Subclinical Atherosclerosis In Systemic Lupus Erythematosus Research Articles

Plasma osteopontin versus intima media thickness of the common carotid arteries in well-characterised patients with systemic lupus erythematosus.

ObjectiveThe progress of accelerated atherosclerosis in systemic lupus erythematosus (SLE) is incompletely understood. Circulating osteopontin (OPN) is increased in autoimmune conditions, e.g. SLE, and its serum concentration was recently reported to associate with subclinical atherosclerosis in SLE, as measured by carotid intima-media thickness. The aim of this study was to investigate whether OPN may be used as a surrogate biomarker of subclinical atherosclerosis in SLE patients with different disease phenotypes.MethodsWe recruited 60 well-characterised SLE cases and 60 age- and sex-matched healthy controls. The SLE cases were divided into three different disease phenotypes: SLE with antiphospholipid syndrome (APS), lupus nephritis, and isolated skin and joint involvement. Plasma OPN was detected by ELISA (Quantikine®, R&D Systems). Common carotid arteries intima media thickness was compared between the studied groups in relation to OPN levels and risk factors for vascular changes. Intima media thickness of common carotid arteries was measured by using a sensitive ultrasound technique (LOGIQ™ E9 ultrasound, GE Healthcare).ResultsOPN levels were significantly higher among the entire SLE group (n = 60) compared to the healthy controls (P = 0.03). SLE cases with concomitant APS (n = 20) showed higher OPN levels than the controls (P = 0.004), whereas none of the other two subgroups differed significantly from the healthy controls. OPN and intima media thickness were correlated to several traditional risk factors of atherosclerosis, as well as to SLE-related factors. Yet, no significant correlation was observed between OPN levels and ultrasound findings of the common carotid arteries.ConclusionsIn line with previous studies, we observed increased OPN levels among SLE patients as compared to matched controls. However, the OPN concentrations did not correlate with intima media thickness of the common carotid arteries. Based on our findings, the use of OPN as a surrogate biomarker of subclinical atherosclerosis in SLE subjects, regardless of clinical phenotypes, cannot be recommended.

Serum Metabolomic Signatures Can Predict Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus.

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Body mass index and glucocorticoid dose contribute to subclinical atherosclerosis in Korean patients with systemic lupus erythematosus: A prospective 4year follow-up study.

Patients with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular disease owing to an immunological abnormality, along with traditional risk factors. We found that carotid artery intima-media thickness (cIMT) and plaque were associated with age, body mass index (BMI) and disease activity in a previous study 4years ago. Our aim was to identify risk factors associated with progression of subclinical atherosclerosis in SLE. We assessed cIMT and plaque using Doppler ultrasonography in 61 Korean women with SLE who were enrolled in the previous study 4years ago. The mean cIMT of the patients was 0.39±0.09mm; 11 patients had carotid plaques, which was similar to the results of the previous study. Twenty-one patients had increased cIMT, and new carotid plaque had developed in seven patients. Patients with increased cIMT had a lower BMI and took fewer non-steroidal anti-inflammatory drugs and higher 4year cumulative glucocorticoid dose than patients without increased cIMT. The 4year cumulative glucocorticoid dose was higher in patients with carotid plaque than in those without. On multivariate regression analysis, BMI (odds ratio [OR]=0.67, P=0.034) was associated with increased cIMT, and the 4year cumulative glucocorticoid dose was associated with increased cIMT (OR=6.994, P=0.025) and carotid plaque (OR=5.651, P=0.031). This prospective follow-up study on cIMT and plaque in patients with SLE showed that low BMI and 4year cumulative glucocorticoid dose were associated with the progression of subclinical atherosclerosis.

Plasma Free Protein S Is Correlated with Disease Activity, but not with Subclinical Atherosclerosis among Patients with Systemic Lupus Erythematosus: A Cross-Sectional Study.

A defect in clearance of apoptotic materials is pivotal in the pathogenesis of systemic lupus erythematosus (SLE). Protein S participates in the removal of apoptotic remnants and the anticoagulation pathway. The aim of the study was to clarify the relationship between plasma levels of free protein S and the disease activity or subclinical atherosclerosis in SLE. Free protein S was measured by an enzyme-linked immunosorbent assay, and patients were classified into two groups of free protein S levels: low (< 50%) and normal (≥ 50%). One hundred-eleven Korean female patients with SLE were enrolled, and the levels of free protein S were 67.4 ± 19.7%. Carotid plaque was detected in 25 (22.5%) patients. Twenty-one patients with low free protein S had lower hemoglobin (11.4 ± 1.4 vs. 12.5 ± 1.4 g/dL) and lymphocytes (1,221 ± 609 vs. 1,720 ± 1,097/µL), higher erythrocyte sedimentation rate (30.1 ± 20.6 vs. 20.8 ± 17.8 mm/h), and lower complement 3 (80.8 ± 27.6 vs. 103.4 ± 25.8 mg/dL) and complement 4 (15.6 ± 10.4 vs. 21.5 ± 7.6 mg/dL) than those with normal protein S. There was no significant difference in the proportion of patients with increased carotid artery intima-media thickness (> 4.6 mm) or with carotid artery plaque between two groups. The low levels of free protein S were associated with hemoglobin (OR = 0.64, p = 0.04) and complement 3 (OR = 0.96, p = 0.005). Free protein S is correlated with disease activity, but not with subclinical atherosclerosis in SLE.

Subclinical atherosclerosis in Systemic Lupus Erythematosus: Comparable risk with Diabetes Mellitus and Rheumatoid Arthritis.

Although a high risk of subclinical atherosclerosis has been reported in Systemic Lupus Erythematosus (SLE), it is not adequately compared with that observed in other rheumatic and non-rheumatic high-cardiovascular (CVD) risk diseases, such as Rheumatoid Arthritis (RA) and Diabetes Mellitus (DM). Our objective was to evaluate the relative risk (RR) of subclinical atherosclerosis in SLE, RA and DM patients compared to healthy controls, and examine potential associations with traditional and disease-related CVD risk factors in SLE. We examined for atherosclerotic plaques 460 individuals (92% female) without CVD history, using carotid and femoral artery ultrasound: 115 SLE patients and matched 1:1 for age and gender RA, DM, and control subjects. Multivariate models were used to determine relative risk estimates for the number of atherosclerotic plaques in patient groups versus controls, and associations of plaques with traditional CVD and disease-related factors in SLE. A nearly two-fold higher number of atherosclerotic plaques in the carotid and femoral arteries was detected in each of SLE, RA and DM groups compared to controls, after adjusting for the effect of traditional CVD risk factors (RR=1.80, 95% CI 1.05-3.08, p=0.033, RR=1.90 (1.11-3.26), p=0.019, RR=1.93 (1.14-3.28), p=0.015, respectively). In SLE patients, the number of atherosclerotic plaques was associated with age (p<0.001), smoking (p=0.016), hypertension (p=0.029), and cumulative corticosteroid dose (p=0.007). The relative risk of subclinical atherosclerosis in SLE was comparable to that found in RA and DM, indicating that SLE patients merit a similar diligence in CVD risk assessment and management measures.

Serum tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and leptin as biomarkers of accelerated atherosclerosis in patients with systemic lupus erythematosus and antiphospholipid syndrome

BackgroundPatients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are at increased risk of atherosclerosis, and occurs much earlier compared to the general population even after accounting for traditional risk factors. Aim of the workTo examine the association between serum TWEAK, leptin and subclinical atherosclerosis in SLE and APS patients. Patients and methodsSerum tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and leptin were measured in 30SLE patients, 26SLE patients with secondary APS (SLE–APS), 14 with primary APS (pAPS) and 20age and sex matched control. The SLE disease activity index (SLEDAI) was assessed in SLE patients. The intima media thickness (IMT) was measured by carotid ultrasound. ResultsSerum TWEAK was significantly higher in patients with pAPS (945.1±16.2pg/ml) than in SLE–APS (755.3±59.9pg/ml), SLE patients (499.2±47.1pg/ml) and control (129.6±18.6pg/ml) (p<0.001). Also, serum leptin was significantly higher in pAPS patients (14.0±2.8ng/ml) compared to that in SLE–APS (6.5±0.9ng/ml), SLE patients (3.8±1.2ng/ml) and control (1.6±0.6ng/ml) (p<0.001). The IMT was significantly increased in the pAPS patients compared to SLE–APS group (p<0.001), SLE patients (p=0.006) and to the control (p<0.001). A significant correlation was found between TWEAK with the body mass index and high density lipoprotein in SLE–APS and inversely with the random blood sugar and the diastolic blood pressure in SLE patients. Serum leptin only significantly correlated with the total leucocytic count in SLE patients. ConclusionPatients with pAPS are more liable to develop premature atherosclerosis even in the absence of the traditional risk factors.

Endocan Levels and Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology. A major cause of morbidity and mortality in SLE is accelerated atherosclerosis. Endothelial-specific molecule 1 (endocan) is a potential predictor of vascular events and is expressed in response to inflammatory cytokines in endothelial cells. We investigated the relationship between endocan and carotid intima-media thickness (cIMT) as a marker of early atherosclerosis. We included 44 women with SLE and 44 healthy women as controls. Disease severity of SLE was evaluated using the SLE Disease Activity Index. Endocan, C-reactive protein, erythrocyte sedimentation rate (ESR), and lipid panel were measured. The cIMT was 0.70 (range: 0.45-1.20) mm in patients with SLE and 0.40 (0.25-0.60) mm in controls (P < .001). Endocan value was 1.6 ± 0.9 ng/mL in controls and 2.2 ± 1.0 ng/mL in patients with SLE (P = .014). Endocan levels were positively correlated with cIMT (r = .469, P < .001), body mass index (r = .373, P = .013), and ESR (r = .393, P = .008). Endocan level may be associated with subclinical atherosclerosis in SLE. Consequently, endocan levels may be a promising clinical tool for patients with SLE as a guide for preventive strategy.

Heterogeneity of peripheral blood monocytes, endothelial dysfunction and subclinical atherosclerosis in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by increased cardiovascular morbidity and mortality. SLE patients have increased prevalence of subclinical atherosclerosis, although the mechanisms of this observation remain unclear. Considering the emerging role of monocytes in atherosclerosis, we aimed to investigate the relationship between subclinical atherosclerosis, endothelial dysfunction and the phenotype of peripheral blood monocytes in SLE patients. We characterized the phenotype of monocyte subsets defined by the expression of CD14 and CD16 in 42 patients with SLE and 42 non-SLE controls. Using ultrasonography, intima-media thickness (IMT) of carotid arteries and brachial artery flow-mediated dilation (FMD) as well as nitroglycerin-induced dilation (NMD) were assessed. Patients with SLE had significantly, but only modestly, increased IMT when compared with non-SLE controls (median (25th/75th percentile) 0.65 (0.60/0.71) mm vs 0.60 (0.56/0.68) mm; p < 0.05). Importantly, in spite of early atherosclerotic complications in the studied SLE group, marked endothelial dysfunction was observed. CD14dimCD16+proinflammatory cell subpopulation was positively correlated with IMT in SLE patients. This phenomenon was not observed in control individuals. Interestingly, endothelial dysfunction assessed by FMD was not correlated with any of the studied monocyte subsets. Our observations suggest that CD14dimCD16+monocytes are associated with subclinical atherosclerosis in SLE, although the mechanism appears to be independent of endothelial dysfunction.

A Panel of Biomarkers Is Associated With Increased Risk of the Presence and Progression of Atherosclerosis in Women With Systemic Lupus Erythematosus

An increased frequency of atherosclerosis (ATH) in systemic lupus erythematosus (SLE) is well-documented but not fully explained by the presence of traditional cardiac risk factors. Several nontraditional biomarkers, including proinflammatory high-density lipoprotein (piHDL) and leptin, have been individually associated with subclinical ATH in SLE. The aim of this study was to examine whether these and other biomarkers can be combined into a risk profile, the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular Disease in Patients with SLE (PREDICTS), that could be used to better predict future progression of ATH. In total, 210 patients with SLE and 100 age-matched healthy control subjects (all women) participated in this prospective cohort study. The longitudinal presence of carotid plaque and intima-media thickness (IMT) were measured at baseline and followup (mean ± SD 29.6 ± 9.7 months). At followup, carotid plaque was present in 29% of SLE patients. Factors significantly associated with plaque, determined using Salford Predictive Modeling and multivariate analysis, included age ≥48 years (odds ratio [OR] 4.1, P = 0.002), high piHDL function (OR 9.1, P < 0.001), leptin levels ≥34 ng/dl (OR 7.3, P = 0.001), plasma soluble TWEAK levels ≥373 pg/ml (OR 28.8, P = 0.004), and history of diabetes (OR 61.8, P < 0.001). Homocysteine levels ≥12 μmoles/liter were also a predictor. However, no single variable demonstrated an ideal combination of good negative predictive values (NPVs), positive predictive values (PPVs), sensitivity, and specificity. A high-risk PREDICTS profile was defined as ≥3 positive biomarkers or ≥1 positive biomarker plus a history of diabetes; for high-risk SLE patients, the PPV was 64%, NPV was 94%, sensitivity was 89%, and specificity was 79%. In multivariate analysis, SLE patients with the high-risk profile had 28-fold increased odds for the longitudinal presence of plaque (P < 0.001) and increased progression of IMT (P < 0.001). A high-risk PREDICTS score confers 28-fold increased odds of the presence of any current, progressive, or acquired carotid plaque, both in patients with SLE and in control subjects, and is significantly associated with higher rates of IMT progression.

Higher circulating levels of OxLDL % of LDL are associated with subclinical atherosclerosis in female patients with systemic lupus erythematosus

Because systemic lupus erythematosus (SLE) is associated with a high risk of atherosclerosis, a process that involves low-density lipoprotein (LDL) oxidation, we examined the hypothesis that raised fraction of LDL that is converted to oxidized (Ox) LDL expressed in OxLDL % of LDL (OxLDL %) is associated with the subclinical atherosclerosis in SLE. A cohort of 60 SLE patients with no previous history of cardiovascular disease had carotid artery ultrasound to identify plaques and to measure intima-media thickness (IMT). Forty females with rheumatoid arthritis (RA) were also enrolled in the study to serve as a control group. Plasma OxLDL concentrations were measured, and the OxLDL % of LDL were calculated. Traditional and SLE-related risk factors for atherosclerosis were evaluated. OxLDL % were significantly higher in SLE patients compared to patients with RA (p=0.0311). OxLDL % were significantly higher in SLE patients with plaques than in those without plaques (p<0.001). SLE patients in the highest IMT quartile have higher OxLDL % than patients in the lower three quartiles (p<0.001). The odd ratio (OR) for the OxLDL % in patients with plaques was 6.143 (p<0.001) when compared to patient without plaques, while OR for the OxLDL % was 8.34 (p<0.001) in the patients with highest IMT quartile as compared to patients in the lower three quartiles after adjustment for confounding factors in logistic regression analysis. Our data provide evidence of an association between the circulating levels of OxLDL % of LDL with the risk for developing atherosclerosis in patients with SLE.

High-sensitivity C-reactive protein (hs-CRP) in systemic lupus erythematosus patients without cardiac involvement; relation to disease activity, damage and intima-media thickness

Aim of the workTo assess the high sensitivity C-reactive protein (hs-CRP level) in systemic lupus erythematosus (SLE) patients without cardiac involvement and find its relation with clinical and laboratory findings, disease activity, damage index and intima-media thickness (IMT). Patients and methodsForty-five female SLE patients were recruited in the present study without any cardiac involvement. History taking, examination and laboratory investigations were performed for patients. Disease activity was evaluated by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and damage by the Systemic Lupus International Collaborating Clinics (SLICC) index. Thirty age matched female healthy subjects were considered as a control group. hs-CRP was measured quantitatively by microplate immunoenzymometric assay and the IMT measured by ultrasonography. ResultsThe hs-CRP in the patients was significantly higher (4.84±3.91mg/l) compared to the control (1.74±0.61mg/l) (p<0.001). The IMT in the patients was significantly increased (0.72±0.37mm) compared to the control (0.54±0.15mm) (p 0.004). There was no difference in the level of hs-CRP according to the presence or absence of clinical manifestations. However, it was significantly higher in those with positive DNA (5.71±4.36mg/L) compared to those with negative results (3.12±1.97mg/L) (p 0.009). There was a significant correlation of the hs-CRP level with the IMT (r 0.49, p 0.001) and SLEDAI (r 0.67, p<0.001). ConclusionsThese findings suggest that SLE patients without traditional major cardiovascular risk factors may have increased risk of future cardiac events. Measuring hs-CRP may be useful as a marker of disease activity, increased IMT and subclinical atherosclerosis in SLE especially those with positive ds-DNA.

Hemorheological parameters are related to subclinical atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis patients

ObjectivesRheological characteristics of blood are strongly linked to atherothrombosis in the general population, but its contribution to atherosclerosis in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) is currently unclear. This work examines the relationship between blood rheology, traditional cardiovascular (CV) risk factors, inflammation and subclinical atherosclerosis in SLE and RA. MethodsWhole blood viscosity (WBV), plasma viscosity (PV), erythrocyte deformability (ED), aggregation (EA) and erythrocyte NO production were measured in 197 patients (96 SLE and 101 RA) and compared to 97 controls, all females without previous CV events. Clinical information was obtained and fasting lipids and acute phase reactants were measured. The relationship between hemorheological parameters, CV risk factors and inflammation was assessed in patients and the impact of these variables on carotid intima-media thickness (cIMT) was evaluated in univariate followed by multivariate regression analyses. ResultsWBV and ED are significantly lower in patients, while EA is elevated as compared with controls. Hemorheological disturbances correlate with CV risk factors and markers of inflammation and are more profound in patients with metabolic syndrome. Multivariable analysis showed that menopause (OR 34.72, 95%CI 4.44–271.77), obesity (OR 4.09, 95%CI 1.00–16.68) and WBV (OR 3.98; 95%CI 1.23–12.83) are positively associated whereas current corticosteroid dose (OR 0.87; 95%CI 0.78–0.98), and erythrocyte NO production (OR 0.16; 95%CI 0.05–0.52) are negatively associated with cIMT. ConclusionDisturbed hemorheological parameters in SLE and RA women are related to the presence of CV risk factors and inflammation. WBV and erythrocyte NO are independently associated with the early stages of atherosclerosis.

High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids

BackgroundPatients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated...

Dysfunctional proinflammatory high‐density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus

Women with systemic lupus erythematosus (SLE) have an increased risk of atherosclerosis. Identification of at-risk patients and the etiology underlying atherosclerosis in SLE remain elusive. The antioxidant capacity of normal high-density lipoproteins (HDLs) is lost during inflammation, and these dysfunctional HDLs might predispose individuals to atherosclerosis. The aim of this study was to determine whether dysfunctional proinflammatory HDL (piHDL) is associated with subclinical atherosclerosis in SLE. Carotid artery ultrasound was performed in 276 women with SLE to identify carotid plaques and measure intima-media thickness (IMT). The antioxidant function of HDL was measured as the change in oxidation of low-density lipoprotein after the addition of HDL cholesterol. Two antiinflammatory HDL components, paraoxonase 1 and apolipoprotein A-I, were also measured. Among the SLE patients, 48.2% were determined to have piHDL on carotid ultrasound, while 86.7% of patients with plaque had piHDL compared with 40.7% of those without plaque (P<0.001). Patients with piHDL also had a higher IMT (P<0.001). After multivariate analysis, the only factors found to be significantly associated with plaque were the presence of piHDL (odds ratio [OR] 16.1, P<0.001), older age (OR 1.2, P<0.001), hypertension (OR 3.0, P=0.04), dyslipidemia (OR 3.4, P=0.04), and mixed racial background (OR 8.3, P=0.04). Factors associated with IMT measurements in the highest quartile were the presence of piHDL (OR 2.5, P=0.02), older age (OR 1.1, P<0.001), a higher body mass index (OR 1.07, P=0.04), a cumulative lifetime prednisone dose>or=20 gm (OR 2.9, P=0.04), and African American race (OR 8.3, P=0.001). Dysfunctional piHDL greatly increases the risk of developing subclinical atherosclerosis in SLE. The presence of piHDL was associated with an increased prevalence of carotid plaque and with a higher IMT. Therefore, determination of piHDL may help identify patients at risk for atherosclerosis.

Accelerated Atherosclerosis in Autoimmune Rheumatic Diseases

Received October 16, 2004; revision received June 4, 2005; accepted June 7, 2005. Atherosclerosis is a multifactorial process that commences in childhood but manifests clinically later in life. Atherosclerosis is increasingly considered an immune system–mediated process of the vascular system. The presence of macrophages and activated lymphocytes within atherosclerotic plaques supports the concept of atherosclerosis as an immune system–mediated inflammatory disorder.1,2 Inflammation can aggravate atherosclerosis via different mechanisms secondary to autoimmunity, infectious diseases, and other proatherogenic changes that occur during the inflammatory state. Autoimmune rheumatic diseases (AIRDs) are associated with higher rates of cardiovascular morbidity and mortality, primarily secondary to accelerated atherosclerosis. This phenomenon can be attributed to traditional risk factors for atherosclerosis and use of specific drugs, such as corticosteroids, but also might be the result of other autoimmune and inflammatory mechanisms that are aggravated in AIRDs. Several AIRDs exhibit increased overt cardiovascular disease (CVD) prevalence as well as findings of advanced subclinical atherosclerosis, which may precede the appearance of a clinical disease and thus be a target of early identification and preventive therapy. Cells of the immune system can be found within atherosclerotic plaques, which suggests that they have a role in the atherogenic process. Their migration and activation within the plaques can be secondary to various stimuli, including infectious agents.3 These cells probably aggravate atherosclerosis, because CD4+ and CD8+ T-cell depletion reduced fatty streak formation in C57BL/6 mice. In addition, after crossing of apolipoprotein E (ApoE)-knockout mice with immunodeficient scid/scid mice, the offspring had a 73% reduction in aortic fatty streak lesions compared with the immunocompetent apoE mice. Moreover, when CD4+ T cells were transferred from the immunocompetent to the immunodeficient mice, they increased lesion area in the latter by 164%.4 It is therefore not surprising that as in autoimmune diseases, the cellular components …