Role of Advanced Glycation End Products as New Biomarkers in Systemic Lupus Erythematosus.

Advanced glycation end-products (AGEs) may play a relevant role as inducers in the chronic inflammatory pathway present in immune-mediated diseases, such as systemic lupus erythematosus (SLE). AGEs concentrations have been associated, with discrepant results to date, with some parameters such as disease activity or accrual damage, suggesting their potential usefulness as biomarkers of the disease. Our objectives are to confirm differences in AGEs levels measured by cutaneous autofluorescence between SLE patients and healthy controls (HC) and to study their correlation with various disease parameters. Cross-sectional study, where AGEs levels were measured by skin autofluorescence, and SLE patients' data were compared with those of sex- and age-matched HC in a 1:3 proportion through a multiple linear regression model. Associations of AGEs levels with demographic and clinical data were analyzed through ANOVA tests. Both analyses were adjusted for confounders. AGEs levels in SLE patients were significantly higher than in HC (p < 0.001). We found statistically significant positive associations with SLE disease activity index (SLEDAI) and damage index (SDI), physician and patient global assessment, C-reactive protein, leukocyturia, complement C4, IL-6 and oral ulcers. We also found a negative statistically significant association with current positivity of anti-nuclear and anti-Ro60 antibodies. AGEs seem to have a contribution in LES pathophysiology, being associated with activity and damage and having a role as a new management and prognosis biomarker in this disease. The association with specific antibodies and disease manifestations may indicate a specific clinical phenotype related to higher or lower AGEs levels.

Serum Advanced Glycation End Products and Their Soluble Receptor as New Biomarkers in Systemic Lupus Erythematosus.

It has been postulated that advanced glycation end products (AGEs) and their soluble receptor (sRAGE) may play a relevant role as inducers in the chronic inflammatory pathway in various conditions, among them, in immune-mediated diseases such as systemic lupus erythematosus (SLE). However, previous studies show conflicting results about their association with SLE characteristics and their usefulness as disease biomarkers. We aimed to study the association of specific serum AGEs (pentosidine, Nξ-(carboxymethyl)lysine (CML), Nξ-(carboxyethyl)lysine (CEL)), sRAGE levels and AGEs (specific serum AGEs and skin AGEs) to sRAGE ratios with various disease parameters, in order to clarify their potential as new biomarkers in SLE and to study their relationship with cardiovascular disease (CVD). To this aim, serum pentosidine, CML, CEL and sRAGE were measured via ELISA, and skin AGEs levels were measured by skin autofluorescence. Correlations of pentosidine levels with demographic and clinical data, indexes of activity, accrual damage and patient-reported outcomes were analyzed through multiple linear regression models, while correlations of the rest of the AGEs, sRAGE and AGE to sRAGE ratios (non-normal) were analyzed using both an OLS regression model and a GML. All of the analyses were adjusted for confounders. A total of 119 SLE patients were recruited. Serum AGEs and sRAGEs were significantly associated with SLE activity indexes and/or demographic or disease characteristics: pentosidine with pulmonary manifestations; CML with anti-dsDNA antibodies, IL-6, disease duration and non-Caucasian ethnicities; CEL with anti-dsDNA antibodies, IL-6 and accumulated number of manifestations; and sRAGE with male gender, photosensitivity and being on specific immunosuppressants. These results suggest that the AGE-sRAGE axis may serve as a novel biomarker for managing and prognosticating this disease. Its correlation with certain antibodies, demographics and disease presentations may indicate a distinct clinical phenotype associated with varying levels of AGEs and/or sRAGE. The significance of specific AGE/sRAGE ratios, introduced in this study for the first time, warrants additional investigation in forthcoming research. Our study did not confirm the link between serum AGEs and CVD, which merits further exploration through studies designed for this specific purpose.

Left ventricular dysfunction and arrhythmias in asymptomatic patients with systemic sclerosis / Disfunción ventricular izquierda y arritmias en pacientes asintomáticos con esclerosis sistémica

Introduction and aims Cardiac involvement in systemic sclerosis (SS) is frequently silent and a major cause of mortality in these patients. This work aims to study the prevalence and associations of left ventricular dysfunction (LVD) and arrhythmias in SS. Methods and results Prospective study of SS patients (n=36), excluding those with symptoms of (or) cardiac disease, pulmonary arterial hypertension or cardiovascular risk factors (CVRF). A clinical, analytical, electrocardiogram (EKG), Holter, and echocardiogram with global longitudinal strain (GLS) assessment were performed. Arrhythmias were classified into clinically significant arrhythmias (CSA) and non-significant.Twenty-eight percent had left ventricular diastolic dysfunction (LVDD), 22% LV systolic dysfunction (LVSD) according to the GLS, 11.1% both, and 16.7% cardiac dysautonomia. Fifty percent presented alterations by EKG (44% CSA), 55.6% by Holter (75% CSA) and 8.3% CSA by both. An association was found between the elevation of troponin T (TnTc) and CSA and between the elevation of both NT-proBNP and TnTc with LVDD. Conclusions We found a higher prevalence of LVSD than in the literature, detected by GLS and being 10 times higher than that detected by LVEF, which justifies the need to incorporate this technique in the routine evaluation of these patients. The association of TnTc and NT-proBNP with LVDD suggests that they can be used as minimally invasive biomarkers of this affectation. The absence of correlation between LVD and CSA indicates that the arrhythmias could be due, not only to a supposed structural alteration of the myocardium, but to an independent and early cardiac involvement, which should be actively investigated even in asymptomatic patients without CVRF. (AU)

Introducción y objetivosLa afectación cardiaca en la esclerosis sistémica (ES) es frecuentemente asintomática y se asocia con una mortalidad importante. Este trabajo tiene como objetivo estudiar la prevalencia y las asociaciones de la disfunción ventricular izquierda (DVI) y las arritmias en la ES. Métodos y resultados Estudio prospectivo de pacientes con ES (n = 36), excluyendo aquellos con síntomas o enfermedad cardiaca, hipertensión arterial pulmonar o factores de riesgo cardiovascular (FRCV). Se les realizó una evaluación clínica, analítica, con electrocardiograma (ECG), Holter y ecocardiograma con strain longitudinal global (SLG). Las arritmias se clasificaron en arritmias clínicamente significativas (ACS) y no significativas.De los pacientes estudiados, 27,8% presentaba disfunción diastólica del ventrículo izquierdo (DDVI), 22% disfunción sistólica del VI (DSVI) según el SLG, 11,1% ambas y 16,7% disautonomía cardiaca; 50% presentó alteraciones por ECG (44% ACS), 55,6% por Holter (75% ACS) y 8,3% ACS por ambos. Se encontró una asociación entre la elevación de troponina T (TnTc) y ACS y entre la elevación NT-proBNP y TnTc con la DDVI. Conclusiones Encontramos una prevalencia de DSVI mayor que en la literatura, detectada por SLG y siendo 10 veces superior a la detectada por FEVI, lo que justifica la necesidad de incorporar esta técnica en la evaluación rutinaria de estos pacientes. La asociación de TnTc y NT-proBNP con DDVI sugiere que pueden ser utilizados como biomarcadores mínimamente invasivos de esta afectación. La ausencia de correlación entre DVI y ACS indica que las arritmias podrían deberse, no solo a una supuesta alteración estructural del miocardio, sino a un compromiso cardiaco independiente y temprano, que debe investigarse activamente incluso en pacientes asintomáticos sin FRCV. (AU)

Left ventricular dysfunction and arrhythmias in asymptomatic patients with systemic sclerosis.

INTRODUCTION AND AIMS: Cardiac involvement in systemic sclerosis (SS) is frequently silent and a major cause of mortality in these patients. This work aims to study the prevalence and associations of left ventricular dysfunction (LVD) and arrhythmias in SS. METHODS AND RESULTS: Prospective study of SS patients (n=36), excluding those with symptoms of (or) cardiac disease, pulmonary arterial hypertension or cardiovascular risk factors (CVRF). A clinical, analytical, electrocardiogram (EKG), Holter, and echocardiogram with global longitudinal strain (GLS) assessment were performed. Arrhythmias were classified into clinically significant arrhythmias (CSA) and non-significant. Twenty-eight percent had left ventricular diastolic dysfunction (LVDD), 22% LV systolic dysfunction (LVSD) according to the GLS, 11.1% both, and 16.7% cardiac dysautonomia. Fifty percent presented alterations by EKG (44% CSA), 55.6% by Holter (75% CSA) and 8.3% CSA by both. An association was found between the elevation of troponin T (TnTc) and CSA and between the elevation of both NT-proBNP and TnTc with LVDD. CONCLUSIONS: We found a higher prevalence of LVSD than in the literature, detected by GLS and being 10 times higher than that detected by LVEF, which justifies the need to incorporate this technique in the routine evaluation of these patients. The association of TnTc and NT-proBNP with LVDD suggests that they can be used as minimally invasive biomarkers of this affectation. The absence of correlation between LVD and CSA indicates that the arrhythmias could be due, not only to a supposed structural alteration of the myocardium, but to an independent and early cardiac involvement, which should be actively investigated even in asymptomatic patients without CVRF.

The use of tocilizumab in the treatment of refractory eosinophilic fasciitis: a case-based review.

Eosinophilic fasciitis (EF) is a rare disorder involving chronic inflammation of the fascia and connective tissue of unknown aetiology and poorly understood pathogenesis. We present the case of a 60-year-old man diagnosed with eosinophilic fasciitis with extensive cutaneous involvement and severe functional repercussion, which appeared weeks after suffering from pneumonia due to Legionella pneumophila. The patient did not experience any clinical response with high-dose corticosteroids, subcutaneous methotrexate, and intravenous immunoglobulins. Consequently, tocilizumab was initiated at 8 mg/Kg monthly achieving clinical response measured by a control MRI at the fifth dose. Response in terms of cutaneous thickness has been slower however favourable, therefore, more months of follow-up are necessary to assess the complete remission at skin level. EF treatment still constitutes a challenge, and experience with tocilizumab in the management of the disease is very limited. Through a systematic search of medical literature, we retrieved two cases describing EF treated with tocilizumab and several cases using another monoclonal antibody or Janus kinase inhibitor. We report the third case to our knowledge of the efficacy of tocilizumab in a refractory EF to corticosteroids and other immunosuppressive drugs.

A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort.

OBJECTIVES: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. METHODS: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. RESULTS: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). CONCLUSIONS: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.