{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:35:39Z","timestamp":1792427739276,"version":"4.5.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tocilizumab, an interleukin-6 receptor antagonist, is increasingly used in moderate-to-severe thyroid eye disease. However, its association with hypofibrinogenemia remains underexplored in this population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single-center retrospective study included 194 TED patients treated with Tocilizumab at Beijing Tongren Hospital between March 2023 and May 2025. Patients were stratified into a positive group (fibrinogen &amp;lt; 1.5 g\/L) and a negative group (fibrinogen \u2265 1.5 g\/L) based on post-treatment fibrinogen levels. Demographic, clinical, and laboratory data were analyzed to identify risk factors using univariate and multivariate logistic regression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 194 patients, 89 (45.88%) developed hypofibrinogenemia (fibrinogen &amp;lt; 1.5 g\/L). The most significant fibrinogen decline occurred after the first Tocilizumab administration (median reduction: 0.88 g\/L). Nadir levels were most common before the third (26.4%) or fifth administration (29.6%). Multivariate analysis identified lower baseline fibrinogen (OR = 0.37, P = 0.001), higher body weight (OR = 1.05, P = 0.001), and lower prothrombin time (OR = 0.45, P = 0.008) as independent risk factors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Hypofibrinogenemia was observed at a higher incidence (45.88%) in thyroid eye disease patients treated with tocilizumab. It typically did not occur immediately after administration but emerged early in the treatment course and persisted with repeated dosing. Baseline fibrinogen level, body weight, and prothrombin time (PT) activity were identified as significant predictors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1781048","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:21:49Z","timestamp":1771564909000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Incidence and risk factors of tocilizumab-induced hypofibrinogenemia in patients with thyroid eye disease: a single-center retrospective study"],"prefix":"10.3389","volume":"17","author":[{"given":"Ente","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyuan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Xuanwu Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbo","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Civil Aviation General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinglong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-8587(25)00066-x","article-title":"Thyroid eye disease (Graves\u2019 Orbitopathy): clinical presentation, epidemiology, pathogenesis, and management","volume":"13","author":"Wiersinga","year":"2025","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s13023-017-0625-1","article-title":"Graves\u2019 Orbitopathy as a rare disease in europe: A european group on graves\u2019 Orbitopathy (Eugogo) position statement","volume":"12","author":"Perros","year":"2017","journal-title":"Orphanet J Rare Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2024.0304","article-title":"The epidemiology of thyroid eye disease in olmsted county, minnesota, 2005-2020","volume":"34","author":"Rachmasari","year":"2024","journal-title":"Thyroid"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/249125","article-title":"Graves\u2019 Ophthalmopathy: visa versus eugogo classification, assessment, and management","volume":"2015","author":"Barrio-Barrio","year":"2015","journal-title":"J Ophthalmol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.654473","article-title":"Cytokines as targets of novel therapies for graves\u2019 Ophthalmopathy","volume":"12","author":"Fallahi","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2020.101388","article-title":"Graves\u2019 Disease: clinical manifestations, immune pathogenesis (Cytokines and chemokines) and therapy","volume":"34","author":"Antonelli","year":"2020","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1177\/25158414211027760","article-title":"Updates on the understanding and management of thyroid eye disease","volume":"13","author":"Men","year":"2021","journal-title":"Ther Adv Ophthalmol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1571427","article-title":"Targeted immunotherapies for graves\u2019 Thyroidal & Orbital diseases","volume":"16","author":"Lee","year":"2025","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.81.8.8768861","article-title":"Increased serum concentrations of interleukin-6 (Il-6) and soluble il-6 receptor in patients with graves\u2019 Disease","volume":"81","author":"Salvi","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2022.0251","article-title":"Management of thyroid eye disease: A consensus statement by the american thyroid association and the european thyroid association","volume":"32","author":"Burch","year":"2022","journal-title":"Thyroid"},{"key":"B11","doi-asserted-by":"publisher","first-page":"Cd012984","DOI":"10.1002\/14651858.CD012984.pub2","article-title":"Tocilizumab for thyroid eye disease","volume":"11","author":"Hamed Azzam","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-025-02595-4","article-title":"Efficacy and safety of tocilizumab for thyroid eye disease: A systemic review and meta-analysis","volume":"48","author":"Lin","year":"2025","journal-title":"J Endocrinol Invest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2018.07.038","article-title":"Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant graves orbitopathy: A randomized clinical trial","volume":"195","author":"Perez-Moreiras","year":"2018","journal-title":"Am J Ophthalmol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-07-818211","article-title":"The multifaceted role of fibrinogen in tissue injury and inflammation","volume":"133","author":"Luyendyk","year":"2019","journal-title":"Blood"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2015-307399","article-title":"Pathogenesis of thyroid eye disease: review and update on molecular mechanisms","volume":"100","author":"Khong","year":"2016","journal-title":"Br J Ophthalmol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-024-05714-1","article-title":"Evaluation of tocilizumab-induced hypofibrinogenemia in rheumatology practice: A retrospective, real-life, single-center experience","volume":"44","author":"Y\u0131ld\u0131r\u0131m","year":"2024","journal-title":"Rheumatol Int"},{"key":"B17","doi-asserted-by":"publisher","first-page":"9050","DOI":"10.1038\/s41598-023-36246-6","article-title":"Tocilizumab-induced hypofibrinogenemia in patients with systemic-onset juvenile idiopathic arthritis","volume":"13","author":"He","year":"2023","journal-title":"Sci Rep"},{"key":"B18","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1097\/eja.0000000000001803","article-title":"Management of severe peri-operative bleeding: guidelines from the european society of anaesthesiology and intensive care: second update 2022","volume":"40","author":"Kietaibl","year":"2023","journal-title":"Eur J Anaesthesiol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/s13054-023-04327-7","article-title":"The european guideline on management of major bleeding and coagulopathy following trauma: sixth edition","volume":"27","author":"Rossaint","year":"2023","journal-title":"Crit Care"},{"key":"B20","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s40360-024-00827-6","article-title":"Characteristics, risk factors and a risk prediction model of tocilizumab-induced hypofibrinogenemia: A retrospective real-world study of inpatients","volume":"26","author":"Cai","year":"2025","journal-title":"BMC Pharmacol Toxicol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1510030","article-title":"Graves\u2019 Disease","volume":"375","author":"Smith","year":"2016","journal-title":"N Engl J Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1011170","article-title":"The coagulopathy of chronic liver disease","volume":"365","author":"Tripodi","year":"2011","journal-title":"N Engl J Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2023.284564","article-title":"Tocilizumab administration in cytokine release syndrome is associated with hypofibrinogenemia after chimeric antigen receptor T-cell therapy for hematologic Malignancies","volume":"109","author":"Perl","year":"2024","journal-title":"Haematologica"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-024-06937-0","article-title":"Clinical observation of hypofibrinogenemia induced by the treatment of tocilizumab in rheumatic diseases and exploration of risk factor for hypofibrinogenemia","volume":"43","author":"An","year":"2024","journal-title":"Clin Rheumatol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(89)80476-4","article-title":"Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes","volume":"242","author":"Castell","year":"1989","journal-title":"FEBS Lett"},{"key":"B26","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s12348-019-0182-y","article-title":"Interleukin-6 inhibition in the management of non-infectious uveitis and beyond","volume":"9","author":"Karkhur","year":"2019","journal-title":"J Ophthalmic Inflammation Infect"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.thromres.2023.08.011","article-title":"Ros-driven structural and functional fibrinogen modifications are reverted by interleukin-6 inhibition in giant cell arteritis","volume":"230","author":"Bettiol","year":"2023","journal-title":"Thromb Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(08)60453-5","article-title":"Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (Option study): A double-blind, placebo-controlled, randomised trial","volume":"371","author":"Smolen","year":"2008","journal-title":"Lancet"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03043-1","article-title":"Il-6 inhibition with clazakizumab in patients receiving maintenance dialysis: A randomized phase 2b trial","volume":"30","author":"Chertow","year":"2024","journal-title":"Nat Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.121","article-title":"Safety and pharmacokinetics of olokizumab, an anti-il-6 monoclonal antibody, administered to healthy male volunteers: A randomized phase I study","volume":"3","author":"Kretsos","year":"2014","journal-title":"Clin Pharmacol Drug Dev"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-05-552729","article-title":"Current concepts in the diagnosis and management of cytokine release syndrome","volume":"124","author":"Lee","year":"2014","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13500","article-title":"Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population pharmacokinetic analysis","volume":"84","author":"Bastida","year":"2018","journal-title":"Br J Clin Pharmacol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1007\/bf03344054","article-title":"Coagulation and fibrinolysis abnormalities in obesity","volume":"25","author":"De Pergola","year":"2002","journal-title":"J Endocrinol Invest"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1042\/bj2650621","article-title":"Interleukin-6 and the acute phase response","volume":"265","author":"Heinrich","year":"1990","journal-title":"Biochem J"},{"key":"B35","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1186\/cc4975","article-title":"Coagulation abnormalities in critically ill patients","volume":"10","author":"Levi","year":"2006","journal-title":"Crit Care"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2016.02.026","article-title":"Non-autoimmune combined factor xiii a and B subunit deficiencies in rheumatoid arthritis patients treated with anti-interleukin-6 receptor monoclonal antibody (Tocilizumab)","volume":"140","author":"Souri","year":"2016","journal-title":"Thromb Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2003.t01-1-00553.x","article-title":"Rare bleeding disorder registry: deficiencies of factorsii, V, vii, X, xiii, fibrinogen and dysfibrinogenemias","volume":"2","author":"Acharya","year":"2004","journal-title":"J Thromb Haemost"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1781048\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:21:49Z","timestamp":1771564909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1781048\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,20]]},"references-count":37,"alternative-id":["10.3389\/fendo.2026.1781048"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1781048","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,20]]},"article-number":"1781048"}}