Utility of cytokines CXCL4, CXCL8 and GDF15 as biomarkers in systemic sclerosis

array:23 ["pii" => "S2387020622004673" "issn" => "23870206" "doi" => "10.1016/j.medcle.2021.12.013" "estado" => "S300" "fechaPublicacion" => "2022-10-21" "aid" => "5886" "copyright" => "Elsevier España, S.L.U.. All rights reserved" "copyrightAnyo" => "2021" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Clin. 2022;159:359-65" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:18 [ "pii" => "S2387020622004661" "issn" => "23870206" "doi" => "10.1016/j.medcle.2021.12.012" "estado" => "S300" "fechaPublicacion" => "2022-10-21" "aid" => "5883" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Clin. 2022;159:366-71" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Characteristics and management of patients with stroke and major hemorrhagic episodes with atrial fibrillation under vitamin K antagonist therapy. EVENTHO study" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "366" "paginaFinal" => "371" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Características y abordaje de pacientes con ictus y episodios hemorrágicos mayores con fibrilación auricular en tratamiento con antagonistas de la vitamina K. Estudio EVENTHO" ] ] "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" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1008 "Ancho" => 2508 "Tamanyo" => 133411 ] ] "descripcion" => array:1 [ "en" => "Most common situations after hospital discharge." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Olga Gavín, Vanessa Roldán, Pilar Llamas-Sillero, Amparo Santamaría, Daniel Arumí, Susana Fernández de Cabo" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Olga" "apellidos" => "Gavín" ] 1 => array:2 [ "nombre" => "Vanessa" "apellidos" => "Roldán" ] 2 => array:2 [ "nombre" => "Pilar" "apellidos" => "Llamas-Sillero" ] 3 => array:2 [ "nombre" => "Amparo" "apellidos" => "Santamaría" ] 4 => array:2 [ "nombre" => "Daniel" "apellidos" => "Arumí" ] 5 => array:2 [ "nombre" => "Susana Fernández de" "apellidos" => "Cabo" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622004661?idApp=UINPBA00004N" "url" => "/23870206/0000015900000008/v1_202210210800/S2387020622004661/v1_202210210800/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020622004545" "issn" => "23870206" "doi" => "10.1016/j.medcle.2021.11.015" "estado" => "S300" "fechaPublicacion" => "2022-10-21" "aid" => "5872" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Clin. 2022;159:351-8" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Clinicopathological characteristics and survival results of patients with ultralow risk breast cancer" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "351" "paginaFinal" => "358" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Características clínico-patológicas y supervivencia de pacientes con cáncer de mama de riesgo muy bajo" ] ] "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" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2252 "Ancho" => 3175 "Tamanyo" => 309937 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Distance metastasis-free interval curves in 110 patients with non-palpable tumours, node-negative, diagnosed by mammography screening and in 88 patients with hormone-sensitive tumours." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "José M. Baena Cañada, Salvador Gámez-Casado, Lourdes Rodríguez-Pérez, Cristina Bandera-López, Andrés Mesas-Ruiz, Alicia Campini-Bermejo, Marta Bernal-Gómez, Manuel Zalabardo-Aguilar, Julio Calvete-Candenas, Gala Martínez-Bernal, Alicia Quílez-Cutillas, Lidia Atienza-Cuevas, Marcial García-Rojo, Encarnación Benítez-Rodríguez, Bella Pajares-Hachero, María José Bermejo-Pérez" "autores" => array:16 [ 0 => array:2 [ "nombre" => "José M." "apellidos" => "Baena Cañada" ] 1 => array:2 [ "nombre" => "Salvador" "apellidos" => "Gámez-Casado" ] 2 => array:2 [ "nombre" => "Lourdes" "apellidos" => "Rodríguez-Pérez" ] 3 => array:2 [ "nombre" => "Cristina" "apellidos" => "Bandera-López" ] 4 => array:2 [ "nombre" => "Andrés" "apellidos" => "Mesas-Ruiz" ] 5 => array:2 [ "nombre" => "Alicia" "apellidos" => "Campini-Bermejo" ] 6 => array:2 [ "nombre" => "Marta" "apellidos" => "Bernal-Gómez" ] 7 => array:2 [ "nombre" => "Manuel" "apellidos" => "Zalabardo-Aguilar" ] 8 => array:2 [ "nombre" => "Julio" "apellidos" => "Calvete-Candenas" ] 9 => array:2 [ "nombre" => "Gala" "apellidos" => "Martínez-Bernal" ] 10 => array:2 [ "nombre" => "Alicia" "apellidos" => "Quílez-Cutillas" ] 11 => array:2 [ "nombre" => "Lidia" "apellidos" => "Atienza-Cuevas" ] 12 => array:2 [ "nombre" => "Marcial" "apellidos" => "García-Rojo" ] 13 => array:2 [ "nombre" => "Encarnación" "apellidos" => "Benítez-Rodríguez" ] 14 => array:2 [ "nombre" => "Bella" "apellidos" => "Pajares-Hachero" ] 15 => array:2 [ "nombre" => "María José" "apellidos" => "Bermejo-Pérez" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775321007156" "doi" => "10.1016/j.medcli.2021.11.008" "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/S0025775321007156?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622004545?idApp=UINPBA00004N" "url" => "/23870206/0000015900000008/v1_202210210800/S2387020622004545/v1_202210210800/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Utility of cytokines CXCL4, CXCL8 and GDF15 as biomarkers in systemic sclerosis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "359" "paginaFinal" => "365" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "José E. Oller-Rodríguez, Elvira Vicens Bernabeu, Roxana Gonzalez-Mazarío, Elena Grau García, Francisco M. Ortiz Sanjuan, José A. Román Ivorra" "autores" => array:6 [ 0 => array:4 [ "nombre" => "José E." "apellidos" => "Oller-Rodríguez" "email" => array:1 [ 0 => "joseeloy1986@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Elvira" "apellidos" => "Vicens Bernabeu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Roxana" "apellidos" => "Gonzalez-Mazarío" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Elena" "apellidos" => "Grau García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Francisco M." "apellidos" => "Ortiz Sanjuan" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "José A." "apellidos" => "Román Ivorra" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Reumatología, Hospital UyP 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" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Utilidad de las citocinas CXCL4, CXCL8 y GDF15 como biomarcadores en la esclerosis sistémica" ] ] "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" => 891 "Ancho" => 2500 "Tamanyo" => 127334 ] ] "descripcion" => array:1 [ "en" => "Association between GDF15 levels and findings in capillaroscopy. Short explanation: We observed an increase in GDF15 levels in patients who had dilated loops, and a tendency for patients with decreased capillary density to show an increase in GDF15." ] ] ] "textoCompleto" => "IntroductionSystemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune alterations and fibrosis.Its diagnosis can be simple when disease is evolved and both cutaneous and organic damage has taken place, but it might be difficult in earlier stages, when its features are more unspecific and insidious.Therefore, it would be useful to find non-invasive markers that allow an early diagnosis, in order to start treatment before irreversible fibrotic changes appear.CXCL4 (also called Platelet Factor 4) is a protein constituted by 70 amino acids, that belongs to CXC chemokine family.<a class="elsevierStyleCrossRef" href="#bib0155">1</a> It is mainly produced by megakaryocytes and plasmacytoid dendritic cells.Indeed, it is released by platelet alpha-granules during platelet aggregation, as in responses to traumatisms, wounds or infections.This cytokine can work as a chaperone, forming crystalline CXCL4-DNA complexes that can activate dendritic cells via TLR9, what enhances IFN-I synthesis. A correlation between circulating levels of CXCL4 and IFN-I has been demonstrated.<a class="elsevierStyleCrossRef" href="#bib0160">2</a> In summary, CXCL4 is overexpressed in SSc and other diseases (SLE, RA, SS), where the signature of IFN-I is important. This signature is present in 50% of SSc patients.<a class="elsevierStyleCrossRef" href="#bib0165">3</a>CXCL4 is also involved in other processes as chemotaxis (attracting neutrophils, monocytes and fibroblasts), atherosclerosis, fibrosis (induces the expression of profibrotic cytokines as IL-4 and IL-13, and reduces the expression of IFN-γ, that is antifibrotic) and angiogenesis inhibition.<a class="elsevierStyleCrossRef" href="#bib0170">4</a>It induces PDGF-BB synthesis by myeloid cells (which is potent mitogen for dermal fibroblasts), and has also been shown to promote the survival of monocytes,<a class="elsevierStyleCrossRef" href="#bib0175">5</a> as well as to aid their extravasation.CXLC4 also blocks HO-1 local expression, so control of HO-1 disappears over aberrant TLR activation.<a class="elsevierStyleCrossRef" href="#bib0180">6</a> A proteome-wide analysis showed it is the prevailing protein produced by plasmocytoid dendritic cells in SSc.<a class="elsevierStyleCrossRef" href="#bib0185">7</a>In addition to the aforementioned influence on the innate immune system, it acts on the adaptive system, being able to induce the activation of Ag-specific CD8+ T cells.<a class="elsevierStyleCrossRef" href="#bib0190">8</a>It has been proposed as a SSc biomarker, especially in early and active Diffuse SSc, but also in an active and early phase in Limited SSc,<a class="elsevierStyleCrossRef" href="#bib0185">7</a> when inflammation has a preponderant role, or even in undifferentiated connective tissue disease at risk for SSc, especially in patients without capillaroscopic alterations.<a class="elsevierStyleCrossRef" href="#bib0195">9</a>Its presence has been demonstrated in SSc patients skin,<a class="elsevierStyleCrossRef" href="#bib0200">10</a> blood and in BALF, has been associated to the extent of cutaneous involvement in Diffuse and Limited SSc,<a class="elsevierStyleCrossRefs" href="#bib0205">11,12</a> and has also been related to early lung involvement (both Pulmonary Arterial Hypertension (PAH) and Interstitial Lung Disease (ILD). It has also been related to spirometric changes, as a decrease in Forced Vital Capacity (FVC) and Carbon Monoxide Diffusing Capacity (DLCO).<a class="elsevierStyleCrossRef" href="#bib0185">7</a> Moreover, its plasma levels can predict progression in skin involvement, ILD and PAH.<a class="elsevierStyleCrossRef" href="#bib0205">11</a>However, it was observed to be present in many patients with Raynaud, who did not progress to SSc (against other studies that point it is a factor of progression from pre-SSc to SSc),<a class="elsevierStyleCrossRef" href="#bib0215">13</a> so we can infer it is related to cutaneous inflammatory phase, more than to fibrosis (next evolutionary stage), where it even collaborates in an initial phase.Turning now to focus on GDF15 (also called Macrophage Inhibitory Cytokine 1), it is a member of the cytokine superfamily TGF-B, but it only shares<30% of its sequence with other members of the family as TGFβ1, GDF-5 or BMPs.<a class="elsevierStyleCrossRef" href="#bib0220">14</a>GDF15 is very expressed in placenta, and then in multiple tissues in lesser quantity, but its expression gets increased in the context of adaptation to stress (due to hypoxia, inflammation, radiation or tissue damage). In fact, it is an independent predictor of long-term mortality in pulmonary<a class="elsevierStyleCrossRef" href="#bib0225">15</a> embolism and in essential pulmonary hypertension. Its synthesis is induced in tissue damage in acute myocardial infarction, as it has a protective effect of myocardiocytes; as well in ischemia-reperfusion.Its levels are high in patients with SSc, but they tend to decrease in late evolutive stages.<a class="elsevierStyleCrossRef" href="#bib0230">16</a>It is an inflammation inductor, involved<a class="elsevierStyleCrossRef" href="#bib0235">17</a> in the expression of proinflammatory cytokines such IL-6 or CCL2, and macrophagues recruitment (by CCR2/CCL2 axis). It also plays a role in fibrosis, starting this process (although it is not essential in its perpetuation (other factors such as TGFβ or CTGF can do so, there is a functional redundancy in this family).<a class="elsevierStyleCrossRef" href="#bib0240">18</a> GDF15 also stimulates the expression of type I collagen and osteopontin. At pulmonary level, among others, it activates resident fibroblasts in the inflammatory context (CCL2, TGFb, IL6), which leads to pulmonary fibrosis.Other functions have been attributed to GDF15, as intercellular signaling, signal transduction and regulation of apoptosis. A consistent finding is its co-localization with CD68 (monocyte/macrophage marker).A correlation between blood levels and the number of organs with fibrosis (as well as the degree of fibrosis) has been described,<a class="elsevierStyleCrossRef" href="#bib0240">18</a> as well as a negative correlation with survival.Attending to the literature, it is associated with Diffuse SSc.<a class="elsevierStyleCrossRef" href="#bib0230">16</a> It is related to the spread of cutaneous fibrosis, ILD and PAH, with a significant correlation with decrease in DLCO and with elevation of FVC/DLCO ratio.<a class="elsevierStyleCrossRef" href="#bib0230">16</a> It also has a positive correlation with BNP and right ventricular systolic pressure.<a class="elsevierStyleCrossRef" href="#bib0240">18</a>Presence of GDF15 in pulmonary parenchyma and plasma from patients with PAH has been demonstrated, and its levels are higher than in patients without PAH or with idiopathic PAH.<a class="elsevierStyleCrossRef" href="#bib0220">14</a> It can be a useful SSc-PAH biomarker.There is also a correlation between GDF15 and antiScl70 (and to a lesser extent with the presence of anticentromere antibodies<a class="elsevierStyleCrossRef" href="#bib0245">19</a>).On the other hand, CXCL8, also called IL8, is a chemokine synthesized by fibroblasts, dendritic cells, endothelial cells, neutrophils and monocytes/macrophages.<a class="elsevierStyleCrossRef" href="#bib0250">20</a>It works as a potent chemotactic factor of neutrophils and other granulocytes, and it amplifies local inflammatory response. In that sense, it also promotes angiogenesis. It is also related to fibrosis, but it seems that to a lesser extent.<a class="elsevierStyleCrossRef" href="#bib0255">21</a>The presence of certain polymorphisms in CXCL8 gene have been associated with greater susceptibility to develop SSc.<a class="elsevierStyleCrossRef" href="#bib0260">22</a> Serum CXCL8 levels are increased in SSc.<a class="elsevierStyleCrossRef" href="#bib0265">23</a> It just appears to be increased during the first year of the disease.It is increased in BALF from patients with SSc+ILD and it was once associated with decreased HAQ.<a class="elsevierStyleCrossRef" href="#bib0270">24</a> It has been associated with Lung involvement objectified by HRCT, with doubtful spirometric results.<a class="elsevierStyleCrossRef" href="#bib0275">25</a> High levels of CXCL8 have been reported in SSc patients with anti Scl70 antibodies.<a class="elsevierStyleCrossRef" href="#bib0280">26</a>In our work, we try to evaluate the clinical implications of the 3 cytokines, their correlation with less studied variables as alterations in capillaroscopy, functional and disease activity rates, and also their usefulness as organic damage biomarkers.Patients and methodsFor this observational study, we recruited patients with a diagnosis of systemic sclerosis according to ACR/EULAR 2013 criteria, as well as a control group constituted by healthy subjects.In both groups, a blood sample was collected to determine levels of CXCL4, GDF15 and CXCL8.On the other hand, only in the group of patients with systemic sclerosis, several variables were collected: demographic (age, sex, time from diagnosis), clinical (type of SSc, cardiovascular risk factors, macrovascular and microvascular involvement, arthritis, myositis, heart disease, cutaneous affectation, pulmonary, renal or digestive), and analytical (RCP, ESR, C3, C4, hemogram, and antibodies as RF, ANA, anti-Scl70, anti-centromere, anti-polymerase III), variables; we also realized Rodnan modified score to assess patient's skin thickness, HAQ index, SF36 as an indicator of quality of life, EUSTAR activity index, Medsger disease severity scale, Cochin Hand Function Scale and Capillaroscopic findings. We used a Videocapilaroscopy equipment with integrated video software videocap 3.0 (DS Medica).All patients had pulmonary HRCT and respiratory function test, in order to check the existence of ILD. Likewise, a transthoracic echocardiography was performed (with measurement of systolic lung pressure and tricuspid regurgitation rate), with the aim of objectifying PAH.We used ELISA (Enzyme Linked Immunosorbent Assay) in order to analyze CXCL4, GDF15 and CXCL8 levels. Serum was obtained in a maximum of 1 hour from the extraction of peripheral blood. Aliquots of 500μL were made and stored at −80°C until used. We used a Multiskan plate reader spectrophotometer to read the absorbance at 450nm. Samples were measured in duplicate (30 patient samples and 10 control samples per 96-well plate).Regarding the statistical analysis, we used R software (version 3.2.2). Data were described by the mean, median, standard deviation and the first and third quartiles in the case of continuous variables and by relative and absolute frequencies in case of categorical variables. Associations between different continuous variables were determined by Pearson correlation in case of linear relationships and by Spearman correlation in case of non-linear relationships. P values less than 0.05 were considered statistically significant.Another point is that and our research protocol was previously approved by the Ethics Committee of Hospital La Fe, called Comité de Ética de la Investigación con Medicamentos del Hospital UyP La Fe. It also complies with the Declaration of Helsinki, and an informed consent has been obtained from the subjects.ResultsA sample of 42 patients with systemic sclerosis (SSc) was obtained, of which 20 corresponded to limited SSc, another 20 patients corresponded to diffuse SSc, while 2 patients presented “Scleroderma sine Scleroderma”.Looking at the distribution by sex, 40 of the patients were female whereas only 2 patients were male.The baseline characteristics of the cohort, attending to clinical features, and the results of the diagnostic procedures are reflected in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The sample of SSc patients was compared to a control group with 42 free SSc individuals.We observed a disparate concentration of them in patients with SSc, and therefore can not objectify any correlation between them; then, if we compare their level in SSc patients with their level in healthy controls, we find that GDF15 levels (mean: 1.05ng/mL, SD: 0.67ng/mL) were significantly higher in SSc patiens (p<0.001) than in healthy controls (mean: 0.41ng/mL, SD: 0.24ng/mL)), with no significant differences in CXCL4 and CXCL8 levels between SSC patients and healthy controls (p: 0.987 and p: 0.129, respectively).Levels of GDF15 were significantly higher (p: 0.009) in diffuse SSc (mean: 1.26ng/mL, SD: 0.74ng/mL) than in limited SSc patients (mean: 0.78ng/mL, SD: 0.49ng/mL), with no association to age, sex or years since diagnosis.In relation to clinical manifestations, a statistically significant increase in levels of GDF15 was observed (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) in those patients with SSc and PAH (p: 0.038) and/or ILD (p: 0.004), as we can see in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>In addition, a statistically significant association was observed between the increase in GDF15 levels and the decrease in FVC (p: 0.002). No association with decrease in DLCO was found (p: 0.291).No association was found with the values of blood analysis except for anti-Scl70 (p: 0.006).Regarding capillaroscopy, we observed an increase in GDF15 levels (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) in patients who had dilated loops (p: 0.015), as well as a tendency for patients with decreased capillary density to show an increase in GDF15 (p: 0.06).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>We also observed increased values of GDF15 in patients with a high score in EUSTAR activity index (p: 0.001). On the other hand, no statistically significant differences were observed according to the Rodnan score, Medsger scale, SF36, HAQ or Cochin.Going on to analyze CXCL4, no statistically significant differences were observed according to sex, age, years of evolution of the disease, classification of SSc in limited or diffuse.On the other hand, no statistically significant differences were observed in relation to the various clinical manifestations of the disease. No association of CXCL4 values with the decrease in FVC and DLCO was observed either.A decrease in CXCL4 levels was observed in patients with lower values of the C3 fraction of the complement (p: 0.008). In the other variables of the blood analysis (including autoantibodies), no statistically significant differences were observed.No statistically significant differences were observed in relation to capillaroscopy parameters.However, an increase in CXCL4 levels was evidenced (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>) in those patients with high scores of mRodnan score (p: 0.001). This fact, like its behavior with C3 could be explained by its potential role in the beginning of the fibrotic process.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>There were no differences in CXCL4 levels depending on punctuation of Medsger scale, Cochin, Eustar activity index, HAQ or SF36.Focusing now on CXCL8, no statistically significant differences were observed according to sex, age, years of evolution of the disease, classification of SSc in limited or diffuse.No statistically significant association was found between CXCL8 levels and any clinical manifestation of the SSc, nor with the measurements of FVC or DLCO.Lower levels of C4 fraction of complement were observed in patients with an increase in CXCL8 levels (p: 0.013). In the other variables, no statistically significant differences were observed.There were no differences in CXCL8 levels depending on punctuation of Rodnan score, Medsger scale, Cochin, Eustar activity index, HAQ or SF36.An association was observed between elevated levels of CXCL8 and the presence of tortuosities in capillaroscopy (p: 0.02). No statistically significant differences were observed with respect to the rest of the capillaroscopy parameters.DiscussionIn this study, we describe the findings of the levels of GDF15, CXCL8 and CXCL4 and their association with systemic sclerosis.The scarce correlation between GDF15, CXCL4 and CXCL8 in the analyzed patients may result striking. This reality implies that the behavior of each of them is different in these patients. In any case, it is not completely surprising, given that they are not physiopathologically related and do not share activation pathways. In addition, CXCL4 and CXCL8 predominate in early stages of the disease, while the importance of GDF15 is maintained during the course of the same.Regarding the elevated levels of GDF15 in patients with systemic sclerosis, we observed, on the one hand, an elevation of the levels of this chemokine in patients with the disease, as well as a greater association with the diffuse forms of the disease, in comparison with limited forms, which agrees with the literature.In line with this interleukin, we observed an increase in the levels of this molecule in patients with high anti-Scl70 antibody values, which is logical if we take into account that up to 70% of patients with diffuse SSc in published series present positivity to said antibody.Likewise, we have observed a clear negative correlation of this molecule with FVC (or positive with the decrease in FVC), without being correlated with DLCO. Previous studies had observed a negative correlation with DLCO and a positive correlation with the FVC/DLCO ratio, with there is no known correlation with FVC. This remark is very meaningful because DLCO performs as a sensitive but not specific parameter in pulmonary function and could be altered in both PAH and ILD.The association between high GDF15 levels and with pulmonary hypertension had been described before.<a class="elsevierStyleCrossRef" href="#bib0220">14</a> However, in our study we have observed that they are not specific to PAH, as we can also see them associated with ILD, reflecting a role in the pulmonary fibrotic process and it might be a potential ILD biomarker.We have also seen an association between increase in GDF15 levels and alterations in capillaroscopy (dilated loops and decreased capillary density), which according to our knowledge had not been objectified in the literature and which, however, is related to the nature and action of said molecule.In the same way, an association between the levels of this cytokine and a higher score in the EUSTAR index of disease activity has been objectified for the first time. We have not found previous studies that have analyzed the relationship between said molecule and the activity of the disease.As argued in recent works,<a class="elsevierStyleCrossRef" href="#bib0285">27</a> this index seems somewhat better than DAS in monitoring SSc activity.A correlation between GDF15 levels and with skin induration (objectified by Rodnan score) had previously been described,<a class="elsevierStyleCrossRef" href="#bib0290">28</a> but our findings do not agree with it. This could be interpreted on the basis that there were relatively low mRodnan scores (with an average of 5.95 in diffuse SSc patients, and 4.15 in limited SSc patients) in our sample.Regarding the elevated levels of CXCL4, we have observed how in our study they were associated mainly with a greater cutaneous induration evaluated by modified Rodnan score, which coincides with recent evidence.<a class="elsevierStyleCrossRefs" href="#bib0205">11,12</a>The relationship between a decrease in CXCL4 levels and lower values of the C3 fraction of the complement has not been described in previous studies in SSc. However, it has been described in other entities with a marked fibrotic signature, such as Renal Fibrosis<a class="elsevierStyleCrossRef" href="#bib0295">29</a> and in a murine model in Idiopathic Pulmonary Fibrosis.<a class="elsevierStyleCrossRef" href="#bib0300">30</a>We could also highlight the discordance among other publications regarding the levels of CXCL4 (not superior to the healthy controls in our study).<a class="elsevierStyleCrossRef" href="#bib0200">10</a> They explained in their exploratory analysis that CXCL4 levels increased gradually and significally by group (primary Raynaud's phenomenon<Raynaud's phenomenon and positive antinuclear antibodies<very early SSc). The cut-off they proposed to discriminate different scenarios was 10ng/mL. It is striking that in our sample, the average levels of CXCL4 were only 7.52ng/mL in SSc patients (for 5.29ng/mL in controls). This could be due to the fact that we included patients in a more advanced stage of the disease. Another possible explanation could be that CXCL4 levels in serum may not reflect physiological conditions because of platelet activation during serum preparation.In reference to CXCL8, a correlation was observed between levels of CXCL8 and a decrease in the C4 fraction of the complement, whose explanation could lie in an activation of the increased complement in those patients with a greater inflammatory component and a greater consumption of it in early phases of the disease. This last point could be logically expected, since said molecule has a proinflammatory function, but no previous evidence had been found about it in the context of SSc.We must remember the importance of CXCL8 as a receptor in the migration of neutrophils to foci of greater inflammatory activity. Therefore, it is to be assumed that in more advanced stages of the disease, in which the vascular damage and the fibrosis component predominate, the importance of said chemokine is diminished.Since the importance of CXCL4 and CXCL8 seems to be greater in early or early stages of the disease, the lack of correlation observed with functional indexes and with the EUSTAR index of disease activity could be accounfied.A finding not yet described in previous articles is the relationship between these cytokines and the findings in the capillaroscopy of patients with SSc. In patients with high GDF15 levels, where we found dilated loops and decreased capillary density. This may mean a relationship with more advanced stages of microvascular damage. However, CXCL8 levels appeared associated with tortuosities in capillaroscopy what could be attributed to incipient affectation capillary nail bed.Finally, it may be interesting to expand the sample size in the future in order to extract more data and reach statistical significance in some parameters that could be relevant.In addition, a larger sample size could facilitate the stratification of the groups depending on the time of evolution of the disease. In patients with less evolution of it, a greater role of the chemokines CXCL4 and CXCL8 is expected.It is a promising line of research, and it is necessary to increase our knowledge about the pathophysiology of the disease and for define them as useful biomarkers for stratification of risk from an early stage, and also possible therapeutic targets.ConclusionsGDF15 levels were significantly higher in SSc patiens, specially in diffuse SSc, and were observed in patients with PAH/ILD and dilated loops in capillaroscopy, while CXCL4 levels were related to higher mRodnan score and CXCL8 levels were related to complement consumption.Ethical considerationsOur research protocol was previously approved by the Ethics Committee of Hospital La Fe, called Comité de Ética de la Investigación con Medicamentos del Hospital UyP La Fe. It also complies with the Declaration of Helsinki, and an informed consent has been obtained from the subjects.Funding statementThis work was financed with the own resources of our Rheumatology Department.Conflict of interestThe authors declare no conflicts of interest:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-José Eloy Oller Rodríguez declares no conflicts of interest.</li><li class="elsevierStyleListItem" id="lsti0010">-Elvira Vicens Bernabeu declares no conflicts of interest.</li><li class="elsevierStyleListItem" id="lsti0015">-Roxana González Mazarío declares no conflicts of interest.</li><li class="elsevierStyleListItem" id="lsti0020">-Elena Grau García declares no conflicts of interest.</li><li class="elsevierStyleListItem" id="lsti0025">-Francisco Ortiz Sanjuan declares no conflicts of interest.</li><li class="elsevierStyleListItem" id="lsti0030">-José A. Román Ivorra declares no conflicts of interest.</li></ul>We also declare that this manuscript has not been published before, neither is under consideration for publication elsewhere. The preliminary results of our work were accepted as Poster Presentation in the 6th Systemic Sclerosis World Congress (planned to be held in Prague in March 2020, but finally held online in July 2020), as Oral Communication in the XLVI Congress of Sociedad Española de Reumatología (October 2020) and the XII Systemic Sclerosis Spanish Meeting (March 2021), and also accepted for publication in the EULAR 2020 Congress Abstract Book.If accepted for publication by Medicina Clínica, it will not be published anywhere else.Furthermore, this manuscript has been read and approved by all of the authors." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1787323" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1566806" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1787322" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1566807" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Patients and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Ethical considerations" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Funding statement" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interest" ] 12 => array:2 [ "identificador" => "xack631180" "titulo" => "Acknowledgements" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-09-11" "fechaAceptado" => "2021-12-03" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1566806" "palabras" => array:5 [ 0 => "Systemic sclerosis" 1 => "CXCL4" 2 => "CXCL8" 3 => "GDF15" 4 => "Capillaroscopy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1566807" "palabras" => array:5 [ 0 => "Esclerosis sistémica" 1 => "CXCL4" 2 => "CXCL8" 3 => "GDF15" 4 => "Capilaroscopia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Background and objectivesSystemic sclerosis (SSc) is an autoinmune disease that can affect several organs and its mortality is fundamentally related to its pulmonary involvement. There are some cytokines with high serum levels of patients with SSc. Our goal is to determine the role of CXCL4, CXCL8 and GDF15 in the physiopathology of SSc and whether they can be considered organic damage biomarkers. Patients and methodsObservational case–control study of SSc patients (ACR/EULAR 2013 criteria). Demographic, clinical, analytical, activity, severity, health perception, and disability variables were collected. Moreover, Videocapillaroscopy, Echocardiography and Respiratory Function Test were made. Serum levels of CXCL4, CXCL8 and GDF15 were measured both in SSc patients and in healthy controls. ResultsA total of 42 patients were included (95.4% women), with an average age of 59.2 years and a median of 4 years from diagnosis. We also included 42 healthy controls. We found significantly higher levels of GDF15 in SSc patients than in controls (p<0.001), but no higher CXCL4 or CXCL8 levels. GDF15 was associated with Diffuse SSc, pulmonary arterial hypertension, interstitial lung disease, less forced vital capacity, high titles of antiScl70, disease activity, and dilated loops in capillaroscopy. CXCL4 levels were associated to a higher Rodnan punctuation, while CXCL8 was associated to C4 fraction consumption and tortuosities in capillaroscopy. ConclusionsGDF15 high levels were associated with diffuse SSc, lung impairment, disease activity and changes in capillaroscopy. Moreover, CXCL4 was only associated with skin impairment, while CXCL8 was not related to organic damage." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Antecedentes y objetivosLa esclerosis sistémica (ES) es una enfermedad autoinmunitaria que afecta a diferentes órganos y cuya mortalidad se relaciona fundamentalmente con su afectación pulmonar. Los pacientes con ES presentan niveles séricos elevados de algunas citocinas. Nuestro objetivo es determinar el papel de CXCL4, CXCL8 y GDF15 en la fisiopatología de la ES, y si pueden considerarse biomarcadores de daño orgánico. Pacientes y métodosEstudio observacional de casos-controles, con pacientes afectados de ES (criterios ACR/EULAR 2013) y controles sanos. Se determinaron los niveles séricos de CXCL4, CXCL8 y GDF15 en ambos grupos, y se registraron variables demográficas, clínicas, analíticas, de actividad, gravedad, percepción de salud y discapacidad de pacientes con ES, a quienes, además, se les realizó videocapilaroscopia, ecocardiograma y espirometría. ResultadosSe incluyeron 42 pacientes (95,4% mujeres), con una edad media de 59,2 años y una mediana de 4 años desde el diagnóstico, con 42 controles sanos. Se hallaron niveles significativamente mayores de GDF15 en pacientes con ES que en controles (p<0,001), pero no de CXCL4 ni CXCL8. GDF15 se asoció a ES difusa, hipertensión pulmonar, enfermedad pulmonar intersticial, menor capacidad vital forzada, títulos altos de anti-Scl70, actividad de ES y dilataciones capilares. Asimismo, los niveles de CXCL4 se asociaron a mayor afectación cutánea (Rodnan), mientras que CXCL8 se asoció a consumo de la fracción C4 del complemento y tortuosidades en la capilaroscopia. ConclusionesLos niveles elevados de GDF15 se asociaron a ES difusa, afectación pulmonar, actividad de la ES y alteraciones en la capilaroscopia. Por otra parte, CXCL4 se asoció a afectación cutánea, no relacionándose CXCL8 con daño orgánico." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1041 "Ancho" => 2500 "Tamanyo" => 96361 ] ] "descripcion" => array:1 [ "en" => "Association between GDF15 levels and the presence of PAH or ILD. Short explanation: A statistically significant increase in levels of GDF15 was observed in those patients with SSc and PAH." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 891 "Ancho" => 2500 "Tamanyo" => 127334 ] ] "descripcion" => array:1 [ "en" => "Association between GDF15 levels and findings in capillaroscopy. Short explanation: We observed an increase in GDF15 levels in patients who had dilated loops, and a tendency for patients with decreased capillary density to show an increase in GDF15." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1414 "Ancho" => 2167 "Tamanyo" => 120914 ] ] "descripcion" => array:1 [ "en" => "Correlation between CXCL4 levels and mRodnan score. Short explanation: An increase in CXCL4 levels was evidenced in those patients with high scores of mRodnan score, showing an increased skin involvement." ] ] 3 => 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" => "Short explanation: It details its clinical features and the results of the diagnostic procedures that were subsequently used to establish the analyses." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><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">Age (mean years, SD) \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">59.21 (13.19) \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">Time since diagnosis (mean years, SD) \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">5.93 (1.66) \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">Time since first non-Raynaud's symptom (mean years, SD) \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">8 (6.67) \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">Sex: females n (%), males n (%) \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">40 (95), 2(5) \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">Rheumatoid factor (% of positives) \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">6 (14.3) \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">ACPA (% of positives) \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">4 (9.5) \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">ANA (% of positives) \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">42 (100) \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">Anti-DNA (% of positives) \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">3 (7.1) \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">C3 fraction (mean mg/dL, SD) \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">122.6 (28.8) \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">Low C3 (%) \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">4 (9.5) \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">C4 fraction (mean mg/dL, SD) \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">22.02 (8.8) \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">Low C4 (%) \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">2 (4.8) \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">HAQ (mean, SD) \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">0.78 (0.76) \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">SF36 (mean, SD) \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">0.51 (0.29) \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">mRodnan (mean, SD) \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">4.81 (5.71) \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">EUSTAR activity index (mean, SD) \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">4.93 (1.45) \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">Medsger severity scale (mean, SD) \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">4.05 (1.17) \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">Cochin (mean, SD) \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">7.5 (1.2) \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">Arterial Hypertension (%) \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">13 (31) \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">Diabetes mellitus (%) \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">0 (0) \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">Dyslipidemia (%) \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">11 (26) \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">Raynaud's phenomenon (%) \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">42 (100) \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">Macrovascular involvement (%) \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">3 (7.1) \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">Heart involvement (%) \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">3 (7.1) \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">Arthralgia/arthritis (%) \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">35 (83.3) \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">Myositis (%) \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">2 (4.8) \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">PAH (%) \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">5 (11.9) \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">ILD (%) \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">14 (33.3) \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">ILD subtype NINE (%) \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">6 (14.3) \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">ILD subtype NIU (%) \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">7 (16.7) \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">ILD subtype bronchiolitis (%) \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">1 (2.4) \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">Reduced FVC (%) \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">7 (16.7) \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">Reduced DLCO (%) \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">25 (59.5) \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">Gastrointestinal involvement (%) \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">14 (33.3) \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">Kidney involvement (%) \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">2 (4.8) \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">Anemia (%) \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">6 (14.3) \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">Neutropenia (%) \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">1 (2.4) \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">Lymphopenia (%) \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">3 (7.2) \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">Thrombopenia (%) \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">2 (4.8) \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">High PCR (% of positives) \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">7 (16.7) \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">High ESR \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">8 (19) \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">Anti-Scl70 (% of positives) \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">7 (16.7) \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">Anti-centromere (% of positives) \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">21 (50) \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">Anti-RNA polymerase (% of positives) \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">4 (9.5) \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">Sclerodermiform pattern in Capillaroscopy (%) \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">35 (83.3) \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">Unspecific pattern in capillaroscopy (%) \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">7 (16.7) \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">Tortuosities (%) \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">16 (38) \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">Ramifications (%) \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">13 (30.9) \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">Dilated loops (%) \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">38 (90.5) \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">Giant capillaries (%) \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">31 (73.8) \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">Microhemorrhages (%) \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">31 (73.8) \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">Avascularity (%) \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">26 (61.9) \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">Decreased capillary density (%) \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">32 (76.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Baseline characteristics of the cohort." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Short explanation: It shows clinical, analytical and spirometric features of patients with ILD and PAH." "tablatextoimagen" => array:1 [ 0 => array:1 [ "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" 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">PAH 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" style="border-bottom: 2px solid black">ILD patients \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-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">Levels of GDF15 in ng/mL (median, SD) \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">1.429 (0.596) \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">1.389 (0.753) \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">Number of patients \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">5 \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">14 \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">HAQ (median) \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">1.25 \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">0.75 \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">EUSTAR activity index (median) \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">6.3 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \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">Cochin (median) \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">5 \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">10.5 \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">SF36 (median) \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">0.42 \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">0.52 \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">Rodnan (median) \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">4 \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">3 \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">Gravedad Medsger (median) \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">5 \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">4 \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">Centromeric nuclear ANA pattern (%) \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">40 \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">7 \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">Homogeneous nuclear ANA pattern (%) \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">20 \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">36 \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">Anti-centromere (%) \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">40 \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">7 \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">Anti-Scl70 (%) \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">20 \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">36 \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">Anti-RNApolymerase III (%) \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">20 \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">14 \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">Reduction in DLCO (%) \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">80 \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">71 \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">Reduction in FVC (%) \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">40 \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">21 \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">Sclerodermiform pattern in VCL (%) \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">100 \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">78.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Characteristics of patients with ILD and PAH in our study." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chemokines beyond chemo-attraction: CXCL10 and its significant role in cancer and autoimmunity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "N. Karin" 1 => "H. Razon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cyto.2018.02.012" "Revista" => array:6 [ "tituloSerie" => "Cytokine" "fecha" => "2018" "volumen" => "109" "paginaInicial" => "24" "paginaFinal" => "28" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29449068" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0160" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Lande" 1 => "E.Y. Lee" 2 => "R. Palazzo" 3 => "B. Marinari" 4 => "I. Pietraforte" 5 => "G.S. Santos" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41467-019-09683-z" "Revista" => array:5 [ "tituloSerie" => "Nat Commun" "fecha" => "2019" "volumen" => "10" "paginaInicial" => "1731" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31043596" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0165" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Innate immunity in systemic sclerosis fibrosis: recent advances" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Laurent" 1 => "V. Sisirak" 2 => "E. Lazaro" 3 => "C. Richez" 4 => "P. Duffau" 5 => "P. Blanco" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fimmu.2018.01702" "Revista" => array:5 [ "tituloSerie" => "Front Immunol" "fecha" => "2018" "volumen" => "9" "paginaInicial" => "1702" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30083163" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0170" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.E. Maione" 1 => "G.S. Gray" 2 => "J. Petro" 3 => "A.J. Hunt" 4 => "A.L. Donner" 5 => "S.I. Bauer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.1688470" "Revista" => array:6 [ "tituloSerie" => "Science" "fecha" => "1990" "volumen" => "247" "paginaInicial" => "77" "paginaFinal" => "79" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1688470" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0175" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Scheuerer" 1 => "M. Ernst" 2 => "I. Dürrbaum-Landmann" 3 => "J. Fleischer" 4 => "E. Grage-Griebenow" 5 => "E. Brandt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2000" "volumen" => "95" "paginaInicial" => "1158" "paginaFinal" => "1166" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10666185" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0180" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Von Hundelshausen" 1 => "R.R. Koenen" 2 => "M. Sack" 3 => "S. Mause" 4 => "W. Adriaens" 5 => "A. Proudfoot" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2004-06-2475" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2005" "volumen" => "105" "paginaInicial" => "924" "paginaFinal" => "930" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15459010" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0185" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Changes in plasma CXCL4 levels are associated with improvements in lung function in patients receiving immunosuppressive therapy for systemic sclerosis-related interstitial lung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.R. Volkmann" 1 => "D.P. Tashkin" 2 => "M.D. Roth" 3 => "P.J. Clements" 4 => "D. Khanna" 5 => "D.E. Furst" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s13075-016-1203-y" "Revista" => array:5 [ "tituloSerie" => "Arthritis Res Ther" "fecha" => "2016" "volumen" => "18" "paginaInicial" => "305" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28038680" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0190" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Low heme oxygenase-1 levels in patients with systemic sclerosis are associated with an altered Toll-like receptor response: another role for CXCL4?" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Van Bon" 1 => "M. Cossu" 2 => "A. Scharstuhl" 3 => "B. Pennings" 4 => "M.C. Vonk" 5 => "H.J. Vreman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/rheumatology/kew251" "Revista" => array:5 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2016" "volumen" => "55" "paginaInicial" => "2066" "paginaFinal" => "2073" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0195" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cartilage oligomeric matrix protein is overexpressed by scleroderma dermal fibroblasts" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G. Farina" 1 => "R. Lemaire" 2 => "J.H. Korn" 3 => "R.L. Widom" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.matbio.2006.01.007" "Revista" => array:6 [ "tituloSerie" => "Matrix Biol" "fecha" => "2006" "volumen" => "25" "paginaInicial" => "213" "paginaFinal" => "222" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16520029" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0200" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "L. Van Bon" 1 => "A.J. Affandi" 2 => "J. Broen" 3 => "B. Romy" 4 => "R.J. Marijnissen" 5 => "L. Stawsky" 6 => "A. Giuseppina" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1114576" "Revista" => array:7 [ "tituloSerie" => "N Engl J Med" "fecha" => "2014" "volumen" => "370" "paginaInicial" => "433" "paginaFinal" => "443" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24350901" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0161642017338204" "estado" => "S300" "issn" => "01616420" ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0205" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CXCL4 in undifferentiated connective tissue disease at risk for systemic sclerosis (SSc) (previously referred to as very early SSc)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Valentini" 1 => "A. Riccardi" 2 => "S. Vettori" 3 => "R. Irace" 4 => "M. Iudici" 5 => "S. Tolone" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10238-016-0437-y" "Revista" => array:6 [ "tituloSerie" => "Clin Exp Med" "fecha" => "2017" "volumen" => "17" "paginaInicial" => "411" "paginaFinal" => "414" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27650429" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0210" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-CXCL4 antibody reactivity is present in systemic sclerosis (SSc) and correlates with the SSc type I interferon signature" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Lande" 1 => "A. Mennella" 2 => "R. Palazzo" 3 => "I. Pietraforte" 4 => "K. Stefanatoni" 5 => "N. Iannace" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/ijms21145102" "Revista" => array:4 [ "tituloSerie" => "Int J Mol Sci" "fecha" => "2020" "volumen" => "21" "paginaInicial" => "5102" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0215" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Plasmocytoid dendritic cells promote systemic sclerosis with a key role fot TLR8" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Kioon" 1 => "C. Tripodo" 2 => "D. Fernández" 3 => "K. Kirou" 4 => "R.F. Spiera" 5 => "M.K. Crow" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/scitranslmed.aam8458" "Revista" => array:4 [ "tituloSerie" => "Sci Transl Med" "fecha" => "2018" "volumen" => "10" "paginaInicial" => "428" ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0220" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased expression of growth differentiation factor 15 in systemic sclerosis associated pulmonary arterial hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.A. Meadows" 1 => "M.G. Risbano" 2 => "L. Zhang" 3 => "M.W. Geraci" 4 => "R.M. Tuder" 5 => "D.H. Collier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1378/chest.10-0302" "Revista" => array:5 [ "tituloSerie" => "Chest" "fecha" => "2011" "volumen" => "139" "paginaInicial" => "994" "paginaFinal" => "1002" ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0225" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Growth differentiation factor 15 for prognostic assessment of patients with acute pulmonary embolism" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Lankeit" 1 => "T. Kempf" 2 => "C. Dellas" 3 => "M. Cuny" 4 => "H. Tapken" 5 => "T. Peter" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.200712-1786OC" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med" "fecha" => "2008" "volumen" => "177" "paginaInicial" => "1018" "paginaFinal" => "1025" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18263797" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0230" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis: association with disease severity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K. Yanaba" 1 => "Y. Asano" 2 => "Y. Tada" 3 => "M. Sugaya" 4 => "T. Kadono" 5 => "S. Sato" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10165-011-0568-7" "Revista" => array:6 [ "tituloSerie" => "Mod Rheumatol" "fecha" => "2012" "volumen" => "22" "paginaInicial" => "668" "paginaFinal" => "675" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22160844" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0235" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Growth differentiation factor-15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.C. De Jager" 1 => "B. Bermudez" 2 => "I. Bot" 3 => "R. Koenen" 4 => "M. Bot" 5 => "A. Kavelaars" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1084/jem.20100370" "Revista" => array:6 [ "tituloSerie" => "J Exp Med" "fecha" => "2011" "volumen" => "208" "paginaInicial" => "217" "paginaFinal" => "225" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21242297" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0240" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Growth differentiation factor 15, a marker of lung involvement in systemic sclerosis, is involved in fibrosis development but is not indispensable for fibrosis development" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Lambrecht" 1 => "V. Smith" 2 => "K. De Wilde" 3 => "J. Coudenys" 4 => "S. Decuman" 5 => "D. Deforce" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.38241" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheumatol" "fecha" => "2014" "volumen" => "66" "paginaInicial" => "418" "paginaFinal" => "427" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24504814" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0245" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The transforming growth factor-β family" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Massagué J:" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1146/annurev.cb.06.110190.003121" "Revista" => array:7 [ "tituloSerie" => "Annu Rev Cell Biol" "fecha" => "1990" "volumen" => "6" "paginaInicial" => "597" "paginaFinal" => "641" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2177343" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0002939418305865" "estado" => "S300" "issn" => "00029394" ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0250" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of the CXCL8-CXCR1/2 axis in cancer and inflammatory diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H. Ha" 1 => "B. Debnath" 2 => "N. Neamati" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7150/thno.15625" "Revista" => array:6 [ "tituloSerie" => "Theranostics" "fecha" => "2017" "volumen" => "7" "paginaInicial" => "1543" "paginaFinal" => "1588" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28529637" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0255" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The CXCL8/IL8 chemokine family and its receptors in inflammatory diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.C. Russo" 1 => "C.C. Garcia" 2 => "M.M. Teixeira" 3 => "F.A. Amaral" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1586/1744666X.2014.894886" "Revista" => array:5 [ "tituloSerie" => "Exp Rev Clin Immunol" "fecha" => "2014" "volumen" => "10" "paginaInicial" => "593" "paginaFinal" => "619" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0260" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Combined effects of CXCL8 and CXCR2 gene polymorphisms on susceptibility to systemic sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.H. Salim" 1 => "M. Jobim" 2 => "M. Brademeier" 3 => "J.A. Bogo" 4 => "J.C. Tavares" 5 => "L.F. Jobim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cyto.2012.05.026" "Revista" => array:6 [ "tituloSerie" => "Cytokine" "fecha" => "2012" "volumen" => "60" "paginaInicial" => "473" "paginaFinal" => "477" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22763041" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0265" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cross-disease innate gene signature: emerging diversity and abundance in RA comparing to SLE and SSc" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Petrackova" 1 => "P. Horak" 2 => "M. Radvansky" 3 => "M. Skacelova" 4 => "R. Fillerova" 5 => "M. Kudelka" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1155/2019/3575803" "Revista" => array:3 [ "tituloSerie" => "J Immunol Res" "fecha" => "2019" "paginaInicial" => "3575803" ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0270" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Serum chemokine levels as prognostic markers in patients with early systemic sclerosis: a multicenter, prospective, observational study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Hasegawa" 1 => "Y. Asano" 2 => "H. Endo" 3 => "M. Fujimoto" 4 => "D. Goto" 5 => "H. Ihn" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3109/s10165-012-0795-6" "Revista" => array:6 [ "tituloSerie" => "Mod Rheumatol" "fecha" => "2013" "volumen" => "23" "paginaInicial" => "1076" "paginaFinal" => "1084" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23180322" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0275" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biomarkers from bronchoalveolar lavage fluid in systemic sclerosis patients with interstitial lung disease relate to severity of lung fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Hesselstrand" 1 => "M. Wildt" 2 => "G. Bozovic" 3 => "A. Andersson-Sjöland" 4 => "K. Andréasson" 5 => "A. Scheja" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.rmed.2013.03.015" "Revista" => array:7 [ "tituloSerie" => "Respir Med" "fecha" => "2013" "volumen" => "107" "paginaInicial" => "1079" "paginaFinal" => "1086" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23660398" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1888429617300705" "estado" => "S300" "issn" => "18884296" ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0280" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Gourh" 1 => "F.C. Arnett" 2 => "S. Assassi" 3 => "F.K. Tan" 4 => "M. Huang" 5 => "L. Diekman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/ar2821" "Revista" => array:5 [ "tituloSerie" => "Arthritis Res Ther" "fecha" => "2009" "volumen" => "11" "paginaInicial" => "R147" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19799786" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0285" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of the disease activity score and the revised EUSTAR activity index in diffuse cutaneous systemic sclerosis patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Doyen" 1 => "F.A. Houssiau" 2 => "B.R. Lauwerys" 3 => "M. Vanthuyne" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Clin Exp Rheumatol" "fecha" => "2020" "volumen" => "38" "numero" => "Suppl. 1253" "paginaInicial" => "53" "paginaFinal" => "58" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33124572" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0290" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Growth differentiation factor-15 (GDF-15) level and relation to clinical manifestations in Egyptian systemic sclerosis patients: preliminary data" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.M. Gamal" 1 => "F.T. Elgengehy" 2 => "A. Kamal" 3 => "S.A. El Bakry" 4 => "E. Shabaan" 5 => "A. Elgendy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/08820139.2017.1360340" "Revista" => array:6 [ "tituloSerie" => "Immunol Invest" "fecha" => "2017" "volumen" => "46" "paginaInicial" => "703" "paginaFinal" => "713" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28872977" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0295" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Complement C3 produced by macrophages promotes renal fibrosis via IL-17A secretion" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Liu" 1 => "K. Wang" 2 => "X. Liang" 3 => "Y. Li" 4 => "Y. Zhang" 5 => "C. Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fimmu.2018.02385" "Revista" => array:5 [ "tituloSerie" => "Front Immunol" "fecha" => "2018" "volumen" => "9" "paginaInicial" => "2385" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30405606" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0300" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The relationship between complement C3 expression and the MUC5B genotype in pulmonary fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Okamoto" 1 => "S.K. Mathai" 2 => "C.E. Hennessy" 3 => "L.A. Hancock" 4 => "A.D. Walts" 5 => "A.L. Stefanski" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/ajplung.00395.2017" "Revista" => array:5 [ "tituloSerie" => "Am J Physiol Lung Cell Mol Physiol" "fecha" => "2018" "volumen" => "315" "paginaInicial" => "1" "paginaFinal" => "10" ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack631180" "titulo" => "Acknowledgements" "texto" => "We thank all participants for kindly agreeing to take part in this study." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015900000008/v1_202210210800/S2387020622004673/v1_202210210800/en/main.assets" "Apartado" => array:4 [ "identificador" => "43310" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015900000008/v1_202210210800/S2387020622004673/v1_202210210800/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622004673?idApp=UINPBA00004N"]

Statistics

Original article

Utility of cytokines CXCL4, CXCL8 and GDF15 as biomarkers in systemic sclerosis

Utilidad de las citocinas CXCL4, CXCL8 y GDF15 como biomarcadores en la esclerosis sistémica

José E. Oller-Rodrígueza,b,

Corresponding author

joseeloy1986@gmail.com

Corresponding author.

, Elvira Vicens Bernabeua, Roxana Gonzalez-Mazaríoa, Elena Grau Garcíaa, Francisco M. Ortiz Sanjuana, José A. Román Ivorraa,b

a Servicio de Reumatología, Hospital UyP La Fe, Valencia, Spain

b Escuela de Doctorado. Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain

Read

Not available

Times
was read the article

Total PDF

Total HTML

Share statistics

 array:23 [
  "pii" => "S2387020622004673"
  "issn" => "23870206"
  "doi" => "10.1016/j.medcle.2021.12.013"
  "estado" => "S300"
  "fechaPublicacion" => "2022-10-21"
  "aid" => "5886"
  "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;. All rights reserved"
  "copyrightAnyo" => "2021"
  "documento" => "article"
  "crossmark" => 1
  "subdocumento" => "fla"
  "cita" => "Med Clin. 2022;159:359-65"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:1 [
    "total" => 0
  ]
  "itemSiguiente" => array:18 [
    "pii" => "S2387020622004661"
    "issn" => "23870206"
    "doi" => "10.1016/j.medcle.2021.12.012"
    "estado" => "S300"
    "fechaPublicacion" => "2022-10-21"
    "aid" => "5883"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "fla"
    "cita" => "Med Clin. 2022;159:366-71"
    "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" => "Characteristics and management of patients with stroke and major hemorrhagic episodes with atrial fibrillation under vitamin K antagonist therapy&#46; EVENTHO study"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "366"
          "paginaFinal" => "371"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Caracter&#237;sticas y abordaje de pacientes con ictus y episodios hemorr&#225;gicos mayores con fibrilaci&#243;n auricular en tratamiento con antagonistas de la vitamina K&#46; Estudio EVENTHO"
        ]
      ]
      "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" => "fig0010"
          "etiqueta" => "Fig&#46; 2"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr2.jpeg"
              "Alto" => 1008
              "Ancho" => 2508
              "Tamanyo" => 133411
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Most common situations after hospital discharge&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Olga Gav&#237;n, Vanessa Rold&#225;n, Pilar Llamas-Sillero, Amparo Santamar&#237;a, Daniel Arum&#237;, Susana Fern&#225;ndez de Cabo"
          "autores" => array:6 [
            0 => array:2 [
              "nombre" => "Olga"
              "apellidos" => "Gav&#237;n"
            ]
            1 => array:2 [
              "nombre" => "Vanessa"
              "apellidos" => "Rold&#225;n"
            ]
            2 => array:2 [
              "nombre" => "Pilar"
              "apellidos" => "Llamas-Sillero"
            ]
            3 => array:2 [
              "nombre" => "Amparo"
              "apellidos" => "Santamar&#237;a"
            ]
            4 => array:2 [
              "nombre" => "Daniel"
              "apellidos" => "Arum&#237;"
            ]
            5 => array:2 [
              "nombre" => "Susana Fern&#225;ndez de"
              "apellidos" => "Cabo"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622004661?idApp=UINPBA00004N"
    "url" => "/23870206/0000015900000008/v1_202210210800/S2387020622004661/v1_202210210800/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S2387020622004545"
    "issn" => "23870206"
    "doi" => "10.1016/j.medcle.2021.11.015"
    "estado" => "S300"
    "fechaPublicacion" => "2022-10-21"
    "aid" => "5872"
    "copyright" => "Elsevier Espa&#241;a&#44; S&#46;L&#46;U&#46;"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "fla"
    "cita" => "Med Clin. 2022;159:351-8"
    "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" => "Clinicopathological characteristics and survival results of patients with ultralow risk breast cancer"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "351"
          "paginaFinal" => "358"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Caracter&#237;sticas cl&#237;nico-patol&#243;gicas y supervivencia de pacientes con c&#225;ncer de mama de riesgo muy bajo"
        ]
      ]
      "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" => "fig0010"
          "etiqueta" => "Figure 2"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr2.jpeg"
              "Alto" => 2252
              "Ancho" => 3175
              "Tamanyo" => 309937
            ]
          ]
          "detalles" => array:1 [
            0 => array:3 [
              "identificador" => "at0010"
              "detalle" => "Figure "
              "rol" => "short"
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Distance metastasis-free interval curves in 110 patients with non-palpable tumours&#44; node-negative&#44; diagnosed by mammography screening and in 88 patients with hormone-sensitive tumours&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Jos&#233; M&#46; Baena Ca&#241;ada, Salvador G&#225;mez-Casado, Lourdes Rodr&#237;guez-P&#233;rez, Cristina Bandera-L&#243;pez, Andr&#233;s Mesas-Ruiz, Alicia Campini-Bermejo, Marta Bernal-G&#243;mez, Manuel Zalabardo-Aguilar, Julio Calvete-Candenas, Gala Mart&#237;nez-Bernal, Alicia Qu&#237;lez-Cutillas, Lidia Atienza-Cuevas, Marcial Garc&#237;a-Rojo, Encarnaci&#243;n Ben&#237;tez-Rodr&#237;guez, Bella Pajares-Hachero, Mar&#237;a Jos&#233; Bermejo-P&#233;rez"
          "autores" => array:16 [
            0 => array:2 [
              "nombre" => "Jos&#233; M&#46;"
              "apellidos" => "Baena Ca&#241;ada"
            ]
            1 => array:2 [
              "nombre" => "Salvador"
              "apellidos" => "G&#225;mez-Casado"
            ]
            2 => array:2 [
              "nombre" => "Lourdes"
              "apellidos" => "Rodr&#237;guez-P&#233;rez"
            ]
            3 => array:2 [
              "nombre" => "Cristina"
              "apellidos" => "Bandera-L&#243;pez"
            ]
            4 => array:2 [
              "nombre" => "Andr&#233;s"
              "apellidos" => "Mesas-Ruiz"
            ]
            5 => array:2 [
              "nombre" => "Alicia"
              "apellidos" => "Campini-Bermejo"
            ]
            6 => array:2 [
              "nombre" => "Marta"
              "apellidos" => "Bernal-G&#243;mez"
            ]
            7 => array:2 [
              "nombre" => "Manuel"
              "apellidos" => "Zalabardo-Aguilar"
            ]
            8 => array:2 [
              "nombre" => "Julio"
              "apellidos" => "Calvete-Candenas"
            ]
            9 => array:2 [
              "nombre" => "Gala"
              "apellidos" => "Mart&#237;nez-Bernal"
            ]
            10 => array:2 [
              "nombre" => "Alicia"
              "apellidos" => "Qu&#237;lez-Cutillas"
            ]
            11 => array:2 [
              "nombre" => "Lidia"
              "apellidos" => "Atienza-Cuevas"
            ]
            12 => array:2 [
              "nombre" => "Marcial"
              "apellidos" => "Garc&#237;a-Rojo"
            ]
            13 => array:2 [
              "nombre" => "Encarnaci&#243;n"
              "apellidos" => "Ben&#237;tez-Rodr&#237;guez"
            ]
            14 => array:2 [
              "nombre" => "Bella"
              "apellidos" => "Pajares-Hachero"
            ]
            15 => array:2 [
              "nombre" => "Mar&#237;a Jos&#233;"
              "apellidos" => "Bermejo-P&#233;rez"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0025775321007156"
        "doi" => "10.1016/j.medcli.2021.11.008"
        "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/S0025775321007156?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622004545?idApp=UINPBA00004N"
    "url" => "/23870206/0000015900000008/v1_202210210800/S2387020622004545/v1_202210210800/en/main.assets"
  ]
  "en" => array:20 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
    "titulo" => "Utility of cytokines CXCL4&#44; CXCL8 and GDF15 as biomarkers in systemic sclerosis"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "359"
        "paginaFinal" => "365"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Jos&#233; E&#46; Oller-Rodr&#237;guez, Elvira Vicens Bernabeu, Roxana Gonzalez-Mazar&#237;o, Elena Grau Garc&#237;a, Francisco M&#46; Ortiz Sanjuan, Jos&#233; A&#46; Rom&#225;n Ivorra"
        "autores" => array:6 [
          0 => array:4 [
            "nombre" => "Jos&#233; E&#46;"
            "apellidos" => "Oller-Rodr&#237;guez"
            "email" => array:1 [
              0 => "joseeloy1986@gmail.com"
            ]
            "referencia" => array:3 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
              2 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Elvira"
            "apellidos" => "Vicens Bernabeu"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Roxana"
            "apellidos" => "Gonzalez-Mazar&#237;o"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Elena"
            "apellidos" => "Grau Garc&#237;a"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
          4 => array:3 [
            "nombre" => "Francisco M&#46;"
            "apellidos" => "Ortiz Sanjuan"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
          5 => array:3 [
            "nombre" => "Jos&#233; A&#46;"
            "apellidos" => "Rom&#225;n 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:2 [
          0 => array:3 [
            "entidad" => "Servicio de Reumatolog&#237;a&#44; Hospital UyP La Fe&#44; Valencia&#44; Spain"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Escuela de Doctorado&#46; Universidad Cat&#243;lica de Valencia San Vicente M&#225;rtir&#44; Valencia&#44; Spain"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Utilidad de las citocinas CXCL4&#44; CXCL8 y GDF15 como biomarcadores en la esclerosis sist&#233;mica"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 891
            "Ancho" => 2500
            "Tamanyo" => 127334
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Association between GDF15 levels and findings in capillaroscopy&#46; Short explanation&#58; We observed an increase in GDF15 levels in patients who had dilated loops&#44; and a tendency for patients with decreased capillary density to show an increase in GDF15&#46;</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 sclerosis &#40;SSc&#41; is an autoimmune disease characterized by vasculopathy&#44; immune alterations and fibrosis&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Its diagnosis can be simple when disease is evolved and both cutaneous and organic damage has taken place&#44; but it might be difficult in earlier stages&#44; when its features are more unspecific and insidious&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Therefore&#44; it would be useful to find non-invasive markers that allow an early diagnosis&#44; in order to start treatment before irreversible fibrotic changes appear&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">CXCL4 &#40;also called Platelet Factor 4&#41; is a protein constituted by 70 amino acids&#44; that belongs to CXC chemokine family&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> It is mainly produced by megakaryocytes and plasmacytoid dendritic cells&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Indeed&#44; it is released by platelet alpha-granules during platelet aggregation&#44; as in responses to traumatisms&#44; wounds or infections&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">This cytokine can work as a chaperone&#44; forming crystalline CXCL4-DNA complexes that can activate dendritic cells via TLR9&#44; what enhances IFN-I synthesis&#46; A correlation between circulating levels of CXCL4 and IFN-I has been demonstrated&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> In summary&#44; CXCL4 is overexpressed in SSc and other diseases &#40;SLE&#44; RA&#44; SS&#41;&#44; where the signature of IFN-I is important&#46; This signature is present in 50&#37; of SSc patients&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">CXCL4 is also involved in other processes as chemotaxis &#40;attracting neutrophils&#44; monocytes and fibroblasts&#41;&#44; atherosclerosis&#44; fibrosis &#40;induces the expression of profibrotic cytokines as IL-4 and IL-13&#44; and reduces the expression of IFN-&#947;&#44; that is antifibrotic&#41; and angiogenesis inhibition&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">It induces PDGF-BB synthesis by myeloid cells &#40;which is potent mitogen for dermal fibroblasts&#41;&#44; and has also been shown to promote the survival of monocytes&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> as well as to aid their extravasation&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">CXLC4 also blocks HO-1 local expression&#44; so control of HO-1 disappears over aberrant TLR activation&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> A proteome-wide analysis showed it is the prevailing protein produced by plasmocytoid dendritic cells in SSc&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In addition to the aforementioned influence on the innate immune system&#44; it acts on the adaptive system&#44; being able to induce the activation of Ag-specific CD8&#43; T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">It has been proposed as a SSc biomarker&#44; especially in early and active Diffuse SSc&#44; but also in an active and early phase in Limited SSc&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> when inflammation has a preponderant role&#44; or even in undifferentiated connective tissue disease at risk for SSc&#44; especially in patients without capillaroscopic alterations&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Its presence has been demonstrated in SSc patients skin&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> blood and in BALF&#44; has been associated to the extent of cutaneous involvement in Diffuse and Limited SSc&#44;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">11&#44;12</span></a> and has also been related to early lung involvement &#40;both Pulmonary Arterial Hypertension &#40;PAH&#41; and Interstitial Lung Disease &#40;ILD&#41;&#46; It has also been related to spirometric changes&#44; as a decrease in Forced Vital Capacity &#40;FVC&#41; and Carbon Monoxide Diffusing Capacity &#40;DLCO&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> Moreover&#44; its plasma levels can predict progression in skin involvement&#44; ILD and PAH&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">However&#44; it was observed to be present in many patients with Raynaud&#44; who did not progress to SSc &#40;against other studies that point it is a factor of progression from pre-SSc to SSc&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> so we can infer it is related to cutaneous inflammatory phase&#44; more than to fibrosis &#40;next evolutionary stage&#41;&#44; where it even collaborates in an initial phase&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Turning now to focus on GDF15 &#40;also called Macrophage Inhibitory Cytokine 1&#41;&#44; it is a member of the cytokine superfamily TGF-B&#44; but it only shares<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30&#37; of its sequence with other members of the family as TGF&#946;1&#44; GDF-5 or BMPs&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">GDF15 is very expressed in placenta&#44; and then in multiple tissues in lesser quantity&#44; but its expression gets increased in the context of adaptation to stress &#40;due to hypoxia&#44; inflammation&#44; radiation or tissue damage&#41;&#46; In fact&#44; it is an independent predictor of long-term mortality in pulmonary<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> embolism and in essential pulmonary hypertension&#46; Its synthesis is induced in tissue damage in acute myocardial infarction&#44; as it has a protective effect of myocardiocytes&#59; as well in ischemia-reperfusion&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Its levels are high in patients with SSc&#44; but they tend to decrease in late evolutive stages&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">It is an inflammation inductor&#44; involved<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> in the expression of proinflammatory cytokines such IL-6 or CCL2&#44; and macrophagues recruitment &#40;by CCR2&#47;CCL2 axis&#41;&#46; It also plays a role in fibrosis&#44; starting this process &#40;although it is not essential in its perpetuation &#40;other factors such as TGF&#946; or CTGF can do so&#44; there is a functional redundancy in this family&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a> GDF15 also stimulates the expression of type I collagen and osteopontin&#46; At pulmonary level&#44; among others&#44; it activates resident fibroblasts in the inflammatory context &#40;CCL2&#44; TGFb&#44; IL6&#41;&#44; which leads to pulmonary fibrosis&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Other functions have been attributed to GDF15&#44; as intercellular signaling&#44; signal transduction and regulation of apoptosis&#46; A consistent finding is its co-localization with CD68 &#40;monocyte&#47;macrophage marker&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">A correlation between blood levels and the number of organs with fibrosis &#40;as well as the degree of fibrosis&#41; has been described&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a> as well as a negative correlation with survival&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Attending to the literature&#44; it is associated with Diffuse SSc&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> It is related to the spread of cutaneous fibrosis&#44; ILD and PAH&#44; with a significant correlation with decrease in DLCO and with elevation of FVC&#47;DLCO ratio&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> It also has a positive correlation with BNP and right ventricular systolic pressure&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Presence of GDF15 in pulmonary parenchyma and plasma from patients with PAH has been demonstrated&#44; and its levels are higher than in patients without PAH or with idiopathic PAH&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> It can be a useful SSc-PAH biomarker&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">There is also a correlation between GDF15 and antiScl70 &#40;and to a lesser extent with the presence of anticentromere antibodies<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a>&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">On the other hand&#44; CXCL8&#44; also called IL8&#44; is a chemokine synthesized by fibroblasts&#44; dendritic cells&#44; endothelial cells&#44; neutrophils and monocytes&#47;macrophages&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">It works as a potent chemotactic factor of neutrophils and other granulocytes&#44; and it amplifies local inflammatory response&#46; In that sense&#44; it also promotes angiogenesis&#46; It is also related to fibrosis&#44; but it seems that to a lesser extent&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The presence of certain polymorphisms in CXCL8 gene have been associated with greater susceptibility to develop SSc&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> Serum CXCL8 levels are increased in SSc&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> It just appears to be increased during the first year of the disease&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">It is increased in BALF from patients with SSc<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ILD and it was once associated with decreased HAQ&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> It has been associated with Lung involvement objectified by HRCT&#44; with doubtful spirometric results&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> High levels of CXCL8 have been reported in SSc patients with anti Scl70 antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">In our work&#44; we try to evaluate the clinical implications of the 3 cytokines&#44; their correlation with less studied variables as alterations in capillaroscopy&#44; functional and disease activity rates&#44; and also their usefulness as organic damage biomarkers&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><p id="par0140" class="elsevierStylePara elsevierViewall">For this observational study&#44; we recruited patients with a diagnosis of systemic sclerosis according to ACR&#47;EULAR 2013 criteria&#44; as well as a control group constituted by healthy subjects&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In both groups&#44; a blood sample was collected to determine levels of CXCL4&#44; GDF15 and CXCL8&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">On the other hand&#44; only in the group of patients with systemic sclerosis&#44; several variables were collected&#58; demographic &#40;age&#44; sex&#44; time from diagnosis&#41;&#44; clinical &#40;type of SSc&#44; cardiovascular risk factors&#44; macrovascular and microvascular involvement&#44; arthritis&#44; myositis&#44; heart disease&#44; cutaneous affectation&#44; pulmonary&#44; renal or digestive&#41;&#44; and analytical &#40;RCP&#44; ESR&#44; C3&#44; C4&#44; hemogram&#44; and antibodies as RF&#44; ANA&#44; anti-Scl70&#44; anti-centromere&#44; anti-polymerase III&#41;&#44; variables&#59; we also realized Rodnan modified score to assess patient&#39;s skin thickness&#44; HAQ index&#44; SF36 as an indicator of quality of life&#44; EUSTAR activity index&#44; Medsger disease severity scale&#44; Cochin Hand Function Scale and Capillaroscopic findings&#46; We used a Videocapilaroscopy equipment with integrated video software videocap 3&#46;0 &#40;DS Medica&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">All patients had pulmonary HRCT and respiratory function test&#44; in order to check the existence of ILD&#46; Likewise&#44; a transthoracic echocardiography was performed &#40;with measurement of systolic lung pressure and tricuspid regurgitation rate&#41;&#44; with the aim of objectifying PAH&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">We used ELISA &#40;Enzyme Linked Immunosorbent Assay&#41; in order to analyze CXCL4&#44; GDF15 and CXCL8 levels&#46; Serum was obtained in a maximum of 1 hour from the extraction of peripheral blood&#46; Aliquots of 500<span class="elsevierStyleHsp" style=""></span>&#956;L were made and stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C until used&#46; We used a Multiskan plate reader spectrophotometer to read the absorbance at 450<span class="elsevierStyleHsp" style=""></span>nm&#46; Samples were measured in duplicate &#40;30 patient samples and 10 control samples per 96-well plate&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Regarding the statistical analysis&#44; we used R software &#40;version 3&#46;2&#46;2&#41;&#46; Data were described by the mean&#44; median&#44; standard deviation and the first and third quartiles in the case of continuous variables and by relative and absolute frequencies in case of categorical variables&#46; Associations between different continuous variables were determined by Pearson correlation in case of linear relationships and by Spearman correlation in case of non-linear relationships&#46; P values less than 0&#46;05 were considered statistically significant&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Another point is that and our research protocol was previously approved by the Ethics Committee of Hospital La Fe&#44; called <span class="elsevierStyleItalic">Comit&#233; de &#201;tica de la Investigaci&#243;n con Medicamentos del Hospital UyP La Fe</span>&#46; It also complies with the Declaration of Helsinki&#44; and an informed consent has been obtained from the subjects&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0175" class="elsevierStylePara elsevierViewall">A sample of 42 patients with systemic sclerosis &#40;SSc&#41; was obtained&#44; of which 20 corresponded to limited SSc&#44; another 20 patients corresponded to diffuse SSc&#44; while 2 patients presented &#8220;Scleroderma sine Scleroderma&#8221;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Looking at the distribution by sex&#44; 40 of the patients were female whereas only 2 patients were male&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">The baseline characteristics of the cohort&#44; attending to clinical features&#44; and the results of the diagnostic procedures are reflected in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">The sample of SSc patients was compared to a control group with 42 free SSc individuals&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">We observed a disparate concentration of them in patients with SSc&#44; and therefore can not objectify any correlation between them&#59; then&#44; if we compare their level in SSc patients with their level in healthy controls&#44; we find that GDF15 levels &#40;mean&#58; 1&#46;05<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; SD&#58; 0&#46;67<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; were significantly higher in SSc patiens &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; than in healthy controls &#40;mean&#58; 0&#46;41<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; SD&#58; 0&#46;24<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41;&#41;&#44; with no significant differences in CXCL4 and CXCL8 levels between SSC patients and healthy controls &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;987 and <span class="elsevierStyleItalic">p</span>&#58; 0&#46;129&#44; respectively&#41;&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Levels of GDF15 were significantly higher &#40;p&#58; 0&#46;009&#41; in diffuse SSc &#40;mean&#58; 1&#46;26<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; SD&#58; 0&#46;74<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; than in limited SSc patients &#40;mean&#58; 0&#46;78<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; SD&#58; 0&#46;49<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41;&#44; with no association to age&#44; sex or years since diagnosis&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">In relation to clinical manifestations&#44; a statistically significant increase in levels of GDF15 was observed &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; in those patients with SSc and PAH &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;038&#41; and&#47;or ILD &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;004&#41;&#44; as we can see in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0210" class="elsevierStylePara elsevierViewall">In addition&#44; a statistically significant association was observed between the increase in GDF15 levels and the decrease in FVC &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;002&#41;&#46; No association with decrease in DLCO was found &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;291&#41;&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">No association was found with the values of blood analysis except for anti-Scl70 &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;006&#41;&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Regarding capillaroscopy&#44; we observed an increase in GDF15 levels &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; in patients who had dilated loops &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;015&#41;&#44; as well as a tendency for patients with decreased capillary density to show an increase in GDF15 &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;06&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0225" class="elsevierStylePara elsevierViewall">We also observed increased values of GDF15 in patients with a high score in EUSTAR activity index &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;001&#41;&#46; On the other hand&#44; no statistically significant differences were observed according to the Rodnan score&#44; Medsger scale&#44; SF36&#44; HAQ or Cochin&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Going on to analyze CXCL4&#44; no statistically significant differences were observed according to sex&#44; age&#44; years of evolution of the disease&#44; classification of SSc in limited or diffuse&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">On the other hand&#44; no statistically significant differences were observed in relation to the various clinical manifestations of the disease&#46; No association of CXCL4 values with the decrease in FVC and DLCO was observed either&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">A decrease in CXCL4 levels was observed in patients with lower values of the C3 fraction of the complement &#40;p&#58; 0&#46;008&#41;&#46; In the other variables of the blood analysis &#40;including autoantibodies&#41;&#44; no statistically significant differences were observed&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">No statistically significant differences were observed in relation to capillaroscopy parameters&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">However&#44; an increase in CXCL4 levels was evidenced &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41; in those patients with high scores of mRodnan score &#40;p&#58; 0&#46;001&#41;&#46; This fact&#44; like its behavior with C3 could be explained by its potential role in the beginning of the fibrotic process&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0255" class="elsevierStylePara elsevierViewall">There were no differences in CXCL4 levels depending on punctuation of Medsger scale&#44; Cochin&#44; Eustar activity index&#44; HAQ or SF36&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Focusing now on CXCL8&#44; no statistically significant differences were observed according to sex&#44; age&#44; years of evolution of the disease&#44; classification of SSc in limited or diffuse&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">No statistically significant association was found between CXCL8 levels and any clinical manifestation of the SSc&#44; nor with the measurements of FVC or DLCO&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">Lower levels of C4 fraction of complement were observed in patients with an increase in CXCL8 levels &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;013&#41;&#46; In the other variables&#44; no statistically significant differences were observed&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">There were no differences in CXCL8 levels depending on punctuation of Rodnan score&#44; Medsger scale&#44; Cochin&#44; Eustar activity index&#44; HAQ or SF36&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">An association was observed between elevated levels of CXCL8 and the presence of tortuosities in capillaroscopy &#40;<span class="elsevierStyleItalic">p</span>&#58; 0&#46;02&#41;&#46; No statistically significant differences were observed with respect to the rest of the capillaroscopy parameters&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0285" class="elsevierStylePara elsevierViewall">In this study&#44; we describe the findings of the levels of GDF15&#44; CXCL8 and CXCL4 and their association with systemic sclerosis&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">The scarce correlation between GDF15&#44; CXCL4 and CXCL8 in the analyzed patients may result striking&#46; This reality implies that the behavior of each of them is different in these patients&#46; In any case&#44; it is not completely surprising&#44; given that they are not physiopathologically related and do not share activation pathways&#46; In addition&#44; CXCL4 and CXCL8 predominate in early stages of the disease&#44; while the importance of GDF15 is maintained during the course of the same&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">Regarding the elevated levels of GDF15 in patients with systemic sclerosis&#44; we observed&#44; on the one hand&#44; an elevation of the levels of this chemokine in patients with the disease&#44; as well as a greater association with the diffuse forms of the disease&#44; in comparison with limited forms&#44; which agrees with the literature&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">In line with this interleukin&#44; we observed an increase in the levels of this molecule in patients with high anti-Scl70 antibody values&#44; which is logical if we take into account that up to 70&#37; of patients with diffuse SSc in published series present positivity to said antibody&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">Likewise&#44; we have observed a clear negative correlation of this molecule with FVC &#40;or positive with the decrease in FVC&#41;&#44; without being correlated with DLCO&#46; Previous studies had observed a negative correlation with DLCO and a positive correlation with the FVC&#47;DLCO ratio&#44; with there is no known correlation with FVC&#46; This remark is very meaningful because DLCO performs as a sensitive but not specific parameter in pulmonary function and could be altered in both PAH and ILD&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">The association between high GDF15 levels and with pulmonary hypertension had been described before&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> However&#44; in our study we have observed that they are not specific to PAH&#44; as we can also see them associated with ILD&#44; reflecting a role in the pulmonary fibrotic process and it might be a potential ILD biomarker&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">We have also seen an association between increase in GDF15 levels and alterations in capillaroscopy &#40;dilated loops and decreased capillary density&#41;&#44; which according to our knowledge had not been objectified in the literature and which&#44; however&#44; is related to the nature and action of said molecule&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">In the same way&#44; an association between the levels of this cytokine and a higher score in the EUSTAR index of disease activity has been objectified for the first time&#46; We have not found previous studies that have analyzed the relationship between said molecule and the activity of the disease&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">As argued in recent works&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> this index seems somewhat better than DAS in monitoring SSc activity&#46;</p><p id="par0330" class="elsevierStylePara elsevierViewall">A correlation between GDF15 levels and with skin induration &#40;objectified by Rodnan score&#41; had previously been described&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> but our findings do not agree with it&#46; This could be interpreted on the basis that there were relatively low mRodnan scores &#40;with an average of 5&#46;95 in diffuse SSc patients&#44; and 4&#46;15 in limited SSc patients&#41; in our sample&#46;</p><p id="par0335" class="elsevierStylePara elsevierViewall">Regarding the elevated levels of CXCL4&#44; we have observed how in our study they were associated mainly with a greater cutaneous induration evaluated by modified Rodnan score&#44; which coincides with recent evidence&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">11&#44;12</span></a></p><p id="par0340" class="elsevierStylePara elsevierViewall">The relationship between a decrease in CXCL4 levels and lower values of the C3 fraction of the complement has not been described in previous studies in SSc&#46; However&#44; it has been described in other entities with a marked fibrotic signature&#44; such as Renal Fibrosis<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> and in a murine model in Idiopathic Pulmonary Fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a></p><p id="par0345" class="elsevierStylePara elsevierViewall">We could also highlight the discordance among other publications regarding the levels of CXCL4 &#40;not superior to the healthy controls in our study&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> They explained in their exploratory analysis that CXCL4 levels increased gradually and significally by group &#40;primary Raynaud&#39;s phenomenon<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>Raynaud&#39;s phenomenon and positive antinuclear antibodies<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>very early SSc&#41;&#46; The cut-off they proposed to discriminate different scenarios was 10<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; It is striking that in our sample&#44; the average levels of CXCL4 were only 7&#46;52<span class="elsevierStyleHsp" style=""></span>ng&#47;mL in SSc patients &#40;for 5&#46;29<span class="elsevierStyleHsp" style=""></span>ng&#47;mL in controls&#41;&#46; This could be due to the fact that we included patients in a more advanced stage of the disease&#46; Another possible explanation could be that CXCL4 levels in serum may not reflect physiological conditions because of platelet activation during serum preparation&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">In reference to CXCL8&#44; a correlation was observed between levels of CXCL8 and a decrease in the C4 fraction of the complement&#44; whose explanation could lie in an activation of the increased complement in those patients with a greater inflammatory component and a greater consumption of it in early phases of the disease&#46; This last point could be logically expected&#44; since said molecule has a proinflammatory function&#44; but no previous evidence had been found about it in the context of SSc&#46;</p><p id="par0355" class="elsevierStylePara elsevierViewall">We must remember the importance of CXCL8 as a receptor in the migration of neutrophils to foci of greater inflammatory activity&#46; Therefore&#44; it is to be assumed that in more advanced stages of the disease&#44; in which the vascular damage and the fibrosis component predominate&#44; the importance of said chemokine is diminished&#46;</p><p id="par0360" class="elsevierStylePara elsevierViewall">Since the importance of CXCL4 and CXCL8 seems to be greater in early or early stages of the disease&#44; the lack of correlation observed with functional indexes and with the EUSTAR index of disease activity could be accounfied&#46;</p><p id="par0365" class="elsevierStylePara elsevierViewall">A finding not yet described in previous articles is the relationship between these cytokines and the findings in the capillaroscopy of patients with SSc&#46; In patients with high GDF15 levels&#44; where we found dilated loops and decreased capillary density&#46; This may mean a relationship with more advanced stages of microvascular damage&#46; However&#44; CXCL8 levels appeared associated with tortuosities in capillaroscopy what could be attributed to incipient affectation capillary nail bed&#46;</p><p id="par0370" class="elsevierStylePara elsevierViewall">Finally&#44; it may be interesting to expand the sample size in the future in order to extract more data and reach statistical significance in some parameters that could be relevant&#46;</p><p id="par0375" class="elsevierStylePara elsevierViewall">In addition&#44; a larger sample size could facilitate the stratification of the groups depending on the time of evolution of the disease&#46; In patients with less evolution of it&#44; a greater role of the chemokines CXCL4 and CXCL8 is expected&#46;</p><p id="par0380" class="elsevierStylePara elsevierViewall">It is a promising line of research&#44; and it is necessary to increase our knowledge about the pathophysiology of the disease and for define them as useful biomarkers for stratification of risk from an early stage&#44; and also possible therapeutic targets&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions</span><p id="par0385" class="elsevierStylePara elsevierViewall">GDF15 levels were significantly higher in SSc patiens&#44; specially in diffuse SSc&#44; and were observed in patients with PAH&#47;ILD and dilated loops in capillaroscopy&#44; while CXCL4 levels were related to higher mRodnan score and CXCL8 levels were related to complement consumption&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ethical considerations</span><p id="par0390" class="elsevierStylePara elsevierViewall">Our research protocol was previously approved by the Ethics Committee of Hospital La Fe&#44; called <span class="elsevierStyleItalic">Comit&#233; de &#201;tica de la Investigaci&#243;n con Medicamentos del Hospital UyP La Fe</span>&#46; It also complies with the Declaration of Helsinki&#44; and an informed consent has been obtained from the subjects&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Funding statement</span><p id="par0395" class="elsevierStylePara elsevierViewall">This work was financed with the own resources of our Rheumatology Department&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflict of interest</span><p id="par0400" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0405" class="elsevierStylePara elsevierViewall">Jos&#233; Eloy Oller Rodr&#237;guez declares no conflicts of interest&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0410" class="elsevierStylePara elsevierViewall">Elvira Vicens Bernabeu declares no conflicts of interest&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0415" class="elsevierStylePara elsevierViewall">Roxana Gonz&#225;lez Mazar&#237;o declares no conflicts of interest&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0420" class="elsevierStylePara elsevierViewall">Elena Grau Garc&#237;a declares no conflicts of interest&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0425" class="elsevierStylePara elsevierViewall">Francisco Ortiz Sanjuan declares no conflicts of interest&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0430" class="elsevierStylePara elsevierViewall">Jos&#233; A&#46; Rom&#225;n Ivorra declares no conflicts of interest&#46;</p></li></ul></p><p id="par0435" class="elsevierStylePara elsevierViewall">We also declare that this manuscript has not been published before&#44; neither is under consideration for publication elsewhere&#46; The preliminary results of our work were accepted as Poster Presentation in the 6th Systemic Sclerosis World Congress &#40;planned to be held in Prague in March 2020&#44; but finally held online in July 2020&#41;&#44; as Oral Communication in the XLVI Congress of Sociedad Espa&#241;ola de Reumatolog&#237;a &#40;October 2020&#41; and the XII Systemic Sclerosis Spanish Meeting &#40;March 2021&#41;&#44; and also accepted for publication in the EULAR 2020 Congress Abstract Book&#46;</p><p id="par0440" class="elsevierStylePara elsevierViewall">If accepted for publication by <span class="elsevierStyleItalic">Medicina Cl&#237;nica</span>&#44; it will not be published anywhere else&#46;</p><p id="par0445" class="elsevierStylePara elsevierViewall">Furthermore&#44; this manuscript has been read and approved by all of the authors&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:14 [
        0 => array:3 [
          "identificador" => "xres1787323"
          "titulo" => "Abstract"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "abst0005"
              "titulo" => "Background and objectives"
            ]
            1 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Patients and methods"
            ]
            2 => array:2 [
              "identificador" => "abst0015"
              "titulo" => "Results"
            ]
            3 => array:2 [
              "identificador" => "abst0020"
              "titulo" => "Conclusions"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1566806"
          "titulo" => "Keywords"
        ]
        2 => array:3 [
          "identificador" => "xres1787322"
          "titulo" => "Resumen"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "abst0025"
              "titulo" => "Antecedentes y objetivos"
            ]
            1 => array:2 [
              "identificador" => "abst0030"
              "titulo" => "Pacientes y m&#233;todos"
            ]
            2 => array:2 [
              "identificador" => "abst0035"
              "titulo" => "Resultados"
            ]
            3 => array:2 [
              "identificador" => "abst0040"
              "titulo" => "Conclusiones"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec1566807"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Patients and methods"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Results"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Discussion"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Conclusions"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Ethical considerations"
        ]
        10 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Funding statement"
        ]
        11 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Conflict of interest"
        ]
        12 => array:2 [
          "identificador" => "xack631180"
          "titulo" => "Acknowledgements"
        ]
        13 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2021-09-11"
    "fechaAceptado" => "2021-12-03"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1566806"
          "palabras" => array:5 [
            0 => "Systemic sclerosis"
            1 => "CXCL4"
            2 => "CXCL8"
            3 => "GDF15"
            4 => "Capillaroscopy"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1566807"
          "palabras" => array:5 [
            0 => "Esclerosis sist&#233;mica"
            1 => "CXCL4"
            2 => "CXCL8"
            3 => "GDF15"
            4 => "Capilaroscopia"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Systemic sclerosis &#40;SSc&#41; is an autoinmune disease that can affect several organs and its mortality is fundamentally related to its pulmonary involvement&#46; There are some cytokines with high serum levels of patients with SSc&#46; Our goal is to determine the role of CXCL4&#44; CXCL8 and GDF15 in the physiopathology of SSc and whether they can be considered organic damage biomarkers&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Observational case&#8211;control study of SSc patients &#40;ACR&#47;EULAR 2013 criteria&#41;&#46; Demographic&#44; clinical&#44; analytical&#44; activity&#44; severity&#44; health perception&#44; and disability variables were collected&#46; Moreover&#44; Videocapillaroscopy&#44; Echocardiography and Respiratory Function Test were made&#46; Serum levels of CXCL4&#44; CXCL8 and GDF15 were measured both in SSc patients and in healthy controls&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 42 patients were included &#40;95&#46;4&#37; women&#41;&#44; with an average age of 59&#46;2 years and a median of 4 years from diagnosis&#46; We also included 42 healthy controls&#46; We found significantly higher levels of GDF15 in SSc patients than in controls &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; but no higher CXCL4 or CXCL8 levels&#46; GDF15 was associated with Diffuse SSc&#44; pulmonary arterial hypertension&#44; interstitial lung disease&#44; less forced vital capacity&#44; high titles of antiScl70&#44; disease activity&#44; and dilated loops in capillaroscopy&#46; CXCL4 levels were associated to a higher Rodnan punctuation&#44; while CXCL8 was associated to C4 fraction consumption and tortuosities in capillaroscopy&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">GDF15 high levels were associated with diffuse SSc&#44; lung impairment&#44; disease activity and changes in capillaroscopy&#46; Moreover&#44; CXCL4 was only associated with skin impairment&#44; while CXCL8 was not related to organic damage&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background and objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Patients and 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">Antecedentes y objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La esclerosis sist&#233;mica &#40;ES&#41; es una enfermedad autoinmunitaria que afecta a diferentes &#243;rganos y cuya mortalidad se relaciona fundamentalmente con su afectaci&#243;n pulmonar&#46; Los pacientes con ES presentan niveles s&#233;ricos elevados de algunas citocinas&#46; Nuestro objetivo es determinar el papel de CXCL4&#44; CXCL8 y GDF15 en la fisiopatolog&#237;a de la ES&#44; y si pueden considerarse biomarcadores de da&#241;o org&#225;nico&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional de casos-controles&#44; con pacientes afectados de ES &#40;criterios ACR&#47;EULAR 2013&#41; y controles sanos&#46; Se determinaron los niveles s&#233;ricos de CXCL4&#44; CXCL8 y GDF15 en ambos grupos&#44; y se registraron variables demogr&#225;ficas&#44; cl&#237;nicas&#44; anal&#237;ticas&#44; de actividad&#44; gravedad&#44; percepci&#243;n de salud y discapacidad de pacientes con ES&#44; a quienes&#44; adem&#225;s&#44; se les realiz&#243; videocapilaroscopia&#44; ecocardiograma y espirometr&#237;a&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 42 pacientes &#40;95&#44;4&#37; mujeres&#41;&#44; con una edad media de 59&#44;2 a&#241;os y una mediana de 4 a&#241;os desde el diagn&#243;stico&#44; con 42 controles sanos&#46; Se hallaron niveles significativamente mayores de GDF15 en pacientes con ES que en controles &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; pero no de CXCL4 ni CXCL8&#46; GDF15 se asoci&#243; a ES difusa&#44; hipertensi&#243;n pulmonar&#44; enfermedad pulmonar intersticial&#44; menor capacidad vital forzada&#44; t&#237;tulos altos de anti-Scl70&#44; actividad de ES y dilataciones capilares&#46; Asimismo&#44; los niveles de CXCL4 se asociaron a mayor afectaci&#243;n cut&#225;nea &#40;Rodnan&#41;&#44; mientras que CXCL8 se asoci&#243; a consumo de la fracci&#243;n C4 del complemento y tortuosidades en la capilaroscopia&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los niveles elevados de GDF15 se asociaron a ES difusa&#44; afectaci&#243;n pulmonar&#44; actividad de la ES y alteraciones en la capilaroscopia&#46; Por otra parte&#44; CXCL4 se asoci&#243; a afectaci&#243;n cut&#225;nea&#44; no relacion&#225;ndose CXCL8 con da&#241;o org&#225;nico&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Antecedentes y objetivos"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Pacientes y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "multimedia" => array:5 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1041
            "Ancho" => 2500
            "Tamanyo" => 96361
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Association between GDF15 levels and the presence of PAH or ILD&#46; Short explanation&#58; A statistically significant increase in levels of GDF15 was observed in those patients with SSc and PAH&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 891
            "Ancho" => 2500
            "Tamanyo" => 127334
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Association between GDF15 levels and findings in capillaroscopy&#46; Short explanation&#58; We observed an increase in GDF15 levels in patients who had dilated loops&#44; and a tendency for patients with decreased capillary density to show an increase in GDF15&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 1414
            "Ancho" => 2167
            "Tamanyo" => 120914
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Correlation between CXCL4 levels and mRodnan score&#46; Short explanation&#58; An increase in CXCL4 levels was evidenced in those patients with high scores of mRodnan score&#44; showing an increased skin involvement&#46;</p>"
        ]
      ]
      3 => 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="spar0065" class="elsevierStyleSimplePara elsevierViewall">Short explanation&#58; It details its clinical features and the results of the diagnostic procedures that were subsequently used to establish the analyses&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><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">Age &#40;mean years&#44; SD&#41;&nbsp;\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&#46;21 &#40;13&#46;19&#41;&nbsp;\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">Time since diagnosis &#40;mean years&#44; SD&#41;&nbsp;\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">5&#46;93 &#40;1&#46;66&#41;&nbsp;\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">Time since first non-Raynaud&#39;s symptom &#40;mean years&#44; SD&#41;&nbsp;\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">8 &#40;6&#46;67&#41;&nbsp;\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">Sex&#58; females <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&#44; males <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\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">40 &#40;95&#41;&#44; 2&#40;5&#41;&nbsp;\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">Rheumatoid factor &#40;&#37; of positives&#41;&nbsp;\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">6 &#40;14&#46;3&#41;&nbsp;\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">ACPA &#40;&#37; of positives&#41;&nbsp;\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">4 &#40;9&#46;5&#41;&nbsp;\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">ANA &#40;&#37; of positives&#41;&nbsp;\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">42 &#40;100&#41;&nbsp;\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">Anti-DNA &#40;&#37; of positives&#41;&nbsp;\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">3 &#40;7&#46;1&#41;&nbsp;\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">C3 fraction &#40;mean mg&#47;dL&#44; SD&#41;&nbsp;\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">122&#46;6 &#40;28&#46;8&#41;&nbsp;\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">Low C3 &#40;&#37;&#41;&nbsp;\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">4 &#40;9&#46;5&#41;&nbsp;\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">C4 fraction &#40;mean mg&#47;dL&#44; SD&#41;&nbsp;\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">22&#46;02 &#40;8&#46;8&#41;&nbsp;\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">Low C4 &#40;&#37;&#41;&nbsp;\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">2 &#40;4&#46;8&#41;&nbsp;\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">HAQ &#40;mean&#44; SD&#41;&nbsp;\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">0&#46;78 &#40;0&#46;76&#41;&nbsp;\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">SF36 &#40;mean&#44; SD&#41;&nbsp;\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">0&#46;51 &#40;0&#46;29&#41;&nbsp;\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">mRodnan &#40;mean&#44; SD&#41;&nbsp;\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">4&#46;81 &#40;5&#46;71&#41;&nbsp;\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">EUSTAR activity index &#40;mean&#44; SD&#41;&nbsp;\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">4&#46;93 &#40;1&#46;45&#41;&nbsp;\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">Medsger severity scale &#40;mean&#44; SD&#41;&nbsp;\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">4&#46;05 &#40;1&#46;17&#41;&nbsp;\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">Cochin &#40;mean&#44; SD&#41;&nbsp;\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">7&#46;5 &#40;1&#46;2&#41;&nbsp;\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">Arterial Hypertension &#40;&#37;&#41;&nbsp;\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">13 &#40;31&#41;&nbsp;\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">Diabetes mellitus &#40;&#37;&#41;&nbsp;\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">0 &#40;0&#41;&nbsp;\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">Dyslipidemia &#40;&#37;&#41;&nbsp;\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">11 &#40;26&#41;&nbsp;\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">Raynaud&#39;s phenomenon &#40;&#37;&#41;&nbsp;\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">42 &#40;100&#41;&nbsp;\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">Macrovascular involvement &#40;&#37;&#41;&nbsp;\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">3 &#40;7&#46;1&#41;&nbsp;\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">Heart involvement &#40;&#37;&#41;&nbsp;\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">3 &#40;7&#46;1&#41;&nbsp;\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">Arthralgia&#47;arthritis &#40;&#37;&#41;&nbsp;\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">35 &#40;83&#46;3&#41;&nbsp;\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">Myositis &#40;&#37;&#41;&nbsp;\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">2 &#40;4&#46;8&#41;&nbsp;\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">PAH &#40;&#37;&#41;&nbsp;\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">5 &#40;11&#46;9&#41;&nbsp;\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">ILD &#40;&#37;&#41;&nbsp;\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">14 &#40;33&#46;3&#41;&nbsp;\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">ILD subtype NINE &#40;&#37;&#41;&nbsp;\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">6 &#40;14&#46;3&#41;&nbsp;\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">ILD subtype NIU &#40;&#37;&#41;&nbsp;\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">7 &#40;16&#46;7&#41;&nbsp;\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">ILD subtype bronchiolitis &#40;&#37;&#41;&nbsp;\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">1 &#40;2&#46;4&#41;&nbsp;\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">Reduced FVC &#40;&#37;&#41;&nbsp;\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">7 &#40;16&#46;7&#41;&nbsp;\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">Reduced DLCO &#40;&#37;&#41;&nbsp;\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">25 &#40;59&#46;5&#41;&nbsp;\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">Gastrointestinal involvement &#40;&#37;&#41;&nbsp;\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">14 &#40;33&#46;3&#41;&nbsp;\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">Kidney involvement &#40;&#37;&#41;&nbsp;\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">2 &#40;4&#46;8&#41;&nbsp;\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">Anemia &#40;&#37;&#41;&nbsp;\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">6 &#40;14&#46;3&#41;&nbsp;\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">Neutropenia &#40;&#37;&#41;&nbsp;\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">1 &#40;2&#46;4&#41;&nbsp;\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">Lymphopenia &#40;&#37;&#41;&nbsp;\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">3 &#40;7&#46;2&#41;&nbsp;\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">Thrombopenia &#40;&#37;&#41;&nbsp;\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">2 &#40;4&#46;8&#41;&nbsp;\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">High PCR &#40;&#37; of positives&#41;&nbsp;\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">7 &#40;16&#46;7&#41;&nbsp;\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">High ESR&nbsp;\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">8 &#40;19&#41;&nbsp;\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">Anti-Scl70 &#40;&#37; of positives&#41;&nbsp;\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">7 &#40;16&#46;7&#41;&nbsp;\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">Anti-centromere &#40;&#37; of positives&#41;&nbsp;\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">21 &#40;50&#41;&nbsp;\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">Anti-RNA polymerase &#40;&#37; of positives&#41;&nbsp;\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">4 &#40;9&#46;5&#41;&nbsp;\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">Sclerodermiform pattern in Capillaroscopy &#40;&#37;&#41;&nbsp;\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">35 &#40;83&#46;3&#41;&nbsp;\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">Unspecific pattern in capillaroscopy &#40;&#37;&#41;&nbsp;\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">7 &#40;16&#46;7&#41;&nbsp;\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">Tortuosities &#40;&#37;&#41;&nbsp;\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">16 &#40;38&#41;&nbsp;\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">Ramifications &#40;&#37;&#41;&nbsp;\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">13 &#40;30&#46;9&#41;&nbsp;\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">Dilated loops &#40;&#37;&#41;&nbsp;\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">38 &#40;90&#46;5&#41;&nbsp;\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">Giant capillaries &#40;&#37;&#41;&nbsp;\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">31 &#40;73&#46;8&#41;&nbsp;\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">Microhemorrhages &#40;&#37;&#41;&nbsp;\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">31 &#40;73&#46;8&#41;&nbsp;\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">Avascularity &#40;&#37;&#41;&nbsp;\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">26 &#40;61&#46;9&#41;&nbsp;\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">Decreased capillary density &#40;&#37;&#41;&nbsp;\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">32 &#40;76&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Baseline characteristics of the cohort&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Short explanation&#58; It shows clinical&#44; analytical and spirometric features of patients with ILD and PAH&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "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" 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">&nbsp;\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">PAH patients&nbsp;\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">ILD patients&nbsp;\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-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">Levels of GDF15 in ng&#47;mL &#40;median&#44; SD&#41;&nbsp;\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">1&#46;429 &#40;0&#46;596&#41;&nbsp;\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">1&#46;389 &#40;0&#46;753&#41;&nbsp;\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">Number of patients&nbsp;\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">5&nbsp;\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">14&nbsp;\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">HAQ &#40;median&#41;&nbsp;\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">1&#46;25&nbsp;\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">0&#46;75&nbsp;\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">EUSTAR activity index &#40;median&#41;&nbsp;\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">6&#46;3&nbsp;\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">6&nbsp;\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">Cochin &#40;median&#41;&nbsp;\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">5&nbsp;\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">10&#46;5&nbsp;\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">SF36 &#40;median&#41;&nbsp;\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">0&#46;42&nbsp;\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">0&#46;52&nbsp;\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">Rodnan &#40;median&#41;&nbsp;\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">4&nbsp;\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">3&nbsp;\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">Gravedad Medsger &#40;median&#41;&nbsp;\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">5&nbsp;\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">4&nbsp;\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">Centromeric nuclear ANA pattern &#40;&#37;&#41;&nbsp;\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">40&nbsp;\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">7&nbsp;\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">Homogeneous nuclear ANA pattern &#40;&#37;&#41;&nbsp;\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">20&nbsp;\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">36&nbsp;\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">Anti-centromere &#40;&#37;&#41;&nbsp;\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">40&nbsp;\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">7&nbsp;\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">Anti-Scl70 &#40;&#37;&#41;&nbsp;\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">20&nbsp;\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">36&nbsp;\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">Anti-RNApolymerase III &#40;&#37;&#41;&nbsp;\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">20&nbsp;\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">14&nbsp;\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">Reduction in DLCO &#40;&#37;&#41;&nbsp;\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">80&nbsp;\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">71&nbsp;\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">Reduction in FVC &#40;&#37;&#41;&nbsp;\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">40&nbsp;\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">21&nbsp;\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">Sclerodermiform pattern in VCL &#40;&#37;&#41;&nbsp;\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">100&nbsp;\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">78&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Characteristics of patients with ILD and PAH in our study&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:30 [
            0 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chemokines beyond chemo-attraction&#58; CXCL10 and its significant role in cancer and autoimmunity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "N&#46; Karin"
                            1 => "H&#46; Razon"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cyto.2018.02.012"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cytokine"
                        "fecha" => "2018"
                        "volumen" => "109"
                        "paginaInicial" => "24"
                        "paginaFinal" => "28"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29449068"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-&#945; production in systemic sclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Lande"
                            1 => "E&#46;Y&#46; Lee"
                            2 => "R&#46; Palazzo"
                            3 => "B&#46; Marinari"
                            4 => "I&#46; Pietraforte"
                            5 => "G&#46;S&#46; Santos"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41467-019-09683-z"
                      "Revista" => array:5 [
                        "tituloSerie" => "Nat Commun"
                        "fecha" => "2019"
                        "volumen" => "10"
                        "paginaInicial" => "1731"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31043596"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Innate immunity in systemic sclerosis fibrosis&#58; recent advances"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Laurent"
                            1 => "V&#46; Sisirak"
                            2 => "E&#46; Lazaro"
                            3 => "C&#46; Richez"
                            4 => "P&#46; Duffau"
                            5 => "P&#46; Blanco"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fimmu.2018.01702"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Immunol"
                        "fecha" => "2018"
                        "volumen" => "9"
                        "paginaInicial" => "1702"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30083163"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46;E&#46; Maione"
                            1 => "G&#46;S&#46; Gray"
                            2 => "J&#46; Petro"
                            3 => "A&#46;J&#46; Hunt"
                            4 => "A&#46;L&#46; Donner"
                            5 => "S&#46;I&#46; Bauer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/science.1688470"
                      "Revista" => array:6 [
                        "tituloSerie" => "Science"
                        "fecha" => "1990"
                        "volumen" => "247"
                        "paginaInicial" => "77"
                        "paginaFinal" => "79"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1688470"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46; Scheuerer"
                            1 => "M&#46; Ernst"
                            2 => "I&#46; D&#252;rrbaum-Landmann"
                            3 => "J&#46; Fleischer"
                            4 => "E&#46; Grage-Griebenow"
                            5 => "E&#46; Brandt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2000"
                        "volumen" => "95"
                        "paginaInicial" => "1158"
                        "paginaFinal" => "1166"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10666185"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Von Hundelshausen"
                            1 => "R&#46;R&#46; Koenen"
                            2 => "M&#46; Sack"
                            3 => "S&#46; Mause"
                            4 => "W&#46; Adriaens"
                            5 => "A&#46; Proudfoot"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2004-06-2475"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2005"
                        "volumen" => "105"
                        "paginaInicial" => "924"
                        "paginaFinal" => "930"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15459010"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Changes in plasma CXCL4 levels are associated with improvements in lung function in patients receiving immunosuppressive therapy for systemic sclerosis-related interstitial lung disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;R&#46; Volkmann"
                            1 => "D&#46;P&#46; Tashkin"
                            2 => "M&#46;D&#46; Roth"
                            3 => "P&#46;J&#46; Clements"
                            4 => "D&#46; Khanna"
                            5 => "D&#46;E&#46; Furst"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13075-016-1203-y"
                      "Revista" => array:5 [
                        "tituloSerie" => "Arthritis Res Ther"
                        "fecha" => "2016"
                        "volumen" => "18"
                        "paginaInicial" => "305"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28038680"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Low heme oxygenase-1 levels in patients with systemic sclerosis are associated with an altered Toll-like receptor response&#58; another role for CXCL4&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Van Bon"
                            1 => "M&#46; Cossu"
                            2 => "A&#46; Scharstuhl"
                            3 => "B&#46; Pennings"
                            4 => "M&#46;C&#46; Vonk"
                            5 => "H&#46;J&#46; Vreman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/rheumatology/kew251"
                      "Revista" => array:5 [
                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
                        "fecha" => "2016"
                        "volumen" => "55"
                        "paginaInicial" => "2066"
                        "paginaFinal" => "2073"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cartilage oligomeric matrix protein is overexpressed by scleroderma dermal fibroblasts"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "G&#46; Farina"
                            1 => "R&#46; Lemaire"
                            2 => "J&#46;H&#46; Korn"
                            3 => "R&#46;L&#46; Widom"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.matbio.2006.01.007"
                      "Revista" => array:6 [
                        "tituloSerie" => "Matrix Biol"
                        "fecha" => "2006"
                        "volumen" => "25"
                        "paginaInicial" => "213"
                        "paginaFinal" => "222"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16520029"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "L&#46; Van Bon"
                            1 => "A&#46;J&#46; Affandi"
                            2 => "J&#46; Broen"
                            3 => "B&#46; Romy"
                            4 => "R&#46;J&#46; Marijnissen"
                            5 => "L&#46; Stawsky"
                            6 => "A&#46; Giuseppina"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1114576"
                      "Revista" => array:7 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2014"
                        "volumen" => "370"
                        "paginaInicial" => "433"
                        "paginaFinal" => "443"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24350901"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0161642017338204"
                          "estado" => "S300"
                          "issn" => "01616420"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CXCL4 in undifferentiated connective tissue disease at risk for systemic sclerosis &#40;SSc&#41; &#40;previously referred to as very early SSc&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Valentini"
                            1 => "A&#46; Riccardi"
                            2 => "S&#46; Vettori"
                            3 => "R&#46; Irace"
                            4 => "M&#46; Iudici"
                            5 => "S&#46; Tolone"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10238-016-0437-y"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Med"
                        "fecha" => "2017"
                        "volumen" => "17"
                        "paginaInicial" => "411"
                        "paginaFinal" => "414"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27650429"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anti-CXCL4 antibody reactivity is present in systemic sclerosis &#40;SSc&#41; and correlates with the SSc type I interferon signature"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Lande"
                            1 => "A&#46; Mennella"
                            2 => "R&#46; Palazzo"
                            3 => "I&#46; Pietraforte"
                            4 => "K&#46; Stefanatoni"
                            5 => "N&#46; Iannace"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/ijms21145102"
                      "Revista" => array:4 [
                        "tituloSerie" => "Int J Mol Sci"
                        "fecha" => "2020"
                        "volumen" => "21"
                        "paginaInicial" => "5102"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Plasmocytoid dendritic cells promote systemic sclerosis with a key role fot TLR8"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Kioon"
                            1 => "C&#46; Tripodo"
                            2 => "D&#46; Fern&#225;ndez"
                            3 => "K&#46; Kirou"
                            4 => "R&#46;F&#46; Spiera"
                            5 => "M&#46;K&#46; Crow"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/scitranslmed.aam8458"
                      "Revista" => array:4 [
                        "tituloSerie" => "Sci Transl Med"
                        "fecha" => "2018"
                        "volumen" => "10"
                        "paginaInicial" => "428"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Increased expression of growth differentiation factor 15 in systemic sclerosis associated pulmonary arterial hypertension"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;A&#46; Meadows"
                            1 => "M&#46;G&#46; Risbano"
                            2 => "L&#46; Zhang"
                            3 => "M&#46;W&#46; Geraci"
                            4 => "R&#46;M&#46; Tuder"
                            5 => "D&#46;H&#46; Collier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1378/chest.10-0302"
                      "Revista" => array:5 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2011"
                        "volumen" => "139"
                        "paginaInicial" => "994"
                        "paginaFinal" => "1002"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Growth differentiation factor 15 for prognostic assessment of patients with acute pulmonary embolism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Lankeit"
                            1 => "T&#46; Kempf"
                            2 => "C&#46; Dellas"
                            3 => "M&#46; Cuny"
                            4 => "H&#46; Tapken"
                            5 => "T&#46; Peter"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.200712-1786OC"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2008"
                        "volumen" => "177"
                        "paginaInicial" => "1018"
                        "paginaFinal" => "1025"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18263797"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis&#58; association with disease severity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "K&#46; Yanaba"
                            1 => "Y&#46; Asano"
                            2 => "Y&#46; Tada"
                            3 => "M&#46; Sugaya"
                            4 => "T&#46; Kadono"
                            5 => "S&#46; Sato"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10165-011-0568-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mod Rheumatol"
                        "fecha" => "2012"
                        "volumen" => "22"
                        "paginaInicial" => "668"
                        "paginaFinal" => "675"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22160844"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Growth differentiation factor-15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;C&#46; De Jager"
                            1 => "B&#46; Bermudez"
                            2 => "I&#46; Bot"
                            3 => "R&#46; Koenen"
                            4 => "M&#46; Bot"
                            5 => "A&#46; Kavelaars"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1084/jem.20100370"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Exp Med"
                        "fecha" => "2011"
                        "volumen" => "208"
                        "paginaInicial" => "217"
                        "paginaFinal" => "225"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21242297"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Growth differentiation factor 15&#44; a marker of lung involvement in systemic sclerosis&#44; is involved in fibrosis development but is not indispensable for fibrosis development"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Lambrecht"
                            1 => "V&#46; Smith"
                            2 => "K&#46; De Wilde"
                            3 => "J&#46; Coudenys"
                            4 => "S&#46; Decuman"
                            5 => "D&#46; Deforce"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.38241"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheumatol"
                        "fecha" => "2014"
                        "volumen" => "66"
                        "paginaInicial" => "418"
                        "paginaFinal" => "427"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24504814"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The transforming growth factor-&#946; family"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Massagu&#233; J&#58;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1146/annurev.cb.06.110190.003121"
                      "Revista" => array:7 [
                        "tituloSerie" => "Annu Rev Cell Biol"
                        "fecha" => "1990"
                        "volumen" => "6"
                        "paginaInicial" => "597"
                        "paginaFinal" => "641"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2177343"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0002939418305865"
                          "estado" => "S300"
                          "issn" => "00029394"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of the CXCL8-CXCR1&#47;2 axis in cancer and inflammatory diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46; Ha"
                            1 => "B&#46; Debnath"
                            2 => "N&#46; Neamati"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.7150/thno.15625"
                      "Revista" => array:6 [
                        "tituloSerie" => "Theranostics"
                        "fecha" => "2017"
                        "volumen" => "7"
                        "paginaInicial" => "1543"
                        "paginaFinal" => "1588"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28529637"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The CXCL8&#47;IL8 chemokine family and its receptors in inflammatory diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46;C&#46; Russo"
                            1 => "C&#46;C&#46; Garcia"
                            2 => "M&#46;M&#46; Teixeira"
                            3 => "F&#46;A&#46; Amaral"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1586/1744666X.2014.894886"
                      "Revista" => array:5 [
                        "tituloSerie" => "Exp Rev Clin Immunol"
                        "fecha" => "2014"
                        "volumen" => "10"
                        "paginaInicial" => "593"
                        "paginaFinal" => "619"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Combined effects of CXCL8 and CXCR2 gene polymorphisms on susceptibility to systemic sclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46;H&#46; Salim"
                            1 => "M&#46; Jobim"
                            2 => "M&#46; Brademeier"
                            3 => "J&#46;A&#46; Bogo"
                            4 => "J&#46;C&#46; Tavares"
                            5 => "L&#46;F&#46; Jobim"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cyto.2012.05.026"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cytokine"
                        "fecha" => "2012"
                        "volumen" => "60"
                        "paginaInicial" => "473"
                        "paginaFinal" => "477"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22763041"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cross-disease innate gene signature&#58; emerging diversity and abundance in RA comparing to SLE and SSc"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Petrackova"
                            1 => "P&#46; Horak"
                            2 => "M&#46; Radvansky"
                            3 => "M&#46; Skacelova"
                            4 => "R&#46; Fillerova"
                            5 => "M&#46; Kudelka"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1155/2019/3575803"
                      "Revista" => array:3 [
                        "tituloSerie" => "J Immunol Res"
                        "fecha" => "2019"
                        "paginaInicial" => "3575803"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serum chemokine levels as prognostic markers in patients with early systemic sclerosis&#58; a multicenter&#44; prospective&#44; observational study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Hasegawa"
                            1 => "Y&#46; Asano"
                            2 => "H&#46; Endo"
                            3 => "M&#46; Fujimoto"
                            4 => "D&#46; Goto"
                            5 => "H&#46; Ihn"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/s10165-012-0795-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mod Rheumatol"
                        "fecha" => "2013"
                        "volumen" => "23"
                        "paginaInicial" => "1076"
                        "paginaFinal" => "1084"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23180322"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Biomarkers from bronchoalveolar lavage fluid in systemic sclerosis patients with interstitial lung disease relate to severity of lung fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Hesselstrand"
                            1 => "M&#46; Wildt"
                            2 => "G&#46; Bozovic"
                            3 => "A&#46; Andersson-Sj&#246;land"
                            4 => "K&#46; Andr&#233;asson"
                            5 => "A&#46; Scheja"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.rmed.2013.03.015"
                      "Revista" => array:7 [
                        "tituloSerie" => "Respir Med"
                        "fecha" => "2013"
                        "volumen" => "107"
                        "paginaInicial" => "1079"
                        "paginaFinal" => "1086"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23660398"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S1888429617300705"
                          "estado" => "S300"
                          "issn" => "18884296"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Plasma cytokine profiles in systemic sclerosis&#58; associations with autoantibody subsets and clinical manifestations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Gourh"
                            1 => "F&#46;C&#46; Arnett"
                            2 => "S&#46; Assassi"
                            3 => "F&#46;K&#46; Tan"
                            4 => "M&#46; Huang"
                            5 => "L&#46; Diekman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/ar2821"
                      "Revista" => array:5 [
                        "tituloSerie" => "Arthritis Res Ther"
                        "fecha" => "2009"
                        "volumen" => "11"
                        "paginaInicial" => "R147"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19799786"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of the disease activity score and the revised EUSTAR activity index in diffuse cutaneous systemic sclerosis patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46; Doyen"
                            1 => "F&#46;A&#46; Houssiau"
                            2 => "B&#46;R&#46; Lauwerys"
                            3 => "M&#46; Vanthuyne"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Exp Rheumatol"
                        "fecha" => "2020"
                        "volumen" => "38"
                        "numero" => "Suppl&#46; 1253"
                        "paginaInicial" => "53"
                        "paginaFinal" => "58"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33124572"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Growth differentiation factor-15 &#40;GDF-15&#41; level and relation to clinical manifestations in Egyptian systemic sclerosis patients&#58; preliminary data"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;M&#46; Gamal"
                            1 => "F&#46;T&#46; Elgengehy"
                            2 => "A&#46; Kamal"
                            3 => "S&#46;A&#46; El Bakry"
                            4 => "E&#46; Shabaan"
                            5 => "A&#46; Elgendy"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/08820139.2017.1360340"
                      "Revista" => array:6 [
                        "tituloSerie" => "Immunol Invest"
                        "fecha" => "2017"
                        "volumen" => "46"
                        "paginaInicial" => "703"
                        "paginaFinal" => "713"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28872977"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Complement C3 produced by macrophages promotes renal fibrosis via IL-17A secretion"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Liu"
                            1 => "K&#46; Wang"
                            2 => "X&#46; Liang"
                            3 => "Y&#46; Li"
                            4 => "Y&#46; Zhang"
                            5 => "C&#46; Zhang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fimmu.2018.02385"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Immunol"
                        "fecha" => "2018"
                        "volumen" => "9"
                        "paginaInicial" => "2385"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30405606"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The relationship between complement C3 expression and the MUC5B genotype in pulmonary fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Okamoto"
                            1 => "S&#46;K&#46; Mathai"
                            2 => "C&#46;E&#46; Hennessy"
                            3 => "L&#46;A&#46; Hancock"
                            4 => "A&#46;D&#46; Walts"
                            5 => "A&#46;L&#46; Stefanski"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1152/ajplung.00395.2017"
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Physiol Lung Cell Mol Physiol"
                        "fecha" => "2018"
                        "volumen" => "315"
                        "paginaInicial" => "1"
                        "paginaFinal" => "10"
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack631180"
        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0450" class="elsevierStylePara elsevierViewall">We thank all participants for kindly agreeing to take part in this study&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/23870206/0000015900000008/v1_202210210800/S2387020622004673/v1_202210210800/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "43310"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Original articles"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015900000008/v1_202210210800/S2387020622004673/v1_202210210800/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622004673?idApp=UINPBA00004N"
]

Article information

ISSN: 23870206
Original language: English

DOI:10.1016/j.medcle.2021.12.013

The statistics are updated each day

Indexed in:

Follow us:

Subscribe:

Statistics

Indexed in:

Follow us:

Subscribe:

Statistics

Subscribe to our newsletter