Atherosclerosis In Systemic Lupus Erythematosus Patients Research Articles

Exploring novel markers for coronary heart disease associated with systemic lupus erythematosus: A review.

Systemic lupus erythematosus (SLE) is an autoimmune condition that is characterized by the production of autoantibodies and sustained inflammatory damage. Coronary heart disease (CHD) is a common complication of SLE, significantly increases CHD-related mortality in SLE patients. Despite conventional risk factors, the mechanisms contributing to a higher CHD risk require further investigation, with the immune and inflammatory aspects of SLE playing a significant role. Endothelial cell damage and dysfunction are key factors in the progression of coronary atherosclerosis in SLE patients. This review specifically focuses on endothelial dysfunction and the role of specific microRNAs in the context of SLE and CHD. In addition, we discuss the effects and functions of oxidative stress markers, endothelial progenitor cells, and circulating endothelial cells in individuals with both SLE and CHD. We also explored the typical inflammatory markers associated with SLE and CHD, addressing their clinical significance and limitations.

Subclinical Atherosclerosis and Endothelial Dysfunction in Cases of Systemic Lupus Erythematosus: A Hospital-Based Case-Control Study.

Background Women are more likely to be affected with systemic lupus erythematosus (SLE), a chronic multisystem inflammatory autoimmune illness. It is well established that SLE increases the risk of cardiovascular (CV) events. This study aimed to determine the prevalence of endothelial dysfunction and subclinical atherosclerosis in patients with SLE. If these conditions are identified early, suitable preventative measures may be advocated to lessen the burden of future CV events. Aim This study aims to calculate the frequency of endothelial dysfunction and subclinical atherosclerosis in SLE patients using the flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thickness (c-IMT). Results There were 50 confirmed cases of SLE. Compared to healthy controls, SLE patients' c-IMT readings were higher, suggesting subclinical atherosclerosis. Thirty-three patients with c-IMT values >0.06 (p<0.00269) out of 50 SLE cases were found to have a high prevalence of subclinical atherosclerosis. Five SLE patients showed FMDs of less than 4.5% (p<0.021) compared to healthy controls, indicating preclinical atherosclerosis with endothelial dysfunction. It was discovered that endothelial dysfunction exhibited a positive linear connection with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) when contrasted with traditional inflammatory indicators such as ESRand CRP. Conclusion Patients with SLE face a higher risk of CV events and mortality compared to those without the condition. They are also more prone to developing endothelial dysfunction and subclinical atherosclerosis. Detecting these issues early can help in implementing primary and secondary prevention strategies effectively.

A predictive model for premature atherosclerosis in systemic lupus erythematosus based on clinical characteristics.

Systemic lupus erythematosus (SLE) is associated with a significant risk of atherosclerotic cardiovascular disease, especially in the development of premature atherosclerosis. Specific prediction models for premature atherosclerosis in SLE patients are still limited. The objective of this study was to establish a predictive model for premature atherosclerosis in SLE. The study collected clinical and laboratory data from 148 SLE patients under the age of 55, between January 2021 and June 2023. The least absolute shrinkage and selection operator logistic regression model was utilized to identify potentially relevant features. Subsequently, a nomogram was developed using multivariable logistic analysis. The performance of the nomogram was evaluated through a receiver-operating characteristic curve, calibration curve, and decision curve analysis (DCA). A total of 148 SLE patients who fulfilled the inclusion criteria were enrolled in the study, of whom 53 patients (35.81%) met the definition of premature atherosclerosis. Hypertension, antiphospholipid syndrome, azathioprine use, duration of glucocorticoid, and age of patients were included in the multivariable regression. The nomogram, based on the non-overfitting multivariable model, was internally validated and demonstrated sufficient clinical utility for assessing the risk of premature atherosclerosis (area under curve: 0.867). The comprehensive nomogram constructed in this study serves as a useful and convenient tool for evaluating the risk of premature atherosclerosis in SLE patients. It is helpful for clinicians to early identify SLE patients with premature atherosclerosis and facilitates the implementation of more effective preventive measures. Key Points • SLE patients are at a significantly higher risk of developing premature atherosclerosis compared to the general population, and this risk persists even in cases with low disease activity. Traditional models used to evaluate and predict premature atherosclerosis in SLE patients often underestimate the risk. • This study establishes a comprehensive and visually orientated predictive model of premature atherosclerosis in SLE patients, based on clinical characteristics. • The scoring system allows for convenient and effective prediction of individual incidence of premature atherosclerosis, and could provide valuable information for identification and making further intervention decision.

The Contribution of Serum Sialic Acid Binding Immunoglobulin-Like Lectin 1(sSIGLEC-1) as an IFN I Signature Biomarker in the Progression of Atherosclerosis in Egyptian Systemic Lupus Erythematosus (SLE) Patients.

Clinical symptoms of systemic lupus erythematosus (SLE), such as atherosclerosis and related cardiovascular diseases, are caused by inflammatory cytokines and endothelial cell damage. The serum sialic acid binding immunoglobulin-like lectin 1 (sSIGLEC-1) is thought to be an alternative biomarker of IFN signature and may have a role in the pathogenesis of atherosclerosis. The aim of the study was to measure the levels of sSIGLEC-1 in the serum of SLE patients in comparison to a control group and examine the associations between sSIGLEC-1, SLEDAI, lipid profile, oxidized low density lipoprotein (oxLDL), and carotid intima media thickness (CIMT) to investigate whether sSIGLEC-1 participates in the development of atherosclerosis. sSIGLEC-1 levels were tested in 53 patients and 20 volunteers using ELISA kit. Duplex measurements were performed on all subjects to measure CIMT. SLE patients had significantly higher values of sSIGLEC-1 (P < 0.0001), total cholesterol (P = 0.029), triglycerides (P = 0.001), low density lipoprotein (P = 0.032), oxLDL (P = 0.001), right CIMT (P = 0.0099) and a significantly lower value of high-density lipoprotein (P = 0.04) when compared to controls. sSIGLEC-1 had significant positive correlations with right CIMT (r = 0.5, P < 0.0002) and oxLDL (r = 0.67, P < 0.0001) in all SLE patients. When compared to non-dyslipidemic patients, the dyslipidemic group exhibited significantly higher levels of all previous parameters except HDL and left CIMT. Circulating form of SIGLEC-1 accelerates atherosclerosis and provides a simple way to predict the occurrence of atherosclerosis in SLE patients.

PREDICTION OF ATHEROSCLEROSIS DEVELOPMENT AND MODIFICATION OF ITS RISK FACTORS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Objective: Early-onset atherosclerosis with cardiovascular (CV) sequelae is the major cause of death in systemic lupus erythematosus (SLE); that cannot be explained only by traditional Framingham risk factors as SLE-related factors may also have an impact. The present study aimed to analyze the determinants of atherosclerosis development and risk factors modification by statin therapy in SLE patients. Design and method: This prospective randomized study included 100 SLE patients aged 40.9±1.4 years (90 females, 10 males) and 32 age-, sex-matched healthy controls. Brachial artery flow-mediated dilation (FMD), ultrasound of extracranial and peripheral arteries, and cardiac calcium scoring were used for the identification of atherosclerosis. 52 SLE patients with dyslipidemia were randomized to receive simvastatin 40 mg/day (n = 27) or placebo (n = 25). Lipid panel, FMD, and inflammatory markers were assessed at baseline and after 6 months. Results: The mean duration of SLE was 9.9±0.88 years. The disease activity index (SLEDAI) and SLE damage score (SLICC) were 11.8±0.6 and 1.85±0.13 points, respectively. In 66% of SLE patients, atherosclerosis was present in at least one vascular area which was 3.5 times more frequently compared with controls. Atherosclerosis of carotid arteries was detected in 41% of SLE patients, lower limb arteries, and coronary arteries in 58% and 39% of patients, respectively. FMD was significantly decreased in SLE patients compared to controls (7.95±0.49% vs 11.6±0.3%, p&lt;0.001). In multiple linear regression, age (p&lt;0.001), nephritis (p = 0.001), polyarthritis (p = 0.019), and Raynaud's syndrome (p = 0.045) were associated with low FMD. In binary logistic regression, independent determinants of the atherosclerosis development in SLE were age (p&lt;0.001), body mass index (BMI) (p = 0.001), anti-dsDNA (p = 0.023), FMD (p = 0.017) and malar rash (p = 0.02). After simvastatin treatment, the level of LDL-Cholesterol reduced by 42%, erythrocyte sedimentation rate, C-reactive protein, and interleukin-6 decreased by 34.7%, 51.1%, and 47.7% respectively, while FMD increased by 26.0% (p&lt;0.05); in the placebo group, there were no significant changes. Conclusions: The independent determinants of atherosclerosis in SLE patients were both traditional CV risk factors (age, BMI) and SLE-specific factors (anti-dsDNA, malar rash, FMD). In SLE patients with dyslipidemia, simvastatin may have not only lipid-lowering but also potentially anti-inflammatory benefits.

Serum Osteoprotegerin Level as a Risk Factor for Atherosclerosis in Systemic Lupus Erythematosus Patients: A Cross Sectional Study

Background: Prediction ofthe risk of atherosclerosis in Egyptian patients with systemic lupus erythematosus (SLE) by measuring serum osteoprotegerin (OPG) level and correlation between OPG levels and SLE disease activity (assessed by Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] score), is the aim of this study. Methods:A cross sectional study in which all patients were subjected to full medical history, full clinical examination (with special emphasis to SLE symptoms and signs e.g. photosensitivity, arthralgia, arthritis, malar rash, blood pressure and lower limb edema), laboratory investigations (CBC, random blood sugar [RBS], ESR, albumin/creatinine ratio, serum urea and creatinine, serum albumin, C3, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, calcium and phosphorus). Electrocardiography (ECG) was done to calculate QTc interval using Bazett’s formula: QTC = QT / √ RR. Serum osteoprotegerin level was measured using ELISA technique. All participants were subjected to imaging in the form of: Carotid duplex: to assess intima-media thickness just two cm before carotid bifurcation, and to assess any plaques, if present. Also brachial artery flow mediated dilatation method: for detection of subclinical atherosclerosis. Results: There was a statistically significant negative correlation between serum levels of osteoprotegerin and brachial flow mediated dilation percentage (FMD %) values (P value &gt; 0.001) which means a significant correlation between high serum OPG levels and subclinical atherosclerosis in SLE patients. There were statistically significant differences between SLE cases and controls in right and left carotid intima-media thickness (P value: 0.034 &amp; 0.036 respectively), serum osteoprotegerin levels (P value: &gt; 0.001) and QTc values (P value: 0.011) which were all statistically significantly higher in SLE patients, while brachial FMD % was statistically significantly lower in SLE patients than in controls (P value: &gt; 0.001). Also, there was a statistically significant positive correlation between serum OPG levels and QTc interval (P value: 0.006). Conclusion: We have concluded that serum OPG level has a significant correlation with subclinical atherosclerosis and endothelial dysfunction, which was measured by CIMT and brachial mediated flow dilation method.

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.

LOX-1: A potential driver of cardiovascular risk in SLE patients.

Traditional cardiovascular disease (CVD) risk factors, such as hypertension, dyslipidemia and diabetes do not explain the increased CVD burden in systemic lupus erythematosus (SLE). The oxidized-LDL receptor, LOX-1, is an inflammation-induced receptor implicated in atherosclerotic plaque formation in acute coronary syndrome, and here we evaluated its role in SLE-associated CVD. SLE patients have increased sLOX-1 levels which were associated with elevated proinflammatory HDL, oxLDL and hsCRP. Interestingly, increased sLOX-1 levels were associated with patients with early disease onset, low disease activity, increased IL-8, and normal complement and hematological measures. LOX-1 was increased on patient-derived monocytes and low-density granulocytes, and activation with oxLDL and immune-complexes increased membrane LOX-1, TACE activity, sLOX-1 release, proinflammatory cytokine production by monocytes, and triggered the formation of neutrophil extracellular traps which can promote vascular injury. In conclusion, perturbations in the lipid content in SLE patients’ blood activate LOX-1 and promote inflammatory responses. Increased sLOX-1 levels may be an indicator of high CVD risk, and blockade of LOX-1 may provide a therapeutic opportunity for ameliorating atherosclerosis in SLE patients.

High-Density Lipoprotein in Lupus: Disease Biomarkers and Potential Therapeutic Strategy.

Systemic lupus erythematosus (SLE) patients exhibit accelerated development of atherosclerosis and increased incidents of cardiovascular disease (CVD) that cannot be explained by traditional risk factors alone. Accumulating evidence suggests that reduced levels of high-density lipoproteins (HDLs), along with altered HDL composition and function, may contribute to the accelerated atherosclerosis in SLE patients. Normally, HDLs play various atheroprotective roles through facilitating cholesterol efflux, inhibiting vascular inflammation, and scavenging oxidative species. However, systemic inflammation, oxidative stress, and autoimmunity in SLE patients induce changes in HDL size distribution and proteomic and lipidomic signatures. These compositional changes in HDLs result in the formation of proinflammatory, dysfunctional HDL. These lupus-altered HDLs have impaired antiatherogenic function with reduced cholesterol efflux capacities, impaired antioxidation abilities, and diminished antiinflammatory properties. In fact, dysfunctional HDL may promote atherogenesis by inducing inflammation. Thus, dysfunctional HDLs could be an important biomarker of accelerated atherosclerosis in lupus. Additionally, HDL-targeted therapies, especially infusion of reconstituted HDLs, may serve as a potential therapeutic intervention for SLE patients with CVD.

Soluble CD163 is a biomarker for accelerated atherosclerosis in systemic lupus erythematosus patients at apparent low risk for cardiovascular disease

Objective: This study aimed to determine whether sCD163, a soluble macrophage marker up-regulated in numerous inflammatory disorders, is predictive of accelerated atherosclerosis associated with systemic lupus erythematosus (SLE).Methods: Carotid ultrasound was prospectively performed, at baseline and during follow-up, in 63 consecutive SLE patients asymptomatic for cardiovascular disease (CVD) and 18 volunteer health workers. Serum sCD163 level was determined at baseline using enzyme-linked immunosorbent assay. The primary outcome was the presence of a carotid plaque. Factors associated with carotid plaques were identified through multivariate analysis.Results: Despite a low risk for cardiovascular events according to Framingham score in both groups (2.1 ± 3.8% in SLE vs 2.1 ± 2.9% in controls; p = 0.416), ultrasound at baseline showed a carotid plaque in 23 SLE patients (36.5%) and two controls (11.1%) (p = 0.039). Multivariate analysis showed that SLE status increased the risk for carotid plaque by a factor of 9 (p = 0.017). In SLE patients, sCD163 level was high (483.7 ± 260.8 ng/mL vs 282.1 ± 97.5 ng/mL in controls; p < 0.001) and independently associated with carotid plaques, as assessed by stratification based on sCD163 quartile values (p = 0.009), receiver operating characteristics (p = 0.001), and multivariate analysis (p = 0.015). sCD163 at baseline was associated with the onset of carotid plaque during follow-up (3 ± 1.4 years) in SLE patients who had no carotid plaque at the first evaluation (p = 0.041).Conclusion: sCD163 is associated with progressing carotid plaque in SLE and may be a useful biomarker for accelerated atherosclerosis in SLE patients at apparent low risk for CVD.

Low-density lipoprotein net charge is a risk factor for atherosclerosis in lupus patients independent of lipid concentrations.

Patients with systemic lupus erythematosus (SLE) suffer from accelerated atherosclerosis. Their most common cause of death is a cardiovascular disease (CVD), in spite of the presence of moderate lipid alterations and normal cardiovascular risk scores. However, cholesterol still accumulates in the arteries of SLE patients, so we aim to identify additional factors that may help explain the residual risk that exists in these patients. We focus on investigating whether the net charge contributes significantly to both the development and the progression of atherosclerosis in patients with SLE. The lipoproteins from 78 patients with SLE and 32 controls were isolated via sequential ultracentrifugation. Lipoprotein subclasses distributions were analyzed via nuclear magnetic resonance spectroscopy and the net charges of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were measured using a Zetasizer Nano-ZS. The degree of atherosclerosis (carotid intima-media thickness [cIMT]) was determined in all the participants. Each lipoprotein class exhibited a negative net charge. IDL and LDL net charge correlated negatively with cIMT (r=-0.274, P=0.034; r=-0.288; P=0.033, respectively) in patients with SLE. This effect was independent of age, body mass index (BMI), gender, tobacco consumption, high-sensitivity C-reactive protein (hsCRP), lipid concentration and lipoprotein particle number. LDL net charge explained 4% of the cIMT variability among these patients; this contribution was also independent of age, BMI, gender, tobacco consumption, lipids levels, apolipoproteins and hsCRP. Low-density lipoprotein net charge may be considered a new independent contributor to subclinical atherosclerosis in SLE patients. The observed relationship was independent of lipid concentrations and extends the prominent role that IDL and LDL play in cardiovascular risk.

Association between Type I interferon and depletion and dysfunction of endothelial progenitor cells in C57BL/6 mice deficient in both apolipoprotein E and Fas ligand

Patients with systemic lupus erythematosus (SLE) have a tremendously increased risk for cardiovascular disease (CVD), which could not be accounted in entirety by traditional Framingham risk factors. To study whether the accelerated atherosclerosis in SLE patients is mediated by type I interferon (IFN-I) through the regulation of endothelial progenitor cells (EPCs), we created a line of C57BL/6 mice with deficiency in both apolipoprotein E (ApoE−/−) and fas ligand (FasL−/−, gld.). As expected, the resultant gld. ApoE−/− mice exhibited both aggravated lupus-like disease and atherosclerosis under normal diet. Increased expression of IFN-I-stimulated genes (ISGs) was closely associated with depletion and dysfunction of EPCs, as well as with accelerated atherosclerotic lesion in gld. ApoE−/− mice. While only IFN-α instead of other interventions, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IRS423 and IRS661, impaired EPC function in vitro. Mechanistically, activation or inhibition of the TLR7/9 signaling could modulate EPC number and function in vivo. Decreased proliferation rate and increased apoptotic rate of EPCs induced by IFN-α might contribute to the results to a certain extent. Thus, our data suggest that excessive expression of IFN-I through the activation of TLR7/9 signaling may induce accelerated atherosclerosis in lupus through the depletion or dysfunction of EPCs, suggesting that targeting IFN-I might have potential therapeutic effects on both lupus disease and premature atherosclerosis in SLE patients.

Anxiety and Extraversion in Lupus-Related Atherosclerosis.

Objectives: Patients with systemic lupus erythematosus (SLE) are characterized by increased cardiovascular disease (CVD) risk as well as heightened rates of psychological distress. Since a link between psychological issues and CV morbidity has been previously suggested, the influence of psychological burden on subclinical atherosclerosis in SLE patients was investigated.Methods: 71 SLE patients were assessed for the presence of subclinical atherosclerosis—defined either as carotid and/or femoral plaque formation or arterial wall thickening [Intima Media Thickness (IMT) levels > 0.90 mm by Doppler ultrasound]; personality traits, anxiety and depression, sleeping habits and fatigue levels were also evaluated by specific questionnaires including Eysenck Personality Questionnaire Scale, State-Trait Anxiety Inventory (STAI), Zung Depression Scale, Athens Insomnia Scale and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Disease related clinical and laboratory features and traditional risk factors for atherosclerosis were documented. Univariate and multivariate analysis were performed.Results: SLE patients with arterial wall thickening displayed higher STAI anxiety scores (either as a current state or as a personality trait) compared to those without (49.8 ± 5.6 vs. 46.9 ± 5.4, p-value: 0.03 and 49.2 ± 4.4 vs. 45.7 ± 6.8, p-value: 0.009, respectively). In a multivariate model, trait anxiety and extraversion personality scores were found to be independently associated with arterial wall thickening and plaque formation, respectively [OR95%(CI):1.2(1.0–1.5) and 0.7(0.6–1.0), respectively], following adjustment for potential confounders. No other associations were detected.Conclusions: Anxiety and extraversion personality traits have been independently associated with subclinical atherosclerosis in lupus patients, implying psychoneuroimmunological interactions as contributors in SLE related atherosclerosis.

Contribution of MTHFR gene variants in lupus related subclinical atherosclerosis

ObjectiveElevated concentrations of homocysteine have been previously identified as an independent risk factor for subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE). Given that heightened homocysteine levels are known to be strongly influenced by genetic factors, in the current study we investigated the contribution of high homocysteine levels as well as of functional polymorphisms of the gene encoding for the enzyme 5, 10- methylenetetrahydrofolate reductase (MTHFR) to atherosclerotic disease characterizing SLE patients. MethodsPeripheral DNA samples from 150 SLE patients, 214 rheumatoid arthritis (RA) patients and 561 age/sex matched apparently healthy volunteers (HC) were genotyped by PCR-based assays for the detection of the MTHFR gene polymorphisms (c. 677C > T and c. 1298A > C). All SLE patients and 30 age sex matched RA patients underwent assessment for subclinical atherosclerosis [ultrasound measurement of intima-media thickness scores (IMT) and detection of carotid and/or femoral (C/F) plaque] and complete clinical and laboratory evaluation including serum homocysteine levels. Data were analyzed using univariate and multivariate models (SPSS 21.0). ResultsHyperhomocysteinemia was detected in 26.0% of SLE patients compared to 6.7% of age/sex matched RA controls (p = 0.02). Higher serum B12 levels and decreased frequency of the MTHFR 677TT variant in RA patients could potentially account for the observed differences between the groups. In SLE patients, both hyperhomocysteinemia and MTHFR 677TT genotype were identified as independent contributors for plaque formation, following adjustment for traditional cardiovascular risk factors and disease related features, including age, sex, BMI, cholesterol and triglyceride levels, presence of arterial hypertension, smoking (pack/years), disease duration and total steroid dose [OR 95% (CI): 5.8 (1.0–35.8) and 5.2 (1.1–24.0), respectively]. MTHFR 677TT genotype, but not hyperhomocysteinemia was also found to confer increased risk for arterial wall thickening, after the above confounders were taken into account [OR (95%) CI: 4.9 (1.2–20.6)]. ConclusionsHyperhomocysteinemia and MTHFR 677TT genetic variant emerged as independent risk factors for subclinical atherosclerosis in SLE patients, implying genetic influences as potential contributors to the increased burden of atherosclerotic disease characterizing SLE.

Assessment of subclinical atherosclerosis in systemic lupus erythematosus: A systematic review and meta-analysis

ObjectivesTo determine whether subclinical atherosclerosis is increased in patients with systemic lupus erythematosus (SLE) compared to healthy individuals, using carotid intima-media thickness (CIMT), carotid plaque (CP) presence or flow-mediated dilatation (FMD). MethodsA systematic literature search was performed using MedLine, Embase and Cochrane databases. Two reviewers independently screened the articles to identify studies that compared the rates of atherosclerosis in SLE patients versus healthy controls. The results were pooled in a meta-analysis. Factors influencing the CIMT, CP or FMD results were collected. ResultsOf the 203 articles initially identified, 68 were selected for the meta-analysis. Compared to healthy controls, SLE patients had a significantly increased CIMT (mean difference [MD] of 0.08mm, 95% CI [0.06–0.09], P<0.05), more CP (odds ratio 2.01, 95% CI [1.63–2.47], P<0.05) and decreased FMD (MD −3.96%, 95% CI [−5.37 to −2.54)], P<0.05). There was marked heterogeneity among the studies. However, the results of the meta-analysis that included only the CIMT per new international recommendations also showed an increased CIMT in SLE patients, but the heterogeneity was low (MD 0.04mm, 95% CI [0.02–0.06], P<0.05; I2=23%). ConclusionSLE patients exhibit increased subclinical atherosclerosis compared to healthy controls. CIMT is a promising measure for cardiovascular risk evaluations because non-invasive, non-radiation-based, reproducible. Thus, CIMT can be proposed as an alternative to the reliable CP evaluation and to FMD, which is influenced by independent factors such as smoking. Future studies should focus on reducing the heterogeneity of these measures using standardized procedures.

Plasma Atherogenic Index is an Independent Indicator of Subclinical Atherosclerosis in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is characterized by chronic inflammation. Plasma atherogenic index (PAI) is a valuable marker for the cardiovascular disease and cardiac risk. The aim of this study was to evaluate the role and clinical use of PAI in atherosclerosis and the cardiac risk in SLE patients. We included 56 female SLE patients who were selected according to the American College of Rheumatology (1997) diagnosis criteria. Furthermore, we selected age-and body mass index (BMI)-matched 56 female healthy individuals. PAI was measured as a logarithmic value of triglyceride to high-density cholesterol ratio. We used carotid intima media thickness (cIMT) as an inflammatory marker because of its widespread use. The lipid and other biochemical parameters of patient and control groups were examined. The PAI and cIMT values of SLE patients were 0.04±0.23 and 0.78±0.18 mm, respectively. Besides, for the control group, the PAI value was -0.09±0.20 and cIMT value was 0.50±0.15 mm (p=0.002, p<0.001; respectively). There was a strong correlation between cIMT and PAI (r=0.273, p=0.003). According to the multiple logistic regression analysis, we found that PAI value is an independent factor for cIMT in SLE patients (odds ratio: 2.6, 95 % confidence interval; 1.506-4.374; p=0.029). We determined that PAI can be used as an independent indicator for subclinical atherosclerosis in SLE patients.

Disease trends over time and CD4+CCR5+ T-cells expansion predict carotid atherosclerosis development in patients with systemic lupus erythematosus

Background and AimPatients with Systemic Lupus Erythematosus (SLE) present increased cardiovascular mortality compared to the general population. Few studies have assessed the long-term development and progression of carotid atherosclerotic plaque in SLE patients. Our aim was to investigate the association of clinical and laboratory markers of disease activity and classical cardiovascular risk factors (CVRF) with carotid atherosclerosis development in SLE patients in a prospective 5-year study. Methods and resultsClinical history and information on principal CVRFs were collected at baseline and after 5 years in 40 SLE patients (36 women, mean age 42 ± 9 years; 14.4 ± 7 years of mean disease duration) and 50 age-matched controls. Carotid Doppler ultrasonography was employed to quantify the atherosclerotic burden at baseline and at follow up. Clinimetrics were applied to assess SLE activity over time (SLEDAI). The association between basal circulating T cell subsets (including CD4+CCR5+; CD4+CXCR3+; CD4+HLADR+; CD4+CD45RA+RO−, CD4+CD45RO+RA− and their subsets) and atherosclerosis development was evaluated. During the 5-year follow up, 32% of SLE patients, developed carotid atherosclerosis compared to 4% of controls. Furthermore, considering SLEDAI changes over time, patients within the highest tertile were those with increased incidence of carotid atherosclerosis independently of CVRF. In addition, increased levels of CD4+CCR5+ T cells were independently associated with the development of carotid atherosclerosis in SLE patients. ConclusionSerial clinical evaluations over time, rather than a single point estimation of disease activity or CVRF burden, are required to define the risk of carotid atherosclerosis development in SLE patients. Specific T cell subsets are associated with long-term atherosclerotic progression and may further be of help in predicting vascular disease progression.

Cross-talk between iNKT cells and monocytes triggers an atheroprotective immune response in SLE patients with asymptomatic plaque.

Accelerated atherosclerosis is a complication of the autoimmune rheumatic disease systemic lupus erythematosus (SLE). We questioned the role played by invariant natural killer T (iNKT) cells in this process because they not only are defective in autoimmunity but also promote atherosclerosis in response to CD1d-mediated lipid antigen presentation. iNKT cells from SLE patients with asymptomatic plaque (SLE-P) had increased proliferation and interleukin-4 production compared with those from SLE patients with no plaque. The anti-inflammatory iNKT cell phenotype was associated with dyslipidemia and was driven by altered monocyte phospholipid expression and CD1d-mediated cross-talk between iNKT cells and monocytes but not B cells. Healthy iNKT cells differentiated in the presence of healthy monocytes and SLE-P serum polarized macrophages toward an anti-inflammatory M2 phenotype. Conversely, patients with clinical cardiovascular disease had unresponsive iNKT cells and increased proinflammatory monocytes. iNKT cell function could link immune responses, lipids, and cardiovascular disease in SLE patients and, together with serum lipid taxonomy, help predict preclinical atherosclerosis in SLE patients.

Overweight Is a Major Contributor to Atherosclerosis in Systemic Lupus Erythematosus Patients at Apparent Low Risk for Cardiovascular Disease: A Cross-Sectional Controlled Study.

Cardiovascular disease (CVD) is the main cause of death in systemic lupus erythematosus (SLE) patients. We aimed to determine whether overweight (defined as a body mass index [BMI] > 25 kg/m2) contributed to subclinical atherosclerosis in SLE patients at low risk for CVD according to traditional factors.Wall thickness of the internal carotid artery (ICWT) measured at the carotid bulb and carotid plaques were assessed in 49 SLE patients asymptomatic for CVD and 49 controls matched on Framingham score. Factors associated to ICWT were identified and multivariate analysis was performed.SLE patients and controls displayed a low 10-year risk for CVD according to Framingham score (mean 1.9 ± 3.5 in SLE vs 1.8 ± 3.2% in controls, P = 0.37). ICWT (P < 0.001) and number of patients with carotid plaques (P = 0.015) were, however, higher in SLE patients as compared to controls. In multivariable analysis, SLE was an independent risk for a carotid atherosclerosis (OR [95% confidence interval, CI]: 3.53 [1.36–9.14]; P = 0.009). Older age, higher BMI, and higher Framingham score were associated with atherosclerosis in SLE patients in univariate analysis. In multivariate analysis, only the association with overweight remained significant (OR [95% CI]: 4.13 [1.02–16.75]; P = 0.047).Overweight is a major contributor to atherosclerosis in SLE patients at apparent low risk for CVD.

CD4+CXCR3+ T cells and plasmacytoid dendritic cells drive accelerated atherosclerosis associated with systemic lupus erythematosus

Cardiovascular disease due to accelerated atherosclerosis is the leading cause of death in patients with systemic lupus erythematosus (SLE). Noteworthy, accelerated atherosclerosis in SLE patients appears to be independant of classical Framingham risk factors. This suggests that aggravated atherosclerosis in SLE patients may be a result of increased inflammation and altered immune responses. However, the mechanisms that mediate the acceleration of atherosclerosis in SLE remain elusive. Based on experimental data which includes both humans (SLE patients and control subjects) and rodents (ApoE−/− mice), we herein propose a multi-step model in which the immune dysfunction associated with SLE (i.e. high level of IFN-α production by TLR 9-stimulated pDCs) is associated with, first, an increased frequency of circulating pro inflammatory CD4+CXCR3+ T cells; second, an increased production of CXCR3 ligands by endothelial cells; third, an increased recruitment of pro-inflammatory CD4+CXCR3+ T cells into the arterial wall, and fourth, the development of atherosclerosis. In showing how SLE may promote accelerated atherosclerosis, our model also points to hypotheses for potential interventions, such as pDCs-targeted therapy, that might be studied in the future.