{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:01:19Z","timestamp":1787022079869,"version":"build-2736575974"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T00:00:00Z","timestamp":1613952000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We assessed the association of suPAR (soluble urokinase plasminogen activator receptor) plasma levels with fibrotic and vascular manifestations in patients with systemic sclerosis (SSc).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>suPAR plasma levels were measured in 121 consecutive patients with SSc and correlated to pulmonary and vascular features of SSc, including interstitial lung disease as characterized by percentage of predicted CO diffusing capacity (DLco) and forced vital capacity (FVC), pulmonary fibrosis by computed tomography, and pulmonary arterial hypertension, telangiectasias, and digital ulcers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Overall, 121 SSc patients (84% females; mean age, 57 \u00b1 12 [range: 22\u201379] years) were enrolled; 35% had diffuse cutaneous SSc. suPAR plasma levels ranged from 1.3\u201310.2 [median: 2.9 (p25\u2013p75: 2.3\u20133.9)] ng\/mL. Log(suPAR) levels correlated with DLco (r = -0.41,\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.0001) and FVC (r = -0.26,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.004), also when adjusted for age, sex, and pulmonary hypertension. A suPAR cut-off level of &gt;2.5 ng\/mL showed a sensitivity of 91% for identifying patients with either DLco &lt;50% or FVC &lt; 60% of the predicted values. Similarly, 19 (90%) had a suPAR &gt;2.5 ng\/mL among those diagnosed with pulmonary fibrosis vs. 59 (60%) among those who did not (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.008). suPAR values were not associated with vascular manifestations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>suPAR levels strongly correlated with pulmonary involvement in SSc. Future studies should test if suPAR estimation can be used for surveillance of severe pulmonary involvement in SSc.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0247256","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T13:31:38Z","timestamp":1614000698000},"page":"e0247256","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Association of soluble urokinase plasminogen activator receptor levels with fibrotic and vascular manifestations in systemic sclerosis"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4389-9162","authenticated-orcid":true,"given":"Sheraz","family":"Butt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f8rgen L.","family":"Jeppesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Line Vinderslev","family":"Iversen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mogens","family":"Fenger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper","family":"Eugen-Olsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Andersson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5654-4993","authenticated-orcid":true,"given":"S\u00f8ren","family":"Jacobsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,22]]},"reference":[{"issue":"17","key":"pone.0247256.ref001","doi-asserted-by":"crossref","first-page":"e013405","DOI":"10.1161\/JAHA.119.013405","article-title":"Cardiovascular Manifestations of Systemic Sclerosis: A Danish Nationwide Cohort Study","volume":"8","author":"SA Butt","year":"2019","journal-title":"J Am Heart Assoc"},{"key":"pone.0247256.ref002","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s41927-018-0043-6","article-title":"Trends in incidence, mortality, and causes of death associated with systemic sclerosis in Denmark between 1995 and 2015: a nationwide cohort study","volume":"2","author":"SA Butt","year":"2018","journal-title":"BMC Rheumatol"},{"issue":"6","key":"pone.0247256.ref003","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1097\/BOR.0000000000000324","article-title":"Emerging biomarkers in systemic sclerosis","volume":"28","author":"M Manetti","year":"2016","journal-title":"Curr Opin Rheumatol"},{"issue":"6","key":"pone.0247256.ref004","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.jaci.2017.10.003","article-title":"Biomarkers in connective tissue diseases","volume":"140","author":"NR Jog","year":"2017","journal-title":"J Allergy Clin Immunol"},{"issue":"6","key":"pone.0247256.ref005","first-page":"S-138","article-title":"Follow-up of serum KL-6 lung fibrosis biomarker levels in 173 patients with systemic sclerosis","volume":"32","author":"G Kumanovics","year":"2014","journal-title":"Clin Exp Rheumatol"},{"issue":"10","key":"pone.0247256.ref006","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1111\/1346-8138.14538","article-title":"Serum interleukin-34 levels in patients with systemic sclerosis: Clinical association with interstitial lung disease","volume":"45","author":"A Kuzumi","year":"2018","journal-title":"J Dermatol"},{"issue":"5","key":"pone.0247256.ref007","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s00281-015-0506-4","article-title":"Update on biomarkers in systemic sclerosis: tools for diagnosis and treatment","volume":"37","author":"AJ Affandi","year":"2015","journal-title":"Semin Immunopathol"},{"issue":"9","key":"pone.0247256.ref008","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1002\/acr.21716","article-title":"Association of C-reactive protein with high disease activity in systemic sclerosis: results from the Canadian Scleroderma Research Group","volume":"64","author":"Canadian Scleroderma Research g","year":"2012","journal-title":"Arthritis Care Res (Hoboken)"},{"issue":"8","key":"pone.0247256.ref009","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1002\/acr.21968","article-title":"Does C-reactive protein predict the long-term progression of interstitial lung disease and survival in patients with early systemic sclerosis?","volume":"65","author":"X Liu","year":"2013","journal-title":"Arthritis Care Res (Hoboken)"},{"issue":"4","key":"pone.0247256.ref010","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1177\/0300060518760955","article-title":"High acute phase protein levels correlate with pulmonary and skin involvement in patients with diffuse systemic sclerosis","volume":"46","author":"A Lis-Swiety","year":"2018","journal-title":"J Int Med Res"},{"issue":"2","key":"pone.0247256.ref011","first-page":"122","article-title":"The significance of interleukin-6 and C-reactive protein in systemic sclerosis: a systematic literature review","volume":"31","author":"C Muangchant","year":"2013","journal-title":"Clin Exp Rheumatol"},{"issue":"4","key":"pone.0247256.ref012","first-page":"126","article-title":"The role of inflammatory markers in assessment of disease activity in systemic sclerosis","volume":"36","author":"L Ross","year":"2018","journal-title":"Clin Exp Rheumatol"},{"issue":"9","key":"pone.0247256.ref013","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1136\/annrheumdis-2013-203706","article-title":"Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: a new model of experimental scleroderma?","volume":"73","author":"M Manetti","year":"2014","journal-title":"Ann Rheum Dis"},{"issue":"7","key":"pone.0247256.ref014","doi-asserted-by":"crossref","first-page":"2716","DOI":"10.1091\/mbc.e06-10-0912","article-title":"Urokinase receptor cleavage: a crucial step in fibroblast-to-myofibroblast differentiation","volume":"18","author":"AM Bernstein","year":"2007","journal-title":"Mol Biol Cell"},{"issue":"1115","key":"pone.0247256.ref015","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1136\/postgradmedj-2018-135839","article-title":"SuPAR, an emerging biomarker in kidney and inflammatory diseases","volume":"94","author":"L Hamie","year":"2018","journal-title":"Postgrad Med J"},{"issue":"2","key":"pone.0247256.ref016","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/jmv.21114","article-title":"Soluble urokinase plasminogen activator receptor is a marker of dysmetabolism in HIV-infected patients receiving highly active antiretroviral therapy","volume":"80","author":"O Andersen","year":"2008","journal-title":"J Med Virol"},{"issue":"7","key":"pone.0247256.ref017","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1373\/clinchem.2006.067595","article-title":"Development and validation of a multiplex add-on assay for sepsis biomarkers using xMAP technology","volume":"52","author":"K Kofoed","year":"2006","journal-title":"Clin Chem"},{"issue":"3","key":"pone.0247256.ref018","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1155\/2009\/504294","article-title":"suPAR: the molecular crystal ball","volume":"27","author":"M Thuno","year":"2009","journal-title":"Dis Markers"},{"issue":"11","key":"pone.0247256.ref019","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1515\/cclm-2015-0079","article-title":"Increased plasma soluble urokinase plasminogen activator receptor levels in systemic sclerosis: possible association with microvascular abnormalities and extent of fibrosis","volume":"53","author":"N Legany","year":"2015","journal-title":"Clin Chem Lab Med"},{"issue":"5","key":"pone.0247256.ref020","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/art.1780230510","article-title":"Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee","volume":"23","year":"1980","journal-title":"Arthritis Rheum"},{"issue":"6","key":"pone.0247256.ref021","doi-asserted-by":"crossref","first-page":"473","DOI":"10.3109\/03009742.2013.796403","article-title":"Circulating microparticles and plasma levels of soluble E- and P-selectins in patients with systemic sclerosis","volume":"42","author":"LV Iversen","year":"2013","journal-title":"Scand J Rheumatol"},{"key":"pone.0247256.ref022","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1186\/s12891-015-0653-8","article-title":"Cross-sectional study of soluble selectins, fractions of circulating microparticles and their relationship to lung and skin involvement in systemic sclerosis","volume":"16","author":"LV Iversen","year":"2015","journal-title":"BMC Musculoskelet Disord"},{"issue":"1","key":"pone.0247256.ref023","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1093\/rheumatology\/ken408","article-title":"Skin sclerosis is only of limited value to identify SSc patients with severe manifestations\u2014an analysis of a distinct patient subgroup of the German Systemic Sclerosis Network (DNSS) Register","volume":"48","author":"LG Hanitsch","year":"2009","journal-title":"Rheumatology (Oxford)"},{"issue":"7","key":"pone.0247256.ref024","first-page":"1281","article-title":"Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis","volume":"22","author":"P Clements","year":"1995","journal-title":"J Rheumatol"},{"issue":"2","key":"pone.0247256.ref025","first-page":"202","article-title":"Scleroderma (systemic sclerosis): classification, subsets and pathogenesis","volume":"15","author":"EC LeRoy","year":"1988","journal-title":"J Rheumatol"},{"issue":"3","key":"pone.0247256.ref026","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/j.1365-2796.2010.02252.x","article-title":"Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population","volume":"268","author":"J Eugen-Olsen","year":"2010","journal-title":"J Intern Med"},{"issue":"3","key":"pone.0247256.ref027","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.ijcard.2012.03.040","article-title":"CRP and suPAR are differently related to anthropometry and subclinical organ damage","volume":"167","author":"S Lyngbaek","year":"2013","journal-title":"Int J Cardiol"},{"issue":"8","key":"pone.0247256.ref028","doi-asserted-by":"crossref","first-page":"758","DOI":"10.3109\/1354750X.2012.728623","article-title":"Plasma soluble urokinase plasminogen activator receptor (suPAR) levels in systemic lupus erythematosus.","volume":"17","author":"G Toldi","year":"2012","journal-title":"Biomarkers"},{"issue":"5","key":"pone.0247256.ref029","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.trsl.2013.07.003","article-title":"Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus","volume":"162","author":"H Enocsson","year":"2013","journal-title":"Transl Res"},{"issue":"1","key":"pone.0247256.ref030","first-page":"36","article-title":"IFN-gamma, CXCL16, uPAR: potential biomarkers for systemic lupus erythematosus","volume":"36","author":"S Wen","year":"2018","journal-title":"Clin Exp Rheumatol"},{"issue":"2","key":"pone.0247256.ref031","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1515\/cclm-2012-0221","article-title":"Soluble urokinase plasminogen activator receptor (suPAR) in the assessment of inflammatory activity of rheumatoid arthritis patients in remission","volume":"51","author":"G Toldi","year":"2013","journal-title":"Clin Chem Lab Med"},{"issue":"8","key":"pone.0247256.ref032","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1136\/ard.58.8.488","article-title":"Soluble urokinase plasminogen activator receptor in plasma of patients with inflammatory rheumatic disorders: increased concentrations in rheumatoid arthritis","volume":"58","author":"O Slot","year":"1999","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"pone.0247256.ref033","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1111\/j.1478-3231.2011.02665.x","article-title":"Circulating soluble urokinase plasminogen activator is elevated in patients with chronic liver disease, discriminates stage and aetiology of cirrhosis and predicts prognosis","volume":"32","author":"HW Zimmermann","year":"2012","journal-title":"Liver Int"},{"issue":"1","key":"pone.0247256.ref034","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12931-018-0803-2","article-title":"Soluble urokinase plasminogen activator receptor predicts mortality in exacerbated COPD","volume":"19","author":"NS Godtfredsen","year":"2018","journal-title":"Respir Res"},{"issue":"43","key":"pone.0247256.ref035","doi-asserted-by":"crossref","first-page":"27027","DOI":"10.18632\/oncotarget.25471","article-title":"Serum levels of soluble urokinase plasminogen activator receptor (suPAR) predict outcome after resection of colorectal liver metastases","volume":"9","author":"SH Loosen","year":"2018","journal-title":"Oncotarget"},{"issue":"1","key":"pone.0247256.ref036","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13049-018-0478-1","article-title":"suPAR is associated with risk of future acute surgery and post-operative mortality in acutely admitted medical patients","volume":"26","author":"J Meyer","year":"2018","journal-title":"Scand J Trauma Resusc Emerg Med"},{"issue":"Suppl 1","key":"pone.0247256.ref037","doi-asserted-by":"crossref","first-page":"S33","DOI":"10.1016\/j.ijantimicag.2015.10.011","article-title":"suPAR: The unspecific marker for disease presence, severity and prognosis","volume":"46","author":"J Eugen-Olsen","year":"2015","journal-title":"Int J Antimicrob Agents"},{"issue":"5","key":"pone.0247256.ref038","first-page":"671","article-title":"The fibrinolytic system components are increased in systemic sclerosis and modulated by Alprostadil (alpha1 ciclodestryn)","volume":"23","author":"F Bandinelli","year":"2005","journal-title":"Clin Exp Rheumatol"},{"issue":"10","key":"pone.0247256.ref039","doi-asserted-by":"crossref","first-page":"3275","DOI":"10.1002\/art.20562","article-title":"Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis","volume":"50","author":"S D\u2019Alessio","year":"2004","journal-title":"Arthritis Rheum"},{"issue":"12","key":"pone.0247256.ref040","doi-asserted-by":"crossref","first-page":"3926","DOI":"10.1002\/art.22263","article-title":"Domain 1 of the urokinase-type plasminogen activator receptor is required for its morphologic and functional, beta2 integrin-mediated connection with actin cytoskeleton in human microvascular endothelial cells: failure of association in systemic sclerosis endothelial cells","volume":"54","author":"F Margheri","year":"2006","journal-title":"Arthritis Rheum"},{"issue":"1","key":"pone.0247256.ref041","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/art.30101","article-title":"A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis","volume":"63","author":"M Manetti","year":"2011","journal-title":"Arthritis Rheum"},{"issue":"6","key":"pone.0247256.ref042","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.1016\/j.ijcard.2012.07.018","article-title":"Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score","volume":"167","author":"S Lyngbaek","year":"2013","journal-title":"Int J Cardiol"},{"issue":"3","key":"pone.0247256.ref043","doi-asserted-by":"crossref","first-page":"G11","DOI":"10.1530\/ERP-17-0071","article-title":"Echocardiographic assessment of pulmonary hypertension: a guideline protocol from the British Society of Echocardiography","volume":"5","author":"DX Augustine","year":"2018","journal-title":"Echo Res Pract"},{"issue":"12","key":"pone.0247256.ref044","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1038\/jid.2008.157","article-title":"The absence of uPAR is associated with the progression of dermal fibrosis","volume":"128","author":"Y Kanno","year":"2008","journal-title":"J Invest Dermatol"},{"issue":"5","key":"pone.0247256.ref045","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1097\/01.ASN.0000064292.37793.FB","article-title":"Urokinase receptor deficiency accelerates renal fibrosis in obstructive nephropathy","volume":"14","author":"G Zhang","year":"2003","journal-title":"J Am Soc Nephrol"},{"issue":"5","key":"pone.0247256.ref046","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.molonc.2014.10.004","article-title":"Biomarker validation and testing","volume":"9","author":"DF Hayes","year":"2015","journal-title":"Mol Oncol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247256","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,24]],"date-time":"2024-08-24T13:27:29Z","timestamp":1724506049000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247256"}},"subtitle":[],"editor":[{"given":"Carol","family":"Feghali-Bostwick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,2,22]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0247256","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,22]]}}}