Nuevos autoantígenos en el síndrome de Sjögren

Tras la obtención de un suero de una paciente con manifestaciones neurológicas de síndrome de Sjögren, este fue testado en una genoteca de cerebro humano con el fin de identificar clones de cDNA que reaccionaran contra dicho suero, con el propósito de identificar nuevos autoantígenos en esta enfermedad y, concretamente, en aquellos pacientes con manifestaciones neurológicas. Entre los clones de cDNA que se obtuvieron habían algunos ya conocidos como autoantígenos en la enfermedad de Sjörgren y otros que no se conocían como tales. Se identificaron los clones que sintetizaban las proteínas tau, WAVE, proteínas fijadora de guanina y una proteína no conocida en humanos que recibió el nombre de proteína hHesB dada la homología que presentaba frente a una proteína similar en levadura. A continuación se procedió a la síntesis de proteína recombinante de las proteínas tau y hHesB. Escogimos estas proteínas por la relación previa de tau con enfermedades neurodegenerativas y hHesB porque era una proteína desconocida hasta la actualidad. Tras esto, ambas proteínas fueron testadas mediante western blot en 20 enfermos con manifestaciones neurológicas o de otro tipo de síndrome de Sjörgren. Las bandas obtenidas en dichos western blot fueron analizadas mediante programa informático y transformados sus valores en unidades de densidad óptica. Se procedió al análisis estadístico de estos valores tanto en enfermos como sanos para dilucidar si había relación entre los autoanticuerpos y esta enfermedad. Obtuvimos, en lo referente a la proteína hHesB una relación estadísticamente significativa en la que los enfermos tenían unos valores de autoanticuerpos inferiores en relación a los controles. Con respecto a la proteína tau no obtuvimos resultados significativamente diferentes entre controles y enfermos, siendo los autoantícuerpos para anti tau prevalentes en población sana y enferma

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)

Impaired beta cell function is present in nondiabetic rheumatoid arthritis patients

Introduction: To investigate how markers of β-cell secretion (proinsulin-processing metabolites) are expressed in rheumatoid arthritis (RA) patients and their potential relation with the insulin resistance (IR) observed in these patients. Methods: The 101 RA patients and 99 nondiabetic sex- and age-matched controls were included. IR by homeostatic model assessment (HOMA2), and β-cell secretion, as measured by insulin, split and intact proinsulin, and C-peptide levels were determined for both groups. Multiple regression analysis was performed to compare IR between groups and to explore the interrelations between RA features, proinsulin metabolites, and IR. Data were adjusted for glucocorticoids intake and for IR classic risk factors. Results: Compared with controls, RA patients showed higher HOMA-IR (β coef., 0.40 (95% CI, 0.20 to 0.59); P = 0.00). When data were adjusted for glucocorticoids intake, noncorticosteroid patients maintained a higher IR index (β, 0.14 (0.05 to 0.24); P = 0.00). Impaired insulin processing in RA patients was detected by the onset of elevated split proinsulin levels (β, 0.70 pmol/L (0.38 to 1.02); P = 0.00). These data remained significant also when adjusted for prednisone intake (b, 0.19 (0.00 to 0.36) pmol/L; P = 0.04). Split proinsulin-to-C-peptide ratios were higher in RA patients undergoing corticosteroid therapy (b, 0.25 (0.12 to 0.38); P = 0.03) and were nearly significant in comparison between noncorticosteroids patients and controls (b, 0.16 (-0.02 to 0.34); P = 0.08). Interestingly, the impact of HOMA-IR on the ratio of intact proinsulin to C-peptide was higher in controls compared with patients (b, 6.23 (1.41 to 11.06) versus 0.43 (-0.86 to 1.71); P = 0.03). Conclusions: b-Cell function is impaired in nondiabetic and in RA patients not taking corticoids by a mechanism that seems to be, at least in part, independent of IR.This work was supported by a grant from the Fundación Española de Reumatología to I. F-A. and by a grant from the Spanish Ministry of Health (Fondo de Investigaciones Sanitarias) to F.D-G. [FIS 09/02209]. The authors are indebted to the entire staff of the Rheumatology Service of Hospital Universitario de Canarias and especially to Drs. Vanesa Hernández-Harnández, Esmeralda Delgado-Frias, and Maria Angeles Gantes, and to Mrs. Rodríguez-Vargas for their steadfast support

Moderate and High Disease Activity Predicts the Development of Carotid Plaque in Rheumatoid Arthritis Patients without Classic Cardiovascular Risk Factors: Six Years Follow-Up Study

Patients with rheumatoid arthritis (RA) have a higher incidence of subclinical atherosclerosis and cardiovascular (CV) disease. It is postulated that the appearance of accelerated atherosclerosis in these patients is a consequence of the inflammation present in the disease. In this study, we aim to determine if baseline disease activity in patients with RA predicts the future development of carotid plaque. A set of consecutive RA patients without a history of CV events, cancer or chronic kidney disease, who did not show carotid plaque in a carotid ultrasound assessment, were prospectively followed up for at least 5 years. At the time of recruitment, CV risk factors and disease-related data, including disease activity scores, were assessed. At the end of the follow-up, a carotid ultrasound was repeated and patients were divided into two groups; those who developed carotid plaque, and those who did not. A multivariable regression analysis was performed to define the predictors for the development of carotid plaque. One hundred and sixty patients with RA were followed up for an average of 6 ± 1 years. After this time, 66 (41%) of the patients had developed carotid plaque, and 94 (59%) did not. Patients with carotid plaque were significantly older (47 ± 13 vs. 55 ± 9 years, p < 0.001) at baseline, were more frequently diabetic (0% vs. 6%, p = 0.028), and had higher total cholesterol (197 ± 36 vs. 214 ± 40 mg/dL, p = 0.004) and LDL cholesterol (114 ± 35 vs. 126 ± 35 mg/dL, p = 0.037) at the beginning of the study. After multivariable adjustment, patients who were in the moderate and high disease activity (DAS28-CRP) categories displayed a higher odds ratio for the appearance of carotid plaque (OR 2.26 [95% CI 1.02?5.00], p = 0.044) compared to those in the DAS-28-CRP remission category. Remarkably, when patients were divided in patients within the low-risk SCORE category, and patients included in the remaining SCORE categories (moderate, high and very high), the relation between DAS28-CRP and the development of carotid plaque was only significant in the low-risk SCORE category. In conclusion, disease activity predicts the future development of subclinical atherosclerosis in patients with RA

Metabolic Syndrome in Rheumatoid Arthritis

Insulin resistance is an essential feature of the metabolic syndrome that has been linked to rheumatoid arthritis (RA). Understanding how inflammation arising in one tissue affects the physiology and pathology of other organs remains an unanswered question with therapeutic implications for chronic conditions including obesity, diabetes mellitus, atherosclerosis, and RA. Adipokines may play a role in the development of atherogenesis in patients with RA. Biologic therapies, such as TNF-α antagonists, that block proinflammatory cytokines have beneficial effects on the insulin resistance that is often observed in patients with RA

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)

Proprotein convertase subtilisin/kexin type 9 is related to disease activity and damage in patients with systemic erythematosus lupus

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism through low-density lipoprotein receptor degradation and that has been linked to cardiovascular (CV) disease. The purpose of the present study was to examine whether PCSK9 levels are disrupted compared with controls in patients with systemic lupus erythematosus (SLE). We additionally sought to establish whether PCSK9 is related to both the abnormalities in the lipid profile and to the disease activity or damage of patients with SLE. Methods: We performed a cross-sectional study that encompassed 366 individuals: 195 SLE patients and 171 age-, sex-, and statin intake-matched controls. PCSK9, lipoproteins serum concentrations, and lipid profiles were assessed in patients and controls. A multivariable analysis, adjusted for standard CV risk factors, was performed to evaluate the role of PCSK9 in SLE-related dyslipidemia. Results: Most lipid related-molecules were decreased in patients with SLE compared with controls. This downregulation included PCSK9, with PCSK9 levels being lower in patients than controls in the full multivariable analysis, including the modifications in lipid profiles that the disease itself produces {beta coefficient ?73 [95% confidence interval (CI) ?91 to ?54] ng/ml, p???0.001}. Both SLICC and SLEDAI scores were independently and positively related to PCSK9. Patients currently on hydroxychloroquine exhibited decreased levels of PCSK9 compared with those that were not taking hydroxychloroquine [beta coefficient ?30 (95% CI ?54 to ?6) ng/ml, p?=?0.015]. Conclusion: PCSK9 is downregulated in SLE compared with controls, but SLE patients with higher disease activity and damage exhibited higher PSCK9 serum levels.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 IF-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). The research of MAG-G 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 program (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 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)