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

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

• References

• 1 Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 2014; 55: 1735-1748
• 2 Smith TJ, Hegedus L. Gravesʼ Disease. N Engl J Med 2016; 375: 1552-1565
• 3 Douglas RS, Gupta S. The pathophysiology of thyroid eye disease: Implications for immunotherapy. Curr Opin Ophthalmol 2011; 22: 385-390
• 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
• 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
• 6 Smith TJ. TSHR as a therapeutic target in Gravesʼ disease. Expert Opin Ther Targets 2017; 21: 427-432
• 7 Bhatti MT, Dutton JJ. Thyroid eye disease: Therapy in the active phase. J Neuro-Ophthalmol 2014; 34: 186-197
• 8 Smith TJ. Pathogenesis of Gravesʼorbitopathy: A 2010 update. J Endocrinol Invest 2010; 33: 414-421
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 18 Tanda ML, Bartalena L. Efficacy and safety of orbital radiotherapy for Gravesʼ orbitopathy. J Clin Endocrinol Metab 2012; 97: 3857-3865
• 19 Mourits MP, van Kempen-Harteveld ML, García MBG. et al. Radiotherapy for Gravesʼ orbitopathy: randomised placebo-controlled study. Lancet 2000; 355: 1505-1509
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 29 Bahn RS. Gravesʼ Ophthalmopathy. N Engl J Med 2010; 362: 726-738
• 30 Scott LJ. Etanercept: a review of its use in autoimmune inflammatory diseases. Drugs 2014; 74: 1379-1410
• 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
• 32 Kahaly GJ. Immunotherapies for thyroid eye disease. Curr Opin Endocrinol Diabetes Obes 2019; 26: 250-255
• 33 Jones TH. Interieukin-6 an endocrine cytokine. Clin Endocrinol 1994; 40: 703-713
• 34 Scott LJ. Tocilizumab: A Review in Rheumatoid Arthritis. Drugs 2017; 77: 1865-1879
• 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
• 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
• 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
• 38 Perez-Moreiras JV, Alvarez-Lopez A, Gomez EC. Treatment of active corticosteroid-resistant Gravesʼ orbitopathy. Ophthalmic Plast Reconstr Surg 2014; 30: 162-167
• 39 Minakaran Neda, Ezra DG. Rituximab for thyroid-associated ophthalmopathy (Review). Cochrane Database Syst Rev 2013; 5: 1-23
• 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
• 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
• 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
• 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
• 44 Wiersinga WM. Advances in treatment of active, moderate-to-severe Gravesʼ ophthalmopathy. Lancet Diabetes Endocrinol 2017; 5: 134-142
• 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
• 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
• 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
• 48 Mohyi M, Smith TJ. IGF-I receptor and thyroid-associated ophthalmopathy. J Mol Endocrinol 2018; 61: T29-T43
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 57 Smith TJ, Kahaly GJ, Ezra DG. et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 2017; 376: 1748-1761
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 65 Krieger CC, Neumann S, Gershengorn MC. TSH/IGF1 receptor crosstalk: Mechanism and clinical implications. Pharmacol Ther 2020; 209: 107502
• 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
• 67 Tabasum A, Khan I, Taylor P. et al. Thyroid antibody-negative euthyroid Gravesʼ ophthalmopathy. Endocrinol Diabetes Metab Case Rep 2016; 2016: 160008
• 68 Gallagher EJ, LeRoith D. Minireview: IGF, insulin, and cancer. Endocrinology 2011; 152: 2546-2551
• 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
• 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
• 71 Weightman DR, Perros P, Sherif IH. et al. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity 1993; 16: 251-257
• 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
• 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
• 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
• 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
• 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
• 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
• 78 Minich WB, Dehina N, Welsink T. et al. Autoantibodies to the IGF1 Receptor in Gravesʼ Orbitopathy. Clin Endocrinol Metab 2013; 98: 752-760
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 91 Baldeschi L, Lupetti A, Vu P. et al. Reactivation of Gravesʼ orbitopathy after rehabilitative orbital decompression. Ophthalmology 2007; 114: 1395-1402
• 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
• 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
• 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
• 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
• 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
• 97 Fatourechi V. Thyroid dermopathy and acropachy. Best Pract Res Clin Endocrinol Metab 2012; 26: 553-565