Review of Current First-Line Pharmacotherapy Strategies for Thyroid Eye Disease
DOI:
https://doi.org/10.12775/QS.2025.37.57699Keywords
Thyroid eye disease (TED), glucocorticoids (GCs), mild TED, moderate-to-severe TED, sight-threatening TED, intravenous glucocorticoids (IVGCs), first-line therapy, anti-inflammatory therapyAbstract
Thyroid eye disease (TED) is a challenging autoimmune disorder that often requires therapeutic intervention. Glucocorticoids (GCs), particularly in intravenous (IV) regimens, remain the first-line treatment due to their strong anti-inflammatory and immunosuppressive effects. This paper focuses on the efficacy, protocols, and safety profiles of selenium supplementation and glucocorticoid therapy, emphasizing its central role in TED management. Alternative therapies, such as teprotumumab, rituximab, and tocilizumab, are briefly discussed as potential options for patients with moderate-to-severe TED, who are unresponsive or intolerant to glucocorticoids. Adherence to recommended dosing protocols and careful monitoring of adverse effects are essential to optimize treatment outcomes.
References
1. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016 Aug 27;388(10047):906-918. doi: 10.1016/S0140-6736(16)00278-6.
2. Antonelli A, Ferrari SM, Ragusa F, Elia G, Paparo SR, Ruffilli I, Patrizio A, Giusti C, Gonnella D, Cristaudo A, Foddis R, Shoenfeld Y, Fallahi P. Graves' disease: Epidemiology, genetic and environmental risk factors and viruses. Best Pract Res Clin Endocrinol Metab. 2020 Jan;34(1):101387. doi: 10.1016/j.beem.2020.101387.
3. Smith, T. J., & Hegedüs, L. (2016). Graves' Disease. The New England Journal of Medicine, 375(16), 1552- 1565. https://doi.org/10.1056/NEJMra1510030
4. Melmed, S., Auchus, R. J., Goldfine, A. B., Rosen, C. J., & Kopp, P. A. (2024). Williams textbook of endocrinology (15th ed.). Elsevier.
5. SKOCZYLAS, Kamila, ROKICKI, Sebastian, SCHOK, Katarzyna & MIKULSKA, Julia. Clinical manifestations of Graves’ disease among adults - a review of literature. Journal of Education, Health and Sport. 2023;37(1):67-73. eISSN 2391-8306. DOI: http://dx.doi.org/10.12775/JEHS.2023.37.01.005
6. Schultz, H., Niknahad, A., Sterling, J., & Rajaii, F. (2023). Clinical features, pathophysiology, and management of thyroid eye disease. Minerva Ophthalmology, 65(4), 81–98. https://doi.org/10.23736/S2785-1265.23.01873-6
7. Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid AssociationHenry B. Burch, Petros Perros, Tomasz Bednarczuk, David S. Cooper, Peter J. Dolman, Angela M. Leung, Ilse Mombaerts, Mario Salvi, and Marius N. Stan, Publication: Thyroid https://doi.org/10.1089/thy.2022.0251
8. Bartley GB (1994) The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmstead County, Minnesota. Trans Am Ophthalmol Soc 92:477–588
9. Khong JJ, McNab AA, Ebeling PR, Craig JE, Selva D. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol. 2016 Jan;100(1):142-50. doi: 10.1136/bjophthalmol-2015-307399.
10. Eckstein AK, Lösch C, Glowacka D, Schott M, Mann K, Esser J, Morgenthaler NG. Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy. Br J Ophthalmol. 2009 Aug;93(8):1052-6. doi: 10.1136/bjo.2007.137265. Epub 2009 Feb 15. PMID: 19221109.
11. Kendler DL, Lippa J, Rootman J. The initial clinical characteristics of Graves' orbitopathy vary with age and sex. Arch Ophthalmol. 1993 Feb;111(2):197-201. doi: 10.1001/archopht.1993.01090020051022.
12. Luigi Bartalena, Prevention of Graves’ ophthalmopathy, Best Practice & Research Clinical Endocrinology & Metabolism, Volume 26, Issue 3, 2012, Pages 371-379, ISSN 1521-690X, https://doi.org/10.1016/j.beem.2011.09.004.
13. Yip Han Chin, Cheng Han Ng, Ming Hui Lee, Jeffery Wei Heng Koh, Jolene Kiew, Samantha Peiling Yang, Gangadhara Sundar, Chin Meng Khoo. Prevalence of thyroid eye disease in Graves’ disease: A meta-analysis and systematic review. 21 July 2020. https://doi.org/10.1111/cen.14296
14. Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc. 1994;92:477-588. PMID: 7886878; PMCID: PMC1298522.
15. Moshkelgosha S, So PW, Deasy N, Diaz-Cano S, Banga JP. Cutting edge: retrobulbar inflammation, adipogenesis, and acute orbital congestion in a preclinical female mouse model of Graves' orbitopathy induced by thyrotropin receptor plasmid-in vivo electroporation. Endocrinology. 2013 Sep;154(9):3008-15. doi: 10.1210/en.2013-1576.
16. Wiersinga, W. M. (2011). Autoimmunity in Graves’ Ophthalmopathy: The Result of an Unfortunate Marriage Between TSH Receptors and IGF-1 Receptors? The Journal of Clinical Endocrinology & Metabolism, 96(8), 2386–2394. doi:10.1210/jc.2011-0307
17. Fang S, Huang Y, Wang S, Zhang Y, Luo X, Liu L, Zhong S, Liu X, Li D, Liang R, Miranda P, Gu P, Zhou H, Fan X, Li B. IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO. J Clin Endocrinol Metab. 2016 Aug;101(8):2955-65. doi: 10.1210/jc.2016-1882.
18. Kahaly GJ, Diana T, Olivo PD. Tsh receptor antibodies: relevance & Utility. Endocr Pract. (2020) 26:97–106. doi: 10.4158/EP-2019-0363
19. Hötte GJ, de Bie M, de Keizer ROB, Kolijn PM, Drexhage RC, Veenbergen S, Versnel MA, van Hagen PM, Paridaens D and Dik WA (2024) Clinical performance of a novel and rapid bioassay for detection of thyroid- stimulating immunoglobulins in Graves’ orbitopathy patients: a comparison with two commonly used immunoassays. Front. Endocrinol. 15:1469179. doi: 10.3389/fendo.2024.1469179
20. Gerding M. N., van der Meer J. W., Broenink M., Bakker O., Wiersinga W. M., Prummel M. F., Association of thyrotrophin receptor antibodies with the clinical features of Graves' ophthalmopathy, Clin Endocrinol (Oxf), 2000, 52(3), 267-271
21. Kumar S., Coenen M. J., Scherer P. E., Bahn R. S., Evidence for Enhanced Adipogenesis in the Orbits of Patients with Graves’ Ophthalmopathy, J Clin Endocrinol Metab, 2004, 89(2), 930-935.
22. Lytton SD, Ponto KA, Kanitz M, et al. A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves’ orbitopathy. J Clin Endocrinol Metab. 2010;95(5):2123–2131
23. Jang, S., Shin, D., Lee, E. et al. Relevance of TSH-receptor antibody levels in predicting disease course in Graves’ orbitopathy: comparison of the third-generation TBII assay and Mc4-TSI bioassay. Eye 27, 964–971 (2013). https://doi.org/10.1038/eye.2013.120
24. Terry J. Smith, Understanding Pathogenesis Intersects With Effective
Treatment for Thyroid Eye Disease, The Journal of Clinical Endocrinology & Metabolism, 2022, 107, S13–S26 https://doi.org/10.1210/clinem/dgac328
25. Smith TJ, Tsai CC, Shih MJ, Tsui S, Chen B, Han R, Naik V, King CS, Press C, Kamat S, Goldberg RA, Phipps RP, Douglas RS, Gianoukakis AG. Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy. Thyroid. 2008 Sep;18(9):983-8. doi: 10.1089/thy.2007.0404
26. Smith TJ, Parikh SJ. HMC-1 mast cells activate human orbital fibroblasts in coculture: evidence for up-regulation of prostaglandin E2 and hyaluronan synthesis. Endocrinology. 1999 Aug;140(8):3518-25. doi: 10.1210/endo.140.8.6881.
27. Koumas L, Smith TJ, Feldon S, Blumberg N, Phipps RP. Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes. Am J Pathol. 2003 Oct;163(4):1291-300. doi: 10.1016/S0002-9440(10)63488-8.
28. Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM. Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma. J Biol Chem. 2007 Aug 3;282(31):22910-20. doi: 10.1074/jbc.M703597200.
29. Fernando R, Atkins SJ, Smith TJ. Slit2 May Underlie Divergent Induction by Thyrotropin of IL-23 and IL-12 in Human Fibrocytes. J Immunol. 2020 Apr 1;204(7):1724-1735. doi: 10.4049/jimmunol.1900434.
30. Fernando R, Lu Y, Atkins SJ, Mester T, Branham K, Smith TJ. Expression of thyrotropin receptor, thyroglobulin, sodium-iodide symporter, and thyroperoxidase by fibrocytes depends on AIRE. J Clin Endocrinol Metab. 2014 Jul;99(7):E1236-44. doi: 10.1210/jc.2013-4271.
31. Huang, Y., Fang, S., Li, D. et al. The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy. Eye 33, 176–182 (2019). https://doi.org/10.1038/s41433-018-0279-9
32. Łacheta, Dominika, Miśkiewicz, Piotr, Głuszko, Alicja, Nowicka, Grażyna, Struga, Maria, Kantor, Ireneusz, Poślednik, Krzysztof B., Mirza, Shafaq, Szczepański, Mirosław J., Immunological Aspects of Graves’ Ophthalmopathy, BioMed Research International, 2019, 7453260, 12 pages, 2019. https://doi.org/10.1155/2019/7453260
33. Lehmann GM, Feldon SE, Smith TJ, Phipps RP. Immune mechanisms in thyroid eye disease. Thyroid. 2008 Sep;18(9):959-65. doi: 10.1089/thy.2007.0407. PMID: 18752427; PMCID: PMC2795569
34. Hou T-Y, Wu S-B, Kau H-C, Tsai C-C. The Role of Oxidative Stress and Therapeutic Potential of Antioxidants in Graves’ Ophthalmopathy. Biomedicines. 2021; 9(12):1871. https://doi.org/10.3390/biomedicines9121871
35. Ma C, Li H, Lu S and Li X (2024) Thyroid-associated ophthalmopathy: the role of oxidative stress. Front. Endocrinol. 15:1400869. doi: 10.3389/fendo.2024.1400869
36. Tortora, F., Cirillo, M., Ferrara, M., Belfiore, M. P., Carella, C., Caranci, F., & Cirillo, S. (2013). Disease Activity in Graves’ Ophthalmopathy: Diagnosis with Orbital MR Imaging and Correlation with Clinical Score. The Neuroradiology Journal, 26(5), 555–564. doi:10.1177/197140091302600509
37. Bartalena, Luigi & Kahaly, George & Baldeschi, Lelio & Dayan, Colin & Eckstein, Anja & Marcocci, Claudio & Marinò, Michele & Vaidya, Bijay & Wiersinga, Wilmar. (2021). The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy. European Journal of Endocrinology. 185. 10.1530/EJE-21-0479.
38. Marcocci C, Kahaly GJ, Krassas GE et al (2011) Selenium and the course of mild Graves’ orbitopathy. N Engl J Med 364:1920–1931
39. Israa Sharabati, Ruaa M. Qafesha, Mahmoud D. Hindawi, Sarah Amro, Baraa M. Ayesh, The efficacy and safety of selenium supplementation versus placebo in the treatment of Graves' orbitopathy: A systematic review and meta-analysis of randomised controlled trials, Clinical EndocrinologyVolume 101, Issue 6, 2024, p. 669-681, https://doi.org/10.1111/cen.15128
40. M. Almanza-Monterrubio, L. Garnica-Hayashi, A. Dávila-Camargo, Á. Nava-Castañeda,
Oral selenium improved the disease activity in patients with mild Graves’ orbitopathy, Journal Français d'Ophtalmologie, Volume 44, Issue 5, 2021, Pages 643-651, ISSN 0181-5512, https://doi.org/10.1016/j.jfo.2020.08.029.
41. Bednarczuk, T., Schomburg, L. Challenges and perspectives of selenium supplementation in Graves’ disease and orbitopathy. Hormones 19, 31–39 (2020). https://doi.org/10.1007/s42000-019-00133-5
42. Längericht J, Krämer I, Kahaly GJ. Glucocorticoids in Graves’ orbitopathy: mechanisms of action and clinical application. Therapeutic Advances in Endocrinology and Metabolism. 2020;11. doi:10.1177/2042018820958335
43. Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol. 2011 May;163(1):29-43. doi: 10.1111/j.1476-5381.2010.01199.x
44. Stephanie Zang, George J. Kahaly, Steroids and the Immune Response in Graves Orbitopathy, Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued); Volume 11, Issue 2, Year 2011, DOI: 10.2174/187152211795495689 → 44
45. S. Zang, K. A. Ponto, G. J. Kahaly, Intravenous Glucocorticoids for Graves' Orbitopathy: Efficacy and Morbidity, The Journal of Clinical Endocrinology & Metabolism, Volume 96, Issue 2, 1 February 2011, Pages 320–332, https://doi.org/10.1210/jc.2010-1962 → 45
46. Kahaly, G. J. (2017). Management of Moderately Severe Graves’ Orbitopathy. Graves’ Orbitopathy, 140–176. doi:10.1159/000475956
47. Rajendram R, Taylor PN, Wilson VJ, Harris N, Morris OC, Tomlinson M, Yarrow S, Garrott H, Herbert HM, Dick AD, Cook A, Gattamaneni R, Jain R, Olver J, Hurel SJ, Bremner F, Drummond SR, Kemp E, Ritchie DM, Rumsey N, Morris D, Lane C, Palaniappan N, Li C, Pell J, Hills R, Ezra DG, Potts MJ, Jackson S, Rose GE, Plowman N, Bunce C, Uddin JM, Lee RWJ, Dayan CM. Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 × 2 factorial, double-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2018 Apr;6(4):299-309. doi: 10.1016/S2213-8587(18)30021-4.
48. Kahaly GJ, Pitz S, Hommel G & Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. Journal of Clinical Endocrinology and Metabolism 2005 90 5234–5240. (https://doi.org/10.1210/jc.2005-0148)
49. Kahaly, G. J. (2017). Management of Moderately Severe Graves’ Orbitopathy. Graves’ Orbitopathy, 140–176. doi:10.1159/000475956
50. Strianese, D. (2018). Efficacy and Safety of Immunosuppressive Agents for Thyroid Eye Disease. Ophthalmic Plastic and Reconstructive Surgery, 1. doi:10.1097/iop.0000000000001131
51. Marcocci C, Watt T, Altea MA, Rasmussen AK, Feldt-Rasmussen U, Orgiazzi J, Bartalena L; European Group of Graves' Orbitopathy. Fatal and non-fatal adverse events of glucocorticoid therapy for Graves' orbitopathy: a questionnaire survey among members of the European Thyroid Association. Eur J Endocrinol. 2012 Feb;166(2):247-53. doi: 10.1530/EJE-11-0779.
52. Zang S, Ponto KA, Kahaly GJ. Clinical review: Intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab. 2011 Feb;96(2):320-32. doi: 10.1210/jc.2010-1962
53. Kahaly, G. J., Riedl, M., König, J., Pitz, S., Ponto, K., Diana, T., Kampmann, E., Kolbe, E., Eckstein, A., Moeller, L. C., Führer, D., Salvi, M., Curro, N., Campi, I., Covelli, D., Leo, M., Marinò, M., Menconi, F., Marcocci, C., ... Brix, T. (2018). Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. The Lancet Diabetes & Endocrinology, 6(4), 287-298. https://doi.org/10.1016/S2213-8587(18)30020-2
54. Insull EA, Sipkova Z, David J, Turner HE, Norris JH. Early low-dose rituximab for active thyroid eye disease: An effective and well-tolerated treatment. Clin Endocrinol (Oxf). 2019 Jul;91(1):179-186. doi: 10.1111/cen.13970. Epub 2019 Apr 11. PMID: 30864162.
55. Mingyang Wang, Bixuan Qin, Cuihong Liu, Honglei Liu, Dongmei Li, Efficacy of Tocilizumab in Refractory Graves Orbitopathy From Real-World Clinical Practice: An Observational Study, Journal of the Endocrine Society, Volume 8, Issue 12, December 2024, bvae193, https://doi.org/10.1210/jendso/bvae193
56. Ugradar, S., Kang, J., Kossler, A.L. et al. Teprotumumab for the treatment of chronic thyroid eye disease. Eye 36, 1553–1559 (2022). https://doi.org/10.1038/s41433-021-01593-z
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Julia Ryniecka, Maciej Wojszczyk, Damian Zys, Piotr Pasek, Julia Kulbacka, Michalina Wójcikiewicz, Marta Chuncia-Ileczko, Julia Kacperczyk, Filip Arczewski, Karol Dziedzic
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Stats
Number of views and downloads: 154
Number of citations: 0
