Associations of diagnostic findings with disease activity in primary Sjӧgren's syndrome: a cluster analysis

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Mohammadi, T. Yavari, S. Ghorbani, B. Mohammadi" "autores" => array:4 [ 0 => array:3 [ "nombre" => "T." "apellidos" => "Mohammadi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "T." "apellidos" => "Yavari" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "S." "apellidos" => "Ghorbani" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:4 [ "nombre" => "B." "apellidos" => "Mohammadi" "email" => array:1 [ 0 => "dr.bbkmmd@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "University of Tehran, College of Science, School of Mathematics, Statistics, and Computer Science, Tehran, Iran" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Tehran University of Medical Sciences, Faculty of Medicine, Shariati Hospital, Tehran, Iran" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Kerman University of Medical Sciences, Shafa Hospital, Department of Otorhinolaryngology, Kerman, Iran" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Independent Researcher, Tehran, Iran" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Unit 5, No 41, 24th Eastern Alley, Azadegan Blvd., Northern Kargar St., Tehran 1437696156, Iran." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Asociaciones de hallazgos diagnósticos con actividad de la enfermedad en el síndrome de Sjӧgren primario: un análisis de conglomerados" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2837 "Ancho" => 1675 "Tamanyo" => 376213 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0035" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "(A) Biplot of individuals and variables on the principal components. Each solid circle represents an individual, and the size of each circle represents the ESSDAI scores for that individual. The arrows represent correlations between the study variables with the principal components. (B) Dendrogram for hierarchical clustering of patients. (C) Biplot of individuals and variables on the principal components using clustered data. The colored concentration ellipses represent patients’ clusters. FANA: Fluorescent Anti-Nuclear Antibody; RF: Rheumatoid Factor; ESSDAI: European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index." ] ] ] "textoCompleto" => "IntroductionPrimary Sjӧgren's syndrome (pSS) is characterized by lymphocytic infiltration of exocrine structures, particularly the lacrimal and salivary glands<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>, and patients with pSS are typically middle-aged women<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a>. As a systemic autoimmune disease, pSS has the potential to affect other organs other than the salivary and lacrimal glands<a class="elsevierStyleCrossRef" href="#bib0020">4</a>. In 30–40% of patients, the disease first presents as an extra-glandular manifestation, making diagnosis more difficult<a class="elsevierStyleCrossRef" href="#bib0020">4</a>. Overall, more than 80% of patients present with mouth and eye dryness, fatigue, and joint pain<a class="elsevierStyleCrossRef" href="#bib0015">3</a>. However, these manifestations are frequently observed among the general population, yet pSS is a relatively rare disease. Consequently, the approaches to diagnostic evaluation of the disease are not uniform and the diagnosis of pSS poses a challenge to clinicians<a class="elsevierStyleCrossRefs" href="#bib0015">3,5</a>.The syndrome evolves slowly while the patient experiences mouth and eye dryness for a long time before being diagnosed with the advanced form of the disease<a class="elsevierStyleCrossRef" href="#bib0030">6</a>. Antinuclear antibodies are detected in 80% of patients. More specifically, autoantibodies are directed against Ro/SSA (Sjögren's syndrome-related antigen A; anti-SSA) or La/SSB (anti–SSB) antigens<a class="elsevierStyleCrossRef" href="#bib0035">7</a>. What’s more, an assessment of salivary beta2-microglobulin has been suggested to assist in evaluating patients for whom SS is suspected<a class="elsevierStyleCrossRef" href="#bib0040">8</a>. Disease activity is assessed by the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI)<a class="elsevierStyleCrossRefs" href="#bib0045">9–11</a>. In the study, supported by the EULAR, data from 96 patients were used to generate realistic vignettes. The experts identified 12 domains contributing to SS activity including constitutional, cutaneous, articular, muscular, lymphadenopathy, glandular, pulmonary, central nervous system, peripheral nervous system, hematological, renal, and biological. Each of the experts scored the disease activity of 5 patient profiles and 20 vignettes. Multiple regression modeling was then used to estimate the weight of each domain<a class="elsevierStyleCrossRef" href="#bib0055">11</a>. The minor salivary gland lip biopsy, sialography, scintigraphy, and salivary gland ultrasonography provided supplementary information for diagnosing pSS<a class="elsevierStyleCrossRefs" href="#bib0060">12–16</a>.Despite the efforts to improve the evaluation of patients suspected of having pSS, there is no definitive diagnostic test to confirm it<a class="elsevierStyleCrossRefs" href="#bib0085">17,18</a>. Diagnosis still relies on a constellation of clinical, laboratory, imaging, and pathological findings<a class="elsevierStyleCrossRefs" href="#bib0020">4,17</a>. Developing diagnostic models with various predictors would be a more realistic approach than using single biomarkers<a class="elsevierStyleCrossRefs" href="#bib0030">6,18</a>. To improve the workup of pSS, a variety of diagnostic modalities should be investigated in subsets of patients with different stages of the disease<a class="elsevierStyleCrossRefs" href="#bib0085">17,19</a>. We conducted this study to evaluate the relation between disease activity and the results of diagnostic tests for pSS. This would help select a more appropriate diagnostic strategy based on the presenting manifestations. We hypothesized that the activity stages would affect diagnostic findings in pSS.Materials and methodsDesign and settingWe carried out a secondary analysis of the data from a cohort study in Brazil that was conducted from November 2013 to May 2016. The study was performed in the Internal Medicine and Ophthalmology Departments at the Universidade Federal de São Paulo<a class="elsevierStyleCrossRef" href="#bib0080">16</a>. Fidelix et al. included 70 patients who met the 2002 American-European Consensus Group diagnostic criteria for pSS<a class="elsevierStyleCrossRefs" href="#bib0080">16,20</a>. Patients were excluded if they had hepatitis B or C, sarcoidosis, and other connective tissue diseases. Participants undergoing biological therapy or patients who received immunosuppressive therapy in the past three months were also not allowed to enter the study. The study evaluated salivary glands by measuring the stimulated salivary flow rate and ultrasonography to see if ESSDAI could be predicted in patients with pSS. The study suggested an association between ultrasound scores and anti-Ro/SSA antibodies. The authors also found direct relations between IgG levels >1600mg/dL and an ESSDAI ≥5, and between disease severity and low salivary flow.Data sourceFidelix et al. made the data from the Brazilian study publicly accessible at <a href="https://doi.org/10.5061/dryad.953dh">https://doi.org/10.5061/dryad.953dh</a> (last access date: July 14, 2022). The dataset included 70 patients and 13 informative variables: duration of the disease (year), stimulated salivary flow rate, salivary ultrasound score, biopsy (positive/not performed), fluorescent antinuclear antibody, anti-SSA, anti-SSB, rheumatic factor, IgG, salivary beta2-microglobulin, serum beta2-microglobulin, and ESSDAI. We extended their results using principal component and cluster analysis and tried to extract further clinical implications from the data.Ethical considerationsOur study was carried out following the Declaration of Helsinki. We did not carry out measurements on participants nor did we have access to identifying information. This is a secondary analysis of open access anonymized data.MeasurementsThe assessment of salivary flow (ml/min) was based on a standard protocol using 2% citric acid for stimulation<a class="elsevierStyleCrossRef" href="#bib0105">21</a>. For the ultrasound, bilateral parotid and submandibular glands were scanned, with the findings graded on a scale of 1–4, and the highest grade reported for each patient<a class="elsevierStyleCrossRef" href="#bib0110">22</a>. In addition, the dataset included the results of the salivary gland lip biopsy for patients (if the 2002 AECG criteria were not met), serological test results for rheumatoid factor (positive/negative), fluorescent antinuclear antibody (positive/negative), anti-Ro/SSA (positive/negative) and anti-La/SSB (positive/negative), immunoglobulin G (IgG) levels (μg/mL), salivary beta2-microglobulin (μg/mL), and serum beta2-microglobulin (μg/mL). Fidelix et al. measured the disease activity based on the ESSDAI scores developed by an international collaboration of SS experts promoted by the EULAR<a class="elsevierStyleCrossRefs" href="#bib0080">16,23</a>.Data analysisWe performed a cluster analysis of the data. The data were normalized and a principal component analysis was carried out. Principal component analysis is used to extract information from multivariate data by representing linear combinations of the original variables. The idea is to identify directions along which the variation in data is maximal. The contribution of individuals to the first two principal components was illustrated with a scatter plot and the identified outliers were excluded from further analysis. We represented both individuals and variables by their correlation with a principal component using biplots. Then, the clustering tendency of the data was assessed with Hopkins statistic. The value of Hopkins statistic >0.5 suggests that the dataset has a significant clustering tendency. We carried out a hierarchical clustering with the Euclidean distance and the ward method of building trees and depicted a dendrogram to show the results. Next, the profiles of the recognized clusters were compared with the Mann-Whitney and χ2 tests, as appropriate. The results are presented as mean (SD) or median [interquartile range] for continuous variables, and as absolute numbers (%) for categorical data. The level of significance was set at a two-tailed α=0.05. All data analyses were performed with R version 4.0.2 for Windows. R is a well-known open-source environment for computing and graphics (R Foundation for Statistical Computing, Vienna, Austria. <a href="https://www.R-project.org/">https://www.R-project.org/</a>).ResultsSampleAccording to the article published by Fidelix et al., the sample included 68 (97%) women and only 2 (3%) men, with a mean (SD) age of 55.74 (11.89) years<a class="elsevierStyleCrossRef" href="#bib0080">16</a>. The two most common symptoms were dryness of the mouth and eyes<a class="elsevierStyleCrossRef" href="#bib0080">16</a>. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the characteristics of the study variables. Only 1.3% of the data were missing. We imputed missing data a single time using predictive mean matching with the maximum iteration of 5, scaled data to unit variance and performed principal component analysis. Five components showed an eigenvalue of ≥1 with a cumulative 66.3% of the total variance (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Patient number 48 was a highly contributing individual and was excluded from further analysis.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Clustering<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A shows the biplot of individuals and variables. Each solid circle represents a single patient, and the size of each circle indicates the ESSDAI score of that patient. The arrows show the correlation between a variable and the principal components. Positively correlated features are close to each other, while negatively correlated variables are on opposite sides. In addition, well-represented features are farther from the origin. The patient on the same side of a given variable has a high value, and the individual on the opposite side has a low value, for that particular variable. It was expected that individuals with larger circle sizes would be scattered around the ESSDAI arrow. However, other clinical implications can be drawn from the plot. First, the ESSDAI values are positively correlated with IgG (Pearson’s correlation coefficient r=0.25, p= 0.041) and RF (r = 0.23, p= 0.055). Second, the anti-SSA, anti-SSB, and ultrasound scores are grouped. The anti-SSA and anti-SSB (r = 0.60, p<0.001), anti-SSA and ultrasound (r = 0.37, p = 0.001), and anti-SSB and ultrasound scores (r = 0.29, p=0.016) were positively correlated as well. Third, salivary beta2-microglobulin was well-represented on the first principal component, while serum beta2-microglobulin was not a well-represented feature. Fourth, patients with active pSS are more frequently located on the right side of the plot. Fifth, the arrows for salivary flow, biopsy results, and the duration of the disease pointed to the area of patients with low disease activity (low ESSDAI). Meanwhile, a biopsy was carried out only if the 2002 AECG criteria were not met. Patients without biopsies did not necessarily have negative biopsies. However, the biplot indicates that a positive biopsy is still prevalent in low ESSDAI patients. The Hopkins statistic value was 0.66, showing a significant clustering tendency of the data. The hierarchical clustering algorithm identified two distinct clusters (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B). <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C was depicted using cluster membership. The comparison of <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A and C implies that patients in cluster 1 had lower disease activity than cluster 2.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Cluster profilingOverall, the cluster profiling results were compatible with <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>. <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the characteristics of the two clusters. Except for disease duration–which was approaching significance (p= 0.090)–and serum beta2-microglobulin, the clusters were significantly different in the other features. In general, patients in cluster 1 had longer disease duration, higher stimulated salivary flow, and lower ESSDAI scores. However, cluster 2 had higher ultrasound scores, more prominent laboratory and ultrasound findings, and higher ESSDAI scores.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>DiscussionWe carried out this research to investigate the relation between disease activity and diagnostic findings in pSS. Our study showed that distinct features of pSS correlate with the active stages of the illness. We found that patients with higher disease activity showed more positive results for serologic testing. Of the laboratory assessments, anti-SSB, anti-SSA, ANA, and IgG were associated with higher activity of pSS. Meanwhile, anti-SSA was more well-represented and successful in explaining variance in the data than other serologic test results. In addition, anti-SSA was more correlated with the ultrasound results. The salivary beta2-microglobulin assessment was more informative than the serum beta2-microglobulin. However, our results showed that salivary flow, biopsy results, and the duration of the disease gained more importance in evaluating patients with low-activity pSS. This implies that in patients with lower disease activity, the biopsy and salivary flow rate are more definitive than serologic or even ultrasound studies.Some of our results are consistent with the findings previously reported in the literature on pSS. As in our study, other researchers reported that anti-SSA and anti-SSB are positively associated with ANA and RF values<a class="elsevierStyleCrossRef" href="#bib0120">24</a>. What’s more, the two autoantibodies have been reported to be associated with more severe glandular symptoms<a class="elsevierStyleCrossRef" href="#bib0120">24</a>. In general, anti-SSA is detected either solely or with anti-SSB, whereas anti-SSB rarely exists in isolation<a class="elsevierStyleCrossRef" href="#bib0125">25</a>. Our analysis confirmed the superiority of anti-SSA in identifying the cluster with highly active pSS. This study showed significant correlations between anti-SSA or anti-SSB and the salivary gland ultrasound evaluation, particularly for anti-SSA. In a study of pSS, Theander and Mandl reported that ultrasound had the potential to identify patients with severe disease and that disease duration did not influence ultrasound results<a class="elsevierStyleCrossRef" href="#bib0130">26</a>. They showed that patients with higher ultrasound scores had higher frequencies of positive anti-SSA and anti-SSB, ANA, and rheumatoid factor. They also suggested that pathologic ultrasound findings were associated with higher disease activity and more frequent markers of lymphoma. A variety of lymphoma markers have been suggested in the literature on pSS<a class="elsevierStyleCrossRef" href="#bib0135">27</a>. Our findings replicated the association of beta2-microglobulin with higher disease activity<a class="elsevierStyleCrossRef" href="#bib0135">27</a>.Based on the patients’ characteristics, we identified two discernible clusters among patients with pSS. It should be noted that the clusters were labeled using unsupervised learning methods, principal components, and cluster analyses. This means that we might be facing two naturally distinct groups of patients with pSS. In addition, the profiling showed a highly significant difference between the two clusters in the activity score. Our cluster profiling confirmed the findings of the principal component analysis: the low-activity cluster was comprised of patients with longer disease duration who were identified better by the salivary gland lip biopsy and flow rate results than the serology and ultrasound results. The inverse relation between disease activity and salivary flow is plausible; however, the inverse correlation between disease activity and biopsy results seems counterintuitive. The reason for this is that biopsies were ordered for patients who did not meet the 2002 AECG criteria. A biopsy is typically recommended to establish a diagnosis of pSS in the absence of anti-SSA<a class="elsevierStyleCrossRef" href="#bib0015">3</a>. In a study in 87 patients with SS, Wicheta et al. found that when serology was negative, minor salivary gland biopsy was the criterion that allowed for a diagnosis to be established<a class="elsevierStyleCrossRef" href="#bib0065">13</a>. In another study, Langerman et al. investigated the utility of lip biopsy in 47 patients with SS and reported that clinical symptoms and serology did not predict positive lip biopsy<a class="elsevierStyleCrossRef" href="#bib0140">28</a>.In a cluster analysis of pSS features using data from 332 patients, Sandhya et al. found two groups of patients, one presenting with major systemic illness with high antibody titers and the other comprised of seronegative patients with mild disease<a class="elsevierStyleCrossRef" href="#bib0145">29</a>. The two highest odds ratios were for anti-SSA and anti-SSB, and the lowest was for chronic pain. These results are in line with the cluster characteristics in our study. The aforementioned authors clustered the pSS characteristics; however, we analyzed both pSS features and patient data regarding principal components and then clustered patients. In addition, they did not describe disease activity, while disease activity was the key concept in our study. Lee et al. clustered pSS symptoms into three classes: high symptom burden, dryness dominant, and low symptom burden<a class="elsevierStyleCrossRef" href="#bib0150">30</a>. Data from 341 patients with pSS from a Korean population were analyzed using the components of the EULAR SS Patient Reported Index and a health questionnaire. The authors investigated inter-class transition over a follow-up period of five years and emphasized the temporal stability of the clusters over said period. However, this might be translated as overlooking the natural history of pSS<a class="elsevierStyleCrossRef" href="#bib0090">18</a>. While their symptom-based clusters were different in ESSDAI scores, the difference does not imply a significant clinical application; ESSDAI=3 [1–6], 4 [2–8], and 3 [1–5.75], respectively (p= 0.03). What’s more, they did not include biopsy or ultrasound findings in their models.To our knowledge, this is the first study on the relationship between disease activity and diagnostic measures in pSS using cluster analysis. The diagnostic modalities included clinical, pathological, imaging, and serological tests. We investigated the contribution of both individuals and diagnostic measures to the principal components and then clustered patients into two distinct groups. The groups were significantly different in disease activity and presented different diagnostic profiles.LimitationsA limitation of our study was that the sample was taken from a single center. This limits the generalizability of the cluster profiling to other populations. However, we incorporated more objective variables than subjective features into the models. This provided greater reliability compared to the characteristics with large international variability or vague definitions (e.g., socioeconomic or subjective characteristics). Applying our method to multinational datasets would establish the existence of different clusters in patients with pSS. Ideally, a large dataset of patients with other differential diagnoses to pSS would allow for the investigation of the existence of clusters with intermediary clinical pictures.ConclusionWe identified two distinct clusters of low or high disease activity among patients with pSS. Our analysis showed that patients with higher syndrome activity were best recognized with serological and ultrasound assessments. The results of IgG and RF assessments were significantly correlated with disease activity. Within the cluster with higher pSS activity, the results of anti-SSA, anti-SSB, ultrasound, and ANA showed direct and significant pairwise associations. However, patients with lower syndrome activity had a longer disease duration, higher stimulated salivary flow rate, and a positive biopsy of minor salivary glands. We suggest performing a minor salivary gland biopsy for diagnosing pSS, even in patients with seemingly low disease activity. We also recommend considering disease activity in further research on the diagnosis of pSS.Competing interestsThe authors declare that they have no competing interests.FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1881018" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1630396" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1881017" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1630397" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Design and setting" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Data source" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Ethical considerations" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Measurements" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Data analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Sample" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Clustering" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Cluster profiling" ] ] ] 7 => array:3 [ "identificador" => "sec0060" "titulo" => "Discussion" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Limitations" ] ] ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0075" "titulo" => "Competing interests" ] 10 => array:2 [ "identificador" => "sec0080" "titulo" => "Funding" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1630396" "palabras" => array:6 [ 0 => "Clinical" 1 => "Clustering" 2 => "Diagnosis" 3 => "Disease activity" 4 => "Serology" 5 => "Sjӧgren" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1630397" "palabras" => array:6 [ 0 => "Clínico" 1 => "Agrupamiento" 2 => "Diagnóstico" 3 => "Actividad de la enfermedad" 4 => "Serología" 5 => "Sjögren" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveThe diagnosis of primary Sjӧgren's syndrome still relies upon a constellation of clinical, laboratory, imaging, and pathological findings. We aimed to evaluate the relation of the disease activity with the results of diagnostic tests for primary Sjӧgren's syndrome. MethodsA principal component with cluster analysis was performed to classify 69 patients with primary Sjӧgren's syndrome based on the results of diagnostic evaluations. ResultsAnti-SSA autoantibody was the most represented feature on the principal components. The anti-SSA and ultrasound score were positively correlated (p=0.001). We identified two distinct clusters of low or high disease activity (p<0.001). Except for disease duration and serum beta2-microglobulin, the clusters were significantly different in salivary flow (p= 0.004), ultrasound findings (p<0.001), IgG (p= 0.001), and salivary beta2-microglobulin (p= 0.048). Also, positive findings were significantly different between the clusters in rheumatoid factor, antinuclear antibody, anti-SSA, and anti-SSB (all p≤0.013). ConclusionPatients with higher syndrome activity were best recognized with serological and ultrasound assessments. However, patients with lower syndrome activity had a longer disease duration, higher stimulated salivary flow rate, and a positive biopsy of minor salivary glands (56%)." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivoEl diagnóstico del síndrome de Sjӧgren primario todavía se basa en una constelación de hallazgos clínicos, de laboratorio, de imagen y patológicos. Nuestro objetivo fue evaluar la relación de la actividad de la enfermedad con los resultados de las pruebas diagnósticas para el síndrome de Sjӧgren primario. MétodosSe realizó un análisis de componentes principales mediante conglomerados para clasificar a 69 pacientes con síndrome de Sjӧgren primario en función de los resultados de las evaluaciones de diagnóstico. ResultadosEl autoanticuerpo anti-SSA fue la característica más representada en los componentes principales. El anti-SSA y la puntuación de ultrasonido se correlacionaron positivamente (p=0,001). Identificamos dos grupos distintos de baja o alta actividad de la enfermedad (p<0,001). Excepto por la duración de la enfermedad y la microglobulina beta2 sérica, los grupos fueron significativamente diferentes en el flujo salival (p=0,004), los hallazgos de ultrasonido (p<0,001), IgG (p=0,001) y microglobulina beta2 salival (p=0,048). Además, los hallazgos positivos fueron significativamente diferentes entre los grupos en factor reumatoide, anticuerpo antinuclear, anti-SSA y anti-SSB (todos p≤0,013). ConclusiónLos pacientes con mayor actividad del síndrome se reconocieron mejor con evaluaciones serológicas y ecográficas. Sin embargo, los pacientes con menor actividad del síndrome tenían una mayor duración de la enfermedad, mayor tasa de flujo salival estimulado y una biopsia productiva de glándulas salivales menores (56%)." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2066 "Ancho" => 2175 "Tamanyo" => 239129 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "The scree plots of the principal components. The first principal component is markedly different than the other components in explaining variance." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2837 "Ancho" => 1675 "Tamanyo" => 376213 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0035" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "(A) Biplot of individuals and variables on the principal components. Each solid circle represents an individual, and the size of each circle represents the ESSDAI scores for that individual. The arrows represent correlations between the study variables with the principal components. (B) Dendrogram for hierarchical clustering of patients. (C) Biplot of individuals and variables on the principal components using clustered data. The colored concentration ellipses represent patients’ clusters. FANA: Fluorescent Anti-Nuclear Antibody; RF: Rheumatoid Factor; ESSDAI: European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0040" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ESSDAI, European League against Rheumatism Sjögren’s Syndrome Disease Activity Index." "tablatextoimagen" => array:2 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristic \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Median [Interquartile Range] \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Disease Duration (year) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.0 [2.0, 10.0] \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stimulated Salivary Flow Rate (ml/min) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.100 [0.025, 0.250] \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Salivary Ultrasound Score \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.0 [2.0, 3.0] \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IgG (μg/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1,269.0 [1,039.2, 1,850.0] \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Salivary beta2-microglobulin (μg/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.4 [0.7, 4.6] \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serum beta2-microglobulin (μg/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.0 [0.8, 3.5] \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ESSDAI Score \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.0 [0.0, 5.0] \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] 1 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristic \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive Biopsy (vs. not performed) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 (30.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive Rheumatoid Factor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37 (52.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive Fluorescent Antinuclear Antibody \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58 (82.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive anti-Ro/SSA Antibody \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39 (55.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive anti-La/SSB Antibody \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 (31.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Patient characteristics (N=70)." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0045" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ESSDAI: European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index." "tablatextoimagen" => array:2 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Characteristic \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cluster</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Cluster 1 (n1=27) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Cluster 2 (n2=42) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">p \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Median [Interquartile Range]</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mann-Whitney U test \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Disease Duration (year) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10.0 [3.5, 15.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.0 (2.0, 10.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.090 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stimulated Salivary Flow Rate (ml/min) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.230 [0.040, 0.300] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.050 [0.020, 0.150] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.004* \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Salivary Ultrasound Score \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.0 [1.0, 3.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.0 [3.0, 4.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><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="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IgG (μg/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1,048.0 [987.5, 1,260.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1,376.0 [1,120.0, 2,019.2] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Salivary beta2-microglobulin (μg/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.0 [1.4, 4.8] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.0 [0.1, 3.7] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.048* \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serum beta2-microglobulin (μg/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.6 [0.5, 2.3] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.3 [0.8, 4.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.213 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ESSDAI Score \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0 [0.0, 2.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.0 [2.0, 6.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.001* \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] 1 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristic \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number (%)</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">χ2 test \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive Biopsy (vs. not performed) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (55.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (12.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><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="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive Rheumatoid Factor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 (33.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 (66.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.013* \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive Fluorescent Antinuclear Antibody \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (59.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 (100.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><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="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive anti-Ro/SSA Antibody \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (7.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37 (88.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><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="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive anti-La/SSB Antibody \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 (52.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.001* \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Cluster profiling (N=69)." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Indications and risk factors for hospitalization in patients with primary Sjogren syndrome: experience from a tertiary center in Turkey" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "M.E. Yayla" 1 => "D. Sahin Eroglu" 2 => "E. Uslu Yurteri" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10067-022-06053-x" "Revista" => array:7 [ "tituloSerie" => "Clin Rheumatol" "fecha" => "2022" "volumen" => "41" "numero" => "5" "paginaInicial" => "1457" "paginaFinal" => "1463" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34988683" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cerebellar degeneration in primary Sjӧgren syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. Heidary" 1 => "S. Alesaeidi" 2 => "K. 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Original article

Associations of diagnostic findings with disease activity in primary Sjӧgren's syndrome: a cluster analysis

Asociaciones de hallazgos diagnósticos con actividad de la enfermedad en el síndrome de Sjӧgren primario: un análisis de conglomerados

T. Mohammadia, T. Yavarib, S. Ghorbanic, B. Mohammadid,

Corresponding author

dr.bbkmmd@gmail.com

Corresponding author at: Unit 5, No 41, 24th Eastern Alley, Azadegan Blvd., Northern Kargar St., Tehran 1437696156, Iran.

a University of Tehran, College of Science, School of Mathematics, Statistics, and Computer Science, Tehran, Iran

b Tehran University of Medical Sciences, Faculty of Medicine, Shariati Hospital, Tehran, Iran

c Kerman University of Medical Sciences, Shafa Hospital, Department of Otorhinolaryngology, Kerman, Iran

d Independent Researcher, Tehran, Iran

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        "titulo" => "Asociaciones de hallazgos diagn&#243;sticos con actividad de la enfermedad en el s&#237;ndrome de Sj&#1255;gren primario&#58; un an&#225;lisis de conglomerados"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Biplot of individuals and variables on the principal components&#46; Each solid circle represents an individual&#44; and the size of each circle represents the ESSDAI scores for that individual&#46; The arrows represent correlations between the study variables with the principal components&#46; &#40;B&#41; Dendrogram for hierarchical clustering of patients&#46; &#40;C&#41; Biplot of individuals and variables on the principal components using clustered data&#46; The colored concentration ellipses represent patients&#8217; clusters&#46;</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">FANA&#58; Fluorescent Anti-Nuclear Antibody&#59; RF&#58; Rheumatoid Factor&#59; ESSDAI&#58; European League Against Rheumatism Sj&#246;gren&#8217;s Syndrome Disease Activity Index&#46;</p>"
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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 Sj&#1255;gren&#39;s syndrome &#40;pSS&#41; is characterized by lymphocytic infiltration of exocrine structures&#44; particularly the lacrimal and salivary glands<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a>&#44; and patients with pSS are typically middle-aged women<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a>&#46; As a systemic autoimmune disease&#44; pSS has the potential to affect other organs other than the salivary and lacrimal glands<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#46; In 30&#8211;40&#37; of patients&#44; the disease first presents as an extra-glandular manifestation&#44; making diagnosis more difficult<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#46; Overall&#44; more than 80&#37; of patients present with mouth and eye dryness&#44; fatigue&#44; and joint pain<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; However&#44; these manifestations are frequently observed among the general population&#44; yet pSS is a relatively rare disease&#46; Consequently&#44; the approaches to diagnostic evaluation of the disease are not uniform and the diagnosis of pSS poses a challenge to clinicians<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;5</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The syndrome evolves slowly while the patient experiences mouth and eye dryness for a long time before being diagnosed with the advanced form of the disease<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&#46; Antinuclear antibodies are detected in 80&#37; of patients&#46; More specifically&#44; autoantibodies are directed against Ro&#47;SSA &#40;Sj&#246;gren&#39;s syndrome-related antigen A&#59; anti-SSA&#41; or La&#47;SSB &#40;anti&#8211;SSB&#41; antigens<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; What&#8217;s more&#44; an assessment of salivary beta2-microglobulin has been suggested to assist in evaluating patients for whom SS is suspected<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#46; Disease activity is assessed by the European League Against Rheumatism &#40;EULAR&#41; Sj&#246;gren&#8217;s Syndrome Disease Activity Index &#40;ESSDAI&#41;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#8211;11</span></a>&#46; In the study&#44; supported by the EULAR&#44; data from 96 patients were used to generate realistic vignettes&#46; The experts identified 12 domains contributing to SS activity including constitutional&#44; cutaneous&#44; articular&#44; muscular&#44; lymphadenopathy&#44; glandular&#44; pulmonary&#44; central nervous system&#44; peripheral nervous system&#44; hematological&#44; renal&#44; and biological&#46; Each of the experts scored the disease activity of 5 patient profiles and 20 vignettes&#46; Multiple regression modeling was then used to estimate the weight of each domain<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#46; The minor salivary gland lip biopsy&#44; sialography&#44; scintigraphy&#44; and salivary gland ultrasonography provided supplementary information for diagnosing pSS<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#8211;16</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Despite the efforts to improve the evaluation of patients suspected of having pSS&#44; there is no definitive diagnostic test to confirm it<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a>&#46; Diagnosis still relies on a constellation of clinical&#44; laboratory&#44; imaging&#44; and pathological findings<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;17</span></a>&#46; Developing diagnostic models with various predictors would be a more realistic approach than using single biomarkers<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;18</span></a>&#46; To improve the workup of pSS&#44; a variety of diagnostic modalities should be investigated in subsets of patients with different stages of the disease<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;19</span></a>&#46; We conducted this study to evaluate the relation between disease activity and the results of diagnostic tests for pSS&#46; This would help select a more appropriate diagnostic strategy based on the presenting manifestations&#46; We hypothesized that the activity stages would affect diagnostic findings in pSS&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Design and setting</span><p id="par0020" class="elsevierStylePara elsevierViewall">We carried out a secondary analysis of the data from a cohort study in Brazil that was conducted from November 2013 to May 2016&#46; The study was performed in the Internal Medicine and Ophthalmology Departments at the Universidade Federal de S&#227;o Paulo<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; Fidelix et al&#46; included 70 patients who met the 2002 American-European Consensus Group diagnostic criteria for pSS<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;20</span></a>&#46; Patients were excluded if they had hepatitis B or C&#44; sarcoidosis&#44; and other connective tissue diseases&#46; Participants undergoing biological therapy or patients who received immunosuppressive therapy in the past three months were also not allowed to enter the study&#46; The study evaluated salivary glands by measuring the stimulated salivary flow rate and ultrasonography to see if ESSDAI could be predicted in patients with pSS&#46; The study suggested an association between ultrasound scores and anti-Ro&#47;SSA antibodies&#46; The authors also found direct relations between IgG levels &#62;1600<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and an ESSDAI &#8805;5&#44; and between disease severity and low salivary flow&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Data source</span><p id="par0025" class="elsevierStylePara elsevierViewall">Fidelix et al&#46; made the data from the Brazilian study publicly accessible at <a href="https://doi.org/10.5061/dryad.953dh">https&#58;&#47;&#47;doi&#46;org&#47;10&#46;5061&#47;dryad&#46;953dh</a> &#40;last access date&#58; July 14&#44; 2022&#41;&#46; The dataset included 70 patients and 13 informative variables&#58; duration of the disease &#40;year&#41;&#44; stimulated salivary flow rate&#44; salivary ultrasound score&#44; biopsy &#40;positive&#47;not performed&#41;&#44; fluorescent antinuclear antibody&#44; anti-SSA&#44; anti-SSB&#44; rheumatic factor&#44; IgG&#44; salivary beta2-microglobulin&#44; serum beta2-microglobulin&#44; and ESSDAI&#46; We extended their results using principal component and cluster analysis and tried to extract further clinical implications from the data&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ethical considerations</span><p id="par0030" class="elsevierStylePara elsevierViewall">Our study was carried out following the Declaration of Helsinki&#46; We did not carry out measurements on participants nor did we have access to identifying information&#46; This is a secondary analysis of open access anonymized data&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Measurements</span><p id="par0035" class="elsevierStylePara elsevierViewall">The assessment of salivary flow &#40;ml&#47;min&#41; was based on a standard protocol using 2&#37; citric acid for stimulation<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46; For the ultrasound&#44; bilateral parotid and submandibular glands were scanned&#44; with the findings graded on a scale of 1&#8211;4&#44; and the highest grade reported for each patient<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46; In addition&#44; the dataset included the results of the salivary gland lip biopsy for patients &#40;if the 2002 AECG criteria were not met&#41;&#44; serological test results for rheumatoid factor &#40;positive&#47;negative&#41;&#44; fluorescent antinuclear antibody &#40;positive&#47;negative&#41;&#44; anti-Ro&#47;SSA &#40;positive&#47;negative&#41; and anti-La&#47;SSB &#40;positive&#47;negative&#41;&#44; immunoglobulin G &#40;IgG&#41; levels &#40;&#956;g&#47;mL&#41;&#44; salivary beta2-microglobulin &#40;&#956;g&#47;mL&#41;&#44; and serum beta2-microglobulin &#40;&#956;g&#47;mL&#41;&#46; Fidelix et al&#46; measured the disease activity based on the ESSDAI scores developed by an international collaboration of SS experts promoted by the EULAR<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;23</span></a>&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Data analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">We performed a cluster analysis of the data&#46; The data were normalized and a principal component analysis was carried out&#46; Principal component analysis is used to extract information from multivariate data by representing linear combinations of the original variables&#46; The idea is to identify directions along which the variation in data is maximal&#46; The contribution of individuals to the first two principal components was illustrated with a scatter plot and the identified outliers were excluded from further analysis&#46; We represented both individuals and variables by their correlation with a principal component using biplots&#46; Then&#44; the clustering tendency of the data was assessed with Hopkins statistic&#46; The value of Hopkins statistic &#62;0&#46;5 suggests that the dataset has a significant clustering tendency&#46; We carried out a hierarchical clustering with the Euclidean distance and the ward method of building trees and depicted a dendrogram to show the results&#46; Next&#44; the profiles of the recognized clusters were compared with the Mann-Whitney and &#967;2 tests&#44; as appropriate&#46; The results are presented as mean &#40;SD&#41; or median &#91;interquartile range&#93; for continuous variables&#44; and as absolute numbers &#40;&#37;&#41; for categorical data&#46; The level of significance was set at a two-tailed &#945;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; All data analyses were performed with R version 4&#46;0&#46;2 for Windows&#46; R is a well-known open-source environment for computing and graphics &#40;R Foundation for Statistical Computing&#44; Vienna&#44; Austria&#46; <a href="https://www.R-project.org/">https&#58;&#47;&#47;www&#46;R-project&#46;org&#47;</a>&#41;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Sample</span><p id="par0045" class="elsevierStylePara elsevierViewall">According to the article published by Fidelix et al&#46;&#44; the sample included 68 &#40;97&#37;&#41; women and only 2 &#40;3&#37;&#41; men&#44; with a mean &#40;SD&#41; age of 55&#46;74 &#40;11&#46;89&#41; years<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; The two most common symptoms were dryness of the mouth and eyes<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the characteristics of the study variables&#46; Only 1&#46;3&#37; of the data were missing&#46; We imputed missing data a single time using predictive mean matching with the maximum iteration of 5&#44; scaled data to unit variance and performed principal component analysis&#46; Five components showed an eigenvalue of &#8805;1 with a cumulative 66&#46;3&#37; of the total variance &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Patient number 48 was a highly contributing individual and was excluded from further analysis&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Clustering</span><p id="par0050" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A shows the biplot of individuals and variables&#46; Each solid circle represents a single patient&#44; and the size of each circle indicates the ESSDAI score of that patient&#46; The arrows show the correlation between a variable and the principal components&#46; Positively correlated features are close to each other&#44; while negatively correlated variables are on opposite sides&#46; In addition&#44; well-represented features are farther from the origin&#46; The patient on the same side of a given variable has a high value&#44; and the individual on the opposite side has a low value&#44; for that particular variable&#46; It was expected that individuals with larger circle sizes would be scattered around the ESSDAI arrow&#46; However&#44; other clinical implications can be drawn from the plot&#46; First&#44; the ESSDAI values are positively correlated with IgG &#40;Pearson&#8217;s correlation coefficient <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;25&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span> 0&#46;041&#41; and RF &#40;<span class="elsevierStyleItalic">r</span> &#61; 0&#46;23&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span> 0&#46;055&#41;&#46; Second&#44; the anti-SSA&#44; anti-SSB&#44; and ultrasound scores are grouped&#46; The anti-SSA and anti-SSB &#40;<span class="elsevierStyleItalic">r</span> &#61; 0&#46;60&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; anti-SSA and ultrasound &#40;<span class="elsevierStyleItalic">r</span> &#61; 0&#46;37&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;001&#41;&#44; and anti-SSB and ultrasound scores &#40;<span class="elsevierStyleItalic">r</span> &#61; 0&#46;29&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;016&#41; were positively correlated as well&#46; Third&#44; salivary beta2-microglobulin was well-represented on the first principal component&#44; while serum beta2-microglobulin was not a well-represented feature&#46; Fourth&#44; patients with active pSS are more frequently located on the right side of the plot&#46; Fifth&#44; the arrows for salivary flow&#44; biopsy results&#44; and the duration of the disease pointed to the area of patients with low disease activity &#40;low ESSDAI&#41;&#46; Meanwhile&#44; a biopsy was carried out only if the 2002 AECG criteria were not met&#46; Patients without biopsies did not necessarily have negative biopsies&#46; However&#44; the biplot indicates that a positive biopsy is still prevalent in low ESSDAI patients&#46; The Hopkins statistic value was 0&#46;66&#44; showing a significant clustering tendency of the data&#46; The hierarchical clustering algorithm identified two distinct clusters &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C was depicted using cluster membership&#46; The comparison of <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A and C implies that patients in cluster 1 had lower disease activity than cluster 2&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Cluster profiling</span><p id="par0055" class="elsevierStylePara elsevierViewall">Overall&#44; the cluster profiling results were compatible with <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the characteristics of the two clusters&#46; Except for disease duration&#8211;which was approaching significance &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span> 0&#46;090&#41;&#8211;and serum beta2-microglobulin&#44; the clusters were significantly different in the other features&#46; In general&#44; patients in cluster 1 had longer disease duration&#44; higher stimulated salivary flow&#44; and lower ESSDAI scores&#46; However&#44; cluster 2 had higher ultrasound scores&#44; more prominent laboratory and ultrasound findings&#44; and higher ESSDAI scores&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">We carried out this research to investigate the relation between disease activity and diagnostic findings in pSS&#46; Our study showed that distinct features of pSS correlate with the active stages of the illness&#46; We found that patients with higher disease activity showed more positive results for serologic testing&#46; Of the laboratory assessments&#44; anti-SSB&#44; anti-SSA&#44; ANA&#44; and IgG were associated with higher activity of pSS&#46; Meanwhile&#44; anti-SSA was more well-represented and successful in explaining variance in the data than other serologic test results&#46; In addition&#44; anti-SSA was more correlated with the ultrasound results&#46; The salivary beta2-microglobulin assessment was more informative than the serum beta2-microglobulin&#46; However&#44; our results showed that salivary flow&#44; biopsy results&#44; and the duration of the disease gained more importance in evaluating patients with low-activity pSS&#46; This implies that in patients with lower disease activity&#44; the biopsy and salivary flow rate are more definitive than serologic or even ultrasound studies&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Some of our results are consistent with the findings previously reported in the literature on pSS&#46; As in our study&#44; other researchers reported that anti-SSA and anti-SSB are positively associated with ANA and RF values<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&#46; What&#8217;s more&#44; the two autoantibodies have been reported to be associated with more severe glandular symptoms<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&#46; In general&#44; anti-SSA is detected either solely or with anti-SSB&#44; whereas anti-SSB rarely exists in isolation<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46; Our analysis confirmed the superiority of anti-SSA in identifying the cluster with highly active pSS&#46; This study showed significant correlations between anti-SSA or anti-SSB and the salivary gland ultrasound evaluation&#44; particularly for anti-SSA&#46; In a study of pSS&#44; Theander and Mandl reported that ultrasound had the potential to identify patients with severe disease and that disease duration did not influence ultrasound results<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#46; They showed that patients with higher ultrasound scores had higher frequencies of positive anti-SSA and anti-SSB&#44; ANA&#44; and rheumatoid factor&#46; They also suggested that pathologic ultrasound findings were associated with higher disease activity and more frequent markers of lymphoma&#46; A variety of lymphoma markers have been suggested in the literature on pSS<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#46; Our findings replicated the association of beta2-microglobulin with higher disease activity<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Based on the patients&#8217; characteristics&#44; we identified two discernible clusters among patients with pSS&#46; It should be noted that the clusters were labeled using unsupervised learning methods&#44; principal components&#44; and cluster analyses&#46; This means that we might be facing two naturally distinct groups of patients with pSS&#46; In addition&#44; the profiling showed a highly significant difference between the two clusters in the activity score&#46; Our cluster profiling confirmed the findings of the principal component analysis&#58; the low-activity cluster was comprised of patients with longer disease duration who were identified better by the salivary gland lip biopsy and flow rate results than the serology and ultrasound results&#46; The inverse relation between disease activity and salivary flow is plausible&#59; however&#44; the inverse correlation between disease activity and biopsy results seems counterintuitive&#46; The reason for this is that biopsies were ordered for patients who did not meet the 2002 AECG criteria&#46; A biopsy is typically recommended to establish a diagnosis of pSS in the absence of anti-SSA<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; In a study in 87 patients with SS&#44; Wicheta et al&#46; found that when serology was negative&#44; minor salivary gland biopsy was the criterion that allowed for a diagnosis to be established<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46; In another study&#44; Langerman et al&#46; investigated the utility of lip biopsy in 47 patients with SS and reported that clinical symptoms and serology did not predict positive lip biopsy<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In a cluster analysis of pSS features using data from 332 patients&#44; Sandhya et al&#46; found two groups of patients&#44; one presenting with major systemic illness with high antibody titers and the other comprised of seronegative patients with mild disease<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&#46; The two highest odds ratios were for anti-SSA and anti-SSB&#44; and the lowest was for chronic pain&#46; These results are in line with the cluster characteristics in our study&#46; The aforementioned authors clustered the pSS characteristics&#59; however&#44; we analyzed both pSS features and patient data regarding principal components and then clustered patients&#46; In addition&#44; they did not describe disease activity&#44; while disease activity was the key concept in our study&#46; Lee et al&#46; clustered pSS symptoms into three classes&#58; high symptom burden&#44; dryness dominant&#44; and low symptom burden<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&#46; Data from 341 patients with pSS from a Korean population were analyzed using the components of the EULAR SS Patient Reported Index and a health questionnaire&#46; The authors investigated inter-class transition over a follow-up period of five years and emphasized the temporal stability of the clusters over said period&#46; However&#44; this might be translated as overlooking the natural history of pSS<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46; While their symptom-based clusters were different in ESSDAI scores&#44; the difference does not imply a significant clinical application&#59; ESSDAI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3 &#91;1&#8211;6&#93;&#44; 4 &#91;2&#8211;8&#93;&#44; and 3 &#91;1&#8211;5&#46;75&#93;&#44; respectively &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span> 0&#46;03&#41;&#46; What&#8217;s more&#44; they did not include biopsy or ultrasound findings in their models&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">To our knowledge&#44; this is the first study on the relationship between disease activity and diagnostic measures in pSS using cluster analysis&#46; The diagnostic modalities included clinical&#44; pathological&#44; imaging&#44; and serological tests&#46; We investigated the contribution of both individuals and diagnostic measures to the principal components and then clustered patients into two distinct groups&#46; The groups were significantly different in disease activity and presented different diagnostic profiles&#46;</p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Limitations</span><p id="par0085" class="elsevierStylePara elsevierViewall">A limitation of our study was that the sample was taken from a single center&#46; This limits the generalizability of the cluster profiling to other populations&#46; However&#44; we incorporated more objective variables than subjective features into the models&#46; This provided greater reliability compared to the characteristics with large international variability or vague definitions &#40;e&#46;g&#46;&#44; socioeconomic or subjective characteristics&#41;&#46; Applying our method to multinational datasets would establish the existence of different clusters in patients with pSS&#46; Ideally&#44; a large dataset of patients with other differential diagnoses to pSS would allow for the investigation of the existence of clusters with intermediary clinical pictures&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conclusion</span><p id="par0090" class="elsevierStylePara elsevierViewall">We identified two distinct clusters of low or high disease activity among patients with pSS&#46; Our analysis showed that patients with higher syndrome activity were best recognized with serological and ultrasound assessments&#46; The results of IgG and RF assessments were significantly correlated with disease activity&#46; Within the cluster with higher pSS activity&#44; the results of anti-SSA&#44; anti-SSB&#44; ultrasound&#44; and ANA showed direct and significant pairwise associations&#46; However&#44; patients with lower syndrome activity had a longer disease duration&#44; higher stimulated salivary flow rate&#44; and a positive biopsy of minor salivary glands&#46; We suggest performing a minor salivary gland biopsy for diagnosing pSS&#44; even in patients with seemingly low disease activity&#46; We also recommend considering disease activity in further research on the diagnosis of pSS&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Competing interests</span><p id="par0095" class="elsevierStylePara elsevierViewall">The authors declare that they have no competing interests&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Funding</span><p id="par0100" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public&#44; commercial&#44; or not-for-profit sectors&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">The diagnosis of primary Sj&#1255;gren&#39;s syndrome still relies upon a constellation of clinical&#44; laboratory&#44; imaging&#44; and pathological findings&#46; We aimed to evaluate the relation of the disease activity with the results of diagnostic tests for primary Sj&#1255;gren&#39;s syndrome&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">A principal component with cluster analysis was performed to classify 69 patients with primary Sj&#1255;gren&#39;s syndrome based on the results of diagnostic evaluations&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Anti-SSA autoantibody was the most represented feature on the principal components&#46; The anti-SSA and ultrasound score were positively correlated &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; We identified two distinct clusters of low or high disease activity &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Except for disease duration and serum beta2-microglobulin&#44; the clusters were significantly different in salivary flow &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span> 0&#46;004&#41;&#44; ultrasound findings &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; IgG &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span> 0&#46;001&#41;&#44; and salivary beta2-microglobulin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span> 0&#46;048&#41;&#46; Also&#44; positive findings were significantly different between the clusters in rheumatoid factor&#44; antinuclear antibody&#44; anti-SSA&#44; and anti-SSB &#40;all <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;013&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Patients with higher syndrome activity were best recognized with serological and ultrasound assessments&#46; However&#44; patients with lower syndrome activity had a longer disease duration&#44; higher stimulated salivary flow rate&#44; and a positive biopsy of minor salivary glands &#40;56&#37;&#41;&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">El diagn&#243;stico del s&#237;ndrome de Sj&#1255;gren primario todav&#237;a se basa en una constelaci&#243;n de hallazgos cl&#237;nicos&#44; de laboratorio&#44; de imagen y patol&#243;gicos&#46; Nuestro objetivo fue evaluar la relaci&#243;n de la actividad de la enfermedad con los resultados de las pruebas diagn&#243;sticas para el s&#237;ndrome de Sj&#1255;gren primario&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Se realiz&#243; un an&#225;lisis de componentes principales mediante conglomerados para clasificar a 69 pacientes con s&#237;ndrome de Sj&#1255;gren primario en funci&#243;n de los resultados de las evaluaciones de diagn&#243;stico&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">El autoanticuerpo anti-SSA fue la caracter&#237;stica m&#225;s representada en los componentes principales&#46; El anti-SSA y la puntuaci&#243;n de ultrasonido se correlacionaron positivamente &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Identificamos dos grupos distintos de baja o alta actividad de la enfermedad &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Excepto por la duraci&#243;n de la enfermedad y la microglobulina beta2 s&#233;rica&#44; los grupos fueron significativamente diferentes en el flujo salival &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;004&#41;&#44; los hallazgos de ultrasonido &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; IgG &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; y microglobulina beta2 salival &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;048&#41;&#46; Adem&#225;s&#44; los hallazgos positivos fueron significativamente diferentes entre los grupos en factor reumatoide&#44; anticuerpo antinuclear&#44; anti-SSA y anti-SSB &#40;todos <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#44;013&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Los pacientes con mayor actividad del s&#237;ndrome se reconocieron mejor con evaluaciones serol&#243;gicas y ecogr&#225;ficas&#46; Sin embargo&#44; los pacientes con menor actividad del s&#237;ndrome ten&#237;an una mayor duraci&#243;n de la enfermedad&#44; mayor tasa de flujo salival estimulado y una biopsia productiva de gl&#225;ndulas salivales menores &#40;56&#37;&#41;&#46;</p></span>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Biplot of individuals and variables on the principal components&#46; Each solid circle represents an individual&#44; and the size of each circle represents the ESSDAI scores for that individual&#46; The arrows represent correlations between the study variables with the principal components&#46; &#40;B&#41; Dendrogram for hierarchical clustering of patients&#46; &#40;C&#41; Biplot of individuals and variables on the principal components using clustered data&#46; The colored concentration ellipses represent patients&#8217; clusters&#46;</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">FANA&#58; Fluorescent Anti-Nuclear Antibody&#59; RF&#58; Rheumatoid Factor&#59; ESSDAI&#58; European League Against Rheumatism Sj&#246;gren&#8217;s Syndrome Disease Activity Index&#46;</p>"
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0 &#91;0&#46;8&#44; 3&#46;5&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ESSDAI Score&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0 &#91;0&#46;0&#44; 5&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
            1 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive Biopsy &#40;vs&#46; not performed&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21 &#40;30&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive Rheumatoid Factor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37 &#40;52&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive Fluorescent Antinuclear Antibody&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58 &#40;82&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive anti-Ro&#47;SSA Antibody&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39 &#40;55&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive anti-La&#47;SSB Antibody&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22 &#40;31&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Patient characteristics &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>70&#41;&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0045"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">ESSDAI&#58; European League Against Rheumatism Sj&#246;gren&#8217;s Syndrome Disease Activity Index&#46;</p>"
          "tablatextoimagen" => array:2 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Characteristic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cluster</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Cluster 1 &#40;n<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Cluster 2 &#40;n<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Median &#91;Interquartile Range&#93;</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mann-Whitney <span class="elsevierStyleItalic">U</span> test&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disease Duration &#40;year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;0 &#91;3&#46;5&#44; 15&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;0 &#40;2&#46;0&#44; 10&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;090&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stimulated Salivary Flow Rate &#40;ml&#47;min&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;230 &#91;0&#46;040&#44; 0&#46;300&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;050 &#91;0&#46;020&#44; 0&#46;150&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;004&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Salivary Ultrasound Score&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0 &#91;1&#46;0&#44; 3&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;0 &#91;3&#46;0&#44; 4&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IgG &#40;&#956;g&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;048&#46;0 &#91;987&#46;5&#44; 1&#44;260&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;376&#46;0 &#91;1&#44;120&#46;0&#44; 2&#44;019&#46;2&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;001&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Salivary beta2-microglobulin &#40;&#956;g&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;0 &#91;1&#46;4&#44; 4&#46;8&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0 &#91;0&#46;1&#44; 3&#46;7&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;048&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serum beta2-microglobulin &#40;&#956;g&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;6 &#91;0&#46;5&#44; 2&#46;3&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;3 &#91;0&#46;8&#44; 4&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;213&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ESSDAI Score&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0 &#91;0&#46;0&#44; 2&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;0 &#91;2&#46;0&#44; 6&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
            1 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number &#40;&#37;&#41;</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> test&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive Biopsy &#40;vs&#46; not performed&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 &#40;55&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;12&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">37 &#40;88&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2023.02.004

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