{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:13:40Z","timestamp":1790046820549,"version":"4.0.1"},"reference-count":19,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T00:00:00Z","timestamp":1581465600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["# UL1TR001866"],"award-info":[{"award-number":["# UL1TR001866"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1\u2010TR000457\u201006"],"award-info":[{"award-number":["UL1\u2010TR000457\u201006"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["P30\u2010AR070254"],"award-info":[{"award-number":["P30\u2010AR070254"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Morning stiffness is a hallmark symptom of rheumatoid arthritis (RA), but its etiology is poorly understood. This study was undertaken to determine whether any histologic features of synovium are associated with this symptom.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data on patient\u2010reported morning stiffness duration and severity, and Disease Activity Score in 28 joints (DAS28) were collected from 176 patients with RA undergoing arthroplasty. Synovium was scored for 10 histopathologic features: synovial lining hyperplasia, lymphocytes, plasma cells, Russell bodies, binucleate plasma cells, fibrin, synovial giant cells, detritus, neutrophils, and mucin. Fibrinolysis of clots seeded with various cell types was measured in turbidimetric lysis assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Stiffness severity and morning stiffness duration were both significantly associated with DAS28 (<jats:italic>P<\/jats:italic> = 0.0001 and <jats:italic>P<\/jats:italic> = 0.001, respectively). None of the synovial features examined were associated with patient\u2010reported stiffness severity. The presence of neutrophils and fibrin in RA synovial tissue were significantly associated (<jats:italic>P<\/jats:italic> &lt; 0.0001) with patient\u2010reported morning stiffness of \u22651 hour, such that 73% of patients with both synovial fibrin and neutrophils reported morning stiffness of \u22651 hour. Further, neutrophils and fibrin deposits colocalized along the synovial lining. In in vitro analyses, fibrin clots seeded with necrotic neutrophils were more resistant to fibrinolysis than those seeded with living neutrophils or no cells (<jats:italic>P<\/jats:italic> = 0.008). DNase I treatment of necrotic neutrophils abrogated the delay in fibrinolysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In RA, prolonged morning stiffness may be related to impaired fibrinolysis of neutrophil\u2010enmeshed fibrin deposits along the synovial membrane. Our findings also suggest that morning stiffness severity and duration may reflect distinct pathophysiologic phenomena.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41141","type":"journal-article","created":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T03:35:45Z","timestamp":1571110545000},"page":"557-564","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Rheumatoid Arthritis Morning Stiffness Is Associated With Synovial Fibrin and Neutrophils"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9859-7199","authenticated-orcid":false,"given":"Dana E.","family":"Orange","sequence":"first","affiliation":[{"name":"Hospital for Special Surgery Howard Hughes Medical Institute, and The Rockefeller University  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie E.","family":"Blachere","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and The Rockefeller University  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward F.","family":"DiCarlo","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serene","family":"Mirza","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Pannellini","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline S.","family":"Jiang","sequence":"additional","affiliation":[{"name":"Rockefeller University Hospital  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu O.","family":"Frank","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and The Rockefeller University  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salina","family":"Parveen","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and The Rockefeller University  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark P.","family":"Figgie","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen M.","family":"Gravallese","sequence":"additional","affiliation":[{"name":"University of Massachusetts Memorial Medical Center  Worcester"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian P.","family":"Bykerk","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8644-8567","authenticated-orcid":false,"given":"Ana\u2010Maria","family":"Orbai","sequence":"additional","affiliation":[{"name":"Johns Hopkins Medicine  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L.","family":"Mackie","sequence":"additional","affiliation":[{"name":"University of Leeds Leeds NIHR Biomedical Research Centre and Leeds Teaching Hospitals NHS Trust  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1197-7864","authenticated-orcid":false,"given":"Susan M.","family":"Goodman","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,12]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-014-3040-0"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-015-3275-4"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780310302"},{"key":"e_1_2_6_6_1","first-page":"1138","article-title":"A reevaluation of the symptom of morning stiffness","volume":"20","author":"Hazes JM","year":"1993","journal-title":"J Rheumatol"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.22592"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.081175"},{"key":"e_1_2_6_9_1","first-page":"1468","article-title":"Morning stiffness: how common is it and does it correlate with physician and patient global assessment of disease activity? 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