Prognostic implications of extra-hepatic clinical manifestations, autoimmunity and microscopic nail capillaroscopy in patients with primary biliary cirrhosis

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"paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "8" "paginaFinal" => "15" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Begoña Marí-Alfonso, María José Amengual-Guedan, Mercè Vergara-Gómez, Carmen Pilar Simeón-Aznar, Vicente Fonollosa-Plà, Esther Jove-Buxeda, Juan Oliva-Morera, Carles Tolosa-Vilella" "autores" => array:8 [ 0 => array:4 [ "nombre" => "Begoña" "apellidos" => "Marí-Alfonso" "email" => array:1 [ 0 => "bmari@tauli.cat" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "María José" "apellidos" => "Amengual-Guedan" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Mercè" "apellidos" => "Vergara-Gómez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Carmen Pilar" "apellidos" 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"aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Laboratorio de Inmunología, UDIAT, Corporación Sanitaria y Universitaria Parc Taulí, Instituto Universitario Parc Taulí, Universidad Autónoma de Barcelona (UAB), Sabadell, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Hepatología, Corporación Sanitaria y Universitaria Parc Taulí, Instituto Universitario Parc Taulí, Universidad Autónoma de Barcelona (UAB), Sabadell, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Universitario Vall d’Hebrón, Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Unidad de Estadística, Fundación Parc Taulí, Corporación Sanitaria y Universitaria Parc Taulí, Instituto Universitario Parc Taulí, Universidad Autónoma de Barcelona (UAB), Sabadell, Barcelona, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Implicación pronóstica de las manifestaciones clínicas extrahepáticas, autoinmunidad y capilaroscopia ungueal microscópica en pacientes con cirrosis biliar primaria" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3137 "Ancho" => 2943 "Tamanyo" => 312690 ] ] "descripcion" => array:1 [ "en" => "Study protocol of patients with primary biliary cirrhosis. ANA: antinuclear antibodies; RA: rheumatoid arthritis; PBC: primary biliary cirrhosis; PBC-SAD: patients with PBC and associated SAD; PBC-no SAD: PBC patients without associated SAD; CCP: cyclic citrullinated anti-peptide antibody; SAD: systemic autoimmune disease; ENA: extractable nuclear antibody; SSc: systemic sclerosis; lSSc: SSc with limited scleroderma; lSSc-RA: SSc associated with limited scleroderma and rheumatoid arthritis; lSSc-SjS: SSc associated with limited scleroderma and Sjogren syndrome; RF: rheumatoid factor; pre-SSc: pre-scleroderma; SjS: Sjögren's syndrome; TSH: thyrotropin." ] ] ] "textoCompleto" => "IntroductionPrimary biliary cirrhosis (PBC) is a chronic cholestatic disease characterized by inflammation and destruction of small and medium calibre bile ducts and deposition of fibrotic tissue with a progressive course that can cause liver failure. The aetiology is unknown, but the most accepted is the autoimmune hypothesis since the PBC is often associated with other autoimmune diseases or is accompanied by non-organ specific autoantibodies. Some studies show that systemic sclerosis (SSc) is the systemic autoimmune disease (SAD) most frequently associated with PBC, in particular, the limited cutaneous subtype (3–50% of cases).<a class="elsevierStyleCrossRefs" href="#bib0195">1–5</a> Thus, anti-centromere antibodies (ACA), specific of SSc and/or microvascular anomalies suggestive of SSc can be detected through microscopic nailfold capillaroscopy (capillaroscopy from now on), in 30% and 42% of patients with PBC, respectively. In some studies, their presence has been linked to a higher incidence of symptoms and/or signs suggestive of SAD, Raynaud's phenomenon in particular.<a class="elsevierStyleCrossRefs" href="#bib0220">6–10</a>Some authors have indicated that PBC and SSc are associated with increased morbidity and mortality compared to the general population. However, at present, it remains a controversial claim.<a class="elsevierStyleCrossRefs" href="#bib0245">11,12</a> Recent prospective studies that compare patients with PBC and SSc and patients with isolated PBC, adjusted for total bilirubin figures, show a similar mortality in both groups. In patients with associated SSc, death causes are related to SSc.<a class="elsevierStyleCrossRef" href="#bib0255">13</a>SSc is characterized by the appearance of microvascular damage, excessive accumulation of collagen fibres in the skin and internal organs, and an inappropriate autoimmune response directed against multiple cellular antigens. Currently, the main prognostic factor for SSc is the extension of cutaneous sclerosis,<a class="elsevierStyleCrossRef" href="#bib0260">14</a> why most disease experts continue to use the classification proposed by LeRoy et al., 1988.<a class="elsevierStyleCrossRef" href="#bib0265">15</a> In it, there are 2 large groups of patients with SSc, the subtype SSc with limited scleroderma (lSSc), and the SSc subtype with diffuse scleroderma. However, there is a significant number of patients with unobvious SSc clinical manifestations which are diagnosed late. Most of these patients belong to the group with limited SSc, with little or no cutaneous sclerosis,<a class="elsevierStyleCrossRef" href="#bib0270">16</a> and a group of patients with pre-scleroderma (pre-SSc), defined according to the classification criteria proposed by LeRoy and Medsger of 2001.<a class="elsevierStyleCrossRef" href="#bib0275">17</a> The latter group with a high probability of developing into established SSc.<a class="elsevierStyleCrossRef" href="#bib0280">18</a>The main objective of this study is to determine the prevalence of associated SAD, particularly SSc, in a cohort of patients with PBC. Secondary objectives investigated are whether patients with PBC associated with a SAD have a specific clinical and biological profile when compared to patients with isolated PBC, as well as the possible prognostic factors related to the association of both autoimmune diseases.Patients and methodsThis is an observational study conducted in the Corporación Sanitaria Universitaria Parc Taulí, Sabadell (Barcelona), with a population catchment area of 430,000 inhabitants. During the study period, from January 1990 to December 2011, 94 patients were identified with the diagnosis of PBC, 62 of which met the following inclusion criteria: (1) diagnosis of PBC, according to the criteria of the American Association of the Study of Liver Diseases<a class="elsevierStyleCrossRefs" href="#bib0285">19,20</a>; (2) 18 years of age or over; (3) current clinical follow-up by the Hepatology Unit and (4) signed informed consent to participate in the study. 32 patients were excluded for the following reasons: death prior to the start of the study, chronic liver disease of toxic or infectious origin associated with PBC and any reason that would hinder completion of the study protocol, which is detailed in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>. The project was approved by the Clinical Research Ethics Committee of the Hospital de Sabadell.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The study protocol included a single medical visit in which the history and physical examination aimed at detecting symptoms and signs suggestive of extrahepatic SAD and capillaroscopy was performed. After the inclusion of patients in the study, serum samples from one of the regular blood tests requested by the physicians responsible for the patients at the Hepatology Unit were identified. The serum aliquots obtained were frozen at −80°C until their biochemical and immunological study.Definition of clinical manifestations<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Peripheral vascular manifestations: presence of Raynaud's phenomenon, with or without digital ulcers or residual scarring ischaemic lesions in fingertips or acroosteolysis.<a class="elsevierStyleCrossRef" href="#bib0295">21</a></li><li class="elsevierStyleListItem" id="lsti0010">-Cutaneous manifestations: presence of sclerodactyly, telangiectasia and skin calcinosis.</li><li class="elsevierStyleListItem" id="lsti0015">-Sicca syndrome: it was assessed when the patients reported ocular or oral dryness spontaneously, with or without ocular signs or hyposecretion in the Schirmer test or salivary scintigraphy, unrelated to the intake of hyposecretion-inducing drugs and considered disproportionate by their doctor.<a class="elsevierStyleCrossRef" href="#bib0295">21</a></li><li class="elsevierStyleListItem" id="lsti0020">-Gastrointestinal disease: the following diagnoses were considered as gastrointestinal disease associated with SSc: oesophageal disease, if hypomotility of the 2 lower thirds of the oesophagus was confirmed by manometry; gastric disease, if gastric hypomotility was detected by barium examination or manometry; intestinal disease, if intestinal hypomotility is demonstrated by manometry, malabsorption syndrome by breath test or intestinal pseudo-obstruction by radiography or computed tomography.<a class="elsevierStyleCrossRefs" href="#bib0295">21,22</a> The presence of gastroesophageal reflux together with consistent symptoms, with or without specific diagnostic tests, was considered.</li><li class="elsevierStyleListItem" id="lsti0025">-Lung disease: defined by the presence of pulmonary hypertension (PHT) or interstitial lung disease (ILD). ILD was diagnosed in the following situations: (1) pulmonary restrictive pattern in pulmonary function tests, with a forced vital capacity (FVC)<80% of the expected value and (2) pulmonary interstitial pattern confirmed by an X-ray or high-resolution chest CT scan; and/or (3) alveolitis confirmed by bronchoalveolar lavage without evidence of germs. The diagnosis of pulmonary hypertension was established when pulmonary arterial systolic pressure estimated by Doppler echocardiography was >40mmHg or mean pulmonary arterial pressure by right heart catheterization, was ≥25mmHg. When the PHT was not related to ILD, or it was mild, with a FVC >70% and the pulmonary capillary wedge pressure was <15mmHg,<a class="elsevierStyleCrossRefs" href="#bib0295">21,22</a> it was then considered pulmonary arterial hypertension.</li><li class="elsevierStyleListItem" id="lsti0030">-Joint disease: if there were arthralgia or arthritis and/or tendon friction.<a class="elsevierStyleCrossRefs" href="#bib0295">21,22</a></li><li class="elsevierStyleListItem" id="lsti0035">-Heart disease: identification of any of the following conditions: pericarditis, ischaemic heart disease with no other obvious aetiology, electrocardiographic changes or anomalies in myocardial contractility, ejection fraction of the left ventricle <55% detected by colour Doppler echocardiogram or radionuclide ventriculography.<a class="elsevierStyleCrossRefs" href="#bib0295">21,22</a></li><li class="elsevierStyleListItem" id="lsti0040">-Kidney disease: the presence of renal damage secondary to SAD was considered when there was evidence of proteinuria >500mg/24h or decreased estimated glomerular filtration rate <60ml/min/1.73m2 during ≥3 months in the absence of another aetiology.<a class="elsevierStyleCrossRef" href="#bib0305">23</a></li></ul>CapillaroscopyA systematic study of the first capillary line of the nailfold in fingers 2–5 in both hands was performed, according to the validated semiquantitative method of Maricq,<a class="elsevierStyleCrossRef" href="#bib0310">24</a> through a Zuzi® Ura Technic Series 234 stereomicroscope (Navarra, Spain) with a cold halogen lamp and a USB 1.3 Mp high resolution camcorder, equipped with capture and image analysis software with up to 200× magnification. Patients were classified into one of the following capillaroscopic patterns: (1) normal pattern: no significant capillary changes, (2) non-specific pattern: with inconclusive capillary anomalies of scleroderma and (3) SSc pattern: capillary bed changes are suggestive of SSc according to the Maricq et al.,<a class="elsevierStyleCrossRef" href="#bib0315">25</a> classification criteria, grouped into two patterns: (a) slow pattern: predominance of capillary dilations with a diameter greater than 4 normal capillary diameters or the presence of mega-capillaries, with minimal or no capillary loss; (b) active pattern: moderate to severe capillary loss and disorganization of the capillary bed that predominates over capillary dilation and/or mega-capillaries.Immunological studyDetermination of antinuclear (ANA) and anticytoplasmic autoantibodies was performed by indirect immunofluorescence with combined HEp-2 cell slides and triple rat tissue (liver, stomach and kidney). For confirmation of the specificities of autoantibodies related to liver disease a Dot blotting was performed by nitrocellulose specific strips with the antigen of interest (M2, LKM, LC1, SLA, Sp100, gp120, F-actin) (D-Tek, Mons, Belgium). The determination of SSc specific antibodies was performed using nitrocellulose specific strips with the antigens of interest, different native (topoisomerase) or recombinant proteins (CENP-A, CENP-B, RP11, RP155, fibrillarin, NOR90, Th/To, PM-Scl 100, PM-Scl 75, Ku, platelet growth factor receptor and Ro-52) (Euroinmun, Lubeck, Germany). Finally, the determination of antibodies to extractable nuclear antigens and citrullinated cyclic peptides was performed by fluorescent enzyme immunoassay in a ImmunoCAP 250® autoanalyzer (Thermo Fisher Scientific (Phadia), Waltham, MA, USA), which allowed the analysis of the U1RNP, Sm, SSA/Ro, SSB/La specificities.Patient classificationAfter completing the study, patients with PBC were grouped according to their association (PBC-SAD) or not (PBC-no SAD) to a SAD, according to the American College of Rheumatology classification criteria for systemic lupus erythematosus,<a class="elsevierStyleCrossRef" href="#bib0320">26</a> Sjogren's syndrome,<a class="elsevierStyleCrossRef" href="#bib0325">27</a> rheumatoid arthritis,<a class="elsevierStyleCrossRef" href="#bib0330">28</a> polymyositis/dermatomyositis<a class="elsevierStyleCrossRef" href="#bib0335">29</a> and mixed connective tissue disease.<a class="elsevierStyleCrossRef" href="#bib0340">30</a> A modification of LeRoy and Medsger 2001 classification criteria<a class="elsevierStyleCrossRef" href="#bib0270">16</a> was used for the diagnosis of SSc, in which 4 clinical subtypes are distinguished, depending on skin extension and organ involvement:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0045">-Pre-SSc: defined by the presence of Raynaud's phenomenon and capillaroscopy pattern suggestive of SSc and/or presence of SSc specific autoantibodies, without established skin or organic disease of SSc.</li><li class="elsevierStyleListItem" id="lsti0050">-SSc with lSSc: patients with distal cutaneous sclerosis in elbows and knees, with or without facial sclerosis.</li><li class="elsevierStyleListItem" id="lsti0055">-SSc with diffuse scleroderma: patients with distal and proximal elbow and knee sclerosis.</li><li class="elsevierStyleListItem" id="lsti0060">-SSc sine scleroderma: defined by the presence of Raynaud's phenomenon or equivalent vascular disease (digital ulcers, scarring lesions of ischaemic origin in fingertips or acroosteolysis), antinuclear antibodies and organic condition typical of SSc (hypomotility in the digestive tract, ILD, PHT, heart disease or scleroderma renal crisis), without skin sclerosis.</li></ul>Statistic analysisA descriptive study of all variables collected was performed. The qualitative variables were described by absolute and relative frequency, and quantitative variables by mean, standard deviation, percentiles 25, 50 and 75 and minimum and maximum range. Chi square test was used for the bivariate analysis. The level of bilateral significance has been set at p<0.05. For the statistical study, the SPSS v19 programme was used, software for Windows® (SPSS Inc., Chicago, IL, USA).ResultsSixty-two patients with PBC met the study inclusion criteria, of whom 59 were women (95.2%). The average age of the cohort at the time of PBC diagnosis was 53.9 years (range: 26–74.7), with a mean age at study inclusion of 62.8 years (range: 29.8–88.7) and a median follow-up of chronic liver disease of 8.9 years (P25=3.8 and P75=13.5). Liver biopsy was performed in 55 patients and showed PBC findings in 47 of them (85.5%). Thirty-eight of the 62 patients (61.3%) were asymptomatic at the time of diagnosis (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The main extrahepatic symptoms collected in the study are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. Fifty-one patients (82.2%) reported some symptoms suggestive of SAD with a median time from first symptom onset and PBC diagnosis of 8.5 years (P25=2.3; P75=16). Sicca syndrome and gastroesophageal reflux were the most common extrahepatic symptoms, present in 32 (51.6%) and 26 (42%) patients, respectively.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Regarding symptoms suggestive of SSc, 18 patients (29%) reported Raynaud's phenomenon. Digital ulcers, sclerodactyly and skin calcinosis were present in a small number of patients, 3 (4.8%), 3 (4.8%) and 2 (3.2%), respectively. The only respiratory symptom, reported by 15 patients (24.2%), was dyspnoea, a functional class I/II according to the NYHA. A chest X-ray study was completed in 14 of them, finding an interstitial pulmonary pattern in 5 (35.7%). The respiratory functional study in 13 patients found a restrictive pattern, with a FVC <80% in 3 of them (23%). A Doppler echocardiography, available in 9 patients, estimated a systolic pulmonary arterial pressure >40mmHg in 2 patients (22.2%) and pulmonary hypertension confirmed by right heart catheterization in one patient.Capillaroscopy was not assessable in 8 patients (12.9%), due to poor visualization of the vascular bed, but a valuable study was possible in 54 patients (87.1%). Morphological anomalies of the capillary bed were observed in 27 studies (50%) with detection of capillary dilations in 20 patients (37%) and vascular leakage, focal or diffuse in 11 (20.3%). The capillaroscopic pattern was suggestive of SSc in 11 of them (40.7%), with a slow pattern in 9 patients (33.3%).Finally, ANA was identified in 47 patients (75.8%) with PBC (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). The ACA were positive in 14 patients (22.6%), all directed against antigens CENP-A/B, and other SSc typical antibodies were identified in 9 patients (14.5%). Four of these patients (57%), also referred some extrahepatic symptoms (3 sicca syndrome, one Raynaud's phenomenon); 2 with a normal capillaroscopy pattern (50%), one non-specific pattern (25%) and one non-assessable pattern (25%). Anti-Ro52 antibodies were identified in 21 patients (33.9%) and anti-Ro60 in 10 (16.1%) and the determination of cyclic citrullinated peptide performed in 50 patients was positive in 2 of them (3.2%).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Characteristics of patients with primary biliary cirrhosis with systemic autoimmune diseaseAfter completing the study protocol, patients were assigned to two groups. Group 1: PBC associated with a SAD (PBC-SAD), consisting of 22 patients and group 2: PBC not associated with a SAD (PBC-no SAD), consisting of 40 patients. The SAD started before the diagnosis of PBC in 12 cases (19.3%) with a mean age at diagnosis of 55.7 years (range 36.3–79.0) and median time between diagnosis of 1.9 years (range: 0.05–20.58 years).SSc was the SAD more frequently associated with PBC, diagnosed in 13 patients (21%), 7 of the lSSc subtype and 6 pre-SSc. Other SAD associated with PBC were Sjögren's syndrome in 7 cases (11%) and rheumatoid arthritis in 4 cases (6.4%). Two of these patients had overlap syndromes, one lSSc and Sjögren's syndrome and one lSSc and rheumatoid arthritis.Five patients (8%) with pre-SSc were diagnosed after completing the study protocol and 2 of them developed lSSc at 7 and 8 months of study entry. Of the remaining patients in whom a specific SSc antibody was detected other than ACA, none met the diagnostic criteria for SSc. Patients with pre-SSc were included in the PBC-SAD group for comparative group analysis.Capillaroscopy anomalies were observed in 16 out of the 20 patients in the PBC-SAD group (80%) with assessable study. The pattern was suggestive of SSc in 10 of them (50%), 8 slow pattern (80%) and 2 active pattern (20%). In 6 patients (30%), 3 had rheumatoid arthritis (30%), 2 with SSc (10%), and one with Sjögren syndrome (5%), the capillaroscopic pattern was unspecific.In the bivariate study (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>) the characteristics of the 22 patients with PBC-SAD were compared to 40 patients with PBC-no SAD. Patients with PBC-SAD had extrahepatic symptoms more often (100 vs. 72.5%; p<0.009), especially the sicca syndrome (68 vs. 42.5%; p<0.025), Raynaud's phenomenon (68 vs. 7.5%; p<0.001), telangiectasia (31.8 vs. 5%; p<0.003), arthritis (41 vs. 2.5%; p<0.001) and dyspnoea (45.4 vs. 12.5%; p<0.002). ACA positivity (54.5 vs. 5%; p<0.001) was the only immune finding, most common in patients with PBC-SAD. No significant differences in the rest of antigenic specificities were observed, although it the high prevalence of anti-Ro52 and anti-Ro60 antibodies in both groups was remarkable: in 8 (36.3%) and 5 (22.7%) patients in PBC-SAD group and in 13 (32.5%) and 5 (12.5%) in PBC-no SAD group, respectively (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).A higher incidence of microvascular anomalies was observed in the PBC-SAD group compared to the PBC-no SAD group (81 vs. 33.3%; p<0.001), capillary dilations in particular (75 vs. 14.7%; p<0.001), mega-capillaries (40 vs. 2.9%; p<0.001), bleeding (25 vs. 2.9%; p<0.002) and vascular leakage (50 vs. 2.9%; p<0.001), which shows a higher incidence of capillaroscopic pattern suggestive of SSc (47.6 vs. 3%; p<0.001) in these patients.Severe disease criteriaAt the end of the study, 10 patients (16.1%) of the PBC cohort met clinical and/or ultrasound criteria for liver cirrhosis, 3 of the PBC-SAD group and 7 of the PBC-no SAD group (13.6 vs. 17.5%; p: ns). All of them were in a Child–Pugh A stage, except one patient of the PBC-no SAD group who was in Child–Pugh B stage. No differences were found in the levels of total bilirubin. Of the PBC-SAD group patients, 2 were associated with Sjögren's syndrome and one with rheumatoid arthritis.DiscussionThe study protocol applied to this cohort of 62 patients with PBC has identified a SAD prevalence of 35.4%. The SSc was the most common SAD, identified in 21% of patients, followed by Sjögren's syndrome and rheumatoid arthritis in 11.3% and 6.4%, respectively.Patients with PBC-SAD had a higher incidence of extrahepatic clinical manifestations such as sicca syndrome, Raynaud's phenomenon, telangiectasia, arthritis and dyspnoea, as well as greater association with ACA and morphological capillary changes suggestive of SSc. At the end of the study, 5 patients (8%) with PBC were classified as pre-SSc, not previously diagnosed, as Raynaud's phenomenon and SSc specific antibodies were observed in them (4 ACA, one anti-U3RNP), plus a pattern of slow capillaroscopy, suggestive of SSc, in 4 cases.The prevalence of SAD, especially SSc, in this cohort of patients with PBC is similar to that described by Marasini et al.,<a class="elsevierStyleCrossRef" href="#bib0205">3</a> (27.6% and 19.4%, respectively), applying a classification criteria similar to this study. However, other methodologically different series, such as Modena et al.,<a class="elsevierStyleCrossRef" href="#bib0200">2</a> (61.5% and 30.7%), Watts et al.,<a class="elsevierStyleCrossRef" href="#bib0345">31</a> (53% and 8%) and Wang et al.,<a class="elsevierStyleCrossRef" href="#bib0215">5</a> (46.6% and 2.8%) obtained divergent results (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). The high percentage of SAD identified in some series is probably due to the large number of patients classified as Sjögren's syndrome, which reaches 25% in Watts et al.,<a class="elsevierStyleCrossRef" href="#bib0345">31</a> and 35% in Wang et al.<a class="elsevierStyleCrossRef" href="#bib0215">5</a> However, if a positive immunology was required for diagnosing Sjögren's syndrome, the prevalence decreased to 4%, similar to this cohort, which also included a 47–70% of patients with sicca syndrome, particularly in the PBC-SAD group. In PBC patients, sicca syndrome is frequently associated with milder glandular symptoms when compared to patients with primary Sjögren's syndrome and absence of serum antibodies.<a class="elsevierStyleCrossRef" href="#bib0350">32</a> In this sense, only patients with glandular dryness and presence of anti-Ro and/or anti-La autoantibodies should be considered as associated with PBC, according to the criteria used in the study cohort. Moreover, the low prevalence of SSc (2.8–8%) diagnosed in the Watts et al.,<a class="elsevierStyleCrossRef" href="#bib0345">31</a> and Wang et al.,<a class="elsevierStyleCrossRef" href="#bib0215">5</a> series is probably related to the use of the ACR preliminary classification criteria for SSc, of 1980.<a class="elsevierStyleCrossRef" href="#bib0355">33</a> 20–30% of patients with lSSc do not meet these classification criteria.<a class="elsevierStyleCrossRef" href="#bib0295">21</a> Two recent prospective studies have shown a SSc prevalence of 18.8–23% (4–19% lSSc and 4–12.5% pre-SSc) in patients with PBC. In both series, 22% of the patients reported Raynaud's phenomenon, a capillaroscopy pattern suggestive of SSc was visualized in 18% and anti-CENP-B antibodies were identified in 18%<a class="elsevierStyleCrossRefs" href="#bib0360">34,35</a> (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). Other SSc specific antibodies such as anti-Th/To and anti-RNA-pol III were positive in 9% and 4% respectively.<a class="elsevierStyleCrossRef" href="#bib0360">34</a> These authors used the classification criteria of LeRoy and Medsger 2001, as in the present cohort. Other characteristics, such as sex, mean age and time of progression of the PBC, were also similar to our cohort.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>In the immunological study, ANA and ACA prevalence was found similar to other series.<a class="elsevierStyleCrossRefs" href="#bib0205">3,6,7</a> All patients with ACA were SSc of the PBC-SAD group. Unlike Joyal et al.,<a class="elsevierStyleCrossRef" href="#bib0360">34</a> other SSc specific antibodies were detected (anti-RNA-pol III, anti-U3RNP, anti-NOR90 or anti-Th/To) in 9.6% of patients with PBC, although without clinical manifestations or microvascular anomalies suggestive of SSc which would allow diagnosis confirmation. A single patient with anti-U3RNP antibodies, not previously diagnosed with SAD, was classified as pre-SSc when showing Raynaud's phenomenon.Although PBC patients have a high incidence of unspecific capillary morphological anomalies when compared to patients with other liver diseases, the finding of a capillary pattern suggestive of SSc is associated with the presence of ACA and/or manifestations suggestive of SSc in 20–75% of cases.<a class="elsevierStyleCrossRefs" href="#bib0235">9,10</a> A SSc pattern was visualized in the present study; this was mostly a slow pattern, in 20.4% of patients with PBC and, in 90% of cases, it corresponded to patients with PBC-SAD. These results support the usefulness of capillaroscopy as a diagnostic tool to discriminate patients with PBC, according to their association to a SAD or lack of it.In this study, the incidence of PBC patients treated with ursodeoxycholic acid was high and similar to other series. It is well known that this drug has managed to slow the progression to liver failure and has significantly improved survival, getting close to that of the general population.<a class="elsevierStyleCrossRef" href="#bib0370">36</a> This may explain that the incidence of liver failure at 9 years of median follow-up of this PBC cohort is very low and similar for both groups, PBC-SAD and PBC-no SAD. Rigamonti et al.<a class="elsevierStyleCrossRef" href="#bib0255">13</a> and Joyal et al.<a class="elsevierStyleCrossRef" href="#bib0360">34</a> have suggested that liver disease is milder and has a slower progression to liver failure in patients with PBC associated with SSc and ACA. However, although in the Rigamonti et al.<a class="elsevierStyleCrossRef" href="#bib0255">13</a> series, the mortality of patients with isolated PBC and associated with SSc was similar, in the second group, the mortality was related to organ dysfunction associated with systemic disease. Interestingly, exertional dyspnoea affected a quarter of patients with PBC, most of them from the PBC-SAD group and was associated with ILD in 80% of patients. Respiratory symptoms and the existence of ILD are common findings in patients with PBC, up to 50% and 15% respectively, especially when associated with Raynaud's phenomenon or a SAD, such as SSc or Sjögren's syndrome.<a class="elsevierStyleCrossRefs" href="#bib0375">37,38</a>The analysis of this PBC cohort has some limitations. First, the small sample size, which makes it difficult to obtain significant differences in some outcomes that tend to be more frequent in patients with PBC-SAD and, secondly, the retrospective design of the study, which has prevented to have all additional tests in order to correctly discriminate patients with pre-SSc and SSc sine scleroderma. In some cases, the follow-up period may be relatively short to identify all patients with SSc progression. However, this protocoled study identified an incidence of PBC associated to SAD of 35.4%, which in most cases is a SSc. This data reinforces the importance of a study aimed at identifying a SAD and not be limited to a liver function assessment. Patients with PBC-SAD often have extrahepatic manifestations such as Raynaud's phenomenon, sicca syndrome, telangiectasia, arthritis and dyspnoea, as well as a significant ACA association and microvascular anomalies suggestive of SSc, which can be predictors of the association of both diseases. It is noteworthy that 8% of patients were classified as previously undiagnosed pre-SSc and that some SSc developed during follow-up. Therefore, in patients with PBC, it is recommended to perform a systemic evaluation that includes a thorough case history and specific physical examination, as well as the determination of an appropriate immunological profile. A capillaroscopy should also be performed, allowing an early identification of the existence of any SAD.Conflict of interestNeither the microscopic nailfold capillaroscopy, nor any other technique used in the study has been financed by the industry. The authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres640222" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec654276" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres640221" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec654275" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Patients and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Definition of clinical manifestations" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Capillaroscopy" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Immunological study" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Patient classification" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistic analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Characteristics of patients with primary biliary cirrhosis with systemic autoimmune disease" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Severe disease criteria" ] ] ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-10-07" "fechaAceptado" => "2015-02-05" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec654276" "palabras" => array:5 [ 0 => "Primary biliary cirrhosis" 1 => "Systemic autoimmune disease" 2 => "Autoimmunity" 3 => "Capillaroscopy" 4 => "Systemic sclerosis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec654275" "palabras" => array:5 [ 0 => "Cirrosis biliar primaria" 1 => "Enfermedad autoinmune sistémica" 2 => "Autoinmunidad" 3 => "Capilaroscopia" 4 => "Esclerodermia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Background and objectivesPrimary biliary cirrhosis (PBC) is associated to any systemic autoimmune disease (SAD), in particular systemic sclerosis (SSc).To investigate the prevalence of SAD in a cohort of patients with PBC, specifically the prevalence of SSc and its clinical subtypes, and determining the clinical and biological profile of patients with associated PBC and SSc. MethodsObservational study of 62 patients with PBC following a protocol that included an anamnesis and physical examination to detect the presence of SAD as well as a nailfold capillaroscopy and an immunological study with specific SSc autoantibodies. A comparative analysis was conducted between patients with isolated PBC and patients with PBC and an associated SAD. ResultsSAD was associated to PBC in 22 patients (35.4%), and SSc was the most frequent illness, identified in 13 cases (21%). Five patients (8%) without previous diagnosis of SAD fulfilled pre-scleroderma criteria, according to LeRoy and Medsger criteria. The presence of anticentromere antibodies (54.5% vs. 5%, P<0.001) was the unique immunological determination identified more frequently in patients with PBC-SAD. The SSc suggestive capillary pattern was visualized in 11 patients (20.4%), mainly the slow pattern. No factors associated with greater morbi-mortality were identified in the PBC-SAD group. ConclusionsIt does exist a subgroup of patients with PBC and clinical–biological features suggestive of an SAD, which advise a protocolized study to detect early the association to an SAD." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Introducción y objetivosLa cirrosis biliar primaria (CBP) se asocia a algunas enfermedades autoinmunes sistémicas (EAS), en particular a la esclerosis sistémica (ES).Determinar la prevalencia de EAS en una cohorte de pacientes con CBP, específicamente la ES y sus diferentes subtipos clínicos, y establecer el perfil clínico-biológico propio de estos pacientes. MétodosEstudio observacional de 62 pacientes con CBP, con un protocolo que incluía una anamnesis y exploración física dirigidas a detectar una EAS, la realización de una capilaroscopia ungueal microscópica y un amplio estudio de autoinmunidad, incluido el perfil de anticuerpos específicos de ES. Se realizó un análisis comparativo entre el grupo de pacientes con CBP aislada y los pacientes con CBP y una EAS asociada. ResultadosSe asoció una EAS en 22 pacientes (35,4%), y la ES fue la entidad más frecuente (21%), del subtipo cutáneo limitado (11%). Cinco pacientes (8%) sin EAS previa cumplían criterios de preesclerodermia, según los criterios de LeRoy y Medsger. Los anticuerpos anticentrómero (54,5 vs. 5%, p<0,001) fueron el único parámetro inmunológico identificado con mayor frecuencia en pacientes con EAS. El patrón capilar sugestivo de ES se visualizó en 11 pacientes (20,4%). No se identificaron factores asociados a mayor morbimortalidad en ningún grupo. ConclusionesExiste un subgrupo de pacientes con CBP con características clínico-biológicas que sugieren la asociación con una EAS, con elevada probabilidad, y que recomiendan el estudio protocolizado de estos pacientes con CBP para detectar de forma precoz EAS." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Marí-Alfonso B, Amengual-Guedan MJ, Vergara-Gómez M, Simeón-Aznar CP, Fonollosa-Plà V, Jove-Buxeda E, et al. Implicación pronóstica de las manifestaciones clínicas extrahepáticas, autoinmunidad y capilaroscopia ungueal microscópica en pacientes con cirrosis biliar primaria. Med Clin (Barc). 2016;146:8–15." ] ] "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" => 3137 "Ancho" => 2943 "Tamanyo" => 312690 ] ] "descripcion" => array:1 [ "en" => "Study protocol of patients with primary biliary cirrhosis. ANA: antinuclear antibodies; RA: rheumatoid arthritis; PBC: primary biliary cirrhosis; PBC-SAD: patients with PBC and associated SAD; PBC-no SAD: PBC patients without associated SAD; CCP: cyclic citrullinated anti-peptide antibody; SAD: systemic autoimmune disease; ENA: extractable nuclear antibody; SSc: systemic sclerosis; lSSc: SSc with limited scleroderma; lSSc-RA: SSc associated with limited scleroderma and rheumatoid arthritis; lSSc-SjS: SSc associated with limited scleroderma and Sjogren syndrome; RF: rheumatoid factor; pre-SSc: pre-scleroderma; SjS: Sjögren's syndrome; TSH: thyrotropin." ] ] 1 => 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" => "AMA: anti-mitochondrial antibodies; ANA: antinuclear antibodies; RA: rheumatoid arthritis; PBC: primary biliary cirrhosis; SD: standard deviation; SAD: systemic autoimmune disease; SSc: systemic sclerosis; lSSc: SSc with limited scleroderma; pre-SSc: systemic pre-scleroderma; SjS: Sjögren's syndrome." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC (No.=62) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Female, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">59 (94.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PBC diagnosis mean age, years (range, SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.96 (26–74.76; 10.26) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PBC asymptomatic at diagnosis, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38 (61.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Treatment with ursodeoxycholic acid, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55 (88.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liver biopsy diagnostic of PBC, n/No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47/55 (85.55) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Asymptomatic at PBC diagnosing, n/No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38/62 (61.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Alkaline phosphatase, U/L (mean, SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">302.08 (194.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total bilirubin, mg/dL (mean, SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.53 (0.28) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prothrombin time, ratio (mean, SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.99 (0.05) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AMA positive, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">46 (74.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Title >1/640, n/No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38/46 (84.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANA positive, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47 (75.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Speckled pattern, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17/47 (36.17) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Homogeneous pattern, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14/47 (29.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nucleolar pattern, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11/47 (23.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Peripheral pattern, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5/47 (10.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Centromeric pattern \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12/47 (25.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Associated SAD n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 (35.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SSc, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 (21) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">lSSc n (%)/pre-SSc, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (11)/6 (9.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SjS, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (11) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RA, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (6.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SAD diagnosis average age, years (range, SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55.70 (36.35–79.03; 10.49) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Previous SAD diagnosis n/No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12/22 (54.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Average time between SAD-PBC, years (range, SSD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.9 (0.05–20.6, 5.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1053358.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Epidemiological data and clinical characteristics of the cohort of patients with PBC." ] ] 2 => 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" => "PBC: primary biliary cirrhosis; PBC-SAD: PBC with associated SAD; PBC-no SAD: PBC without associated SAD; SAD: systemic autoimmune disease; ILD: interstitial lung disease; PHT: pulmonary hypertension; GOR: gastro-oesophageal reflux." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC (No.=62) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-no SAD (No.=40) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-SAD (No.=22) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Extrahepatic symptoms, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">51 (82.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29 (72.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.009 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Raynaud's phenomenon, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 (29) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (7.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 (68) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Digital ulcers, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (4.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (13.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.035 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sclerodactyly, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (4.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (13.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.035 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Telangiectasia, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 (14.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 (31.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.003 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Calcinosis, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (3.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sicca syndrome, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32 (51.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17 (42.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 (68) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.025 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gastrointestinal disease, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35 (56.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">23 (57.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 (54.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GOR, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26 (42) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17 (42.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 (41) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dyspnoea, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 (24.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (12.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (45.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.002 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ILD, n/No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (13.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PHT, n/No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Arthritis, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (16.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (2.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 (41) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Heart disease (n, %) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (6.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kidney disease (n, %) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (2.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (4.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pathological capillaroscopy, n/No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27/54 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/6 (0.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16/20 (80) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Non-specific pattern, n/No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16/54 (29.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/34 (29.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6/20 (30) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Scleroderma pattern, n/No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11/54 (20.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1/34 (2.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/20 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">“Slow pattern” \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9/11 (81.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1/1 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8/10 (80) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">“Active pattern” \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/11 (18) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/10 (20) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1053360.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Extrahepatic symptoms and signs at some point of the disease. Comparative study between groups." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ACA: centromere antibodies; ANA: antinuclear antibodies; AMA: anti-mitochondrial antibodies; RNA pol III: Anti-RNA polymerase antibodies III; PBC: primary biliary cirrhosis; PBC-SAD: PBC with SAD; PBC-SSc: PBC with associated SSc; PBC-no SAD: PBC without associated SAD; PBC-no SSc: PBC with an associated SAD other than SSc; SAD: systemic autoimmune disease; CCP: antipeptide cyclic citrullinated antibodies; SSc: systemic sclerosis; PDGFR: platelet derived growth factor receptor; Topo I: antitopoisomerase antibodies I; U1RNP: anti-U1 ribonucleoprotein antibodies; U3RNP: anti-fibrillarin antibodies." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Antinuclear antibodies directed against \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">4a. PBC (No.=62)</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">4b. PBC-SAD (No.=22)</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-no SAD (No.=40) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-SAD (No.=22) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-SSc (No.=13) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-no SSc (No.=9) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANA, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27 (67.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 (91) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (77.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AMA, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">31 (77.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 (68) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (61.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (77.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">S100, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 (20) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (22.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gp210, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (4.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (11.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Topo I, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ACA, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 (54.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 (92.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CENP-A/B, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/2 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/12 (83) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (83) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RNA-pol III (RP 11, RP 155), n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">U3RNP (fibrillarin), n/No. (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (4.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (7.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NOR90, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Th/To, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (2.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pm-Scl (100, 75), n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ku, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PDGFR, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ro52, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 (32.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 (36.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (23) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (55.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">U1RNP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (2.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sm, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ro60, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (12.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (22.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (7.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (44.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">La, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CCP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/13 (15) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (22) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1053359.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Immunological study results and comparative analysis between groups: 4a PBC-no SAD group vs. PBC-SAD; 4b. PBC-SSc group vs. PBC-no SSc." ] ] 4 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ANA: antinuclear antibodies; RA: rheumatoid arthritis; PBC: primary biliary cirrhosis; SAD: systemic autoimmune disease; MCTD: mixed connective tissue disease; SSc systemic sclerosis; SLE: systemic lupus erythematosus; PM: polymyositis; SjS: primary Sjögren's syndrome." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC, No. \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ANA, n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SAD, n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SSc, n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Raynaud's phenomenon, n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sicca syndrome, n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Others, n (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clarcke et al.<a class="elsevierStyleCrossRef" href="#bib0195">1</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (9.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23 (27.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (9.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Makinen et al.<a class="elsevierStyleCrossRef" href="#bib0220">6</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">37 (77) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (19) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Modena et al.<a class="elsevierStyleCrossRef" href="#bib0200">2</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 (53.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 (61.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (30.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (27) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 (27) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Marasini et al.<a class="elsevierStyleCrossRef" href="#bib0205">3</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">170 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">96 (56.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47 (27.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33 (19.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54 (31.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (3.5) SjS 3 (1.7) RA 3 (1.7) SLE 1 (0.5) MCTD 1 (0.5) PM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Watts et al.<a class="elsevierStyleCrossRef" href="#bib0345">31</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">160 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 (11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">84 (53) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 (8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38 (24) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33 (21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 (25) SjS 12 (17) RA 2 (1) SLE \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wang et al.<a class="elsevierStyleCrossRef" href="#bib0215">5</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">322 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">275 (85) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">150 (46.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (2.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">64 (20) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">112 (35) SjS 9 (2.8) RA 12 (3.7) SLE 10 (3.1) PM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mari et al. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">62 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47 (75.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21 (33.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 (19.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 (29) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32 (51.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (9.6) SjS 3 (4.8) RA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tovoli et al.<a class="elsevierStyleCrossRef" href="#bib0365">35</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42 (52.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 (18.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 (22.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total, n/No. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">951 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">537 (56.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">341 (35.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">106 (11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14/21 (0.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14/21 (0.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1053357.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Comparison of SAD and SSC prevalence in different PBC series." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:38 [ 0 => array:3 [ "identificador" => "bib0195" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rheumatic disorders in primary biliary cirrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A.K. 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Original article

Prognostic implications of extra-hepatic clinical manifestations, autoimmunity and microscopic nail capillaroscopy in patients with primary biliary cirrhosis

Implicación pronóstica de las manifestaciones clínicas extrahepáticas, autoinmunidad y capilaroscopia ungueal microscópica en pacientes con cirrosis biliar primaria

Begoña Marí-Alfonsoa,

Corresponding author

bmari@tauli.cat

Corresponding author.

, María José Amengual-Guedanb, Mercè Vergara-Gómezc, Carmen Pilar Simeón-Aznard, Vicente Fonollosa-Plàd, Esther Jove-Buxedaa, Juan Oliva-Morerae, Carles Tolosa-Vilellaa

a Servicio de Medicina Interna, Corporación Sanitaria y Universitaria Parc Tauli, Instituto Universitario Parc Taulí, Sabadell, Barcelona, Spain

b Servicio de Laboratorio de Inmunología, UDIAT, Corporación Sanitaria y Universitaria Parc Taulí, Instituto Universitario Parc Taulí, Universidad Autónoma de Barcelona (UAB), Sabadell, Barcelona, Spain

c Servicio de Hepatología, Corporación Sanitaria y Universitaria Parc Taulí, Instituto Universitario Parc Taulí, Universidad Autónoma de Barcelona (UAB), Sabadell, Barcelona, Spain

d Servicio de Medicina Interna, Hospital Universitario Vall d’Hebrón, Barcelona, Spain

e Unidad de Estadística, Fundación Parc Taulí, Corporación Sanitaria y Universitaria Parc Taulí, Instituto Universitario Parc Taulí, Universidad Autónoma de Barcelona (UAB), Sabadell, Barcelona, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Primary biliary cirrhosis &#40;PBC&#41; is a chronic cholestatic disease characterized by inflammation and destruction of small and medium calibre bile ducts and deposition of fibrotic tissue with a progressive course that can cause liver failure&#46; The aetiology is unknown&#44; but the most accepted is the autoimmune hypothesis since the PBC is often associated with other autoimmune diseases or is accompanied by non-organ specific autoantibodies&#46; Some studies show that systemic sclerosis &#40;SSc&#41; is the systemic autoimmune disease &#40;SAD&#41; most frequently associated with PBC&#44; in particular&#44; the limited cutaneous subtype &#40;3&#8211;50&#37; of cases&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">1&#8211;5</span></a> Thus&#44; anti-centromere antibodies &#40;ACA&#41;&#44; specific of SSc and&#47;or microvascular anomalies suggestive of SSc can be detected through microscopic nailfold capillaroscopy &#40;capillaroscopy from now on&#41;&#44; in 30&#37; and 42&#37; of patients with PBC&#44; respectively&#46; In some studies&#44; their presence has been linked to a higher incidence of symptoms and&#47;or signs suggestive of SAD&#44; Raynaud&#39;s phenomenon in particular&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">6&#8211;10</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Some authors have indicated that PBC and SSc are associated with increased morbidity and mortality compared to the general population&#46; However&#44; at present&#44; it remains a controversial claim&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">11&#44;12</span></a> Recent prospective studies that compare patients with PBC and SSc and patients with isolated PBC&#44; adjusted for total bilirubin figures&#44; show a similar mortality in both groups&#46; In patients with associated SSc&#44; death causes are related to SSc&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">13</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">SSc is characterized by the appearance of microvascular damage&#44; excessive accumulation of collagen fibres in the skin and internal organs&#44; and an inappropriate autoimmune response directed against multiple cellular antigens&#46; Currently&#44; the main prognostic factor for SSc is the extension of cutaneous sclerosis&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">14</span></a> why most disease experts continue to use the classification proposed by LeRoy et al&#46;&#44; 1988&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">15</span></a> In it&#44; there are 2 large groups of patients with SSc&#44; the subtype SSc with limited scleroderma &#40;lSSc&#41;&#44; and the SSc subtype with diffuse scleroderma&#46; However&#44; there is a significant number of patients with unobvious SSc clinical manifestations which are diagnosed late&#46; Most of these patients belong to the group with limited SSc&#44; with little or no cutaneous sclerosis&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">16</span></a> and a group of patients with pre-scleroderma &#40;pre-SSc&#41;&#44; defined according to the classification criteria proposed by LeRoy and Medsger of 2001&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">17</span></a> The latter group with a high probability of developing into established SSc&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">18</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The main objective of this study is to determine the prevalence of associated SAD&#44; particularly SSc&#44; in a cohort of patients with PBC&#46; Secondary objectives investigated are whether patients with PBC associated with a SAD have a specific clinical and biological profile when compared to patients with isolated PBC&#44; as well as the possible prognostic factors related to the association of both autoimmune diseases&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">This is an observational study conducted in the Corporaci&#243;n Sanitaria Universitaria Parc Taul&#237;&#44; Sabadell &#40;Barcelona&#41;&#44; with a population catchment area of 430&#44;000 inhabitants&#46; During the study period&#44; from January 1990 to December 2011&#44; 94 patients were identified with the diagnosis of PBC&#44; 62 of which met the following inclusion criteria&#58; &#40;1&#41; diagnosis of PBC&#44; according to the criteria of the <span class="elsevierStyleItalic">American Association of the Study of Liver Diseases</span><a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">19&#44;20</span></a>&#59; &#40;2&#41; 18 years of age or over&#59; &#40;3&#41; current clinical follow-up by the Hepatology Unit and &#40;4&#41; signed informed consent to participate in the study&#46; 32 patients were excluded for the following reasons&#58; death prior to the start of the study&#44; chronic liver disease of toxic or infectious origin associated with PBC and any reason that would hinder completion of the study protocol&#44; which is detailed in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46; The project was approved by the Clinical Research Ethics Committee of the Hospital de Sabadell&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The study protocol included a single medical visit in which the history and physical examination aimed at detecting symptoms and signs suggestive of extrahepatic SAD and capillaroscopy was performed&#46; After the inclusion of patients in the study&#44; serum samples from one of the regular blood tests requested by the physicians responsible for the patients at the Hepatology Unit were identified&#46; The serum aliquots obtained were frozen at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C until their biochemical and immunological study&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Definition of clinical manifestations</span><p id="par0035" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Peripheral vascular manifestations</span>&#58; presence of Raynaud&#39;s phenomenon&#44; with or without digital ulcers or residual scarring ischaemic lesions in fingertips or acroosteolysis&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">21</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Cutaneous manifestations</span>&#58; presence of sclerodactyly&#44; telangiectasia and skin calcinosis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Sicca syndrome</span>&#58; it was assessed when the patients reported ocular or oral dryness spontaneously&#44; with or without ocular signs or hyposecretion in the Schirmer test or salivary scintigraphy&#44; unrelated to the intake of hyposecretion-inducing drugs and considered disproportionate by their doctor&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">21</span></a></p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Gastrointestinal disease</span>&#58; the following diagnoses were considered as gastrointestinal disease associated with SSc&#58; <span class="elsevierStyleItalic">oesophageal disease</span>&#44; if hypomotility of the 2 lower thirds of the oesophagus was confirmed by manometry&#59; <span class="elsevierStyleItalic">gastric disease</span>&#44; if gastric hypomotility was detected by barium examination or manometry&#59; <span class="elsevierStyleItalic">intestinal disease</span>&#44; if intestinal hypomotility is demonstrated by manometry&#44; malabsorption syndrome by breath test or intestinal pseudo-obstruction by radiography or computed tomography&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">21&#44;22</span></a> The presence of gastroesophageal reflux together with consistent symptoms&#44; with or without specific diagnostic tests&#44; was considered&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Lung disease</span>&#58; defined by the presence of pulmonary hypertension &#40;PHT&#41; or interstitial lung disease &#40;ILD&#41;&#46; ILD was diagnosed in the following situations&#58; &#40;1&#41; pulmonary restrictive pattern in pulmonary function tests&#44; with a forced vital capacity &#40;FVC&#41;<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>80&#37; of the expected value and &#40;2&#41; pulmonary interstitial pattern confirmed by an X-ray or high-resolution chest CT scan&#59; and&#47;or &#40;3&#41; alveolitis confirmed by bronchoalveolar lavage without evidence of germs&#46; The diagnosis of pulmonary hypertension was established when pulmonary arterial systolic pressure estimated by Doppler echocardiography was &#62;40<span class="elsevierStyleHsp" style=""></span>mmHg or mean pulmonary arterial pressure by right heart catheterization&#44; was &#8805;25<span class="elsevierStyleHsp" style=""></span>mmHg&#46; When the PHT was not related to ILD&#44; or it was mild&#44; with a FVC &#62;70&#37; and the pulmonary capillary wedge pressure was &#60;15<span class="elsevierStyleHsp" style=""></span>mmHg&#44;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">21&#44;22</span></a> it was then considered pulmonary arterial hypertension&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Joint disease</span>&#58; if there were arthralgia or arthritis and&#47;or tendon friction&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">21&#44;22</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Heart disease</span>&#58; identification of any of the following conditions&#58; pericarditis&#44; ischaemic heart disease with no other obvious aetiology&#44; electrocardiographic changes or anomalies in myocardial contractility&#44; ejection fraction of the left ventricle &#60;55&#37; detected by colour Doppler echocardiogram or radionuclide ventriculography&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">21&#44;22</span></a></p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Kidney disease</span>&#58; the presence of renal damage secondary to SAD was considered when there was evidence of proteinuria &#62;500<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h or decreased estimated glomerular filtration rate &#60;60<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> during &#8805;3 months in the absence of another aetiology&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">23</span></a></p></li></ul></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Capillaroscopy</span><p id="par0080" class="elsevierStylePara elsevierViewall">A systematic study of the first capillary line of the nailfold in fingers 2&#8211;5 in both hands was performed&#44; according to the validated semiquantitative method of Maricq&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">24</span></a> through a Zuzi<span class="elsevierStyleSup">&#174;</span> Ura Technic Series 234 stereomicroscope &#40;Navarra&#44; Spain&#41; with a cold halogen lamp and a USB 1&#46;3 Mp high resolution camcorder&#44; equipped with capture and image analysis <span class="elsevierStyleItalic">software</span> with up to 200&#215; magnification&#46; Patients were classified into one of the following capillaroscopic patterns&#58; &#40;1&#41; <span class="elsevierStyleItalic">normal pattern</span>&#58; no significant capillary changes&#44; &#40;2&#41; <span class="elsevierStyleItalic">non-specific pattern</span>&#58; with inconclusive capillary anomalies of scleroderma and &#40;3&#41; <span class="elsevierStyleItalic">SSc pattern</span>&#58; capillary bed changes are suggestive of SSc according to the Maricq et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">25</span></a> classification criteria&#44; grouped into two patterns&#58; &#40;a&#41; <span class="elsevierStyleItalic">slow pattern</span>&#58; predominance of capillary dilations with a diameter greater than 4 normal capillary diameters or the presence of mega-capillaries&#44; with minimal or no capillary loss&#59; &#40;b&#41; <span class="elsevierStyleItalic">active pattern</span>&#58; moderate to severe capillary loss and disorganization of the capillary bed that predominates over capillary dilation and&#47;or mega-capillaries&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Immunological study</span><p id="par0085" class="elsevierStylePara elsevierViewall">Determination of antinuclear &#40;ANA&#41; and anticytoplasmic autoantibodies was performed by indirect immunofluorescence with combined HEp-2 cell slides and triple rat tissue &#40;liver&#44; stomach and kidney&#41;&#46; For confirmation of the specificities of autoantibodies related to liver disease a Dot blotting was performed by nitrocellulose specific strips with the antigen of interest &#40;M2&#44; LKM&#44; LC1&#44; SLA&#44; Sp100&#44; gp120&#44; F-actin&#41; &#40;D-Tek&#44; Mons&#44; Belgium&#41;&#46; The determination of SSc specific antibodies was performed using nitrocellulose specific strips with the antigens of interest&#44; different native &#40;topoisomerase&#41; or recombinant proteins &#40;CENP-A&#44; CENP-B&#44; RP11&#44; RP155&#44; fibrillarin&#44; NOR90&#44; Th&#47;To&#44; PM-Scl 100&#44; PM-Scl 75&#44; Ku&#44; platelet growth factor receptor and Ro-52&#41; &#40;Euroinmun&#44; Lubeck&#44; Germany&#41;&#46; Finally&#44; the determination of antibodies to extractable nuclear antigens and citrullinated cyclic peptides was performed by fluorescent enzyme immunoassay in a ImmunoCAP 250<span class="elsevierStyleSup">&#174;</span> autoanalyzer &#40;Thermo Fisher Scientific &#40;Phadia&#41;&#44; Waltham&#44; MA&#44; USA&#41;&#44; which allowed the analysis of the U1RNP&#44; Sm&#44; SSA&#47;Ro&#44; SSB&#47;La specificities&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Patient classification</span><p id="par0090" class="elsevierStylePara elsevierViewall">After completing the study&#44; patients with PBC were grouped according to their association &#40;PBC-SAD&#41; or not &#40;PBC-no SAD&#41; to a SAD&#44; according to the <span class="elsevierStyleItalic">American College of Rheumatology</span> classification criteria for systemic lupus erythematosus&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">26</span></a> Sjogren&#39;s syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">27</span></a> rheumatoid arthritis&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">28</span></a> polymyositis&#47;dermatomyositis<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">29</span></a> and mixed connective tissue disease&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">30</span></a> A modification of LeRoy and Medsger 2001 classification criteria<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">16</span></a> was used for the diagnosis of SSc&#44; in which 4 clinical subtypes are distinguished&#44; depending on skin extension and organ involvement&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0095" class="elsevierStylePara elsevierViewall">Pre-SSc&#58; defined by the presence of Raynaud&#39;s phenomenon and capillaroscopy pattern suggestive of SSc and&#47;or presence of SSc specific autoantibodies&#44; without established skin or organic disease of SSc&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0100" class="elsevierStylePara elsevierViewall">SSc with lSSc&#58; patients with distal cutaneous sclerosis in elbows and knees&#44; with or without facial sclerosis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">-</span><p id="par0105" class="elsevierStylePara elsevierViewall">SSc with diffuse scleroderma&#58; patients with distal and proximal elbow and knee sclerosis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">SSc <span class="elsevierStyleItalic">sine scleroderma</span>&#58; defined by the presence of Raynaud&#39;s phenomenon or equivalent vascular disease &#40;digital ulcers&#44; scarring lesions of ischaemic origin in fingertips or acroosteolysis&#41;&#44; antinuclear antibodies and organic condition typical of SSc &#40;hypomotility in the digestive tract&#44; ILD&#44; PHT&#44; heart disease or scleroderma renal crisis&#41;&#44; without skin sclerosis&#46;</p></li></ul></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistic analysis</span><p id="par0115" class="elsevierStylePara elsevierViewall">A descriptive study of all variables collected was performed&#46; The qualitative variables were described by absolute and relative frequency&#44; and quantitative variables by mean&#44; standard deviation&#44; percentiles 25&#44; 50 and 75 and minimum and maximum range&#46; Chi square test was used for the bivariate analysis&#46; The level of bilateral significance has been set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; For the statistical study&#44; the SPSS v19 programme was used&#44; <span class="elsevierStyleItalic">software</span> for Windows<span class="elsevierStyleSup">&#174;</span> &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><p id="par0120" class="elsevierStylePara elsevierViewall">Sixty-two patients with PBC met the study inclusion criteria&#44; of whom 59 were women &#40;95&#46;2&#37;&#41;&#46; The average age of the cohort at the time of PBC diagnosis was 53&#46;9 years &#40;range&#58; 26&#8211;74&#46;7&#41;&#44; with a mean age at study inclusion of 62&#46;8 years &#40;range&#58; 29&#46;8&#8211;88&#46;7&#41; and a median follow-up of chronic liver disease of 8&#46;9 years &#40;P25<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;8 and P75<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#46;5&#41;&#46; Liver biopsy was performed in 55 patients and showed PBC findings in 47 of them &#40;85&#46;5&#37;&#41;&#46; Thirty-eight of the 62 patients &#40;61&#46;3&#37;&#41; were asymptomatic at the time of diagnosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">The main extrahepatic symptoms collected in the study are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; Fifty-one patients &#40;82&#46;2&#37;&#41; reported some symptoms suggestive of SAD with a median time from first symptom onset and PBC diagnosis of 8&#46;5 years &#40;P25<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;3&#59; P75<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#41;&#46; Sicca syndrome and gastroesophageal reflux were the most common extrahepatic symptoms&#44; present in 32 &#40;51&#46;6&#37;&#41; and 26 &#40;42&#37;&#41; patients&#44; respectively&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">Regarding symptoms suggestive of SSc&#44; 18 patients &#40;29&#37;&#41; reported Raynaud&#39;s phenomenon&#46; Digital ulcers&#44; sclerodactyly and skin calcinosis were present in a small number of patients&#44; 3 &#40;4&#46;8&#37;&#41;&#44; 3 &#40;4&#46;8&#37;&#41; and 2 &#40;3&#46;2&#37;&#41;&#44; respectively&#46; The only respiratory symptom&#44; reported by 15 patients &#40;24&#46;2&#37;&#41;&#44; was dyspnoea&#44; a functional class I&#47;II according to the NYHA&#46; A chest X-ray study was completed in 14 of them&#44; finding an interstitial pulmonary pattern in 5 &#40;35&#46;7&#37;&#41;&#46; The respiratory functional study in 13 patients found a restrictive pattern&#44; with a FVC &#60;80&#37; in 3 of them &#40;23&#37;&#41;&#46; A Doppler echocardiography&#44; available in 9 patients&#44; estimated a systolic pulmonary arterial pressure &#62;40<span class="elsevierStyleHsp" style=""></span>mmHg in 2 patients &#40;22&#46;2&#37;&#41; and pulmonary hypertension confirmed by right heart catheterization in one patient&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Capillaroscopy was not assessable in 8 patients &#40;12&#46;9&#37;&#41;&#44; due to poor visualization of the vascular bed&#44; but a valuable study was possible in 54 patients &#40;87&#46;1&#37;&#41;&#46; Morphological anomalies of the capillary bed were observed in 27 studies &#40;50&#37;&#41; with detection of capillary dilations in 20 patients &#40;37&#37;&#41; and vascular leakage&#44; focal or diffuse in 11 &#40;20&#46;3&#37;&#41;&#46; The capillaroscopic pattern was suggestive of SSc in 11 of them &#40;40&#46;7&#37;&#41;&#44; with a slow pattern in 9 patients &#40;33&#46;3&#37;&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Finally&#44; ANA was identified in 47 patients &#40;75&#46;8&#37;&#41; with PBC &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; The ACA were positive in 14 patients &#40;22&#46;6&#37;&#41;&#44; all directed against antigens CENP-A&#47;B&#44; and other SSc typical antibodies were identified in 9 patients &#40;14&#46;5&#37;&#41;&#46; Four of these patients &#40;57&#37;&#41;&#44; also referred some extrahepatic symptoms &#40;3 sicca syndrome&#44; one Raynaud&#39;s phenomenon&#41;&#59; 2 with a normal capillaroscopy pattern &#40;50&#37;&#41;&#44; one non-specific pattern &#40;25&#37;&#41; and one non-assessable pattern &#40;25&#37;&#41;&#46; Anti-Ro52 antibodies were identified in 21 patients &#40;33&#46;9&#37;&#41; and anti-Ro60 in 10 &#40;16&#46;1&#37;&#41; and the determination of cyclic citrullinated peptide performed in 50 patients was positive in 2 of them &#40;3&#46;2&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Characteristics of patients with primary biliary cirrhosis with systemic autoimmune disease</span><p id="par0145" class="elsevierStylePara elsevierViewall">After completing the study protocol&#44; patients were assigned to two groups&#46; Group 1&#58; PBC associated with a SAD &#40;PBC-SAD&#41;&#44; consisting of 22 patients and group 2&#58; PBC not associated with a SAD &#40;PBC-no SAD&#41;&#44; consisting of 40 patients&#46; The SAD started before the diagnosis of PBC in 12 cases &#40;19&#46;3&#37;&#41; with a mean age at diagnosis of 55&#46;7 years &#40;range 36&#46;3&#8211;79&#46;0&#41; and median time between diagnosis of 1&#46;9 years &#40;range&#58; 0&#46;05&#8211;20&#46;58 years&#41;&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">SSc was the SAD more frequently associated with PBC&#44; diagnosed in 13 patients &#40;21&#37;&#41;&#44; 7 of the lSSc subtype and 6 pre-SSc&#46; Other SAD associated with PBC were Sj&#246;gren&#39;s syndrome in 7 cases &#40;11&#37;&#41; and rheumatoid arthritis in 4 cases &#40;6&#46;4&#37;&#41;&#46; Two of these patients had overlap syndromes&#44; one lSSc and Sj&#246;gren&#39;s syndrome and one lSSc and rheumatoid arthritis&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Five patients &#40;8&#37;&#41; with pre-SSc were diagnosed after completing the study protocol and 2 of them developed lSSc at 7 and 8 months of study entry&#46; Of the remaining patients in whom a specific SSc antibody was detected other than ACA&#44; none met the diagnostic criteria for SSc&#46; Patients with pre-SSc were included in the PBC-SAD group for comparative group analysis&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Capillaroscopy anomalies were observed in 16 out of the 20 patients in the PBC-SAD group &#40;80&#37;&#41; with assessable study&#46; The pattern was suggestive of SSc in 10 of them &#40;50&#37;&#41;&#44; 8 slow pattern &#40;80&#37;&#41; and 2 active pattern &#40;20&#37;&#41;&#46; In 6 patients &#40;30&#37;&#41;&#44; 3 had rheumatoid arthritis &#40;30&#37;&#41;&#44; 2 with SSc &#40;10&#37;&#41;&#44; and one with Sj&#246;gren syndrome &#40;5&#37;&#41;&#44; the capillaroscopic pattern was unspecific&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">In the bivariate study &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; the characteristics of the 22 patients with PBC-SAD were compared to 40 patients with PBC-no SAD&#46; Patients with PBC-SAD had extrahepatic symptoms more often &#40;100 vs&#46; 72&#46;5&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;009&#41;&#44; especially the sicca syndrome &#40;68 vs&#46; 42&#46;5&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;025&#41;&#44; Raynaud&#39;s phenomenon &#40;68 vs&#46; 7&#46;5&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; telangiectasia &#40;31&#46;8 vs&#46; 5&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#44; arthritis &#40;41 vs&#46; 2&#46;5&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and dyspnoea &#40;45&#46;4 vs&#46; 12&#46;5&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#46; ACA positivity &#40;54&#46;5 vs&#46; 5&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; was the only immune finding&#44; most common in patients with PBC-SAD&#46; No significant differences in the rest of antigenic specificities were observed&#44; although it the high prevalence of anti-Ro52 and anti-Ro60 antibodies in both groups was remarkable&#58; in 8 &#40;36&#46;3&#37;&#41; and 5 &#40;22&#46;7&#37;&#41; patients in PBC-SAD group and in 13 &#40;32&#46;5&#37;&#41; and 5 &#40;12&#46;5&#37;&#41; in PBC-no SAD group&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">A higher incidence of microvascular anomalies was observed in the PBC-SAD group compared to the PBC-no SAD group &#40;81 vs&#46; 33&#46;3&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; capillary dilations in particular &#40;75 vs&#46; 14&#46;7&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; mega-capillaries &#40;40 vs&#46; 2&#46;9&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; bleeding &#40;25 vs&#46; 2&#46;9&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41; and vascular leakage &#40;50 vs&#46; 2&#46;9&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; which shows a higher incidence of capillaroscopic pattern suggestive of SSc &#40;47&#46;6 vs&#46; 3&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; in these patients&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Severe disease criteria</span><p id="par0175" class="elsevierStylePara elsevierViewall">At the end of the study&#44; 10 patients &#40;16&#46;1&#37;&#41; of the PBC cohort met clinical and&#47;or ultrasound criteria for liver cirrhosis&#44; 3 of the PBC-SAD group and 7 of the PBC-no SAD group &#40;13&#46;6 vs&#46; 17&#46;5&#37;&#59; <span class="elsevierStyleItalic">p</span>&#58; ns&#41;&#46; All of them were in a Child&#8211;Pugh A stage&#44; except one patient of the PBC-no SAD group who was in Child&#8211;Pugh B stage&#46; No differences were found in the levels of total bilirubin&#46; Of the PBC-SAD group patients&#44; 2 were associated with Sj&#246;gren&#39;s syndrome and one with rheumatoid arthritis&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0180" class="elsevierStylePara elsevierViewall">The study protocol applied to this cohort of 62 patients with PBC has identified a SAD prevalence of 35&#46;4&#37;&#46; The SSc was the most common SAD&#44; identified in 21&#37; of patients&#44; followed by Sj&#246;gren&#39;s syndrome and rheumatoid arthritis in 11&#46;3&#37; and 6&#46;4&#37;&#44; respectively&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Patients with PBC-SAD had a higher incidence of extrahepatic clinical manifestations such as sicca syndrome&#44; Raynaud&#39;s phenomenon&#44; telangiectasia&#44; arthritis and dyspnoea&#44; as well as greater association with ACA and morphological capillary changes suggestive of SSc&#46; At the end of the study&#44; 5 patients &#40;8&#37;&#41; with PBC were classified as pre-SSc&#44; not previously diagnosed&#44; as Raynaud&#39;s phenomenon and SSc specific antibodies were observed in them &#40;4 ACA&#44; one anti-U3RNP&#41;&#44; plus a pattern of slow capillaroscopy&#44; suggestive of SSc&#44; in 4 cases&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">The prevalence of SAD&#44; especially SSc&#44; in this cohort of patients with PBC is similar to that described by Marasini et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">3</span></a> &#40;27&#46;6&#37; and 19&#46;4&#37;&#44; respectively&#41;&#44; applying a classification criteria similar to this study&#46; However&#44; other methodologically different series&#44; such as Modena et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">2</span></a> &#40;61&#46;5&#37; and 30&#46;7&#37;&#41;&#44; Watts et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">31</span></a> &#40;53&#37; and 8&#37;&#41; and Wang et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">5</span></a> &#40;46&#46;6&#37; and 2&#46;8&#37;&#41; obtained divergent results &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; The high percentage of SAD identified in some series is probably due to the large number of patients classified as Sj&#246;gren&#39;s syndrome&#44; which reaches 25&#37; in Watts et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">31</span></a> and 35&#37; in Wang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">5</span></a> However&#44; if a positive immunology was required for diagnosing Sj&#246;gren&#39;s syndrome&#44; the prevalence decreased to 4&#37;&#44; similar to this cohort&#44; which also included a 47&#8211;70&#37; of patients with sicca syndrome&#44; particularly in the PBC-SAD group&#46; In PBC patients&#44; sicca syndrome is frequently associated with milder glandular symptoms when compared to patients with primary Sj&#246;gren&#39;s syndrome and absence of serum antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">32</span></a> In this sense&#44; only patients with glandular dryness and presence of anti-Ro and&#47;or anti-La autoantibodies should be considered as associated with PBC&#44; according to the criteria used in the study cohort&#46; Moreover&#44; the low prevalence of SSc &#40;2&#46;8&#8211;8&#37;&#41; diagnosed in the Watts et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">31</span></a> and Wang et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">5</span></a> series is probably related to the use of the ACR preliminary classification criteria for SSc&#44; of 1980&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">33</span></a> 20&#8211;30&#37; of patients with lSSc do not meet these classification criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">21</span></a> Two recent prospective studies have shown a SSc prevalence of 18&#46;8&#8211;23&#37; &#40;4&#8211;19&#37; lSSc and 4&#8211;12&#46;5&#37; pre-SSc&#41; in patients with PBC&#46; In both series&#44; 22&#37; of the patients reported Raynaud&#39;s phenomenon&#44; a capillaroscopy pattern suggestive of SSc was visualized in 18&#37; and anti-CENP-B antibodies were identified in 18&#37;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">34&#44;35</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; Other SSc specific antibodies such as anti-Th&#47;To and anti-RNA-pol III were positive in 9&#37; and 4&#37; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">34</span></a> These authors used the classification criteria of LeRoy and Medsger 2001&#44; as in the present cohort&#46; Other characteristics&#44; such as sex&#44; mean age and time of progression of the PBC&#44; were also similar to our cohort&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">In the immunological study&#44; ANA and ACA prevalence was found similar to other series&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">3&#44;6&#44;7</span></a> All patients with ACA were SSc of the PBC-SAD group&#46; Unlike Joyal et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">34</span></a> other SSc specific antibodies were detected &#40;anti-RNA-pol III&#44; anti-U3RNP&#44; anti-NOR90 or anti-Th&#47;To&#41; in 9&#46;6&#37; of patients with PBC&#44; although without clinical manifestations or microvascular anomalies suggestive of SSc which would allow diagnosis confirmation&#46; A single patient with anti-U3RNP antibodies&#44; not previously diagnosed with SAD&#44; was classified as pre-SSc when showing Raynaud&#39;s phenomenon&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Although PBC patients have a high incidence of unspecific capillary morphological anomalies when compared to patients with other liver diseases&#44; the finding of a capillary pattern suggestive of SSc is associated with the presence of ACA and&#47;or manifestations suggestive of SSc in 20&#8211;75&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">9&#44;10</span></a> A SSc pattern was visualized in the present study&#59; this was mostly a slow pattern&#44; in 20&#46;4&#37; of patients with PBC and&#44; in 90&#37; of cases&#44; it corresponded to patients with PBC-SAD&#46; These results support the usefulness of capillaroscopy as a diagnostic tool to discriminate patients with PBC&#44; according to their association to a SAD or lack of it&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">In this study&#44; the incidence of PBC patients treated with ursodeoxycholic acid was high and similar to other series&#46; It is well known that this drug has managed to slow the progression to liver failure and has significantly improved survival&#44; getting close to that of the general population&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">36</span></a> This may explain that the incidence of liver failure at 9 years of median follow-up of this PBC cohort is very low and similar for both groups&#44; PBC-SAD and PBC-no SAD&#46; Rigamonti et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">13</span></a> and Joyal et al&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">34</span></a> have suggested that liver disease is milder and has a slower progression to liver failure in patients with PBC associated with SSc and ACA&#46; However&#44; although in the Rigamonti et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">13</span></a> series&#44; the mortality of patients with isolated PBC and associated with SSc was similar&#44; in the second group&#44; the mortality was related to organ dysfunction associated with systemic disease&#46; Interestingly&#44; exertional dyspnoea affected a quarter of patients with PBC&#44; most of them from the PBC-SAD group and was associated with ILD in 80&#37; of patients&#46; Respiratory symptoms and the existence of ILD are common findings in patients with PBC&#44; up to 50&#37; and 15&#37; respectively&#44; especially when associated with Raynaud&#39;s phenomenon or a SAD&#44; such as SSc or Sj&#246;gren&#39;s syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">37&#44;38</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">The analysis of this PBC cohort has some limitations&#46; First&#44; the small sample size&#44; which makes it difficult to obtain significant differences in some outcomes that tend to be more frequent in patients with PBC-SAD and&#44; secondly&#44; the retrospective design of the study&#44; which has prevented to have all additional tests in order to correctly discriminate patients with pre-SSc and SSc <span class="elsevierStyleItalic">sine scleroderma</span>&#46; In some cases&#44; the follow-up period may be relatively short to identify all patients with SSc progression&#46; However&#44; this protocoled study identified an incidence of PBC associated to SAD of 35&#46;4&#37;&#44; which in most cases is a SSc&#46; This data reinforces the importance of a study aimed at identifying a SAD and not be limited to a liver function assessment&#46; Patients with PBC-SAD often have extrahepatic manifestations such as Raynaud&#39;s phenomenon&#44; sicca syndrome&#44; telangiectasia&#44; arthritis and dyspnoea&#44; as well as a significant ACA association and microvascular anomalies suggestive of SSc&#44; which can be predictors of the association of both diseases&#46; It is noteworthy that 8&#37; of patients were classified as previously undiagnosed pre-SSc and that some SSc developed during follow-up&#46; Therefore&#44; in patients with PBC&#44; it is recommended to perform a systemic evaluation that includes a thorough case history and specific physical examination&#44; as well as the determination of an appropriate immunological profile&#46; A capillaroscopy should also be performed&#44; allowing an early identification of the existence of any SAD&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interest</span><p id="par0215" class="elsevierStylePara elsevierViewall">Neither the microscopic nailfold capillaroscopy&#44; nor any other technique used in the study has been financed by the industry&#46; The authors declare no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Patients and methods"
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              "titulo" => "Definition of clinical manifestations"
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              "titulo" => "Capillaroscopy"
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              "identificador" => "sec0025"
              "titulo" => "Immunological study"
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          "titulo" => "Results"
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              "identificador" => "sec0045"
              "titulo" => "Characteristics of patients with primary biliary cirrhosis with systemic autoimmune disease"
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              "titulo" => "Severe disease criteria"
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    "fechaRecibido" => "2014-10-07"
    "fechaAceptado" => "2015-02-05"
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            0 => "Primary biliary cirrhosis"
            1 => "Systemic autoimmune disease"
            2 => "Autoimmunity"
            3 => "Capillaroscopy"
            4 => "Systemic sclerosis"
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            0 => "Cirrosis biliar primaria"
            1 => "Enfermedad autoinmune sist&#233;mica"
            2 => "Autoinmunidad"
            3 => "Capilaroscopia"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Primary biliary cirrhosis &#40;PBC&#41; is associated to any systemic autoimmune disease &#40;SAD&#41;&#44; in particular systemic sclerosis &#40;SSc&#41;&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To investigate the prevalence of SAD in a cohort of patients with PBC&#44; specifically the prevalence of SSc and its clinical subtypes&#44; and determining the clinical and biological profile of patients with associated PBC and SSc&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Observational study of 62 patients with PBC following a protocol that included an anamnesis and physical examination to detect the presence of SAD as well as a nailfold capillaroscopy and an immunological study with specific SSc autoantibodies&#46; A comparative analysis was conducted between patients with isolated PBC and patients with PBC and an associated SAD&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">SAD was associated to PBC in 22 patients &#40;35&#46;4&#37;&#41;&#44; and SSc was the most frequent illness&#44; identified in 13 cases &#40;21&#37;&#41;&#46; Five patients &#40;8&#37;&#41; without previous diagnosis of SAD fulfilled pre-scleroderma criteria&#44; according to LeRoy and Medsger criteria&#46; The presence of anticentromere antibodies &#40;54&#46;5&#37; vs&#46; 5&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; was the unique immunological determination identified more frequently in patients with PBC-SAD&#46; The SSc suggestive capillary pattern was visualized in 11 patients &#40;20&#46;4&#37;&#41;&#44; mainly the slow pattern&#46; No factors associated with greater morbi-mortality were identified in the PBC-SAD group&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">It does exist a subgroup of patients with PBC and clinical&#8211;biological features suggestive of an SAD&#44; which advise a protocolized study to detect early the association to an SAD&#46;</p></span>"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n y objetivos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La cirrosis biliar primaria &#40;CBP&#41; se asocia a algunas enfermedades autoinmunes sist&#233;micas &#40;EAS&#41;&#44; en particular a la esclerosis sist&#233;mica &#40;ES&#41;&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Determinar la prevalencia de EAS en una cohorte de pacientes con CBP&#44; espec&#237;ficamente la ES y sus diferentes subtipos cl&#237;nicos&#44; y establecer el perfil cl&#237;nico-biol&#243;gico propio de estos pacientes&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional de 62 pacientes con CBP&#44; con un protocolo que inclu&#237;a una anamnesis y exploraci&#243;n f&#237;sica dirigidas a detectar una EAS&#44; la realizaci&#243;n de una capilaroscopia ungueal microsc&#243;pica y un amplio estudio de autoinmunidad&#44; incluido el perfil de anticuerpos espec&#237;ficos de ES&#46; Se realiz&#243; un an&#225;lisis comparativo entre el grupo de pacientes con CBP aislada y los pacientes con CBP y una EAS asociada&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Se asoci&#243; una EAS en 22 pacientes &#40;35&#44;4&#37;&#41;&#44; y la ES fue la entidad m&#225;s frecuente &#40;21&#37;&#41;&#44; del subtipo cut&#225;neo limitado &#40;11&#37;&#41;&#46; Cinco pacientes &#40;8&#37;&#41; sin EAS previa cumpl&#237;an criterios de preesclerodermia&#44; seg&#250;n los criterios de LeRoy y Medsger&#46; Los anticuerpos anticentr&#243;mero &#40;54&#44;5 vs&#46; 5&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; fueron el &#250;nico par&#225;metro inmunol&#243;gico identificado con mayor frecuencia en pacientes con EAS&#46; El patr&#243;n capilar sugestivo de ES se visualiz&#243; en 11 pacientes &#40;20&#44;4&#37;&#41;&#46; No se identificaron factores asociados a mayor morbimortalidad en ning&#250;n grupo&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Existe un subgrupo de pacientes con CBP con caracter&#237;sticas cl&#237;nico-biol&#243;gicas que sugieren la asociaci&#243;n con una EAS&#44; con elevada probabilidad&#44; y que recomiendan el estudio protocolizado de estos pacientes con CBP para detectar de forma precoz EAS&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Introducci&#243;n y objetivos"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Mar&#237;-Alfonso B&#44; Amengual-Guedan MJ&#44; Vergara-G&#243;mez M&#44; Sime&#243;n-Aznar CP&#44; Fonollosa-Pl&#224; V&#44; Jove-Buxeda E&#44; et al&#46; Implicaci&#243;n pron&#243;stica de las manifestaciones cl&#237;nicas extrahep&#225;ticas&#44; autoinmunidad y capilaroscopia ungueal microsc&#243;pica en pacientes con cirrosis biliar primaria&#46; Med Clin &#40;Barc&#41;&#46; 2016&#59;146&#58;8&#8211;15&#46;</p>"
      ]
    ]
    "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" => 3137
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            "Tamanyo" => 312690
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Study protocol of patients with primary biliary cirrhosis&#46; ANA&#58; antinuclear antibodies&#59; RA&#58; rheumatoid arthritis&#59; PBC&#58; primary biliary cirrhosis&#59; PBC-SAD&#58; patients with PBC and associated SAD&#59; PBC-no SAD&#58; PBC patients without associated SAD&#59; CCP&#58; cyclic citrullinated anti-peptide antibody&#59; SAD&#58; systemic autoimmune disease&#59; ENA&#58; extractable nuclear antibody&#59; SSc&#58; systemic sclerosis&#59; lSSc&#58; SSc with limited scleroderma&#59; lSSc-RA&#58; SSc associated with limited scleroderma and rheumatoid arthritis&#59; lSSc-SjS&#58; SSc associated with limited scleroderma and Sjogren syndrome&#59; RF&#58; rheumatoid factor&#59; pre-SSc&#58; pre-scleroderma&#59; SjS&#58; Sj&#246;gren&#39;s syndrome&#59; TSH&#58; thyrotropin&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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            "identificador" => "at1"
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            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">AMA&#58; anti-mitochondrial antibodies&#59; ANA&#58; antinuclear antibodies&#59; RA&#58; rheumatoid arthritis&#59; PBC&#58; primary biliary cirrhosis&#59; SD&#58; standard deviation&#59; SAD&#58; systemic autoimmune disease&#59; SSc&#58; systemic sclerosis&#59; lSSc&#58; SSc with limited scleroderma&#59; pre-SSc&#58; systemic pre-scleroderma&#59; SjS&#58; Sj&#246;gren&#39;s syndrome&#46;</p>"
          "tablatextoimagen" => array:1 [
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                  <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="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC &#40;No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>62&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Female&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">59 &#40;94&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">PBC diagnosis mean age&#44; years &#40;range&#44; SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;96 &#40;26&#8211;74&#46;76&#59; 10&#46;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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">PBC asymptomatic at diagnosis&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38 &#40;61&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Treatment with ursodeoxycholic acid&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55 &#40;88&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Liver biopsy diagnostic of PBC&#44; n&#47;No&#46; &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&#47;55 &#40;85&#46;55&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Asymptomatic at PBC diagnosing&#44; n&#47;No&#46; &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&#47;62 &#40;61&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Alkaline phosphatase&#44; U&#47;L &#40;mean&#44; SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">302&#46;08 &#40;194&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Total bilirubin&#44; mg&#47;dL &#40;mean&#44; SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;53 &#40;0&#46;28&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Prothrombin time&#44; ratio &#40;mean&#44; SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;99 &#40;0&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">AMA positive&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">46 &#40;74&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Title &#62;1&#47;640&#44; <span class="elsevierStyleItalic">n</span>&#47;<span class="elsevierStyleItalic">No&#46;</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&#47;46 &#40;84&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">ANA positive&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47 &#40;75&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Speckled pattern&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&#47;47 &#40;36&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Homogeneous pattern&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#47;47 &#40;29&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nucleolar pattern&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&#47;47 &#40;23&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Peripheral pattern&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#47;47 &#40;10&#46;6&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Centromeric pattern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#47;47 &#40;25&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Associated SAD n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22 &#40;35&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>SSc&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13 &#40;21&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>lSSc n &#40;&#37;&#41;&#47;pre-SSc&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;11&#41;&#47;6 &#40;9&#46;6&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>SjS&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;11&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>RA&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;6&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">SAD diagnosis average age&#44; years &#40;range&#44; SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&#46;70 &#40;36&#46;35&#8211;79&#46;03&#59; 10&#46;49&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Previous SAD diagnosis n&#47;No&#46; &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#47;22 &#40;54&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Average time between SAD-PBC&#44; years &#40;range&#44; SSD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;9 &#40;0&#46;05&#8211;20&#46;6&#44; 5&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Epidemiological data and clinical characteristics of the cohort of patients with PBC&#46;</p>"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">PBC&#58; primary biliary cirrhosis&#59; PBC-SAD&#58; PBC with associated SAD&#59; PBC-no SAD&#58; PBC without associated SAD&#59; SAD&#58; systemic autoimmune disease&#59; ILD&#58; interstitial lung disease&#59; PHT&#58; pulmonary hypertension&#59; GOR&#58; gastro-oesophageal reflux&#46;</p>"
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                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="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC<br>&#40;No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>62&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-no SAD<br>&#40;No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-SAD<br>&#40;No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Extrahepatic symptoms&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">51 &#40;82&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;72&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;009&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Raynaud&#39;s phenomenon&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18 &#40;29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;7&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;68&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Digital ulcers&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;4&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;13&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;035&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sclerodactyly&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;4&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;13&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;035&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Telangiectasia&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;14&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7 &#40;31&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Calcinosis&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;3&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sicca syndrome&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32 &#40;51&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17 &#40;42&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;68&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;025&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Gastrointestinal disease&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35 &#40;56&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23 &#40;57&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 &#40;54&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">GOR&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26 &#40;42&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17 &#40;42&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;41&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Dyspnoea&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;24&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;12&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;45&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">ILD&#44; n&#47;No&#46; &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;13&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">PHT&#44; n&#47;No&#46; &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Arthritis&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;16&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;2&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;41&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Heart disease &#40;n&#44; &#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;6&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Kidney disease &#40;n&#44; &#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;2&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;4&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Pathological capillaroscopy&#44; n&#47;No&#46; &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27&#47;54 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;6 &#40;0&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#47;20 &#40;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Non-specific pattern&#44; n&#47;No&#46; &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#47;54 &#40;29&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;34 &#40;29&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#47;20 &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Scleroderma pattern&#44; n&#47;No&#46; &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#47;54 &#40;20&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;34 &#40;2&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;20 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8220;Slow pattern&#8221;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#47;11 &#40;81&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;1 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#47;10 &#40;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8220;Active pattern&#8221;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;11 &#40;18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;10 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">ACA&#58; centromere antibodies&#59; ANA&#58; antinuclear antibodies&#59; AMA&#58; anti-mitochondrial antibodies&#59; RNA pol III&#58; Anti-RNA polymerase antibodies III&#59; PBC&#58; primary biliary cirrhosis&#59; PBC-SAD&#58; PBC with SAD&#59; PBC-SSc&#58; PBC with associated SSc&#59; PBC-no SAD&#58; PBC without associated SAD&#59; PBC-no SSc&#58; PBC with an associated SAD other than SSc&#59; SAD&#58; systemic autoimmune disease&#59; CCP&#58; antipeptide cyclic citrullinated antibodies&#59; SSc&#58; systemic sclerosis&#59; PDGFR&#58; platelet derived growth factor receptor&#59; Topo I&#58; antitopoisomerase antibodies I&#59; U1RNP&#58; anti-U1 ribonucleoprotein antibodies&#59; U3RNP&#58; anti-fibrillarin antibodies&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Antinuclear antibodies directed against&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">4a&#46; PBC &#40;No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>62&#41;</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">4b&#46; PBC-SAD &#40;No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>22&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-no SAD<br>&#40;No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-SAD<br>&#40;No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-SSc<br>&#40;No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC-no SSc<br>&#40;No&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANA&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27 &#40;67&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;91&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;77&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AMA&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31 &#40;77&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;68&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;61&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;77&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">S100&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;22&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gp210&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;4&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;11&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Topo I&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ACA&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 &#40;54&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;92&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CENP-A&#47;B&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;2 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;12 &#40;83&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10 &#40;83&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RNA-pol III &#40;RP 11&#44; RP 155&#41;&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">U3RNP &#40;fibrillarin&#41;&#44; n&#47;No&#46; &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;4&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;7&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NOR90&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Th&#47;To&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;2&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pm-Scl &#40;100&#44; 75&#41;&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ku&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PDGFR&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ro52&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;32&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 &#40;36&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;55&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">U1RNP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;2&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sm&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ro60&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;12&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;22&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;7&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;44&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">La&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CCP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;13 &#40;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Immunological study results and comparative analysis between groups&#58; 4a PBC-no SAD group vs&#46; PBC-SAD&#59; 4b&#46; PBC-SSc group vs&#46; PBC-no SSc&#46;</p>"
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          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">ANA&#58; antinuclear antibodies&#59; RA&#58; rheumatoid arthritis&#59; PBC&#58; primary biliary cirrhosis&#59; SAD&#58; systemic autoimmune disease&#59; MCTD&#58; mixed connective tissue disease&#59; SSc systemic sclerosis&#59; SLE&#58; systemic lupus erythematosus&#59; PM&#58; polymyositis&#59; SjS&#58; primary Sj&#246;gren&#39;s syndrome&#46;</p>"
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                  <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="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PBC&#44; No&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ANA&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SAD&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SSc&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Raynaud&#39;s phenomenon&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sicca syndrome&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Others&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clarcke et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;9&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">23 &#40;27&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;9&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10 &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Makinen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">37 &#40;77&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Modena et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">2</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14 &#40;53&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16 &#40;61&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;30&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7 &#40;27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Marasini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">3</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">170&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">96 &#40;56&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47 &#40;27&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33 &#40;19&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54 &#40;31&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;3&#46;5&#41; SjS<br>3 &#40;1&#46;7&#41; RA<br>3 &#40;1&#46;7&#41; SLE<br>1 &#40;0&#46;5&#41; MCTD<br>1 &#40;0&#46;5&#41; PM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Watts et al&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">160&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18 &#40;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">84 &#40;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38 &#40;24&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33 &#40;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40 &#40;25&#41; SjS<br>12 &#40;17&#41; RA<br>2 &#40;1&#41; SLE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">5</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">322&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">275 &#40;85&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">150 &#40;46&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;2&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">64 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">112 &#40;35&#41; SjS<br>9 &#40;2&#46;8&#41; RA<br>12 &#40;3&#46;7&#41; SLE<br>10 &#40;3&#46;1&#41; PM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mari et al&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47 &#40;75&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21 &#40;33&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;19&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18 &#40;29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32 &#40;51&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;9&#46;6&#41; SjS<br>3 &#40;4&#46;8&#41; RA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tovoli et al&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">35</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42 &#40;52&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;18&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18 &#40;22&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total&#44; n&#47;No&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">951&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">537 &#40;56&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">341 &#40;35&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">106 &#40;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#47;21 &#40;0&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&#47;21 &#40;0&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Comparison of SAD and SSC prevalence in different PBC series&#46;</p>"
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      "titulo" => "References"
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            0 => array:3 [
              "identificador" => "bib0195"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatic disorders in primary biliary cirrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;K&#46; Clarke"
                            1 => "R&#46;M&#46; Galbraith"
                            2 => "E&#46;B&#46;D&#46; Hamilton"
                            3 => "R&#46; Williams"
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                    ]
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "1978"
                        "volumen" => "37"
                        "paginaInicial" => "42"
                        "paginaFinal" => "47"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/305233"
                            "web" => "Medline"
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              "identificador" => "bib0200"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Primary biliary cirrhosis and rheumatic diseases&#58; a clinical&#44; immunological and immunogenetical study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46; Modena"
                            1 => "C&#46; Marengo"
                            2 => "A&#46; Amoroso"
                            3 => "F&#46; Rosina"
                            4 => "P&#46; Constantini"
                            5 => "P&#46; Bellando"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Rheumatol"
                        "fecha" => "1986"
                        "volumen" => "4"
                        "paginaInicial" => "129"
                        "paginaFinal" => "134"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3488154"
                            "web" => "Medline"
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                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0205"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatic disorders and primary biliary cirrhosis&#58; an appraisal of 170 Italian patients"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "B&#46; Marasini"
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                            2 => "V&#46; Rossi"
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                    ]
                  ]
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2001"
                        "volumen" => "60"
                        "paginaInicial" => "1046"
                        "paginaFinal" => "1049"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11602476"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Wesierska-Gadek"
                            1 => "E&#46; Penner"
                            2 => "P&#46;M&#46; Battezzati"
                            3 => "C&#46; Selmi"
                            4 => "M&#46; Zuin"
                            5 => "E&#46; Hitchman"
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                    0 => array:2 [
                      "doi" => "10.1002/hep.21172"
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                        "tituloSerie" => "Hepatology"
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                    0 => array:2 [
                      "titulo" => "Connective tissue diseases in primary biliary cirrhosis&#58; a population-based cohort study"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Wang"
                            1 => "F&#46;C&#46; Zhang"
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