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  • Review Article
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New insights into the pathogenesis and nonsurgical management of Graves orbitopathy

Nature Reviews Endocrinology volume 16, pages 104–116 (2020)Cite this article

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Abstract

Graves orbitopathy, also known as thyroid eye disease or thyroid-associated orbitopathy, is visually disabling, cosmetically disfiguring and has a substantial negative impact on a patient’s quality of life. There is increasing awareness of the need for early diagnosis and rapid specialist input from endocrinologists and ophthalmologists. Glucocorticoids are the mainstay of treatment; however, recurrence occurs frequently once these are withdrawn. Furthermore, in >60% of cases, normal orbital anatomy is not restored, and skilled rehabilitative surgery is required. Clinical trials have shown that considerable benefit can be derived from the addition of antiproliferative agents (such as mycophenolate or azathioprine) in preventing deterioration after steroid cessation. In addition, targeted biologic therapies have shown promise, including teprotumumab, which reduces proptosis, rituximab (anti-CD20), which reduces inflammation, and tocilizumab, which potentially benefits both of these parameters. Other strategies such as orbital radiotherapy have had their widespread role in combination therapy called into question. The pathophysiology of Graves orbitopathy has also been revised with identification of new potential therapeutic targets. In this Review we provide an up-to-date overview of the field, outline the optimal management of Graves orbitopathy and summarize the research developments in this area to highlight future research questions and direct future clinical trials.

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Fig. 1: Proposed management of Graves orbitopathy.
Fig. 2: Overview of potential therapeutic targets in Graves orbitopathy.

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References

  1. Smith, T. J. & Hegedus, L. Graves’ disease. N. Engl. J. Med. 375, 1552–1565 (2016).

    PubMed  Google Scholar 

  2. Bahn, R. S. Graves’ ophthalmopathy. N. Engl. J. Med. 362, 726–738 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Ponto, K. A. et al. Quality of life in a German Graves orbitopathy population. Am. J. Ophthalmol. 152, 483–490 (2011).

    PubMed  Google Scholar 

  4. Kahaly, G. J., Petrak, F., Hardt, J., Pitz, S. & Egle, U. T. Psychosocial morbidity of Graves’ orbitopathy. Clin. Endocrinol. (Oxf.) 63, 395–402 (2005).

    CAS  Google Scholar 

  5. Wiersinga, W. M. & Kahaly, G. J. Graves’ orbitopathy: a multidisciplinary approach. 3rd edn, (Karger, 2017).

  6. Ponto, K. A. et al. Public health relevance of Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 98, 145–152 (2013).

    CAS  PubMed  Google Scholar 

  7. De Leo, S., Lee, S. Y. & Braverman, L. E. Hyperthyroidism. Lancet 388, 906–918 (2016).

    PubMed  PubMed Central  Google Scholar 

  8. Taylor, P. N. et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat. Rev. Endocrinol. 14, 301–316 (2018).

    PubMed  Google Scholar 

  9. Perros, P. et al. Graves’ orbitopathy as a rare disease in Europe: a European Group on Graves’ Orbitopathy (EUGOGO) position statement. Orphanet J. Rare Dis. 12, 72 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wiersinga, W. et al. Predictive score for the development or progression of Graves’ orbitopathy in patients with newly diagnosed Graves’ hyperthyroidism. Eur. J. Endocrinol. 178, 635–643 (2018).

    CAS  PubMed  Google Scholar 

  11. Perros, P. & Wiersinga, W. M. The Amsterdam declaration on Graves’ orbitopathy. Thyroid 20, 245–246 (2010).

    PubMed  Google Scholar 

  12. Hansen, C., Rouhi, R., Forster, G. & Kahaly, G. J. Increased sulfatation of orbital glycosaminoglycans in Graves’ ophthalmopathy. J. Clin. Endocrinol. Metab. 84, 1409–1413 (1999).

    CAS  PubMed  Google Scholar 

  13. Zang, S. & Kahaly, G. Steroids and the immune response in Graves orbitopathy. Immunol. Endocr. Metab. Agents Med. Chem. 11, 90–98 (2011).

    CAS  Google Scholar 

  14. Lee, R. A., Harris, C. A. & Wang, J. C. Glucocorticoid receptor and adipocyte biology. Nucl. Receptor Res. 5, 101373 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Tomlinson, J. W. et al. The role of 11beta-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy. J. Clin. Endocrinol. Metab. 95, 398–406 (2010).

    CAS  PubMed  Google Scholar 

  16. Bujalska, I. J. et al. Characterisation of 11beta-hydroxysteroid dehydrogenase 1 in human orbital adipose tissue: a comparison with subcutaneous and omental fat. J. Endocrinol. 192, 279–288 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bartalena, L. et al. Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur. J. Endocrinol. 158, 273–285 (2008).

    CAS  PubMed  Google Scholar 

  18. Dolman, P. J. & Rootman, J. VISA classification for Graves orbitopathy. Ophthalmic Plast. Reconstr. Surg. 22, 319–324 (2006).

    PubMed  Google Scholar 

  19. Mourits, M. P., Prummel, M. F., Wiersinga, W. M. & Koornneef, L. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin. Endocrinol. (Oxf.) 47, 9–14 (1997).

    CAS  Google Scholar 

  20. Werner, S. C. Classification of the eye changes of Graves’ disease. Am. J. Ophthalmol. 68, 646–648 (1969).

    CAS  PubMed  Google Scholar 

  21. Werner, S. C. 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. 44, 203–204 (1977).

    CAS  PubMed  Google Scholar 

  22. Perros, P., Crombie, A. L., Matthews, J. N. & Kendall-Taylor, P. Age and gender influence the severity of thyroid-associated ophthalmopathy: a study of 101 patients attending a combined thyroid-eye clinic. Clin. Endocrinol. (Oxf.) 38, 367–372 (1993).

    CAS  Google Scholar 

  23. Bartalena, L. et al. The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy guidelines for the management of Graves’ orbitopathy. Eur. Thyroid. J. 5, 9–26 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Barrio-Barrio, J., Sabater, A. L., Bonet-Farriol, E., Velazquez-Villoria, A. & Galofre, J. C. Graves’ ophthalmopathy: VISA versus EUGOGO classification, assessment, and management. J. Ophthalmol. 2015, 249125 (2015).

    PubMed  PubMed Central  Google Scholar 

  25. Bartalena, L. et al. Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 18, 333–346 (2008).

    PubMed  Google Scholar 

  26. Terwee, C. B. et al. Interpretation and validity of changes in scores on the Graves’ ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. Clin. Endocrinol. (Oxf.) 54, 391–398 (2001).

    CAS  Google Scholar 

  27. Terwee, C. B., Gerding, M. N., Dekker, F. W., Prummel, M. F. & Wiersinga, W. M. Development of a disease specific quality of life questionnaire for patients with Graves’ ophthalmopathy: the GO-QOL. Br. J. Ophthalmol. 82, 773–779 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Dietrich, A. et al. Establishing the usefulness of the GO-QOL in a UK hospital-treated population with thyroid eye disease in the CIRTED trial. Psychol. Health Med 23, 1341–1355 (2018).

    PubMed  Google Scholar 

  29. Rajendram, R. et al. Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 × 2 factorial, double-blind, randomised controlled trial. Lancet Diabetes Endocrinol 6, 299–309 (2018).

    PubMed  Google Scholar 

  30. Kahaly, G. J. et al. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. Lancet. Diabetes Endocrinol. 6, 287–298 (2018).

    CAS  PubMed  Google Scholar 

  31. Perros, P. 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. 99, 1531–1535 (2015).

    PubMed  Google Scholar 

  32. British Thyroid Foundation. TEAMeD-5, http://www.btf-thyroid.org/TEAMeD-5 (2018).

  33. Marcocci, C., Bartalena, L., Bogazzi, F., Panicucci, M. & Pinchera, A. Studies on the occurrence of ophthalmopathy in Graves’ disease. Acta Endocrinol. 120, 473–478 (1989).

    CAS  PubMed  Google Scholar 

  34. Bartalena, L. The dilemma of how to manage Graves’ hyperthyroidism in patients with associated orbitopathy. J. Clin. Endocrinol. Metab. 96, 592–599 (2011).

    CAS  PubMed  Google Scholar 

  35. Bartalena, L. et al. More on smoking habits and Graves’ ophthalmopathy. J. Endocrinol. Invest. 12, 733–737 (1989).

    CAS  PubMed  Google Scholar 

  36. Wiersinga, W. M. Smoking and thyroid. Clin. Endocrinol. (Oxf.) 79, 145–151 (2013).

    CAS  Google Scholar 

  37. Prummel, M. F. & Wiersinga, W. M. Smoking and risk of Graves’ disease. Jama 269, 479–482 (1993).

    CAS  PubMed  Google Scholar 

  38. Bartalena, L. et al. Cigarette smoking and treatment outcomes in Graves ophthalmopathy. Ann. Intern. Med. 129, 632–635 (1998).

    CAS  PubMed  Google Scholar 

  39. Eckstein, A. et al. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br. J. Ophthalmol. 87, 773–776 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Pfeilschifter, J. & Ziegler, R. Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs lifetime cigarette consumption. Clin. Endocrinol. (Oxf.) 45, 477–481 (1996).

    CAS  Google Scholar 

  41. Cawood, T. J., Moriarty, P., O’Farrelly, C. & O’Shea, D. Smoking and thyroid-associated ophthalmopathy: a novel explanation of the biological link. J. Clin. Endocrinol. Metab. 92, 59–64 (2007).

    CAS  PubMed  Google Scholar 

  42. Regensburg, N. I., Wiersinga, W. M., Berendschot, T. T., Saeed, P. & Mourits, M. P. Effect of smoking on orbital fat and muscle volume in Graves’ orbitopathy. Thyroid 21, 177–181 (2011).

    CAS  PubMed  Google Scholar 

  43. Marcocci, C. et al. Selenium and the course of mild Graves’ orbitopathy. N. Engl. J. Med. 364, 1920–1931 (2011).

    CAS  PubMed  Google Scholar 

  44. Marcocci, C. et al. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J. Clin. Endocrinol. Metab. 86, 3562–3567 (2001).

    CAS  PubMed  Google Scholar 

  45. Kahaly, G. J., Pitz, S., Hommel, G. & Dittmar, M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 90, 5234–5240 (2005).

    CAS  PubMed  Google Scholar 

  46. Bartalena, L., Pinchera, A. & Marcocci, C. Management of Graves’ ophthalmopathy: reality and perspectives. Endocr. Rev. 21, 168–199 (2000).

    CAS  PubMed  Google Scholar 

  47. Bartalena, L. 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. 97, 4454–4463 (2012).

    CAS  PubMed  Google Scholar 

  48. Ye, X. et al. Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves’ orbitopathy. Clin. Endocrinol. (Oxf.) 86, 247–255 (2017).

    CAS  Google Scholar 

  49. Prummel, M. F. et al. Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N. Engl. J. Med. 321, 1353–1359 (1989).

    CAS  PubMed  Google Scholar 

  50. Kahaly, G. J. et al. 2018 European Thyroid Association guideline for the management of Graves’ hyperthyroidism. Eur. Thyroid. J. 7, 167–186 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wiersinga, W. M. Advances in treatment of active, moderate-to-severe Graves’ ophthalmopathy. lancet. Diabetes & Endocrinol. 5, 134–142 (2017).

    CAS  Google Scholar 

  52. Salvi, M. & Campi, I. Medical treatment of Graves’ orbitopathy. Horm. Metab. Res. 47, 779–788 (2015).

    CAS  PubMed  Google Scholar 

  53. Zang, S., Ponto, K. A. & Kahaly, G. J. Clinical review: intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J. Clin. Endocrinol. Metab. 96, 320–332 (2011).

    CAS  PubMed  Google Scholar 

  54. Matheis, N. et al. Proteomics of orbital tissue in thyroid-associated orbitopathy. J. Clin. Endocrinol. Metab. 100, E1523–E1530 (2015).

    CAS  PubMed  Google Scholar 

  55. Kahaly, G. J., Rosler, H. P., Pitz, S. & Hommel, G. Low- versus high-dose radiotherapy for Graves’ ophthalmopathy: a randomized, single blind trial. J. Clin. Endocrinol. Metab. 85, 102–108 (2000).

    CAS  PubMed  Google Scholar 

  56. Prummel, M. F. et al. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves’ ophthalmopathy. J. Clin. Endocrinol. Metab. 89, 15–20 (2004).

    CAS  PubMed  Google Scholar 

  57. Prummel, M. F. et al. Randomized double-blind trial of prednisone versus radiotherapy in Graves’ ophthalmopathy. Lancet 342, 949–954 (1993).

    CAS  PubMed  Google Scholar 

  58. Christiansen, E. & Kofoed-Enevoldsen, A. Graves’ ophthalmopathy. J. Clin. Endocrinol. Metab. 86, 2327–2328 (2001).

    CAS  PubMed  Google Scholar 

  59. Gorman, C. A. et al. A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves’ ophthalmopathy. Ophthalmology 108, 1523–1534 (2001).

    CAS  PubMed  Google Scholar 

  60. Mourits, M. P. et al. Radiotherapy for Graves’ orbitopathy: randomised placebo-controlled study. Lancet 355, 1505–1509 (2000).

    CAS  PubMed  Google Scholar 

  61. Godfrey, K. J. & Kazim, M. Radiotherapy for active thyroid eye disease. Ophthalmic Plast. Reconstr. Surg. 34, S98–S104 (2018).

    PubMed  Google Scholar 

  62. Verity, D. H. & Rose, G. E. Acute thyroid eye disease (TED): principles of medical and surgical management. Eye (Lond.) 27, 308–319 (2013).

    CAS  Google Scholar 

  63. Eugui, E. M. & Allison, A. C. Immunosuppressive activity of mycophenolate mofetil. Ann. NY Acad. Sci. 685, 309–329 (1993).

    CAS  PubMed  Google Scholar 

  64. Allison, A. C. Mechanisms of action of mycophenolate mofetil in preventing chronic rejection. Transplant. Proc. 34, 2863–2866 (2002).

    CAS  PubMed  Google Scholar 

  65. Riedl, M., Kuhn, A., Kramer, I., Kolbe, E. & Kahaly, G. J. Prospective, systematically recorded mycophenolate safety data in Graves’ orbitopathy. J. Endocrinol. Invest. 39, 687–694 (2016).

    CAS  PubMed  Google Scholar 

  66. Eugui, E. M. & Allison, A. C. Immunosuppressive activity of mycophenolate mofetil. Ann. NY Acad. Sci. 685, 309–329 (1993).

    CAS  PubMed  Google Scholar 

  67. Mazumder, A. G., Patial, V. & Singh, D. Mycophenolate mofetil contributes to downregulation of the hippocampal interleukin type 2 and 1beta mediated PI3K/AKT/mTOR pathway hyperactivation and attenuates neurobehavioral comorbidities in a rat model of temporal lobe epilepsy. Brain, Behav. Immun. 75, 84–93 (2019).

    CAS  Google Scholar 

  68. Perros, P., Weightman, D. R., Crombie, A. L. & Kendall-Taylor, P. Azathioprine in the treatment of thyroid-associated ophthalmopathy. Acta Endocrinol. 122, 8–12 (1990).

    CAS  PubMed  Google Scholar 

  69. Smith, T. J. & Janssen, J. A. Building the case for insulin-like growth factor receptor-1 involvement in thyroid-associated ophthalmopathy. Front. Endocrinol. 7, 167 (2016).

    Google Scholar 

  70. Smith, T. J. & Janssen, J. Insulin-like growth factor-1 receptor and thyroid-associated ophthalmopathy. Endocr. Rev. 40, 236–267 (2016).

    Google Scholar 

  71. Pritchard, J., Han, R., Horst, N., Cruikshank, W. W. & Smith, T. J. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves’ disease is mediated through the insulin-like growth factor 1 receptor pathway. J. Immunol. 170, 6348–6354 (2003).

    CAS  PubMed  Google Scholar 

  72. Smith, T. J., Hegedus, L. & Douglas, R. S. Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves’ orbitopathy. Best. Pract. Clin. Endocrinol. Metab. 26, 291–302 (2012).

    CAS  Google Scholar 

  73. Smith, T. J. et al. Teprotumumab for thyroid-associated ophthalmopathy. N. Engl. J. Med. 376, 1748–1761 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Piro, L. D. et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann. Oncol. 10, 655–661 (1999).

    CAS  PubMed  Google Scholar 

  75. Stan, M. N. et al. Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 100, 432–441 (2015).

    CAS  PubMed  Google Scholar 

  76. Salvi, M. 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. 100, 422–431 (2015).

    CAS  PubMed  Google Scholar 

  77. Stan, M. N. & Salvi, M. Management of endocrine disease: rituximab therapy for Graves’ orbitopathy — lessons from randomized control trials. Eur. J. Endocrinol. 176, R101–R109 (2017).

    CAS  PubMed  Google Scholar 

  78. Salvi, M. & Covelli, D. B cells in Graves’ orbitopathy: more than just a source of antibodies? Eye (Lond.) 33, 230–234 (2019).

    CAS  Google Scholar 

  79. Perez-Moreiras, J. V., Alvarez-Lopez, A. & Gomez, E. C. Treatment of active corticosteroid-resistant graves’ orbitopathy. Ophthalmic Plast. Reconstr. Surg. 30, 162–167 (2014).

    PubMed  Google Scholar 

  80. Russell, D. J., Wagner, L. H. & Seiff, S. R. Tocilizumab as a steroid sparing agent for the treatment of Graves’ orbitopathy. Am. J. Ophthalmol. Case Rep. 7, 146–148 (2017).

    PubMed  PubMed Central  Google Scholar 

  81. Perez-Moreiras, J. V. et al. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant graves orbitopathy: a randomized clinical trial. Am. J. Ophthalmol. 195, 181–190 (2018).

    CAS  PubMed  Google Scholar 

  82. Stohl, W. Inhibition of B cell activating factor (BAFF) in the management of systemic lupus erythematosus (SLE). Expert. Rev. Clin. Immunol. 13, 623–633 (2017).

    CAS  PubMed  Google Scholar 

  83. Draman, M. S. et al. Effects of prostaglandin F2alpha on adipocyte biology relevant to graves’ orbitopathy. Thyroid 23, 1600–1608 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Draman, M. S. et al. Prostaglandin F2-alpha eye drops (bimatoprost) in Graves’ orbitopathy: a randomized controlled double-masked crossover trial (BIMA trial). Thyroid 29, 563–572 (2019).

    CAS  PubMed  Google Scholar 

  85. Kozdon, K., Fitchett, C., Rose, G. E., Ezra, D. G. & Bailly, M. Mesenchymal stem cell-like properties of orbital fibroblasts in Graves’ orbitopathy. Invest. Ophthalmol. Vis. Sci. 56, 5743–5750 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Brandau, S. et al. Orbital fibroblasts from Graves’ orbitopathy patients share functional and immunophenotypic properties with mesenchymal stem/stromal cells. Investig. Ophthalmol. Vis. Sci. 56, 6549–6557 (2015).

    CAS  Google Scholar 

  87. Starkey, K. J. et al. Adipose thyrotrophin receptor expression is elevated in Graves’ and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo. J. Mol. Endocrinol. 30, 369–380 (2003).

    CAS  PubMed  Google Scholar 

  88. Potgieser, P. W., Wiersinga, W. M., Regensburg, N. I. & Mourits, M. P. Some studies on the natural history of Graves’ orbitopathy: increase in orbital fat is a rather late phenomenon. Eur. J. Endocrinol. 173, 149–153 (2015).

    CAS  PubMed  Google Scholar 

  89. Smith, T. J. Insights into the role of fibroblasts in human autoimmune diseases. Clin. Exp. Immunol. 141, 388–397 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Lehmann, G. M., Garcia-Bates, T. M., Smith, T. J., Feldon, S. E. & Phipps, R. P. Regulation of lymphocyte function by PPARgamma: relevance to thyroid eye disease-related inflammation. PPAR Res. 2008, 895901 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Kahaly, G. J. et al. Regulatory T-cells in Graves’ orbitopathy: baseline findings and immunomodulation by anti-T lymphocyte globulin. J. Clin. Endocrinol. Metab. 96, 422–429 (2011).

    CAS  PubMed  Google Scholar 

  92. Douglas, R. S. et al. Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J. Clin. Endocrinol. Metab. 95, 430–438 (2010).

    CAS  PubMed  Google Scholar 

  93. Lu, Y. et al. CD34– orbital fibroblasts from patients with thyroid-associated ophthalmopathy modulate TNF-alpha expression in CD34+ fibroblasts and fibrocytes. Investig. Ophthalmol. Vis. Sci. 59, 2615–2622 (2018).

    CAS  Google Scholar 

  94. Fernando, R. et al. Human fibrocytes coexpress thyroglobulin and thyrotropin receptor. Proc. Natl Acad. Sci. USA 109, 7427–7432 (2012).

    CAS  PubMed  Google Scholar 

  95. Rotondo Dottore, G. et al. Association of T and B cells infiltrating orbital tissues with clinical features of graves orbitopathy. JAMA Ophthalmol. 136, 613–619 (2018).

    PubMed  PubMed Central  Google Scholar 

  96. Pawlowski, P. et al. Markers of inflammation and fibrosis in the orbital fat/connective tissue of patients with Graves’ orbitopathy: clinical implications. Mediators. Inflamm. 2014, 412158 (2014).

    PubMed  PubMed Central  Google Scholar 

  97. van Steensel, L. et al. Orbit-infiltrating mast cells, monocytes, and macrophages produce PDGF isoforms that orchestrate orbital fibroblast activation in Graves’ ophthalmopathy. J. Clin. Endocrinol. Metab. 97, E400–E408 (2012).

    PubMed  Google Scholar 

  98. Draman, M. S. & Ludgate, M. Thyroid eye disease — an update. Expert. Rev. Ophthalmol. 11, 273–284 (2016).

    CAS  Google Scholar 

  99. Tsui, S. 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. 181, 4397–4405 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Weightman, D. R., Perros, P., Sherif, I. H. & Kendall-Taylor, P. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity 16, 251–257 (1993).

    CAS  PubMed  Google Scholar 

  101. Moshkelgosha, S., So, P. W., Deasy, N., Diaz-Cano, S. & Banga, J. P. 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 154, 3008–3015 (2013).

    CAS  PubMed  Google Scholar 

  102. Berchner-Pfannschmidt, U. et al. Comparative assessment of female mouse model of Graves’ orbitopathy under different environments, accompanied by proinflammatory cytokine and T-cell responses to thyrotropin hormone receptor antigen. Endocrinology 157, 1673–1682 (2016).

    CAS  PubMed  Google Scholar 

  103. Feliciello, A. et al. Expression of thyrotropin-receptor mRNA in healthy and Graves’ disease retro-orbital tissue. Lancet 342, 337–338 (1993).

    CAS  PubMed  Google Scholar 

  104. Crisp, M. S., Lane, C., Halliwell, M., Wynford-Thomas, D. & Ludgate, M. Thyrotropin receptor transcripts in human adipose tissue. J. Clin. Endocrinol. Metab. 82, 2003–2005 (1997).

    CAS  PubMed  Google Scholar 

  105. Boschi, A. et al. Quantification of cells expressing the thyrotropin receptor in extraocular muscles in thyroid associated orbitopathy. Br. J. Ophthalmol. 89, 724–729 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Ludgate, M. et al. The thyrotropin receptor in thyroid eye disease. Thyroid 8, 411–413 (1998).

    CAS  PubMed  Google Scholar 

  107. Zhang, L. et al. Biological effects of thyrotropin receptor activation on human orbital preadipocytes. Investig. Ophthalmol. Vis. Sci. 47, 5197–5203 (2006).

    Google Scholar 

  108. Lu, M. & Lin, R. Y. TSH stimulates adipogenesis in mouse embryonic stem cells. J. Endocrinol. 196, 159–169 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Kumar, S., Nadeem, S., Stan, M. N., Coenen, M. & Bahn, R. S. A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves’ ophthalmopathy. J. Mol. Endocrinol. 46, 155–163 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhang, L. et al. Thyrotropin receptor activation increases hyaluronan production in preadipocyte fibroblasts: contributory role in hyaluronan accumulation in thyroid dysfunction. J. Biol. Chem. 284, 26447–26455 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Morshed, S. A., Ando, T., Latif, R. & Davies, T. F. Neutral antibodies to the TSH receptor are present in Graves’ disease and regulate selective signaling cascades. Endocrinology 151, 5537–5549 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhang, L. et al. Adipose tissue depot-specific differences in the regulation of hyaluronan production of relevance to Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 97, 653–662 (2012).

    CAS  PubMed  Google Scholar 

  113. Billon, N. & Dani, C. Developmental origins of the adipocyte lineage: new insights from genetics and genomics studies. Stem Cell Rev. 8, 55–66 (2012).

    CAS  Google Scholar 

  114. Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007).

    CAS  PubMed  Google Scholar 

  115. DeGroot, L. J. in Endotext (eds K. R. Feingold et al.) 1–135 (MDText.com, Inc., 2000).

  116. Peyster, R. G., Ginsberg, F., Silber, J. H. & Adler, L. P. Exophthalmos caused by excessive fat: CT volumetric analysis and differential diagnosis. AJR. Am. J. Roentgenol. 146, 459–464 (1986).

    CAS  PubMed  Google Scholar 

  117. Smolders, M. H. et al. Exophthalmos in obesity. Ophthalmic. Res. 36, 78–81 (2004).

    CAS  PubMed  Google Scholar 

  118. Zhang, L. et al. Possible targets for nonimmunosuppressive therapy of Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 99, E1183–E1190 (2014).

    CAS  PubMed  Google Scholar 

  119. Krieger, C. C. et al. TSH/IGF-1 receptor cross talk in Graves’ ophthalmopathy pathogenesis. J. Clin. Endocrinol. Metab. 101, 2340–2347 (2016).

    PubMed  PubMed Central  Google Scholar 

  120. Krieger, C. C., Neumann, S., Place, R. F., Marcus-Samuels, B. & Gershengorn, M. C. Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by Graves’ disease immunoglobins. J. Clin. Endocrinol. Metab. 100, 1071–1077 (2015).

    CAS  PubMed  Google Scholar 

  121. Zhang, L. et al. Reversal of pathological features of Graves’ orbitopathy by activation of forkhead transcription factors, FOXOs. J. Clin. Endocrinol. Metab. 101, 114–122 (2016).

    CAS  PubMed  Google Scholar 

  122. Kumar, S., Coenen, M., Iyer, S. & Bahn, R. S. Forkhead transcription factor FOXO1 is regulated by both a stimulatory thyrotropin receptor antibody and insulin-like growth factor-1 in orbital fibroblasts from patients with Graves’ ophthalmopathy. Thyroid 25, 1145–1150 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Tardy, M., Dold, M., Engel, R. R. & Leucht, S. Trifluoperazine versus low-potency first-generation antipsychotic drugs for schizophrenia. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD009396.pub2 (2014).

  124. Eckstein, A. K. et al. Patients with severe Graves’ ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission. Clin. Endocrinol. (Oxf.) 67, 607–612 (2007).

    Google Scholar 

  125. Khoo, D. H. et al. The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves’ disease identifies a group at markedly increased risk of ophthalmopathy. Thyroid 9, 1175–1180 (1999).

    CAS  PubMed  Google Scholar 

  126. Kahaly, G. J., Wuster, C., Olivo, P. D. & Diana, T. High titers of thyrotropin receptor antibodies are associated with orbitopathy in patients with Graves disease. J. Clin. Endocrinol. Metab. 104, 2561–2568 (2019).

    PubMed  Google Scholar 

  127. Ponto, K. A. et al. Clinical relevance of thyroid-stimulating immunoglobulins in Graves’ ophthalmopathy. Ophthalmology 118, 2279–2285 (2011).

    PubMed  Google Scholar 

  128. Metcalfe, R. et al. Demonstration of immunoglobulin G, A, and E autoantibodies to the human thyrotropin receptor using flow cytometry. J. Clin. Endocrinol. Metab. 87, 1754–1761 (2002).

    CAS  PubMed  Google Scholar 

  129. Minich, W. B. et al. Autoantibodies to the IGF1 receptor in Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 98, 752–760 (2013).

    CAS  PubMed  Google Scholar 

  130. Marino, M. et al. Serum antibodies against the insulin-like growth factor-1 receptor (IGF-1R) in Graves’ disease and Graves’ orbitopathy. J. Endocrinol. Invest. 42, 471–480 (2019).

    CAS  PubMed  Google Scholar 

  131. Fang, S. et al. IL-17A exacerbates fibrosis by promoting the proinflammatory and profibrotic function of orbital fibroblasts in TAO. J. Clin. Endocrinol. Metab. 101, 2955–2965 (2016).

    CAS  PubMed  Google Scholar 

  132. Fang, S. et al. Regulation of orbital fibrosis and adipogenesis by pathogenic Th17 cells in graves orbitopathy. J. Clin. Endocrinol. Metab. 102, 4273–4283 (2017).

    PubMed  Google Scholar 

  133. Banga, J. P., Moshkelgosha, S., Berchner-Pfannschmidt, U. & Eckstein, A. Modeling Graves’ orbitopathy in experimental Graves’ disease. Horm. Metab. Res. 47, 797–803 (2015).

    CAS  PubMed  Google Scholar 

  134. McLachlan, S. M. & Rapoport, B. Breaking tolerance to thyroid antigens: changing concepts in thyroid autoimmunity. Endocr. Rev. 35, 59–105 (2014).

    CAS  PubMed  Google Scholar 

  135. Ludgate, M. Animal models of Graves’ disease. Eur. J. Endocrinol. 142, 1–8 (2000).

    CAS  PubMed  Google Scholar 

  136. Many, M. C. et al. Development of an animal model of autoimmune thyroid eye disease. J. Immunol. 162, 4966–4974 (1999).

    CAS  PubMed  Google Scholar 

  137. Baker, G., Mazziotti, G., von Ruhland, C. & Ludgate, M. Reevaluating thyrotropin receptor-induced mouse models of graves’ disease and ophthalmopathy. Endocrinology 146, 835–844 (2005).

    CAS  PubMed  Google Scholar 

  138. Zhao, S. X. et al. Orbital fibrosis in a mouse model of Graves’ disease induced by genetic immunization of thyrotropin receptor cDNA. J. Endocrinol. 210, 369–377 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Masetti, G. et al. Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease. Microbiome 6, 97 (2018).

    PubMed  PubMed Central  Google Scholar 

  140. Eckstein, A., Esser, J., Oeverhaus, M., Saeed, P. & Jellema, H. M. Surgical treatment of diplopia in Graves orbitopathy patients. Ophthalmic Plast. Reconstr. Surg. 34, S75–S84 (2018).

    PubMed  Google Scholar 

  141. Barker, L., Mackenzie, K., Adams, G. G. & Hancox, J. Long-term surgical outcomes for vertical deviations in thyroid eye disease. Strabismus 25, 67–72 (2017).

    PubMed  Google Scholar 

  142. Mourits, M. P. & Sasim, I. V. A single technique to correct various degrees of upper lid retraction in patients with Graves’ orbitopathy. Br. J. Ophthalmol. 83, 81–84 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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Author notes

  1. These authors contributed equally: Peter N. Taylor, Lei Zhang.

  2. These authors share senior authorship: George J. Kahaly, Marian Ludgate.

Authors and Affiliations

  1. Thyroid Research Group, Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK

    Peter N. Taylor, Lei Zhang, Ilaria Muller, Colin M. Dayan & Marian Ludgate

  2. Moorfields Eye Hospital NHS Foundation Trust, London, UK

    Richard W. J. Lee & Daniel G. Ezra

  3. University of Bristol, Bristol, UK

    Richard W. J. Lee

  4. Fondazione IRRCS Ca’ Granda Ospedale Maggiore Policinico, Department of Endocrinology, Milan, Italy

    Ilaria Muller

  5. Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany

    George J. Kahaly

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The Johannes Gutenberg University (JGU) Medical Center and the JGU Thyroid Laboratory received research grants from Novartis, Germany, and River Vision, USA, when performing the MINGO and teprotumumab trials.

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Glossary

Proptosis

Abnormal protrusion of the eyeball.

Diplopia

Double vision.

Observer masked

The observer assessing outcomes does not know the treatment allocation (the same as “blinded” in clinical trials); masked is used instead of blinded in ophthalmology trials to not alarm patients.

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Taylor, P.N., Zhang, L., Lee, R.W.J. et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol 16, 104–116 (2020). https://doi.org/10.1038/s41574-019-0305-4

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