R. Acosta, C. Castell, M. Hernandez, and A. Pernas, “Comorbilidad y mortalidad en una cohorte de pacientes cubanos con artritis reumatoide,” Revista Cubana de Medicina, vol. 48, pp. 1–12, 2009. [119] C. Gomez-Vaquero, A. Corrales, A. Zacarias et al., “SCORE and REGICOR function charts underestimate the cardiovascular risk in Spanish patients with rheumatoid arthritis,” Arthritis Research & Therapy, vol. 15, article R91, 2013. [120] A. Corrales, C. Gonzalez-Juanatey, ME. Peir ´ o, R. Blanco, ´ J. Llorca, and M. A. Gonzalez-Gay, “Carotid ultrasound is ´ useful for the cardiovascular risk stratification of patients with rheumatoid arthritis: results of a population-based study,” Annals of the Rheumatic Diseases, vol. 73, pp. 722–727, 2014. [121] X. Sheng, M. J. Murphy, T. M. MacDonald, and L. Wei, “Effectiveness of statins on total cholesterol and cardiovascular disease and all-cause mortality in osteoarthritis and rheumatoid arthritis,” Journal of Rheumatology, vol. 39, no. 1, pp. 32–40, 2012. [122] M. A. De Vera, H. Choi, M. Abrahamowicz, J. Kopec, and D. Lacaille, “Impact of statin discontinuation on mortality in patients with rheumatoid arthritis: a population-based study,” Arthritis Care and Research, vol. 64, no. 6, pp. 809–816, 2012. [123] A. J. Flammer, I. Sudano, F. Hermann et al., “Angiotensinconverting enzyme inhibition improves vascular function in rheumatoid arthritis,” Circulation, vol. 117, no. 17, pp. 2262–2269, 2008. [124] M. J. L. Peters, D. P. M. Symmons, D. McCarey et al., “EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis,” Annals of the Rheumatic Diseases, vol. 69, no. 2, pp. 325–331, 2010. [125] F. Atzeni, M. Turiel, R. Caporali et al., “The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases,” Autoimmunity Reviews, vol. 9, no. 12, pp. 835–839, 2010. BioMed Research International 21 [126] W. G. Dixon, K. D. Watson, M. Lunt et al., “Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor 𝛼 therapy: results from the British Society for Rheumatology Biologics Register,” Arthritis and Rheumatism, vol. 56, no. 9, pp. 2905– 2912, 2007. [127] V. P. van Halm, M. T. Nurmohamed, J.W. R. Twisk, B. A. C. Dijkmans, and A. E. Voskuyl, “Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study,” Arthritis Research and Therapy, vol. 8, article R151, 2006. [128] H. K. Choi, M. A. Hernan, J. D. Seeger, J. M. Robins, and F. ´ Wolfe, “Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study,” Lancet, vol. 359, pp. 1173–1177, 2002. [129] A. B. Reiss, S. E. Carsons, K. Anwar et al., “Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages,” Arthritis & Rheumatism, vol. 58, no. 12, pp. 3675–3683, 2008. [130] G. J. Pons-Estel, G. S. Alarcon, L. Hachuel et al., “Anti-malarials ´ exert a protective effect while mestizo patients are at increased risk of developing SLE renal disease: data from a LatinAmerican cohort,” Rheumatology, vol. 51, no. 7, pp. 1293–1298, 2012. [131] I. Ben-Zvi, S. Kivity, P. Langevitz, and Y. Shoenfeld, “Hydroxychloroquine: from malaria to autoimmunity,” Clinical Reviews in Allergy and Immunology, vol. 42, no. 2, pp. 145–153, 2012. [132] M. A. Mart´ın-Mart´ınez, C. Gonzalez-Juanatey, S. Casta ´ neda et ˜ al., “Recommendations for the management of cardiovascular risk in patients with rheumatoid arthritis: scientific evidence and expert opinion,” Seminars in Arthritis and Rheumatism, 2014. [133] Z. Al-Aly, H. Pan, A. Zeringue et al., “Tumor necrosis factor-𝛼 blockade, cardiovascular outcomes, and survival in rheumatoid arthritis,” Translational Research, vol. 157, no. 1, pp. 10–18, 2011. [134] L.-S. Tam, G. D. Kitas, and M. A. Gonzalez-Gay, “Can sup- ´ pression of inflammation by anti-TNF prevent progression of subclinical atherosclerosis in inflammatory arthritis?” Rheumatology, 2014. [135] M. A. Gonzalez-Gay, J. M. de Matias, C. Gonzalez-Juanatey et al., “Anti-tumor necrosis factor-𝛼 blockade improves insulin resistance in patients with rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 24, no. 1, pp. 83–86, 2006. [136] M. A. Gonzales-Gay, M. T. Garcia-Unzueta, J. M. de Matias et al., “Influence of anti-TNF-𝛼 infliximab therapy on adhesion molecules associated with atherogenesis in patients with rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 24, no. 4, pp. 373–379, 2006. [137] C. Gonzalez-Juanatey, J. Llorca, A. Sanchez Andrade, C. GarciaPorrua, J. Martin, and M. A. Gonzalez-Gay, “Short-term adalimumab therapy improves endothelial function in patients with rheumatoid arthritis refractory to infliximab,” Clinical and Experimental Rheumatology, vol. 24, no. 3, pp. 309–312, 2006. [138] C. Gonzalez-Juanatey, T. R. Vazquez-Rodriguez, J. A. MirandaFilloy et al., “Anti-TNF-alpha-adalimumab therapy is associated with persistent improvement of endothelial function without progression of carotid intima-media wall thickness in patients with rheumatoid arthritis refractory to conventional therapy,” Mediators of Inflammation, vol. 2012, Article ID 674265, 8 pages, 2012. [139] O. Schultz, F. Oberhauser, J. Saech et al., “Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (A) levels in human subjects with rheumatoid diseases,” PLoS ONE, vol. 5, no. 12, Article ID e14328, 2010. [140] C. Gonzalez-Juanatey, J. Llorca, T. R. Vazquez-Rodriguez, N. Diaz-Varela, H. Garcia-Quiroga, and M. A. Gonzalez-Gay, “Short-term improvement of endothelial function in rituximabtreated rheumatoid arthritis patients refractory to tumor necrosis factor 𝛼 blocker therapy,” Arthritis Care and Research, vol. 59, no. 12, pp. 1821–1824, 2008. [141] S. G. Guerra, T. J. Vyse, and D. S. C. Graham, “The genetics of lupus: a functional perspective,” Arthritis Research & Therapy, vol. 14, no. 3, article 211, 2012. [142] J. R. Elliott and S. Manzi, “Cardiovascular risk assessment and treatment in systemic lupus erythematosus,” Best Practice and Research: Clinical Rheumatology, vol. 23, no. 4, pp. 481–494, 2009. [143] M. B. Urowitz, A. A. M. Bookman, B. E. Koehler, D. A. Gordon, H. A. Smythe, and M. A. Ogryzlo, “The bimodal mortality pattern of systemic lupus erythematosus,”The American Journal of Medicine, vol. 60, no. 2, pp. 221–225, 1976. [144] L. Bjorn ¨ adal, L. Yin, F. Granath, L. Klareskog, and A. Ekbom, ˚ “Cardiovascular disease a hazard despite improved prognosis in patients with systemic lupus erythematosus: results from a Swedish population based study 1964–95,” Journal of Rheumatology, vol. 31, no. 4, pp. 713–719, 2004. [145] P. Solteszz, G. Kerekes, H. D ´ er et al., “Comparative assess- ´ ment of vascular function in autoimmune rheumatic diseases: considerations of prevention and treatment,” Autoimmunity Reviews, vol. 10, pp. 416–425, 2011. [146] M. M. Ward, “Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 42, pp. 338–346, 1999. [147] T. Thompson, K. Sutton-Tyrrell, R. P. Wildman et al., “Progression of carotid intima-media thickness and plaque in women with systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 58, no. 3, pp. 835–842, 2008. [148] B. Zoller, X. Li, J. Sundquist, and K. Sundquist, “Risk of subse- ¨ quent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden,” BMC Neurology, vol. 12, article 41, 2012. [149] S. Manzi, E. N. Meilahn, J. E. Rairie et al., “Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham study,” The American Journal of Epidemiology, vol. 145, no. 5, pp. 408–415, 1997. [150] L. M. Fischer, R. G. Schlienger, C. Matter, H. Jick, and C. R. Meier, “Effect of rheumatoid arthritis or systemic lupus erythematosus on the risk of First-Time acute myocardial infarction,” American Journal of Cardiology, vol. 93, no. 2, pp. 198–200, 2004. [151] A. E. Hak, E. W. Karlson, D. Feskanich, M. J. Stampfer, and K. H. Costenbader, “Systemic lupus erythematosus and the risk of cardiovascular disease: results from the nurses’ health study,” Arthritis Care and Research, vol. 61, no. 10, pp. 1396–1402, 2009. [152] C. Bengtsson, M.-L. Ohman, O. Nived, and S. R. Rantap ¨ a¨a¨ Dahlqvist, “Cardiovascular event in systemic lupus erythematosus in northern Sweden: incidence and predictors in a 7-year follow-up study,” Lupus, vol. 21, no. 4, pp. 452–459, 2012. [153] M. B. Urowitz, D. Gladman, D. Ibanez et al., “Atherosclerotic ˜ vascular events in a multinational inception cohort of systemic 22 BioMed Research International lupus erythematosus,” Arthritis Care and Research, vol. 62, no. 6, pp. 881–887, 2010. [154] P. I. Burgos, L. M. Vila, J. D. Reveille, and G. S. Alarc ´ on, ´ “Peripheral vascular damage in systemic lupus erythematosus: data from LUMINA, a large multi-ethnic U.S. cohort (LXIX).,” Lupus, vol. 18, no. 14, pp. 1303–1308, 2009. [155] M. Petri, S. Perez-Gutthann, D. Spence, and M. C. Hochberg, “Risk factors for coronary artery disease in patients with systemic lupus erythematosus,” The American Journal of Medicine, vol. 93, no. 5, pp. 513–519, 1992. [156] M. B. Urowitzx, D. Ibanez, and D. D. Gladman, “Atherosclerotic ˜ vascular events in a single large lupus cohort: prevalence and risk factors,” Journal of Rheumatology, vol. 34, no. 1, pp. 70–75, 2007. [157] J. Gustafsson, I. Gunnarsson, O. Borjesson et al., “Predictors ¨ of the first cardiovascular event in patients with systemic lupus erythematosus—a prospective cohort study,” Arthritis Research & Therapy, vol. 11, no. 6, article R186, 2009. [158] E. Svenungsson, K. Jensen-Urstad, M. Heimburger et al., “Risk ¨ factors for cardiovascular disease in systemic lupus erythematosus,” Circulation, vol. 104, no. 16, pp. 1887–1893, 2001. [159] M. J. Roman, J. E. Salmon, R. Sobel et al., “Prevalence and relation to risk factors of carotid atherosclerosis and left ventricular hypertrophy in systemic lupus erythematosus and antiphospholipid antibody syndrome,” American Journal of Cardiology, vol. 87, no. 5, pp. 663–666, 2001. [160] J. Amaya-Amaya, JC. Sarmiento-Monroy, J. Caro-Moreno et al., “Cigarette smoking and coffee consumption independently influence the risk of developing cardiovascular disease in systemic lupus erythematosus,” Lupus, vol. 22, no. 164, 2013. [161] J. M. Esdaile, M. Abrahamowicz, T. Grodzicky et al., “Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus,” Arthritis & Rheumatology, vol. 44, no. 10, pp. 2331–2337, 2001. [162] P. E.Westerweel, R. K. M. A. C. Luyten, H. A. Koomans, R. H.W. M. Derksen, and M. C. Verhaar, “Premature atherosclerotic cardiovascular disease in systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 56, no. 5, pp. 1384–1396, 2007. [163] E. Y. Rhew and R. Ramsey-Goldman, “Premature atherosclerotic disease in systemic lupus erythematosus: role of inflammatory mechanisms,” Autoimmunity Reviews, vol. 5, no. 2, pp. 101–105, 2006. [164] M. McMahon, B. H. Hahn, and B. J. Skaggs, “Systemic lupus erythematosus and cardiovascular disease: prediction and potential for therapeutic intervention,” Expert Review of Clinical Immunology, vol. 7, no. 2, pp. 227–241, 2011. [165] M. Nikpour, M. B. Urowitz, and D. D. Gladman, “Premature atherosclerosis in systemic lupus erythematosus,” Rheumatic Disease Clinics of North America, vol. 31, no. 2, pp. 329–354, 2005. [166] L. E. Full, C. Ruisanchez, and C. Monaco, “The inextricable link between atherosclerosis and prototypical inflammatory diseases rheumatoid arthritis and systemic lupus erythematosus.,” Arthritis research & therapy, vol. 11, no. 2, p. 217, 2009. [167] J. R. Elliott, S. Manzi, and D. Edmundowicz, “The role of preventive cardiology in systemic lupus erythematosus,” Current Rheumatology Reports, vol. 9, no. 2, pp. 125–130, 2007. [168] I. N. Bruce, “Cardiovascular disease in lupus patients: Should all patients be treated with statins and aspirin?” Best Practice and Research: Clinical Rheumatology, vol. 19, no. 5, pp. 823–838, 2005. [169] S. J. Katz and A. S. Russell, “Re-evaluation of antimalarials in treating rheumatic diseases: re-appreciation and insights into new mechanisms of action,” Current Opinion in Rheumatology, vol. 23, no. 3, pp. 278–281, 2011. [170] S. J. Morris, M. C. M. Wasko, J. L. Antohe et al., “Hydroxychloroquine use associated with improvement in lipid profiles in rheumatoid arthritis patients,” Arthritis Care & Research, vol. 63, no. 4, pp. 530–534, 2011. [171] R. Kaiser, C. M. Cleveland, and L. A. Criswell, “Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort,” Annals of the Rheumatic Diseases, vol. 68, no. 2, pp. 238–241, 2009. [172] H. Jung, R. Bobba, J. Su et al., “The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 62, no. 3, pp. 863–868, 2010. [173] M. Petri, “Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients,” Current Rheumatology Reports, vol. 13, no. 1, pp. 77–80, 2011. [174] G. S. Alarcon, G. McGwin, A. M. Bertoli et al., “Effect of ´ hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L),” Annals of the Rheumatic Diseases, vol. 66, no. 9, pp. 1168–1172, 2007. [175] G. Ruiz-Irastorza, M. V. Egurbide, J. I. Pijoan et al., “Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus,” Lupus, vol. 15, no. 9, pp. 577– 583, 2006. [176] M. Nikpour, M. B. Urowitz, D. Ibanez, P. J. Harvey, and D. D. Gladman, “Importance of cumulative exposure to elevated cholesterol and blood pressure in development of atherosclerotic coronary artery disease in systemic lupus erythematosus: a prospective proof-of-concept cohort study,” Arthritis Research & Therapy, vol. 13, article R156, 2011. [177] C. C. Belizna, V. Richard, C. Thuillez, H. Levesque, and Y. ´ Shoenfeld, “Insights into atherosclerosis therapy in antiphospholipid syndrome,”Autoimmunity Reviews, vol. 7, no. 1, pp. 46– 51, 2007. [178] M. J. Roman, B.-A. Shanker, A. Davis et al., “Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus,” The New England Journal of Medicine, vol. 349, no. 25, pp. 2399–2406, 2003. [179] S. M. Greenstein, S. Sun, T. M. Calderon et al., “Mycophenolate mofetil treatment reduces atherosclerosis in the cholesterol-fed rabbit,” Journal of Surgical Research, vol. 91, no. 2, pp. 123–129, 2000. [180] B. Giannakopoulos and S. A. Krilis, “The pathogenesis of the antiphospholipid syndrome,” The New England Journal of Medicine, vol. 368, no. 11, pp. 1033–1044, 2013. [181] F. Tenedios, D. Erkan, and M. D. Lockshin, “Cardiac involvement in the antiphospholipid syndrome,” Lupus, vol. 14, no. 9, pp. 691–696, 2005. [182] L. J. Jara, G. Medina, and O. Vera-Lastra, “Systemic antiphospholipid syndrome and atherosclerosis,” Clinical Reviews in Allergy and Immunology, vol. 32, no. 2, pp. 172–177, 2007. [183] A. Tufano, A. Guida, M. N. D. Di Minno, A. M. De Gregorio, A. M. Cerbone, and G. Di Minno, “Cardiovascular events in patients with antiphospholipid antibodies: Strategies of prevention,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 20, no. 4, pp. 217–223, 2010. BioMed Research International 23 [184] P. J. Levy, C. F. Cooper, and M. F. Gonzalez, “Massive lower extremity arterial thrombosis and acute hepatic insufficiency in a young adult with premature atherosclerosis associated with hyperlipoprotein(a)emia and antiphospholipid syndrome: a case report,” Angiology, vol. 46, no. 9, pp. 853–858, 1995. [185] C. K. Shortell, K. Ouriel, R. M. Green, J. J. Condemi, and J. A. DeWeese, “Vascular disease in the antiphospholipid syndrome: a comparison with the patient population with atherosclerosis,” Journal of Vascular Surgery, vol. 15, no. 1, pp. 158–166, 1992. [186] O. Vaarala, M. Mantt ¨ ari, V. Manninen et al., “Anti-cardiolipin ¨ antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men,” Circulation, vol. 91, no. 1, pp. 23–27, 1995. [187] Y. Sherer and Y. Shoenfeld, “Antiphospholipid syndrome, antiphospholipid antibodies, and atherosclerosis,” Current atherosclerosis Reports, vol. 3, no. 4, pp. 328–333, 2001. [188] A. Bili, A. J. Moss, C. W. Francis, W. Zareba, L. F. M. Watelet, and I. Sanz, “Anticardiolipin antibodies and recurrent coronary events: a prospective study of 1150 patients,”Circulation, vol. 102, no. 11, pp. 1258–1263, 2000. [189] P. Soltesz, Z. Szekanecz, E. Kiss, and Y. Shoenfeld, “Cardiac ´ manifestations in antiphospholipid syndrome,” Autoimmunity Reviews, vol. 6, no. 6, pp. 379–386, 2007. [190] I. Koniari, S. N. Siminelakis, N. G. Baikoussis, G. Papadopoulos, J. Goudevenos, and E. Apostolakis, “Antiphospholipid syndrome; its implication in cardiovascular diseases: a review,” Journal of Cardiothoracic Surgery, vol. 5, no. 1, article 101, 2010. [191] M. Turiel, S. Muzzupappa, B. Gottardi, C. Crema, P. SarziPuttini, and E. Rossi, “Evaluation of cardiac abnormalities and embolic sources in primary antiphospholipid syndrome by transesophageal echocardiography,” Lupus, vol. 9, no. 6, pp. 406–412, 2000. [192] V. A. P. Hegde, Y. Vivas, H. Shah et al., “Cardiovascular surgical outcomes in patients with the antiphospholipid syndrome—a case-series,” Heart Lung and Circulation, vol. 16, no. 6, pp. 423– 427, 2007. [193] Y. Shoenfeld, R. Gerli, A. Doria et al., “Accelerated atherosclerosis in autoimmune rheumatic diseases,” Circulation, vol. 112, no. 21, pp. 3337–3347, 2005. [194] R. G. Espinola, S. S. Pierangeli, A. E. Ghara, and E. N. Harris, “Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies,” Thrombosis & Haemostasis, vol. 87, no. 3, pp. 518–522, 2002. [195] C. Lopez-Pedrera, P. Ruiz-Limon, A. Valverde-Estepa, N. Bar- ´ barroja, and A. Rodriguez-Ariza, “To cardiovascular disease and beyond: New therapeutic perspectives of statins in autoimmune diseases and cancer,” Current Drug Targets, vol. 13, no. 6, pp. 829–841, 2012. [196] P. L. Meroni, E. Raschi, C. Testoni et al., “Statins prevent endothelial cell activation induced by antiphospholipid (antibeta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype,” Arthritis & Rheumatology, vol. 44, pp. 2870–2878, 2001. [197] S. Dunoyer-Geindre, B. R. Kwak, G. Pelli et al., “Immunization of LDL receptor-deficient mice with beta2-glycoprotein 1 or human serum albumin induces a more inflammatory phenotype in atherosclerotic plaques,” Thrombosis and Haemostasis, vol. 97, no. 1, pp. 129–138, 2007. [198] U. Laufs, V. La Fata, J. Plutzky, and J. K. Liao, “Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors,” Circulation, vol. 97, no. 12, pp. 1129–1135, 1998. [199] I. N. Bruce, “Cardiovascular disease in lupus patients: should all patients be treated with statins and aspirin?” Best Practice and Research: Clinical Rheumatology, vol. 19, no. 5, pp. 823–838, 2005. [200] E. C. Jury and M. R. Ehrenstein, “Statins: immunomodulators for autoimmune rheumatic disease?” Lupus, vol. 14, no. 3, pp. 192–196, 2005. [201] S. Dunoyer-Geindre, E. K. O. Kruithof, F. Boehlen, N. SattaPoschung, G. Reber, and P. de Moerloose, “Aspirin inhibits endothelial cell activation induced by antiphospholipid antibodies,” Journal of Thrombosis and Haemostasis, vol. 2, no. 7, pp. 1176–1181, 2004. [202] N. Grosser and H. Schroder, “Aspirin protects endothelial cells ¨ from oxidant damage via the nitric oxide-cGMP pathway,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 23, no. 8, pp. 1345–1351, 2003. [203] S. Baldus, V. Rudolph, M. Roiss et al., “Heparins increase endothelial nitric oxide bioavailability by liberating vesselimmobilized myeloperoxidase,” Circulation, vol. 113, no. 15, pp. 1871–1878, 2006. [204] C. Comarmond and P. Cacoub, “Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies,” Autoimmunity Reviews, vol. 12, no. 7, pp. 752–757, 2013. [205] M. Ramos-Casals, A. G. Tzioufas, and J. Font, “Primary Sjogren’s syndrome: new clinical and therapeutic concepts,” ¨ Annals of the Rheumatic Diseases, vol. 64, no. 3, pp. 347–354, 2005. [206] S. S. Kassan and H. M. Moutsopoulos, “Clinical manifestations and early diagnosis of Sjogren syndrome,” ¨ Archives of Internal Medicine, vol. 164, no. 12, pp. 1275–1284, 2004. [207] A. L. Fauchais, B. Ouattara, G. Gondran, F. Lalloue, D. Petit, and ´ K. Ly, “Articular manifestations in primary Sjogren’s syndrome: ¨ clinical significance and prognosis of 188 patients,” Rheumatology, vol. 49, pp. 1164–1172, 2010. [208] M. Ramos-Casals, P. Brito-Zeron, and J. Font, “The overlap of ´ Sjogren’s syndrome with other systemic autoimmune diseases,” ¨ Seminars in Arthritis and Rheumatism, vol. 36, no. 4, pp. 246– 255, 2007. [209] A. Akyel, Y. Tavil, C. Yayla et al., “Endothelial dysfunction in primary Sjogren syndrome,” ¨ West Indian Medical Journal, vol. 61, pp. 61–870, 2012. [210] M. Perez-De-Lis, M. Akasbi, A. Sis ´ o et al., “Cardiovascular risk ´ factors in primary Sjogren’s syndrome: a case-control study in ¨ 624 patients,” Lupus, vol. 19, pp. 941–948, 2010. [211] G. Vaudo, E. B. Bocci, Y. Shoenfeld et al., “Precocious intimamedia thickening in patients with primary Sjogren’s syndrome,” ¨ Arthritis & Rheumatism, vol. 52, no. 12, pp. 3890–3897, 2005. [212] K. Au, M. K. Singh, V. Bodukam et al., “Atherosclerosis in systemic sclerosis: a systematic review and meta-analysis,” Arthritis and Rheumatism, vol. 63, no. 7, pp. 2078–2090, 2011. [213] M. R. Akram, C. E. Handler, M. Williams et al., “Angiographically proven coronary artery disease in scleroderma,” Rheumatology, vol. 45, no. 11, pp. 1395–1398, 2006. [214] V. Khurma, C. Meyer, G. S. Park, M. McMahon, J. Lin, and R. R. Singh, “A pilot study of subclinical coronary atherosclerosis in systemic sclerosis: coronary artery calcification in cases and controls,” Arthritis and Rheumatology, vol. 59, pp. 591–597, 2008. [215] A. Kahan and Y. Allanore, “Primary myocardial involvement in systemic sclerosis,” Rheumatology, vol. 45, supplement 4, pp. iv14–iv17, 2006. 24 BioMed Research International [216] F. Bartoli, J. Blagojevic, M. Bacci et al., “Flow-mediated vasodilation and carotid intima-media thickness in systemic sclerosis,” Annals of the New York Academy of Sciences, vol. 1108, pp. 283– 290, 2007. [217] R. Montisci, A. Vacca, P. Garau et al., “Detection of early impairment of coronary flow reserve in patients with systemic sclerosis,” Annals of the Rheumatic Diseases, vol. 62, no. 9, pp. 890–893, 2003. [218] G. Szucs, O. T ¨ ´ımar, Z. Szekanecz et al., “Endothelial dysfunction ´ precedes atherosclerosis in systemic sclerosis—relevance for prevention of vascular complications,” Rheumatology, vol. 46, no. 5, pp. 759–762, 2007. [219] M. E. Hettema, H. Bootsma, and C. G. M. Kallenberg, “Macrovascular disease and atherosclerosis in SSc,” Rheumatology, vol. 47, no. 5, pp. 578–583, 2008. [220] Y. Sherer, M. M. Cerinic, F. Bartoli et al., “Early atherosclerosis and autoantibodies to heat-shock proteins and oxidized LDL in systemic sclerosis,” Annals of the New York Academy of Sciences, vol. 1108, pp. 259–267, 2007. [221] M. Matucci-Cerinic, B. Kahaleh, and F. M. Wigley, “Review: evidence that systemic sclerosis is a vascular disease,” Arthritis and Rheumatism, vol. 65, no. 8, pp. 1953–1962, 2013. [222] F. Genre, J. A. Miranda-Filloy, R. Lopez-Mejias et al., “Anti- ´ tumour necrosis factor-𝛼 therapy modulates angiopoietin-2 serum levels in non-diabetic ankylosing spondylitis patients,” Annals of the Rheumatic Diseases, vol. 72, no. 7, pp. 1265–1267, 2013. [223] F. Genre, R. Lopez-Mej ´ ´ıas, J. A. Miranda-Filloy et al., “Asymmetric dimethylarginine serum levels in non-diabetic ankylosing spondylitis patients undergoing TNF-𝛼 antagonist therapy,” Clinical and Experimental Rheumatology, vol. 31, no. 5, pp. 749– 755, 2013. [224] F. Genre, R. Lopez-Mej ´ ´ıas, J. A. Miranda-Filloy et al., “Correlation between two biomarkers of atherosclerosis, osteopontin and angiopoietin-2, in non-diabetic ankylosing spondylitis patients undergoing TNF-𝛼 antagonist therapy,” Clinical and Experimental Rheumatology, vol. 32, no. 2, pp. 231–236, 2014. [225] F. Genre, R. Lopez-Mej ´ ´ıas, J. A. Miranda-Filloy, B. CarneroLopez, I. G ´ omez-Acebo, and R. Blanco, “Correlation between ´ insulin resistance and serum ghrelin in non-diabetic ankylosing spondylitis patients undergoing anti-TNF-𝛼 therapy,” Clinical and Experimental Rheumatology, vol. 31, pp. 913–918, 2013. [226] F. Genre, R. Lopez-Mej ´ ´ıas, J. A. Miranda-Filloy, B. Ubilla, B. Carnero-Lopez, and I. G ´ omez-Acebo, “Antitumour necrosis ´ factor a treatment reduces retinol-binding protein 4 serum levels in non-diabetic ankylosing spondylitis patients,” Annals of the Rheumatic Diseases, vol. 73, pp. 941–943, 2014. [227] J. A. Miranda-Filloy, J. Llorca, B. Carnero-Lopez, C. Gonz ´ alez- ´ Juanatey, R. Blanco, and M. A. Gonzalez-Gay, “TNF-alpha ´ antagonist therapy improves insulin sensitivity in non-diabetic ankylosing spondylitis patients,” Clinical and Experimental Rheumatology, vol. 30, no. 6, pp. 850–855, 2012. [228] C. Gonzalez-Juanatey, T. R. Vazquez-Rodriguez, J. A. MirandaFilloy et al., “The high prevalence of subclinical atherosclerosis in patients with ankylosing spondylitis without clinically evident cardiovascular disease,” Medicine, vol. 88, no. 6, pp. 358– 365, 2009. [229] C. Gonzalez-Juanatey, J. Llorca, J. A. Miranda-Filloy et al., “Endothelial dysfunction in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors,” Arthritis Care and Research, vol. 57, no. 2, pp. 287–293, 2007. [230] C. Gonzalez-Juanatey, J. Llorca, E. Amigo-Diaz, T. Dierssen, J. Martin, and M. A. Gonzalez-Gay, “High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors,” Arthritis Care & Research, vol. 57, no. 6, pp. 1074–1080, 2007. [231] S. M. Szabo, A. R. Levy, S. R. Rao et al., “Increased risk of cardiovascular and cerebrovascular diseases in individuals with ankylosing spondylitis: a population-based study,” Arthritis and Rheumatism, vol. 63, no. 11, pp. 3294–3304, 2011. [232] M. J. Peters, I. E. van der Horst-Bruinsma, B. A. Dijkmans, and M. T. Nurmohamed, “Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis,” Seminars in Arthritis and Rheumatism, vol. 34, no. 3, pp. 585–592, 2004. [233] Y. S. Kim, Y. K. Sung, C. B. Choi et al., “The major determinants of arterial stiffness in Korean patients with rheumatoid arthritis are age and systolic blood pressure, not disease-related factors,” Rheumatology International, vol. 32, no. 11, pp. 3455–3461, 2012. [234] S. E. Gabriel and C. S. Crowson, “Risk factors for cardiovascular disease in rheumatoid arthritis,” Current Opinion in Rheumatology, vol. 24, no. 2, pp. 171–176, 2012. [235] J. Willers and A. Hahn, “Cardiovascular risk in patients with rheumatoid arthritis: assessment of several traditional risk parameters and a German risk score model,” Rheumatology International, vol. 32, no. 12, pp. 3741–3749, 2012. [236] P. H. Dessein, G. R. Norton, B. I. Joffe, A. T. Abdool-Carrim, A. J. Woodiwiss, and A. Solomon, “Metabolic cardiovascular risk burden and atherosclerosis in African black and Caucasian women with rheumatoid arthritis: a cross-sectional study,” Clinical and Experimental Rheumatology, vol. 31, no. 1, pp. 53– 61, 2013. [237] T. E. Toms, V. F. Panoulas, and G. D. Kitas, “Dyslipidaemia in rheumatological autoimmune diseases,” Open Cardiovascular Medicine Journal, vol. 5, pp. 64–75, 2011. [238] B. Seriolo, S. Accardo, D. Fasciolo, S. Bertolini, and M. Cutolo, “Lipoproteins, anticardiolipin antibodies and thrombotic events in rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 14, no. 6, pp. 593–599, 1996. [239] H.-J. Priebe, “The aged cardiovascular risk patient,” British Journal of Anaesthesia, vol. 85, no. 5, pp. 763–778, 2000. [240] O. Ortega-Hernandez, R. Pineda-Tamayo, A. L. Pardo, A. RojasVillarraga, and J. Anaya, “Cardiovascular disease is associated with extra-articular manifestations in patients with rheumatoid arthritis,” Clinical Rheumatology, vol. 28, no. 7, pp. 767–775, 2009. [241] S. S. McCoy, C. S. Crowson, S. E. Gabriel, and E. L. Matteson, “Hypothyroidism as a risk factor for development of cardiovascular disease in patients with rheumatoid arthritis,” Journal of Rheumatology, vol. 39, no. 5, pp. 954–958, 2012. [242] E. Gremese and G. Ferraccioli, “The metabolic syndrome: the crossroads between rheumatoid arthritis and cardiovascular risk,” Autoimmunity Reviews, vol. 10, no. 10, pp. 582–589, 2011. [243] O. Karadag, M. Calguneri, E. Atalar et al., “Novel cardiovascular risk factors and cardiac event predictors in female inactive systemic lupus erythematosus patients,” Clinical Rheumatology, vol. 26, no. 5, pp. 695–699, 2007. [244] O. I. Galiutina and O. V. Bychak, “Relationship of silent myocardial ischiemia with the course of rheumatoid arthritis and hyperhomocysteinemia,” Likars’ka Sprava/Ministerstvo okhorony zdorov’ia Ukra¨ıny, no. 1-2, pp. 48–52, 2011. BioMed Research International 25 [245] M. A. Lopez-Olivo, L. Gonzalez-Lopez, A. Garcia-Gonzalez et al., “Factors associated with hyperhomocysteinaemia in Mexican patients with rheumatoid arthritis,” Scandinavian Journal of Rheumatology, vol. 35, no. 2, pp. 112–116, 2006. [246] N. Sattar, D. W. McCarey, H. Capell, and I. B. McInnes, “Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis,” Circulation, vol. 108, no. 24, pp. 2957–2963, 2003. [247] C. P. Chung, A. Oeser, J. F. Solus et al., “Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis,” Atherosclerosis, vol. 196, no. 2, pp. 756–763, 2008. [248] C. P. Chung, J. T. Giles, M. Petri et al., “Prevalence of traditional modifiable cardiovascular risk factors in patients with rheumatoid arthritis: comparison with control subjects from the multi-ethnic study of atherosclerosis,” Seminars in Arthritis and Rheumatism, vol. 41, no. 4, pp. 535–544, 2012. [249] R. M. R. Pereira, J. F. de Carvalho, and E. Bonfa, “Metabolic ´ syndrome in rheumatological diseases,” Autoimmunity Reviews, vol. 8, pp. 415–419, 2009. [250] M. Vadacca, D. Margiotta, A. Rigon et al., “Adipokines and systemic lupus erythematosus: relationship with metabolic syndrome and cardiovascular disease risk factors,” Journal of Rheumatology, vol. 36, no. 2, pp. 295–297, 2009. [251] V. R. da Cunha, C. V. Brenol, J. C. T. Brenol et al., “Metabolic syndrome prevalence is increased in rheumatoid arthritis patients and is associated with disease activity,” Scandinavian Journal of Rheumatology, vol. 41, no. 3, pp. 186–191, 2012. [252] A. Zonana-Nacach, E. Santana-Sahagun, F. J. Jim ´ enez-Balderas, ´ and A. Camargo-Coronel, “Prevalence and factors associated with metabolic syndrome in patients with rheumatoid arthritis and systemic lupus erythematosus,” Journal of Clinical Rheumatology, vol. 14, no. 2, pp. 74–77, 2008. [253] C. Turesson and E. L. Matteson, “Cardiovascular risk factors, fitness and physical activity in rheumatic diseases,” Current Opinion in Rheumatology, vol. 19, no. 2, pp. 190–196, 2007. [254] V. F. Panoulas, K. M. J. Douglas, H. J. Milionis et al., “Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis,” Rheumatology, vol. 46, no. 9, pp. 1477– 1482, 2007. [255] J. Mikdashi, B. Handwerger, P. Langenberg, M. Miller, and S. Kittner, “Baseline disease activity, hyperlipidemia, and hypertension are predictive factors for ischemic stroke and stroke severity in systemic lupus erythematosus,” Stroke, vol. 38, no. 2, pp. 281–285, 2007. [256] J. H. Kang, J. J. Keller, and H. C. Lin, “Outcomes of nonstenting percutaneous coronary intervention in patients with rheumatoid arthritis,” American Journal of Cardiology, vol. 109, no. 8, pp. 1160–1163, 2012. [257] J.-H. Kang, J. J. Keller, Y.-K. Lin, and H-C. Lin, “A populationbased case-control study on the association between rheumatoid arthritis and deep vein thrombosis,” Journal of Vascular Surgery, vol. 56, no. 6, pp. 1642–1648, 2012. [258] H. J. I. de Jong, R. J. Vandebriel, S. R. F. Saldi et al., “Angiotensinconverting enzyme inhibitors or angiotensin II receptor blockers and the risk of developing rheumatoid arthritis in antihypertensive drug users,” Pharmacoepidemiology and Drug Safety, vol. 21, no. 8, pp. 835–843, 2012. [259] C. Fan, Z. Zhang, Y. Mei, C.Wu, and B. Shen, “Impaired brachial artery flow-mediated dilation and increased carotid intimamedia thickness in rheumatoid arthritis patients,” Chinese Medical Journal, vol. 125, no. 5, pp. 832–837, 2012. [260] H. Maradit-Kremers, P. J. Nicola, C. S. Crowson, K. V. Ballman, and S. E. Gabriel, “Cardiovascular death in rheumatoid arthritis: a population-based study,” Arthritis and Rheumatism, vol. 52, no. 3, pp. 722–732, 2005. [261] S.-Y. Bang, K.-H. Lee, S.-K. Cho, H.-S. Lee, K. W. Lee, and S.-C. Bae, “Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status,” Arthritis & Rheumatism, vol. 62, no. 2, pp. 369–377, 2010. [262] T. M. Farragher, N. J. Goodson, H. Naseem et al., “Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis,” Arthritis and Rheumatism, vol. 58, no. 2, pp. 359–369, 2008. [263] M. A. Gonzalez-Gay, C. Gonzalez-Juanatey, M. J. Lopez-Diaz et al., “HLA-DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis,” Arthritis Care and Research, vol. 57, no. 1, pp. 125–132, 2007. [264] M. A. Gonzalez-Gay, C. Gonzalez-Juanatey, and W. E. Ollier, “Endothelial dysfunction in rheumatoid arthritis: influence of HLA-DRB1 alleles,” Autoimmunity Reviews, vol. 3, no. 4, pp. 301–304, 2004. [265] C. Turesson, W. M. O’Fallon, C. S. Crowson, S. E. Gabriel, and E. L. Matteson, “Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis,” Journal of Rheumatology, vol. 29, no. 1, pp. 62–67, 2002. [266] C. Turesson, R. L. McClelland, T. J. H. Christianson, and E. L. Matteson, “Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis,” The Annals of the Rheumatic Diseases, vol. 66, no. 1, pp. 70–75, 2007. [267] C. Gonzalez-Juanatey, A. Testa, A. Garcia-Castelo et al., “HLADRB1 status affects endothelial function in treated patients with rheumatoid arthritis,”American Journal of Medicine, vol. 114, no. 8, pp. 647–652, 2003. [268] D. L. Mattey, W. Thomson, W. E. R. Ollier et al., “Association of DRB1 shared epitope genotypes with early mortality in rheumatoid arthritis: results of eighteen years of followup from the early rheumatoid arthritis study,” Arthritis and Rheumatism, vol. 56, no. 5, pp. 1408–1416, 2007. [269] R. Palomino-Morales, C. Gonzalez-Juanatey, T. R. VazquezRodriguez et al., “A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis,” Arthritis Research and Therapy, vol. 12, no. 2, article R71, 2010. [270] L. Rodr´ıguez-Rodr´ıguez, C. Gonzalez-Juanatey, R. Palomino- ´ Morales et al., “TNFA-308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular disease in patients with rheumatoid arthritis,” Atherosclerosis, vol. 216, pp. 125–130, 2011. [271] R. Lopez-Mej ´ ´ıas, M. Garc´ıa-Bermudez, C. Gonz ´ alez-Juanatey ´ et al., “NFKB1-94ATTG ins/del polymorphism (rs28362491) is associated with cardiovascular disease in patients with rheumatoid arthritis,” Atherosclerosis, vol. 224, pp. 426–429, 2012. [272] T. E. Toms, V. F. Panoulas, J. P. Smith et al., “Rheumatoid arthritis susceptibility genes associate with lipid levels in patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 70, no. 6, pp. 1025–1032, 2011. 26 BioMed Research International [273] M. Teruel, J. E. Martin, C. Gonzalez-Juanatey et al., “Association ´ of acid phosphatase locus 1∗C allele with the risk of cardiovascular events in rheumatoid arthritis patients,” Arthritis Research and Therapy, vol. 13, no. 4, article R116, 2011. [274] Y. Chen, P. T. Dawes, J. C. Packham, and D. L. Mattey, “Interaction between smoking and polymorphism in the promoter region of the VEGFA gene is associated with ischemic heart disease and myocardial infarction in rheumatoid arthritis,” Journal of Rheumatology, vol. 38, no. 5, pp. 802–809, 2011. [275] L. N. Troelsen, P. Garred, and S. Jacobsen, “Mortality and predictors of mortality in rheumatoid arthritis: a role for mannose-binding lectin?” Journal of Rheumatology, vol. 37, no. 3, pp. 536–543, 2010. [276] L. Arlestig, S. Wallberg Jonsson, B. Stegmayr, and S. Rantap ˚ a¨a-¨ Dahlqvist, “Polymorphism of genes related to cardiovascular disease in patients with rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 25, pp. 866–871, 2007. [277] Y. Chen, P. T. Dawes, J. C. Packham, and D. L. Mattey, “Interaction between smoking and functional polymorphism in the TGFB1 gene is associated with ischaemic heart disease and myocardial infarction in patients with rheumatoid arthritis: a cross-sectional study,” Arthritis Research and Therapy, vol. 14, article R81, 2012. [278] R. Lertnawapan, A. Bian, Y. H. Rho et al., “Cystatin C, renal function, and atherosclerosis in rheumatoid arthritis,” Journal of Rheumatology, vol. 38, no. 11, pp. 2297–2300, 2011. [279] R. Palomino-Morales, C. Gonzalez-Juanatey, T. R. VazquezRodriguez et al., “Interleukin-6 gene -174 promoter polymorphism is associated with endothelial dysfunction but not with disease susceptibility in patients with rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 27, no. 6, pp. 964– 970, 2009. [280] V. F. Panoulas, K. M. J. Douglas, J. P. Smith et al., “Polymorphisms of the endothelin-1 gene associate with hypertension in patients with rheumatoid arthritis,” Endothelium: Journal of Endothelial Cell Research, vol. 15, no. 4, pp. 203–212, 2008. [281] V. F. Panoulas, S. N. Nikas, J. P. Smith et al., “Lymphotoxin 252A>G polymorphism is common and associates with myocardial infarction in patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 67, no. 11, pp. 1550–1556, 2008. [282] V. F. Panoulas, K. M. J. Douglas, J. P. Smith et al., “Galectin-2 (LGALS2) 3279C/T polymorphism may be independently associated with diastolic blood pressure in patients with rheumatoid arthritis,” Clinical and Experimental Hypertension, vol. 31, no. 2, pp. 93–104, 2009. [283] V. F. Panoulas, A. Stavropoulos-Kalinoglou, G. S. Metsios et al., “Association of interleukin-6 (IL-6)-174G/C gene polymorphism with cardiovascular disease in patients with rheumatoid arthritis: the role of obesity and smoking,” Atherosclerosis, vol. 204, no. 1, pp. 178–183, 2009. [284] J. Park, A. El-Sohemy, M. C. Cornelis, H. Kim, S. Kim, and S. Bae, “Glutathione S-transferase M1, T1, and P1 gene polymorphisms and carotid atherosclerosis in Korean patients with rheumatoid arthritis,” Rheumatology International, vol. 24, no. 3, pp. 157–163, 2004. [285] L. N. Troelsen, P. Garred, B. Christiansen, C. Torp-Pedersen, and S. Jacobsen, “Genetically determined serum levels of mannose-binding lectin correlate negatively with common carotid intima-media thickness in systemic lupus erythematosus,” Journal of Rheumatology, vol. 37, no. 9, pp. 1815–1821, 2010. [286] L. N. Troelsen, P. Garred, H. O. Madsen, and S. Jacobsen, “Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis,” Arthritis & Rheumatism, vol. 56, no. 1, pp. 21–29, 2007. [287] S. O. Keeling, M. Teo, and D. Fung, “Lack of cardiovascular risk assessment in inflammatory arthritis and systemic lupus erythematosus patients at a tertiary care center,” Clinical Rheumatology, vol. 30, no. 10, pp. 1311–1317, 2011. [288] K. P. Cheung, K. R. Taylor, and J. M. Jameson, “Immunomodulation at epithelial sites by obesity and metabolic disease,” Immunologic Research, vol. 52, no. 3, pp. 182–199, 2012. [289] M. Mazzantini, R. Talarico, M. Doveri et al., “Incident comorbidity among patients with rheumatoid arthritis treated or not with low-dose glucocorticoids: a retrospective study,” Journal of Rheumatology, vol. 37, no. 11, pp. 2232–2236, 2010. [290] M. R. Evans, A. Escalante, D. F. Battafarano, G. L. Freeman, D. H. O’Leary, and I. Del Rincon, “Carotid atherosclerosis predicts ˜ incident acute coronary syndromes in rheumatoid arthritis,” Arthritis and Rheumatism, vol. 63, no. 5, pp. 1211–1220, 2011. [291] V. F. Panoulas, K. M. J. Douglas, A. Stavropoulos-Kalinoglou et al., “Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis,” Rheumatology, vol. 47, no. 1, pp. 72–75, 2008. [292] S. Sihvonen, M. Korpela, J. Mustonen, H. Huhtala, K. Karstila, and A. Pasternack, “Mortality in patients with rheumatoid arthritis treated with low-dose oral glucocorticoids. A population-based cohort study,” Journal of Rheumatology, vol. 33, no. 9, pp. 1740–1746, 2006. [293] D. H. Solomon, J. Avorn, J. N. Katz et al., “Immunosuppressive medications and hospitalization for cardiovascular events in patients with rheumatoid arthritis,” Arthritis and Rheumatism, vol. 54, no. 12, pp. 3790–3798, 2006. [294] S. Suissa, S. Bernatsky, and M. Hudson, “Antirheumatic drug use and the risk of acute myocardial infarction,” Arthritis Care & Research, vol. 55, no. 4, pp. 531–536, 2006. [295] K. P. Liang, E. Myasoedova, C. S. Crowson et al., “Increased prevalence of diastolic dysfunction in rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 69, no. 9, pp. 1665–1670, 2010. [296] B. Targonska-Stepniak, A. Drelich-Zbroja, and M. Majdan, “The ´ relationship between carotid intima-media thickness and the activity of rheumatoid arthritis,” Journal of Clinical Rheumatology, vol. 17, no. 5, pp. 249–255, 2011. [297] H. J. Hinkema, H. L. A. Nienhuis, L. de Groot et al., “Is small artery elasticity decreased prior to intima-media thickening in patients with longstanding rheumatoid arthritis?” Journal of Rheumatology, vol. 38, no. 10, pp. 2133–2140, 2011. [298] Y. Kumeda, M. Inaba, H. Goto et al., “Increased thickness of the arterial intima-media detected by ultrasonography in patients with rheumatoid arthritis,” Arthritis and Rheumatism, vol. 46, no. 6, pp. 1489–1497, 2002. [299] A. Rojas-Villarraga, J. Amaya-Amaya, A. Rodriguez-Rodriguez, R. D. Mantilla, and J. Anaya, “Introducing polyautoimmunity: secondary autoimmune diseases no longer exist,” Autoimmune Diseases, vol. 1, no. 1, Article ID 254319, 2012. [300] I. A. Pereira, I. M. M. Laurindo, A. F. Zimmermann, G. R. W. Castro, F. Mello, and E. F. Borba, “Single measurements of Creactive protein and disease activity scores are not predictors of carotid at herosclerosis in rheumatoid arthritis patients,” Acta Reumatologica Portuguesa, vol. 34, no. 1, pp. 58–64, 2009. BioMed Research International 27 [301] S. Ajeganova, C. Ehrnfelt, R. Alizadeh et al., “Longitudinal levels of apolipoproteins and antibodies against phosphorylcholine are independently associated with carotid artery atherosclerosis 5 years after rheumatoid arthritis onset: a prospective cohort study,” Rheumatology, vol. 50, no. 10, pp. 1785–1793, 2011. [302] J. Wang, B. Hu, Y. Meng, C. Zhang, K. Li, and C. Hui, “The level of malondialdehyde-modified LDL and LDL immune complexes in patients with rheumatoid arthritis,” Clinical Biochemistry, vol. 42, no. 13-14, pp. 1352–1357, 2009. [303] G. Hjeltnes, I. Hollan, Ø. Førre, A. Wiik, K. Mikkelsen, and S. Agewall, “Anti-CCP and RF IgM: predictors of impaired endothelial function in rheumatoid arthritis patients,” Scandinavian Journal of Rheumatology, vol. 40, no. 6, pp. 422–427, 2011. [304] A. M. El-Barbary, E. M. Kassem, M. A. S. El-Sergany, S. A. Essa, and M. A. Eltomey, “Association of anti-modified citrullinated vimentin with subclinical atherosclerosis in early rheumatoid arthritis compared with anti-cyclic citrullinated peptide,” Journal of Rheumatology, vol. 38, no. 5, pp. 828–834, 2011. [305] J. Trifunovic Cvetkovic, S. Wallberg-Jonsson, B. Stegmayr, S. ˚ Rantapa¨a-Dahlqvist, and A. K. Lefvert, “Susceptibility for and ¨ clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-𝛼, IL-1𝛽, and IL-1Ra genes,” Journal of Rheumatology, vol. 29, no. 2, pp. 212–219, 2002. [306] F. J. Lopez-Longo, D. Oliver-Mi ´ narro, I. de la Torre et al., “Asso- ˜ ciation between anti-cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis,” Arthritis & Rheumatology, vol. 61, pp. 419–424, 2009. [307] D. Marasovic-Krstulovic, D. Martinovic-Kaliterna, D. Fabijanic, and J. Morovic-Vergles, “Are the anti-cyclic citrullinated peptide antibodies independent predictors of myocardial involvement in patients with active rheumatoid arthritis?” Rheumatology, vol. 50, no. 8, pp. 1505–1512, 2011. [308] D. L. Mattey, P. T. Dawes, N. B. Nixon, L. Goh, M. J. Banks, and G. D. Kitas, “Increased levels of antibodies to cytokeratin 18 in patients with rheumatoid arthritis and ischaemic heart disease,” Annals of the Rheumatic Diseases, vol. 63, no. 4, pp. 420–425, 2004. [309] M. J. L. Peters, V. P. van Halm, M. T. Nurmohamed et al., “Relations between autoantibodies against oxidized lowdensity lipoprotein, inflammation, subclinical atherosclerosis, and cardiovascular disease in rheumatoid arthritis,” Journal of Rheumatology, vol. 35, no. 8, pp. 1495–1499, 2008. [310] Y. Sherer, R. Gerli, B. Gilburd et al., “Thickened carotid artery intima-media in rheumatoid arthritis is associated with elevated anticardiolipin antibodies,” Lupus, vol. 16, no. 4, pp. 259–264, 2007. [311] N. Vuilleumier, S. Bas, S. Pagano et al., “Anti-apolipoprotein A-1 IgG predicts major cardiovascular events in patients with rheumatoid arthritis,” Arthritis and Rheumatism, vol. 62, no. 9, pp. 2640–2650, 2010. [312] N. Vuilleumier, J. Bratt, R. Alizadeh, T. Jogestrand, I. Hafstrom, ¨ and J. Frostegard, “Anti-apoA-1 IgG and oxidized LDL are ˚ raised in rheumatoid arthritis (RA): potential associations with cardiovascular disease and RA disease activity,” Scandinavian Journal of Rheumatology, vol. 39, no. 6, pp. 447–453, 2010. [313] E. Walewska, R. Rupiniski, A. Filipowicz-Sosnowska, and B. ´ Wojciechowska, “Follow-up studies of rheumatoid arthritis patients with the presence of antiphospholipid antibodies,” Polskie Archiwum Medycyny Wewnętrznej, vol. 115, pp. 438–442, 2006. [314] A. Gonzalez, M. Icen, H. M. Kremers et al., “Mortality trends in rheumatoid arthritis: the role of rheumatoid factor,” Journal of Rheumatology, vol. 35, no. 6, pp. 1009–1014, 2008. [315] S. Sarkar and D. A. Fox, “Targeting il-17 and th17 cells in rheumatoid arthritis,” Rheumatic Disease Clinics of North America, vol. 36, no. 2, pp. 345–366, 2010. [316] S. Banerjee, A. P. Compton, R. S. Hooker et al., “Cardiovascular outcomes in male veterans with rheumatoid arthritis,” The American Journal of Cardiology, vol. 101, no. 8, pp. 1201–1205, 2008. [317] E. Myasoedova, C. S. Crowson, H. M. Kremers et al., “Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease,” Annals of the Rheumatic Diseases, vol. 70, no. 3, pp. 482–487, 2011. [318] J. Westra, L. de Groot, S. L. Plaxton et al., “Angiopoietin-2 is highly correlated with inflammation and disease activity in recent-onset rheumatoid arthritis and could be predictive for cardiovascular disease,” Rheumatology, vol. 50, no. 4, pp. 665– 673, 2011. [319] P. H. Dessein, B. I. Joffe, M. G. Veller et al., “Traditional and nontraditional cardiovascular risk factors are associated with atherosclerosis in rheumatoid arthritis,” The Journal of Rheumatology, vol. 32, no. 3, pp. 435–442, 2005. [320] C. Book, T. Saxne, and L. T. H. Jacobsson, “Prediction of mortality in rheumatoid arthritis based on disease activity markers,” Journal of Rheumatology, vol. 32, no. 3, pp. 430–434, 2005. [321] L. Innala, B. Moller, L. Ljung et al., “Cardiovascular events in ¨ early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study,” Arthritis Research and Therapy, vol. 13, no. 4, article R131, 2011. [322] P. Fietta and G. Delsante, “Atherogenesis in rheumatoid arthritis: the “rheumatoid vasculopathy”?” Acta Biomedica de l’Ateneo Parmense, vol. 80, no. 3, pp. 177–186, 2009. [323] C. Baerwald, C. Kneitz, M. Bach, and M. Licht, “Extra-articular manifestations of rheumatoid arthritis,” Zeitschrift fur Rheuma- ¨ tologie, vol. 71, no. 10, pp. 841–849, 2012. [324] S. Norton, G. Koduri, E. Nikiphorou, J. Dixey, P. Williams, and A. Young, “A study of baseline prevalence and cumulative incidence of comorbidity and extra-articular manifestations in ra and their impact on outcome,” Rheumatology, vol. 52, no. 1, pp. 99–110, 2013. [325] G. Habib, S. Artul, N. Ratson, and P. Froom, “Household work disability of Arab housewives with rheumatoid arthritis,” Clinical Rheumatology, vol. 26, no. 5, pp. 759–763, 2007. [326] S. T. Reisine, C. Goodenow, and K. E. Grady, “The impact of rheumatoid arthritis on the homemaker,” Social Science and Medicine, vol. 25, no. 1, pp. 89–95, 1987. [327] H. G. Raterman and M. T. Nurmohamed, “Hypothyroidism in rheumatoid arthritis–to screen or not to screen?” Journal of Rheumatology, vol. 39, no. 5, pp. 885–886, 2012. [328] H. G. Raterman, V. P. van Halm, A. E. Voskuyl, S. Simsek, B. A. C. Dijkmans, and M. T. Nurmohamed, “Rheumatoid arthritis is associated with a high prevalence of hypothyroidism that amplifies its cardiovascular risk,” Annals of the Rheumatic Diseases, vol. 67, no. 2, pp. 229–232, 2008. [329] V. F. Panoulas, G. S. Metsios, A. V. Pace et al., “Hypertension in rheumatoid arthritis,” Rheumatology, vol. 47, no. 9, pp. 1286– 1298, 2008. 28 BioMed Research International [330] M. M. Mabrouk, M. A. Ghazy, and T. M. Hassan, “Serum pentraxin 3 and interleukin-6 are associated with subclinical atherosclerosis in recent-onset rheumatoid arthritis,” The Egyptian journal of immunology, vol. 17, no. 1, pp. 87–99, 2010. [331] P. A. Mac Mullan, A. J. Peace, A. M. Madigan, A. F. Tedesco, D. Kenny, and G. M. McCarthy, “Platelet hyper-reactivity in active inflammatory arthritis is unique to the adenosine diphosphate pathway: a novel finding and potential therapeutic target,” Rheumatology, vol. 49, no. 2, pp. 240–245, 2010. [332] M. A. Abdel-Khalek, A. M. El-Barbary, S. A. Essa, and A. S. Ghobashi, “Serum hepcidin: a direct link between anemia of inflammation and coronary artery atherosclerosis in patients with rheumatoid arthritis,” Journal of Rheumatology, vol. 38, no. 10, pp. 2153–2159, 2011. [333] S. Abou-Raya, A. Abou-Raya, A. Naim, and H. Abuelkheir, “Rheumatoid arthritis, periodontal disease and coronary artery disease,” Clinical Rheumatology, vol. 27, no. 4, pp. 421–427, 2008. [334] Y. Asanuma, C. P. Chung, A. Oeser et al., “Serum osteoprotegerin is increased and independently associated with coronaryartery atherosclerosis in patients with rheumatoid arthritis,” Atherosclerosis, vol. 195, no. 2, pp. e135–e141, 2007. [335] L. Bazzichi, L. Ghiadoni, A. Rossi et al., “Osteopontin is associated with increased arterial stiffness in rheumatoid arthritis,” Molecular Medicine, vol. 15, no. 11-12, pp. 402–406, 2009. [336] A. Elkan, N. Hakansson, J. Frosteg ˚ ard, T. Cederholm, and I. ˚ Hafstrom, “Rheumatoid cachexia is associated with dyslipi- ¨ demia and low levels of atheroprotective natural antibodies against phosphorylcholine but not with dietary fat in patients with rheumatoid arthritis: a cross-sectional study,” Arthritis Research and Therapy, vol. 11, no. 2, article R37, 2009. [337] A. McEntegart, H. A. Capell, D. Creran, A. Rumley, M. Woodward, and G. D. O. Lowe, “Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis,” Rheumatology, vol. 40, no. 6, pp. 640–644, 2001. [338] V. F. Panoulas, K. M. J. Douglas, H. J. Milionis et al., “Serum uric acid is independently associated with hypertension in patients with rheumatoid arthritis,” Journal of Human Hypertension, vol. 22, no. 3, pp. 177–182, 2008. [339] K. Tanaka, M. Inaba, H. Goto et al., “Paraarticular trabecular bone loss at the ultradistal radius and increased arterial stiffening in postmenopausal patients with rheumatoid arthritis,” Journal of Rheumatology, vol. 33, no. 4, pp. 652–658, 2006. [340] L. N. Troelsen, P. Garred, B. Christiansen et al., “Double role of mannose-binding lectin in relation to carotid intima-media thickness in patients with rheumatoid arthritis,” Molecular Immunology, vol. 47, no. 4, pp. 713–718, 2010. [341] S. Wallberg-Jonsson, G. H. Dahl ˚ en, T. K. Nilsson, M. R ´ anby, ˚ and S. Rantapa¨a-Dahlqvist, “Tissue plasminogen activator, ¨ plasminogen activator inhibitor-1 and von Willebrand factor in rheumatoid arthritis,” Clinical Rheumatology, vol. 12, no. 3, pp. 318–324, 1993. [342] A. Stavropoulos-Kalinoglou, G. S. Metsios, Y. Koutedakis et al., “Redefining overweight and obesity in rheumatoid arthritis patients,” Annals of the Rheumatic Diseases, vol. 66, no. 10, pp. 1316–1321, 2007. [343] G. D. Summers, G. S. Metsios, A. Stavropoulos-Kalinoglou, and G. D. Kitas, “Rheumatoid cachexia and cardiovascular disease,” Nature Reviews Rheumatology, vol. 6, no. 8, pp. 445–451, 2010. [344] V. Bellomio, A. Spindler, E. Lucero et al., “Systemic lupus erythematosus: mortality and survival in Argentina. A multicenter study,” Lupus, vol. 9, no. 5, pp. 377–381, 2000. [345] R. A. M. Cadaval, J. E. Martinez, M. A. Mazzolin, R. G. T. Barros, and F. A. Almeida, “Avaliac¸ao do risco coronariano em ˜ mulheres com lupus eritematoso sist ´ emico,” ˆ Revista Brasileira de Reumatologia, vol. 49, no. 6, pp. 658–669, 2009. [346] M. C. B. T. Rocha, S. S. Teixeira, C. Bueno, M. B. G. Vendramini, R. P. Martinelli, and M. B. Santiago, “Demographic, clinical, and laboratory profile of 100 patients with systemic lupus erythematosus in the State of Bahia,” Revista Brasileira de Reumatologia, vol. 40, no. 5, pp. 221–230, 2000. [347] W. H. Chahade, E. I. Sato, J. E. Moura Jr., L. T. Costallat, and L. E. Andrade, “Occasional series: lupus around the world: systemic lupus erythematosus in Sao Paulo, Brazil: a clinical and ˜ laboratory overview,” Lupus, vol. 4, no. 2, pp. 100–103, 1995. [348] S. Finkielman, N. M. Bleichmar, M. Norymberg, and A. Agrest, “Arterial hypertension in systemic lupus erythematosus,” Medicina, vol. 29, no. 3, pp. 165–170, 1969. [349] F. de Miranda Moura dos Santos, M. C. Borges, R. W. Telles, M. I. T. D. Correia, and C. C. D. Lanna, “Excess weight and associated risk factors in patients with systemic lupus erythematosus,” Rheumatology International, vol. 33, no. 3, pp. 681–688, 2013. [350] J. Romero-D´ıaz, I. Garc´ıa-Sosa, and J. Sanchez-Guerrero, ´ “Thrombosis in systemic lupus erythematosus and other autoimmune diseases of recent onset,” Journal of Rheumatology, vol. 36, no. 1, pp. 68–75, 2009. [351] J. Romero-D´ıaz, F. Vargas-Vorackov ´ a, E. Kimura-Hayama et al., ´ “Systemic lupus erythematosus risk factors for coronary artery calcifications,” Rheumatology, vol. 51, no. 1, pp. 110–119, 2012. [352] R. W. Telles, C. C. D. Lanna, G. A. Ferreira, A. J. Souza, T. P. Navarro, and A. L. Ribeiro, “Carotid atherosclerotic alterations in systemic lupus erythematosus patients treated at a Brazilian university setting,” Lupus, vol. 17, no. 2, pp. 105–113, 2008. [353] M. Soares, L. Reis, J. A. S. Papi, and C. R. L. Cardoso, “Rate, pattern and factors related to damage in Brazilian systemic lupus erythematosus patients,” Lupus, vol. 12, no. 10, pp. 788– 794, 2003. [354] G. G. Ribeiro, E. Bonfa, R. S. Neto et al., “Premature coronary ´ artery calcification is associated with disease duration and bone mineral density in young female systemic lupus erythematosus patients,” Lupus, vol. 19, no. 1, pp. 27–33, 2010. [355] E. Badui, D. Garcia-Rubi, E. Robles et al., “Cardiovascular manifestations in systemic lupus erythematosus. Prospective study of 100 patients,” Angiology, vol. 36, no. 7, pp. 431–441, 1985. [356] E. M. C. Sella, E. I. Sato, and A. Barbieri, “Coronary artery angiography in systemic lupus erythematosus patients with abnormal myocardial perfusion scintigraphy,” Arthritis and Rheumatism, vol. 48, no. 11, pp. 3168–3175, 2003. [357] E. M. C. Sella, E. I. Sato, W. A. Leite, J. A. Oliveira Filho, and A. Barbieri, “Myocardial perfusion scintigraphy and coronary disease risk factors in systemic lupus erythematosus,” Annals of the Rheumatic Diseases, vol. 62, no. 11, pp. 1066–1070, 2003. [358] R. W. Telles, C. C. D. Lanna, G. A. Ferreira, and A. L. Ribeiro, “Metabolic syndrome in patients with systemic lupus erythematosus: association with traditional risk factors for coronary heart disease and lupus characteristics,” Lupus, vol. 19, no. 7, pp. 803–809, 2010. [359] V. Bellomio, A. Spindler, E. Lucero et al., “Metabolic syndrome in Argentinean patients with systemic lupus erythematosus,” Lupus, vol. 18, no. 11, pp. 1019–1025, 2009. [360] B. A. Pons-Estel, L. J. Catoggio, M. H. Cardiel et al., “The GLADEL multinational latin american prospective inception BioMed Research International 29 cohort of 1,214 patients with systemic lupus erythematosus: ethnic and disease heterogeneity among ‘Hispanics’,” Medicine, vol. 83, no. 1, pp. 1–17, 2004. [361] G. J. Pons-Estel, L. A. Gonzalez, J. Zhang et al., “Predictors ´ of cardiovascular damage in patients with systemic lupus erythematosus: data from LUMINA (LXVIII), a multiethnic US cohort,” Rheumatology, vol. 48, no. 7, pp. 817–822, 2009. [362] H. Zald´ıvar-Alcantara, LE. Herrera-Jim ´ enez, E. Dehesa-L ´ opez, ´ and R. Correa-Rotter, “Risk factors for the development of thrombotic complication in patients with lupus erythematosus and lupus nephropatic,” Revista de Investigacion Clinica, vol. 65, pp. 199–208, 2013. [363] M. McMahon, B. J. Skaggs, L. Sahakian et al., “High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids,”Annals of the Rheumatic Diseases, vol. 70, no. 9, pp. 1619–1624, 2011. [364] M. McMahon, J. Grossman, B. Skaggs et al., “Dysfunctional proinflammatory high-density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 60, no. 8, pp. 2428– 2437, 2009. [365] A. C. Travassos, M. C. Rocha, S. Souza, C. Brandao, and J. F. Silva, “Freqtiencia dos anticorpos antifosfolfpides (aFL) em portadores de lupus eritematoso sistemico (LES) no Estado da Bahia,” Revista Brasileira de Reumatologia, vol. 40, pp. 183–188, 2000. [366] E. Alexanderson, J. M. Ochoa, R. Calleja et al., “Endothelial ´ dysfunction in systemic lupus erythematosus: evaluation with 13N-ammonia PET,” Journal of Nuclear Medicine, vol. 51, pp. 1927–1931, 2010. [367] R. W. Telles, C. C. D. Lanna, G. A. Ferreira, and M. A. P. de Carvalho, “Frequ¨encia de doenc ˆ ¸a cardiovascular aterosclerotica ´ e de seus fatores de risco em pacientes com lupus eritematoso ´ sistemico,” ˆ Revista de Investigacion Clinica, vol. 47, pp. 165–173, 2007. [368] C. R. L. Cardoso, F. V. Signorelli, J. A. Papi, and G. F. Salles, “Prevalence and factors associated with dyslipoproteinemias in Brazilian systemic lupus erythematosus patients,” Rheumatology International, vol. 28, no. 4, pp. 323–327, 2008. [369] A. W. Silva de Souza, F. Satomi Hatta, F. Miranda Jr., and E. Inoue Sato, “Atherosclerotic plaque in carotid arteries in systemic lupus erythematosus: Frequency and associated risk factors,” Sao Paulo Medical Journal, vol. 123, no. 3, pp. 137–142, 2005. [370] S. M. A. Toloza, J. M. Roseman, G. S. Alarcon et al., “Systemic ´ lupus erythematosus in a multiethnic US cohort (LUMINA): XXII. Predictors of time to the occurrence of initial damage,” Arthritis and Rheumatism, vol. 50, no. 10, pp. 3177–3186, 2004. [371] A. Zonana-Nacach, A. Camargo-Coronel, P. Ya´nez et al., ˜ “Measurement of damage in 210 Mexican patients with systemic lupus erythematosus: relationship with disease duration,” Lupus, vol. 7, no. 2, pp. 119–123, 1998. [372] M. A. B. Lozovoy, A. N. C. Simao, M. S. N. Hohmann et al., ˜ “Inflammatory biomarkers and oxidative stress measurements in patients with systemic lupus erythematosus with or without metabolic syndrome,” Lupus, vol. 20, no. 13, pp. 1356–1364, 2011. [373] A. M. Negron, M. J. Molina, A. M. Mayor, V. E. Rodr ´ ´ıguez, and L. M. Vila, “Factors associated with metabolic syndrome in ´ patients with systemic lupus erythematosus from Puerto Rico,” Lupus, vol. 17, no. 4, pp. 348–354, 2008. [374] S.-Y. Liu, L.-S. Han, J.-Y. Guo et al., “Metabolic syndrome in Chinese patients with systemic lupus erythematosus: no association with plasma cortisol level,” Lupus, vol. 22, no. 5, pp. 519–526, 2013. [375] M. J. Ormseth, L. L. Swift, S. Fazio et al., “Free fatty acids are associated with metabolic syndrome and insulin resistance but not inflammation in systemic lupus erythematosus,” Lupus, vol. 22, no. 1, pp. 26–33, 2013. [376] T. A. Gheita, H. A. Raafat, S. Sayed, H. El-Fishawy, M. M. Nasrallah, and E. Abdel-Rasheed, “Metabolic syndrome and insulin resistance comorbidity in systemic lupus erythematosus—effect on carotid intima-media thickness,” Zeitschrift fur Rheumatologie, vol. 72, no. 2, pp. 172–177, 2013. [377] S. Liu, J. Guo, L. Zhang et al., “[Incidence of metabolic syndrome in systemic lupus erythematosus and its influence by glucocorticoids].,” Zhonghua Nei Ke Za Zhi, vol. 51, no. 6, pp. 441–444, 2012. [378] F. D. M. M. dos Santos, M. C. Borges, M. I. T. D. Correia, R. W. Telles, and C. C. D. Lanna, “Assessment of nutritional status and physical activity in systemic lupus erythematosus patients,” Revista Brasileira de Reumatologia, vol. 50, no. 6, pp. 631–645, 2010. [379] C. R. L. Cardoso, M. A. O. Sales, J. A. S. Papi, and G. F. Salles, “QT-interval parameters are increased in systemic lupus erythematosus patients,” Lupus, vol. 14, no. 10, pp. 846–852, 2005. [380] A. Rizk, T. A. Gheita, S. Nassef, and A. Abdallah, “The impact of obesity in systemic lupus erythematosus on disease parameters, quality of life, functional capacity and the risk of atherosclerosis,” International Journal of Rheumatic Diseases, vol. 15, no. 3, pp. 261–267, 2012. [381] K. T. Ho, C. W. Ahn, G. S. Alarcon et al., “Systemic lupus ´ erythematosus in a multiethnic cohort (LUMINA): XXVIII. Factors predictive of thrombotic events,” Rheumatology, vol. 44, no. 10, pp. 1303–1307, 2005. [382] A. J. Szalai, G. S. Alarcon, J. Calvo-Al ´ en et al., “Systemic ´ lupus erythematosus in a multiethnic US Cohort (LUMINA). XXX: Association between C-reactive protein (CRP) gene polymorphisms and vascular events,” Rheumatology, vol. 44, no. 7, pp. 864–868, 2005. [383] B. F. A. Freire, R. C. da Silva, A. T. Fabro, and D. C. dos Santos, “Is systemic lupus erithematosus a new risk factor for atherosclerosis?” Arquivos Brasileiros de Cardiologia, vol. 87, no. 3, pp. 300–306, 2006. [384] S. Haque, C. Rakieh, F. Marriage et al., “Brief report: shortened telomere length in patients with systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 65, no. 5, pp. 1319–1323, 2013. [385] C. Maric-Bilkan, E. L. Gilbert, and M. J. Ryan, “Impact of ovarian function on cardiovascular health in women: focus on hypertension,” International Journal of Women’s Health, vol. 6, pp. 131–139, 2014. [386] L. R. Sammaritano, “Menopause in patients with autoimmune diseases,” Autoimmunity Reviews, vol. 11, no. 6-7, pp. A430– A436, 2012. [387] L. Onetti, S. Villafane, E. Menso et al., “Hyperhomocystinemia ˜ as a thrombotic risk factor in patients suffering from systemic lupus erithematosus and antiphospholipid syndrome,” Revista de la Facultad de Ciencias Medicas ´ , vol. 62, no. 3, pp. 19–23, 2005. [388] G. J. Pons-Estel, V. Saurit, G. S. Alarcon et al., “The impact ´ of rural residency on the expression and outcome of systemic lupus erythematosus: data from a multiethnic Latin American cohort,” Lupus, vol. 21, no. 13, pp. 1397–1404, 2012. 30 BioMed Research International [389] R. Kaiser, Y. Li, M. Chang et al., “Genetic risk factors for thrombosis in systemic lupus erythematosus,” Journal of Rheumatology, vol. 39, no. 8, pp. 1603–1610, 2012. [390] C. Perricone, C. Ciccacci, F. Ceccarelli et al., “TRAF3IP2 gene and systemic lupus erythematosus: association with disease susceptibility and pericarditis development,” Immunogenetics, vol. 65, pp. 703–709, 2013. [391] D. Leonard, E. Svenungsson, J. K. Sandling, O. Berggren, A. Jonsen, and C. Bengtsson, “Coronary heart disease in systemic ¨ lupus erythematosus is associated with interferon regulatory factor-8 gene variants,” Circulation: Cardiovascular Genetics, vol. 6, pp. 255–263, 2013. [392] F. Salcido-Ochoa, J. Cabiedes, D. Alarcon-Segovia, and A. R. ´ Cabral, “Antiprothrombin antibodies in patients with systemic lupus erythematosus or with primary antiphospholipid syndrome,” Journal of Clinical Rheumatology, vol. 8, no. 5, pp. 251– 255, 2002. [393] M. M. Shinzato, C. Bueno, V. S. T. Viana, E. F. Borba, C. R. Gonc¸alves, and E. Bonfa, “Complement-fixing activity of anti- ´ cardiolipin antibodies in patients with and without thrombosis,” Lupus, vol. 14, no. 12, pp. 953–958, 2005. [394] F. V. Signorelli, G. F. Salles, and J. A. Papi, “Antiphospholipid syndrome as predictor of mortality in Brazilian patients with systemic lupus erythematosus,” Lupus, vol. 20, article 419, 2011. [395] L. Gomez-Pacheco, A. R. Villa, C. Drenkard, J. Cabiedes, A. R. ´ Cabral, and D. Alarcon-Segovia, “Serum anti- ´ 𝛽2-glycoproteinI and anticardiolipin antibodies during thrombosis in systemic lupus erythematosus patients,” The American Journal of Medicine, vol. 106, no. 4, pp. 417–423, 1999. [396] V. E. Rodriguez, E. N. Gonzalez-Pares, and C. Rivera, “Clinical manifestations and vascular events in patients with lupus erythematosus anticardiolipin antibodies and raynaud’s phenomenon,” Puerto Rico Health Sciences Journal, vol. 25, no. 4, pp. 307–313, 2006. [397] P. Abumohor, C. Cerda, O. Neira et al., “Anticardiolipin antibodies in systemic lupus erythematosus: prevalence and clinical associations,” Revista Medica de Chile, vol. 119, no. 5, pp. 517–523, 1991. [398] C. A. Falcao, I. C. Alves, W. H. Chahade, A. L. B. Pinto Duarte, ˜ and N. Lucena-Silva, “Echocardiographic abnormalities and antiphospholipid antibodies in patients with systemic lupus erythematosus,” Arquivos Brasileiros de Cardiologia, vol. 79, no. 3, pp. 285–291, 2002. [399] C. Carmona-Rivera, W. Zhao, S. Yalavarthi, and M. J. Kaplan, “Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2,” Annals of the Rheumatic Diseases, 2014. [400] J. G. Juarez-Rojas, A. X. Medina-Urrutia, R. Posadas-S ´ anchez et ´ al., “High-density lipoproteins are abnormal in young women with uncomplicated systemic lupus erythematosus,” Lupus, vol. 17, no. 11, pp. 981–987, 2008. [401] L. M. Yassin, J. Londono, G. Montoya et al., “Atherosclerosis ˜ development in SLE patients is not determined by monocytes ability to bind/endocytose Ox-LDL,” Autoimmunity, vol. 44, no. 3, pp. 201–210, 2011. [402] E. F. Borba and E. Bonfa, “Dyslipoproteinemias in systemic ´ lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies,” Lupus, vol. 6, no. 6, pp. 533–539, 1997. [403] A. Lertratanakul, P. Wu, A. Dyer et al., “25-Hydroxyvitamin D and cardiovascular disease in patients with systemic lupus erythematosus: Data from a large international inception cohort,” Arthritis Care & Research, 2014. [404] Q. Shang, G. W. K. Yip, L. S. Tam et al., “SLICC/ACR damage index independently associated with left ventricular diastolic dysfunction in patients with systemic lupus erythematosus,” Lupus, vol. 21, no. 10, pp. 1057–1062, 2012. [405] C. R. L. Cardoso, F. V. Signorelli, J. A. S. Papi, and G. F. Salles, “Initial and accrued damage as predictors of mortality in Brazilian patients with systemic lupus erythematosus: a cohort study,” Lupus, vol. 17, no. 11, pp. 1042–1048, 2008. [406] S. Valero-Gonzalez, R. Castejon, C. Jimenez-Ortiz, S. Rosado, P. Tutor-Ureta, and J. A. Vargas, “Increased arterial stiffness is independently associated with metabolic syndrome and damage index in systemic lupus erythematosus patients,” Scandinavian Journal of Rheumatology, vol. 43, pp. 54–58, 2014. [407] J. A. Reynolds, S. Haque, J. L. Berry et al., “25-hydroxyvitamin D deficiency is associated with increased aortic stiffness in patients with systemic lupus erythematosus,” Rheumatology, vol. 51, no. 3, pp. 544–551, 2012. [408] C. C. Mok, D. J. Birmingham, H. W. Leung, L. A. Hebert, H. Song, and B. H. Rovin, “Vitamin D levels in Chinese patients with systemic lupus erythematosus: relationship with disease activity, vascular risk factors and atherosclerosis,” Rheumatology, vol. 51, no. 4, Article ID ker212, pp. 644–652, 2012. [409] G. Medina, A. L. Gutierrez-Moreno, O. Vera-Lastra, M. A. ´ Saavedra, and L. J. Jara, “Prevalence of metabolic syndrome in primary antiphospholipid syndrome patients,” Autoimmunity Reviews, vol. 10, no. 4, pp. 214–217, 2011. [410] L. J. Jara, G. Medina, O. Vera-Lastra, and Y. Shoenfeld, “Atherosclerosis and antiphospholipid syndrome,” Clinical Reviews in Allergy and Immunology, vol. 25, no. 1, pp. 79–87, 2003. [411] A. Broder, J. N. Tobin, and C. Putterman, “High antiphospholipid antibody levels are associated with statin use and may reflect chronic endothelial damage in non-autoimmune thrombosis: cross-sectional study,” Journal of Clinical Pathology, vol. 65, no. 6, pp. 551–556, 2012. [412] A. R. Ribeiro and J. F. Carvalho, “Traditional risk factors for cardiovascular disease in primary antiphospholipid syndrome (APS) when compared with secondary APS: a study with 96 patients,” Acta reumatologica portuguesa ´ , vol. 35, no. 1, pp. 36– 41, 2010. [413] R. Li, Y. Zhou, Y. Jia, and Z. Li, “Analysis of risk factors in development of thrombosis in patients with antiphospholipid syndrome,” Beijing Da Xue Xue Bao, vol. 44, pp. 788–791, 2012. [414] G. Medina, D. Casaos, L. J. Jara et al., “Increased carotid artery intima-media thickness may be associated with stroke in primary antiphospholipid syndrome,” Annals of the Rheumatic Diseases, vol. 62, no. 7, pp. 607–610, 2003. [415] A. Theodoridou, L. Bento, D. P. D’Cruz, M. A. Khamashta, and G. R. V. Hughes, “Prevalence and associations of an abnormal ankle-brachial index in systemic lupus erythematosus: a pilot study,”Annals of the Rheumatic Diseases, vol. 62, no. 12, pp. 1199– 1203, 2003. [416] AT. Erkkila, O. N ¨ arv ¨ anen, S. Lehto, M. I. J. Uusitupa, and ¨ S. Yla-Herttuala, “Antibodies against oxidized LDL and cardi- ¨ olipin and mortality in patients with coronary heart disease,” Atherosclerosis, vol. 183, pp. 157–162, 2005. [417] V. Betapudi, G. Lominadze, L. Hsi, B. Willard, M. Wu, and K. R. McCrae, “Anti-𝛽 2GPI antibodies stimulate endothelial cell BioMed Research International 31 microparticle release via a nonmuscle myosin II motor proteindependent pathway,” Blood, vol. 122, pp. 3808–3817, 2013. [418] K. Veres, G. Lakos, A. Kerenyi et al., “Antiphospholipid anti- ´ bodies in acute coronary syndrome,” Lupus, vol. 13, no. 6, pp. 423–427, 2004. [419] J. George, D. Harats, B. Gilburd et al., “Immunolocalization of 𝛽2-glycoprotein I (apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression,” Circulation, vol. 99, no. 17, pp. 2227–2230, 1999. [420] R. Gerli, E. Bartoloni Bocci, G. Vaudo, S. Marchesi, C. Vitali, and Y. Shoenfeld, “Traditional cardiovascular risk factors in primary Sjogren’s syndrome—role of dyslipidaemia,” ¨ Rheumatology, vol. 45, no. 12, pp. 1580–1582, 2006. [421] G. Lippi, P. Caramaschi, M. Montagnana, G. L. Salvagno, A. Volpe, and G. Guidi, “Lipoprotein[a] and the lipid profile in patients with systemic sclerosis,” Clinica Chimica Acta, vol. 364, no. 1-2, pp. 345–348, 2006. [422] M. M. Cerinic, G. Valentini, G. G. Sorano et al., “Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis,” Seminars in Arthritis and Rheumatism, vol. 32, no. 5, pp. 285–295, 2003. [423] E. F. Borba, C. T. L. Borges, and E. Bonfa, “Lipoprotein profile ´ in limited systemic sclerosis,” Rheumatology International, vol. 25, pp. 379–383, 2005. [424] N. Tsifetaki, A. N. Georgiadis, Y. Alamanos, S. Fanis, M. I. Argyropoulou, and A. A. Drosos, “Subclinical atherosclerosis in scleroderma patients,” Scandinavian Journal of Rheumatology, vol. 39, no. 4, pp. 326–329, 2010. [425] A. L. Herrick, K. J. Illingworth, S. Hollis, J. M. GomezZumaquero, and F. J. Tinahones, “Antibodies against oxidized low-density lipoproteins in systemic sclerosis,” Rheumatology, vol. 40, no. 4, pp. 401–405, 2001. [426] U. Nussinovitch and Y. Shoenfeld, “Autoimmunity and heart diseases: pathogenesis and diagnostic criteria,” Archivum Immunologiae et Therapiae Experimentalis, vol. 57, no. 2, pp. 95– 104, 2009. [427] L. R. Lopez, D. F. Simpson, B. L. Hurley, and E. Matsuura, “OxLDL/𝛽2GPI complexes and autoantibodies in patients with systemic lupus erythematosus, systemic sclerosis, and antiphospholipid syndrome: pathogenic implications for vascular involvement,” Annals of the New York Academy of Sciences, vol. 1051, pp. 313–322, 2005. [428] M. Kodera, I. Hayakawa, K. Komura et al., “Anti-lipoprotein lipase antibody in systemic sclerosis: association with elevated serum triglycride concentrations,” Journal of Rheumatology, vol. 32, no. 4, pp. 629–636, 2005. [429] O. Timar, P. Solt ´ esz, S. Szamosi et al., “Increased arterial stiffness ´ as the marker of vascular involvement in systemic sclerosis,