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OBJECTIVES: Traditional cardiovascular risk calculators such as the Framingham Risk Score (FRS) have been shown to underestimate risk in patients with SLE. The QRISK3 calculator is unique in including SLE and corticosteroid use as risk factors. This study aims to assess the validity of QRISK3 compared with other cardiovascular risk models in a cohort of patients with SLE in the USA. METHODS: We studied a prospective cohort of 366 adult patients with SLE without history of any cardiovascular event and followed them for 10 years. We compared the diagnostic performance of QRISK3 with FRS, modified FRS, Atherosclerotic Cardiovascular Disease (ASCVD), and Predictors of Risk for Elevated Flares, Damage Progression and Increased Cardiovascular Disease in Patients with SLE (PREDICTS). RESULTS: Sixty-four of the 366 patients (17.4%) experienced at least one cardiovascular event during the 10-year follow-up period. Of these patients 45% had a QRISK3 score >10%, whereas 20.5% of patients who did not have an event had a QRISK3 score >10% (p<0.001). The corresponding numbers for FRS, modified FRS, ASCVD and PREDICTS were 11.0% vs 7.2% (p=ns), 40.6% vs 28.0% (p=0.05), 12.2% vs 5.9% (p=ns), and 77% vs 32.1% (p<0.001), respectively. The areas under the receiver operating characteristic curve using QRISK3 >10% and high-risk PREDICTS were both larger than those using ASCVD >10%, FRS >10% and modified FRS >10%. CONCLUSIONS: Both QRISK3 and PREDICTS demonstrated better performance in predicting risk of cardiovascular disease in this cohort of patients with SLE compared with FRS, modified FRS and ASCVD.
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Doenças Cardiovasculares , Lúpus Eritematoso Sistêmico , Adulto , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Humanos , Lúpus Eritematoso Sistêmico/complicações , Estudos Prospectivos , Medição de Risco , Fatores de RiscoRESUMO
Prevention and treatment of orthopedic device-related infection (ODRI) is complicated by the formation of bacterial biofilms. Biofilm formation involves dynamic production of macromolecules that contribute to the structure of the biofilm over time. Limitations to clinically relevant and translational biofilm visualization and measurement hamper advances in this area of research. In this paper, we present a multimodal methodology for improved characterization of Pseudomonas aeruginosa grown on polyether ether ketone (PEEK) as a model for ODRI. PEEK discs were inoculated with P. aeruginosa, incubated for 4-48 h time intervals, and fixed with 10% neutral-buffered formalin. Samples were stained with fluorescent dyes to measure biofilm components, imaged with confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM), and quantified. We were able to visualize and quantify P. aeruginosa biofilm growth on PEEK implants over 48 h. Based on imaging data, we propose a generalized growth cycle that can inform orthopedic diagnostic and treatment for this pathogen on PEEK. These results demonstrate the potential of using a combined CLSM and SEM approach for determining biofilm structure, composition, post-adherence development on orthopedic materials. This model may be used for quantitative biofilm analysis for other pathogens and other materials of orthopedic relevance for translational study of ODRI.
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Corantes Fluorescentes , Pseudomonas aeruginosa , Benzofenonas , Biofilmes , Éteres , Formaldeído , Cetonas/farmacologia , PolímerosRESUMO
OBJECTIVE: The increase in cardiovascular events (CVEs) in systemic lupus erythematosus (SLE) is not fully explained by traditional risk factors. We previously identified four biomarkers (proinflammatory high-density lipoprotein, leptin, soluble TNF-like weak inducer of apoptosis (sTWEAK), and homocysteine) that we combined with age and diabetes to create the predictors of risk for elevated flares, damage progression, and increased cardiovascular diseasein patients with SLE (PREDICTS) risk profile. PREDICTS more accurately identified patients with SLE at risk for progression of subclinical atherosclerosis than any individual variable. We examined whether PREDICTS can also identify patients with SLE at risk for future CVEs. METHODS: A total of 342 patients with SLE and 155 matched control subjects participated in this longitudinal prospective study. A high PREDICTS score was defined as three or more predictors or diabetes + one or more predictor. The biomarkers were measured at baseline using published methods. All major adverse CVEs (MACEs) were confirmed by medical record review. RESULTS: During 116 months of follow-up, 5% of patients with SLE died, 12% had a cerebrovascular event, and 5% had a cardiac event. Overall, 20% of patients with lupus experienced any new MACE compared with 5% of control subjects (P < 0.0001). More patients with SLE with a new MACE had high PREDICTS score at baseline (77%) versus patients with no new events (34%) (P < 0.0001). High baseline PREDICTS score also associated with cerebrovascular (P < 0.0001) and cardiac events (P < 0.0001) in SLE. Using Cox regression, a baseline high PREDICTS score associated with a 3.7-fold increased hazard ratio (HR) for a new MACE (P < 0.0001) in SLE. Hypertension (HR = 2.1; P = 0.006) was also a risk. CONCLUSION: A high PREDICTS score and hypertension confer increased risk for new MACEs in patients with SLE.
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OBJECTIVE: Patients with SLE have an increased risk of atherosclerosis (ATH) that is not adequately explained by traditional risk factors. We previously described the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular disease in PaTients with SLE (PREDICTS) atherosclerosis-risk panel, which includes proinflammatory HDL (piHDL), leptin, soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) and homocysteine, as well as age and diabetes. A high PREDICTS score confers 28-fold increased odds for future atherosclerosis in SLE. The aim of this study is to determine whether PREDICTS biomarkers are modifiable by common lupus therapies. METHODS: This prospective observational study included SLE subjects started on new lupus treatments. Leptin, sTWEAK, homocysteine and antioxidant function of HDL were measured at baseline (prior to drug initiation), 6 weeks and 12 weeks. RESULTS: 16 subjects started mycophenolate (MMF), 18 azathioprine (AZA) and 25 hydroxychloroquine (HCQ). In MMF-treated subjects, HDL function progressively improved from 2.23 ± 1.32 at baseline to 1.37±0.81 at 6 weeks (p=0.02) and 0.93±0.54 at 12 weeks (p=0.009). sTWEAK levels also improved in MMF-treated subjects from 477.5±447.1 to 290.3±204.6 pg/mL after 12 weeks (p=0.04), but leptin and homocysteine levels were not significantly changed. In HCQ-treated subjects, only HDL function improved from 1.80±1.29 at baseline to 1.03±0.74 after 12 weeks (p=0.05). There were no changes in the AZA group. MMF treatment was still associated with significant improvements in HDL function after accounting for potential confounders such as total prednisone dose and changes in disease activity. Overall, the mean number of high-risk PREDICTS biomarkers at week 12 significantly decreased in the entire group of patients started on a new lupus therapy (2.1±0.9 to 1.8±0.9, p=0.02) and in the MMF-treated group (2.4±0.8 vs 1.8±0.9, p=0.003), but not in the AZA or HCQ groups. In multivariate analysis, the odds of having a high PREDICTS atherosclerosis risk score at 12 weeks were lower with MMF treatment (OR 0.002, 95% CI 0.000 to 0.55, p=0.03). CONCLUSIONS: 12 weeks of MMF therapy improves the overall PREDICTS atherosclerosis biomarker profile. Further studies will determine whether biomarker changes reflect decreases in future cardiovascular events.
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OBJECTIVE: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.
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Biomarcadores/sangue , Doenças das Artérias Carótidas/diagnóstico , Lúpus Eritematoso Sistêmico/diagnóstico , Adiponectina/sangue , Adulto , Fatores Etários , Apolipoproteína A-I/sangue , Aterosclerose/sangue , Aterosclerose/complicações , Aterosclerose/diagnóstico , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/complicações , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , HDL-Colesterol/sangue , HDL-Colesterol/imunologia , LDL-Colesterol/sangue , Estudos de Coortes , Citocina TWEAK , Complicações do Diabetes , Diabetes Mellitus , Progressão da Doença , Feminino , Homocisteína/sangue , Humanos , Leptina/sangue , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Placa Aterosclerótica/sangue , Placa Aterosclerótica/complicações , Placa Aterosclerótica/diagnóstico , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Fatores de Necrose Tumoral/sangueRESUMO
BACKGROUND: Patients 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 with both atherosclerosis and immunomodulatory functions in the general population. OBJECTIVE: To examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis. METHODS: Carotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed. RESULTS: Leptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p<0.001). Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4±32.3 vs 20.9±26.4 ng/ml, p=0.002). After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (≥29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p<0.001), age (OR=1.1, p<0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01). Adiponectin levels were not significantly associated with plaque in our cohort. A significant correlation between leptin and piHDL function (p<0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present. CONCLUSIONS: High leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100. High leptin levels may help to identify patients with SLE at risk of atherosclerosis.
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Aterosclerose/etiologia , Mediadores da Inflamação/sangue , Leptina/sangue , Lúpus Eritematoso Sistêmico/complicações , Adipocinas/sangue , Adulto , Aterosclerose/sangue , Aterosclerose/diagnóstico por imagem , Biomarcadores/sangue , Índice de Massa Corporal , Artéria Carótida Primitiva/diagnóstico por imagem , Métodos Epidemiológicos , Feminino , Humanos , Lipídeos/sangue , Lúpus Eritematoso Sistêmico/sangue , Pessoa de Meia-Idade , Oxirredução , UltrassonografiaRESUMO
Accelerated atherosclerosis is a major co-morbid condition in autoimmune diseases. Monocytes are the main immune cell involved in atherosclerosis initiation. We hypothesized that dysfunctional, pro-inflammatory HDL (piHDL), which occurs in approximately half of SLE patients, might directly influence monocyte gene expression and function. SLE subjects were stratified into three groups: 1) carotid artery plaque+piHDL+,2) plaque-piHDL+,and 3) plaque-piHDL- (n=18/group). PDGFRß was upregulated in primary monocytes from plaque+piHDL+patients and in THP-1 cells acutely treated in vitro with piHDL compared to normal HDL. THP-1 chemotaxis was enhanced after treatment with piHDL versus normal HDL. Abnormal migration was restored to normal levels by treatment with imatinib or an apoJ mimetic peptide. Increased piHDL-mediated TNFα protein levels were reduced with both inhibitors. Dysfunctional piHDL directly influences expression of a small number of transcripts and proteins, and piHDL inhibition through reducing piHDL oxidation or blocking PDGFRß kinase activity restored normal monocyte chemotaxis.
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Quimiotaxia/efeitos dos fármacos , Lipoproteínas HDL/farmacologia , Lúpus Eritematoso Sistêmico/metabolismo , Monócitos/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Apolipoproteína A-I/química , Benzamidas , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Colesterol/sangue , Clusterina/química , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Cardiopatias/epidemiologia , Humanos , Mesilato de Imatinib , Lipoproteínas HDL/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Pessoa de Meia-Idade , Mimetismo Molecular , Monócitos/citologia , Monócitos/efeitos dos fármacos , Peptídeos/farmacologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fatores de Risco , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/genéticaRESUMO
OBJECTIVE: To investigate the association between physical activity, functional activity of high-density lipoprotein (HDL), and subclinical cardiovascular disease in patients with systemic lupus erythematosus (SLE). METHODS: A total of 242 SLE patients (all women) participated in this cross-sectional study from February 2004 to February 2008. Carotid plaque and intima-media thickness (IMT), antioxidant function of HDL, and traditional cardiac risk factors were measured. Physical activity was assessed from self-reports by calculating the metabolic equivalents (METS) per week and by the physical function domain of the Medical Outcomes Study Short Form 36 (SF-36). Data were analyzed using bivariate and multivariate regression analyses. RESULTS: Number of METS per week spent performing strenuous exercise was negatively correlated with IMT (r = -0.4, P = 0.002) and number of plaques (r = -0.30, P = 0.0001). Physical function as assessed by the SF-36 was also negatively correlated with IMT (r = -0.14, P = 0.03) and number of plaques (r = -0.14, P = 0.04). In multivariate analyses, number of strenuous exercise METS was significantly associated with IMT (t = -2.2, P = 0.028) and number of plaques (t = -2.5, P = 0.014) when controlling for markers of SLE disease activity and damage, but not after controlling for traditional cardiac risk factors. Low physical activity, defined as <225 total METS per week, was associated with the presence of proinflammatory HDL (P = 0.03). CONCLUSION: Low physical activity is associated with increased subclinical atherosclerosis and proinflammatory HDL in patients with SLE. Increased strenuous exercise may reduce the risk of atherosclerosis in SLE.
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Aterosclerose/complicações , Mediadores da Inflamação/sangue , Lipoproteínas LDL/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/fisiopatologia , Atividade Motora , Adulto , Artérias Carótidas/diagnóstico por imagem , Estenose das Carótidas/complicações , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Pessoa de Meia-Idade , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , UltrassonografiaRESUMO
OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.