{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T20:43:04Z","timestamp":1789850584891,"version":"4.0.1"},"reference-count":62,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100011747","name":"Novo Nordisk Foundation Center for Basic Metabolic Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011747","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Ophthalmologica"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To examine ocular surface changes and inflammatory tear fluid biomarkers in patients with thyroid eye disease (TED).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We included 106 Graves' disease (GD) patients (36 without TED, 32 with active and 38 with inactive TED) and 106 age\u2010 and sex\u2010matched healthy subjects for ophthalmological evaluation, including ocular surface status and Meibomian gland function. Tear fluid was analysed for 40 inflammatory biomarkers by a Luminex multiplex bead assay. The parameters were compared across subgroups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      GD patients with TED had significantly higher median (min\u2013max) Ocular Surface Disease Index (OSDI) score than GD patients without TED, with a median score of 31.4 (0\u201386.4) compared to 7.3 (0\u201345.8) (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). Eleven of 50 patients with moderate\u2010to\u2010severe and sight\u2010threatening TED had a meibum quality score above seven, compared to none of the 20 patients with mild TED (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.027).\n                    <\/jats:p>\n                    <jats:p>\n                      Tear fluid levels of chemokine (C\u2013C motif) ligand 2 (CCL2) were significantly (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003) higher in GD patients compared to healthy subjects. CD40 ligand (CD40L) and CCL2 were higher in GD patients with TED compared with GD patients without TED (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002 and 0.013, respectively). As a combined biomarker to distinguish between GD patients with and without TED, OSDI score together with tear fluid levels of CCL2 and CD40L produced an area under the receiver operating characteristic (ROC) curve of 0.80, with sensitivity of 0.69 at a fixed specificity of 0.80.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings demonstrate increased tear fluid levels of CD40L and CCL2 in patients with TED, indicating their potential as diagnostic biomarkers. Increased ocular discomfort in patients with TED could be related to impaired meibum quality.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/aos.17556","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T11:28:54Z","timestamp":1751887734000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exploring tear fluid biomarkers and the ocular surface in thyroid eye disease"],"prefix":"10.1111","volume":"104","author":[{"given":"Mikael Thomassen","family":"Neset","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Medicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy Miodini","family":"Nilsen","sequence":"additional","affiliation":[{"name":"Faculty of Health and Social Sciences Western Norway University of Applied Sciences  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"L\u00f8v\u00e5s","sequence":"additional","affiliation":[{"name":"Department of Medicine Haukeland University Hospital  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrine","family":"Hals\u00f8y","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Medicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5kon","family":"Reikvam","sequence":"additional","affiliation":[{"name":"Department of Medicine Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann\u2010Elin Meling","family":"Stokland","sequence":"additional","affiliation":[{"name":"Department of Medicine Stavanger University Hospital  Stavanger Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grethe \u00c5str\u00f8m","family":"Ueland","sequence":"additional","affiliation":[{"name":"Department of Medicine Haukeland University Hospital  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anette S. B.","family":"Wolff","sequence":"additional","affiliation":[{"name":"Department of Medicine Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans Christian D.","family":"Aass","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sjur","family":"Reppe","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Oslo University Hospital  Oslo Norway"},{"name":"Department of Plastic and Reconstructive Surgery Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eystein Sverre","family":"Husebye","sequence":"additional","affiliation":[{"name":"Department of Medicine Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyvind","family":"R\u00f8dahl","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Medicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tor Paaske","family":"Utheim","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Oslo University Hospital  Oslo Norway"},{"name":"Department of Ophthalmology Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7993-9739","authenticated-orcid":false,"given":"Hans Olav","family":"Ueland","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Medicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175274"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-11-0548"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.4103\/joco.joco_176_23"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.2147\/OPTH.S317708"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/02713680591005931"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-21-0479"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1159\/000510700"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003226-200310000-00008"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2008.03219.x"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.14296"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.2003.035915"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002341-199803000-00008"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10792-023-02702-5"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-01626"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.05-0605"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgac045"},{"key":"e_1_2_8_18_1","first-page":"e368","article-title":"The Th1 chemokine MIG in Graves' ophthalmopathy","volume":"170","author":"Gonnella D.","year":"2019","journal-title":"La Clinica Terapeutica"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1996.tb00921.x"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3109\/02713683.2010.526285"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13167-016-0065-3"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22031115"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.13-13704"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-011-1863-x"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2021.0671"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.08-2328"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2020.9383"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.4183\/aeb.2021.291"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqad004"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2005.02352.x"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgz013"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtos.2018.07.003"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcjo.2015.05.012"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2017.09.001"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.18-24027"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-017-3892-6"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.15-16699"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgad538"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.1997.2331047.x"},{"key":"e_1_2_8_40_1","first-page":"479","article-title":"Tear film profile in patients with active thyroid orbithopathy","volume":"107","author":"Nowak M.","year":"2005","journal-title":"Klinika Oczna"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0029-1214413"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.84.5.517"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/aos.14000"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/412158"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2011.02.018"},{"key":"e_1_2_8_46_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2023"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0250617"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.118.5.615"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1998.274.3.C707"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.2174\/1871530319666190618142215"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.2001.01241.x"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.10-6997f"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1097\/IOP.0000000000002466"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-22-0247"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.61.8.17"},{"key":"e_1_2_8_56_1","first-page":"1","article-title":"Mice: multivariate imputation by chained equations in R","volume":"45","author":"Van Buuren S.","year":"2011","journal-title":"Journal of Statistical Software"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-0506"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2614"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2011.11.001"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03350193"},{"key":"e_1_2_8_61_1","first-page":"911","article-title":"CD4+ T cells and the Th1\/Th2 imbalance are implicated in the pathogenesis of Graves' ophthalmopathy","volume":"17","author":"Xia N.","year":"2006","journal-title":"International Journal of Molecular Medicine"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-019-01174-8"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-017-1467-2"}],"container-title":["Acta Ophthalmologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/aos.17556","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/aos.17556","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/aos.17556","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T20:42:46Z","timestamp":1769719366000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/aos.17556"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,7]]},"references-count":62,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1111\/aos.17556"],"URL":"https:\/\/doi.org\/10.1111\/aos.17556","archive":["Portico"],"relation":{},"ISSN":["1755-375X","1755-3768"],"issn-type":[{"value":"1755-375X","type":"print"},{"value":"1755-3768","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,7]]},"assertion":[{"value":"2025-04-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}