Graves’ Ophthalmopathy

  • Claudio Marcocci
  • Terry J. Smith
Reference work entry
Part of the Endocrinology book series (ENDOCR)


Thyroid-associated ophthalmopathy aka Graves’ orbitopathy (GO), represents the periocular component of Graves’ disease (GD), for which safe and effective therapies remain elusive. The central pathogenic event in GD is loss of immune tolerance to the thyrotropin receptor (TSHR) and generation of activating anti-TSHR antibodies. Recent evidence suggests that TSHR might collaborate with other proteins, such as the insulin-like growth factor-I receptor in the pathogenesis of GO. In this chapter we have attempted to review the most most recent insights into disease mechanisms underlying GO, strategies for evaluating patients, and currently available therapeutic strategies and those remedies that are in development.


Ophthalmopathy Autoimmune Inflammation 



Protein kinase B




Clinical activity score


Cluster of differentiation


Cytotoxic T-lymphocyte-associated protein 4, also known as CD152


Dysthyroid optic neuropathy


FK506-binding protein 12-rapamycin-associated protein


Graves’ disease


Graves’ orbitopathy, also known as thyroid-associated ophthalmopathy




Human leukocyte antigen DRβ


Insulin-like growth factor-I receptor




Mechanistic target of rapamycin


Orbital radiotherapy


Prostaglandin E2


Prostaglandin endoperoxide H synthase-2


Protein tyrosine phosphatase, non-receptor type 22


Quality of life


Regulated on activation, normal T cell expressed and secreted


Transforming growth factor beta


Thyroid patient reported outcome


Tumor necrosis factor


Thyrotropin receptor antibodies


Thyrotropin receptor


Stimulating TSHR Ab


Uridine diphosphate


  1. Abraham-Nordling M, Byström K, Törring O, Lantz M, et al. Incidence of hyperthyroidism in Sweden. Eur J Endocrinol. 2011;165:899–905.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Agretti P, Chiovato L, De Marco G, et al. Real-time PCR provides evidence for thyrotropin receptor mRNA expression in orbital as well as in extraorbital tissues. Eur J Endocrinol. 2002;147:733–9.PubMedCrossRefPubMedCentralGoogle Scholar
  3. Alkawas AA, Hussein AM, Shahien EA. Orbital steroid injection versus oral steroid therapy in management of thyroid-related ophthalmopathy. Clin Exp Ophthalmol. 2010;38:692–7.PubMedCrossRefPubMedCentralGoogle Scholar
  4. Baldeschi L. Rehabilitative surgery. In: Wiersinga WM, Kahaly GJ, editors. Graves’ orbitopathy: a multidisciplinary approach – questions and answers. Basel: Karger; 2010. p. 167–70. CrossRefGoogle Scholar
  5. Bartalena L. The dilemma of how to manage Graves’ hyperthyroidism in patients with associated orbitopathy. J Clin Endocrinol Metab. 2011;96:592–9.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bartalena L. Prevention of Graves’ ophthalmopathy. Best Pract Res Clin Endocrinol Metab. 2012;26:371–9.PubMedCrossRefPubMedCentralGoogle Scholar
  7. Bartalena L, Chiovato L. Graves’-like orbitopathy: do not forget IgG4-related disease. J Endocrinol Invest. 2014;37:1233–5.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Bartalena L, Tanda ML. Clinical practice. Graves’ ophthalmopathy. N Engl J Med. 2009;360:994–1001.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Bartalena L, Pinchera A, Marcocci C. Management of Graves’ ophthalmopathy: reality and perspectives. Endocr Rev. 2000;21:168–99.PubMedPubMedCentralGoogle Scholar
  10. Bartalena L, Baldeschi L, Dickinson A, et al. Consensus statement of the European Group on Graves’ Orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol. 2008;158:273–85.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 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 Graves’ orbitopathy. J Clin Endocrinol Metab. 2012;97:4454–63.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bartalena L, Macchia PE, Marcocci C, et al. Effects of treatment modalities for Graves’ hyperthyroidism on Graves’ orbitopathy: a 2015 Italian Society of Endocrinology Consensus Statement. J Endocrinol Invest. 2015;38:481–7.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Bartalena L, Baldeschi L, Boboridis K, et al. The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy guidelines for the management of Graves’ orbitopathy. Eur Thyroid J. 2016;5:9–26.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bartley GB, Fatourechi V, Kadrmas EF, et al. The incidence of Graves’ ophthalmopathy in Olmsted County, Minnesota. Am J Ophthalmol. 1995;120:511–7. doi:10.1016/S0002-9394(14)72666-2.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Ben Simon GJ, Syed HM, Douglas R, et al. Extraocular muscle enlargement with tendon involvement in thyroid-associated orbitopathy. Am J Ophthalmol. 2004;137:1145–7.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Boehm N, Funke S, Wiegand M, et al. Alterations in the tear proteome of dry eye patients – a matter of the clinical phenotype. Invest Ophthalmol Vis Sci. 2013;54:2385–92.PubMedCrossRefPubMedCentralGoogle Scholar
  17. Bonnema SJ, Hegedus L. Radioiodine therapy in benign thyroid diseases: effects, side effects, and factors affecting therapeutic outcome. Endocr Rev. 2012;33:920–80.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Boross P, Leusen JH. Mechanisms of action of CD20 antibodies. Am J Cancer Res. 2012;2:676–90.PubMedPubMedCentralGoogle Scholar
  19. Cao HJ, Wang HS, Zhang Y, et al. Activation of human orbital fibroblasts through CD40 engagement results in a dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression. Insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy. J Biol Chem. 1998;273:29615–25.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Chen H, Mester T, Raychaudhuri N, et al. Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. J Clin Endocrinol Metab. 2014;99:E1635–40.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Coles AJ, Wing M, Smith S, et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet. 1999;354:1691–5.CrossRefPubMedGoogle Scholar
  22. Cramon P, Winther KH, Watt T, et al. Nodular goiter: a prospective cohort study. Thyroid. 2016;26:1010–8.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  24. de Carli M, D’Elios MM, Mariotti S, et al. Cytolytic T cells with Th1-like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves’ ophthalmopathy. J Clin Endocrinol Metab. 1993;77:1120–4.PubMedPubMedCentralGoogle Scholar
  25. Dickinson AJ, Perros P. Controversies in the clinical evaluation of active thyroid-associated orbitopathy: use of a detailed protocol with comparative photographs for objective assessment. Clin Endocrinol. 2001;55:283–303.CrossRefGoogle Scholar
  26. Dolman PJ, Rootman J. VISA Classification for Graves orbitopathy. Ophthal Plast Reconstr Surg. 2006;22:319–24.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Douglas RS, Afifiyan NF, Hwang CJ, et al. Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2010;95:430–8.PubMedCrossRefPubMedCentralGoogle Scholar
  28. Ebner R, Devoto MH, Weil D, et al. Treatment of thyroid associated ophthalmopathy with periocular injections of triamcinolone. Br J Ophthalmol. 2004;88:1380–6.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Eckstein AK, Finenrath A, Heiligenhaus A, et al. Dry eye syndrome in thyroid-associated ophthalmopathy: lacrimal expression of TSH receptor suggests involvement of TSHR-specific autoantibodies. Acta Ophthalmol Scand. 2004;82:291–7.PubMedCrossRefPubMedCentralGoogle Scholar
  30. Effraimidis G, Wiersinga WM. Mechanisms in endocrinology: autoimmune thyroid disease: old and new players. Eur J Endocrinol. 2014;170:R241–52.PubMedPubMedCentralCrossRefGoogle Scholar
  31. El Fassi D, Nielsen CH, Junker P, et al. Systemic adverse events following rituximab therapy in patients with Graves’ disease. J Endocrinol Invest. 2011;34:e163. doi:10.3275/7411.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Elner VM, Hassan AS, Frueh BR. Graded full-thickness anterior blepharotomy for upper eyelid retraction. Arch Ophthalmol. 2004;122:55–60.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Eskridge JB, Wick B, Perrigin D. The Hirschberg test: a double-masked clinical evaluation. Am J Optom Physiol Opt. 1988;65:745–50.PubMedCrossRefPubMedCentralGoogle Scholar
  34. European Group on Graves’ Orbitopathy (EUGOGO), Wiersinga WM, Perros P, et al. Clinical assessment of patients with Graves’ orbitopathy: the European Group on Graves’ Orbitopathy recommendations to generalists, specialists and clinical researchers. Eur J Endocrinol. 2006;155:387–9.CrossRefGoogle Scholar
  35. Feliciello A, Porcellini A, Ciullo I, et al. Expression of thyrotropin-receptor mRNA in healthy and Graves’ disease retro-orbital tissue. Lancet. 1993;342:337–8.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Fernando R, Atkins S, Raychaudhuri N, et al. Human fibrocytes coexpress thyroglobulin and thyrotropin receptor. Proc Natl Acad Sci U S A. 2012;109:7427–32.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Fernando R, Lu Y, Atkins SJ, et al. Expression of thyrotropin receptor, thyroglobulin, sodium-iodide symporter, and thyroperoxidase by fibrocytes depends on AIRE. J Clin Endocrinol Metab. 2014;99:E1236–44.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Furmaniak J, Sanders J, Rees Smith B. Blocking type TSH receptor antibodies. Autoimmun Highlights. 2012;4:11–26.CrossRefGoogle Scholar
  39. Grubeck-Loebenstein B, Tribe K, Sztankay A, et al. Retrobulbar T cells from patients with Graves’ ophthalmopathy are CD8+ and specifically recognize autologous fibroblasts. J Clin Invest. 1994;96:2783–43.Google Scholar
  40. Gupta A, Sadeghi PB, Akpek EK. Occult thyroid eye disease in patients presenting with dry eye symptoms. Am J Ophthalmol. 2009;147:919–23.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Han R, Tsui S, Smith TJ. Up-regulation of prostaglandin E2 synthesis by interleukin-1beta in human orbital fibroblasts involves coordinate induction of prostaglandin-endoperoxide H synthase-2 and glutathione-dependent prostaglandin E2 synthase expression. J Biol Chem. 2002;277:16355–64.PubMedCrossRefPubMedCentralGoogle Scholar
  42. Hegedüs L, Smith TJ, Douglas RS, et al. Targeted biological therapies for Graves’ disease and thyroid-associated ophthalmopathy. Focus on B-cell depletion with Rituximab. Clin Endocrinol. 2011;74:1–8.CrossRefGoogle Scholar
  43. Hegedus L, Bonnema SJ, Smith TJ, et al. Treating the thyroid in the presence of Graves’ Ophthalmopathy. Best Pract Res Clin Endocrinol Metab. 2012;26:313–24. Scholar
  44. Hegedüs L, Bonnema SJ, Winther KH. Selenium in the treatment of thyroid diseases: an element in search of the relevant indications. Eur Thyroid J. 2016;5:149–51.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Heufelder AE, Bahn RS. Detection and localization of cytokine immunoreactivity in retro-ocular connective tissue in Graves’ ophthalmopathy. Eur J Clin Invest. 1993;23:10–7.PubMedCrossRefPubMedCentralGoogle Scholar
  46. Hufnagel TJ, Hickey WF, Cobbs WH, et al. Immunohistochemical and ultrastructural studies on the exenterated orbital tissues of a patient with Graves’ disease. Ophthalmology. 1984;91:1411–9.PubMedCrossRefPubMedCentralGoogle Scholar
  47. Jaume JC, Portolano S, Prummel FF, et al. Molecular cloning and characterization of genes for antibodies generated by orbital tissue-infiltrating B-cells in Graves’ ophthalmopathy. J Clin Endocrinol Metab. 1994;78:348–52.PubMedPubMedCentralGoogle Scholar
  48. Kaback LA, Smith TJ. Expression of hyaluronan synthase messenger ribonucleic acids and their induction by interleukin-1beta in human orbital fibroblasts: potential insight into the molecular pathogenesis of thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 1999;84:4079–84.PubMedPubMedCentralGoogle Scholar
  49. Kahaly G, Schrezenmeir J, Krause U, et al. Ciclosporin and prednisone v. prednisone in treatment of Graves’ ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest. 1986;16:415–22.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kahaly GJ, Roesler HP, Kutzner J, et al. Radiotherapy for thyroid-associated orbitopathy. Exp Clin Endocrinol Diabetes. 1999;107(Suppl 5):S201–7.PubMedPubMedCentralGoogle Scholar
  51. Kahaly GJ. Management of moderately severe Graves’ orbitopathy. In: Wiersinga WM, Kahaly GJ, editors. Graves’ orbitopathy: a multidisciplinary approach – questions and answers. 2nd ed. Basel: Karger; 2010. p. 120–58. CrossRefGoogle Scholar
  52. Kahaly GJ, Shimony O, Gellman YN, et al. Regulatory T-cells in Graves’ orbitopathy: baseline findings and immunomodulation by anti-T lymphocyte globulin. J Clin Endocrinol Metab. 2011;96:422–9.PubMedCrossRefPubMedCentralGoogle Scholar
  53. Kalmann R, Mourits MP. Prevalence and management of elevated intraocular pressure in patients with Graves’ orbitopathy. Br J Ophthalmol. 1998;82:754–7.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kleinau G, Kalveram L, Köhrle J, et al. Minireview: insights into the structural and molecular consequences of the TSH-β mutation C105Vfs114X. Mol Endocrinol. 2016;30:954–64.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kriss JP. Radioisotopic thyroidolymphography in patients with Graves’ disease. J Clin Endocrinol Metab. 1970;31:315–23.PubMedCrossRefPubMedCentralGoogle Scholar
  56. Kumar S, Coenen MJ, Scherer PE, et al. Evidence for enhanced adipogenesis in the orbits of patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab. 2004;89:930–5.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Laurberg P, Berman DC, Bülow Pedersen I, et al. Incidence and clinical presentation of moderate to severe graves’ orbitopathy in a Danish population before and after iodine fortification of salt. J Clin Endocrinol Metab. 2012;97:2325–32.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Lee SJ, Rim TH, Sy J, et al. Treatment of upper eyelid retraction related to thyroid-associated ophthalmopathy using subconjunctival triamcinolone injections. Graefes Arch Clin Exp Ophthalmol. 2013;251:261–70. doi:10.1007/s00417-012-2153-y.CrossRefPubMedPubMedCentralGoogle Scholar
  59. Li B, Smith TJ. Divergent expression of IL-1 receptor antagonists in CD34+ fibrocytes and orbital fibroblasts in thyroid-associated ophthalmopathy: contribution of fibrocytes to orbital inflammation. J Clin Endocrinol Metab. 2013;98:2783–90.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Limbach M, Saare M, Tserel L, et al. Epigenetic profiling in CD4+ and CD8+ T cells from Graves’ disease patients reveals changes in genes associated with T cell receptor signaling. J Autoimmun. 2016;67:46–56.PubMedCrossRefPubMedCentralGoogle Scholar
  61. Lisi S, Marinò M, Pinchera A, et al. Thyroglobulin in orbital tissues from patients with thyroid-associated ophthalmopathy: predominant localization in fibroadipose tissue. Thyroid. 2002;12:351–60.PubMedCrossRefPubMedCentralGoogle Scholar
  62. Marcocci C, Pinchera A. Thyroid treatment. In: Wiersinga WM, Kahaly GJ, editors. Graves’ orbitopathy: a multidisciplinary approach – questions and answers. 2nd ed. Basel: Karger; 2010. p. 100–10. CrossRefGoogle Scholar
  63. Marcocci C, Marinò M. Treatment of mild, moderate-to-severe and very severe Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab. 2012;26:13.CrossRefGoogle Scholar
  64. Marcocci C, Bartalena L, Pinchera A. Ablative or non-ablative therapy for Graves’ hyperthyroidism in patients with ophthalmopathy? J Endocrinol Invest. 1998;21:468–71.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Marcocci C, Bruno-Bossio G, Manetti L, et al. The course of Graves’ ophthalmopathy is not influenced by near total thyroidectomy: a case-control study. Clin Endocrinol. 1999;51:503–8.CrossRefGoogle Scholar
  66. Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild Graves’ orbitopathy. N Engl J Med. 2001;364:1920–31.CrossRefGoogle Scholar
  67. Marcocci C, Bartalena L, Rocchi R, et al. Long-term safety of orbital radiotherapy for Graves’ ophthalmopathy. J Clin Endocrinol Metab. 2003;88:3561–6.PubMedCrossRefGoogle Scholar
  68. Marcocci C, Watt T, Altea MA, et al. 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;166:247–53.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Matheis N, Lantz M, Grus FH, et al. Proteomics of orbital tissue in thyroid-associated orbitopathy. J Clin Endocrinol Metab. 2015;100:E1523–30.PubMedCrossRefPubMedCentralGoogle Scholar
  70. McKeag D, Lane C, Lazarus JH, et al. Clinical features of dysthyroid optic neuropathy: a European Group on Graves’ Orbitopathy (EUGOGO) survey. Br J Ophthalmol. 2007;91:455–8.PubMedCrossRefPubMedCentralGoogle Scholar
  71. Mehred B, Burdick MD, Zisman DA, et al. Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. Biochem Biophys Res Commun. 2007;353:104–8.CrossRefGoogle Scholar
  72. Menconi F, Marcocci C, Marinò F. Diagnosis and classification of Graves’ disease. Autoimmun Rev. 2014a;13:398–402.PubMedCrossRefPubMedCentralGoogle Scholar
  73. Menconi F, Profilo MA, Leo M, et al. Spontaneous improvement of untreated mild Graves’ ophthalmopathy: Rundle’s curve revisited. Thyroid. 2014b;24:60–6.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Mourits MP, Koornneef L, Wiersinga WM, et al. Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: a novel approach. Br J Ophthalmol. 1989;73:639–44.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Mourits MP, Prummel MF, Wiersinga WM, et al. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol. 1997;47:9–14.CrossRefGoogle Scholar
  76. Negro R, Attanasio R, Grimaldi F, on behalf of AME (Associazione Medici Endocrinologi) and AACE (American Association of Clinical Endocrinologists) Italian Chapter, et al. A 2016 Italian survey about the clinical use of selenium in thyroid disease. Eur Thyroid J. 2016;5:164–70.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Neumann S, Neumann S, Kleinau G, et al. A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism. Endocrinology. 2008;149:5945–50.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Nielsen CH, El Fassi D, Hasselbalch HC, et al. B-cell depletion with rituximab in the treatment of autoimmune diseases. Graves’ ophthalmopathy the latest addition to an expanding family. Expert Opin Biol Ther. 2007;7:1061–78.PubMedCrossRefPubMedCentralGoogle Scholar
  79. Noth D, Gebauer M, Müller B, et al. Graves’ ophthalmopathy: natural history and treatment outcomes. Swiss Med Wkly. 2001;131:603–9.Google Scholar
  80. Parmentier M, Libert F, Maenhaut C, et al. Molecular cloning of the thyrotropin receptor. Science. 1989;246:1620–2.PubMedCrossRefPubMedCentralGoogle Scholar
  81. Pérez-Moreiras JV, Alvarez-López A, Gómez EC. Treatment of active corticosteroid-resistant graves’ orbitopathy. Ophthal Plast Reconstr Surg. 2014;30:162–7.PubMedCrossRefPubMedCentralGoogle Scholar
  82. Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin Endocrinol. 1995;42:45–50.CrossRefGoogle Scholar
  83. Perros P, Žarković M, Azzolini C, et al. PREGO (presentation of Graves’ orbitopathy) study: changes in referral patterns to European Group On Graves’ Orbitopathy (EUGOGO) centres over the period from 2000 to 2012. Br J Ophthalmol. 2015;99:1531–5.PubMedCrossRefPubMedCentralGoogle Scholar
  84. Pfeilschifter J, Ziegler R. Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs lifetime cigarette consumption. Clin Endocrinol. 1996;45:477–81.CrossRefGoogle Scholar
  85. Pinchera A, Viersinga W, Glinoer D, et al. Classification of eye changes of Graves’ disease. Thyroid. 1992;2:235–6.CrossRefGoogle Scholar
  86. Pritchard J, Horst N, Cruikshank W, et al. Igs from patients with Graves’ disease induce the expression of T cell chemoattractants in their fibroblasts. J Immunol. 2002;168:942–50.PubMedCrossRefPubMedCentralGoogle Scholar
  87. Pritchard J, Han R, Horst N, et al. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves’ disease is mediated though the insulin-like growth factor I receptor pathway. J Immunol. 2003;170:6348–54.PubMedCrossRefPubMedCentralGoogle Scholar
  88. Prummel MF, Mourits MP, Berghout A, et al. Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N Engl J Med. 1989;321:1353–9.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Rapoport B, McLachlan SM. TSH receptor cleavage into subunits and shedding of the a-subunit; a molecular and clinical perspective. Endocr Rev. 2016;37:114–34.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Raychaudhuri N, Fernando R, Smith TJ. Thyroptropin regulates IL-6 expression in CD34+ fibrocytes: clear delineation of its cAMP-independent actions. PLoS One. 2013;8:e75100.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 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.PubMedPubMedCentralGoogle Scholar
  92. Salvi M, Campi I. Medical treatment of Graves’ orbitopathy. Horm Metab Res. 2015;47:779–88.PubMedCrossRefPubMedCentralGoogle Scholar
  93. Salvi M, Vannucchi G, Currò N, et al. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves’ orbitopathy: a randomized controlled study. J Clin Endocrinol Metab. 2015;100:422–31.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Sciaky D, Brazer W, Center DM, et al. Cultured human fibroblasts express constitutive IL-16 mRNA: cytokine induction of active IL-16 protein synthesis through a caspase-3 dependent mechanism. J Immunol. 2000;164:3806–14.PubMedCrossRefPubMedCentralGoogle Scholar
  95. Shimura H, Miyazaki A, Haraguchi K, et al. Analysis of differentiation-induced expression mechanisms of thyrotropin receptor gene in adipocytes. Mol Endocrinol. 1998;12:1473–86.PubMedCrossRefPubMedCentralGoogle Scholar
  96. Shin JI, Kim MJ, Lee JS. Graves’ disease, rheumatoid arthritis, and anti-tumor necrosis factor-alpha therapy. J Rheumatol. 2009;36:449–50.PubMedCrossRefPubMedCentralGoogle Scholar
  97. Shorr N, Baylis HI, Goldberg RA, et al. Transcaruncular approach to the medial orbit and orbital apex. Ophthalmology. 2000;107:1459–63.PubMedCrossRefPubMedCentralGoogle Scholar
  98. Sisti E, Coco B, Menconi F, et al. Intravenous glucocorticoid therapy for Graves’ ophthalmopathy and acute liver damage: an epidemiological study. Eur J Endocrinol. 2015;172:269–76.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med. 2016;375:1552–65.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Smith TJ, Bahn RS, Gorman CA. Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocr Rev. 1989;10:366–91.PubMedCrossRefPubMedCentralGoogle Scholar
  101. Smith TJ, Wang HS, Hogg MG, et al. Prostaglandin E2 elicits a morphological change in cultured orbital fibroblasts from patients with Graves ophthalmopathy. Proc Natl Acad Sci U S A. 1994;91:5094–8.PubMedPubMedCentralCrossRefGoogle Scholar
  102. Smith TJ, Sempowski GD, Wang HS, et al. Evidence for cellular heterogeneity in primary cultures of human orbital fibroblasts. J Clin Endocrinol Metab. 1995;80:2620–5.PubMedPubMedCentralGoogle Scholar
  103. Smith TJ, Koumas L, Gagnon A, et al. Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2002;87:385–92.PubMedCrossRefPubMedCentralGoogle Scholar
  104. Spicer AP, Kaback LA, Smith TJ, et al. Molecular cloning and characterization of the human and mouse UDP-glucose dehydrogenase genes. J Biol Chem. 1998;273:25117–24.PubMedCrossRefPubMedCentralGoogle Scholar
  105. Stan MN, Garrity JA, Carranza Leon BG, et al. Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J Clin Endocrinol Metab. 2015;100:432–41.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539–51.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 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;98:1443–9.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Teng CS, Yeo PP. Ophthalmic Graves’s disease: natural history and detailed thyroid function studies. Br Med J. 1977;1:273–5.PubMedPubMedCentralCrossRefGoogle Scholar
  109. Terwee CB, Gerding MN, Dekker FW, et al. Development of a disease specific quality of life questionnaire for patients with Graves’ ophthalmopathy: the GO-QOL. Br J Ophthalmol. 1998;82:773–9.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Terwee CB, Prummel MF, Gerding MN, et al. Measuring disease activity to predict therapeutic outcome in Graves’ ophthalmopathy. Clin Endocrinol. 2005;62:145–55.CrossRefGoogle Scholar
  111. Tomer Y. Mechanisms of autoimmune thyroid disease: from genetics to epigenetics. Annu Rev Pathol Mech Dis. 2014;9:147–56.CrossRefGoogle Scholar
  112. Traisk F, Tallstedt L, Abraham-Nordling M, et al. Thyroid-associated ophthalmopathy after treatment for Graves’ hyperthyroidism with antithyroid drugs or iodine-131. J Clin Endocrinol Metab. 2009;94:3700–7.PubMedCrossRefPubMedCentralGoogle Scholar
  113. Tsui S, Naik V, Hoa N, et al. Evidence for an association between thyroid-stimulating hormone and insulin-like grown factor 1 receptors: a tale of two antigens implicated in Graves’ disease. J Immunol. 2008;181:4397–405.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Valyasevi RW, Erickson DZ, Harteneck DA, et al. Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor. J Clin Endocrinol Metab. 1999;84:2557–62.PubMedPubMedCentralGoogle Scholar
  115. van Steensel L, Hooijkaas H, Paridaens D, et al. PDGF enhances orbital fibroblast responses in TSHR stimulating autoantibodies in Graves’ ophthalmopathy patients. J Clin Endocrinol Metab. 2012;97:E944–53.PubMedCrossRefPubMedCentralGoogle Scholar
  116. Vassart G, Kleinau G. TSH receptor mutations and disease. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth:; 2014.
  117. Wakelkamp IM, Tan H, Saeed P, et al. Orbital irradiation for Graves’ ophthalmopathy: is it safe? A long-term follow-up study. Ophthalmology. 2004;111:1557–62.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 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. 2005;63:323–8.CrossRefGoogle Scholar
  119. Walsh TE, Ogura JH. Transantral orbital decompression for malignant exophthalmos. Laryngoscope. 1957;67:544–68.PubMedCrossRefPubMedCentralGoogle Scholar
  120. Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci. 2014;55:1735–48.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Watt T, Hegedüs L, Groenvold M, et al. Validity and reliability of the novel thyroid-specific quality of life questionnaire, ThyPRO. Eur J Endocrinol. 2010;162:161–7.PubMedCrossRefPubMedCentralGoogle Scholar
  122. Watt T, Cramon P, Bjorner JB, et al. Selenium supplementation for patients with Graves’ hyperthyroidism (the GRASS trial): study protocol for a randomized controlled trial. Trials. 2013;14:119.PubMedPubMedCentralCrossRefGoogle Scholar
  123. Weightman DR, Perros P, Sherif IH, et al. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity. 1993;16:251–7.PubMedCrossRefPubMedCentralGoogle Scholar
  124. Werner SC. Modification of the classification of the eye changes of Graves’ disease: recommendations of the Ad Hoc Committee of the American Thyroid Association. J Clin Endocrinol Metab. 1977;44:203–4.PubMedCrossRefPubMedCentralGoogle Scholar
  125. Wiersinga WM. Preventing Graves’ ophthalmopathy. N Engl J Med. 1998;338:121–2.PubMedCrossRefPubMedCentralGoogle Scholar
  126. Wiersinga WM. Combined thyroid-eye clinic. In: Wiersinga WM, Kahaly GJ, editors. Graves’ orbitopathy: a multidisciplinary approach – questions and answers. Basel: Karger; 2010a. p. 96–9. CrossRefGoogle Scholar
  127. Wiersinga WM. Quality of life. In: Wiersinga WM, Kahaly GJ, editors. Graves’ orbitopathy: a multidisciplinary approach – questions and answers. 2nd ed. Basel: Karger; 2010b. p. 211–20. CrossRefGoogle Scholar
  128. Ye X, Bo X, Hu X, et al. Efficacy and safety of mycophenolate mofetil in patients with active moderate to severe Graves’ orbitopathy. Clin Endocrinol. 2017;86:247–55.PubMedCrossRefPubMedCentralGoogle Scholar
  129. Young DA, Evans CH, Smith TJ. Leukoregulin induction of protein expression in human orbital fibroblasts: evidence for anatomical site-restricted cytokine-target cell interactions. Proc Natl Acad Sci U S A. 1998;95:8904–9.PubMedPubMedCentralCrossRefGoogle Scholar
  130. Zang S, Ponto KA, Kahaly GJ. Clinical review: intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab. 2011;96:320–32.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  2. 2.Department of Ophthalmology and Visual Sciences Kellogg Eye Center and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborUSA

Personalised recommendations