1932

Abstract

Thyroid-associated ophthalmopathy (TAO), the ocular manifestation of Graves’ disease, is a process in which orbital connective tissues and extraocular muscles undergo inflammation and remodeling. The condition seems to result from autoimmune responses to antigens shared by the thyroid and orbit. The thyrotropin receptor (TSHR), expressed at low levels in orbital tissues, is a leading candidate antigen. Recent evidence suggests that another protein, the insulin-like growth factor-I receptor (IGF-IR), is overexpressed in TAO, and antibodies against IGF-IR have been detected in patients with the disease. Furthermore, TSHR and IGF-IR form a physical and functional complex, and signaling initiated at TSHR requires IGF-IR activity. Identification of therapy for this rare disease has proven challenging and currently relies on nonspecific and inadequate agents, thus representing an important unmet need. A recently completed therapeutic trial suggests that inhibiting IGF-IR activity with a monoclonal antibody may be an effective and safe treatment for active TAO.

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2019-01-06
2024-03-29
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Literature Cited

  1. 1.  Smith TJ, Hegedus L 2016. Graves' disease. N. Engl. J. Med. 375:1552–65
    [Google Scholar]
  2. 2.  Wang Y, Smith TJ 2014. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest. Ophthalmol. Vis. Sci. 55:1735–48
    [Google Scholar]
  3. 3.  Rundle FF, Wilson CW 1945. Development and course of exophthalmos and ophthalmoplegia in Graves' disease with special reference to the effect of thyroidectomy. Clin. Sci. 5:177–94
    [Google Scholar]
  4. 4.  Bartalena L, Piantanida E 2016. Cigarette smoking: number one enemy for Graves ophthalmopathy. Pol. Arch. Med. Wewn. 126:725–26
    [Google Scholar]
  5. 5.  Chu X, Pan CM, Zhao SX, Liang J, Gao GQ et al. 2011. A genome-wide association study identifies two new risk loci for Graves' disease. Nat. Genet. 43:897–901
    [Google Scholar]
  6. 6.  Ungerer M, Fassbender J, Li Z, Munch G, Holthoff HP 2017. Review of mouse models of Graves' disease and orbitopathy-novel treatment by induction of tolerance. Clin. Rev. Allergy Immunol. 52:182–93
    [Google Scholar]
  7. 7.  Novaes P, Diniz Grisolia AB, Smith TJ 2016. Update on thyroid-associated ophthalmopathy with a special emphasis on the ocular surface. Clin. Diabetes Endocrinol. 2:19
    [Google Scholar]
  8. 8.  Chen CR, Pichurin P, Nagayama Y, Latrofa F, Rapoport B, McLachlan SM 2003. The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim. J. Clin. Invest. 111:1897–904
    [Google Scholar]
  9. 9.  Morshed SA, Davies TF 2015. Graves' disease mechanisms: the role of stimulating, blocking, and cleavage region TSH receptor antibodies. Horm. Metab. Res. 47:727–34
    [Google Scholar]
  10. 10.  Feliciello A, Porcellini A, Ciullo I, Bonavolonta G, Avvedimento EV, Fenzi G 1993. Expression of thyrotropin-receptor mRNA in healthy and Graves' disease retro-orbital tissue. Lancet 342:337–38
    [Google Scholar]
  11. 11.  Kriss JP 1970. Radioisotopic thyroidolymphography in patients with Graves' disease. J. Clin. Endocrinol. Met. 31:315–23
    [Google Scholar]
  12. 12.  Adams DD, Purves HD, Sirett NE 1961. The response of hypophysectomized mice to injections of human serum containing long-acting thyroid stimulator. Endocrinology 68:154–55
    [Google Scholar]
  13. 13.  Raychaudhuri N, Fernando R, Smith TJ 2013. Thyrotropin regulates IL-6 expression in CD34+ fibrocytes: clear delineation of its cAMP-independent actions. PLOS ONE 8:e75100
    [Google Scholar]
  14. 14.  Jang SY, Shin DY, Lee EJ, Lee SY, Yoon JS 2013. Relevance of TSH-receptor antibody levels in predicting disease course in Graves' orbitopathy: comparison of the third-generation TBII assay and Mc4-TSI bioassay. Eye 27:964–71
    [Google Scholar]
  15. 15.  Jang SY, Shin DY, Lee EJ, Yoon JS 2014. Clinical characteristics of Graves' orbitopathy in patients showing discrepancy between levels from TBII assays and TSI bioassay. Clin. Endocrinol. 80:591–97
    [Google Scholar]
  16. 16.  Sikorska HM 1986. Anti-thyroglobulin anti-idiotypic antibodies in sera of patients with Hashimoto's thyroiditis and Graves' disease. J. Immunol. 137:3786–95
    [Google Scholar]
  17. 17.  Chardes T, Chapal N, Bresson D, Bes C, Giudicelli V et al. 2002. The human anti-thyroid peroxidase autoantibody repertoire in Graves' and Hashimoto's autoimmune thyroid diseases. Immunogenetics 54:141–57
    [Google Scholar]
  18. 18.  Tabasum A, Khan I, Taylor P, Das G, Okosieme OE 2016. Thyroid antibody-negative euthyroid Graves' ophthalmopathy. Endocrinol. Diabetes Metab. Case Rep. 2016:160008
    [Google Scholar]
  19. 19.  Kumar S, Coenen MJ, Scherer PE, Bahn RS 2004. Evidence for enhanced adipogenesis in the orbits of patients with Graves' ophthalmopathy. J. Clin. Endocrinol. Metab. 89:930–35
    [Google Scholar]
  20. 20.  Smith TJ, Bahn RS, Gorman CA 1989. Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocr. Rev. 10:366–91
    [Google Scholar]
  21. 21.  Sorisky A, Pardasani D, Gagnon A, Smith TJ 1996. Evidence of adipocyte differentiation in human orbital fibroblasts in primary culture. J. Clin. Endocrinol. Metab. 81:3428–31
    [Google Scholar]
  22. 22.  Smith TJ 2002. Role of orbital fat in thyroid-associated ophthalmopathy. Thyroid Eye Disease: Diagnosis and Treatment JJ Dutton, BG Haik 215–21 New York: Marcel Dekker
    [Google Scholar]
  23. 23.  Smith TJ 2002. Fibroblast biology in thyroid diseases. Curr. Opin. Endocrinol. Diabetes Obes. 9:393–400
    [Google Scholar]
  24. 24.  Smith TJ, Koumas L, Gagnon A, Bell A, Sempowski GD et al. 2002. Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy. J. Clin. Endocrinol. Metab. 87:385–92
    [Google Scholar]
  25. 25.  Fang S, Huang Y, Wang S, Zhang Y, Luo X et al. 2016. IL-17A exacerbates fibrosis by promoting the proinflammatory and profibrotic function of orbital fibroblasts in TAO. J. Clin. Endocrinol. Metab. 101:2955–65
    [Google Scholar]
  26. 26.  Kaback LA, Smith TJ 1999. Expression of hyaluronan synthase messenger ribonucleic acids and their induction by interleukin-1β in human orbital fibroblasts: potential insight into the molecular pathogenesis of thyroid-associated ophthalmopathy. J. Clin. Endocrinol. Metab. 84:4079–84
    [Google Scholar]
  27. 27.  Cao HJ, Wang HS, Zhang Y, Lin HY, Phipps RP, Smith TJ 1998. 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. 273:29615–25
    [Google Scholar]
  28. 28.  de Carli M, D'Elios MM, Mariotti S, Marcocci C, Pinchera A et al. 1993. Cytolytic T cells with Th1-like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves' ophthalmopathy. J. Clin. Endocrinol. Metab. 77:1120–24
    [Google Scholar]
  29. 29.  McLachlan SM, Prummel MF, Rapoport B 1994. Cell-mediated or humoral immunity in Graves' ophthalmopathy? Profiles of T-cell cytokines amplified by polymerase chain reaction from orbital tissue. J. Clin. Endocrinol. Metab. 78:1070–74
    [Google Scholar]
  30. 30.  Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A 1994. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol. Med. 1:71–81
    [Google Scholar]
  31. 31.  Douglas RS, Afifiyan NF, Hwang CJ, Chong K, Haider U et al. 2010. Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J. Clin. Endocrinol. Metab. 95:430–38
    [Google Scholar]
  32. 32.  Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM 2007. Differentiation of human circulating fibrocytes as mediated by transforming growth factor-β and peroxisome proliferator-activated receptor γ. J. Biol. Chem. 282:22910–20
    [Google Scholar]
  33. 33.  Fernando R, Atkins S, Raychaudhuri N, Lu Y, Li B et al. 2012. Human fibrocytes coexpress thyroglobulin and thyrotropin receptor. PNAS 109:7427–32
    [Google Scholar]
  34. 34.  Chesney J, Bacher M, Bender A, Bucala R 1997. The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. PNAS 94:6307–12
    [Google Scholar]
  35. 35.  Grab DJ, Lanners H, Martin LN, Chesney J, Cai C et al. 1999. Interaction of Borrelia burgdorferi with peripheral blood fibrocytes, antigen-presenting cells with the potential for connective tissue targeting. Mol. Med. 5:46–54
    [Google Scholar]
  36. 36.  Fernando R, Lu Y, Atkins SJ, Mester T, Branham K, Smith TJ 2014. Expression of thyrotropin receptor, thyroglobulin, sodium-iodide symporter, and thyroperoxidase by fibrocytes depends on AIRE. J. Clin. Endocrinol. Metab. 99:E1236–44
    [Google Scholar]
  37. 37.  Pitkanen J, Peterson P 2003. Autoimmune regulator: from loss of function to autoimmunity. Genes Immun 4:12–21
    [Google Scholar]
  38. 38.  Gallagher EJ, LeRoith D 2011. Minireview: IGF, insulin, and cancer. Endocrinology 152:2546–51
    [Google Scholar]
  39. 39.  Smith TJ 2010. Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases?. Pharmacol. Rev. 62:199–236
    [Google Scholar]
  40. 40.  Smith TJ 2013. Is IGF-I receptor a target for autoantibody generation in Graves' disease?. J. Clin. Endocrinol. Metab. 98:515–18
    [Google Scholar]
  41. 41.  De Meyts P, Whittaker J 2002. Structural biology of insulin and IGF1 receptors: implications for drug design. Nat. Rev. Drug Discov. 1:769–83
    [Google Scholar]
  42. 42.  Mastick CC, Kato H, Roberts CT Jr., LeRoith D, Saltiel AR 1994. Insulin and insulin-like growth factor-I receptors similarly stimulate deoxyribonucleic acid synthesis despite differences in cellular protein tyrosine phosphorylation. Endocrinology 135:214–22
    [Google Scholar]
  43. 43.  Soos MA, Whittaker J, Lammers R, Ullrich A, Siddle K 1990. Receptors for insulin and insulin-like growth factor-I can form hybrid dimers. Characterisation of hybrid receptors in transfected cells. Biochem. J. 270:383–90
    [Google Scholar]
  44. 44.  Zheng H, Shen H, Oprea I, Worrall C, Stefanescu R et al. 2012. β-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing's sarcoma. PNAS 109:20620–25
    [Google Scholar]
  45. 45.  Girnita L, Girnita A, Larsson O 2003. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. PNAS 100:8247–52
    [Google Scholar]
  46. 46.  Adams TE, Epa VC, Garrett TP, Ward CW 2000. Structure and function of the type 1 insulin-like growth factor receptor. Cell. Mol. Life Sci. 57:1050–93
    [Google Scholar]
  47. 47.  Dupont J, Fernandez AM, Glackin CA, Helman L, LeRoith D 2001. Insulin-like growth factor 1 (IGF-1)-induced twist expression is involved in the anti-apoptotic effects of the IGF-1 receptor. J. Biol. Chem. 276:26699–707
    [Google Scholar]
  48. 48.  Girnita L, Worrall C, Takahashi S, Seregard S, Girnita A 2014. Something old, something new and something borrowed: emerging paradigm of insulin-like growth factor type 1 receptor (IGF-1R) signaling regulation. Cell. Mol. Life Sci. 71:2403–27
    [Google Scholar]
  49. 49.  Reiter E, Ayoub MA, Pellissier LP, Landomiel F, Musnier A et al. 2017. β-arrestin signalling and bias in hormone-responsive GPCRs. Mol. Cell. Endocrinol. 449:28–41
    [Google Scholar]
  50. 50.  Kim MS, Lee DY 2015. Insulin-like growth factor (IGF)-I and IGF binding proteins axis in diabetes mellitus. Ann. Pediatr. Endocrinol. Metab. 20:69–73
    [Google Scholar]
  51. 51.  Weightman DR, Perros P, Sherif IH, Kendall-Taylor P 1993. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity 16:251–57
    [Google Scholar]
  52. 52.  Pritchard J, Han R, Horst N, Cruikshank WW, Smith TJ 2003. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves' disease is mediated through the insulin-like growth factor I receptor pathway. J. Immunol. 170:6348–54
    [Google Scholar]
  53. 53.  Smith TJ, Hoa N 2004. Immunoglobulins from patients with Graves' disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor. J. Clin. Endocrinol. Metab. 89:5076–80
    [Google Scholar]
  54. 54.  Douglas RS, Gianoukakis AG, Kamat S, Smith TJ 2007. Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves' disease may carry functional consequences for disease pathogenesis. J. Immunol. 178:3281–87
    [Google Scholar]
  55. 55.  Douglas RS, Naik V, Hwang CJ, Afifiyan NF, Gianoukakis AG et al. 2008. B cells from patients with Graves' disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis. J. Immunol. 181:5768–74
    [Google Scholar]
  56. 56.  Pritchard J, Tsui S, Horst N, Cruikshank WW, Smith TJ 2004. Synovial fibroblasts from patients with rheumatoid arthritis, like fibroblasts from Graves' disease, express high levels of IL-16 when treated with Igs against insulin-like growth factor-1 receptor. J. Immunol. 173:3564–69
    [Google Scholar]
  57. 57.  Zhao SX, Tsui S, Cheung A, Douglas RS, Smith TJ, Banga JP 2011. Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA. J. Endocrinol. 210:369–77
    [Google Scholar]
  58. 58.  Berchner-Pfannschmidt U, Moshkelgosha S, Diaz-Cano S, Edelmann B, Gortz GE et al. 2016. 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 157:1673–82
    [Google Scholar]
  59. 59.  Minich WB, Dehina N, Welsink T, Schwiebert C, Morgenthaler NG et al. 2013. Autoantibodies to the IGF1 receptor in Graves' orbitopathy. J. Clin. Endocrinol. Metab. 98:752–60
    [Google Scholar]
  60. 60.  Krieger CC, Place RF, Bevilacqua C, Marcus-Samuels B, Abel BS et al. 2016. TSH/IGF-1 receptor cross talk in Graves' ophthalmopathy pathogenesis. J. Clin. Endocrinol. Metab. 101:2340–47
    [Google Scholar]
  61. 61.  Varewijck AJ, Boelen A, Lamberts SW, Fliers E, Hofland LJ et al. 2013. Circulating IgGs may modulate IGF-I receptor stimulating activity in a subset of patients with Graves' ophthalmopathy. J. Clin. Endocrinol. Metab. 98:769–76
    [Google Scholar]
  62. 62.  Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF et al. 2008. 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. 181:4397–405
    [Google Scholar]
  63. 63.  Tramontano D, Cushing GW, Moses AC, Ingbar SH 1986. Insulin-like growth factor-I stimulates the growth of rat thyroid cells in culture and synergizes the stimulation of DNA synthesis induced by TSH and Graves'-IgG. Endocrinology 119:940–42
    [Google Scholar]
  64. 64.  Tramontano D, Moses AC, Veneziani BM, Ingbar SH 1988. Adenosine 3′,5′-monophosphate mediates both the mitogenic effect of thyrotropin and its ability to amplify the response to insulin-like growth factor I in FRTL5 cells. Endocrinology 122:127–32
    [Google Scholar]
  65. 65.  Alfonso-Cristancho R, Armstrong N, Arjunji R, Riemsma R, Worthy G et al. 2017. Comparative effectiveness of biologics for the management of rheumatoid arthritis: systematic review and network meta-analysis. Clin. Rheumatol. 36:25–34
    [Google Scholar]
  66. 66.  Chandler GN, Hartfall SJ 1952. Cortisone and ACTH in exophthalmic ophthalmoplegia. Lancet 1:847–51
    [Google Scholar]
  67. 67.  Bartalena L, Krassas GE, Wiersinga W, Marcocci C, Salvi M et al. 2012. Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves' orbitopathy. J. Clin. Endocrinol. Metab. 97:4454–63
    [Google Scholar]
  68. 68.  Sisti E, Coco B, Menconi F, Leo M, Rocchi R et al. 2015. Intravenous glucocorticoid therapy for Graves' ophthalmopathy and acute liver damage: an epidemiological study. Eur. J. Endocrinol. 172:269–76
    [Google Scholar]
  69. 69.  Sisti E, Coco B, Menconi F, Leo M, Rocchi R et al. 2015. Age and dose are major risk factors for liver damage associated with intravenous glucocorticoid pulse therapy for Graves' orbitopathy. Thyroid 25:846–50
    [Google Scholar]
  70. 70.  Marino M, Morabito E, Altea MA, Ambrogini E, Oliveri F et al. 2005. Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves' ophthalmopathy treated successfully with glucocorticoids themselves. J. Endocrinol. Investig. 28:280–84
    [Google Scholar]
  71. 71.  Kim JW, Han SH, Son BJ, Rim TH, Keum KC, Yoon JS 2016. Efficacy of combined orbital radiation and systemic steroids in the management of Graves' orbitopathy. Graefes Arch. Clin. Exp. Ophthalmol. 254:991–98
    [Google Scholar]
  72. 72.  Marcocci C, Bartalena L, Tanda ML, Manetti L, Dell'Unto E et al. 2001. 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. 86:3562–67
    [Google Scholar]
  73. 73.  Donaldson SS, Bagshaw MA, Kriss JP 1973. Supervoltage orbital radiotherapy for Graves' ophthalmopathy. J. Clin. Endocrinol. Metab. 37:276–85
    [Google Scholar]
  74. 74.  Bartalena L, Marcocci C, Tanda ML, Pinchera A 2002. Management of thyroid eye disease. Eur. J. Nucl. Med. Mol. Imaging 29:Suppl. 2S458–65
    [Google Scholar]
  75. 75.  Del Monte MA 2002. 2001 an ocular odyssey: lessons learned from 25 years of surgical treatment for Graves eye disease. Am. Orthopt. J. 52:40–57
    [Google Scholar]
  76. 76.  Braun TL, Bhadkamkar MA, Jubbal KT, Weber AC, Marx DP 2017. Orbital decompression for thyroid eye disease. Semin. Plast. Surg. 31:40–45
    [Google Scholar]
  77. 77.  Boboridis KG, Uddin J, Mikropoulos DG, Bunce C, Mangouritsas G et al. 2015. Critical appraisal on orbital decompression for thyroid eye disease: a systematic review and literature search. Adv. Ther. 32:595–611
    [Google Scholar]
  78. 78.  Zhang-Nunes SX, Dang S, Garneau HC, Hwang C, Isaacs D et al. 2015. Characterization and outcomes of repeat orbital decompression for thyroid-associated orbitopathy. Orbit 34:57–65
    [Google Scholar]
  79. 79.  Boergen KP 1989. Surgical repair of motility impairment in Graves' orbitopathy. Dev. Ophthalmol. 20:159–68
    [Google Scholar]
  80. 80.  Papageorgiou KI, Ang M, Chang SH, Kohn J, Martinez S, Goldberg RA 2012. Aesthetic considerations in upper eyelid retraction surgery. Ophthal. Plast. Reconstr. Surg. 28:419–23
    [Google Scholar]
  81. 81.  Olmos D, Tan DS, Jones RL, Judson IR 2010. Biological rationale and current clinical experience with anti-insulin-like growth factor 1 receptor monoclonal antibodies in treating sarcoma: twenty years from the bench to the bedside. Cancer J 16:183–94
    [Google Scholar]
  82. 82.  Mahadevan D, Sutton GR, Arteta-Bulos R, Bowden CJ, Miller PJ et al. 2014. Phase 1b study of safety, tolerability and efficacy of R1507, a monoclonal antibody to IGF-1R in combination with multiple standard oncology regimens in patients with advanced solid malignancies. Cancer Chemother. Pharmacol. 73:467–73
    [Google Scholar]
  83. 83.  Ramalingam SS, Spigel DR, Chen D, Steins MB, Engelman JA et al. 2011. Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer. J. Clin. Oncol. 29:4574–80
    [Google Scholar]
  84. 84.  Fleuren ED, Versleijen-Jonkers YM, Heskamp S, Roeffen MH, Bouwman WH et al. 2013. The strength of small: improved targeting of insulin-like growth factor-1 receptor (IGF-1R) with F(ab′)2-R1507 fragments in Ewing sarcomas. Eur. J. Cancer 49:2851–58
    [Google Scholar]
  85. 85.  Ferte C, Loriot Y, Clemenson C, Commo F, Gombos A et al. 2013. IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: an opportunity to increase the efficacy of standard therapy. Mol. Cancer Ther. 12:1213–22
    [Google Scholar]
  86. 86.  Qu X, Wu Z, Dong W, Zhang T, Wang L et al. 2017. Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy. Oncotarget 8:29501–18
    [Google Scholar]
  87. 87.  Smith TJ 2015. TSH-receptor-expressing fibrocytes and thyroid-associated ophthalmopathy. Nat. Rev. Endocrinol. 11:171–81
    [Google Scholar]
  88. 88.  Chen H, Mester T, Raychaudhuri N, Kauh CY, Gupta S et al. 2014. Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. J. Clin. Endocrinol. Metab. 99:E1635–40
    [Google Scholar]
  89. 89.  Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA et al. 2017. Teprotumumab for thyroid-associated ophthalmopathy. N. Engl. J. Med. 376:1748–61
    [Google Scholar]
  90. 90.  Terwee CB, Dekker FW, Mourits MP, Gerding MN, Baldeschi L et al. 2001. Interpretation and validity of changes in scores on the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. Clin. Endocrinol. 54:391–98
    [Google Scholar]
  91. 91.  Terwee CB, Gerding MN, Dekker FW, Prummel MF, Wiersinga WM 1998. Development of a disease specific quality of life questionnaire for patients with Graves' ophthalmopathy: the GO-QOL. Br. J. Ophthalmol. 82:773–79
    [Google Scholar]
  92. 92.  Kurzrock R, Patnaik A, Aisner J, Warren T, Leong S et al. 2010. A phase I study of weekly R1507, a human monoclonal antibody insulin-like growth factor-I receptor antagonist, in patients with advanced solid tumors. Clin. Cancer Res. 16:2458–65
    [Google Scholar]
  93. 93.  Scott SD 1998. Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin's lymphoma. Cancer Pract 6:195–97
    [Google Scholar]
  94. 94.  Franks SE, Getahun A, Hogarth PM, Cambier JC 2016. Targeting B cells in treatment of autoimmunity. Curr. Opin. Immunol. 43:39–45
    [Google Scholar]
  95. 95.  Salvi M, Vannucchi G, Campi I, Curro N, Dazzi D et al. 2007. Treatment of Graves' disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur. J. Endocrinol. 156:33–40
    [Google Scholar]
  96. 96.  Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS 2015. Randomized controlled trial of rituximab in patients with Graves' orbitopathy. J. Clin. Endocrinol. Metab. 100:432–41
    [Google Scholar]
  97. 97.  Salvi M, Vannucchi G, Curro N, Campi I, Covelli D et al. 2015. 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. 100:422–31
    [Google Scholar]
  98. 98.  Nakahara H, Nishimoto N 2006. Anti-interleukin-6 receptor antibody therapy in rheumatic diseases. Endocr. Metab. Immune Disord. Drug Targets 6:373–81
    [Google Scholar]
  99. 99.  Paul-Pletzer K 2006. Tocilizumab: blockade of interleukin-6 signaling pathway as a therapeutic strategy for inflammatory disorders. Drugs Today 42:559–76
    [Google Scholar]
  100. 100.  Perez-Moreiras JV, Alvarez-Lopez A, Gomez EC 2014. Treatment of active corticosteroid-resistant Graves' orbitopathy. Ophthal. Plast. Reconstr. Surg. 30:162–67
    [Google Scholar]
  101. 101.  Ye X, Bo X, Hu X, Cui H, Lu B et al. 2017. Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves' orbitopathy. Clin. Endocrinol. 86:247–55
    [Google Scholar]
  102. 102.  Kahaly GJ, Riedl M, Konig J, Pitz S, Ponto K et al. 2018. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. Lancet Diabet. Endocrinol. 6:287–98
    [Google Scholar]
  103. 103.  Allison AC, Eugui EM 2000. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 47:85–118
    [Google Scholar]
  104. 104.  Sanders J, Allen F, Jeffreys J, Bolton J, Richards T et al. 2005. Characteristics of a monoclonal antibody to the thyrotropin receptor that acts as a powerful thyroid-stimulating autoantibody antagonist. Thyroid 15:672–82
    [Google Scholar]
  105. 105.  Chen CR, McLachlan SM, Rapoport B 2009. A monoclonal antibody with thyrotropin (TSH) receptor inverse agonist and TSH antagonist activities binds to the receptor hinge region as well as to the leucine-rich domain. Endocrinology 150:3401–8
    [Google Scholar]
  106. 106.  Sanders P, Young S, Sanders J, Kabelis K, Baker S et al. 2011. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J. Mol. Endocrinol. 46:81–99
    [Google Scholar]
  107. 107.  Sanders J, Miguel RN, Furmaniak J, Smith BR 2010. TSH receptor monoclonal antibodies with agonist, antagonist, and inverse agonist activities. Methods Enzymol 485:393–420
    [Google Scholar]
  108. 108.  Jaschke H, Neumann S, Moore S, Thomas CJ, Colson AO et al. 2006. A low molecular weight agonist signals by binding to the transmembrane domain of thyroid-stimulating hormone receptor (TSHR) and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). J. Biol. Chem. 281:9841–44
    [Google Scholar]
  109. 109.  Neumann S, Nir EA, Eliseeva E, Huang W, Marugan J et al. 2014. A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology 155:310–14
    [Google Scholar]
  110. 110.  Neumann S, Eliseeva E, McCoy JG, Napolitano G, Giuliani C et al. 2011. A new small-molecule antagonist inhibits Graves' disease antibody activation of the TSH receptor. J. Clin. Endocrinol. Metab. 96:548–54
    [Google Scholar]
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