Brief report
Decreased DNA hydroxymethylation and increased DNA demethylation are associated with high antioxidant response in systemic lupus erythematosus patients
Asociación entre la disminución de hidroximetilación y el incremento de la desmetilación del ADN y la respuesta antioxidante en los pacientes de lupus eritematoso sistémico
Jorge Juan Fragío Gila,b, Elena Grau Garcíaa,
, Meritxell Fernández Matillac, Francisco Miguel Ortiz Sanjuana, Regina Rodrigo Nicolásd,e, José Andrés Román Ivorraa,b
Corresponding author
a Rheumatology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain
b Escuela de Doctorado, Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain
c Rheumatology Section, Hospital Arnau de Vilanova, Valencia, Spain
d Molecular, Cellular and Genomic Biomedicine Group, IIS La Fe, Valencia, Spain
e CIBERER, Spain
Read
Not available
Timeswas read the article
Total PDF
Total HTML
Share statistics
array:24 [ "pii" => "S2387020621006173" "issn" => "23870206" "doi" => "10.1016/j.medcle.2020.10.020" "estado" => "S300" "fechaPublicacion" => "2021-12-24" "aid" => "5536" "copyright" => "Elsevier España, S.L.U.. All rights reserved" "copyrightAnyo" => "2020" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Med Clin. 2021;157:575-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "en" => array:19 [ "pii" => "S0025775320308770" "issn" => "00257753" "doi" => "10.1016/j.medcli.2020.10.023" "estado" => "S300" "fechaPublicacion" => "2021-12-24" "aid" => "5536" "copyright" => "Elsevier España, S.L.U." "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Med Clin. 2021;157:575-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief report</span>" "titulo" => "Decreased DNA hydroxymethylation and increased DNA demethylation are associated with high antioxidant response in systemic lupus erythematosus patients" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "575" "paginaFinal" => "579" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Asociación entre la disminución de hidroximetilación y el incremento de la desmetilación del ADN y la respuesta antioxidante en los pacientes de lupus eritematoso sistémico" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 959 "Ancho" => 3000 "Tamanyo" => 123069 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Relationship between TAC levels with 5-hmC (A) and 5-mC (B) in SLE patients.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jorge Juan Fragío Gil, Elena Grau García, Meritxell Fernández Matilla, Francisco Miguel Ortiz Sanjuan, Regina Rodrigo Nicolás, José Andrés Román Ivorra" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Jorge Juan" "apellidos" => "Fragío Gil" ] 1 => array:2 [ "nombre" => "Elena" "apellidos" => "Grau García" ] 2 => array:2 [ "nombre" => "Meritxell" "apellidos" => "Fernández Matilla" ] 3 => array:2 [ "nombre" => "Francisco Miguel" "apellidos" => "Ortiz Sanjuan" ] 4 => array:2 [ "nombre" => "Regina" "apellidos" => "Rodrigo Nicolás" ] 5 => array:2 [ "nombre" => "José Andrés" "apellidos" => "Román Ivorra" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020621006173" "doi" => "10.1016/j.medcle.2020.10.020" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020621006173?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775320308770?idApp=UINPBA00004N" "url" => "/00257753/0000015700000012/v1_202112010528/S0025775320308770/v1_202112010528/en/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020621006148" "issn" => "23870206" "doi" => "10.1016/j.medcle.2021.11.001" "estado" => "S300" "fechaPublicacion" => "2021-12-24" "aid" => "5788" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Clin. 2021;157:580-2" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial article</span>" "titulo" => "Bronchiectasis: The disease that was never orphan" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "580" "paginaFinal" => "582" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Bronquiectasias: la enfermedad que nunca fue huérfana" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Miguel Ángel Martínez-García" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Miguel Ángel" "apellidos" => "Martínez-García" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775321005078" "doi" => "10.1016/j.medcli.2021.09.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775321005078?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020621006148?idApp=UINPBA00004N" "url" => "/23870206/0000015700000012/v1_202112201710/S2387020621006148/v1_202112201710/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S238702062100615X" "issn" => "23870206" "doi" => "10.1016/j.medcle.2020.10.019" "estado" => "S300" "fechaPublicacion" => "2021-12-24" "aid" => "5533" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Clin. 2021;157:569-74" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Study of the effect of chronic kidney disease on the incidence of cardiovascular events in a native Spanish population" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "569" "paginaFinal" => "574" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efecto de la enfermedad renal crónica sobre la incidencia de episodios cardiovasculares en población española" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0030" "etiqueta" => "Fig. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 1042 "Ancho" => 1675 "Tamanyo" => 110649 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Life survival. Patients are compared in 4 groups (without chronic kidney disease [CKD], with glomerular filtration rate [GFR] < 60 ml with normal urinary albumin excretion [UAE], with elevated albuminuria and normal GFR, and with decreased GFR and elevated albuminuria). The difference is significant (p < 0.001, log-rank).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Bárbara Cancho, Nicolás Roberto Robles, Francisco Javier Felix-Redondo, Luis Lozano, Daniel Fernandez-Berges" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Bárbara" "apellidos" => "Cancho" ] 1 => array:2 [ "nombre" => "Nicolás Roberto" "apellidos" => "Robles" ] 2 => array:2 [ "nombre" => "Francisco Javier" "apellidos" => "Felix-Redondo" ] 3 => array:2 [ "nombre" => "Luis" "apellidos" => "Lozano" ] 4 => array:2 [ "nombre" => "Daniel" "apellidos" => "Fernandez-Berges" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775320308745" "doi" => "10.1016/j.medcli.2020.10.021" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775320308745?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S238702062100615X?idApp=UINPBA00004N" "url" => "/23870206/0000015700000012/v1_202112201710/S238702062100615X/v1_202112201710/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief report</span>" "titulo" => "Decreased DNA hydroxymethylation and increased DNA demethylation are associated with high antioxidant response in systemic lupus erythematosus patients" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "575" "paginaFinal" => "579" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Jorge Juan Fragío Gil, Elena Grau García, Meritxell Fernández Matilla, Francisco Miguel Ortiz Sanjuan, Regina Rodrigo Nicolás, José Andrés Román Ivorra" "autores" => array:6 [ 0 => array:3 [ "nombre" => "Jorge Juan" "apellidos" => "Fragío Gil" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 1 => array:4 [ "nombre" => "Elena" "apellidos" => "Grau García" "email" => array:1 [ 0 => "grau_elegar@gva.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "Meritxell" "apellidos" => "Fernández Matilla" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Francisco Miguel" "apellidos" => "Ortiz Sanjuan" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Regina" "apellidos" => "Rodrigo Nicolás" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 5 => array:3 [ "nombre" => "José Andrés" "apellidos" => "Román Ivorra" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Rheumatology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Escuela de Doctorado, Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Rheumatology Section, Hospital Arnau de Vilanova, Valencia, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Molecular, Cellular and Genomic Biomedicine Group, IIS La Fe, Valencia, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "CIBERER, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Asociación entre la disminución de hidroximetilación y el incremento de la desmetilación del ADN y la respuesta antioxidante en los pacientes de lupus eritematoso sistémico" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2934 "Ancho" => 3167 "Tamanyo" => 282850 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Relationship of serum levels of SOD (A), GSH (B) and GSSG (C) with SLICC-ACR score in SLE patients.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a heterogeneous range of symptoms due to its genetic background and immunologic and environmental factors.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,2</span></a> The genetic factors that influence on SLE include epigenetic processes such as DNA methylation and hydroxymethylation (an intermediate step, where the 5-methylcytosine (5-mC) is oxidized to 5-hydroxymethylcytosine (5-hmC) by ten-eleven translocation (TET) enzyme family) but their functional role is still unknown.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3,4</span></a> Oxidative stress is closely related to chronic inflammation, and has a key role in the pathology of autoimmune diseases.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Hence, to obtain a better knowledge of the role of 5-hmC related to the oxidative stress in SLE and to the disease pathogenesis, we have investigated the global 5-hmC and 5-mC content in SLE patients and healthy controls, and we have compared it with antioxidant enzymes serum activity, as well as with their clinical features and autoimmune profiling.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients and controls</span><p id="par0015" class="elsevierStylePara elsevierViewall">Biomedical Research Ethics Committee of La Fe Hospital approval was obtained, and all participants provided informed consent. 142 SLE patients who fulfilled the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria and 34 healthy subjects were recruited. Cumulative clinical manifestations were reflected as defined in the RELESSER study.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> SLE disease activity was assessed using the SELENA-SLEDAI Index, and accumulative damage by the SLICC-ACR score.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Antioxidant enzymes activity determination</span><p id="par0020" class="elsevierStylePara elsevierViewall">Blood samples were stored in La Fe Biobank (PT13/0010/0026), integrated in the Biobank National Platform.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Serum concentration of glutathione (GSH) and glutathione disulphide (GSSG) were measured by UPLC-MS/MS (Acquity UPLC System). Superoxide dismutase activity (SOD) and Total Antioxidant Capacity (TAC) were measured using a commercial kit (Superoxide Dismutase Assay Kit and Antioxidant Assay Kit, Cayman, Michigan USA). All samples were analyzed by duplicate.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Global DNA methylation and hydroxymethylation level detection</span><p id="par0030" class="elsevierStylePara elsevierViewall">The global DNA methylation and hydroxymethylation level were determined using the MethylFlash™ Global DNA Methylation (5-mC) ELISA Easy Kit (Colorimetric) to quantify 5-mC and the MethylFlash™ Global DNA Hydroxymethylation (5-hmC) ELISA Easy Kit (Colorimetric) (Epigentek Group Inc., NY, USA) to detect 5-hmC levels. All samples were run by duplicate.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0035" class="elsevierStylePara elsevierViewall">Differences in continuous variables among groups were assessed using Wilcoxon rank-sum test. Relationships among different variables were evaluated using linear regression, ordinal regression and logistic regression as appropriate. Differences were considered significant at <span class="elsevierStyleItalic">P</span>-values less than 0.05. All statistical analyses and graphs were performed using <span class="elsevierStyleItalic">R</span>.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0040" class="elsevierStylePara elsevierViewall">The mean duration of SLE disease was 9.99 years, the mean SLEDAI score was 5.92 and SLICC-ACR score 1.04. Anti-double stranded DNA positivity was reported in the 36.6% of patients, complement consumption was reported in approximately 42% and increased antiphospholipid antibodies in the 35.2%. The most prevalent pathology was mucocutaneous affection (64.8%), followed by musculoskeletal affection (56.3%). Clinical and laboratory parameters of SLE patients are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The mean 5-mC level was 0.96% and 0.62% in SLE patients and controls respectively, and no significant differences between both groups were found. The mean 5-hmC level was 0.017% and 0.021% in SLE patients and controls respectively, being these values lower in patients than in healthy controls (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001). No correlation between 5-mC and 5-hmC levels was found. There were no differences in either of epigenetic processes according to the age of individuals.</p><p id="par0050" class="elsevierStylePara elsevierViewall">SOD levels were increased (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.029) and GSH and GSSG levels were reduced (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.03 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.003, respectively) in SLE patients compared to healthy controls. No differences in the TAC between both groups were observed and no correlation between the TAC and SOD, GSH and GSSG were observed.</p><p id="par0055" class="elsevierStylePara elsevierViewall">We found statistically significant relationship between increased 5-mC and decreased 5-hmC levels with increased TAC (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.006 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.003, respectively) in SLE patients (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). No differences in both epigenetic processes according to SOD, GSH and GSSG levels were found.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">We found no significant relationship between 5-hmC levels and age or gender in SLE patients.</p><p id="par0065" class="elsevierStylePara elsevierViewall">A significant association between increased 5-hmC levels and longer disease evolution was observed (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001). But there was no statistically significant association between 5-mC and 5-hmC with the disease activity score, the accumulative damage score and age at diagnosis. We also found no relationship between 5-mC, 5-hmC with CRP, ESR, C3-C4 and anti-dsDNA levels.</p><p id="par0070" class="elsevierStylePara elsevierViewall">No association of lupus anticoagulant positivity, ANAs titers, anticardiolipin antibodies, anti-beta2-glycoprotein antibodies, anti-RNP, anti-Sm, anti-Ro and anti-La antibodies with 5-mC and 5-hmC was found.</p><p id="par0075" class="elsevierStylePara elsevierViewall">A statistically significant association between cytopenia and lower 5-mC levels was observed (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.024). No association with phenotypes in mucocutaneous system, musculoskeletal system, renal disease, cardiovascular disease, Sjögren syndrome and antiphospholipid syndrome was observed.</p><p id="par0080" class="elsevierStylePara elsevierViewall">No significant relationship among antioxidant molecules levels with age or gender in SLE patients was found. We observed a significant relationship between increased SOD activity levels and higher SLICC-ACR score (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.011), just like low GSH and GSSG levels with high SLICC-ACR score (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.009 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.002, respectively) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). No significant association between TAC and SLICC-ACR score was observed.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Increased GSH and GSSG levels were significantly associated to positive antiphospholipid antibodies (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.009, respectively) and with low C3 levels (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.001 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.04, respectively).</p><p id="par0090" class="elsevierStylePara elsevierViewall">No statistically significant association between TAC, SOD and GSH-GSSG levels, with disease activity score, disease duration or clinical manifestations was found.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">There were no differences in the demethylation rate between patients and controls, but the hydroxymethylation rate was lower in patients. Our results differ from previous studies performed specifically in CD4+ T cells of SLE patients, where an increased 5-hmC level in genomic DNA T cells compared to healthy controls was found.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3,4</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">We have not observed a correlation between the methylation and hydroxymethylation rate in SLE patients. The global DNA hydroxymethylation levels were not correlated with age in SLE patients. These findings do not necessarily correspond to other studies with different biological samples.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> In addition, it should be pointed out that the relationship between low levels of 5-mC and citopenia, has been reported in refractory citopenia in myelodysplastic syndrome, also related to low levels of 5-mC.</p><p id="par0105" class="elsevierStylePara elsevierViewall">We found statistically significant relationship between increased 5-mC levels and enhanced antioxidant capacity in SLE patients. Additionally, increased Trolox values are associated with lower rates of 5-hmC in SLE patients. In contrast, no association with SOD levels with 5-mC and 5-hmC was found, in spite of the fact that SOD was increased in SLE patients more than in healthy controls.</p><p id="par0110" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">In vitro</span> studies postulated that increased oxidative stress leads to DNA hypomethylation. SOD is one of the major antioxidant defense systems against the production of oxygen free radicals, and our findings pointed out to increased SOD levels in SLE patients, in contrast to other studies where a significant reduction in the activity of SOD was found in SLE patients against healthy controls.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">8–10</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Moreover, oxidized glutathione and reduced glutathione levels have been used as an important cellular redox balance biomarker, and lower levels of both molecules in SLE patients than in healthy controls were found. In contrast, TAC showed no differences between both groups. The fact that there is an imbalance in SOD, GSH and GSSG levels between SLE patients and healthy volunteers, and there are no differences in the TAC, probably leads to the fact that other antioxidant enzymes involved in the reactive oxygen species homeostasis, as catalase and glutathione peroxidases, would be dysregulated to compensate the TAC status. In this way, the persistent inflammation state of SLE patients with accumulative damage may promote the imbalance between an excess of reactive oxygen species production and alteration in the activity levels of antioxidant enzymes, as we could see in the association of SOD and GSH levels with high accumulative damage in SLE patients.</p><p id="par0120" class="elsevierStylePara elsevierViewall">In conclusion, our study shows a statistical association between epigenetic processes and antioxidant response imbalance in SLE patients. We also report a significant association between low methylation and cytopenia. SLE patients with an alteration in the activity of antioxidant defense system may have increased oxidative stress, which may contribute to tissue damage, and hence, to the chronicity of the disease. Anyway, independent replications in blood samples of SLE patients are needed to confirm these novel findings. Finally, deeper epigenetic studies in SLE patients will be very useful to complete the understanding of SLE mechanisms to develop the disease and the highly heterogeneous phenotypes, as well as maybe to lead to the discovery of new specific therapeutic molecules.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethics approval</span><p id="par0125" class="elsevierStylePara elsevierViewall">The study was approved by the Hospital La Fe Biomedicine Ethics Board, in Valencia (Spain) (Ref. 2014/0607).</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Funding</span><p id="par0130" class="elsevierStylePara elsevierViewall">This work was made possible by <span class="elsevierStyleGrantSponsor" id="gs1">GVA</span> Grant Number <span class="elsevierStyleGrantNumber" refid="gs1">GV15/83</span>.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflict of interests</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that there is no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1632674" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1456831" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1632675" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1456830" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients and controls" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Antioxidant enzymes activity determination" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Global DNA methylation and hydroxymethylation level detection" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Statistical analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Ethics approval" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of interests" ] 11 => array:2 [ "identificador" => "xack576365" "titulo" => "Acknowledgements" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-07-09" "fechaAceptado" => "2020-10-14" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1456831" "palabras" => array:5 [ 0 => "5-Methylcytosine" 1 => "5-Hydroxymethylcytosine" 2 => "Systemic lupus erythematosus" 3 => "Superoxide dismutase" 4 => "Antioxidant response" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1456830" "palabras" => array:5 [ 0 => "5-Metilcitosina" 1 => "5-Hidroximetilcitosina" 2 => "Lupus eritematoso sistémico" 3 => "Superóxido dismutasa" 4 => "Respuesta antioxidante" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">DNA hydroxymethylation may be induced by oxidative stress in lupus patients, so we investigated the association between DNA hydroxymethylation and demethylation with the antioxidant response.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A case–control study was performed including lupus patients and matched healthy controls. Serum concentration of glutathione (GSH), glutathione disulphide (GSSG), superoxide dismutase (SOD) and total antioxidant capacity (TAC), 5-mC and 5-hmC were determined.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">One hundred and forty-two patients and 34 controls were included. 5-hmC levels were lower in SLE patients than in controls. GSH and GSSG values were lower in patients, while SOD levels were higher in patients. TAC did not show significant differences, but higher demethylation and lower hydroxydemethylation were associated to increased TAC values. Lower demethylation was associated with cytopenia and lower hydroxymethylation with longer course of the disease. Lower levels of GSH and GSSG and higher SOD values were associated with accumulated damage assessed by SLICC-ACR.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Lower hydroxymethylation in patients than in controls was observed. Moreover, higher demethylation and lower hydroxymethylation leads to high TAC levels. DNA hydroxymethylation seems to be related to longer course of the disease.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La hidroximetilación del ADN puede estar inducida por el estrés oxidativo en pacientes de lupus, por lo que estudiamos la asociación entre hidroximetilación del ADN y desmetilación sin respuesta antioxidante.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se realizó un control de casos que incluyó a pacientes de lupus pareados con controles sanos. Se calcularon la concentración sérica de glutatión (GSH), glutatión disulfuro (GSSG), superóxido dismutasa (SOD), capacidad antioxidante total (CAT), 5-mC y 5-hmC.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 142 pacientes y 34 controles. Los niveles de 5-hmC fueron menores en el grupo de pacientes de LES que en el de controles. Los valores de GSH y GSSG fueron menores en el grupo de pacientes, mientras que los valores de SOD fueron superiores en el grupo de pacientes. La CAT no reflejó diferencias significativas, pero el incremento de desmetilación y la disminución de hidroximetilación estuvieron asociados al incremento de los valores de la CAT. La disminución de la desmetilación estuvo asociada a citopenia, y la disminución de la hidroximetilación a un curso más corto de la enfermedad. Los niveles menores de GSH y GSSG, y los valores superiores de SOD estuvieron asociados a una acumulación del daño, según lo evaluado mediante SLICC-ACR.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se observó menor hidroximetilación en los pacientes que en los controles. Además, el incremento de la desmetilación y la disminución de la hidroximetilación conllevan unos altos niveles de CAT. La hidroximetilación del ADN parece estar relacionada con un curso más largo de la enfermedad.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 959 "Ancho" => 3000 "Tamanyo" => 123069 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Relationship between TAC levels with 5-hmC (A) and 5-mC (B) in SLE patients.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2934 "Ancho" => 3167 "Tamanyo" => 282850 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Relationship of serum levels of SOD (A), GSH (B) and GSSG (C) with SLICC-ACR score in SLE patients.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">aB2GP, anti-beta2-glycoprotein antibodies; aCLA, anticardiolipin antibodies; ANAs, antinuclear antibodies; CRP, C-reactive protein; dsDNA, anti-double stranded DNA; ESR, erythrocyte sedimentation rate; GPL, IgG phospholipid unit; MPU, IgM phospholipid unit; SGU, standard IgG unit; SMU, standard IgM unit.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Clinical parameters \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">SLE patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Laboratory parameters \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">SLE patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"><span class="elsevierStyleItalic">N</span> (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Mean (SD) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Median (1st, 3rd Q.) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mucocutaneous affection</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">92 (64.8%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hemoglobin (g/dL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13.24 (1.27) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13.3 (12.3, 14.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Musculoskeletal affection</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80 (56.3%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Erythrocytes (x 10^3/μL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.45 (0.44) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.42 (4.2, 4.71) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vascular affection</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58 (40.8%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leucocytes (x 10^3/μL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.09 (2.83) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.50 (4.23, 6.98) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cytopenia</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44 (31%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphocytes (x 10^3/μL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.48 (0.76) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.28 (0.99, 1.78) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Renal affection</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23 (16.2%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophils (x 10^3/μL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.96 (2.50) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.61 (2.43, 4.67) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neurological affection</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 (15.5%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Platelets (x 10^3/μL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">237.15 (88.94) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">238 (190, 290) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cardiac affection</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 (12.7%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CRP (mg/L)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.31 (11.42) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.3 (0.98, 4.62) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Respiratory affection</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (7.7%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ESR (mm/h)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17.29 (20.94) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19 (9, 30.75) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ophthalmic affection</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (9.2%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">aCLA IgG (GPU)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14.38 (75.71) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.6 (1.5, 7.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hormonal affection</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 (8.5%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">aCLA IgM (MPU)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.93 (13.52) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.8 (3.2, 8.38) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gastrointestinal affection</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (2.1%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">aB2GP IgG (SGU/mL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50.64 (395.26) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (3.2, 8.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comorbidities</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49 (34.5%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">aB2GP IgM (SMU/mL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.17 (12.96) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.9 (1.6, 6.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypertension</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 (26.8)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">dsDNA (UI/mL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28.8 (57.91) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.7 (0.3, 31) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dyslipemia</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26 (18.3)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ANAs titer</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">520.87 (502.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">320 (160, 1280) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diabetes</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (7.7%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-Ro (U/mL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62.38 (81.72) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.8 (0.8, 128.35) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Raynaud's phenomenon</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49 (34.5%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-La (U/mL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.81 (59.25) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.2 (0.75, 8.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sjögren syndrome</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26 (18.3)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-Sm (U/mL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.08 (24.15) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.1 (0.52, 3.35) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antiphospholipid syndrome</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (9.1)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-RNP (U/mL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13.91 (43.61) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.2 (0, 2.93) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive Lupus Anticoagulant</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 (26.3)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C3 (mg/dL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">106.62 (29.41) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">109 (83, 128) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive ENAs</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">74 (52.1%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C4 (mg/dL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17.86 (8.77) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 (11, 23) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive anti-dsDNA</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52 (36.6%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Creatinine (mg/dL)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.73 (0.25) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.69 (0.62, 0.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive antiphospholipid antibodies</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 (35.2%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Estimated glomerular filtration rate (mL/min)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">97.09 (18.78) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">98 (89, 109) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Complement consumption \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59 (41.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Moderate/Severe Clinical activity (SLEDAI<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70 (49.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2782142.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Clinical and laboratory parameters of SLE patients.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "I.T.W. Harley" 1 => "K.M. Kaufman" 2 => "C.D. Langefeld" 3 => "J.B. Harley" 4 => "J.A. Kelly" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrg2571" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Genet" "fecha" => "2009" "volumen" => "10" "paginaInicial" => "285" "paginaFinal" => "290" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19337289" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0060" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Environmental factors, toxicants and systemic lupus erythematosus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. Mak" 1 => "S.H. Tay" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/ijms150916043" "Revista" => array:6 [ "tituloSerie" => "Int J Mol Sci" "fecha" => "2014" "volumen" => "15" "paginaInicial" => "16043" "paginaFinal" => "16056" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25216337" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0065" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genome-wide analysis of 5-hmC in the peripheral blood of systemic lupus erythematosus patients using an hMeDIP-chip" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W. Sui" 1 => "Q. Tan" 2 => "M. Yang" 3 => "Q. Yan" 4 => "H. Lin" 5 => "M. Ou" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3892/ijmm.2015.2149" "Revista" => array:6 [ "tituloSerie" => "Int J Mol Med" "fecha" => "2015" "volumen" => "35" "paginaInicial" => "1467" "paginaFinal" => "1479" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25813249" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0070" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased 5-hydroxymethylcytosine in CD4(+) T cells in systemic lupus erythematosus" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Zhao" 1 => "J. Wang" 2 => "W. Liao" 3 => "D. Li" 4 => "M. Li" 5 => "H. Wu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaut.2016.03.001" "Revista" => array:6 [ "tituloSerie" => "J Autoimmun" "fecha" => "2016" "volumen" => "69" "paginaInicial" => "64" "paginaFinal" => "73" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26984631" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0075" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oxidative stress as a potential causal factor for autoimmune hemolytic anemia and systemic lupus erythematosus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J. Fujii" 1 => "T. Kurahashi" 2 => "T. Konno" 3 => "T. Homma" 4 => "Y. Iuchi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5527/wjn.v4.i2.213" "Revista" => array:6 [ "tituloSerie" => "World J Nephrol" "fecha" => "2015" "volumen" => "4" "paginaInicial" => "213" "paginaFinal" => "222" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25949934" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0080" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "National registry of patients with systemic lupus erythematosus of the Spanish Society of Rheumatology: objectives and methodology" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "I. Rúa-Figueroa" 1 => "F.J. López-Longo" 2 => "J. Calvo-Alén" 3 => "M. Galindo-Izquierdo" 4 => "E. Loza" 5 => "M.J. García de Yebens" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.reuma.2013.04.013" "Revista" => array:6 [ "tituloSerie" => "Reumatol Clin" "fecha" => "2014" "volumen" => "10" "paginaInicial" => "17" "paginaFinal" => "24" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23871155" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0085" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Age-dependent decrease of DNA hydroxymethylation in human T cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.P. Truong" 1 => "M. Sakata-Yanagimoto" 2 => "M. Yamada" 3 => "G. Nagae" 4 => "T. Enami" 5 => "R. Nakamoto-Matsubara" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3960/jslrt.55.1" "Revista" => array:6 [ "tituloSerie" => "J Clin Exp Hematop JCEH" "fecha" => "2015" "volumen" => "55" "paginaInicial" => "1" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26105999" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0090" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interaction between oxidative stress and chemokines: possible pathogenic role in systemic lupus erythematosus and rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D. Shah" 1 => "A. Wanchu" 2 => "A. Bhatnagar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.imbio.2011.04.001" "Revista" => array:6 [ "tituloSerie" => "Immunobiology" "fecha" => "2011" "volumen" => "216" "paginaInicial" => "1010" "paginaFinal" => "1017" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21601309" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0095" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Markers of oxidative and nitrosative stress in systemic lupus erythematosus: correlation with disease activity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "G. Wang" 1 => "S.S. Pierangeli" 2 => "E. Papalardo" 3 => "G.A. Ansari" 4 => "M.F. Khan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.27442" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2010" "volumen" => "62" "paginaInicial" => "2064" "paginaFinal" => "2072" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20201076" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0100" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Circulating antioxidant levels in systemic lupus erythematosus patients: a systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "N.B. Sam" 1 => "B.Z. Li" 2 => "R.X. Leng" 3 => "H.F. Pan" 4 => "D.Q. Ye" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2217/bmm-2019-0034" "Revista" => array:6 [ "tituloSerie" => "Biomark Med" "fecha" => "2019" "volumen" => "13" "paginaInicial" => "1137" "paginaFinal" => "1152" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31475863" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack576365" "titulo" => "Acknowledgements" "texto" => "<p id="par0140" class="elsevierStylePara elsevierViewall">The authors are thankful to David Hervás and Victoria Fornés from Biostatistic Unit IIS La Fe, Dr. Marta Roca and Dr. Marina López from Unidad Analítica IIS La Fe and Biobanco La Fe from the HUP La Fe for their help with this study. The authors are also grateful for the professional English language editing to Mr. Arash Javadinejad, English Instructor and Publication Editor at the IIS La Fe, Valencia, Spain.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Authors thank specially to all SLE patients and healthy volunteers the participation in this study.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015700000012/v1_202112201710/S2387020621006173/v1_202112201710/en/main.assets" "Apartado" => array:4 [ "identificador" => "46797" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Editorial article" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015700000012/v1_202112201710/S2387020621006173/v1_202112201710/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020621006173?idApp=UINPBA00004N" ]
