{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:21:29Z","timestamp":1790986889067,"version":"4.1.0"},"reference-count":130,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:00:00Z","timestamp":1741737600000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Graves\u2019 hyperthyroidism and its associated Graves\u2019 orbitopathy are common autoimmune disorders associated with significant adverse health impact. Current standard treatments have limitations regarding efficacy and safety, and most do not specifically target the pathogenic mechanisms. We aim to review the latest development of targeted immunotherapies in these two closely related disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>Targeted immunotherapies of Graves\u2019 hyperthyroidism have recently demonstrated clinical efficacy in early phase clinical studies. They include rituximab, an anti-CD20 monoclonal antibody which causes rapid B cell depletion; ATX-GD-59, an antigen specific immunotherapy which restores immune tolerance to thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 co-stimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor blocking monoclonal antibody. Furthermore, there have been major therapeutic advances in the management of Graves\u2019 orbitopathy. Mycophenolate has a dual mechanism of action both inhibiting the proliferation of activated B &amp;amp; T cells as well as the mammalian target of rapamycin growth intracellular pathway. Rituximab appears to be effective in active disease of recent onset without impending dysthyroid optic neuropathy. Both tocilizumab (anti-interleukin 6 receptor monoclonal antibody) and sirolimus (mammalian target of rapamycin inhibitor) showed promise in glucocorticoid resistant active disease. Teprotumumab, an anti-insulin-like growth factor-1 receptor monoclonal antibody, demonstrated remarkable all-round efficacy across a wide disease spectrum. Linsitinib, a dual small molecule inhibitor of insulin-like growth factor-1 receptor and insulin receptor, displayed significant proptosis reduction in its phase 2b\/3 study. Finally, Batoclimab, an anti-neonatal fragment crystallizable receptor monoclonal antibody, which blocks recycling of pathogenic thyrotropin receptor antibody, showed promising signals for significant proptosis reduction, disease inactivation, overall response, and improvement of quality of life.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Therapeutic advances will continue to optimize our management of Graves\u2019 hyperthyroidism and its associated orbitopathy in an effective and safe manner.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1571427","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T03:51:47Z","timestamp":1741751507000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Targeted immunotherapies for Graves\u2019 thyroidal &amp; orbital diseases"],"prefix":"10.3389","volume":"16","author":[{"given":"Alan Chun Hong","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George J.","family":"Kahaly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","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":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1530\/EJE-16-0576","article-title":"Acute cardiovascular events and all-cause mortality in patients with hyperthyroidism: a population-based cohort study","volume":"176","author":"Dekkers","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2019.0543","article-title":"Incidence and mortality of myocardial infarction and stroke in patients with hyperthyroidism: A nationwide cohort study in Korea","volume":"30","author":"Kim","year":"2020","journal-title":"Thyroid"},{"key":"B4","doi-asserted-by":"publisher","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 (Oxf)"},{"key":"B5","doi-asserted-by":"publisher","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":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2017.12.012","article-title":"Quality of life and neuropsychiatric disorders in patients with Graves\u2019 Orbitopathy: Current concepts","volume":"17","author":"Bruscolini","year":"2018","journal-title":"Autoimmun Rev"},{"key":"B7","doi-asserted-by":"publisher","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":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-022-03193-7","article-title":"2021 Asia-Pacific graves\u2019 Disease consortium survey of clinical practice patterns in the management of graves\u2019 Disease","volume":"79","author":"Parameswaran","year":"2023","journal-title":"Endocrine"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgae222","article-title":"A 2023 international survey of clinical practice patterns in the management of graves disease: A decade of change","volume":"109","author":"Villagelin","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(20)30025-5","article-title":"Methimazole and risk of acute pancreatitis","volume":"8","author":"Brix","year":"2020","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2019.0132","article-title":"Patterns of use, efficacy, and safety of treatment options for patients with graves\u2019 Disease: A nationwide population-based study","volume":"30","author":"Brito","year":"2020","journal-title":"Thyroid"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa646","article-title":"Management of graves thyroidal and extrathyroidal disease: an update","volume":"105","author":"Kahaly","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"B13","doi-asserted-by":"publisher","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":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-021-01730-1","article-title":"Appropriate duration of antithyroid drug treatment as a predictor for relapse of Graves\u2019 disease: a systematic scoping review","volume":"45","author":"Azizi","year":"2022","journal-title":"J Endocrinol Invest"},{"key":"B15","doi-asserted-by":"publisher","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":"B16","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1159\/000339444","article-title":"2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism","volume":"1","author":"Wiersinga","year":"2012","journal-title":"Eur Thyroid J"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41433-018-0285-y","article-title":"B cells in Graves\u2019 Orbitopathy: more than just a source of antibodies","volume":"33","author":"Salvi","year":"2019","journal-title":"Eye (Lond)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2020.1822318","article-title":"Anti-CD20 treatment for B-cell Malignancies: current status and future directions","volume":"21","author":"Klein","year":"2021","journal-title":"Expert Opin Biol Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01990","article-title":"Systematic review of safety and efficacy of rituximab in treating immune-mediated disorders","volume":"10","author":"Kaegi","year":"2019","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-2388","article-title":"B lymphocyte depletion with the monoclonal antibody rituximab in Graves\u2019 disease: a controlled pilot study","volume":"92","author":"El Fassi","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2008.09.007","article-title":"Treatment of Graves\u2019 disease with rituximab specifically reduces the production of thyroid stimulating autoantibodies","volume":"130","author":"El Fassi","year":"2009","journal-title":"Clin Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-08-0084","article-title":"Rituximab in relapsing Graves\u2019 disease, a phase II study","volume":"159","author":"Heemstra","year":"2008","journal-title":"Eur J Endocrinol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab763","article-title":"Adjuvant rituximab-exploratory trial in young people with graves disease","volume":"107","author":"Cheetham","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3275\/7411","article-title":"Systemic adverse events following rituximab therapy in patients with Graves\u2019 disease","volume":"34","author":"El Fassi","year":"2011","journal-title":"J Endocrinol Invest"},{"key":"B25","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s13223-018-0282-5","article-title":"Allergen-specific immunotherapy","volume":"14","author":"Moote","year":"2018","journal-title":"Allergy Asthma Clin Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf7779","article-title":"Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes","volume":"9","author":"Alhadj Ali","year":"2017","journal-title":"Sci Transl Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/cei\/uxac115","article-title":"Antigen-specific immunotherapy to restore antigen-specific tolerance in Type 1 diabetes and Graves\u2019 disease","volume":"211","author":"Zala","year":"2023","journal-title":"Clin Exp Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000005118","article-title":"Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis","volume":"90","author":"Chataway","year":"2018","journal-title":"Neurology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-024-01201-w","article-title":"Antigen-specific immunotherapies for autoimmune disease","volume":"21","author":"Buckner","year":"2025","journal-title":"Nat Rev Rheumatol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.654201","article-title":"The mechanism of action of antigen processing independent T cell epitopes designed for immunotherapy of autoimmune diseases","volume":"12","author":"Shepard","year":"2021","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1210\/en.2018-00306","article-title":"Immunotherapy with apitopes blocks the immune response to TSH receptor in HLA-DR transgenic mice","volume":"159","author":"Jansson","year":"2018","journal-title":"Endocrinology"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2019.0036","article-title":"Antigen-specific immunotherapy with thyrotropin receptor peptides in graves\u2019 Hyperthyroidism: A phase I study","volume":"29","author":"Pearce","year":"2019","journal-title":"Thyroid"},{"key":"B33","article-title":"Costimulatory molecule CD40 expression in thyroid tissue of Graves\u2019 disease patients and its immune pathogenetic significance","volume":"93","author":"Wang","year":"2013","journal-title":"Zhonghua Yi Xue Za Zhi"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.14872","article-title":"Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody","volume":"18","author":"Ristov","year":"2018","journal-title":"Am J Transplant"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01211-X","article-title":"Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjogren\u2019s disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study","volume":"404","author":"Fisher","year":"2024","journal-title":"Lancet"},{"key":"B36","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.jocn.2023.11.013","article-title":"Efficacy and safety of iscalimab, a novel anti-CD40 monoclonal antibody, in moderate-to-severe myasthenia gravis: A phase 2 randomized study","volume":"119","author":"GomezMancilla","year":"2024","journal-title":"J Clin Neurosci"},{"key":"B37","doi-asserted-by":"publisher","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":"B38","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-3644","article-title":"Predicting the\u00a0risk 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":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2010.03831.x","article-title":"Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample","volume":"73","author":"Evans","year":"2010","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B40","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s13317-011-0025-9","article-title":"In vivo effects of a human thyroid-stimulating monoclonal autoantibody (M22) and a human thyroid-blocking autoantibody (K1-70)","volume":"3","author":"Furmaniak","year":"2012","journal-title":"Auto Immun Highlights"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2021.0053","article-title":"Blocking the thyrotropin receptor with K1-70 in a patient with follicular thyroid cancer, graves\u2019 Disease, and graves\u2019 Ophthalmopathy","volume":"31","author":"Ryder","year":"2021","journal-title":"Thyroid"},{"key":"B42","doi-asserted-by":"publisher","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 (Oxf)"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-0836","article-title":"A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism","volume":"149","author":"Neumann","year":"2008","journal-title":"Endocrinology"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01709.x","article-title":"Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid-stimulating hormone receptor","volume":"165","author":"van Koppen","year":"2012","journal-title":"Br J Pharmacol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-1835","article-title":"A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice","volume":"155","author":"Neumann","year":"2014","journal-title":"Endocrinology"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2016.00130","article-title":"TSH receptor signaling abrogation by a novel small molecule","volume":"7","author":"Latif","year":"2016","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-0199","article-title":"A small molecule inverse agonist for the human thyroid-stimulating hormone receptor","volume":"151","author":"Neumann","year":"2010","journal-title":"Endocrinology"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1935","article-title":"A new small-molecule antagonist inhibits Graves\u2019 disease antibody activation of the TSH receptor","volume":"96","author":"Neumann","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B49","doi-asserted-by":"publisher","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":"B50","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":"B51","doi-asserted-by":"publisher","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":"B52","doi-asserted-by":"publisher","DOI":"10.1080\/01676830.2024.2315566","article-title":"Selenium supplementation in inactive moderate to severe Graves\u2019 orbitopathy patients: a randomized controlled trial","volume":"43","author":"Potita","year":"2024","journal-title":"Orbit"},{"key":"B53","doi-asserted-by":"publisher","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":"B54","doi-asserted-by":"publisher","first-page":"2042018820958335","DOI":"10.1177\/2042018820958335","article-title":"Glucocorticoids in Graves\u2019 orbitopathy: mechanisms of action and clinical application","volume":"11","author":"Langericht","year":"2020","journal-title":"Ther Adv Endocrinol Metab"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-020-01361-y","article-title":"Dysthyroid optic neuropathy: evaluation and management","volume":"44","author":"Dolman","year":"2021","journal-title":"J Endocrinol Invest"},{"key":"B56","doi-asserted-by":"publisher","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"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1962","article-title":"Clinical review: Intravenous glucocorticoids for Graves\u2019 orbitopathy: efficacy and morbidity","volume":"96","author":"Zang","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-014-1247-1","article-title":"Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update","volume":"88","author":"Staatz","year":"2014","journal-title":"Arch Toxicol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1046\/j.1523-1755.2000.00140.x","article-title":"Mycophenolate mofetil reduces myofibroblast infiltration and collagen III deposition in rat remnant kidney","volume":"58","author":"Badid","year":"2000","journal-title":"Kidney Int"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.87.11.1397","article-title":"Mycophenolate mofetil inhibits human Tenon fibroblast proliferation by guanosine depletion","volume":"87","author":"Heinz","year":"2003","journal-title":"Br J Ophthalmol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1097\/01.TP.0000101822.50960.AB","article-title":"Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation","volume":"77","author":"Azzola","year":"2004","journal-title":"Transplantation"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e3181e44260","article-title":"Mycophenolic acid displays IMPDH-dependent and IMPDH-independent effects on renal fibroblast proliferation and function","volume":"32","author":"Petrova","year":"2010","journal-title":"Ther Drug Monit"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.117051","article-title":"In vitro evidence for a direct antifibrotic role of the immunosuppressive drug mycophenolate mofetil","volume":"321","author":"Roos","year":"2007","journal-title":"J Pharmacol Exp Ther"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1006\/cyto.2002.0885","article-title":"Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms","volume":"19","author":"Miljkovic","year":"2002","journal-title":"Cytokine"},{"key":"B65","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.bbi.2018.09.020","article-title":"Mycophenolate mofetil contributes to downregulation of the hippocampal interleukin type 2 and 1beta mediated PI3K\/AKT\/mTOR pathway hyperactivation and attenuates neurobehavioral comorbidities in a rat model of temporal lobe epilepsy","volume":"75","author":"Mazumder","year":"2019","journal-title":"Brain Behav Immun"},{"key":"B66","doi-asserted-by":"publisher","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 Invest"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-019-01161-z","article-title":"Systemic safety analysis of mycophenolate in Graves\u2019 orbitopathy","volume":"43","author":"Lee","year":"2020","journal-title":"J Endocrinol Invest"},{"key":"B68","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1080\/14740338.2022.2069239","article-title":"Drug safety in thyroid eye disease - a systematic review","volume":"21","author":"Wolf","year":"2022","journal-title":"Expert Opin Drug Saf"},{"key":"B69","doi-asserted-by":"publisher","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 Invest"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-3014","article-title":"Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves\u2019 orbitopathy: a randomized controlled study","volume":"100","author":"Salvi","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-2572","article-title":"Randomized controlled trial of rituximab in patients with Graves\u2019 orbitopathy","volume":"100","author":"Stan","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-16-0552","article-title":"MANAGEMENT OF ENDOCRINE DISEASE: Rituximab therapy for Graves\u2019 orbitopathy - lessons from randomized control trials","volume":"176","author":"Stan","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"B73","doi-asserted-by":"publisher","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":"B74","doi-asserted-by":"publisher","DOI":"10.1177\/1120672119845224","article-title":"The effects of Rituximab on Graves\u2019orbitopathy: A retrospective study of 14 patients","volume":"30","author":"Eid","year":"2020","journal-title":"Eur J Ophthalmol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-020-04651-6","article-title":"Efficacy of rituximab in patients with Graves\u2019 orbitopathy: a retrospective multicenter nationwide study","volume":"258","author":"Deltour","year":"2020","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1111\/cen.2019.91.issue-1","article-title":"Early low-dose rituximab for active thyroid eye disease: An effective and well-tolerated treatment","volume":"91","author":"Insull","year":"2019","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2020.0269","article-title":"Efficacy profile and safety of very low-dose rituximab in patients with graves\u2019 Orbitopathy","volume":"31","author":"Vannucchi","year":"2021","journal-title":"Thyroid"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.2.1310","article-title":"IL-1 beta induces IL-6 expression in human orbital fibroblasts: identification of an anatomic-site specific phenotypic attribute relevant to thyroid-associated ophthalmopathy","volume":"175","author":"Chen","year":"2005","journal-title":"J Immunol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.08-2328","article-title":"Orbital fibroblasts from patients with thyroid-associated ophthalmopathy overexpress CD40: CD154 hyperinduces IL-6, IL-8, and MCP-1","volume":"50","author":"Hwang","year":"2009","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B80","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1089\/thy.2009.0278","article-title":"A stimulatory thyrotropin receptor antibody (M22) and thyrotropin increase interleukin-6 expression and secretion in Graves\u2019 orbital preadipocyte fibroblasts","volume":"20","author":"Kumar","year":"2010","journal-title":"Thyroid"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1089\/105072501753210984","article-title":"Interleukin-6 stimulates thyrotropin receptor expression in human orbital preadipocyte fibroblasts from patients with Graves\u2019 ophthalmopathy","volume":"11","author":"Jyonouchi","year":"2001","journal-title":"Thyroid"},{"key":"B82","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":"B83","doi-asserted-by":"publisher","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":"B84","doi-asserted-by":"publisher","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":"B85","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.coi.2018.09.002","article-title":"IL-6: a cytokine at the crossroads of autoimmunity","volume":"55","author":"Jones","year":"2018","journal-title":"Curr Opin Immunol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.3109\/08916939708996275","article-title":"High circulating IL-6 level in Graves\u2019 ophthalmopathy","volume":"25","author":"Molnar","year":"1997","journal-title":"Autoimmunity"},{"key":"B87","doi-asserted-by":"publisher","first-page":"10792","DOI":"10.1038\/s41598-018-29113-2","article-title":"Differential profiling of lacrimal cytokines in patients suffering from thyroid-associated orbitopathy","volume":"8","author":"Kishazi","year":"2018","journal-title":"Sci Rep"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-019-01174-8","article-title":"Tear inflammatory cytokines and ocular surface\u00a0changes in patients with active thyroid eye disease treated with high-dose intravenous glucocorticoids","volume":"43","author":"Xu","year":"2020","journal-title":"J Endocrinol Invest"},{"key":"B89","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":"B90","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgae711","article-title":"The efficacy and safety of intravenous tocilizumab to treat Graves\u2019 ophthalmopathy: A systematic review and single-arm meta-analysis","volume":"110","author":"Sun","year":"2024","journal-title":"J\u00a0Clin Endocrinol Metab"},{"key":"B91","doi-asserted-by":"publisher","first-page":"101620","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":"B92","doi-asserted-by":"publisher","DOI":"10.1097\/IOP.0000000000001876","article-title":"Inhibition of fibrotic contraction by sirolimus (Rapamycin) in an ex vivo model of thyroid eye disease","volume":"37","author":"Roos","year":"2021","journal-title":"Ophthalmic Plast Reconstr Surg"},{"key":"B93","doi-asserted-by":"publisher","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":"B94","doi-asserted-by":"publisher","DOI":"10.1097\/IOP.0b013e3180500d57","article-title":"Rapamycin for treatment of refractory dysthyroid compressive optic neuropathy","volume":"23","author":"Chang","year":"2007","journal-title":"Ophthalmic Plast Reconstr Surg"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1038\/s41433-019-0340-3","article-title":"Sirolimus (rapamycin) for the targeted treatment of the fibrotic sequelae of Graves\u2019 orbitopathy","volume":"33","author":"Roos","year":"2019","journal-title":"Eye (Lond)"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1111\/ceo.14290","article-title":"Sirolimus versus mycophenolate mofetil for triple immunosuppression in thyroid eye disease patients with recent-onset intractable diplopia: A prospective comparative case series","volume":"51","author":"Lai","year":"2023","journal-title":"Clin Exp Ophthalmol"},{"key":"B97","doi-asserted-by":"publisher","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 Invest"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-024-02470-8","article-title":"Long-term outcome of Graves\u2019 orbitopathy following treatment with sirolimus","author":"Comi","year":"2024","journal-title":"J\u00a0Endocrinol Invest"},{"key":"B99","doi-asserted-by":"publisher","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":"B100","doi-asserted-by":"publisher","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":"B101","doi-asserted-by":"publisher","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":"B102","doi-asserted-by":"publisher","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":"B103","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1614949","article-title":"Teprotumumab for thyroid-associated ophthalmopathy","volume":"376","author":"Smith","year":"2017","journal-title":"N Engl J Med"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910434","article-title":"Teprotumumab for the treatment of active thyroid eye disease","volume":"382","author":"Douglas","year":"2020","journal-title":"N Engl J Med"},{"key":"B105","doi-asserted-by":"publisher","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":"B106","doi-asserted-by":"publisher","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":"B107","doi-asserted-by":"publisher","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":"B108","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2024.07.018","article-title":"The rate of re-treatment in patients treated with teprotumumab: A multicenter study of 119 patients with 1 year of follow-up","volume":"132","author":"Ugradar","year":"2025","journal-title":"Ophthalmology"},{"key":"B109","doi-asserted-by":"publisher","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":"B110","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanwpc.2025.101464","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 Regional Health \u2013 Western Pacific"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgac627","article-title":"Teprotumumab-related hyperglycemia","volume":"108","author":"Amarikwa","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2024.01.023","article-title":"Glycemic trends in patients with thyroid eye disease treated with teprotumumab in 3 clinical trials","volume":"131","author":"Smith","year":"2024","journal-title":"Ophthalmology"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2023.10.018","article-title":"Teprotumumab-related adverse events in thyroid eye disease: A multicenter study","volume":"131","author":"Shah","year":"2024","journal-title":"Ophthalmology"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1002\/ohn.955","article-title":"Patterns of teprotumumab-induced hearing dysfunction: A systematic review","author":"Wong","year":"2024","journal-title":"Otolaryngol Head Neck Surg"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2023.08.001","article-title":"Frequency and patterns of hearing dysfunction in patients treated with teprotumumab","volume":"131","author":"Keen","year":"2024","journal-title":"Ophthalmology"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2023.0466","article-title":"A prospective study examining audiometry outcomes following teprotumumab treatment for thyroid eye disease","volume":"34","author":"Douglas","year":"2024","journal-title":"Thyroid"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1097\/WNO.0000000000001994","article-title":"Real-world experience with teprotumumab in patients with dysthyroid optic neuropathy","volume":"44","author":"Tamhankar","year":"2024","journal-title":"J Neuroophthalmol"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1211473","article-title":"Linsitinib, an IGF-1R inhibitor, attenuates disease development and progression in a model of thyroid eye disease","volume":"14","author":"Gulbins","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0311093","article-title":"Linsitinib inhibits IGF-1-induced cell proliferation and hyaluronic acid secretion by suppressing PI3K\/Akt and ERK pathway in orbital fibroblasts from patients with thyroid-associated ophthalmopathy","volume":"19","author":"Lee","year":"2024","journal-title":"PloS One"},{"key":"B120","doi-asserted-by":"publisher","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":"B121","unstructured":"Sling therapeutics"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00821-1","article-title":"The therapeutic age of the neonatal Fc receptor","volume":"23","author":"Pyzik","year":"2023","journal-title":"Nat Rev Immunol"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.v99.12","article-title":"Current state and potential applications of neonatal Fc receptor (FcRn) inhibitors in hematologic conditions","volume":"99","author":"Jacobs","year":"2024","journal-title":"Am J Hematol"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-024-01090-3","article-title":"FcRn inhibitor therapies in neurologic diseases","volume":"38","author":"Alfaidi","year":"2024","journal-title":"CNS Drugs"},{"key":"B125","doi-asserted-by":"publisher","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":"B126","doi-asserted-by":"publisher","DOI":"10.1016\/j.eprac.2023.04.002","article-title":"A novel monoclonal antibody degrades the thyrotropin receptor autoantibodies in graves\u2019 Disease","volume":"29","author":"Wolf","year":"2023","journal-title":"Endocr Pract"},{"key":"B127","doi-asserted-by":"publisher","DOI":"10.37349\/ei","article-title":"Safety and tolerability of anti-FcRn monoclonal\u00a0antibody in thyroid autoimmunity","volume":"4","author":"Wolf","year":"2024","journal-title":"Explor Immunol"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.892534","article-title":"Clinical significance of serum albumin and implications of fcRn inhibitor treatment in igG-mediated autoimmune disorders","volume":"13","author":"Ward","year":"2022","journal-title":"Front Immunol"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.17.7.1369","article-title":"Lipoprotein kinetics in patients with analbuminemia. Evidence for the role of serum albumin in controlling lipoprotein metabolism","volume":"17","author":"Maugeais","year":"1997","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgad693","article-title":"The race for new treatments for graves orbitopathy (Thyroid eye disease)","volume":"109","author":"Dayan","year":"2024","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1571427\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T03:51:52Z","timestamp":1741751512000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1571427\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,12]]},"references-count":130,"alternative-id":["10.3389\/fimmu.2025.1571427"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1571427","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,12]]},"article-number":"1571427"}}