{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T03:41:14Z","timestamp":1791690074360,"version":"4.3.4"},"reference-count":180,"publisher":"Bioscientifica","issue":"5","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":284,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:p>Graves\u2019 orbitopathy (GO) is characterized by orbital inflammatory infiltration, expansion of orbital tissues due to de novo adipogenesis and over-production of hydrophilic glycosaminoglycans, as well as myofibroblastic differentiation resulting in tissue fibrosis. Thyrotropin receptor antibody (TSH-R-Ab) is the major stimulus, which activates thyrotropin receptor (TSH-R)\/insulin-like growth factor-1 receptor (IGF-1R) and its downstream signalling in orbital fibroblasts (OF). Clinical evaluation of TSH-R-Ab, the specific biomarker of Graves\u2019 disease (GD) and the associated orbitopathy, provides important clinical information concerning diagnosis, disease monitoring and prognosis of GO. TSH-R\/IGF-1R crosstalk represents the principal mechanism of activation of OF, the key effector cells in GO. T cells and monocytes\/macrophages predominate in the inflammatory infiltrates and B-T cell co-stimulation results in mutual activation. Mast cell-derived products also activate OF. In the presence of various pro-inflammatory molecules, activated OF and lymphocytes perpetuate orbital inflammation and mediate tissue remodelling. Enhanced oxidative stress drives various pathological processes in GO and many antioxidant agents have shown inhibitory effects on OF. Highly differential gene and protein expression exists between GO and normal subjects, as well as between active\/severe and inactive\/mild GO, providing important insights into the disease mechanisms. The lack of confirmed genetic susceptibility to GO development suggests that epigenetic mechanisms (e.g. DNA methylation and microRNAs) may play a role in regulating gene and protein expression, and hence disease phenotypes. The gut microbiome differs significantly between GO patients and healthy individuals. Modifying gut microbiota in GO animal models improves GO. Emerging evidence indicates that hypercholesterolaemia is associated with increased risk of developing GO, while statin use is a protective factor.<\/jats:p>","DOI":"10.1530\/etj-25-0200","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T11:41:42Z","timestamp":1756986102000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-17","source":"Crossref","is-referenced-by-count":14,"title":["Unravelling the pathogenic mechanisms in Graves\u2019 orbitopathy"],"prefix":"10.1530","volume":"14","author":[{"given":"Alan Chun Hong","family":"Lee","sequence":"first","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0441-430X","authenticated-orcid":true,"given":"George J","family":"Kahaly","sequence":"additional","affiliation":[{"name":"2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"2026070713592447000_bib1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/cen.14296","article-title":"Prevalence of thyroid eye disease in Graves\u2019 disease: a meta-analysis and systematic review","volume":"93","author":"Chin","year":"2020","journal-title":"Clin Endocrinol"},{"key":"2026070713592447000_bib2","doi-asserted-by":"crossref","first-page":"G43","DOI":"10.1530\/EJE-21-0479","article-title":"The 2021 European group on Graves\u2019 orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves\u2019 orbitopathy","volume":"185","author":"Bartalena","year":"2021","journal-title":"Eur J Endocrinol"},{"key":"2026070713592447000_bib3","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1097\/IOP.0000000000002467","article-title":"Thyroid eye disease: epidemiology, natural history, and risk factors","volume":"39","author":"Bartalena","year":"2023","journal-title":"Ophthalmic Plast Reconstr Surg"},{"key":"2026070713592447000_bib4","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.ajo.2011.02.018","article-title":"Quality of life in a German Graves orbitopathy population","volume":"152","author":"Ponto","year":"2011","journal-title":"Am J Ophthalmol"},{"key":"2026070713592447000_bib5","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1210\/jc.2012-3119","article-title":"Public health relevance of Graves\u2019 orbitopathy","volume":"98","author":"Ponto","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib6","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1159\/000508071","article-title":"Predictive factors for changes in quality of life after steroid treatment for active moderate-to-severe Graves\u2019 orbitopathy: a prospective trial","volume":"9","author":"Hoppe","year":"2021","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib7","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1089\/thy.2017.0365","article-title":"Death by suicide in Graves\u2019 Disease and Graves\u2019 orbitopathy: A nationwide Danish register study","volume":"27","author":"Ferlov-Schwensen","year":"2017","journal-title":"Thyroid"},{"key":"2026070713592447000_bib8","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1530\/EJE-16-0954","article-title":"Mortality in Graves\u2019 orbitopathy is increased and influenced by gender, age and pre-existing morbidity: a nationwide Danish register study","volume":"176","author":"Schwensen","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"2026070713592447000_bib9","doi-asserted-by":"crossref","first-page":"1439","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":"2026070713592447000_bib10","article-title":"Targeted immunotherapies for Graves\u2019 thyroidal & orbital diseases","volume":"16","author":"Lee","year":"2025","journal-title":"Front Immunol"},{"key":"2026070713592447000_bib11","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1159\/000508790","article-title":"A novel long-term Graves\u2019 disease animal model confirmed by functional thyrotropin receptor antibodies","volume":"9","author":"Diana","year":"2020","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib12","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaut.2021.102666","article-title":"A cyclic peptide significantly improves thyroid function, thyrotropin-receptor antibodies and orbital mucine\/collagen content in a long-term Graves\u2019 disease mouse model","volume":"122","author":"Diana","year":"2021","journal-title":"J Autoimmun"},{"key":"2026070713592447000_bib13","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1089\/thy.2020.0088","article-title":"A promising mouse model of Graves\u2019 Orbitopathy induced by adenovirus expressing thyrotropin receptor A subunit","volume":"31","author":"Zhang","year":"2021","journal-title":"Thyroid"},{"key":"2026070713592447000_bib14","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s40168-018-0478-4","article-title":"Gut microbiota in experimental murine model of Graves\u2019 orbitopathy established in different environments may modulate clinical presentation of disease","volume":"6","author":"Masetti","year":"2018","journal-title":"Microbiome"},{"key":"2026070713592447000_bib15","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1055\/a-0653-3766","article-title":"Gut microbiome in BALB\/c and C57BL\/6J mice undergoing experimental thyroid autoimmunity associate with differences in immunological responses and thyroid function","volume":"50","author":"Moshkelgosha","year":"2018","journal-title":"Horm Metab Res"},{"key":"2026070713592447000_bib16","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1007\/s40618-024-02344-z","article-title":"Mouse model of Graves\u2019 orbitopathy induced by the immunization with TSHR A and IGF-1R alpha subunit gene","volume":"47","author":"Wu","year":"2024","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib17","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40168-020-00952-4","article-title":"Modulating gut microbiota in a mouse model of Graves\u2019 orbitopathy and its impact on induced disease","volume":"9","author":"Moshkelgosha","year":"2021","journal-title":"Microbiome"},{"key":"2026070713592447000_bib18","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2024.1420024","article-title":"Impact of ibrutinib on inflammation in a mouse model of Graves\u2019 orbitopathy","volume":"15","author":"Kim","year":"2024","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib19","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.clnu.2010.04.002","article-title":"Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission","volume":"29","author":"Hamer","year":"2010","journal-title":"Clin Nutr"},{"key":"2026070713592447000_bib20","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1167\/iovs.66.3.5","article-title":"Butyrate ameliorates Graves\u2019 orbitopathy through regulating orbital fibroblast phenotypes and gut microbiota","volume":"66","author":"Ouyang","year":"2025","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"2026070713592447000_bib21","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/s41586-022-05159-1","article-title":"Autoantibody mimicry of hormone action at the thyrotropin receptor","volume":"609","author":"Faust","year":"2022","journal-title":"Nature"},{"key":"2026070713592447000_bib22","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/s41586-022-05173-3","article-title":"Hormone- and antibody-mediated activation of the thyrotropin receptor","volume":"609","author":"Duan","year":"2022","journal-title":"Nature"},{"key":"2026070713592447000_bib23","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jaut.2013.07.009","article-title":"How one TSH receptor antibody induces thyrocyte proliferation while another induces apoptosis","volume":"47","author":"Morshed","year":"2013","journal-title":"J Autoimmun"},{"key":"2026070713592447000_bib24","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaut.2021.102746","article-title":"Rescue of thyroid cells from antibody induced cell death via induction of autophagy","volume":"126","author":"Morshed","year":"2022","journal-title":"J Autoimmun"},{"key":"2026070713592447000_bib25","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaut.2023.103012","article-title":"Signal responses to neutral TSH receptor antibody \u2013 a cycle of damage in the pathophysiology of Graves\u2019 disease","volume":"136","author":"Morshed","year":"2023","journal-title":"J Autoimmun"},{"key":"2026070713592447000_bib26","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41572-020-0184-y","article-title":"Graves\u2019 disease","volume":"6","author":"Davies","year":"2020","journal-title":"Nat Rev Dis Primers"},{"key":"2026070713592447000_bib27","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvae182","article-title":"The TSH receptor antibody reactome contributes to retro-orbital inflammation","volume":"8","author":"Morshed","year":"2024","journal-title":"J Endocr Soc"},{"key":"2026070713592447000_bib28","doi-asserted-by":"crossref","first-page":"97","DOI":"10.4158\/EP-2019-0363","article-title":"Tsh receptor antibodies: relevance & utility","volume":"26","author":"Kahaly","year":"2020","journal-title":"Endocr Pract"},{"key":"2026070713592447000_bib29","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1007\/s40618-020-01380-9","article-title":"Thyrotropin receptor antibodies and Graves\u2019 orbitopathy","volume":"44","author":"Diana","year":"2021","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib30","doi-asserted-by":"crossref","DOI":"10.1016\/j.beem.2022.101620","article-title":"Pathophysiology of thyroid-associated orbitopathy","volume":"37","author":"Lee","year":"2023","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2026070713592447000_bib31","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2024.1463379","article-title":"A novel bioassay for thyroid-blocking immunoglobulins","volume":"15","author":"George","year":"2024","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib32","article-title":"Analytical validation of a novel bioassay for thyroid-stimulating immunoglobulin","volume":"15","author":"Olivo","year":"2024","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib33","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1159\/000490384","article-title":"2018 European Thyroid Association Guideline for the management of Graves\u2019 hyperthyroidism","volume":"7","author":"Kahaly","year":"2018","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib34","first-page":"e1","article-title":"TSI assay utilization: impact on costs of Graves\u2019 hyperthyroidism diagnosis","volume":"18","author":"McKee","year":"2012","journal-title":"Am J Manag Care"},{"key":"2026070713592447000_bib35","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/cen.14130","article-title":"Diagnostic testing for Graves\u2019 or non-Graves\u2019 hyperthyroidism: a comparison of two thyrotropin receptor antibody immunoassays with thyroid scintigraphy and ultrasonography","volume":"92","author":"Scappaticcio","year":"2020","journal-title":"Clin Endocrinol"},{"key":"2026070713592447000_bib36","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1530\/EJE-14-0254","article-title":"Predictive value of maternal second-generation thyroid-binding inhibitory immunoglobulin assay for neonatal autoimmune hyperthyroidism","volume":"171","author":"Abeillon-du Payrat","year":"2014","journal-title":"Eur J Endocrinol"},{"key":"2026070713592447000_bib37","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1210\/js.2017-00189","article-title":"Study of the factors leading to fetal and neonatal dysthyroidism in children of patients with Graves disease","volume":"1","author":"Banige","year":"2017","journal-title":"J Endocr Soc"},{"key":"2026070713592447000_bib38","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1111\/cen.13327","article-title":"Measuring TSH receptor antibody to influence treatment choices in Graves\u2019 disease","volume":"86","author":"Hesarghatta Shyamasunder","year":"2017","journal-title":"Clin Endocrinol"},{"key":"2026070713592447000_bib39","doi-asserted-by":"crossref","first-page":"e1881","DOI":"10.1210\/clinem\/dgae456","article-title":"Approach to the patient considering long-term antithyroid drug therapy for Graves\u2019 disease","volume":"109","author":"Azizi","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib40","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1210\/jc.2015-3644","article-title":"Predicting the risk of recurrence before the start of antithyroid drug therapy in patients with Graves\u2019 hyperthyroidism","volume":"101","author":"Vos","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib41","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1530\/EJE-16-0986","article-title":"External validation of the GREAT score to predict relapse risk in Graves\u2019 disease: results from a multicenter, retrospective study with 741 patients","volume":"176","author":"Struja","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"2026070713592447000_bib42","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1055\/a-0974-3991","article-title":"External validation of the GREAT score in Turkish patients with Graves\u2019 hyperthyroidism treated with the titration regimen method of antithyroid drugs: a multicenter study","volume":"51","author":"Zuhur","year":"2019","journal-title":"Horm Metab Res"},{"key":"2026070713592447000_bib43","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s12020-023-03656-5","article-title":"Risk of recurrence at the time of withdrawal of short- or long-term methimazole therapy in patients with Graves\u2019 hyperthyroidism: a randomized trial and a risk-scoring model","volume":"84","author":"Azizi","year":"2024","journal-title":"Endocrine"},{"key":"2026070713592447000_bib44","doi-asserted-by":"crossref","first-page":"e1006","DOI":"10.1210\/clinem\/dgz292","article-title":"Prospective trial of functional thyrotropin receptor antibodies in Graves disease","volume":"105","author":"Kahaly","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib45","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s40618-019-01141-3","article-title":"Orbital diseases mimicking Graves\u2019 orbitopathy: a long-standing challenge in differential diagnosis","volume":"43","author":"Marino","year":"2020","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib46","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1210\/jc.2009-2470","article-title":"A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves\u2019 orbitopathy","volume":"95","author":"Lytton","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib47","doi-asserted-by":"crossref","first-page":"211","DOI":"10.5937\/jomb0-34718","article-title":"Sensitivity of three thyrotropin receptor antibody assays in thyroid-associated orbitopathy","volume":"41","author":"Saric-Matutinovic","year":"2022","journal-title":"J Med Biochem"},{"key":"2026070713592447000_bib48","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s40618-021-01652-y","article-title":"Clinical value of functional thyrotropin receptor antibodies in Serbian patients with Graves\u2019 orbitopathy","volume":"45","author":"Saric Matutinovic","year":"2022","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib49","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1530\/EJE-18-0039","article-title":"Eugogo. Predictive score for the development or progression of Graves\u2019 orbitopathy in patients with newly diagnosed Graves\u2019 hyperthyroidism","volume":"178","author":"Wiersinga","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"2026070713592447000_bib50","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1210\/jc.2018-02705","article-title":"High titers of thyrotropin receptor antibodies are associated with orbitopathy in patients with Graves disease","volume":"104","author":"Kahaly","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib51","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1016\/j.ophtha.2011.03.030","article-title":"Clinical relevance of thyroid-stimulating immunoglobulins in Graves\u2019 ophthalmopathy","volume":"118","author":"Ponto","year":"2011","journal-title":"Ophthalmology"},{"key":"2026070713592447000_bib52","doi-asserted-by":"crossref","DOI":"10.1155\/2015\/678194","article-title":"Thyroid stimulating but not blocking autoantibodies are highly prevalent in severe and active thyroid-associated orbitopathy: a prospective study","volume":"2015","author":"Kampmann","year":"2015","journal-title":"Int J Endocrinol"},{"key":"2026070713592447000_bib53","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s40618-020-01353-y","article-title":"Correlation between serum anti-TSH receptor autoantibodies (TRAbs) and the clinical feature of Graves\u2019 orbitopathy","volume":"44","author":"Nicoli","year":"2021","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib54","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1007\/s40618-023-02085-5","article-title":"The phenotype of Graves\u2019 orbitopathy is associated with thyrotropin receptor antibody levels","volume":"46","author":"Saric Matutinovic","year":"2023","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib55","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s40618-015-0254-2","article-title":"Thyroid-stimulating immunoglobulins indicate the onset of dysthyroid optic neuropathy","volume":"38","author":"Ponto","year":"2015","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib56","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/j.eprac.2022.07.007","article-title":"Thyroid-stimulating antibody\/thyroid-stimulating hormone receptor antibody ratio as a sensitive screening test for active Graves\u2019 orbitopathy","volume":"28","author":"Nakano","year":"2022","journal-title":"Endocr Pract"},{"key":"2026070713592447000_bib57","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2023.1153312","article-title":"Prognostic significance of thyroid-stimulating hormone receptor antibodies in moderate-to-severe Graves\u2019 orbitopathy","volume":"14","author":"Park","year":"2023","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib58","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2024.1340415","article-title":"Thyroid stimulating immunoglobulin concentration is associated with disease activity and predicts response to treatment with intravenous methylprednisolone in patients with Graves\u2019 orbitopathy","volume":"15","author":"Hotte","year":"2024","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib59","first-page":"90","article-title":"Graves\u2019 autoantibodies exhibit different stimulating activities in cultures of thyrocytes and orbital fibroblasts not reflected by clinical assays","volume":"32","author":"Krieger","year":"2022","journal-title":"Thyroid"},{"key":"2026070713592447000_bib60","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1089\/thy.2022.0173","article-title":"A multicenter, single-blind, case-control, immunohistochemical study of orbital tissue in thyroid eye disease","volume":"32","author":"Hai","year":"2022","journal-title":"Thyroid"},{"key":"2026070713592447000_bib61","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1210\/clinem\/dgac045","article-title":"It takes two to tango: IGF-I and TSH receptors in thyroid eye disease","volume":"107","author":"Girnita","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib62","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1089\/thy.2024.0606","article-title":"Controversies surrounding IGF-I receptor involvement in thyroid-associated ophthalmopathy","volume":"35","author":"Smith","year":"2025","journal-title":"Thyroid"},{"key":"2026070713592447000_bib63","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1159\/000508789","article-title":"Novel approaches for immunosuppression in Graves\u2019 hyperthyroidism and associated orbitopathy","volume":"9","author":"Lee","year":"2020","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib64","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1159\/000511538","article-title":"Targeting TSH and IGF-1 receptors to treat thyroid eye disease","volume":"9","author":"Neumann","year":"2020","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib65","doi-asserted-by":"crossref","DOI":"10.1210\/endocr\/bqaf009","article-title":"Mechanisms in thyroid eye disease: the TSH receptor interacts directly with the IGF-1 receptor","volume":"166","author":"Latif","year":"2025","journal-title":"Endocrinology"},{"key":"2026070713592447000_bib66","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1056\/NEJMoa1614949","article-title":"Teprotumumab for thyroid-associated ophthalmopathy","volume":"376","author":"Smith","year":"2017","journal-title":"N Engl J Med"},{"key":"2026070713592447000_bib67","first-page":"1959","article-title":"Teprotumumab for active thyroid eye disease","volume":"382","author":"Douglas","year":"2020","journal-title":"Reply N Engl J Med"},{"key":"2026070713592447000_bib68","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/S2213-8587(21)00056-5","article-title":"Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials","volume":"9","author":"Kahaly","year":"2021","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2026070713592447000_bib69","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.ophtha.2021.10.017","article-title":"Teprotumumab efficacy, safety, and durability in longer-duration thyroid eye disease and Re-treatment: OPTIC-X study","volume":"129","author":"Douglas","year":"2022","journal-title":"Ophthalmology"},{"key":"2026070713592447000_bib70","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1210\/clinem\/dgad637","article-title":"Efficacy and safety of teprotumumab in patients with thyroid eye disease of long duration and low disease activity","volume":"109","author":"Douglas","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib71","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1089\/thy.2023.0656","article-title":"Long-term efficacy of teprotumumab in thyroid eye disease: follow-up outcomes in three clinical trials","volume":"34","author":"Kahaly","year":"2024","journal-title":"Thyroid"},{"key":"2026070713592447000_bib72","article-title":"A randomised, double-masked, placebo-controlled trial evaluating the efficacy and safety of teprotumumab for active thyroid eye disease in Japanese patients","volume":"55","author":"Hiromatsu","year":"2025","journal-title":"Lancet Reg Health West Pac"},{"key":"2026070713592447000_bib73","doi-asserted-by":"crossref","first-page":"e1653","DOI":"10.1210\/clinem\/dgab824","article-title":"Inhibition of TSH\/IGF-1 receptor crosstalk by teprotumumab as a treatment modality of thyroid eye disease","volume":"107","author":"Krieger","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib74","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1089\/thy.2021.0176","article-title":"Mechanisms in Graves eye disease: apoptosis as the end point of insulin-like growth factor 1 receptor inhibition","volume":"32","author":"Morshed","year":"2022","journal-title":"Thyroid"},{"key":"2026070713592447000_bib75","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2024.1488220","article-title":"Linsitinib inhibits proliferation and induces apoptosis of both IGF-1R and TSH-R expressing cells","volume":"15","author":"Luffy","year":"2024","journal-title":"Front Immunol"},{"key":"2026070713592447000_bib76","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.182352","article-title":"Transcriptomic profiling of thyroid eye disease orbital fat demonstrates differences in adipogenicity and IGF-1R pathway","volume":"9","author":"Kim","year":"2024","journal-title":"JCI Insight"},{"key":"2026070713592447000_bib77","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1111\/cen.14681","article-title":"TSH receptor specific monoclonal autoantibody K1-70(TM) targeting of the TSH receptor in subjects with Graves\u2019 disease and Graves\u2019 orbitopathy-results from a phase I clinical trial","volume":"96","author":"Furmaniak","year":"2022","journal-title":"Clin Endocrinol"},{"key":"2026070713592447000_bib78","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1089\/thy.2022.0694","article-title":"Thyrotropin receptor antagonism by a novel small molecule: preclinical in vitro observations","volume":"33","author":"Kahaly","year":"2023","journal-title":"Thyroid"},{"key":"2026070713592447000_bib79","doi-asserted-by":"crossref","first-page":"3122","DOI":"10.1210\/clinem\/dgad381","article-title":"Proof-of-concept and randomized, placebo-controlled trials of an FcRn inhibitor, batoclimab, for thyroid eye disease","volume":"108","author":"Kahaly","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib80","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1007\/s40618-022-01862-y","article-title":"Sirolimus as a second-line treatment for Graves\u2019 orbitopathy","volume":"45","author":"Lanzolla","year":"2022","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib81","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s40618-024-02470-8","article-title":"Long-term outcome of Graves\u2019 orbitopathy following treatment with sirolimus","volume":"48","author":"Comi","year":"2024","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib82","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1007\/s40618-025-02567-8","article-title":"Serum levels of rapamycin predict the response of Graves\u2019 orbitopathy to sirolimus","volume":"48","author":"Comi","year":"2025","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib83","first-page":"1","volume-title":"Graves\u2019 Orbitopathy: A Multidisciplinary Approach: Questions and Answers.","author":"Dickinson","year":"2017","edition":"3rd Revised and"},{"key":"2026070713592447000_bib84","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s40618-019-01116-4","article-title":"Immunohistochemical analysis of human orbital tissue in Graves\u2019 orbitopathy","volume":"43","author":"Hai","year":"2020","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib85","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/s41433-018-0279-9","article-title":"The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy","volume":"33","author":"Huang","year":"2019","journal-title":"Eye"},{"key":"2026070713592447000_bib86","doi-asserted-by":"crossref","DOI":"10.1155\/2019\/7453260","article-title":"Immunological aspects of Graves\u2019 ophthalmopathy","volume":"2019","author":"Lacheta","year":"2019","journal-title":"BioMed Res Int"},{"key":"2026070713592447000_bib87","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.1210\/jc.2016-1882","article-title":"IL-17A exacerbates fibrosis by promoting the proinflammatory and profibrotic function of orbital fibroblasts in TAO","volume":"101","author":"Fang","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib88","doi-asserted-by":"crossref","first-page":"6123","DOI":"10.1167\/iovs.16-20199","article-title":"IL-17A promotes RANTES expression, but not IL-16, in orbital fibroblasts via CD40-CD40L combination in thyroid-associated ophthalmopathy","volume":"57","author":"Fang","year":"2016","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"2026070713592447000_bib89","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1210\/jc.2017-01349","article-title":"Regulation of orbital fibrosis and adipogenesis by pathogenic Th17 cells in Graves orbitopathy","volume":"102","author":"Fang","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib90","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1089\/thy.2021.0671","article-title":"Immunophenotype of lacrimal glands in Graves orbitopathy: implications for the pathogenesis of Th1 and Th17 immunity","volume":"32","author":"Huang","year":"2022","journal-title":"Thyroid"},{"key":"2026070713592447000_bib91","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1167\/iovs.18-24008","article-title":"Interaction between CCR6+ Th17 cells and CD34+ fibrocytes promotes inflammation: implications in Graves\u2019 orbitopathy in Chinese population","volume":"59","author":"Fang","year":"2018","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"2026070713592447000_bib92","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ophtha.2009.05.029","article-title":"Rituximab treatment of patients with severe, corticosteroid-resistant thyroid-associated ophthalmopathy","volume":"117","author":"Khanna","year":"2010","journal-title":"Ophthalmology"},{"key":"2026070713592447000_bib93","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1507\/endocrj.EJ16-0108","article-title":"Implications of FoxP3-positive and -negative CD4(+) CD25(+) T cells in Graves\u2019 ophthalmopathy","volume":"63","author":"Matsuzawa","year":"2016","journal-title":"Endocr J"},{"key":"2026070713592447000_bib94","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1210\/jc.2010-1424","article-title":"Regulatory T-cells in Graves\u2019 orbitopathy: baseline findings and immunomodulation by anti-T lymphocyte globulin","volume":"96","author":"Kahaly","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib95","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1007\/s40618-021-01565-w","article-title":"Effect of systemic steroid therapy in Graves\u2019 orbitopathy on regulatory T cells and Th17\/Treg ratio","volume":"44","author":"Siomkajlo","year":"2021","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib96","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1210\/clinem\/dgz013","article-title":"A novel Anti-CD40 monoclonal antibody, iscalimab, for control of Graves hyperthyroidism-A proof-of-concept trial","volume":"105","author":"Kahaly","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib97","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S2213-8587(18)30020-2","article-title":"Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves\u2019 orbitopathy (MINGO): a randomised, observer-masked, multicentre trial","volume":"6","author":"Kahaly","year":"2018","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2026070713592447000_bib98","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s40618-016-0441-9","article-title":"Prospective, systematically recorded mycophenolate safety data in Graves\u2019 orbitopathy","volume":"39","author":"Riedl","year":"2016","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib99","article-title":"Therapeutic outcomes of mycophenolate mofetil and glucocorticoid in thyroid-associated ophthalmopathy patients","volume":"14","author":"Li","year":"2023","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib100","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.2147\/OPTH.S305717","article-title":"Real-world efficacy and safety of mycophenolate mofetil in active moderate-to-sight-threatening thyroid eye disease","volume":"15","author":"Quah Qin Xian","year":"2021","journal-title":"Clin Ophthalmol"},{"key":"2026070713592447000_bib101","doi-asserted-by":"crossref","first-page":"E400","DOI":"10.1210\/jc.2011-2697","article-title":"Orbit-infiltrating mast cells, monocytes, and macrophages produce PDGF isoforms that orchestrate orbital fibroblast activation in Graves\u2019 ophthalmopathy","volume":"97","author":"van Steensel","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib102","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.exer.2016.05.005","article-title":"Histamine induces NF-kappaB controlled cytokine secretion by orbital fibroblasts via histamine receptor type-1","volume":"147","author":"Virakul","year":"2016","journal-title":"Exp Eye Res"},{"key":"2026070713592447000_bib103","doi-asserted-by":"crossref","first-page":"15794","DOI":"10.1074\/jbc.M109.074534","article-title":"Mast cell-derived prostaglandin D2 controls hyaluronan synthesis in human orbital fibroblasts via DP1 activation: implications for thyroid eye disease","volume":"285","author":"Guo","year":"2010","journal-title":"J Biol Chem"},{"key":"2026070713592447000_bib104","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1159\/000367968","article-title":"Platelet-derived growth factor: a key factor in the pathogenesis of Graves\u2019 ophthalmopathy and potential target for treatment","volume":"3","author":"Virakul","year":"2014","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib180","first-page":"41","volume-title":"Graves\u2019 Orbitopathy: A Multidisciplinary Approach: Questions and Answers","author":"Salvi","year":"2017","edition":"3rd, Revised an"},{"key":"2026070713592447000_bib105","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1210\/jcem.87.1.8164","article-title":"Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy","volume":"87","author":"Smith","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib106","doi-asserted-by":"crossref","first-page":"18856","DOI":"10.1074\/jbc.M110.179317","article-title":"Peroxisome proliferator-activated receptor gamma ligands inhibit transforming growth factor-beta-induced, hyaluronan-dependent, T cell adhesion to orbital fibroblasts","volume":"286","author":"Guo","year":"2011","journal-title":"J Biol Chem"},{"key":"2026070713592447000_bib107","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/S0002-9440(10)63488-8","article-title":"Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes","volume":"163","author":"Koumas","year":"2003","journal-title":"Am J Pathol"},{"key":"2026070713592447000_bib108","doi-asserted-by":"crossref","first-page":"C672","DOI":"10.1152\/ajpcell.00451.2009","article-title":"Novel anti-adipogenic activity produced by human fibroblasts","volume":"299","author":"Lehmann","year":"2010","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026070713592447000_bib109","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1210\/er.2018-00066","article-title":"Insulin-like growth factor-I receptor and thyroid-associated ophthalmopathy","volume":"40","author":"Smith","year":"2019","journal-title":"Endocr Rev"},{"key":"2026070713592447000_bib110","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1210\/jc.2018-01493","article-title":"Potential roles of CD34+ fibrocytes masquerading as orbital fibroblasts in thyroid-associated ophthalmopathy","volume":"104","author":"Smith","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib111","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1097\/IOP.0000000000002509","article-title":"Fibrocyte participation in thyroid-associated ophthalmopathy suggests new approaches to therapy","volume":"39","author":"Smith","year":"2023","journal-title":"Ophthalmic Plast Reconstr Surg"},{"key":"2026070713592447000_bib112","doi-asserted-by":"crossref","first-page":"3942","DOI":"10.4049\/jimmunol.1800259","article-title":"Slit2 modulates the inflammatory phenotype of orbit-infiltrating fibrocytes in Graves\u2019 disease","volume":"200","author":"Fernando","year":"2018","journal-title":"J Immunol"},{"key":"2026070713592447000_bib113","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.4049\/jimmunol.1900434","article-title":"Slit2 may underlie divergent induction by thyrotropin of IL-23 and IL-12 in human fibrocytes","volume":"204","author":"Fernando","year":"2020","journal-title":"J Immunol"},{"key":"2026070713592447000_bib114","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1210\/clinem\/dgaa684","article-title":"Slit2 regulates hyaluronan & cytokine synthesis in fibrocytes: potential relevance to thyroid-associated ophthalmopathy","volume":"106","author":"Fernando","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib115","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1159\/000509615","article-title":"Oxidative stress in Graves disease and Graves orbitopathy","volume":"9","author":"Lanzolla","year":"2020","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib116","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2020.608733","article-title":"Antioxidant therapy in Graves\u2019 orbitopathy","volume":"11","author":"Lanzolla","year":"2020","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib117","doi-asserted-by":"crossref","DOI":"10.1016\/j.autrev.2024.103534","article-title":"Redox mechanisms in autoimmune thyroid eye disease","volume":"23","author":"Buonfiglio","year":"2024","journal-title":"Autoimmun Rev"},{"key":"2026070713592447000_bib118","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1530\/JME-21-0057","article-title":"PERK mediates oxidative stress and adipogenesis in Graves\u2019 orbitopathy pathogenesis","volume":"66","author":"Ko","year":"2021","journal-title":"J Mol Endocrinol"},{"key":"2026070713592447000_bib119","doi-asserted-by":"crossref","first-page":"4834","DOI":"10.1210\/jc.2016-1279","article-title":"Hypoxia-dependent HIF-1 activation impacts on tissue remodeling in Graves\u2019 ophthalmopathy-implications for smoking","volume":"101","author":"Gortz","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib120","doi-asserted-by":"crossref","first-page":"153","DOI":"10.3390\/ijms23010153","article-title":"miR-199a downregulation as a driver of the NOX4\/HIF-1\u03b1\/VEGF-A pathway in thyroid and orbital adipose tissues from Graves\u2019 patients","volume":"23","author":"Craps","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2026070713592447000_bib121","doi-asserted-by":"crossref","first-page":"767","DOI":"10.3803\/EnM.2024.1952","article-title":"In vitro investigation of HIF-1\u03b1 as a therapeutic target for thyroid-associated ophthalmopathy","volume":"39","author":"Lee","year":"2024","journal-title":"Endocrinol Metab"},{"key":"2026070713592447000_bib122","first-page":"1103","article-title":"Traditional Chinese medicine in thyroid-associated orbitopathy","volume":"46","author":"Hai","year":"2023","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib123","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1056\/NEJMoa1012985","article-title":"Selenium and the course of mild Graves\u2019 orbitopathy","volume":"364","author":"Marcocci","year":"2011","journal-title":"N Engl J Med"},{"key":"2026070713592447000_bib124","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1001\/jamaophthalmol.2024.6337","article-title":"Selenium vs control for Graves ophthalmopathy in a selenium-sufficient area: a randomized clinical trial","volume":"143","author":"Ahn","year":"2025","journal-title":"JAMA Ophthalmol"},{"key":"2026070713592447000_bib125","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/S0002-9394(00)00359-7","article-title":"Antioxidant agents in the treatment of Graves\u2019 ophthalmopathy","volume":"129","author":"Bouzas","year":"2000","journal-title":"Am J Ophthalmol"},{"key":"2026070713592447000_bib126","doi-asserted-by":"crossref","first-page":"57","DOI":"10.4331\/wjbc.v12.i5.57","article-title":"Proteomics: concepts and applications in human medicine","volume":"12","author":"Al-Amrani","year":"2021","journal-title":"World J Biol Chem"},{"key":"2026070713592447000_bib127","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1038\/s41374-022-00830-7","article-title":"High-throughput proteomics: a methodological mini-review","volume":"102","author":"Cui","year":"2022","journal-title":"Lab Invest"},{"key":"2026070713592447000_bib128","doi-asserted-by":"crossref","first-page":"6038","DOI":"10.7150\/ijbs.103977","article-title":"Multi-omics approaches to discover biomarkers of thyroid eye disease: a systematic review","volume":"20","author":"Zhang","year":"2024","journal-title":"Int J Biol Sci"},{"key":"2026070713592447000_bib129","doi-asserted-by":"crossref","first-page":"E1523","DOI":"10.1210\/jc.2015-2976","article-title":"Proteomics of orbital tissue in thyroid-associated orbitopathy","volume":"100","author":"Matheis","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib130","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1089\/thy.2012.0119","article-title":"Proteomics of tear fluid in thyroid-associated orbitopathy","volume":"22","author":"Matheis","year":"2012","journal-title":"Thyroid"},{"key":"2026070713592447000_bib131","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1055\/s-0029-1214413","article-title":"Proteomics in autoimmune thyroid eye disease","volume":"41","author":"Okrojek","year":"2009","journal-title":"Horm Metab Res"},{"key":"2026070713592447000_bib132","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.1167\/iovs.15-16699","article-title":"Proteomics differentiate between thyroid-associated orbitopathy and dry eye syndrome","volume":"56","author":"Matheis","year":"2015","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"2026070713592447000_bib133","first-page":"In press","article-title":"High-throughput proteomics and immunohistochemistry of orbital connective tissue in Graves\u2019 orbitopathy","author":"Hai","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib134","doi-asserted-by":"crossref","first-page":"6438","DOI":"10.1167\/iovs.15-17185","article-title":"Differential gene expression profiling of orbital adipose tissue in thyroid orbitopathy","volume":"56","author":"Khong","year":"2015","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"2026070713592447000_bib135","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1136\/bjophthalmol-2020-318330","article-title":"Enrichment of IGF-1R and PPAR\u03b3 signalling pathways in orbital inflammatory diseases: steps toward understanding pathogenesis","volume":"106","author":"Verma","year":"2022","journal-title":"Br J Ophthalmol"},{"key":"2026070713592447000_bib136","doi-asserted-by":"crossref","first-page":"e2176","DOI":"10.1210\/clinem\/dgab035","article-title":"Genetic profiling of orbital fibroblasts from patients with Graves\u2019 orbitopathy","volume":"106","author":"Rotondo","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib137","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.5114\/aoms\/153478","article-title":"Changes of mRNA expression underlying orbital adipogenesis in thyroid-associated orbitopathy","volume":"18","author":"Bai","year":"2022","journal-title":"Arch Med Sci"},{"key":"2026070713592447000_bib138","doi-asserted-by":"crossref","first-page":"5504","DOI":"10.1038\/s41467-020-19365-w","article-title":"Optimized design of single-cell RNA sequencing experiments for cell-type-specific eQTL analysis","volume":"11","author":"Mandric","year":"2020","journal-title":"Nat Commun"},{"key":"2026070713592447000_bib139","doi-asserted-by":"crossref","first-page":"554","DOI":"10.4103\/tjo.TJO-D-23-00096","article-title":"Single-cell transcriptomics in thyroid eye disease","volume":"14","author":"Ahsanuddin","year":"2024","journal-title":"Taiwan J Ophthalmol"},{"key":"2026070713592447000_bib140","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1210\/jc.2018-01626","article-title":"Insights into local orbital immunity: evidence for the involvement of the Th17 cell pathway in thyroid-associated ophthalmopathy","volume":"104","author":"Fang","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib141","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/s41423-020-00615-2","article-title":"A novel CD4+ CTL subtype characterized by chemotaxis and inflammation is involved in the pathogenesis of Graves\u2019 orbitopathy","volume":"18","author":"Wang","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"2026070713592447000_bib142","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.160377","article-title":"Rapamycin improves Graves\u2019 orbitopathy by suppressing CD4+ cytotoxic T lymphocytes","volume":"8","author":"Zhang","year":"2023","journal-title":"JCI Insight"},{"key":"2026070713592447000_bib143","article-title":"Single-cell RNA sequencing depicts the local cell landscape in thyroid-associated ophthalmopathy","volume":"3","author":"Li","year":"2022","journal-title":"Cell Rep Med"},{"key":"2026070713592447000_bib144","article-title":"IL-11 is elevated and drives the profibrotic phenotype transition of orbital fibroblasts in thyroid-associated ophthalmopathy","volume":"13","author":"Wu","year":"2022","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib145","article-title":"CD169(+) classical monocyte as an important participant in Graves\u2019 ophthalmopathy through CXCL12-CXCR4 axis","volume":"27","author":"Wang","year":"2024","journal-title":"iScience"},{"key":"2026070713592447000_bib146","first-page":"8217","article-title":"Single-cell BCR and transcriptome analysis reveals peripheral immune signatures in patients with thyroid-associated ophthalmopathy","volume":"16","author":"Li","year":"2024","journal-title":"Aging"},{"key":"2026070713592447000_bib147","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1186\/s12967-025-06443-0","article-title":"The CD163 + tissue-infiltrating macrophages regulate ferroptosis in thyroid-associated ophthalmopathy orbital fibroblasts via the TGF-\u03b2\/Smad2\/3 signaling pathway","volume":"23","author":"Li","year":"2025","journal-title":"J Transl Med"},{"key":"2026070713592447000_bib148","doi-asserted-by":"crossref","first-page":"9851","DOI":"10.1038\/s41598-022-14099-9","article-title":"An optimized protocol for single nuclei isolation from clinical biopsies for RNA-seq","volume":"12","author":"Rousselle","year":"2022","journal-title":"Sci Rep"},{"key":"2026070713592447000_bib149","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1167\/iovs.62.9.24","article-title":"Transcriptomic profiling of control and thyroid-associated orbitopathy (TAO) orbital fat and TAO orbital fibroblasts undergoing adipogenesis","volume":"62","author":"Kim","year":"2021","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"2026070713592447000_bib150","doi-asserted-by":"crossref","DOI":"10.1530\/ETJ-24-0179","article-title":"Role of genetics and epigenetics in Graves\u2019 orbitopathy","volume":"13","author":"Marino","year":"2024","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib151","article-title":"Integrative analysis of proteomics and DNA methylation in orbital fibroblasts from Graves\u2019 ophthalmopathy","volume":"11","author":"Virakul","year":"2020","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib152","doi-asserted-by":"crossref","first-page":"e160","DOI":"10.1210\/clinem\/dgac645","article-title":"Insights into the role of DNA methylation and gene expression in Graves orbitopathy","volume":"108","author":"Rotondo","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib153","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.ncrna.2023.04.001","article-title":"Non-coding RNA-mediated epigenetic alterations in Grave\u2019s ophthalmopathy: a scoping systematic review","volume":"8","author":"Shahraki","year":"2023","journal-title":"Noncoding RNA Res"},{"key":"2026070713592447000_bib154","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1167\/iovs.66.3.46","article-title":"LncRNA ENST00000581911 regulates extraocular muscle remodeling by interacting with KHSRP in thyroid eye disease","volume":"66","author":"Shi","year":"2025","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"2026070713592447000_bib155","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1007\/s40618-019-1010-9","article-title":"Alterations in the intestinal microbiota of patients with severe and active Graves\u2019 orbitopathy: a cross-sectional study","volume":"42","author":"Shi","year":"2019","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib156","doi-asserted-by":"crossref","DOI":"10.1155\/2019\/9736968","article-title":"The potential link between gut microbiota and serum TRAb in Chinese patients with severe and active Graves\u2019 orbitopathy","volume":"2019","author":"Shi","year":"2019","journal-title":"Int J Endocrinol"},{"key":"2026070713592447000_bib157","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s40618-020-01298-2","article-title":"Comparative assessment of gut microbial composition and function in patients with Graves\u2019 disease and Graves\u2019 orbitopathy","volume":"44","author":"Shi","year":"2021","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib158","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1210\/clinem\/dgad030","article-title":"Gut microbiome associated with Graves disease and Graves orbitopathy: the INDIGO multicenter european study","volume":"108","author":"Biscarini","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib159","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1159\/000512255","article-title":"Microbiome and Graves\u2019 orbitopathy","volume":"9","author":"Masetti","year":"2020","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib160","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/nbt.2942","article-title":"An integrated catalog of reference genes in the human gut microbiome","volume":"32","author":"Li","year":"2014","journal-title":"Nat Biotechnol"},{"key":"2026070713592447000_bib161","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1089\/thy.2017.0430","article-title":"High serum cholesterol is a novel risk factor for Graves\u2019 orbitopathy: results of a cross-sectional study","volume":"28","author":"Sabini","year":"2018","journal-title":"Thyroid"},{"key":"2026070713592447000_bib162","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1007\/s40618-018-0915-z","article-title":"Relationship between serum cholesterol and Graves\u2019 orbitopathy (GO): a confirmatory study","volume":"41","author":"Lanzolla","year":"2018","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib163","doi-asserted-by":"crossref","first-page":"16941","DOI":"10.3390\/ijerph192416941","article-title":"Novel insight into non-genetic risk factors of Graves\u2019 orbitopathy","volume":"19","author":"Zawadzka-Starczewska","year":"2022","journal-title":"Int J Environ Res Public Health"},{"key":"2026070713592447000_bib164","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.1038\/s41433-023-02513-z","article-title":"Sex-specific risk factors associated with Graves\u2019 orbitopathy in Korean patients with newly diagnosed Graves\u2019 disease","volume":"37","author":"Lee","year":"2023","journal-title":"Eye"},{"key":"2026070713592447000_bib165","doi-asserted-by":"crossref","DOI":"10.1530\/ETJ-24-0133","article-title":"The relationship between cholesterol levels and thyroid eye disease","volume":"14","author":"Cardo","year":"2025","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib166","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1007\/s40618-025-02556-x","article-title":"Analysis of non-cholesterol sterols and fatty acids in patients with Graves\u2019 orbitopathy: insights into lipid metabolism in relation to the clinical phenotype of disease","volume":"48","author":"Matutinovic","year":"2025","journal-title":"J Endocrinol Investig"},{"key":"2026070713592447000_bib167","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.3390\/genes14061209","article-title":"Associations between lipid profiles and Graves\u2019 orbitopathy can be HLA-dependent","volume":"14","author":"Stasiak","year":"2023","journal-title":"Genes"},{"key":"2026070713592447000_bib168","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2020.609895","article-title":"Evidence that baseline levels of low-density lipoproteins cholesterol affect the clinical response of Graves\u2019 ophthalmopathy to parenteral corticosteroids","volume":"11","author":"Naselli","year":"2020","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib169","doi-asserted-by":"crossref","DOI":"10.1530\/ETJ-23-0109","article-title":"Predicting glucocorticoid effectiveness in thyroid eye disease: combined value from serological lipid metabolism and an orbital MRI parameter","volume":"13","author":"Zhang","year":"2024","journal-title":"Eur Thyroid J"},{"key":"2026070713592447000_bib170","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1136\/bjo-2024-325180","article-title":"Effect of intravenous methylprednisolone on serum antibody levels in thyroid eye disease","volume":"109","author":"Lee","year":"2025","journal-title":"Br J Ophthalmol"},{"key":"2026070713592447000_bib171","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1001\/jamaophthalmol.2014.5103","article-title":"Risk factors for developing thyroid-associated ophthalmopathy among individuals with Graves disease","volume":"133","author":"Stein","year":"2015","journal-title":"JAMA Ophthalmol"},{"key":"2026070713592447000_bib172","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1210\/clinem\/dgab070","article-title":"Statins decrease the risk of orbitopathy in newly diagnosed patients with Graves disease","volume":"106","author":"Nilsson","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070713592447000_bib173","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1089\/thy.2024.0536","article-title":"Statin use and the risk of Graves\u2019 orbitopathy: a nationwide population-based cohort study","volume":"35","author":"Chou","year":"2025","journal-title":"Thyroid"},{"key":"2026070713592447000_bib174","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1530\/EC-19-0319","article-title":"Simvastatin downregulates adipogenesis in 3T3-L1 preadipocytes and orbital fibroblasts from Graves\u2019 ophthalmopathy patients","volume":"8","author":"Shahida","year":"2019","journal-title":"Endocr Connect"},{"key":"2026070713592447000_bib175","article-title":"Simvastatin and ROCK inhibitor Y-27632 inhibit myofibroblast differentiation of Graves\u2019 ophthalmopathy-derived orbital fibroblasts via RhoA-Mediated ERK and p38 signaling pathways","volume":"11","author":"Wei","year":"2020","journal-title":"Front Endocrinol"},{"key":"2026070713592447000_bib176","doi-asserted-by":"crossref","DOI":"10.1155\/2021\/8888913","article-title":"Simvastatin inhibits CYR61 expression in orbital fibroblasts in Graves\u2019 ophthalmopathy through the regulation of FoxO3a signaling","volume":"2021","author":"Wei","year":"2021","journal-title":"Mediators Inflamm"},{"key":"2026070713592447000_bib177","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1167\/iovs.66.1.56","article-title":"Simvastatin-induced ferroptosis in orbital fibroblasts in Graves\u2019 ophthalmopathy","volume":"66","author":"Wang","year":"2025","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"2026070713592447000_bib178","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.jaapos.2018.04.009","article-title":"The effect of oral statin therapy on strabismus in patients with thyroid eye disease","volume":"22","author":"Reynolds","year":"2018","journal-title":"J AAPOS"},{"key":"2026070713592447000_bib179","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S2213-8587(21)00238-2","article-title":"Statins for Graves\u2019 orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial","volume":"9","author":"Lanzolla","year":"2021","journal-title":"Lancet Diabetes Endocrinol"}],"container-title":["European Thyroid Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/etj.bioscientifica.com\/view\/journals\/etj\/14\/5\/ETJ-25-0200.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/etj.bioscientifica.com\/downloadpdf\/journals\/etj\/14\/5\/ETJ-25-0200.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/etj\/article-pdf\/doi\/10.1530\/ETJ-25-0200\/506256\/etj-25-0200.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/etj\/article-pdf\/doi\/10.1530\/ETJ-25-0200\/506256\/etj-25-0200.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T17:59:48Z","timestamp":1783447188000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/etj\/article\/14\/5\/e250200\/75584\/Unravelling-the-pathogenic-mechanisms-in-Graves"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,4]]},"references-count":180,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,10,1]]}},"URL":"https:\/\/doi.org\/10.1530\/etj-25-0200","relation":{},"ISSN":["2235-0802","2235-0640"],"issn-type":[{"value":"2235-0802","type":"electronic"},{"value":"2235-0640","type":"print"}],"subject":[],"published":{"date-parts":[[2025,9,4]]},"article-number":"e250200"}}