Gravesʼ Orbitopathy: Current Concepts for Medical Treatment

Abstract

Background The therapy of severe manifestations of Gravesʼ orbitopathy (GO) is still a challenge and requires good interdisciplinary cooperation. It is especially important to use stage-adapted anti-inflammatory therapy to avoid irreversible damage.

Material and Methods Discussion of the latest results of multicentre randomised therapy studies on anti-inflammatory treatments for Gravesʼ orbitopathy, as well as new therapeutic concepts.

Results Mild cases of GO can be treated with only selenium supplementation and a watchful waiting strategy. In the moderate-to-severe active form of GO, primary therapy consists of i. v. steroids (cumulative 4 – 5 g) in combination with orbital irradiation in patients with impaired motility. In patients with insufficient therapeutic response after 6 weeks, treatment should be switched to other immunosuppressive agents. In severe sight-threatening disease, bony orbital decompression is usually necessary. As basic research has improved our understanding of the underlying pathophysiology of GO, it has been possible to develop targeted therapies for GO. Teprotumumab, an IGF-1 receptor antibody, was effective in treating GO patients in a phase III trial and should soon be awarded approval for Europe.

Conclusion The current therapy concept for Gravesʼ orbitopathy is as follows: first anti-inflammatory therapy then surgical correction of the permanent defects. This may soon be modified, due to the use of targeted therapies.

Key words

Graves - Graves orbitopathy - treatment - lids - orbit - strabismus

Publication History

Received: 02 September 2020

Accepted: 01 December 2020

Article published online:
27 January 2021

• References/Literatur

• 1 Bahn RS. Current Insights into the Pathogenesis of Gravesʼ Ophthalmopathy. Horm Metab Res 2015; 47: 773-778 doi:10.1055/s-0035-1555762
• 2 Wiersinga WM, Perros P, Kahaly GJ. et al. Clinical assessment of patients with Gravesʼ orbitopathy: the European Group on Gravesʼ Orbitopathy recommendations to generalists, specialists and clinical researchers. Eur J Endocrinol 2006; 155: 387-389 doi:10.1530/eje.1.02230
• 3 Bartalena L, Baldeschi L, Boboridis K. et al. The 2016 European Thyroid Association/European Group on Gravesʼ Orbitopathy Guidelines for the Management of Gravesʼ Orbitopathy. Eur Thyroid J 2016; 5: 9-26 doi:10.1159/000443828
• 4 Bartalena L, Baldeschi L, Dickinson A. et al. Consensus statement of the European Group on Gravesʼ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 2008; 158: 273-285 doi:10.1530/EJE-07-0666
• 5 Bartalena L, Baldeschi L, Dickinson AJ. et al. Consensus statement of the European group on Gravesʼ orbitopathy (EUGOGO) on management of Gravesʼ orbitopathy. Thyroid 2008; 18: 333-346 doi:10.1089/thy.2007.0315
• 6 Wiersinga WM. Smoking and thyroid. Clin Endocrinol (Oxf) 2013; 79: 145-151 doi:10.1111/cen.12222
• 7 Eckstein A, Quadbeck B, Mueller G. et al. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br J Ophthalmol 2003; 87: 773-776
• 8 Marcocci C, Kahaly GJ, Krassas GE. et al. Selenium and the course of mild Gravesʼ orbitopathy. N Engl J Med 2011; 364: 1920-1931 doi:10.1056/NEJMoa1012985
• 9 Kahaly GJ, Pitz S, Hommel G. et al. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Gravesʼ orbitopathy. J Clin Endocrinol Metab 2005; 90: 5234-5240
• 10 Bartalena L, Krassas GE, Wiersinga W. et al. Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Gravesʼ orbitopathy. J Clin Endocrinol Metab 2012; 97: 4454-4463 doi:10.1210/jc.2012-2389
• 11 Zhu W, Ye L, Shen L. et al. A prospective, randomized trial of intravenous glucocorticoids therapy with different protocols for patients with Gravesʼ ophthalmopathy. J Clin Endocrinol Metab 2014; 99: 1999-2007 doi:10.1210/jc.2013-3919
• 12 Oeverhaus M, Witteler T, Lax H. et al. Combination Therapy of Intravenous Steroids and Orbital Irradiation is More Effective Than Intravenous Steroids Alone in Patients with Gravesʼ Orbitopathy. Horm Metab Res 2017; 49: 739-747 doi:10.1055/s-0043-116945
• 13 Mourits MP, van Kempen-Harteveld ML, Garcia MB. et al. Radiotherapy for Gravesʼ orbitopathy: randomised placebo-controlled study. Lancet 2000; 355: 1505-1509 doi:10.1016/S0140-6736(00)02165-6
• 14 Johnson KT, Wittig A, Loesch C. et al. A retrospective study on the efficacy of total absorbed orbital doses of 12, 16 and 20 Gy combined with systemic steroid treatment in patients with Gravesʼ orbitopathy. Graefes Arch Clin Exp Ophthalmol 2010; 248: 103-109 doi:10.1007/s00417-009-1214-3
• 15 Zang S, Ponto KA, Kahaly GJ. Clinical review: Intravenous glucocorticoids for Gravesʼ orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab 2011; 96: 320-332 doi:10.1210/jc.2010-1962
• 16 Zhou X, Zhou D, Wang J. et al. Treatment strategies for Gravesʼ ophthalmopathy: a network meta-analysis. Br J Ophthalmol 2020; 104: 551-556 doi:10.1136/bjophthalmol-2018-313697
• 17 Salvi M, Vannucchi G, Curro N. et al. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Gravesʼ orbitopathy: a randomized controlled study. J Clin Endocrinol Metab 2015; 100: 422-431 doi:10.1210/jc.2014-3014
• 18 Rajendram R, Taylor PN, Wilson VJ. et al. Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 × 2 factorial, double-blind, randomised controlled trial. Lancet Diabetes Endocrinol 2018; 6: 299-309 doi:10.1016/S2213-8587(18)30021-4
• 19 Kahaly GJ, Riedl M, Konig J. et al. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Gravesʼ orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. Lancet Diabetes Endocrinol 2018;
• 20 Stan MN, Garrity JA, Carranza Leon BG. et al. Randomized controlled trial of rituximab in patients with Gravesʼ orbitopathy. J Clin Endocrinol Metab 2015; 100: 432-441 doi:10.1210/jc.2014-2572
• 21 Kahaly G, Schrezenmeir J, Krause U. et al. Ciclosporin and prednisone v. prednisone in treatment of Gravesʼ ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest 1986; 16: 415-422
• 22 Onaran Z, Konuk O, Oktar SO. et al. Intraocular pressure lowering effect of orbital decompression is related to increased venous outflow in Graves orbitopathy. Curr Eye Res 2014; 39: 666-672 doi:10.3109/02713683.2013.867355
• 23 Ye X, Bo X, Hu X. et al. Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Gravesʼ orbitopathy. Clin Endocrinol (Oxf) 2017; 86: 247-255 doi:10.1111/cen.13170
• 24 Kahaly GJ, Riedl M, Konig J. et al. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Gravesʼ orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. Lancet Diabetes Endocrinol 2018; 6: 287-298 doi:10.1016/S2213-8587(18)30020-2
• 25 Pérez-Moreiras JV, Alvarez-López A, Gómez EC. Treatment of active corticosteroid-resistant Gravesʼ orbitopathy. Ophthalmic Plast Reconstr Surg 2014; 30: 162-167 doi:10.1097/IOP.0000000000000037
• 26 Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR. et al. Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial. Am J Ophthalmol 2018; 195: 181-190 doi:10.1016/j.ajo.2018.07.038
• 27 Sanchez-Bilbao L, Martinez-Lopez D, Revenga M. et al. Anti-IL-6 Receptor Tocilizumab in Refractory Gravesʼ Orbitopathy: National Multicenter Observational Study of 48 Patients. J Clin Med 2020; 9: 2816 doi:10.3390/jcm9092816
• 28 Khong JJ, McNab A. Medical treatment in thyroid eye disease in 2020. Br J Ophthalmol 2020;
• 29 Rubinov A, Zommer H, Aghazadeh H. et al. Role of methotrexate in thyroid-related orbitopathy. Can J Ophthalmol 2018; 53: 34-38 doi:10.1016/j.jcjo.2017.07.009
• 30 Sipkova Z, Insull EA, David J. et al. Early use of steroid-sparing agents in the inactivation of moderate-to-severe active thyroid eye disease: a step-down approach. Clin Endocrinol (Oxf) 2018; 89: 834-839 doi:10.1111/cen.13834
• 31 Saeed P, Tavakoli Rad S, Bisschop PHLT. Dysthyroid Optic Neuropathy. Ophthalmic Plast Reconstr Surg 2018; 34 (4S Suppl. 1): S60-S67 doi:10.1097/IOP.0000000000001146
• 32 Görtz GE, Horstmann M, Aniol B. et al. Hypoxia-Dependent HIF-1 Activation Impacts on Tissue Remodeling in Gravesʼ Ophthalmopathy-Implications for Smoking. J Clin Endocrinol Metab 2016; 101: 4834-4842 doi:10.1210/jc.2016-1279
• 33 Uddin JM, Rubinstein T, Hamed-Azzam S. Phenotypes of Thyroid Eye Disease. Ophthalmic Plast Reconstr Surg 2018; 34 (4S Suppl. 1): S28-S33 doi:10.1097/IOP.0000000000001147
• 34 Curro N, Covelli D, Vannucchi G. et al. Therapeutic outcomes of high-dose intravenous steroids in the treatment of dysthyroid optic neuropathy. Thyroid 2014; 24: 897-905 doi:10.1089/thy.2013.0445
• 35 Douglas RS, Kahaly GJ, Patel A. et al. Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med 2020; 382: 341-352 doi:10.1056/NEJMoa1910434
• 36 Smith TJ, Kahaly GJ, Ezra DG. et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med 2017; 376: 1748-1761 doi:10.1056/NEJMoa1614949
• 37 Pearce SHS, Dayan C, Wraith DC. et al. Antigen-Specific Immunotherapy with Thyrotropin Receptor Peptides in Gravesʼ Hyperthyroidism: A Phase I Study. Thyroid 2019; 29: 1003-1011 doi:10.1089/thy.2019.0036
• 38 Eckstein A, Schittkowski M, Esser J. Surgical treatment of Gravesʼ ophthalmopathy. Best Pract Res Clin Endocrinol Metab 2012; 26: 339-358 doi:10.1016/j.beem.2011.11.002
• 39 Eckstein A, Esser J, Oeverhaus M. et al. Surgical Treatment of Diplopia in Graves Orbitopathy Patients. Ophthalmic Plast Reconstr Surg 2018; 34 (4S Suppl. 1): S75-S84 doi:10.1097/IOP.0000000000001148
• 40 Eckstein A, Esser J, Mattheis S. et al. Endokrine Orbitopathie. Klin Monbl Augenheilkd 2016; 233: 1385-1407 doi:10.1055/s-0042-118040