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Graves Orbitopathy: Update on Diagnosis and Therapy

Eugen Melcescu, MD, William B. Horton, MD, Daniel Kim, MD, Vani Vijayakumar, MD, James J. Corbett, MD, Kimberly W. Crowder, MD, Karen T. Pitman, MD, Gabriel I. Uwaifo, MD, Christian A. Koch, DrMedHabil
Volume: 107 Issue: 1 January, 2014

Abstract:

Graves orbitopathy (GO) is an autoimmune disorder representing the most frequent extrathyroidal manifestation of Graves disease. It is rare, with an age-adjusted incidence of approximately 16.0 cases per 100,000 population per year in women and 2.9 cases per 100,000 population per year in men. GO is an inflammatory process characterized by edema and inflammation of the extraocular muscles and an increase in orbital connective tissue and fat. Despite recent progress in the understanding of its pathogenesis, GO often remains a major diagnostic and therapeutic challenge. It has become increasingly important to classify patients into categories based on disease activity at initial presentation. A Hertel exophthalmometer measurement of >2 mm above normal for race usually categorizes a patient as having moderate-to-severe GO. Encouraging smoking cessation and achieving euthyroidism in the individual patient are important. Simple treatment measures such as lubricants for lid retraction, nocturnal ointments for incomplete eye closure, prisms in diplopia, or botulinum toxin injections for upper-lid retraction can be effective in mild cases of GO. Glucocorticoids, orbital radiotherapy, and decompression/rehabilitative surgery are generally indicated for moderate-to-severe GO and for sight-threatening optic neuropathy. Future therapies, including rituximab aimed at treating the molecular and immunological basis of GO, are under investigation and hold promise for the future.

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References:

1. Bartalena L, Pinchera A, Marcocci C. Management of Graves’ ophthalmopathy: reality and perspectives. Endocr Rev. 2000; 21: 168–199.
 
2. Melcescu E, Kemp EH, Majithia V, et al. Graves’ disease, hypoparathyroidism, systemic lupus erythematosus, alopecia, and angioedema: autoimmune polyglandular syndrome variant or coincidence? Int J Immunopathol Pharmacol. 2013; 26: 217–222.
 
3. Antonelli A, Fallahi P, Tolari S, et al. Thyroid-associated ophthalmopathy and TSH receptor autoantibodies in nonmetastatic thyroid cancer after total thyroidectomy. Am J Med Sci. 2008; 336: 288–290.
 
4. Brent GA. Graves’ disease. N Engl J Med. 2008; 358: 2594–2605.
 
5. Bartalena L, Tanda ML. Clinical practice. Graves’ ophthalmopathy. N Engl J Med. 2009; 360: 994–1001.
 
6. Tanda ML, Piantanida E, Liparulo L, et al. Prevalence and natural history of Graves’ orbitopathy in a large series of patients with newly diagnosed Graves’ hyperthyroidism seen at a single center. J Clin Endocrinol Metab. 2013; 98: 1443–1449.
 
7. Lesho E, Jones RE. Hypothyroid Graves’ disease. South Med J. 1997; 90: 1201–1203.
 
8. Khoo DH, Eng PH, Ho SC, et al. Graves’ ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels. Thyroid. 2000; 10: 1093–1100.
 
9. Marcocci C, Bartelena L, Bogazzi F, et al. Studies on the occurrence of ophthalmopathy in Graves’ disease. Acta Endocrinol (Copenh). 1989; 120: 473–478.
 
10. Melcescu E, Horton WB, Pitman KT, et al. Euthyroid Graves’ orbitopathy and incidental papillary thyroid microcarcinoma. Hormones (Athens). 2013; 12: 298–304.
 
11. Fernando R, Atkins S, Raychaudhuri N, et al. Human fibrocytes coexpress thyroglobulin and thyrotropin receptor. Proc Natl Acad Sci U S A. 2012; 109: 7427–7432.
 
12. Gillespie EF, Papagerogiou KI, Fernando R, et al. Increased expression of TSH receptor by fibrocytes in thyroid-associated ophthalmopathy leads to chemokine production. J Clin Endocrinol Metab. 2012; 97: E70–E76.
 
13. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010; 362: 726–738.
 
14. Bartley GB, Fatourechi V, Kadrmas EF, et al. The incidence of Graves’ ophthalmopathy in Olmsted County, Minnesota. Am J Ophthalmol. 1995; 120: 511–517.
 
15. Guarneri F, Benvenga S. Environmental factors and genetic background that interact to cause autoimmune thyroid disease. Curr Opin Endocrinol Diabetes Obes. 2007; 14: 398–409.
 
16. Tallstedt L, Lundell G, Torring O, et al. Occurrence of ophthalmopathy after treatment for Graves’ hyperthyroidism: the thyroid study group. N Engl J Med. 1992; 326: 1733–1738.
 
17. Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med. 1998; 338: 73–78.
 
18. Bartalena L, Marcocci C, Tanda ML, et al. Cigarette smoking and treatment outcomes in Graves’ ophthalmopathy. Ann Intern Med. 1998; 129: 632–635.
 
19. 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: 3464–3470.
 
20. Tallstedt L, Lundell G, Blomgren H, et al. Does early administration of thyroxine reduce the development of Graves’ ophthalmopathy after radioiodine treatment? Eur J Endocrinol. 1994; 130: 494–497.
 
21. Pfeilschifter J, Ziegler R. Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs lifetime cigarette consumption. Clin Endocrinol (Oxf). 1996; 45: 477–481.
 
22. Prummel MF, Wiersinga WM, Mourits MP, et al. Amelioration of eye changes of Graves’ ophthalmopathy by achieving euthyroidism. Acta Endocrinol (Copenh). 1989; 121: 185–189.
 
23. Prummel MF, Wiersinga WM, Mourits MP, et al. Effect of abnormal thyroid function on the severity of Graves’ ophthalmopathy. Arch Intern Med. 1990; 150: 109–1101.
 
24. Bartalena L, Marcocci C, Pinchera A. Graves’ ophthalmopathy: a preventable disease? Eur J Endocrinol. 2002; 146: 457–461.
 
25. Dragan LR, Seiff SR, Lee DC. Longitudinal correlation of thyroid-stimulating immunoglobulin with clinical activity of disease in thyroid-associated orbitopathy. Ophthal Plast Reconstr Surg. 2006; 22: 13–19.
 
26. Bahn RS, Heufelder AE. Mechanisms of disease: pathogenesis of Graves’ophthalmopathy. N Engl J Med. 1993; 329: 1468–1475.
 
27. Hiromatsu Y, Yang D, Bednarczuk T, et al. Cytokine profiles in eye muscle tissue and orbital fat tissue from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2000; 85: 1194–1199.
 
28. Antonelli A, Ferrari SM, Fallahi P, et al. Monokine induced by interferon gamma (IFNgamma) (CXCL9) and IFNgamma inducible T-cell alpha-chemoattractant (CXCL11) involvement in Graves’ disease and ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists. J Clin Endocrinol Metab. 2009; 94: 1803–1809.
 
29. Antonelli A, Ferrari SM, Frascerra S, et al. CXCL9 and CXCL11 chemokines modulation by peroxisome proliferator-activated receptor-alpha agonists secretion in Graves’ and normal thyrocytes. J Clin Endocrinol Metab. 2010; 95: E413–E420.
 
30. Leschik JJ, Diana T, Olivo PD, et al. Analytical performance and clinical utility of a bioassay for thyroid-stimulating immunoglobulins. Am J Clin Pathol. 2013; 139: 192–200.
 
31. Gerding MN, van der Meer JW, Broenink M, et al. Association of thyrotropin receptor antibodies with the clinical features of Graves’ ophthalmopathy. Clin Endocrinol (Oxf). 2000; 52: 267–271.
 
32. Schott M, Minich WB, Willenberg HS, et al. Relevance of TSH receptor stimulating and blocking autoantibody measurement for the prediction of relapse in Graves’ disease. Horm Metab Res. 2005; 37: 741–744.
 
33. Antonelli A, Rotondi M, Ferrari SM, et al. Interferon-gamma-inducible alpha-chemokine CXCL10 involvement in Graves’ ophthalmopathy: modulation by peroxisome proliferator-activated receptor gamma agonists. J Clin Endocrinol Metab. 2006; 91: 614–620.
 
34. Kahaly GJ. Imaging in thyroid-associated orbitopathy. Eur J Endocrinol. 2001; 145: 107–118.
 
35. Müller-Forell W, Kahaly GJ. Neuroimaging of Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab. 2012; 26: 259–271.
 
36. Forbes G, Gorman CA, Brennan MD, et al. Ophthalmopathy of Graves’ disease: computerized volume measurements of the orbital fat and muscle. Am J Neuroradiol. 1986; 7: 651–656.
 
37. Werner SC, Coleman DJ, Franzen LA. Ultrasonographic evidence of a consistent orbital involvement in Graves’ disease. N Engl J Med. 1974; 290: 1447–1450.
 
38. Erickson BA, Harris GJ, Lewandowski MF, et al. Echographic monitoring of response of extraocular muscles to irradiation in Graves’ ophthalmopathy. Int J Rad Oncol Biol Phys. 1995; 31: 651–660.
 
39. Batch JA, Lepre F. Early diagnosis of Graves’ optic neuropathy using visual evoked responses. Postgrad Med J. 1990; 66: 664–666.
 
40. Gasser P, Flammer J. Optic neuropathy of Graves’ disease. Ophthalmologica. 1986; 192: 22–27.
 
41. Ladenson PW, Stakes JW, Ridgway EC. Reversible alteration of the visual evoked potential in hypothyroidism. Am J Med. 1984; 77: 1010–1014.
 
42. Salvi M, Spaggiari E, Neri F, et al. The study of visual evoked potentials in patients with thyroid-associated ophthalmopathy identifies asymptomatic optic nerve involvement. J Clin Endocrinol Metab. 1997; 82: 1027–1030.
 
43. Fatourechi V. Thyroid dermopathy and acropachy. Best Pract Res Clin Endocrinol Metab. 2012; 26: 553–565.
 
44. Mourits MP, Koorneef L, Wiersinga WM, et al. Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: a novel approach. Br J Ophthalmol. 1989; 73: 639–644.
 
45. Gerding MN, Prummel MF, Kalmann R, et al. The use of colour slides in the assessment of changes in soft tissue involvement in Graves’ ophthalmopathy. J Endocrinol Invest. 1998; 21: 459–462.
 
46. Mourits MP, Prummel MF, Wiersinga WM, et al. Measuring eye movements in Graves’ ophthalmopathy. Ophthalmology. 1994; 101: 1341–1346.
 
47. 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: 9–14.
 
48. Dolman PJ, Rootman J. VISA classification for Graves orbitopathy. Ophthal Plast Reconstr Surg. 2006; 22: 319–324.
 
49. Bartalena L, Baldeschi L, Dickinson AJ, et al. Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid. 2008; 18: 333–346.
 
50. Griepentrog GJ, Garrity JA. Update on the medical treatment of Graves’ ophthalmopathy. Int J Gen Med. 2009; 2: 263–269.
 
51. Bradley EL 3rd, DiGirolamo M. Remnant function after subtotal thyroidectomy for Graves’ disease. South Med J. 1975; 68: 1245–1258.
 
52. Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract. 2011; 17: 456–520.
 
53. Barczynski M, Konturek A, Hubalewska-Dydejczyk A, et al. Randomized clinical trial of bilateral subtotal thyroidectomy versus total thyroidectomy for Graves’ disease with a 5-year follow-up. Br J Surg. 2012; 99: 515–522.
 
54. Jarhult J, Rudberg C, Larsson E, et al. Graves’ disease with moderate-severe endocrine ophthalmopathy—long term results of a prospective randomized study of total or subtotal thyroid resection. Thyroid. 2005; 15: 1157–1165.
 
55. 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: 69–75.
 
56. Migliori ME, Gladstone GJ. Determination of the normal range of exophthalmometric values for black and white adults. Am J Ophthalmol. 1984; 98: 438–442.
 
57. Wu CH, Chang TC, Liao SL. Results and predictability of fat-removal orbital decompression for disfiguring Graves’ exophthalmos in an Asian patient population. Am J Ophthalmol. 2008; 145: 755–759.
 
58. Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid. 2002; 12: 855–860.
 
59. Thornton J, Kelly SP, Harrison RA, et al. Cigarette smoking and thyroid eye disease: a systematic review. Eye (Lon). 2007; 21: 1135–1145.
 
60. Frueh BR. Why the NOSPECS classification of Graves’ eye disease should be abandoned, with suggestions for the characterization of this disease. Thyroid. 1992; 2: 85–88.
 
61. Gorman CA. The measurement of change in Graves’ ophthalmopathy. Thyroid. 1998; 8: 539–543.
 
62. Prummel MF, Suttorp-Schulten MS, Wiersinga WM, et al. A new ultrasonographic method to detect disease activity and predict response to immunosuppressive treatment in Graves’ ophthalmopathy. Ophthalmology. 1993; 100: 556–561.
 
63. Kahaly G, Forster G, Hansen C. Glycosaminoglycans in thyroid eye disease. Thyroid. 1998; 8: 429–432.
 
64. Utech CI, Khatibnia U, Winter PF, et al. T2 relaxation time for the assessment of retrobulbar inflammation in Graves’ ophthalmopathy. Thyroid. 1995; 5: 185–193.
 
65. Postema PTE, Krenning EP, Wijngaarde R, et al. [111In-DTPA-D-Phe1] octreotide scintigraphy in thyroidal and orbital Graves’ disease: a parameter for disease activity? J Clin Endocrinol Metab. 1994; 79: 1845–1851.
 
66. Uddin JM, Davies PD. Treatment of upper eyelid retraction associated with thyroid eye disease with subconjunctival botulinum toxin injection. Ophthalmology. 2002; 109: 1183–1187.
 
67. Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild Graves’ orbitopathy. N Engl J Med. 2011; 364: 1920–1931.
 
68. Marcocci C, Marino M. Treatment of mild, moderate-to-severe and very severe Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab. 2012; 26: 325–337.
 
69. Drutel A, Archambeaud F, Caron P. Selenium and the thyroid gland: more good news for clinicians. Clin Endocrinol. 2013; 78: 155–164.
 
70. Stiebel-Kalish H, Robenshtok E, Hasanreisoglu M, et al. Treatment modalities for Graves’ ophthalmopathy: systematic review and metaanalysis. J Clin Endocrinol Metab. 2009; 94: 2708–2716.
 
71. Zang S, Ponto KA, Kahaly GJ. Intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab. 2011; 96: 320–332.
 
72. Marcocci C, Bartalena L, Tanda ML, et al. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab. 2001; 86: 3562–3567.
 
73. Kahaly GJ, Pitz S, Hommel G, et al. Randomized, single-blind trial of intravenous v oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab. 2005; 90: 5234–5240.
 
74. 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: 403–406.
 
75. Le Moli R, Baldeschi L, Saeed P, et al. Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in patients with Graves’ ophthalmopathy. Thyroid. 2007; 17: 357–362.
 
76. Lai A, Sassi L, Compri E, et al. Lower dose prednisone prevents radioiodine-associated exacerbation of initially mild or absent Graves’ orbitopathy: a retrospective cohort study. J Clin Endocrinol Metab. 2010; 95: 1333–1337.
 
77. Mourits MP, van Kempen-Harteveld ML, Garcia MB, et al. Radiotherapy for Graves’ orbitopathy: randomized placebo-controlled study. Lancet. 2000; 355: 1505–1509.
 
78. Kahaly GJ, Rosler HP, Pitz S, et al. Low- versus high-dose radiotherapy for Graves’ ophthalmopathy: a randomized, single blind trial. J Clin Endocrinol Metab. 2000; 85: 102–108.
 
79. Marcocci C, Bartalena L, Rocchi R, et al. Long-term safety of orbital radiotherapy for Graves’ ophthalmopathy. J Clin Endocrinol Metab. 2003; 88: 3561–3566.
 
80. Wakelkamp IM, Tan H, Saeed P, et al. Orbital irradiation for Graves’ ophthalmopathy: is it safe? A long-term follow-up study. Ophthalmology. 2004; 111: 1557–1562.
 
81. Robertson DM, Buettner H, Gorman CA, et al. Retinal microvascular abnormalities in patients treated with external radiation for Graves’ ophthalmopathy. Arch Ophthalmol. 2003; 121: 652–657.
 
82. Cockerham KP, Kennerdell JS. Does radiotherapy have a role in the management of thyroid orbitopathy? Br J Ophthalmol. 2002; 86: 102–104.
 
83. Ng CM, Yuen HK, Choi KL, et al. Combined orbital irradiation and systemic steroids compared with systemic steroids alone in the management of moderate-to-severe Graves’ ophthalmopathy: a preliminary study. Hong Kong Med J. 2005; 11: 322–330.
 
84. Bradley EA, Gower EW, Bradley DJ, et al. Orbital radiation for Graves’ ophthalmopathy: a report by the American Academy of Ophthalmology. Ophthalmology. 2008; 115: 398–409.
 
85. Borumandi F, Hammer B, Kamer L, et al. How predictable is exophthalmos reduction in Graves’ orbitopathy? A review of the literature. Br J Ophthalmol. 2011; 95: 1625–1630.
 
86. Wakelkamp IM, Baldeschi L, Saeed P, et al. Surgical or medical decompression as a first-line treatment of optic neuropathy in Graves’ ophthalmopathy? A randomized controlled trial. Clin Endocrinol (Oxf). 2005; 63: 323–328.
 
87. Wemeau JL, Caron P, Beckers A, et al. Octreotide (long-acting release formulation) treatment in patients with Graves’ orbitopathy: clinical results of a four month, randomized, placebo-controlled, double-blind study. J Clin Endocrinol Metab. 2005; 90: 841–848.
 
88. Perros P, Weightman DR, Crombie AL, et al. Azathioprine in the treatment of thyroid-associated ophthalmopathy. Acta Endocrinol (Copenh). 1990; 122: 8–12.
 
89. Kahaly G, Lieb W, Muller-Forell W, et al. Ciamexone in endocrine orbitopathy. A randomized, double-blind, placebo-controlled study. Acta Endocrinol (Copenh). 1990; 122: 13–21.
 
90. Antonelli A, Saracino A, Alberti B, et al. High-dose intravenous immunoglobulin treatment in Graves’ ophthalmopathy. Acta Endocrinol (Copenh). 1992; 126: 13–23.
 
91. Salvi M, Vannucchi G, Campi I, et al. Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol. 2007; 156: 33–40.
 
92. Paridaens D, van den Bosch WA, van der Loos TL, et al. The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye (Lond). 2005; 19: 1286–1289.
 
93. Madaschi S, Rossini A, Formenti I, et al. Treatment of thyroid-associated orbitopathy with rituximab—a novel therapy for an old disease: case report and literature review. Endocr Pract. 2010; 16: 677–685.
 
94. Salvi M, Vannucchi G, Curro N, et al. Small dose of rituximab for Graves’ orbitopathy: new insights into the mechanism of action. Arch Ophthalmol. 2012; 130: 122–124.
 
95. Kahaly G, Schrezenmeir J, Krause U, et al. Ciclosporin and prednisone vs. prednisone in treatment of Graves’ ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest. 1986; 16: 415–422.
 
96. Prummel MF, Mourits MP, Berghout A, et al. Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N Engl J Med. 1989; 321: 1353–1359.
 
97. Dinarello CA, Wolff SM. The role of interleukin-1 in disease. N Engl J Med. 1993; 328: 106–113.

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