{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:21:49Z","timestamp":1792588909234,"version":"4.5.0"},"reference-count":36,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2017,10,30]],"date-time":"2017-10-30T00:00:00Z","timestamp":1509321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["ERC\u20102011\u2010StG"],"award-info":[{"award-number":["ERC\u20102011\u2010StG"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Patients with definite systemic sclerosis (<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c) who lack fibrotic features can be stratified into an intermediate stage of disease severity between preclinical\/early <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c (Ea<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c) and fibrotic subsets (limited cutaneous <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c [lc<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c] and diffuse cutaneous <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c [dc<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c]). The aim of the present study was to molecularly characterize nonfibrotic <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c and Ea<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c on the basis of a broad panel of serum markers of inflammation and tissue damage, in order to increase the knowledge of the pathophysiologic mechanisms underlying <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c progression before the development of fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An 88\u2010plex immunoassay was performed in serum samples from a discovery cohort composed of 21 patients with Ea<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c (meeting the LeRoy and Medsger criteria), 15 with nonfibrotic <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c (meeting the American College of Rheumatology\/European League Against Rheumatism 2013 classification criteria, without skin or lung fibrosis), and 11 healthy controls. Analyte concentrations that were consistently significantly different at the exploratory <jats:italic>P<\/jats:italic> value threshold of 0.1 were selected for replication analysis in a larger group composed of 47 patients with Ea<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c, 48 with nonfibrotic <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c, and 43 healthy controls, as well as 51 patients with lc<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c and 35 with dc<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c. The value of the replicated molecules in predicting <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c progression (at a family\u2010wise error rate of 0.05) was tested.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Based on the results of the explorative analysis, 16 molecules were selected for testing in the replication set. The results showed that <jats:styled-content style=\"fixed-case\">CXCL<\/jats:styled-content>10, <jats:styled-content style=\"fixed-case\">CXCL<\/jats:styled-content>11, tumor necrosis factor receptor type <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">TNFRII<\/jats:styled-content>), and chitinase 3\u2013like protein 1 levels were significantly increased in patients with Ea<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c and those with nonfibrotic <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c as compared to healthy controls. The disease in patients with high concentrations of <jats:styled-content style=\"fixed-case\">CXCL<\/jats:styled-content>10 and <jats:styled-content style=\"fixed-case\">TNFRII<\/jats:styled-content> was also characterized by a faster rate of progression from Ea<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c and from nonfibrotic <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c to worse disease stages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c patients with preclinical\/early <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c and those with established, yet nonfibrotic, disease exhibit clear molecular alterations that are associated with faster rates of disease evolution. These data open novel avenues for disease interception in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40243","type":"journal-article","created":{"date-parts":[[2017,8,31]],"date-time":"2017-08-31T18:10:54Z","timestamp":1504203054000},"page":"2359-2369","source":"Crossref","is-referenced-by-count":45,"title":["Earliest Phase of Systemic Sclerosis Typified by Increased Levels of Inflammatory Proteins in the Serum"],"prefix":"10.1002","volume":"69","author":[{"given":"Marta","family":"Cossu","sequence":"first","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenny","family":"van Bon","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Preti","sequence":"additional","affiliation":[{"name":"Referral Center for Systemic Autoimmune Diseases Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia","family":"Rossato","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Beretta","sequence":"additional","affiliation":[{"name":"Referral Center for Systemic Autoimmune Diseases Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy R. 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