Factors affecting the course of Graves’ Orbitopathy and poor response to glucocorticoid treatment followed by orbital radiotherapy Original research study

Main Article Content

Agnieszka Jagiełło-Korzeniowska
Andrzej Sokołowski
Alicja Hubalewska-Dydejczyk
Bożena Romanowska-Dixon
Agata Bałdys-Waligórska


Graves’ orbitopathy is a rare autoimmune disorder characterized by the inflammation of orbital tissues. The course of disease can be described in terms of its activity and severity.

Aim: The aim of our study was to determine the factors affecting the activity and severity of Graves’ orbitopathy, as well as to identify the predictive factors of poor response to glucocorticoid treatment followed by orbital irradiation.

Methods: We performed a prospective observational study of 214 patients with Graves’ orbitopathy who were divided into two groups depending on the treatment they had previously obtained for their Graves’ disease. They received i.v. methylprednisolone pulses followed by orbital radiotherapy. They were examined and had their TSH, TRAb and FT4 levels evaluated prior to treatment and after 1, 6 and 12 months.

Results: A pre-treatment TRAb concentration higher by one unit (U/L) implied a mean increase in the relative risk of active orbitopathy by 4.7% (p = 0.0362). A TRAb concentration higher by one U/L 1 month after treatment implied a mean increase in the relative risk of moderate-to-severe and severe GO by 8.7% (p = 0.0167) 6 months after treatment. As regards poor response to treatment, patients with moderate-to-severe and severe Graves’ orbitopathy on admission carried a higher risk of being non-responders. Each point scored on the NOSPECS scale prior to treatment increased the relative risk of the patient being a non-responder by 30%.

Conclusions: Patients with higher TRAb levels have a higher risk of active Graves’ orbitopathy and moderate-to-severe and severe Graves’ orbitopathy. Monitoring TRAb serum concentration in those patients is of great importance. Patients with more severe Graves’ orbitopathy carry a higher risk of being poor responders to immunosuppressive treatment. Therefore, careful monitoring of patients with Graves’ orbitopathy and their early referral to specialized centers is essential.


Download data is not yet available.

Article Details

How to Cite
Jagiełło-Korzeniowska A, Sokołowski A, Hubalewska-Dydejczyk A, Romanowska-Dixon B, Bałdys-Waligórska A. Factors affecting the course of Graves’ Orbitopathy and poor response to glucocorticoid treatment followed by orbital radiotherapy. Ophthatherapy [Internet]. 2022May19 [cited 2023Jun.8];9(2):98-105. Available from: https://journalsmededu.pl/index.php/ophthatherapy/article/view/1783
Conservative treatment


1. Wilmar WM, Kahaly GJ. Graves’ Orbitopathy A Multidisciplinary Approach-Questions and Answers. 3rd, revised and expanded edition. Basel 2017.
2. Tsui S, Naik V, Hoa N et al. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease. J Immunol. 2008; 181(6): 4397-405.
3. Krieger CC, Place RF, Bevilacqua C et al. TSH/IGF-1 receptor cross talk in Graves’ ophthalmopathy pathogenesis. J Clin Endocrinol Metab. 2016; 101(6): 2340-7.
4. Rundle FF, Wilson CW. Development and course of exophthalmos and ophthalmoplegia in Graves’ disease with special reference to the effect of thyroidectomy. Clin Sci 1945; 5: 177-94.
5. Bartalena L, Piantanida E, Gallo D et al. Epidemiology, Natural History, Risk Factors, and Prevention of Graves’ Orbitopathy. Front Endocrinol (Lausanne). 2020; 11: 615993. http://doi.org/10.3389/fendo.2020.615993.
6. Bartalena L, Kahaly GJ, Baldeschi L et al.; EUGOGO †.The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. Eur J Endocrinol. 2021; 185(4): G43-G67. http://doi.org/10.1530/EJE-21-0479.
7. Mourits MP, Prummel MF, Wiersinga WM et al. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol (Oxf). 1997; 47(1): 9-14. http://doi.org/10.1046/j.1365-2265.1997.2331047.
8. Bartalena L, Baldeschi L, Boboridis K et al.; European Group on Graves’ Orbitopathy (EUGOGO). The 2016 European Thyroid Association/ European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. Eur Thyroid J. 2016; 5(1): 9-26. http://doi.org/10.1159/000443828.
9. Werner SC. Modification of the classification of the eye changes of Graves’ disease. Am J Ophthalmol. 1977; 83: 725-7. http://doi.org/10.1016/0002-9394(77)90140-4.
10. Barrio-Barrio J, Sabater AL, Bonet-Farriol E et al. Graves’ Ophthalmopathy: VISA versus EUGOGO Classification, Assessment, and Management. J Ophthalmol. 2015; 2015: 249125. http://doi.org/10.1155/2015/249125.
11. Bartalena L. Graves’ orbitopathy: imperfect treatments for a rare disease. Eur Thyroid J. 2013; 2(4): 259-69. http://doi.org/10.1159/000356042.
12. Kim JW, Han SH, Son BJ et al. Efficacy of combined orbital radiation and systemic steroids in the management of Graves’ orbitopathy. Graefes Arch Clin Exp Ophthalmol. 2016; 254(5): 991-8. http://doi.org/10.1007/s00417-016-3280-7.
13. Prummel MF, Terwee CB, Gerding MN et al. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves’ ophthalmopathy. J Clin Endocrinol Metab. 2004; 89(1): 15-20. http://doi.org/10.1210/jc.2003-030809.
14. van Geest RJ, Sasim IV, Koppeschaar HP et al. Methylprednisolone pulse therapy for patients with moderately severe Graves’ orbitopathy: a prospective, randomized, placebo-controlled study. Eur J Endocrinol. 2008; 158(2): 229-37. http://doi.org/10.1530/EJE-07-0558.
15. Längericht J, Krämer I, Kahaly GJ. Glucocorticoids in Graves’ orbitopathy: mechanisms of action and clinical application. Ther Adv Endocrinol Metab. 2020; 11: 2042018820958335. http://doi.org/10.1177/2042018820958335. eCollection 2020.
16. Zang S, Ponto KA, Kahaly GJ. Clinical review: Intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab. 2011; 96(2): 320-32. http://doi.org/10.1210/jc.2010-1962.
17. Mourits MP, van Kempen-Harteveld ML, García MB et al. Radiotherapy for Graves’ orbitopathy: randomised placebo-controlled study. Lancet. 2000; 355(9214): 1505-9. http://doi.org/10.1016/S0140-6736(00)02165-6.
18. Kahaly GJ, Roesler HP, Kutzner J et al. Radiotherapy for thyroid-associated orbitopathy. Exp Clin Endocrinol Diabetes. 1999; 107(suppl 5): S201-7. http://doi.org/10.1055/s-0029-1212186.
19. Ahn HY, Lee JK. Intravenous Glucocorticoid Treatment for Korean Graves’ Ophthalmopathy Patients. J Korean Med Sci. 2020; 35(23): e177. http://doi.org/10.3346/jkms.2020.35.e177.
20. Kahaly GJ. Management of Graves Thyroidal and Extrathyroidal Disease: An Update. J Clin Endocrinol Metab. 2020; 105(12): 3704-20. http://doi.org/10.1210/clinem/dgaa646.
21. Laurberg P, Wallin G, Tallstedt L et al. TSH-receptor autoimmunity in Graves’ disease after therapy with anti thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur J Endocrinol. 2008; 158(1): 69-75. http://doi.org/10.1530/EJE-07-0450.
22. Stan MN, Durski JM, Brito JP et al. Cohort study on radioactive iodine-induced hypothyroidism: implications for Graves’ ophthalmopathy and optimal timing for thyroid hormone assessment. Thyroid. 2013; 23(5): 620-5. http://doi.org/10.1089/thy.2012.0258.
23. Acharya SH, Avenell A, Philip S et al. Radioiodine therapy (RAI) for Graves’ disease (GD) and the effect on ophthalmopathy: a systematic review. Clin Endocrinol (Oxf). 2008; 69(6): 943-50. http://doi.org/10.1111/j.1365-2265.2008.03279.x.
24. Jagiełło-Korzeniowska A, Sokołowski A, Krzentowska-Korek A et al. The efficacy of immunosuppressive treatment of Graves’ orbitopathy is not affected by previous anti-thyroid drugs or by radioiodine therapy of Graves’ disease. Endokrynol Pol. 2016; 67(6): 554-61. http://doi.org/10.5603/EP.2016.0073.
25. Eckstein AK, Plicht M, Lax H et al. Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab. 2006; 91(9): 3464-70. http://doi.org/10.1210/jc.2005-2813.
26. Eckstein AK, Plicht M, Lax H et al. Clinical results of anti-inflammatory therapy in Graves’ ophthalmopathy and association with thyroidal autoantibodies. Clin Endocrinol (Oxf). 2004; 61(5): 612-8. http://doi.org/10.1111/j.1365-2265.2004.02143.x.
27. Jang SY, Shin DY, Lee EJ et al. Correlation between TSH receptor antibody assays and clinical manifestations of Graves’ orbitopathy. Yonsei Med J. 2013; 54(4): 1033-9. http://doi.org/10.3349/ymj.2013.54.4.1033.
28. Gerding MN, van der Meer JW, Broenink M et al. Association of thyrotrophin receptor antibodies with the clinical features of Graves’ ophthalmopathy. Clin Endocrinol (Oxf). 2000 Mar; 52(3): 267-71. http://doi.org/10.1046/j.1365-2265.2000.00959.x.
29. Ohtsuka K, Sato A, Kawaguchi S et al. Effect of steroid pulse therapy with and without orbital radiotherapy on Graves’ ophthalmopathy. Am J Ophthalmol. 2003; 135: 285-90.
30. Currò N, Covelli D, Vannucchi G et al. Therapeutic outcomes of high-dose intravenous steroids in the treatment of dysthyroid optic neuropathy. Thyroid. 2014; 24(5): 897-905. http://doi.org/10.1089/thy.2013.0445.
31. Le Moli R, Baldeschi L, Saeed P et al. Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves’ ophthalmopathy. Thyroid. 2007; 17(4): 357-62. http://doi.org/10.1089/thy.2006.0267.
32. Marino M, Morabito E, Brunetto MR et al. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy. Thyroid. 2004; 14: 403-6.
33. Bartalena L, Krassas GE, Wiersinga W et al. European Group on Graves’ Orbitopathy. Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves’ orbitopathy. J Clin Endocrinol Metab. 2012; 97(12): 4454-63. http://doi.org/10.1210/jc.2012-2389.
34. Cawood TJ, Moriarty P, O’Farrelly C et al. Smoking and thyroid-associated ophthalmopathy: A novel explanation of the biological link. J Clin Endocrinol Metab. 2007; 92(1): 59-64. http://doi.org/10.1210/jc.2006-1824.
35. Bartalena L, Veronesi G, Krassas GE et al.; European Group on Graves’ Orbitopathy (EUGOGO). Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves’ orbitopathy? J Endocrinol Invest. 2017; 40(5): 547-53. http://doi.org/10.1007/s40618-017-0608-z.
36. Uddin JM, Rubinstein T, Hamed-Azzam S. Phenotypes of Thyroid Eye Disease. Ophthalmic Plast Reconstr Surg. 2018; 34(4S suppl 1): S28-S33. http://doi.org/10.1097/IOP.0000000000001147.
37. Smith TJ, Kahaly GJ, Ezra DG et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. 2017; 376(18): 1748-61. http://doi.org/10.1056/NEJMoa1614949.
38. Bartalena L, Marcocci C, Tanda ML et al. Orbital radiotherapy for Graves’ ophthalmopathy. Thyroid. 2002; 12(3): 245-50. http://doi.org/10.1089/105072502753600223.
39. Vannucchi G, Covelli D, Campi I et al. The therapeutic outcome to intravenous steroid therapy for active Graves’ orbitopathy is influenced by the time of response but not polymorphisms of the glucocorticoid receptor. Eur J Endocrinol. 2013; 170(1): 55 61. http://doi.org/10.1530/EJE-13-0611.
40. Prummel MF, Bakker A, Wiersinga WM et al. A. Multi-center study on the characteristics and treatment strategies of patients with Graves’ orbitopathy: the first European Group on Graves’ Orbitopathy experience. Eur J Endocrinol. 2003; 148(5): 491-5. http://doi.org/10.1530/eje.0.1480491.
41. Gharib S, Moazezi Z, Bayani MA. Prevalence and severity of ocular involvement in Graves’ disease according to sex and age: A clinical study from Babol, Iran. Caspian J Intern Med. 2018; 9(2): 178-83. http://doi.org/10.22088/cjim.9.2.178.
42. Thornton J, Kelly SP, Harrison RA et al. Cigarette smoking and thyroid eye disease: a systematic review. Eye (Lond). 2007; 21(9): 1135-45. http://doi.org/10.1038/sj.eye.6702603.
43. Naselli A, Moretti D, Regalbuto C et al. Evidence That Baseline Levels of Low-Density Lipoproteins Cholesterol Affect the Clinical Response of Graves’ Ophthalmopathy to Parenteral Corticosteroids. Front Endocrinol (Lausanne). 2020; 11: 609895. http://doi.org/10.3389/fendo.2020.609895.
44. Kahaly GJ, Douglas RS, Holt RJ et al. 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. Lancet Diabetes Endocrinol. 2021; 9(6): 360-72. http://doi.org/10.1016/S2213-8587(21)00056-5.