SCORE2 versus SCORE in patients with systemic lupus erythematosus

Introduction: Systemic lupus erythematosus (SLE) has been associated with an increased risk of cardiovascular (CV) disease. Recently, the Systematic Coronary Risk Assessment (SCORE), a well-known CV risk algorithm, has been updated to a new predictive model (SCORE2). This new algorithm improves the identification of individuals at high risk of developing CV disease across Europe. Since carotid atherosclerosis is a predictor of future CV events and CV death, our objective was to compare the predictive capacity of SCORE2 versus SCORE for the presence of subclinical carotid atherosclerosis in patients with SLE. Methods: Two hundred and thirty-five individuals over 40 years of age diagnosed with SLE were consecutively recruited in this cross-sectional study. SCORE and SCORE2 were calculated. The relationship of SCORE and SCORE2 with each other, and with the presence of subclinical carotid atherosclerosis (both carotid plaque and carotid intima media thickness -cIMT-), was studied. Results: SCORE2 and SCORE did not correlate with each other (Spearman's Rho = 0.125, p = 0.065). Although SCORE did not correlate with cIMT (Spearman?s Rho = -0.022, p = 0.75), the correlation of SCORE2 with cIMT was statistically significant (Spearman?s Rho = 0.367, p < 0.001). Similarly, SCORE did not show significant discrimination for the presence of carotid plaque [AUC = 0.521 (95% CI = 0.443?0.600)], while SCORE2 did [AUC = 0.720 (95% CI = 0.656-0.785)]. The difference between AUCs was found to be statistically significant (p < 0.001), thus showing that the prediction capacity of SCORE2 was significantly higher than that of SCORE. Conclusion: In SLE patients, the ability of SCORE2 to predict the presence of subclinical atherosclerosis is higher than that of SCORE. According to our results, SCORE2, rather than SCORE, should be used in the CV risk stratification of patients with SLE. Prospective studies are needed to confirm these findings.Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a grant to I.F.-A. from the Spanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 and by Fondo Europeo de Desarrollo Regional-FEDER-(Fondo de Investigaciones Sanitarias, FIS PI14/00394, PI17/00083, PI20/00084). Prof. González-Gay's research is supported by the Instituto de Salud Carlos III (ISCIII) (Fondo de Investigación Sanitaria grants PI06/0024, PI09/00748, PI12/00060, PI15/00525, PI18/00043) and the ISCIII RETICS programs (RD12/0009 and RD16/0012)

Key molecules of triglycerides pathway metabolism are disturbed in patients with systemic lupus erythematosus

Background: Elevated triglycerides or triglyceride-rich lipoproteins are an additional cause of cardiovascular (CV) disease. Given that patients with systemic lupus erythematosus (SLE) have a high prevalence of premature CV disease and show an altered lipid profile, our objective was to study whether three molecules that play a central role in the triglyceride metabolism: apolipoprotein C-III (ApoC3), angiopoietin-like protein 4 (ANGPLT4), and lipoprotein lipase (LPL) differ between SLE patients and controls, and how they are related to disease characteristics, including disease damage. Methods: Cross-sectional study that included 347 women, 185 of them diagnosed with SLE and 162 age-matched controls. ANGPTL4, ApoC3 and LPL, and standard lipid profiles were analyzed in SLE patients and controls. A multivariable analysis was performed to assess whether ANGPTL4, ApoC3 and LPL molecules differ between patients and controls and to study their relationship with SLE disease damage. Results: After fully multivariable analysis that included classic CV risk factors, and the modifications that the disease itself produces over the lipid profile, it was found that ApoC3 was significantly lower (beta coef. -1.2 [95%CI -1.6- -0.8) mg/dl, <0.001), and ANGPTL4 (beta coef. 63 [95%CI 35-90] ng/ml, <0.001) and LPL (beta coef. 79 [95%CI 30-128] ng/ml, p=0.002) significantly higher in patients with SLE compared to controls. Disease damage score was significantly and independently associated with higher serum levels of LPL (beta coef. 23 [95%CI 10-35] ng/ml, p=0.001). Mediation analysis suggested that the relationship between disease damage and LPL was direct and not mediated by ApoC3 or ANGPLT4. Conclusion: The ApoC3, ANGPLT4 and LPL axis is disrupted in patients with SLE. Disease damage explains this disturbance.Funding: This work was supported by a grant to IF-A from the Spanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Cientı́fica y Técnica y de Innovación 2013-2016 and by Fondo Europeo de Desarrollo Regional - FEDER - (Fondo de Investigaciones Sanitarias, PI17/00083)

Disease activity influences the reclassification of rheumatoid arthritis into very high cardiovascular risk

Background: Previous studies have shown that risk chart algorithms, such as the Systematic Coronary Risk Assessment (SCORE), often underestimate the actual cardiovascular (CV) risk of patients with rheumatoid arthritis (RA). In contrast, carotid ultrasound was found to be useful to identify RA patients at high CV. In the present study, we aimed to determine if specific disease features influence the CV risk reclassification of RA patients assessed by SCORE risk charts and carotid ultrasound. Methods: 1279 RA patients without previous CV events, diabetes, or chronic kidney disease were studied. Disease characteristics including disease activity scores, CV comorbidity, SCORE calculation, and the presence of carotid plaque by carotid ultrasound were assessed. A multivariable regression analysis was performed to evaluate if the reclassification into very high CV risk category was independently associated with specific features of the disease including disease activity. Additionally, a prediction model for reclassification was constructed in RA patients. Results: After carotid ultrasound assessments, 54% of the patients had carotid plaque and consequently fulfilled definition for very high CV risk. Disease activity was statistically significantly associated with reclassification after fully multivariable analysis. A predictive model containing the presence of dyslipidemia and hypertension, an age exceeding 54 years, and a DAS28-ESR score equal or higher than 2.6 yielded the highest discrimination for reclassification. Conclusion: Reclassification into very high CV risk after carotid ultrasound assessment occurs in more than the half of patients with RA. This reclassification can be independently explained by the activity of the disease.Funding: This work was supported by a grant to I.F-A. from the Spanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016, and by Fondo Europeo de Desarrollo Regional — FEDER (Fondo de Investigaciones Sanitarias, FIS PI14/00394, PI17/00083). Prof. González-Gay’s research is supported by the Instituto de Salud Carlos III (ISCIII) (Fondo de Investigación Sanitaria grants PI06/0024, PI09/00748, PI12/00060, PI15/00525, PI18/00043) and the ISCIII RETICS programs (RD12/0009 and RD16/0012)

The performance of vascular age in the assessment of cardiovascular risk of patients with rheumatoid arthritis

Background: Cardiovascular (CV) disease risk prediction models developed for use in the general population have suboptimal performance in patients with rheumatoid arthritis (RA). Vascular age (VA) is a new concept that has been proposed as a measure of CV "relative" risk instead of the "absolute" risk that current prediction models provide. In the present study we aim to study the performance of vascular age (VA) in the assessment of CV risk in patients with RA. We additionally aimed to analyze its relation with subclinical atherosclerosis as measured through carotid plaque ultrasound. Methods: A total of 1173 non-diabetic RA patients without previous CV events were included. Disease characteristics, SCORE, VA determined on SCORE and on carotid intima media thickness (cIMT), and the presence of plaque through carotid ultrasound were assessed. The interrelations of VA with SCORE, and its associations with subclinical carotid atherosclerosis were studied. Results: On average, RA patients had both a SCORE determined VA (4.7 years) and a cIMT-based VA (2.4 years) significantly higher than the chronological age. When these differences were analyzed in different age intervals, while VA based on SCORE was significantly higher compared to chronological age in all age ranges, VA determined on cIMT was significantly elevated only in RA patients younger than 60 years. The area under the curve analysis for the association of SCORE and VA with the presence of carotid plaque disclosed no differences between both parameters. VA was associated with the presence of carotid plaque after multivariable regression analysis in patients younger than 60 years old. Conclusion: VA is significantly higher than chronological age in patients with RA. The performance of VA in its relation to carotid plaque is similar to that of the SCORE.This research was funded by a grant to MAG-G from the Instituto de Salud Carlos III (ISCIII) (Fondo de Investigación Sanitaria grants PI06/0024, PI09/00748, PI12/00060, PI15/00525, PI18/00043) and the ISCIII RETICS programs (RD12/0009 and RD16/0012)

Apolipoprotein C-III is linked to the insulin resistance and beta-cell dysfunction that are present in rheumatoid arthritis

Background: Insulin resistance and beta-cell dysfunction are manifestations of rheumatoid arthritis (RA). Apolipoprotein C-III (ApoC3) has been associated with such insulin resistance and beta-cell dysfunction in the general population. Our purpose was to study whether ApoC3 is also related to the insulin resistance and beta-cell dysfunction that are present in patients with RA. Methods: Three hundred thirty-eight non-diabetic patients with RA who had a glycemia lower than 110 mg/dl were recruited. Insulin, C-peptide, and ApoC3 were assessed. Insulin resistance and beta-cell function were calculated using the Homeostasis Model Assessment (HOMA2) indices. A multivariable regression analysis was performed to study the relationship of ApoC3 with those molecules and indices adjusting for classic factors associated with insulin resistance that included glucocorticoids. Results: ApoC3 was related to significant higher levels of circulating insulin (beta coef. 0.37 [95%CI 0.01–0.73] μU/ml, p = 0.044) and C-peptide (beta coef. 0.13 [95%CI 0.05–0.22] ng/ml, p = 0.003), and higher insulin resistance —HOMA2- IR— (beta coef. 0.05 [95%CI 0.00–0.09], p = 0.041) and beta-cell dysfunction —HOMA2-%B— (beta coef. 2.94 [95%CI0.07–5.80], p = 0.044) indices. This was found after a fully multivariable analysis that included, among others, prednisone intake and the classic factors associated with carbohydrate metabolism such as triglycerides, waist circumference, and obesity. Conclusion: ApoC3, insulin resistance, and beta-cell dysfunction are independently associated in patients RA.This work was supported by a grant to I.F-A. from the Spanish Ministry of Health, Subdireccion General de Evaluacion y Fomento de la Investigacion, Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013–2016 and by Fondo Europeo de Desarrollo Regional—FEDER—(Fondo de Investigaciones Sanitarias, PI17/00083

Apolipoprotein C-III in patients with systemic lupus erythematosus

Background: Systemic lupus erythematosus (SLE) has been associated with atherosclerotic cardiovascular disease (CV) and an altered lipid profile. High levels of apolipoprotein C-III (ApoC3) are associated with elevated triglyceride levels and an increased risk of CV. In the present study, we aimed to study circulating ApoC3 in patients with SLE and describe its relationship with the manifestations of the disease. Methods: This is a cross-sectional study that included 186 patients with SLE. Disease-related data, CV comorbidity, full lipid profile, and serum levels of ApoC3 were assessed. A multivariable regression analysis was performed to study how ApoC3 was related to SLE features. Results: Classic CV risk factors were significantly and strongly associated with circulating ApoC3. After a fully multivariable analysis that included classic CV risk factors and lipid profile molecules, SLICC damage (beta coef. 0.10 [95% CI 0.02?0.19] mg/dl, 0.020) and Katz severity (beta coef. 0.11 [95% CI 0.03-0.19] mg/dl, p = 0.011) indices and SLEDAI activity score (beta coef. 0.05 [95% CI 0.05-0.08] mg/dl, p = 0.004) were all independently associated with higher levels of circulating ApoC3. Conclusion: Among SLE patients, disease activity, severity, and disease damage are independently associated with higher ApoC3 serum levels.Funding: This work was supported by a grant to I.F-A. from the Spanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016 and by Fondo Europeo de Desarrollo Regional—FEDER—(Fondo de Investigaciones Sanitarias, PI17/00083)

The angiopoietin-like protein 4, apolipoprotein C3, and lipoprotein lipase axis is disrupted in patients with rheumatoid arthritis

Background: Modulators of triglyceride metabolism include lipoprotein lipase (LPL), angiopoietin-like protein 4 (ANGPTL4), and apolipoprotein C-3 (ApoC3). There is evidence on the influence of this triangle of molecules on an increased risk of atherosclerotic cardiovascular disease (CV) in the general population. Patients with rheumatoid arthritis (RA) present changes in lipid profiles and accelerated CV disease. In the present study, we set out to study whether the ANGPTL4, ApoC3, and LPL axis differs in subjects with RA compared to controls. In a further step, we investigated the relationship of this axis with subclinical atherosclerosis in patients with RA. Methods: Cross-sectional study that included 569 individuals, 323 patients with RA and 246 age-matched controls. ANGPTL4, ApoC3 and LPL, and standard lipid profiles were analyzed in patients and controls. Carotid intima-media thickness (cIMT) and carotid plaques were assessed in RA patients. A multivariable analysis was performed to assess whether the ANGPTL4, ApoC3, and LPL axis was altered in RA and to study its relationship with RA dyslipidemia and subclinical carotid atherosclerosis. Results: Most lipid profile molecules did not differ between patients and controls. Despite this, and after fully multivariable analysis including CV risk factors, use of statins, and changes in the lipid profile caused by the disease itself, patients with RA showed higher serum levels of ANGPTL4 (beta coef. 295 [95% CI 213-376] ng/ml, p<0.001) and ApoC3 (beta coef. 2.9 [95% CI 1.7-4.0] mg/dl, p<0.001), but lower circulating LPL (beta coef. -174 [95% CI -213 to - 135] ng/ml, p<0.001). ANGPTL4 serum levels were positively and independently associated with a higher cIMT in patients with RA after fully multivariable adjustment. Conclusion: The axis consisting in ANGPTL4, ApoC3, and LPL is disrupted in patients with RA. ANGPTL4 serum levels are positively and independently associated with a higher cIMT in RA patients.Funding: This work was supported by a grant to IFA from the Spanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 and by Fondo Europeo de Desarrollo Regional - FEDER - (Fondo de Investigaciones Sanitarias, PI17/00083)

SCORE2 Assessment in the Calculation of Cardiovascular Risk in Patients with Rheumatoid Arthritis

Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease (CVD). Risk chart algorithms, such as the Systematic Coronary Risk Assessment (SCORE), often underestimate the risk of CVD in patients with RA. In this sense, the use of noninvasive tools, such as the carotid ultrasound, has made it possible to identify RA patients at high risk of CVD who had subclinical atherosclerosis disease and who had been included in the low or moderate CVD risk categories when the SCORE risk tables were applied. The 2003 SCORE calculator was recently updated to a new prediction model: SCORE2. This new algorithm improves the identification of individuals from the general population at high risk of developing CVD in Europe. Our objective was to compare the predictive capacity between the original SCORE and the new SCORE2 to identify RA patients with subclinical atherosclerosis and, consequently, high risk of CVD. 1168 non-diabetic patients with RA and age > 40 years were recruited. Subclinical atherosclerosis was searched for by carotid ultrasound. The presence of carotid plaque and the carotid intima media wall thickness (cIMT) were evaluated. SCORE and SCORE2 were also calculated. The relationships of SCORE and SCORE2 to each other and to the presence of subclinical carotid atherosclerosis were studied. The correlation between SCORE and SCORE2 was found to be high in patients with RA (Spearman´s Rho = 0.961, p < 0.001). Both SCORE (Spearman?s Rho = 0.524) and SCORE2 (Spearman?s Rho = 0.521) were similarly correlated with cIMT (p = 0.92). Likewise, both calculators showed significant and comparable discriminations for the presence of carotid plaque: SCORE AUC 0.781 (95%CI 0.755-0.807) and SCORE2 AUC 0.774 (95%CI 0.748-0.801). Using SCORE, 80% and 20% of the patients were in the low or moderate and high or very high CVD risk categories, respectively. However, when the same categories were evaluated using SCORE2, the percentages were different (58% and 42%, respectively). Consequently, the number of RA patients included in the high or very high CVD risk categories was significantly higher with SCORE2 compared to the original SCORE. (p < 0.001). In conclusion, although predictive capacity for the presence of carotid plaque is equivalent between SCORE and SCORE2, SCORE2 identifies a significantly higher proportion of patients with RA who are at high or very high risk of CVD

Vascular endothelial growth factor and its soluble receptor in systemic lupus erythematosus patients

Vascular endothelial growth factor (VEGF) is a major regulator of physiological and pathological angiogenesis. Its soluble receptor (sVEGFR) is a potent VEGF antagonist. Systemic lupus erythematosus (SLE) is an autoimmune disease with a diverse array of clinical manifestations that affect virtually any organ. We aimed to analyze the relationship of VEGF and sVEGFR with SLE disease-related features including disease activity, damage, and severity. Serum levels of VEGF165 isoform and sVEGFR (receptor 1) were assessed in 284 well-characterized patients with SLE. Linear regression analysis was performed to analyze the relationship of disease characteristics with both VEGF and sVEGFR. Patients with a disease damage index (SLICC score) equal to or greater than 1 had significantly elevated serum levels of VEGF and sVEGFR. Regarding disease-specific features, musculoskeletal manifestations were the disease feature most commonly associated with the upregulation of both VEGF and sVEGFR. SLE disease damage is associated with higher levels of VEGF and sVEGFR.Funding: This work was supported by a grant to I.F-A. from the Spanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016 and by Fondo Europeo de Desarrollo Regional—FEDER—(Fondo de Investigaciones Sanitarias, PI20/00084)

Omentin: a biomarker of cardiovascular risk in individuals with axial spondyloarthritis

ABSTRACT: Cardiovascular (CV) disease is the main cause of mortality in axial spondyloarthritis (axSpA). CV risk is enhanced by dysregulation of adipokines. Low omentin levels were associated with metabolic dysfunction and CV disease in conditions different from axSpA. Accordingly, we evaluated the genetic and functional implication of omentin in CV risk and subclinical atherosclerosis in a cohort of 385 axSpA patients. Subclinical atherosclerosis was evaluated by carotid ultrasound. Omentin rs12409609, in linkage disequilibrium with a polymorphism associated with CV risk, was genotyped in 385 patients and 84 controls. Serum omentin levels were also determined. omentin mRNA expression was assessed in a subgroup of individuals. Serum and mRNA omentin levels were lower in axSpA compared to controls. Low serum omentin levels were related to male sex, obesity, inflammatory bowel disease (IBD) and high atherogenic index. rs12409609 minor allele was associated with low omentin mRNA expression in axSpA. No association was observed with subclinical atherosclerosis at the genetic or functional level. In conclusion, in our study low omentin serum levels were associated with CV risk factors in axSpA. Furthermore, rs12409609 minor allele may be downregulating the expression of omentin. These data support a role of omentin as a CV risk biomarker in axSpA.We wish to thank all the patients and controls that participated in this study. This work was supported by funds of a NEXT-VAL grant (NVAL17/10) (Instituto de Investigación Sanitaria IDIVAL) awarded to FG. SR-M is supported by funds of the RETICS Program (RD16/0012/0009) from the ‘Instituto de Salud Carlos III´ (ISCIII), co-funded by the European Regional Development Fund (ERDF). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). VM is supported by funds of a Miguel Servet type I programme (grant CP16/00033) (ISCIII, co-funded by the European Social Fund (ESF)). LL-G is supported by funds of PI18/00042 (ISCIII, co-funded by ERDF). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the ESF (grant CP16/00033)