Quantitative assessment of interstitial lung disease in Sjögren’s syndrome
Identifieur interne : 000777 ( Pmc/Corpus ); précédent : 000776; suivant : 000778Quantitative assessment of interstitial lung disease in Sjögren’s syndrome
Auteurs : Pablo Guisado-Vasco ; Mario Silva ; Miguel Angel Duarte-Millán ; Gianluca Sambataro ; Chiara Bertolazzi ; Mauro Pavone ; Isabel Martín-Garrido ; Oriol Martín-Segarra ; José Manuel Luque-Pinilla ; Daniele Santilli ; Domenico Sambataro ; Sebastiano E. Torrisi ; Ada Vancheri ; Marwin Gutiérrez ; Mayra Mejia ; Stefano Palmucci ; Flavio Mozzani ; Jorge Rojas-Serrano ; Carlo Vanchieri ; Nicola Sverzellati ; Alarico ArianiSource :
- PLoS ONE [ 1932-6203 ] ; 2019.
Abstract
Interstitial lung disease (ILD) is a frequent manifestation of Sjögren’s syndrome (SS), an autoimmune disease of salivary and lacrimal glands, and affects approximately 20% of patients. No clinical or serological features appear to be useful to predict its presence, severity or progression, and chest high-resolution computed tomography (CT) remains the gold standard for diagnosis. Semiquantitative CT (SQCT) based on visual assessment (Goh and Taouli scoring) can estimate ILD extent, although it is burdened by relevant intra- and interobserver variability. Quantitative chest CT (QCT) is a promising alternative modality to assess ILD severity.
To determine whether QCT assessment can identify extensive or limited lung disease in patients with SS and ILD.
This multi-center, cross-sectional and retrospective study enrolled patients with SS and a chest CT scan. SQCT assessment was carried out in a blinded and centralized manner to calculate both Goh and Taouli scores. An operator-independent analysis of all CT scans with the open-source software platform Horos was used to evaluate the QCT indices. Patients were classified according to the extent of ILD and differences in QCT index distribution were investigated with non-parametric tests.
From a total of 102 consecutive patients with SS, the prevalence of ILD was 35.3% (36/102). There was a statistically significant difference in QCT index distribution between the SS with ILD and SS without ILD groups (p<0.001). Moreover, SS-ILD patients with ILD >20% (by Goh score) had a QCT index statistically different from those with limited ILD extent (p<0.001). Finally, QCT indices showed a moderate-to-good correlation with the Goh and Taouli scores (from 0.44 to 0.65; p<0.001).
QCT indices can identify patients with SS and ILD and discriminate those with lesser or greater lung disease.
Url:
DOI: 10.1371/journal.pone.0224772
PubMed: 31703067
PubMed Central: 6839858
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Quantitative assessment of interstitial lung disease in Sjögren’s syndrome</title><author><name sortKey="Guisado Vasco, Pablo" sort="Guisado Vasco, Pablo" uniqKey="Guisado Vasco P" first="Pablo" last="Guisado-Vasco">Pablo Guisado-Vasco</name><affiliation><nlm:aff id="aff001"><addr-line>Internal Medicine, Complejo hospitalario Ruber Juan Bravo, Universidad Europea (Madrid), Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Silva, Mario" sort="Silva, Mario" uniqKey="Silva M" first="Mario" last="Silva">Mario Silva</name><affiliation><nlm:aff id="aff002"><addr-line>Scienze Radiologiche, Dipartimento di Medicina e Chirurgia (DiMeC), University of Parma, Parma, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Duarte Millan, Miguel Angel" sort="Duarte Millan, Miguel Angel" uniqKey="Duarte Millan M" first="Miguel Angel" last="Duarte-Millán">Miguel Angel Duarte-Millán</name><affiliation><nlm:aff id="aff003"><addr-line>Internal Medicine, Hospital universitario Fuenlabrada, Fuenlabrada, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sambataro, Gianluca" sort="Sambataro, Gianluca" uniqKey="Sambataro G" first="Gianluca" last="Sambataro">Gianluca Sambataro</name><affiliation><nlm:aff id="aff004"><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bertolazzi, Chiara" sort="Bertolazzi, Chiara" uniqKey="Bertolazzi C" first="Chiara" last="Bertolazzi">Chiara Bertolazzi</name><affiliation><nlm:aff id="aff005"><addr-line>Division of Musculoskeletal and Rheumatic Disorders, Instituto Nacional de Rehabilitación—“Luis Guillermo Ibarra Ibarra”, Mexico City, Mexico</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pavone, Mauro" sort="Pavone, Mauro" uniqKey="Pavone M" first="Mauro" last="Pavone">Mauro Pavone</name><affiliation><nlm:aff id="aff004"><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Martin Garrido, Isabel" sort="Martin Garrido, Isabel" uniqKey="Martin Garrido I" first="Isabel" last="Martín-Garrido">Isabel Martín-Garrido</name><affiliation><nlm:aff id="aff001"><addr-line>Internal Medicine, Complejo hospitalario Ruber Juan Bravo, Universidad Europea (Madrid), Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Martin Segarra, Oriol" sort="Martin Segarra, Oriol" uniqKey="Martin Segarra O" first="Oriol" last="Martín-Segarra">Oriol Martín-Segarra</name><affiliation><nlm:aff id="aff001"><addr-line>Internal Medicine, Complejo hospitalario Ruber Juan Bravo, Universidad Europea (Madrid), Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Luque Pinilla, Jose Manuel" sort="Luque Pinilla, Jose Manuel" uniqKey="Luque Pinilla J" first="José Manuel" last="Luque-Pinilla">José Manuel Luque-Pinilla</name><affiliation><nlm:aff id="aff001"><addr-line>Internal Medicine, Complejo hospitalario Ruber Juan Bravo, Universidad Europea (Madrid), Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Santilli, Daniele" sort="Santilli, Daniele" uniqKey="Santilli D" first="Daniele" last="Santilli">Daniele Santilli</name><affiliation><nlm:aff id="aff006"><addr-line>Internal Medicine and Rheumatoloy Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sambataro, Domenico" sort="Sambataro, Domenico" uniqKey="Sambataro D" first="Domenico" last="Sambataro">Domenico Sambataro</name><affiliation><nlm:aff id="aff007"><addr-line>Department of Clinical and Experimental Medicine, Internal Medicine Unit, Cannizaro Hospital, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Torrisi, Sebastiano E" sort="Torrisi, Sebastiano E" uniqKey="Torrisi S" first="Sebastiano E." last="Torrisi">Sebastiano E. Torrisi</name><affiliation><nlm:aff id="aff004"><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vancheri, Ada" sort="Vancheri, Ada" uniqKey="Vancheri A" first="Ada" last="Vancheri">Ada Vancheri</name><affiliation><nlm:aff id="aff004"><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gutierrez, Marwin" sort="Gutierrez, Marwin" uniqKey="Gutierrez M" first="Marwin" last="Gutiérrez">Marwin Gutiérrez</name><affiliation><nlm:aff id="aff005"><addr-line>Division of Musculoskeletal and Rheumatic Disorders, Instituto Nacional de Rehabilitación—“Luis Guillermo Ibarra Ibarra”, Mexico City, Mexico</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mejia, Mayra" sort="Mejia, Mayra" uniqKey="Mejia M" first="Mayra" last="Mejia">Mayra Mejia</name><affiliation><nlm:aff id="aff008"><addr-line>Interstitial Lung Disease and Rheumatology Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Mexico City, Mexico</addr-line></nlm:aff></affiliation></author><author><name sortKey="Palmucci, Stefano" sort="Palmucci, Stefano" uniqKey="Palmucci S" first="Stefano" last="Palmucci">Stefano Palmucci</name><affiliation><nlm:aff id="aff009"><addr-line>Department of Medica Surgical Sciences and Advanced Technologies "GR Ingrassia", Radiology I unit, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mozzani, Flavio" sort="Mozzani, Flavio" uniqKey="Mozzani F" first="Flavio" last="Mozzani">Flavio Mozzani</name><affiliation><nlm:aff id="aff006"><addr-line>Internal Medicine and Rheumatoloy Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rojas Serrano, Jorge" sort="Rojas Serrano, Jorge" uniqKey="Rojas Serrano J" first="Jorge" last="Rojas-Serrano">Jorge Rojas-Serrano</name><affiliation><nlm:aff id="aff008"><addr-line>Interstitial Lung Disease and Rheumatology Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Mexico City, Mexico</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vanchieri, Carlo" sort="Vanchieri, Carlo" uniqKey="Vanchieri C" first="Carlo" last="Vanchieri">Carlo Vanchieri</name><affiliation><nlm:aff id="aff004"><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sverzellati, Nicola" sort="Sverzellati, Nicola" uniqKey="Sverzellati N" first="Nicola" last="Sverzellati">Nicola Sverzellati</name><affiliation><nlm:aff id="aff002"><addr-line>Scienze Radiologiche, Dipartimento di Medicina e Chirurgia (DiMeC), University of Parma, Parma, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ariani, Alarico" sort="Ariani, Alarico" uniqKey="Ariani A" first="Alarico" last="Ariani">Alarico Ariani</name><affiliation><nlm:aff id="aff006"><addr-line>Internal Medicine and Rheumatoloy Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31703067</idno><idno type="pmc">6839858</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839858</idno><idno type="RBID">PMC:6839858</idno><idno type="doi">10.1371/journal.pone.0224772</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000777</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000777</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Quantitative assessment of interstitial lung disease in Sjögren’s syndrome</title><author><name sortKey="Guisado Vasco, Pablo" sort="Guisado Vasco, Pablo" uniqKey="Guisado Vasco P" first="Pablo" last="Guisado-Vasco">Pablo Guisado-Vasco</name><affiliation><nlm:aff id="aff001"><addr-line>Internal Medicine, Complejo hospitalario Ruber Juan Bravo, Universidad Europea (Madrid), Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Silva, Mario" sort="Silva, Mario" uniqKey="Silva M" first="Mario" last="Silva">Mario Silva</name><affiliation><nlm:aff id="aff002"><addr-line>Scienze Radiologiche, Dipartimento di Medicina e Chirurgia (DiMeC), University of Parma, Parma, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Duarte Millan, Miguel Angel" sort="Duarte Millan, Miguel Angel" uniqKey="Duarte Millan M" first="Miguel Angel" last="Duarte-Millán">Miguel Angel Duarte-Millán</name><affiliation><nlm:aff id="aff003"><addr-line>Internal Medicine, Hospital universitario Fuenlabrada, Fuenlabrada, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sambataro, Gianluca" sort="Sambataro, Gianluca" uniqKey="Sambataro G" first="Gianluca" last="Sambataro">Gianluca Sambataro</name><affiliation><nlm:aff id="aff004"><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bertolazzi, Chiara" sort="Bertolazzi, Chiara" uniqKey="Bertolazzi C" first="Chiara" last="Bertolazzi">Chiara Bertolazzi</name><affiliation><nlm:aff id="aff005"><addr-line>Division of Musculoskeletal and Rheumatic Disorders, Instituto Nacional de Rehabilitación—“Luis Guillermo Ibarra Ibarra”, Mexico City, Mexico</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pavone, Mauro" sort="Pavone, Mauro" uniqKey="Pavone M" first="Mauro" last="Pavone">Mauro Pavone</name><affiliation><nlm:aff id="aff004"><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Martin Garrido, Isabel" sort="Martin Garrido, Isabel" uniqKey="Martin Garrido I" first="Isabel" last="Martín-Garrido">Isabel Martín-Garrido</name><affiliation><nlm:aff id="aff001"><addr-line>Internal Medicine, Complejo hospitalario Ruber Juan Bravo, Universidad Europea (Madrid), Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Martin Segarra, Oriol" sort="Martin Segarra, Oriol" uniqKey="Martin Segarra O" first="Oriol" last="Martín-Segarra">Oriol Martín-Segarra</name><affiliation><nlm:aff id="aff001"><addr-line>Internal Medicine, Complejo hospitalario Ruber Juan Bravo, Universidad Europea (Madrid), Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Luque Pinilla, Jose Manuel" sort="Luque Pinilla, Jose Manuel" uniqKey="Luque Pinilla J" first="José Manuel" last="Luque-Pinilla">José Manuel Luque-Pinilla</name><affiliation><nlm:aff id="aff001"><addr-line>Internal Medicine, Complejo hospitalario Ruber Juan Bravo, Universidad Europea (Madrid), Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Santilli, Daniele" sort="Santilli, Daniele" uniqKey="Santilli D" first="Daniele" last="Santilli">Daniele Santilli</name><affiliation><nlm:aff id="aff006"><addr-line>Internal Medicine and Rheumatoloy Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sambataro, Domenico" sort="Sambataro, Domenico" uniqKey="Sambataro D" first="Domenico" last="Sambataro">Domenico Sambataro</name><affiliation><nlm:aff id="aff007"><addr-line>Department of Clinical and Experimental Medicine, Internal Medicine Unit, Cannizaro Hospital, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Torrisi, Sebastiano E" sort="Torrisi, Sebastiano E" uniqKey="Torrisi S" first="Sebastiano E." last="Torrisi">Sebastiano E. Torrisi</name><affiliation><nlm:aff id="aff004"><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vancheri, Ada" sort="Vancheri, Ada" uniqKey="Vancheri A" first="Ada" last="Vancheri">Ada Vancheri</name><affiliation><nlm:aff id="aff004"><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gutierrez, Marwin" sort="Gutierrez, Marwin" uniqKey="Gutierrez M" first="Marwin" last="Gutiérrez">Marwin Gutiérrez</name><affiliation><nlm:aff id="aff005"><addr-line>Division of Musculoskeletal and Rheumatic Disorders, Instituto Nacional de Rehabilitación—“Luis Guillermo Ibarra Ibarra”, Mexico City, Mexico</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mejia, Mayra" sort="Mejia, Mayra" uniqKey="Mejia M" first="Mayra" last="Mejia">Mayra Mejia</name><affiliation><nlm:aff id="aff008"><addr-line>Interstitial Lung Disease and Rheumatology Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Mexico City, Mexico</addr-line></nlm:aff></affiliation></author><author><name sortKey="Palmucci, Stefano" sort="Palmucci, Stefano" uniqKey="Palmucci S" first="Stefano" last="Palmucci">Stefano Palmucci</name><affiliation><nlm:aff id="aff009"><addr-line>Department of Medica Surgical Sciences and Advanced Technologies "GR Ingrassia", Radiology I unit, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mozzani, Flavio" sort="Mozzani, Flavio" uniqKey="Mozzani F" first="Flavio" last="Mozzani">Flavio Mozzani</name><affiliation><nlm:aff id="aff006"><addr-line>Internal Medicine and Rheumatoloy Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rojas Serrano, Jorge" sort="Rojas Serrano, Jorge" uniqKey="Rojas Serrano J" first="Jorge" last="Rojas-Serrano">Jorge Rojas-Serrano</name><affiliation><nlm:aff id="aff008"><addr-line>Interstitial Lung Disease and Rheumatology Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Mexico City, Mexico</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vanchieri, Carlo" sort="Vanchieri, Carlo" uniqKey="Vanchieri C" first="Carlo" last="Vanchieri">Carlo Vanchieri</name><affiliation><nlm:aff id="aff004"><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sverzellati, Nicola" sort="Sverzellati, Nicola" uniqKey="Sverzellati N" first="Nicola" last="Sverzellati">Nicola Sverzellati</name><affiliation><nlm:aff id="aff002"><addr-line>Scienze Radiologiche, Dipartimento di Medicina e Chirurgia (DiMeC), University of Parma, Parma, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ariani, Alarico" sort="Ariani, Alarico" uniqKey="Ariani A" first="Alarico" last="Ariani">Alarico Ariani</name><affiliation><nlm:aff id="aff006"><addr-line>Internal Medicine and Rheumatoloy Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title><p>Interstitial lung disease (ILD) is a frequent manifestation of Sjögren’s syndrome (SS), an autoimmune disease of salivary and lacrimal glands, and affects approximately 20% of patients. No clinical or serological features appear to be useful to predict its presence, severity or progression, and chest high-resolution computed tomography (CT) remains the gold standard for diagnosis. Semiquantitative CT (SQCT) based on visual assessment (Goh and Taouli scoring) can estimate ILD extent, although it is burdened by relevant intra- and interobserver variability. Quantitative chest CT (QCT) is a promising alternative modality to assess ILD severity.</p></sec><sec id="sec002"><title>Aim</title><p>To determine whether QCT assessment can identify extensive or limited lung disease in patients with SS and ILD.</p></sec><sec id="sec003"><title>Methods</title><p>This multi-center, cross-sectional and retrospective study enrolled patients with SS and a chest CT scan. SQCT assessment was carried out in a blinded and centralized manner to calculate both Goh and Taouli scores. An operator-independent analysis of all CT scans with the open-source software platform Horos was used to evaluate the QCT indices. Patients were classified according to the extent of ILD and differences in QCT index distribution were investigated with non-parametric tests.</p></sec><sec id="sec004"><title>Results</title><p>From a total of 102 consecutive patients with SS, the prevalence of ILD was 35.3% (36/102). There was a statistically significant difference in QCT index distribution between the SS with ILD and SS without ILD groups (p<0.001). Moreover, SS-ILD patients with ILD >20% (by Goh score) had a QCT index statistically different from those with limited ILD extent (p<0.001). Finally, QCT indices showed a moderate-to-good correlation with the Goh and Taouli scores (from 0.44 to 0.65; p<0.001).</p></sec><sec id="sec005"><title>Conclusions</title><p>QCT indices can identify patients with SS and ILD and discriminate those with lesser or greater lung disease.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Gao, H" uniqKey="Gao H">H Gao</name></author><author><name sortKey="Zou, Yd" uniqKey="Zou Y">YD Zou</name></author><author><name sortKey="Zhang, Xw" uniqKey="Zhang X">XW Zhang</name></author><author><name sortKey="He, J" uniqKey="He J">J He</name></author><author><name sortKey="Zhang, J" uniqKey="Zhang J">J Zhang</name></author><author><name sortKey="Sun, Y" uniqKey="Sun Y">Y Sun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ramos Casals, M" uniqKey="Ramos Casals M">M Ramos-Casals</name></author><author><name sortKey="Brito Zer N, P" uniqKey="Brito Zer N P">P 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31703067</article-id><article-id pub-id-type="pmc">6839858</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0224772</article-id><article-id pub-id-type="publisher-id">PONE-D-19-20968</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Imaging Techniques</subject><subj-group><subject>Neuroimaging</subject><subj-group><subject>Computed Axial Tomography</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Neuroscience</subject><subj-group><subject>Neuroimaging</subject><subj-group><subject>Computed Axial Tomography</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Diagnostic Medicine</subject><subj-group><subject>Diagnostic Radiology</subject><subj-group><subject>Tomography</subject><subj-group><subject>Computed Axial Tomography</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Imaging Techniques</subject><subj-group><subject>Diagnostic Radiology</subject><subj-group><subject>Tomography</subject><subj-group><subject>Computed Axial Tomography</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Radiology and Imaging</subject><subj-group><subject>Diagnostic Radiology</subject><subj-group><subject>Tomography</subject><subj-group><subject>Computed Axial Tomography</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pulmonology</subject><subj-group><subject>Interstitial Lung Diseases</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pulmonology</subject><subj-group><subject>Pulmonary Function</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pulmonology</subject><subj-group><subject>Pneumonia</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Clinical Medicine</subject><subj-group><subject>Clinical Immunology</subject><subj-group><subject>Autoimmune Diseases</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Clinical Immunology</subject><subj-group><subject>Autoimmune Diseases</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Clinical Immunology</subject><subj-group><subject>Autoimmune Diseases</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Mathematics</subject><subj-group><subject>Statistics</subject><subj-group><subject>Statistical Data</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Digestive System</subject><subj-group><subject>Salivary Glands</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Digestive System</subject><subj-group><subject>Salivary Glands</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Exocrine Glands</subject><subj-group><subject>Salivary Glands</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Exocrine Glands</subject><subj-group><subject>Salivary Glands</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Mathematics</subject><subj-group><subject>Probability Theory</subject><subj-group><subject>Statistical Distributions</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Quantitative assessment of interstitial lung disease in Sjögren’s syndrome</article-title><alt-title alt-title-type="running-head">Quantitative indices and Sjögren's syndrome</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-3019-4398</contrib-id><name><surname>Guisado-Vasco</surname><given-names>Pablo</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Silva</surname><given-names>Mario</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Software</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Duarte-Millán</surname><given-names>Miguel Angel</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sambataro</surname><given-names>Gianluca</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bertolazzi</surname><given-names>Chiara</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff005"><sup>5</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pavone</surname><given-names>Mauro</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Martín-Garrido</surname><given-names>Isabel</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Martín-Segarra</surname><given-names>Oriol</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Luque-Pinilla</surname><given-names>José Manuel</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Santilli</surname><given-names>Daniele</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sambataro</surname><given-names>Domenico</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff007"><sup>7</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Torrisi</surname><given-names>Sebastiano E.</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vancheri</surname><given-names>Ada</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gutiérrez</surname><given-names>Marwin</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff005"><sup>5</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mejia</surname><given-names>Mayra</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff008"><sup>8</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Palmucci</surname><given-names>Stefano</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff009"><sup>9</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mozzani</surname><given-names>Flavio</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rojas-Serrano</surname><given-names>Jorge</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff008"><sup>8</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vanchieri</surname><given-names>Carlo</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Sverzellati</surname><given-names>Nicola</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Ariani</surname><given-names>Alarico</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Software</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Internal Medicine, Complejo hospitalario Ruber Juan Bravo, Universidad Europea (Madrid), Madrid, Spain</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Scienze Radiologiche, Dipartimento di Medicina e Chirurgia (DiMeC), University of Parma, Parma, Italy</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Internal Medicine, Hospital universitario Fuenlabrada, Fuenlabrada, Spain</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Regional Referral Center for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dpt. of Clinical and Experimental Medicine, University of Catania, Catania, Italy</addr-line></aff><aff id="aff005"><label>5</label><addr-line>Division of Musculoskeletal and Rheumatic Disorders, Instituto Nacional de Rehabilitación—“Luis Guillermo Ibarra Ibarra”, Mexico City, Mexico</addr-line></aff><aff id="aff006"><label>6</label><addr-line>Internal Medicine and Rheumatoloy Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy</addr-line></aff><aff id="aff007"><label>7</label><addr-line>Department of Clinical and Experimental Medicine, Internal Medicine Unit, Cannizaro Hospital, University of Catania, Catania, Italy</addr-line></aff><aff id="aff008"><label>8</label><addr-line>Interstitial Lung Disease and Rheumatology Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Mexico City, Mexico</addr-line></aff><aff id="aff009"><label>9</label><addr-line>Department of Medica Surgical Sciences and Advanced Technologies "GR Ingrassia", Radiology I unit, University of Catania, Catania, Italy</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Kuwana</surname><given-names>Masataka</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Nippon Medical School, JAPAN</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>Prof. Carlo Vanchieri is part of F. Hoffmann-La Roche Ltd. Scientific Board. He has received consulting fees and/or speaker fees from Astrazeneca, Boehringer Ingelheim, Chiesi, F. Hoffmann-La Roche Ltd and Menarini. Prof. Stefano Palmucci has reveived personal fees and honoraria for lectures from Boehringer Ingelheim, Delphi International srl and F. Hoffmann-La Roche Ltd. He has been included in the scientific board for Boehringer Ingelheim. This does not alter our adherence to PLOS ONE policies on sharing data and materials. None of the other authors have any potential conflicts of interest to disclose in relation to this work.</p></fn><fn fn-type="other" id="econtrib001"><p>‡ These authors also contributed equally to this work.</p></fn><corresp id="cor001">* E-mail: <email>pablogvasco@gmail.com</email></corresp></author-notes><pub-date pub-type="epub"><day>8</day><month>11</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>14</volume><issue>11</issue><elocation-id>e0224772</elocation-id><history><date date-type="received"><day>25</day><month>7</month><year>2019</year></date><date date-type="accepted"><day>21</day><month>10</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 Guisado-Vasco et al</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Guisado-Vasco et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0224772.pdf"></self-uri><abstract><sec id="sec001"><title>Background</title><p>Interstitial lung disease (ILD) is a frequent manifestation of Sjögren’s syndrome (SS), an autoimmune disease of salivary and lacrimal glands, and affects approximately 20% of patients. No clinical or serological features appear to be useful to predict its presence, severity or progression, and chest high-resolution computed tomography (CT) remains the gold standard for diagnosis. Semiquantitative CT (SQCT) based on visual assessment (Goh and Taouli scoring) can estimate ILD extent, although it is burdened by relevant intra- and interobserver variability. Quantitative chest CT (QCT) is a promising alternative modality to assess ILD severity.</p></sec><sec id="sec002"><title>Aim</title><p>To determine whether QCT assessment can identify extensive or limited lung disease in patients with SS and ILD.</p></sec><sec id="sec003"><title>Methods</title><p>This multi-center, cross-sectional and retrospective study enrolled patients with SS and a chest CT scan. SQCT assessment was carried out in a blinded and centralized manner to calculate both Goh and Taouli scores. An operator-independent analysis of all CT scans with the open-source software platform Horos was used to evaluate the QCT indices. Patients were classified according to the extent of ILD and differences in QCT index distribution were investigated with non-parametric tests.</p></sec><sec id="sec004"><title>Results</title><p>From a total of 102 consecutive patients with SS, the prevalence of ILD was 35.3% (36/102). There was a statistically significant difference in QCT index distribution between the SS with ILD and SS without ILD groups (p<0.001). Moreover, SS-ILD patients with ILD >20% (by Goh score) had a QCT index statistically different from those with limited ILD extent (p<0.001). Finally, QCT indices showed a moderate-to-good correlation with the Goh and Taouli scores (from 0.44 to 0.65; p<0.001).</p></sec><sec id="sec005"><title>Conclusions</title><p>QCT indices can identify patients with SS and ILD and discriminate those with lesser or greater lung disease.</p></sec></abstract><funding-group><funding-statement>This work was supported by Internal/own funds of the Complejo Hospitalario Ruber Juan Bravo for clinical research. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><fig-count count="2"></fig-count><table-count count="4"></table-count><page-count count="13"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>A public repository of the data will be held in: <ext-link ext-link-type="uri" xlink:href="http://www.datadryad.org/stash/">www.datadryad.org/stash/</ext-link> (DOI <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.5061/dryad.sbcc2fr22">https://doi.org/10.5061/dryad.sbcc2fr22</ext-link>). Direct download of the data are available from: <ext-link ext-link-type="uri" xlink:href="https://datadryad.org/stash/share/1HiLI_7GxvhUu2wIAQNCCUK5ScptshXoJuCggR4g9Js">https://datadryad.org/stash/share/1HiLI_7GxvhUu2wIAQNCCUK5ScptshXoJuCggR4g9Js</ext-link>. An independent researcher could contact with the Ethics Committee (E-Mail: <email>ceic@fjd.es</email>), for full access to confidential data, after requesting personal authorization.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>A public repository of the data will be held in: <ext-link ext-link-type="uri" xlink:href="http://www.datadryad.org/stash/">www.datadryad.org/stash/</ext-link> (DOI <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.5061/dryad.sbcc2fr22">https://doi.org/10.5061/dryad.sbcc2fr22</ext-link>). Direct download of the data are available from: <ext-link ext-link-type="uri" xlink:href="https://datadryad.org/stash/share/1HiLI_7GxvhUu2wIAQNCCUK5ScptshXoJuCggR4g9Js">https://datadryad.org/stash/share/1HiLI_7GxvhUu2wIAQNCCUK5ScptshXoJuCggR4g9Js</ext-link>. An independent researcher could contact with the Ethics Committee (E-Mail: <email>ceic@fjd.es</email>), for full access to confidential data, after requesting personal authorization.</p></notes></front><body><sec sec-type="intro" id="sec006"><title>Background</title><p>Sjögren’s syndrome (SS) is systemic autoimmune disease characterized by chronic lymphocytic inflammation of ductal epithelial structures. The disease affects principally the exocrine glands, in particular the lacrimal and salivary glands, causing dryness of mucosal surfaces–termed sicca syndrome–and glandular parenchymal damage. The pathogenesis of SS is poorly understood, and manifestations are heterogeneous [<xref rid="pone.0224772.ref001" ref-type="bibr">1</xref>]. Accordingly, there is increasing interest in its systemic involvement [<xref rid="pone.0224772.ref002" ref-type="bibr">2</xref>] and how to reach a precise diagnosis using molecular profiling [<xref rid="pone.0224772.ref003" ref-type="bibr">3</xref>–<xref rid="pone.0224772.ref004" ref-type="bibr">4</xref>].</p><p>Interstitial lung disease (ILD) remains one of most frequent pulmonary complications in primary SS and sub-clinical disease is even more common [<xref rid="pone.0224772.ref005" ref-type="bibr">5</xref>–<xref rid="pone.0224772.ref006" ref-type="bibr">6</xref>]. Pulmonary disease is a singular clinical and histopathological scenario among the organ-specific SS involvement and leads to increased risk of mortality [<xref rid="pone.0224772.ref007" ref-type="bibr">7</xref>–<xref rid="pone.0224772.ref008" ref-type="bibr">8</xref>]; and it is considered in the high systemic activity domain of the European League against Rheumatism (EULAR) Sjögren’s syndrome disease activity index (ESSDAI).</p><p>An accurate differential diagnosis of ILD, obstructive disease, bronchial hyper-responsiveness, bronchiolitis, bronchiectasis or xerotrachea can be challenging [<xref rid="pone.0224772.ref009" ref-type="bibr">9</xref>]. High-resolution chest computer tomography (HRCT) is currently considered the gold standard imaging modality in confirming a diagnosis of SS and has clear improvements over classical chest x-ray [<xref rid="pone.0224772.ref010" ref-type="bibr">10</xref>–<xref rid="pone.0224772.ref012" ref-type="bibr">12</xref>]. It also allows for the discrimination and estimation of the extent of the ILD and can inform on treatment decisions. Likewise, semiquantitative CT (SQCT) assessment, such as the Goh [<xref rid="pone.0224772.ref013" ref-type="bibr">13</xref>] and Tauli [<xref rid="pone.0224772.ref014" ref-type="bibr">14</xref>] visual scores, can estimate ILD severity–in terms of limited or extensive disease–in autoimmune systemic diseases. However, these classification systems suffer from intra- and interobserver variability [<xref rid="pone.0224772.ref015" ref-type="bibr">15</xref>]. Quantitative CT (QCT) analysis is a promising tool to assess primary or secondary ILD and its extent. It is based on software providing highly accurate and operator-independent measurements, termed QCT indices [<xref rid="pone.0224772.ref016" ref-type="bibr">16</xref>], which have been rapidly developed and validated in specific clinical settings, including systemic autoimmune diseases [<xref rid="pone.0224772.ref017" ref-type="bibr">17</xref>].</p><p>To the best of our knowledge, there have been no studies focused on the use of QCT for SS with ILD. Herein, we designed a study to evaluate whether QCT indices have clinical utility to screen for ILD and to appraise differences between limited and extensive ILD.</p></sec><sec sec-type="materials|methods" id="sec007"><title>Methods</title><p>We performed a multicenter, cross-sectional, and retrospective study in patients with SS enrolled in four university-affiliated centers.</p><p>The following inclusion criteria were applied: 2016 American College of Rheumatology (ACR)/EULAR criteria [<xref rid="pone.0224772.ref018" ref-type="bibr">18</xref>], a chest CT scan ordered by a primary care physician for any reason, and age older than 18 years. The exclusion criteria included those specified by the 2016 ACR/EULAR consensus, including IgG4 disease, any immunosuppressive therapy with any biological agent in the last 3 months, or methotrexate or leflunomide in the year prior to study inclusion. Prednisone (or equivalent) at a dose ≤7.5 mg (on a tapering plan only) or low-dose hydroxychloroquine was allowed. The research protocol was approved by the local ethics committees and was conducted in accordance with the tenets of the Helsinki Declaration. The protocol was developed following the STROBE statement [<xref rid="pone.0224772.ref019" ref-type="bibr">19</xref>]</p><p>The following data were collected from all patients: demographic variables (age, sex), date of disease onset, symptoms suspicion of pulmonary disease, smoking habit, chest CT scan, pulmonary function tests [diffusing capacity of carbon monoxide (DLco), DLco divided by alveolar volume (DLco/VA), forced vital capacity (FVC) and total volume capacity (TLC)], and autoantibodies profile (SSA/Ro, SSB/La). The laboratories of all the participating centers used the same methodology, which was adopted from the current standards of the American Thoracic Society/European Respiratory Society.</p><p>A DICOM (digital imaging and communications in medicine) viewer, open-source software (Horos <bold><ext-link ext-link-type="uri" xlink:href="http://www.horosproject.org/">www.horosproject.org</ext-link></bold>) was used for analyses and the following QCT indices were obtained after scan processing: kurtosis (Kurt), mean lung attenuation (MLA), skewness (Skew) and standard deviation (Sdev). The entire procedure including the lung segmentation algorithm was performed as described previously [<xref rid="pone.0224772.ref016" ref-type="bibr">16</xref>]. Accordingly, the region of interest between -950 HU and 400 HU was considered as ‘pulmonary parenchyma’ (namely, lung parenchyma without vessels or bronchioles and not affected by fibrosis). Those voxels included in the whole lung volume with higher HU values were identified as non-parenchymal structures. The QTC indices were calculated according to these definitions, as parenchymal (i.e., pKurt, pSkew, etc.) and total (i.e., tKurt, tSkew, etc.) QTC. These indices are based on the histograms obtained from the computed analysis of the volumetric region of interest [<xref rid="pone.0224772.ref017" ref-type="bibr">17</xref>, <xref rid="pone.0224772.ref020" ref-type="bibr">20</xref>].</p><p>All CT images were centrally and blindly reviewed by the same board-certified radiologists (MS, NS) and QCT indices were then calculated. The SQCT assessment was carried out to calculate both Goh and Taouli scores for each CT scan. On the basis of the SQCT assessment, two groups were established: patients with SS and with/without ILD.</p><p>Data were reported as mean and SD for continuous variables and numbers and percentages for categorical variables. The Kolgomorov-Smirnov test was used to check the assumption of normality of the continuous variables. Differences between subgroups were analyzed using a non-parametric test, as appropriate. The Spearman rank test was used to determine correlations of QCT indices with SQCT scores, pulmonary function tests, and the other collected variables. A Youden index, according to the area under the curve, was run to select the best cut-off point value of QCT indices to assess the ILD.</p><p>The research was approved by the ethics committee of Fundación Jiménez Díaz, Madrid.</p><p>Approval Number: PIC 17–2017 The data were analyzed anonymously.</p><p>A two-tailed probability of p<0.05 was considered statistically significant. All analyses were conducted using SPSS 20.0 (Chicago, IL, USA) and R (version 3.5.2) statistical software package (<bold><ext-link ext-link-type="uri" xlink:href="http://www.R-project.org/">http://www.R-project.org/</ext-link></bold>) (Vienna, Austria).</p></sec><sec sec-type="results" id="sec008"><title>Results</title><p>A total of 102 patients were enrolled between January 2017 and September 2018. Patient characteristics are listed in <xref rid="pone.0224772.t001" ref-type="table">Table 1</xref>.</p><table-wrap id="pone.0224772.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0224772.t001</object-id><label>Table 1</label><caption><title>Baseline characteristics of the patients with Sjögren’s syndrome.</title></caption><alternatives><graphic id="pone.0224772.t001g" xlink:href="pone.0224772.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1"></th><th align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">Total cohort</th><th align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">SS without ILD</th><th align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">SS-ILD</th><th align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">p-value</th></tr></thead><tbody><tr><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">N</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">102</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">66</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">36</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">-</td></tr><tr><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">Age, median (yrs) (95% CI)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">69<break></break>(65–71)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">68<break></break> (63–71)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">69<break></break> (63–74)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">Sex (M:F)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">7:95</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">3:63</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">4:32</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">Smoker (no:former:yes)<xref ref-type="table-fn" rid="t001fn002">*</xref></td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">74:8:11</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">47:8:4</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">27:0:7</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">Disease duration, median (yrs) (95% CI)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">4<break></break>(3–5)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">3<break></break> (2–5)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">5<break></break> (3–7)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">pSS prevalence (%)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">79</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">83</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">72</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">Onset symptoms (sicca:dyspnoea:other)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">51:27:24</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">41:7:18</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">10:20:6</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">Antibodies Ro/SSA<break></break> prevalence (%)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">52</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">47</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">63</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">Antibodies La/SSB<break></break> prevalence (%)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">25</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">21</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">31</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">FVC (%) (95% CI) <xref ref-type="table-fn" rid="t001fn003">**</xref></td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">97<break></break>(93–108)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">108<break></break> (93–116)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">94<break></break> (83–99)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.03</td></tr><tr><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">DLco (%) (95% CI) <xref ref-type="table-fn" rid="t001fn004">***</xref></td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">71<break></break>(62–81)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">82<break></break> (73–87)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">63<break></break> (53–71)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">0.01</td></tr><tr><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">ILD pattern (NSIP:UIP:Other)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">-</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">-</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">27:6:3</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">-</td></tr><tr><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">Goh score (95% CI)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">0</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">0</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">12,5<break></break> (7.7–25.3)</td><td align="justify" style="background-color:#C0C0C0" rowspan="1" colspan="1">-</td></tr><tr><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">Taouli score (95% CI)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">0</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">0</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">8,0<break></break> (5.7–11.0)</td><td align="justify" style="background-color:#F2F2F2" rowspan="1" colspan="1">-</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>Abbreviations: M, male; F, female; CI, confidence interval; pSS, primary SS; ILD, interstitial lung disease; Nss, not statistically significant; FVC, forced vital capacity; DLCO, diffusion of lung CO; TLC, total lung capacity; FEV1, forced expiratory volume in first second; NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia.</p></fn><fn id="t001fn002"><p>* 9/102 patients data missing.</p></fn><fn id="t001fn003"><p>** 41/102 patients data missing.</p></fn><fn id="t001fn004"><p>*** 58/102 patients data missing</p></fn></table-wrap-foot></table-wrap><p>The diseases associated to the development of SS, secondary SS, were: rheumatoid arthritis (5,9%), systemic lupus erythematosus (2%), systemic sclerosis (12,7%), and undifferentiated connective tissue disease (9,8%). Of the, just 10 cases have associated ILD.</p><p>Pulmonary function tests were incomplete in more than half of all patients (41% and 58% of patients did not have FCV and DLco data, respectively). No differences were found for patients with SS with ILD (SS-ILD) and those without ILD in terms of age, disease duration and autoimmune profile. The most common onset symptom in the SS-ILD group was dyspnea (52%), whereas mouth or eye dryness was the most common onset symptom in the SS without ILD group (59%). Pulmonary function tests showed that %FCV and %DLco were lower in the SS-ILD group than in the SS without ILD group (p = 0.03 and p = 0.01, respectively). As expected, there was a strong correlation between the Goh and Taouli scores (rho = 0.98; p<0.001). <xref rid="pone.0224772.t002" ref-type="table">Table 2</xref>.</p><table-wrap id="pone.0224772.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0224772.t002</object-id><label>Table 2</label><caption><title>Correlations of quantitative indices and semiquantiative methods and lung function tests.</title></caption><alternatives><graphic id="pone.0224772.t002g" xlink:href="pone.0224772.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="right" style="background-color:#FFFFFF" rowspan="1" colspan="1"></th><th align="left" style="background-color:#FFFFFF" rowspan="1" colspan="1"><italic>pKurt</italic></th><th align="left" style="background-color:#FFFFFF" rowspan="1" colspan="1"><italic>pMLA</italic></th><th align="left" style="background-color:#FFFFFF" rowspan="1" colspan="1"><italic>pSdev</italic></th><th align="left" style="background-color:#FFFFFF" rowspan="1" colspan="1"><italic>pSkew</italic></th><th align="left" style="background-color:#FFFFFF" rowspan="1" colspan="1"><italic>tKurt</italic></th><th align="left" style="background-color:#FFFFFF" rowspan="1" colspan="1"><italic>tMLA</italic></th><th align="left" style="background-color:#FFFFFF" rowspan="1" colspan="1"><italic>tSdev</italic></th><th align="left" style="background-color:#FFFFFF" rowspan="1" colspan="1"><italic>tSkew</italic></th></tr></thead><tbody><tr><td align="right" rowspan="1" colspan="1"><italic>Goh score</italic><break></break><italic>N = 102</italic></td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0,58</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.48</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.55</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0,56</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0,62</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.44</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.36</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0,65</td></tr><tr><td align="right" rowspan="1" colspan="1"><italic>Taouli score</italic><break></break><italic>N = 102</italic></td><td align="left" rowspan="1" colspan="1">-0.58</td><td align="left" rowspan="1" colspan="1">0.48</td><td align="left" rowspan="1" colspan="1">0.56</td><td align="left" rowspan="1" colspan="1">-0.55</td><td align="left" rowspan="1" colspan="1">-0.63</td><td align="left" rowspan="1" colspan="1">0.45</td><td align="left" rowspan="1" colspan="1">0.36</td><td align="left" rowspan="1" colspan="1">-0.65</td></tr><tr><td align="right" rowspan="1" colspan="1"><italic>PTF FVC (%)</italic><break></break><italic>N = 61</italic></td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.52</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0.55</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0.48</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.52</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.49</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0.41</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0.33<break></break>p = 0.03</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.49</td></tr><tr><td align="right" rowspan="1" colspan="1"><italic>PRF DLco</italic><break></break><italic>N = 44</italic></td><td align="left" rowspan="1" colspan="1">0.61</td><td align="left" rowspan="1" colspan="1">-0.54</td><td align="left" rowspan="1" colspan="1">-0.58</td><td align="left" rowspan="1" colspan="1">0.6</td><td align="left" rowspan="1" colspan="1">0.39<break></break>p = 0.009</td><td align="left" rowspan="1" colspan="1">-0.51</td><td align="left" rowspan="1" colspan="1">-0.22<break></break>ns</td><td align="left" rowspan="1" colspan="1">0.46<break></break>p = 0.002</td></tr><tr><td align="right" rowspan="1" colspan="1"><italic>PFT TLC</italic><break></break><italic>N = 27</italic></td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.77</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0.64</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0.71</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.76</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.63</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0.49</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-0.34<break></break>ns</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.70</td></tr><tr><td align="right" rowspan="1" colspan="1"><italic>PFT FEV1 (%)</italic><break></break><italic>N = 61</italic></td><td align="left" rowspan="1" colspan="1">0.4<break></break>p = 0.002</td><td align="left" rowspan="1" colspan="1">-0.43</td><td align="left" rowspan="1" colspan="1">-0.34<break></break>p = 0.007</td><td align="left" rowspan="1" colspan="1">0.39<break></break>p = 0.002</td><td align="left" rowspan="1" colspan="1">0.48</td><td align="left" rowspan="1" colspan="1">-0.41<break></break>p = 0.001</td><td align="left" rowspan="1" colspan="1">-0.29<break></break>p = 0.03</td><td align="left" rowspan="1" colspan="1">0.49</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p>All correlations have a p-value <0.001, except where specified. Abbreviations. ILD, interstitial lung disease; p(X), pulmonary quantitative indices, t(X), total quantitative indices. Kurtosis (Kurt), Sweetness (Skew), standard deviation (Sdev) and mean lung attenuation (MLA). PFT, pulmonary function test; FVC, forced vital capacity; DLCO, diffusion of lung carbon monoxide; TLC, total lung capacity; FEV1, forced expiratory volume in first second.</p></fn></table-wrap-foot></table-wrap><p>All QCT indices (with the exception of tSdev) had a good correlation with the Goh and Taouli scores (rho ranges from 0.36 to 0.65; p<0.001). The QCT indices (except for tSdev) strength of correlation with FVC and DLco ranged from moderate to good (rho from 0.33 to 0.55 and from 0.39 to 0.61, respectively; p<0.001). Data are reported in <xref rid="pone.0224772.t001" ref-type="table">Table 1</xref>.</p><p>Both Goh and Taouli scores had a moderate strength of correlation with FVC (rho = -0.36 and -0.38, respectively; p<0.004) and with DLco (rho = -0.42 and -0.44, respectively; p<0.004).</p><p>In the SS-ILD group, 44% (16/36) of patients had extensive lung disease (Goh score ≥20%). These patients had similar characteristics to those with limited SS-ILD (<xref rid="pone.0224772.t003" ref-type="table">Table 3</xref>), except for lower FVC and DLco values, and a lower prevalence of nonspecific interstitial pneumonia (69% <italic>vs</italic> 80%).</p><table-wrap id="pone.0224772.t003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0224772.t003</object-id><label>Table 3</label><caption><title>Characteristics of SS-ILD patients with limited <italic>versus</italic> extensive lung disease.</title></caption><alternatives><graphic id="pone.0224772.t003g" xlink:href="pone.0224772.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1"></th><th align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">SS-ILD cohort</th><th align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">SS-ILD (limited)</th><th align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">SS-ILD<break></break>(extensive)</th><th align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">p</th></tr></thead><tbody><tr><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">N</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">36</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">20</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">16</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">-</td></tr><tr><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">Age, median (yrs) (95% CI)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">69<break></break>(63–74)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">68<break></break> (62–76)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">70<break></break> (61–75)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">Sex (M:F)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">4:32</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">2:18</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">2:14</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">Smoke habit (no:former:yes) <xref ref-type="table-fn" rid="t003fn002">*</xref></td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">27:0:7</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">16:0:3</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">11:0:4</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">Disease duration, median (yrs) (95% CI)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">5<break></break>(3–7)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">6<break></break> (3–12)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">4<break></break> (1–7)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">pSS prevalence (%)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">72</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">80</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">63</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">Onset symptoms (sicca:dyspnoea:other)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">10:20:6</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">5:11:4</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">5:9:2</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">SSA prevalence (%)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">63</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">70</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">56</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">SSB prevalence (%)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">31</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">35</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">25</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">nss</td></tr><tr><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">FVC (%)(95% CI) <xref ref-type="table-fn" rid="t003fn003">**</xref></td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">94<break></break>(83–99)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">100<break></break> (86–115)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">84<break></break> (73–97)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">0.03</td></tr><tr><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">DLCO (%)(95% CI) <xref ref-type="table-fn" rid="t003fn004">***</xref></td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">63<break></break>(53–71)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">70<break></break> (61–85)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">51<break></break> (47–65)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">0.02</td></tr><tr><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">ILD pattern (NSIP:UIP:Other)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">27:6:3</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">16.1:3</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">11:5:0</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">0.05</td></tr><tr><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">Goh score (95% CI)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">12,5<break></break>(7.7–25.3)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">7.0<break></break> (4.0–8.0)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">28.5<break></break> (25.6–46.7)</td><td align="justify" style="background-color:#F0F0F0" rowspan="1" colspan="1">-</td></tr><tr><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">Taouli score (95% CI)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">8,0<break></break>(5.7–11.0)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">5.0<break></break> (2.2–6.0)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1">13.0<break></break> (11.0–13.7)</td><td align="justify" style="background-color:#E0E0E0" rowspan="1" colspan="1"><0.001</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t003fn001"><p>Abbreviations: M, male; F, female; CI, confidence interval; pSS, primary SS; ILD, interstitial lung disease; Nss, not statistically significant; FVC, forced vital capacity; DLCO, diffusion of lung CO; TLC, total lung capacity; NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia.</p></fn><fn id="t003fn002"><p>* 2/36 missing data</p></fn><fn id="t003fn003"><p>** 7/36 missing data</p></fn><fn id="t003fn004"><p>*** 13/36 missing data</p></fn></table-wrap-foot></table-wrap><p>All QCT indices except tSDev had a different distribution in the SS-ILD <italic>versus</italic> SS without ILD (p<0.001) group–defining the groups as follows: 0, SS non-affected; 1, SS limited ILD; and 2, SS extensive ILD. After clustering the SS-ILD patients according to ILD extent, the QCT indices (except for tSDev) had a statistically different distribution in the three subgroups (<xref ref-type="fig" rid="pone.0224772.g001">Fig 1</xref> and <xref ref-type="fig" rid="pone.0224772.g002">Fig 2</xref>).</p><fig id="pone.0224772.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0224772.g001</object-id><label>Fig 1</label><caption><title>Quantitative CT indices distribution in Sjögren’s syndrome according to non-affected (group 0), limited ILD (group 1) and extensive (group 2) ILD.</title><p>A. Pulmonary kurtosis; B. Pulmonary skewness; C. Pulmonary standard deviation; D. Pulmonary mean lung attenuation.Differences through multiple comparisons. A. Group 0 vs 1, p = 0.011; group 1 vs 2, p = 0.003; group 0 vs 2, p< 0.001. B. Group 0 vs 1, p = 0.07; group 1 vs 2, p<0.001; group 0 vs 2, p< 0.001.C. Group 0 vs 1, p = 0.28; group 1 vs 2, p = 0.12; group 0 vs 2, p< 0.001.D. Group 0 vs 1, p = NS; group 1 vs 2, p<0.001; group 0 vs 2, p< 0.001.</p></caption><graphic xlink:href="pone.0224772.g001"></graphic></fig><fig id="pone.0224772.g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0224772.g002</object-id><label>Fig 2</label><caption><title>Quantitative CT indices distribution in Sjögren’s syndrome according to non-affected (group 0), limited ILD (group 1) and extensive (group 2) ILD.</title><p>A. Total kurtosis; B. total skewness; C. Total standard deviation; D. Total mean lung attenuation. Differences through multiple comparisons. A. Group 0 vs 1, p = NS; group 1 vs 2, p = 0.04; group 0 vs 2, p = 0.03. B. Group 0 vs 1, p = 0.001; group 1 vs 2, p<0.001; group 0 vs 2, p< 0.001.C. Group 0 vs 1, p = NS; group 1 vs 2, p = 0.004; group 0 vs 2, p< 0.001.D. Group 0 vs 1, p = NS; group 1 vs 2, p<0.001; group 0 vs 2, p< 0.001.</p></caption><graphic xlink:href="pone.0224772.g002"></graphic></fig><p>Of all QCT indices, tSkew and tKurt were the best ones to differentiate ILD pattern, or not, according to AUC, 0.87 (CI95% 0.79–0.94) and 0.84 (CI95% 0.76–0.93), respectively (<xref rid="pone.0224772.t004" ref-type="table">Table 4</xref>).</p><table-wrap id="pone.0224772.t004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0224772.t004</object-id><label>Table 4</label><caption><title>Cut-off point of quantitative indices according to the Youden index, and its corresponding sensitivity and specificity, to diagnosis interstitial lung disease in Sjögren’s syndrome.</title></caption><alternatives><graphic id="pone.0224772.t004g" xlink:href="pone.0224772.t004"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="right" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"><italic>Cut-off point</italic></th><th align="left" rowspan="1" colspan="1"><italic>AUC</italic></th><th align="left" rowspan="1" colspan="1"><italic>CI95%</italic></th><th align="left" rowspan="1" colspan="1"><italic>Sensitivity (CI95%)</italic></th><th align="left" rowspan="1" colspan="1"><italic>Specificity</italic><break></break><italic>(CI95%)</italic></th><th align="left" rowspan="1" colspan="1"><italic>Best p value</italic></th></tr></thead><tbody><tr><td align="right" rowspan="1" colspan="1">pKurt</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">2.97</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.81</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.73–0.9</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.73(0.6–0.83)</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.81(0.64–0.92)</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1"><0.001*</td></tr><tr><td align="right" rowspan="1" colspan="1"><sup>Δ</sup>pMLA</td><td align="left" rowspan="1" colspan="1">-826.2</td><td align="left" rowspan="1" colspan="1">0.74</td><td align="left" rowspan="1" colspan="1">0.64–0.84</td><td align="left" rowspan="1" colspan="1">0.83(0.67–0.94)</td><td align="left" rowspan="1" colspan="1">0.58(0.45–0.7)</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="right" rowspan="1" colspan="1"><sup>Δ</sup>pSdev</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">104.5</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.82</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.73–0.9</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.78 (0.61–0.9)</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.71(0.59–0.82)</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="right" rowspan="1" colspan="1">pSkew</td><td align="left" rowspan="1" colspan="1">1.66</td><td align="left" rowspan="1" colspan="1">0.8</td><td align="left" rowspan="1" colspan="1">0.71–0.89</td><td align="left" rowspan="1" colspan="1">0.74(0.62–0.84)</td><td align="left" rowspan="1" colspan="1">0.78(0.61–0.9)</td><td align="left" rowspan="1" colspan="1"><0.001*</td></tr><tr><td align="right" rowspan="1" colspan="1">pVol</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">3318.7</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.67</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.55–0.79</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.71(0.59–0.82)</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.64(0.46–0.79)</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.004</td></tr><tr><td align="right" rowspan="1" colspan="1">tKurt</td><td align="left" rowspan="1" colspan="1">7.62</td><td align="left" rowspan="1" colspan="1">0.84</td><td align="left" rowspan="1" colspan="1">0.76–0.93</td><td align="left" rowspan="1" colspan="1">0.85(0.74–0.92)</td><td align="left" rowspan="1" colspan="1">0.78(0.61–0.9)</td><td align="left" rowspan="1" colspan="1"><0.001*</td></tr><tr><td align="right" rowspan="1" colspan="1">tMLA<sup>Δ</sup></td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">-773.0</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.71</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.6–0.82</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.64(0.46–0.79)</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.73(0.6–0.83)</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="right" rowspan="1" colspan="1">tSdev<sup>Δ</sup></td><td align="left" rowspan="1" colspan="1">200.6</td><td align="left" rowspan="1" colspan="1">0.69</td><td align="left" rowspan="1" colspan="1">0.58–0.79</td><td align="left" rowspan="1" colspan="1">0.72(0.55–0.86)</td><td align="left" rowspan="1" colspan="1">0.65(0.52–0.76)</td><td align="left" rowspan="1" colspan="1">0.002</td></tr><tr><td align="right" rowspan="1" colspan="1">tSkew</td><td align="left" rowspan="1" colspan="1">2.72</td><td align="left" rowspan="1" colspan="1">0.87</td><td align="left" rowspan="1" colspan="1">0.79–0.94</td><td align="left" rowspan="1" colspan="1">0.82(0.7–0.9)</td><td align="left" rowspan="1" colspan="1">0.81(0.64–0.92)</td><td align="left" rowspan="1" colspan="1"><0.001*</td></tr><tr><td align="right" rowspan="1" colspan="1">tVol</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">2937.08</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.62</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.5–0.75</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.92(0.83–0.97)</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.42(0.26–0.59)</td><td align="left" style="background-color:#F2F2F2" rowspan="1" colspan="1">0.04</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t004fn001"><p>Abbreviations. ILD, interstitial lung disease; p(X), pulmonary quantitative indices, t(X), total quantitative indices. Kurtosis (Kurt), Sweetness (Skew), standard deviation (Sdev), volume (Vol) and mean lung attenuation (MLA).</p></fn><fn id="t004fn002"><p>* Both pKurt/pSkew and tKurt/tSkew, were statistically equivalent. <sup><italic>Δ</italic></sup> Assuming normal pulmonary patterns.</p></fn></table-wrap-foot></table-wrap></sec><sec sec-type="conclusions" id="sec009"><title>Discussion</title><p>To the best of our knowledge, this is the first study showing that QCT indices can characterize subjects with SS -ILD as compared to the standard visual semi-quantitative methods.</p><p>Pulmonary manifestations in SS (e.g., asthenia, cough, dyspnea) are variable in intensity and severity, and are often present before a diagnosis of SS is made. The prevalence of lung involvement in SS reported in different series ranges from 12 to 61%, which underscores the clinical necessity of a correct diagnosis [<xref rid="pone.0224772.ref021" ref-type="bibr">21</xref>]. Moreover, abnormalities in pulmonary parenchyma can be found in up to 50% of cases and an abnormal pulmonary function test typically reflects a restrictive (lung) rather than an obstructive (airways) pattern [<xref rid="pone.0224772.ref009" ref-type="bibr">9</xref>]. Whereas a reduction in DLco is generally the most common abnormality, pulmonary function tests are frequently unable to correctly describe lung involvement in SS–being more accurate in the advanced stage of the disease–and hence have poor sensitivity to detect subclinical pulmonary involvement. Accordingly, HRCT quantification could be useful for monitoring disease, its evolution and response to therapies. The QCT indices described here provide an operator-independent assessment of lung involvement by ILD, as compared with the Taouli and Goh scores, which are operator-dependent. Indeed, the latter score results might be ambiguous in a proportion of cases, even when combined with abnormalities in pulmonary function tests, and may be unable to correctly classify some cases in the corresponding category of severity. By contrast, QCT measurements have proven to provide highly accurate and reproductible diagnoses [<xref rid="pone.0224772.ref015" ref-type="bibr">15</xref>], although they require some level of training to follow a standardized imaging acquisition protocol. Moreover, fully automated QCT measurements could eliminate intra- and interobserver variability, particularly when used in diagnostic decision making.</p><p>The performance of QCT indices has been previously explored in other autoimmune diseases such as systemic sclerosis (SSc). For instance, in a recent series by Ariani et al., the authors reported a moderate-to-good agreement of all values for ILD associated with SSc, and also in cases with extensive or limited lung disease. Some pulmonary function tests also showed a relatively good correlation with QCT indices (FVC and DLco <70%) (16). Moreover, QTC indices could distinguish between high and low mortality groups [<xref rid="pone.0224772.ref022" ref-type="bibr">22</xref>] in those cases of SSc with ILD, in relation to 1-year mortality prediction clinical scales such as ILD-GAP score (ILD subtype, gender, age, FVC and DLco) or dBi (age, history of respiratory hospitalization, and FVC value and its change after 6 months).</p><p>Few studies have quantified pulmonary fibrosis related to SS. In the present study, we compared, for the first time, a QCT analysis of lung involvement against a specific SQCT score (Taouli) and a generic SQCT score (Goh) developed for secondary pulmonary fibrosis. The Goh score, which has been validated in SSc [<xref rid="pone.0224772.ref013" ref-type="bibr">13</xref>,<xref rid="pone.0224772.ref023" ref-type="bibr">23</xref>] and rheumatoid arthritis [<xref rid="pone.0224772.ref024" ref-type="bibr">24</xref>], here it shows excellent correlation with the more complex Taouli score. Hence, the Goh score appears a suitable method also for the quantification of SS-ILD. Likewise, it is reasonable to presume that the Goh score might have a similar predictive value for mortality [<xref rid="pone.0224772.ref025" ref-type="bibr">25</xref>, <xref rid="pone.0224772.ref026" ref-type="bibr">26</xref>].</p><p>Although used as the only laboratory criteria, serologic/immunological parameters are not a definitive guide to diagnosis or to monitor the severity of ILD in SS, and the correlations across different studies are heterogenous. Indeed, we failed to find any significant association between QTC indices and anti-Ro, anti-La or ANA titers. However, anti-Ro/SSA titers were low in the general cohort but were higher in the ILD cohort.</p><p>The influence of the principal immunological markers on SS disease diagnosis was recently addressed by Brito-Zerón and colleagues using a Big Data analysis approach in 10,500 patients [<xref rid="pone.0224772.ref027" ref-type="bibr">27</xref>]. Regarding the phenotypes of patients, the frequency of the immunological markers ANA, Ro and La were quite similar in the pulmonary domain of the ESSDAI (approximately 10%) at diagnosis. When the authors analyzed the impact of three combinations of anti-Ro/La antibodies, no statistically differences were found in the pulmonary domain. These analyses suggest that novel autoantibodies should be developed to detect ILD with sufficient sensitivity or specificity. The use of more sophisticated profiling should be incorporated as soon as possible in the daily clinical practice, for example, the ratio of blood T cells [<xref rid="pone.0224772.ref028" ref-type="bibr">28</xref>], or microRNA profiles [<xref rid="pone.0224772.ref029" ref-type="bibr">29</xref>].</p><p>In a cross-sectional study aimed to evaluate the prevalence of respiratory symptoms in SS, Kampolis et al. found that up to 20% of all cases were affected [<xref rid="pone.0224772.ref010" ref-type="bibr">10</xref>]. As described in the aforementioned study, it is important to differentiate those respiratory symptoms/complaints that have an onset prior to SS diagnosis, such as any underlying respiratory disease–chronic obstructive pulmonary disease, bronchial asthma, or upper chronic airway cough–as approximately one-third of these cases had an established chronic respiratory disease that preceded the onset of SS. Along this line, the impact of smoking (or former smokers) is not infrequent; however, it should be differentiated from symptoms directly related to pulmonary involvement in SS. In some selected cases, however, both diseases could coexist in smokers with SS. Interestingly, the same authors did not report any specific alterations in pulmonary function tests (FEV<sub>1</sub>, FVC, ratio FEV/FVC, DLco) in those patients with pulmonary disease and SS. In our series, there were some missing data for smoking habit in a small percentage of patients (<10%). Thus, we believe that the issue concerning smoking habit does not significantly impact our results.</p><p>Theoretically, pulmonary function tests might not be substantially modified in ILD in SS until the disease is more advanced. Regarding this issue, lung ultrasound showed a good performance when compared with high-resolution thorax CT [<xref rid="pone.0224772.ref030" ref-type="bibr">30</xref>]. Indeed, this modality could be potentially useful to detect ILD earlier in SS, independently of the patient’s complaints; however, more research is needed to better understand the precise use of ultrasound as an imaging tool for identification of ILD and SS.</p><p>Our study has some limitations that should be considered, such as its retrospective design. Also, the CT protocols might be not homogenous across the participating centers–although the percentage of pulmonary disease in the global series fits well with recent data. Some differences could be expected in the immunological profile between ethnic groups and may affect the prevalence of ILD in our series [<xref rid="pone.0224772.ref031" ref-type="bibr">31</xref>]. Also, some degree of variable conditions when performing the CT images across the participating centers should be assumed–for example, a degree of heterogenicity in multiple slices and time points [<xref rid="pone.0224772.ref032" ref-type="bibr">32</xref>]. Another limitation is that while the reported pulmonary functional tests did not show obstructive profiles in most of the cases, FVC and DLco were not performed in all enrolled cases. Pulmonary function tests were often not requested at the same time as CT by the physicians. The reasons for this irregularity might be that they are not systematically assessed in SS in daily practice–considering they are likely not sufficient to help the clinician assess the extent of the ILD, or its severity. Some other biological/immunological profiles, such as cryoglobulinemia [<xref rid="pone.0224772.ref008" ref-type="bibr">8</xref>,<xref rid="pone.0224772.ref027" ref-type="bibr">27</xref>], were not collected. Our pooled analysis included primary and secondary SS, and this might impact on the QCT indices and patterns of ILD [<xref rid="pone.0224772.ref033" ref-type="bibr">33</xref>]. Finally, the QCT scores might be also influenced by the differences in ILD patterns in SS, such as bronchiolitis, bronchiectasis, non-specific interstitial pneumonia, usual interstitial pneumonia, lymphocytic interstitial pneumonitis, or organizing pneumonitis, among others.</p><p>QTC indices are becoming a useful tool in imaging analyses because they improve consistency of imaging diagnosis and might aid the treatment decisions in patients with ILD. This method is also promising for patient stratification according to ILD severity and extent [<xref rid="pone.0224772.ref011" ref-type="bibr">11</xref>, <xref rid="pone.0224772.ref022" ref-type="bibr">22</xref>, <xref rid="pone.0224772.ref025" ref-type="bibr">25</xref>, <xref rid="pone.0224772.ref026" ref-type="bibr">26</xref>, <xref rid="pone.0224772.ref034" ref-type="bibr">34</xref>]. In clinical practice, a quantitative ILD assessment with a user-friendly staging system (i.e., QCT index) could improve the outcomes of proposed SS-ILD treatments [<xref rid="pone.0224772.ref035" ref-type="bibr">35</xref>, <xref rid="pone.0224772.ref036" ref-type="bibr">36</xref>].</p><p>Finally, the operator-independent algorithm we used in this study is free and time-saving. Accordingly, this method might be extremely suitable for multi-center trials focused on ILD. QCT indices are a promising alternative to visual scorings in ILD related to autoimmune diseases such as SS. We believe that this innovative tool will open new horizons for research into SS, as it has the capability to select ILD patients with extensive lung impairment and, correspondingly, a worse prognosis. QTC indices might potentially represent a pivotal tool at the time of diagnosis, and through management of ILD associated with SS.</p></sec></body><back><ack><p>We thank K. 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As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.</p></sec></boxed-text><p><named-content content-type="letter-date">21 Aug 2019</named-content></p><p>PONE-D-19-20968</p><p>Quantitative assessment of interstitial lung disease in Sjögren’s syndrome.</p><p>PLOS ONE</p><p>Dear Dr. Guisado-Vasco,</p><p>Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.</p><p>Specifically, both reviewers found out some interests in this study, but also pointed out a number of criticisms that require improvement or even amendment. 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Has the statistical analysis been performed appropriately and rigorously? </p><p>Reviewer #1: No</p><p>Reviewer #2: Yes</p><p>**********</p><p>3. Have the authors made all data underlying the findings in their manuscript fully available?</p><p>The <ext-link ext-link-type="uri" xlink:href="http://www.plosone.org/static/policies.action#sharing">PLOS Data policy</ext-link> requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.</p><p>Reviewer #1: Yes</p><p>Reviewer #2: Yes</p><p>**********</p><p>4. Is the manuscript presented in an intelligible fashion and written in standard English?</p><p>PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.</p><p>Reviewer #1: Yes</p><p>Reviewer #2: Yes</p><p>**********</p><p>5. Review Comments to the Author</p><p>Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)</p><p>Reviewer #1: The authors reported quantitative assessment of interstitial lung disease in Sjögren’s syndrome. It is interesting to focus the usefulness of quantitative CT in Sjögren’s syndrome-ILD, but I have some major concerns about the data</p><p>Major;</p><p>1. CTD-ILD and quantitative CT scores have already been studied, but most patients were scleroderma. Therefore, it was very interesting to examine the quantitative CT score for Sjogren's syndrome in a large number of people. However, only association between CT analysis by histogram and ILD type are not appropriate as a paper.</p><p>Regarding scleroderma, CT scores and prognosis have already been examined. Did you classify ILD as limited and extensive, but was it related to prognosis as well as scleroderma? You need to consider if CT score affects prognosis in Sjogren's syndrome.</p><p>2. The percentage of patients with pSS-ILD is 72% (Table 1).</p><p>The secondary SS needs to be described in detail.</p><p>3. It seems necessary to create a table of correlation between quantitative CT analysis and clinical findings, respiratory function tests, and semi-quantitative CT analysis.</p><p>Minor</p><p>1.The figure is difficult to see and should be considered.</p><p>2 .In figure1. 2, the statistical differences between the three groups need to be clearly stated.</p><p>Reviewer #2: The authors reported the usefulness of quantitative chest computed tomography</p><p>(QCT) assessment of interstitial lung disease (ILD) in patients with Sjögren’s syndrome (SS). In this multi-center and retrospective study, QCT indices identified patients with SS and ILD (SS-ILD), and discriminated those with lesser or greater lung disease.</p><p>This is an important study that demonstrates that QCT indices can characterize subjects with SS-ILD in comparison to the standard visual, semi-quantitative methods such as Goh and Taouli scoring.</p><p>Major</p><p>1. This study showed that QCT indices discriminated the severity of ILD in patients with SS. However, optimal cut-off points for each indicator were not determined. How QCT indices can be utilized in future research.</p><p>2. With respect to Taouli scores, in their original paper (Eur Radiol 2002; 12:1504-1511), the authors calculated scores including ground-glass attenuation, honeycombing, centrilobular nodules, reticular pattern, mosaic perfusion, and air trapping. In the present study, how were the Taouli scores determined ?</p><p>Minor</p><p>1. There were no descriptions of the correlation between QCT indices and the Goh and Taouli scores or pulmonary function test findings in Table 1. Please modify the descriptions.</p><p>**********</p><p>6. PLOS authors have the option to publish the peer review history of their article (<ext-link ext-link-type="uri" xlink:href="https://journals.plos.org/plosone/s/editorial-and-peer-review-process#loc-peer-review-history">what does this mean?</ext-link>). If published, this will include your full peer review and any attached files.</p><p>If you choose “no”, your identity will remain anonymous but your review may still be made public.</p><p><bold>Do you want your identity to be public for this peer review?</bold> For information about this choice, including consent withdrawal, please see our <ext-link ext-link-type="uri" xlink:href="https://www.plos.org/privacy-policy">Privacy Policy</ext-link>.</p><p>Reviewer #1: No</p><p>Reviewer #2: No</p><p>[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]</p><p>While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, <ext-link ext-link-type="uri" xlink:href="https://pacev2.apexcovantage.com/">https://pacev2.apexcovantage.com/</ext-link>. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at <email>figures@plos.org</email>. Please note that Supporting Information files do not need this step.</p></body></sub-article><sub-article id="pone.0224772.r002" article-type="author-comment"><front-stub><article-id pub-id-type="doi">10.1371/journal.pone.0224772.r002</article-id><title-group><article-title>Author response to Decision Letter 0</article-title></title-group><related-article id="rel-obj002" ext-link-type="doi" xlink:href="10.1371/journal.pone.0224772" related-article-type="editor-report"></related-article><custom-meta-group><custom-meta><meta-name>Submission Version</meta-name><meta-value>1</meta-value></custom-meta></custom-meta-group></front-stub><body><p><named-content content-type="author-response-date">26 Sep 2019</named-content></p><p>Dear Editor, </p><p> Thank you for considering our manuscript, ‘Quantitative assessment of interstitial lung disease in Sjögren’s syndrome’ (PONE-D-19-20968), sent to PLOS One.</p><p>We really appreciate the opportunity to review our manuscript in order to fully address your concerns and comments of the referee. </p><p> Then, we are going to address point by point the reviewer’s recommendations. </p><p>Journal Requirements:</p><p>1. When submitting your revision, we need you to address these additional requirements.</p><p>Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at</p><p><ext-link ext-link-type="uri" xlink:href="http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf">http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf">http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf</ext-link></p><p>I have reviewed the POLS ONE’s style guidelines, as you pointed out.</p><p>First, I have added a title page to the manuscript body, according to the format recommended by your editorial office. </p><p>Second, I have done some changes in the body of the template/manuscript according to them -mainly headings, as required. </p><p>2. Thank you for stating the following in the Competing Interests section:</p><p>Prof. Carlo Vancheri is part of F. Hoffmann-La Roche Ltd. Scientific Board. He has received consulting fees and/or speaker fees from Astrazeneca, Boehringer Ingelheim, Chiesi, F. Hoffmann-La Roche Ltd and Menarini.</p><p>Prof. Stefano Palmucci has reveived personal fees and honoraria for lectures from Boehringer Ingelheim, Delphi International srl and F. Hoffmann-La Roche Ltd. He has been included in the scientific board for Boehringer Ingelheim.</p><p>None of the other authors have any potential conflicts of interest to disclose in relation to this work.</p><p>Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors <ext-link ext-link-type="uri" xlink:href="http://journals.plos.org/plosone/s/competing-interests">http://journals.plos.org/plosone/s/competing-interests</ext-link>). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.</p><p>Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.</p><p>Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: <ext-link ext-link-type="uri" xlink:href="http://journals.plos.org/plosone/s/competing-interests">http://journals.plos.org/plosone/s/competing-interests</ext-link></p><p>I confirm, it does not alter the conflict of interest policy of your journal. I have added the following sentence, as recommended: ‘This does not alter our adherence to PLOS ONE policies on sharing data and materials’.</p><p>Reviewer #1: The authors reported quantitative assessment of interstitial lung disease in Sjögren’s syndrome. It is interesting to focus the usefulness of quantitative CT in Sjögren’s syndrome-ILD, but I have some major concerns about the data</p><p>Major;</p><p>1. CTD-ILD and quantitative CT scores have already been studied, but most patients were scleroderma. Therefore, it was very interesting to examine the quantitative CT score for Sjogren's syndrome in a large number of people. However, only association between CT analysis by histogram and ILD type are not appropriate as a paper.</p><p>Regarding scleroderma, CT scores and prognosis have already been examined. Did you classify ILD as limited and extensive, but was it related to prognosis as well as scleroderma? You need to consider if CT score affects prognosis in Sjogren's syndrome.</p><p>Before any new diagnostic technique can be used as an outcome measurement instrument, it should be tested its reliability comparing to actual standards. It is the aim of the present research. Later, it could be used as a prognostic tool – it is our next step in the research. In fact, the development of the quantitative indices in systemic sclerosis followed up the same idea of our working group – the count with some members whose developed this scoring system in scleroderma. First, it was release a publication assessing the reliability of these indices (2015), and them, a model of prediction of mortality was developed (2017).</p><p>References </p><p>Jousse-Joulin S, et al. Video clip assessment of a salivary gland ultrasound scoring system in Sjögren’s syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise. Ann Rheum Dis 2019;78:967–973 </p><p>Ariani A et al. Operator-independent quantitative chest computed tomography versus standard assessment of interstitial lung disease related to systemic sclerosis: a multi-center study. Mod Rheumatol 2015; 25(5):724-30.</p><p>Ariani A et al. Quantitative chest computed tomography is associated to two prediction models of mortality in interstitial lung disease related to systemic sclerosis. Rheumatology (Oxford), 2017; 56(6): 922-927. </p><p>2. The percentage of patients with pSS-ILD is 72% (Table 1). The secondary SS needs to be described in detail.</p><p> A paragraph was added at the beginning of the results section, detailing the diseases associated to SS. </p><p>The diseases associated to the development of SS, secondary SS, were: rheumatoid arthritis (5,9%), systemic lupus erythematosus (2%), systemic sclerosis (12,7%), and undifferentiated connective tissue disease (9,8%). Not all cases were affected of ILD, of course: just 10 have secondary SS.</p><p>3. It seems necessary to create a table of correlation between quantitative CT analysis and clinical findings, respiratory function tests, and semi-quantitative CT analysis.</p><p>This table has been inserted in the text – previously it was designed as supplementary material. It has been named as table 2. Hence, the former table 2 as labeled now as table 3. </p><p>Minor</p><p>1.The figure is difficult to see and should be considered.</p><p>The figures have been edited and introduced some changes to maximize its resolution. </p><p>2 .In figure1. 2, the statistical differences between the three groups need to be clearly stated.</p><p> Thank you very much for this comment. In order to a better understanding and simplified of the images, it has been added a footnote in both set of figures, which explains the differences between every group (0,1,2), and corresponding p-values. </p><p>Reviewer #2: The authors reported the usefulness of quantitative chest computed tomography</p><p>(QCT) assessment of interstitial lung disease (ILD) in patients with Sjögren’s syndrome (SS). In this multi-center and retrospective study, QCT indices identified patients with SS and ILD (SS-ILD), and discriminated those with lesser or greater lung disease.</p><p>This is an important study that demonstrates that QCT indices can characterize subjects with SS-ILD in comparison to the standard visual, semi-quantitative methods such as Goh and Taouli scoring.</p><p>Major</p><p>1. This study showed that QCT indices discriminated the severity of ILD in patients with SS. However, optimal cut-off points for each indicator were not determined. How QCT indices can be utilized in future research.</p><p>It was inserted/added a new table (number 4) to sum up these cut-off points, according to the Youden index applying using the model of area under the curve. A brief comment has been inserted in the results section. </p><p>I am agreeing with the point, that these cut-off points could be use in the next step of the research as predictive models of mortality in ILD related to SS. </p><p>2. With respect to Taouli scores, in their original paper (Eur Radiol 2002; 12:1504-1511), the authors calculated scores including ground-glass attenuation, honeycombing, centrilobular nodules, reticular pattern, mosaic perfusion, and air trapping. In the present study, how were the Taouli scores determined ?</p><p>These scores were calculating by two expert radiologists, properly trainee in semiquantitative scores. Hence, the score was calculated by the sum of all the categories that represent lung fibrosis, namely: honeycombing, reticular pattern, and ground-glass attenuation.</p><p>Minor</p><p>1. There were no descriptions of the correlation between QCT indices and the Goh and Taouli scores or pulmonary function test findings in Table 1. Please modify the descriptions.</p><p> A new table (Table 2) has been inserted where the correlations are described as recommended. It is mentioned in the results paragraph. </p><p>We hope that these comments and improvements have fulfilled the referees’ recommendations. </p><p>Such way, your editorial office could consider the current version of the manuscript for its final acceptance.</p><p>If there are any further questions or comments after this revision, please do not hesitate to contact us. </p><p>Sincerely, </p><p>Pablo Guisado Vasco</p><supplementary-material content-type="local-data" id="pone.0224772.s001"><label>Attachment</label><caption><p>Submitted filename: <named-content content-type="submitted-filename">Response to reviewers v.1.0.docx</named-content></p></caption><media xlink:href="pone.0224772.s001.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></body></sub-article><sub-article id="pone.0224772.r003" article-type="aggregated-review-documents"><front-stub><article-id pub-id-type="doi">10.1371/journal.pone.0224772.r003</article-id><title-group><article-title>Decision Letter 1</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kuwana</surname><given-names>Masataka</given-names></name><role>Academic Editor</role></contrib></contrib-group><permissions><copyright-statement>© 2019 Masataka Kuwana</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Masataka Kuwana</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><related-article id="rel-obj003" ext-link-type="doi" xlink:href="10.1371/journal.pone.0224772" related-article-type="reviewed-article"></related-article><custom-meta-group><custom-meta><meta-name>Submission Version</meta-name><meta-value>1</meta-value></custom-meta></custom-meta-group></front-stub><body><p><named-content content-type="letter-date">22 Oct 2019</named-content></p><p>Quantitative assessment of interstitial lung disease in Sjögren’s syndrome.</p><p>PONE-D-19-20968R1</p><p>Dear Dr. Guisado-Vasco,</p><p>We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.</p><p>Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.</p><p>Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at <ext-link ext-link-type="uri" xlink:href="https://www.editorialmanager.com/pone/">https://www.editorialmanager.com/pone/</ext-link>, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at <email>authorbilling@plos.org</email>.</p><p>If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact <email>onepress@plos.org</email>.</p><p>With kind regards,</p><p>Masataka Kuwana, MD, PhD</p><p>Academic Editor</p><p>PLOS ONE</p><p>Additional Editor Comments (optional):</p><p>Reviewers' comments:</p><p>Reviewer's Responses to Questions</p><p><bold>Comments to the Author</bold></p><p>1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.</p><p>Reviewer #2: All comments have been addressed</p><p>**********</p><p>2. Is the manuscript technically sound, and do the data support the conclusions?</p><p>The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. </p><p>Reviewer #2: Yes</p><p>**********</p><p>3. Has the statistical analysis been performed appropriately and rigorously? </p><p>Reviewer #2: Yes</p><p>**********</p><p>4. Have the authors made all data underlying the findings in their manuscript fully available?</p><p>The <ext-link ext-link-type="uri" xlink:href="http://www.plosone.org/static/policies.action#sharing">PLOS Data policy</ext-link> requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.</p><p>Reviewer #2: Yes</p><p>**********</p><p>5. Is the manuscript presented in an intelligible fashion and written in standard English?</p><p>PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.</p><p>Reviewer #2: Yes</p><p>**********</p><p>6. Review Comments to the Author</p><p>Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)</p><p>Reviewer #2: Thank you for addressing my comments from initial review.The data are potentially interesting and worthy of evaluation for SS-ILD.</p><p>**********</p><p>7. PLOS authors have the option to publish the peer review history of their article (<ext-link ext-link-type="uri" xlink:href="https://journals.plos.org/plosone/s/editorial-and-peer-review-process#loc-peer-review-history">what does this mean?</ext-link>). If published, this will include your full peer review and any attached files.</p><p>If you choose “no”, your identity will remain anonymous but your review may still be made public.</p><p><bold>Do you want your identity to be public for this peer review?</bold> For information about this choice, including consent withdrawal, please see our <ext-link ext-link-type="uri" xlink:href="https://www.plos.org/privacy-policy">Privacy Policy</ext-link>.</p><p>Reviewer #2: No</p></body></sub-article><sub-article id="pone.0224772.r004" article-type="editor-report"><front-stub><article-id pub-id-type="doi">10.1371/journal.pone.0224772.r004</article-id><title-group><article-title>Acceptance letter</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kuwana</surname><given-names>Masataka</given-names></name><role>Academic Editor</role></contrib></contrib-group><permissions><copyright-statement>© 2019 Masataka Kuwana</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Masataka Kuwana</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><related-article id="rel-obj004" ext-link-type="doi" xlink:href="10.1371/journal.pone.0224772" related-article-type="reviewed-article"></related-article></front-stub><body><p><named-content content-type="letter-date">1 Nov 2019</named-content></p><p>PONE-D-19-20968R1 </p><p>Quantitative assessment of interstitial lung disease in Sjögren’s syndrome </p><p>Dear Dr. Guisado-Vasco:</p><p>I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. </p><p>If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact <email>onepress@plos.org</email>.</p><p>For any other questions or concerns, please email <email>plosone@plos.org</email>. </p><p>Thank you for submitting your work to PLOS ONE.</p><p>With kind regards,</p><p>PLOS ONE Editorial Office Staff</p><p>on behalf of</p><p>Prof. Masataka Kuwana </p><p>Academic Editor</p><p>PLOS ONE</p></body></sub-article></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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