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Horm Metab Res 2021; 53(04): 211-218
DOI: 10.1055/a-1386-4512
Review

Teprotumumab: The Dawn of Therapies in Moderate-to-Severe Thyroid-Associated Ophthalmopathy

Yizhi Ding
Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
,
Shaoqin Yang
Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
,
Hua Gao
Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
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Abstract

Thyroid-associated ophthalmopathy (TAO) is a potentially sight-threatening ocular disease. About 3–5% of patients with TAO have severe disease with intense pain, inflammation, and sight-threatening corneal ulceration or compressive optic neuropathy. The current treatments of TAO are often suboptimal, mainly because the existing therapies do not target the pathogenesis of the disease. TAO mechanism is unclear. Ocular fibrocytes express relatively high levels of the functional TSH receptor (TSHR), and many indirect evidences support its participation. Over expression of insulin-like growth factor-1 receptor (IGF-IR) in fibroblasts, leading to inappropriate expression of inflammatory factors, production of hyaluronic acid and cell activation in orbital fibroblasts are also possible mechanisms. IGF-1R and TSHR form a physical and functional signaling complex. Inhibition of IGF-IR activity leads to the attenuation of signaling initiated at either receptor. Teprotumumab (TMB) is a human immunoglobulin G1 monoclonal antibody, binding to IGF-IR. Recently two TMB clinical trials had been implemented in TAO patients, indicating dramatic reductions in disease activity and severity, which approved its use for the treatment of TAO in the US. This review summarizes the treatments of TAO, focusing on the pathogenesis of IGF-1R in TAO and its application prospects.

Key words

thyroid eye disease - proptosis - treatment - insulin-like growth factor I receptor - monoclonal antibody - teprotumumab


Publication History

Received: 15 November 2020

Accepted after revision: 31 January 2021

Article published online:
14 April 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 2014; 55: 1735-1748
    CrossrefPubMedGoogle Scholar
  • 2 Smith TJ, Hegedus L. Gravesʼ Disease. N Engl J Med 2016; 375: 1552-1565
    CrossrefPubMedGoogle Scholar
  • 3 Douglas RS, Gupta S. The pathophysiology of thyroid eye disease: Implications for immunotherapy. Curr Opin Ophthalmol 2011; 22: 385-390
    CrossrefPubMedGoogle Scholar
  • 4 Cyranska-Chyrek E, Olejarz M, Szczepanek-Parulska E. et al. Severe unilateral orbitopathy in a patient with Hashimoto's thyroiditis - a case report. BMC Ophthalmol 2019; 19: 9
    CrossrefPubMedGoogle Scholar
  • 5 Gillespie EF, Smith TJ, Douglas RS. Thyroid eye disease: towards an evidence base for treatment in the 21st century. Curr Neurol Neurosci Rep 2012; 12: 318-324
    CrossrefPubMedGoogle Scholar
  • 6 Smith TJ. TSHR as a therapeutic target in Gravesʼ disease. Expert Opin Ther Targets 2017; 21: 427-432
    CrossrefPubMedGoogle Scholar
  • 7 Bhatti MT, Dutton JJ. Thyroid eye disease: Therapy in the active phase. J Neuro-Ophthalmol 2014; 34: 186-197
    CrossrefPubMedGoogle Scholar
  • 8 Smith TJ. Pathogenesis of Gravesʼorbitopathy: A 2010 update. J Endocrinol Invest 2010; 33: 414-421
    CrossrefPubMedGoogle Scholar
  • 9 Tsui S, Naik V, Hoa N. et al. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: A tale of two antigens implicated in Gravesʼ disease. J Immunol 2008; 181: 4397-4405
    CrossrefPubMedGoogle Scholar
  • 10 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-E1640
    CrossrefPubMedGoogle Scholar
  • 11 Bartalena L, Baldeschi L. Boboridis. et al. The 2016 European Thyroid Association/European Group on Gravesʼ Orbitopathy Guidelines for the Management of Gravesʼ Orbitopathy. Eur Thyroid J 2016; 5: 9-26
    CrossrefPubMedGoogle Scholar
  • 12 Stiebel-Kalish H, Robenshtok E, Hasanreisoglu M. et al. Treatment modalities for Gravesʼ ophthalmopathy: Systematic review and metaanalysis. J Clin Endocrinol Metab 2009; 94: 2708-2716
    CrossrefPubMedGoogle Scholar
  • 13 Zhu W, Ye L, Shen L. et al. A prospective, randomized trial of intravenous glucocorticoids therapy with different protocols for patients with Gravesʼ ophthalmopathy. J Clin Endocrinol Metab 2014; 99: 1999-2007
    CrossrefPubMedGoogle Scholar
  • 14 Bartalena L, Baldeschi L, Dickinson A. et al. Consensus statement of the European Group on Gravesʼ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 2008; 158: 273-285
    CrossrefPubMedGoogle Scholar
  • 15 Bartalena L, Krassas GE, Wiersinga W. et al. Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active gravesʼ orbitopathy. J Clin Endocrinol Metab 2012; 97: 4454-4463
    CrossrefPubMedGoogle Scholar
  • 16 Marcocci C, Watt T, Altea MA. et al. Fatal and non-fatal adverse events of glucocorticoid therapy for Gravesʼ orbitopathy: A questionnaire survey among members of the European Thyroid Association. Eur J Endocrinol 2012; 166: 247-253
    CrossrefPubMedGoogle Scholar
  • 17 Sisti E, Coco B, Menconi F. et al. Intravenous glucocorticoid therapy for Gravesʼ ophthalmopathy and acute liver damage: an epidemiological study. Eur J Endocrinol 2015; 172: 269-276
    CrossrefPubMedGoogle Scholar
  • 18 Tanda ML, Bartalena L. Efficacy and safety of orbital radiotherapy for Gravesʼ orbitopathy. J Clin Endocrinol Metab 2012; 97: 3857-3865
    CrossrefPubMedGoogle Scholar
  • 19 Mourits MP, van Kempen-Harteveld ML, García MBG. et al. Radiotherapy for Gravesʼ orbitopathy: randomised placebo-controlled study. Lancet 2000; 355: 1505-1509
    CrossrefPubMedGoogle Scholar
  • 20 Prummel MF, Terwee CB, Gerding MN. et al. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Gravesʼ ophthalmopathy. J Clin Endocrinol Metab 2004; 89: 15-20
    CrossrefPubMedGoogle Scholar
  • 21 Johnson KT, Wittig A, Loesch C. et al. A retrospective study on the efficacy of total absorbed orbital doses of 12, 16 and 20 Gy combined with systemic steroid treatment in patients with Gravesʼ orbitopathy. Graefes Arch Clin Exp Ophthalmol 2010; 248: 103-109
    CrossrefPubMedGoogle Scholar
  • 22 Oeverhaus M, Witteler T, Lax H. et al. Combination therapy of intravenous steroids and orbital irradiation is more effective than intravenous steroids alone in patients with gravesʼ orbitopathy. Horm Metab Res 2017; 49: 739-747
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Rajendram Rathie, Taylor PeterN, Victoria J. Wilson. et al. Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre. 2 × 2 factorial, double-blind, randomised controlled trial. Lancet Diabetes Endocrinol 2018; 6: 299-309
    CrossrefPubMedGoogle Scholar
  • 24 Gao G, Dai J, Qian Y. et al. Meta-analysis of methylprednisolone pulse therapy for Gravesʼ ophthalmopathy. Clin Exp Ophthalmol 2014; 42: 769-777
    CrossrefPubMedGoogle Scholar
  • 25 Wu CY, Niziol LM, Musch DC. et al. Thyroid-related orbital decompression surgery: a multivariate analysis of risk factors and outcomes. Ophthalmic Plast Reconstr Surg 2017; 33: 189-195
    CrossrefPubMedGoogle Scholar
  • 26 Garrity JA, Fatourechi V, Bergstralh EJ. et al. Results of transantral orbital decompression in 428 patients with severe gravesʼ ophthalmopathy. Am J Ophthalmol 1993; 116: 533-547
    CrossrefPubMedGoogle Scholar
  • 27 Gortz GE, Horstmann M, Aniol B. et al. Hypoxia-dependent HIF-1 activation impacts on tissue remodeling in gravesʼ ophthalmopathy-implications for smoking. J Clin Endocrinol Metab 2016; 101: 4834-4842
    CrossrefPubMedGoogle Scholar
  • 28 Kahaly GJ, Riedl M, König J. et al. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Gravesʼ orbitopathy (MINGO): A randomised, observer-masked, multicentre trial. Lancet Diabetes Endocrinol 2018; 6: 287-298
    CrossrefPubMedGoogle Scholar
  • 29 Bahn RS. Gravesʼ Ophthalmopathy. N Engl J Med 2010; 362: 726-738
    CrossrefPubMedGoogle Scholar
  • 30 Scott LJ. Etanercept: a review of its use in autoimmune inflammatory diseases. Drugs 2014; 74: 1379-1410
    CrossrefPubMedGoogle Scholar
  • 31 Paridaens D, van den Bosch WA, van der Loos TL. et al. The effect of etanercept on Gravesʼ ophthalmopathy: a pilot study. Eye (Lond) 2005; 19: 1286-1289
    CrossrefPubMedGoogle Scholar
  • 32 Kahaly GJ. Immunotherapies for thyroid eye disease. Curr Opin Endocrinol Diabetes Obes 2019; 26: 250-255
    CrossrefPubMedGoogle Scholar
  • 33 Jones TH. Interieukin-6 an endocrine cytokine. Clin Endocrinol 1994; 40: 703-713
    CrossrefPubMedGoogle Scholar
  • 34 Scott LJ. Tocilizumab: A Review in Rheumatoid Arthritis. Drugs 2017; 77: 1865-1879
    CrossrefPubMedGoogle Scholar
  • 35 Yokota S, Imagawa T, Mori M. et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008; 371: 998-1006
    CrossrefPubMedGoogle Scholar
  • 36 Salvi Mario, Girasole Giuseppe, Pedrazzoni Mario. et al. Increased serum concentrations of Interleukin-6 (IL-6) and soluble IL-6 receptor in patients with Gravesʼ disease. Clin Endocrinol Metab 1996; 81: 2976-2979
    PubMedGoogle Scholar
  • 37 Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR. et al. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant graves orbitopathy: A randomized clinical trial. Am J Ophthalmol 2018; 195: 181-190
    CrossrefPubMedGoogle Scholar
  • 38 Perez-Moreiras JV, Alvarez-Lopez A, Gomez EC. Treatment of active corticosteroid-resistant Gravesʼ orbitopathy. Ophthalmic Plast Reconstr Surg 2014; 30: 162-167
    CrossrefPubMedGoogle Scholar
  • 39 Minakaran Neda, Ezra DG. Rituximab for thyroid-associated ophthalmopathy (Review). Cochrane Database Syst Rev 2013; 5: 1-23
    PubMedGoogle Scholar
  • 40 Salvi M, Vannucchi G, Curro N. et al. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Gravesʼ orbitopathy: a randomized controlled study. J Clin Endocrinol Metab 2015; 100: 422-431
    CrossrefPubMedGoogle Scholar
  • 41 Insull EA, Sipkova Z, David J. et al. Early low-dose rituximab for active thyroid eye disease: An effective and well-tolerated treatment. Clin Endocrinol (Oxf) 2019; 91: 179-186
    CrossrefPubMedGoogle Scholar
  • 42 Eid Laura, Coste-Verdier Valentine, Longueville Eric. et al. The effects of Rituximab on Gravesʼorbitopathy: A retrospective study of 14 patients. Eur J Ophthalmol 2019; 1-6
    PubMedGoogle Scholar
  • 43 Stan MN, Garrity JA, Carranza Leon BG. et al. Randomized controlled trial of rituximab in patients with Gravesʼ orbitopathy. J Clin Endocrinol Metab 2015; 100: 432-441
    CrossrefPubMedGoogle Scholar
  • 44 Wiersinga WM. Advances in treatment of active, moderate-to-severe Gravesʼ ophthalmopathy. Lancet Diabetes Endocrinol 2017; 5: 134-142
    CrossrefPubMedGoogle Scholar
  • 45 Turcu AF, Kumar S, Neumann S. et al. A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J Clin Endocrinol Metab 2013; 98: 2153-2159
    CrossrefPubMedGoogle Scholar
  • 46 Furmaniak J, Sanders J, Clark J. et al. Preclinical studies on the toxicology, pharmacokinetics and safety of K1-70(TM) a human monoclonal autoantibody to the TSH receptor with TSH antagonist activity. Auto Immun Highlights 2019; 10: 11
    CrossrefPubMedGoogle Scholar
  • 47 Marcinkowski P, Hoyer I, Specker E. et al. A new highly thyrotropin receptor-selective small-molecule antagonist with potential for the treatment of gravesʼ orbitopathy. Thyroid 2019; 29: 111-123
    CrossrefPubMedGoogle Scholar
  • 48 Mohyi M, Smith TJ. IGF-I receptor and thyroid-associated ophthalmopathy. J Mol Endocrinol 2018; 61: T29-T43
    CrossrefPubMedGoogle Scholar
  • 49 Kumar S, Iyer S, Bauer H. et al. A stimulatory thyrotropin receptor antibody enhances hyaluronic acid synthesis in Gravesʼ orbital fibroblasts: Inhibition by an IGF-I receptor blocking antibody. J Clin Endocrinol Metab 2012; 97: 1681-1687
    CrossrefPubMedGoogle Scholar
  • 50 Douglas RS. Teprotumumab, an insulin-like growth factor-1 receptor antagonist antibody, in the treatment of active thyroid eye disease: A focus on proptosis. Eye (Lond) 2019; 33: 183-190
    CrossrefPubMedGoogle Scholar
  • 51 Douglas RS, Afifiyan NF, Hwang CJ. et al. Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2010; 95: 430-438
    CrossrefPubMedGoogle Scholar
  • 52 Gillespie EF, Papageorgiou 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: E740-E746
    CrossrefPubMedGoogle Scholar
  • 53 Ujhelyi B, Gogolak P, Erdei A. et al. Gravesʼ orbitopathy results in profound changes in tear composition: A study of plasminogen activator inhibitor-1 and seven cytokines. Thyroid 2012; 22: 407-414
    CrossrefPubMedGoogle Scholar
  • 54 Bossowski A, Urban M. Serum levels of cytokines in children and adolescents with Gravesʼ disease and non-toxic nodular goiter. Pediatr Endocrinol Metab 2001; 14: 741-747
    PubMedGoogle Scholar
  • 55 Raychaudhuri N, Fernando R, Smith TJ. Thyrotropin regulates IL-6 expression in CD34+ fibrocytes: clear delineation of its cAMP-independent actions. PLoS One 2013; 8: e75100
    CrossrefPubMedGoogle Scholar
  • 56 Smith TJ, JAMJL Janssen. Building the case for insulin-like growth factor receptor-i involvement in thyroid-associated ophthalmopathy. Front Endocrinol (Lausanne) 2017; 7: 167
    CrossrefPubMedGoogle Scholar
  • 57 Smith TJ, Kahaly GJ, Ezra DG. et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 2017; 376: 1748-1761
    CrossrefPubMedGoogle Scholar
  • 58 Douglas RS, Kahaly GJ, Patel A. et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med 2020; 382: 341-352
    CrossrefPubMedGoogle Scholar
  • 59 Adams DD, Purves HD, Sirett NE. The response of hypophysectomized mice to injections of human serum containing long-acting thyroid stimulator. Endocrinology 1961; 68: 154-155
    CrossrefPubMedGoogle Scholar
  • 60 Diana T, Wuster C, Kanitz M. et al. Highly variable sensitivity of five binding and two bio-assays for TSH-receptor antibodies. J Endocrinol Invest 2016; 39: 1159-1165
    CrossrefPubMedGoogle Scholar
  • 61 Bahn RS, Dutton CM, Natt N. et al. Thyrotropin receptor expression in Gravesʼ Orbital adipose/connective tissues: Potential autoantigen in Gravesʼ ophthalmopathy. Endocr Soc 1998; 83: 998-1002
    PubMedGoogle Scholar
  • 62 IMMJ Wakelkamp, Bakker O, Baldeschi L. et al. TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Gravesʼ ophthalmopathy patients. Clin Endocrinol (Oxf) 2003; 58: 280-287
    CrossrefPubMedGoogle Scholar
  • 63 Cao HJ, Wang H-S, 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: 29615-29625
    CrossrefPubMedGoogle Scholar
  • 64 Zhang Y, Cao HJ, Graf B. et al. CD40 engagement upregulates cyclooxygenase-2 expression and prostaglandin E2 production in human lung fibroblasts. J Immunol 1998; 160: 1053-1057
    CrossrefPubMedGoogle Scholar
  • 65 Krieger CC, Neumann S, Gershengorn MC. TSH/IGF1 receptor crosstalk: Mechanism and clinical implications. Pharmacol Ther 2020; 209: 107502
    CrossrefPubMedGoogle Scholar
  • 66 Jang SY, Shin DY, Lee EJ. et al. Relevance of TSH-receptor antibody levels in predicting disease course in Gravesʼ orbitopathy: Comparison of the third-generation TBII assay and Mc4-TSI bioassay. Eye (Lond) 2013; 27: 964-971
    CrossrefPubMedGoogle Scholar
  • 67 Tabasum A, Khan I, Taylor P. et al. Thyroid antibody-negative euthyroid Gravesʼ ophthalmopathy. Endocrinol Diabetes Metab Case Rep 2016; 2016: 160008
    PubMedGoogle Scholar
  • 68 Gallagher EJ, LeRoith D. Minireview: IGF, insulin, and cancer. Endocrinology 2011; 152: 2546-2551
    CrossrefPubMedGoogle Scholar
  • 69 Smith TJ. Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases?. Pharmacol Rev 2010; 62: 199-236
    CrossrefPubMedGoogle Scholar
  • 70 Smith TJ, Hegedus L, Douglas RS. Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Gravesʼ orbitopathy. Best Pract Res Clin Endocrinol Metab 2012; 26: 291-302
    CrossrefPubMedGoogle Scholar
  • 71 Weightman DR, Perros P, Sherif IH. et al. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity 1993; 16: 251-257
    CrossrefPubMedGoogle Scholar
  • 72 Pritchard J, Horst N, Cruikshank W. et al. Igs from patients with Gravesʼ disease induce the expression of T cell chemoattractants in their fibroblasts. J Immunol 2002; 168: 942-950
    CrossrefPubMedGoogle Scholar
  • 73 Pritchard J, Han R, Horst N. et al. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Gravesʼ disease is mediated through the insulin-like growth factor I receptor pathway. J Immunol 2003; 170: 6348-6354
    CrossrefPubMedGoogle Scholar
  • 74 Smith TJ, Hoa N. Immunoglobulins from patients with Gravesʼ disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor. J Clin Endocrinol Metab 2004; 89: 5076-5080
    CrossrefPubMedGoogle Scholar
  • 75 Smith TJ, Tsai CC, Shih M-J. et al. Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy. Thyroid 2008; 18: 983-988
    CrossrefPubMedGoogle Scholar
  • 76 Douglas RS, Naik V, Hwang CJ. et al. B cells from patients with Gravesʼ disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis. J Immunol (Baltimore, Md 1950; 2008: 5768-5774
    PubMedGoogle Scholar
  • 77 Krieger CC, Place RF, Bevilacqua C. et al. TSH/IGF-1 receptor cross talk in Gravesʼ ophthalmopathy pathogenesis. Clin Endocrinol Metab 2016; 101: 2340-2347
    CrossrefPubMedGoogle Scholar
  • 78 Minich WB, Dehina N, Welsink T. et al. Autoantibodies to the IGF1 Receptor in Gravesʼ Orbitopathy. Clin Endocrinol Metab 2013; 98: 752-760
    CrossrefPubMedGoogle Scholar
  • 79 Wiersinga WM. Autoimmunity in Gravesʼ ophthalmopathy: the result of an unfortunate marriage between TSH receptors and IGF-1 receptors?. J Clin Endocrinol Metab 2011; 96: 2386-2394
    CrossrefPubMedGoogle Scholar
  • 80 Krieger CC, Neumann S, Marcus-Samuels B. et al. TSHR/IGF-1R cross-talk, not IGF-1R stimulating antibodies, mediates gravesʼ ophthalmopathy pathogenesis. Thyroid 2017; 27: 746-747
    CrossrefPubMedGoogle Scholar
  • 81 Smith TJ, Janssen J. Response to Krieger et al. re: "TSHR/IGF-1R Cross-Talk, Not IGF-1R stimulating antibodies, mediates gravesʼ Ophthalmopathy Pathogenesis" (Thyroid 2017;27:746–747). Thyroid 2017; 27: 1458-1459
    CrossrefPubMedGoogle Scholar
  • 82 Marcus-Samuels B, Krieger CC, Boutin A. et al. Evidence that Gravesʼ ophthalmopathy immunoglobulins do not directly activate IGF-1 receptors. Thyroid 2018; 28: 650-655
    CrossrefPubMedGoogle Scholar
  • 83 Varewijck AJ, Boelen A, Lamberts SW. et al. Circulating IgGs may modulate IGF-I receptor stimulating activity in a subset of patients with Gravesʼ ophthalmopathy. J Clin Endocrinol Metab 2013; 98: 769-776
    CrossrefPubMedGoogle Scholar
  • 84 Pritchard J, Tsui S, Horst N. et al. Synovial fibroblasts from patients with rheumatoid arthritis, like fibroblasts from Gravesʼ disease, express high levels of IL-16 when treated with Igs against insulin-like growth factor-1 receptor. J Immunol 2004; 173: 3564-3569
    CrossrefPubMedGoogle Scholar
  • 85 Marino M, Rotondo Dottore G, Ionni I. et al. Serum antibodies against the insulin-like growth factor-1 receptor (IGF-1R) in Gravesʼ disease and Gravesʼ orbitopathy. J Endocrinol Invest 2019; 42: 471-480
    CrossrefPubMedGoogle Scholar
  • 86 Tramontano D, Cushing G, Moses A. et al. 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 Gravesʼ-IgG. Endocrinology 1986; 119: 940-942
    CrossrefPubMedGoogle Scholar
  • 87 Ock S, Ahn J, Lee SH. et al. IGF-1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH-stimulated goiter. FASEB J 2013; 27: 4899-4908
    CrossrefPubMedGoogle Scholar
  • 88 Latif R, Morshed SA, Zaidi M. et al. The thyroid-stimulating hormone receptor: impact of thyroid-stimulating hormone and thyroid-stimulating hormone receptor antibodies on multimerization, cleavage, and signaling. Endocrinol Metab Clin North Am 2009; 38: 319-341
    CrossrefPubMedGoogle Scholar
  • 89 Morshed SA, Ando T, Latif R. et al. Neutral Antibodies to the TSH Receptor Are Present in Gravesʼ Disease and Regulate Selective Signaling Cascades. Endocrinology 2010; 151: 5537-5549
    CrossrefPubMedGoogle Scholar
  • 90 Terwee CB, Dekker FW, Mourits MP. et al. Interpretation and validity of changes in scores on the Gravesʼ ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. Clin Endocrinol 2001; 54: 391-398
    CrossrefPubMedGoogle Scholar
  • 91 Baldeschi L, Lupetti A, Vu P. et al. Reactivation of Gravesʼ orbitopathy after rehabilitative orbital decompression. Ophthalmology 2007; 114: 1395-1402
    CrossrefPubMedGoogle Scholar
  • 92 Qu XW, Dong Z, Zhang W. et al. Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy. Oncotarget 2017; 8: 29501-29518
    CrossrefPubMedGoogle Scholar
  • 93 Ma H, Zhang T, Shen H. et al. The adverse events profile of anti-IGF-1R monoclonal antibodies in cancer therapy. Br J Clin Pharmacol 2014; 77: 917-928
    CrossrefPubMedGoogle Scholar
  • 94 Robertson JFR, Ferrero J-M, Bourgeois H. et al. Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet Oncol 2013; 14: 228-235
    CrossrefPubMedGoogle Scholar
  • 95 Marcocci C, Marino M. Treatment of mild, moderate-to-severe and very severe Gravesʼ orbitopathy. Best Pract Res Clin Endocrinol Metab 2012; 26: 325-337
    CrossrefPubMedGoogle Scholar
  • 96 Menconi F, Profilo MA, Leo M. et al. Spontaneous improvement of untreated mild Gravesʼ ophthalmopathy: Rundle's curve revisited. Thyroid 2014; 24: 60-66
    CrossrefPubMedGoogle Scholar
  • 97 Fatourechi V. Thyroid dermopathy and acropachy. Best Pract Res Clin Endocrinol Metab 2012; 26: 553-565
    CrossrefPubMedGoogle Scholar