Current status and progress of targeted therapy in Graves’ ophthalmopathy_West China Medical Journal

Authors：

HAI Yuanping ¹ ,  LIU Haiwei ²

1. Department of Endocrinology, Hainan Women and Children’s Medical Center, Haikou, Hainan 5700206, P. R. China;
2. Department of Endocrinology, Hainan General Hospital / Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, P. R. China;

Corresponding author：

LIU Haiwei, Email: hndxlhw@163.com

Keywords：

Graves’ ophthalmopathy; Targeted therapy; Teprotumumab; Rituximab; Tocilizumab

DOI：

10.7507/1002-0179.202004228

Video：

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Abstract Full text Figures/Tables Video References Cited by

Graves’ ophthalmopathy (GO) is an autoimmune disease, and there is no specific treatment drug. Glucocorticoid (GC) therapy is still the first-line therapy for patients with moderate to severe GO. Targeted therapy may become a novel treatment due to GC’s adverse drug reactions. As the in-depth study of the pathogenesis of GO, many targeted drugs with randomized clinical trial (RCT) treatment have appeared in recent years, such as anti-insulin growth factor 1 receptor (teprotumumab), anti-CD20 (rituximab) and anti-interleukin(IL)-6 receptor (tocilizumab). It is worth noting that teprotumumab has been approved by US Food and Drug Administration in recently, and may quickly become the first-line therapy for GO. The anti-B cell stimulating factor (belimumab) which is undergoing RCT is waiting for the result of RCT to reveal. Anti-tumor necrosis factor-α (such as etanercept, adalimumab, and infliximab) which only used in case reports requires RCT further verification. In addition, anti-IL-17/IL-23, thyroid stimulating hormone receptor, CD40 targets and target therapies may have potential clinical value for GO due to the successful use of these target therapies in vitro experiments and other autoimmune diseases. This paper focus on the progress of targeted therapy of GO in China and abroad in recent years.

Citation： HAI Yuanping, LIU Haiwei. Current status and progress of targeted therapy in Graves’ ophthalmopathy. West China Medical Journal, 2021, 36(10): 1444-1449. doi: 10.7507/1002-0179.202004228 Copy

1.	Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med, 2016, 375(16): 1552-1565.
2.	Hai YP, Lee ACH, Frommer L, et al. Immunohistochemical analysis of human orbital tissue in Graves’ orbitopathy. J Endocrinol Invest, 2020, 43(2): 123-137.
3.	Bahn RS. Graves’ ophthalmopathy. N Engl J Med, 2010, 362(8): 726-738.
4.	李凯军, 何剑峰. 甲状腺相关眼病的治疗进展. 眼科学报, 2019, 34(1): 52-56.
5.	马超, 刘薇, 李凯军, 等. 甲状腺相关眼病免疫相关发病机制的研究现状与进展. 眼科新进展, 2019, 39(8): 790-794.
6.	Huang Y, Fang S, Li D, et al. The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy. Eye (Lond), 2019, 33(2): 176-182.
7.	Khong JJ, McNab AA, Ebeling PR, et al. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol, 2016, 100(1): 142-150.
8.	Fang S, Huang Y, Wang S, et al. IL-17A exacerbates fbrosis by promoting the proinfammatory and profibrotic function of orbital fibroblasts in TAO. J Clin Endocrinol Metab, 2016, 101(8): 2955-2965.
9.	陆燕, 张鹏, 魏锐利. CD40-CD40配体共刺激通路在甲状腺相关性眼病发病中作用研究进展. 眼科新进展, 2011, 31(7): 695-697.
10.	Salvi M, Covelli D. B cells in Graves’ Orbitopathy: more than just a source of antibodies?. Eye (Lond), 2019, 33(2): 230-234.
11.	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(2): 183-190.
12.	Piantanida E, Bartalena L. Teprotumumab: a new avenue for the management of moderate-to-severe and active Graves’ orbitopathy?. J Endocrinol Invest, 2017, 40(8): 885-887.
13.	Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med, 2017, 376(18): 1748-1761.
14.	Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med, 2020, 382(4): 341-352.
15.	Markham A. Teprotumumab: first approval. Drugs, 2020, 80(5): 509-512.
16.	Smith TJ. Teprotumumab in thyroid-associated ophthalmopathy: rationale for therapeutic insulin-like growth factor-i receptor inhibition. J Neuroophthalmol, 2020, 40(1): 74-83.
17.	Stan MN, Salvi M. Management of endocrine disease: rituximab therapy for Graves’ orbitopathy-lessons from randomized control trials. Eur J Endocrinol, 2017, 176(2): R101-R109.
18.	Strianese D, Rossi F. Interruption of autoimmunity for thyroid eye disease: B-cell and T-cell strategy. Eye (Lond), 2019, 33(2): 191-199.
19.	Salvi M, Vannucchi G, Currò N, et al. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves’ orbitopathy: a randomized controlled study. J Clin Endocrinol Metab, 2015, 100(2): 422-431.
20.	Stan MN, Garrity JA, Carranza Leon BG, et al. Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J Clin Endocrinol Metab, 2015, 100(2): 432-441.
21.	Wiersinga WM. Advances in treatment of active, moderate-to-severe Graves’ ophthalmopathy. Lancet Diabetes Endocrinol, 2017, 5(2): 134-142.
22.	Genere N, Stan MN. Current and emerging treatment strategies for Graves’ orbitopathy. Drugs, 2019, 79(2): 109-124.
23.	Bartalena L, Baldeschi L, Boboridis K, et al. The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. Eur Thyroid J, 2016, 5(1): 9-26.
24.	Li J, Xiao Z, Hu X, et al. The efficacy of rituximab combined with 131I for ophthalmic outcomes of Graves’ ophthalmopathy patients. Pharmacology, 2017, 99(3-4): 144-152.
25.	Shen WC, Lee CH, Loh EW, et al. Efficacy and safety of rituximab for the treatment of Graves’ orbitopathy: a meta-analysis of randomized controlled trials. Pharmacotherapy, 2018, 38(5): 503-510.
26.	Hamed Azzam S, Kang S, Salvi M, et al. Tocilizumab for thyroid eye disease. Cochrane Database Syst Rev, 2018, 11(11): CD012984.
27.	Reiner SL. Development in motion: helper T cells at work. Cell, 2007, 129(1): 33-36.
28.	Pérez-Moreiras JV, Alvarez-López A, Gómez EC. Treatment of active corticosteroid-resistant Graves’ orbitopathy. Ophthalmic Plast Reconstr Surg, 2014, 30(2): 162-167.
29.	Sy A, Eliasieh K, Silkiss RZ. Clinical response to tocilizumab in severe thyroid eye disease. Ophthalmic Plast Reconstr Surg, 2017, 33(3): e55-e57.
30.	Canas CA, Bonilla-Abadia F, Vallejo K, et al. Successful treatment for severe thyroid-associated ophthalmopathy with tocilizumab. Endocr Metab Immune Disord Drug Targets, 2018, 18(6): 665-667.
31.	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.
32.	Leszczynska A, Molins B, Fernández E, et al. Cytokine production in thyroid eye disease: in vitro effects of dexamethasone and IL-6 blockade with tocilizumab. Graefes Arch Clin Exp Ophthalmol, 2019, 257(10): 2307-2314.
33.	Tang F, Chen X, Mao Y, et al. Orbital fibroblasts of Graves’ orbitopathy stimulated with proinflammatory cytokines promote B cell survival by secreting BAFF. Mol Cell Endocrinol, 2017(446): 1-11.
34.	Paridaens D, van den Bosch WA, van der Loos TL, et al. The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye (Lond), 2005, 19(12): 1286-1289.
35.	Ayabe R, Rootman DB, Hwang CJ, et al. Adalimumab as steroid-sparing treatment of inflammatory-stage thyroid eye disease. Ophthalmic Plast Reconstr Surg, 2014, 30(5): 415-419.
36.	Beringer A, Noack M, Miossec P. IL-17 in chronic inflammation: from discovery to targeting. Trends Mol Med, 2016, 22(3): 230-241.
37.	Zheng L, Ye P, Liu C. The role of the IL-23/IL-17 axis in the pathogenesis of Graves’ disease. Endocr J, 2013, 60(5): 591-597.
38.	Rajaii F, McCoy AN, Smith TJ. Cytokines are both villains and potential therapeutic targets in thyroid-associated ophthalmopathy: from bench to bedside. Expert Rev Ophthalmol, 2014, 9(3): 227-234.
39.	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(5): 2153-2159.
40.	Sanders P, Young S, Sanders J, et al. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol, 2011, 46(2): 81-99.
41.	Kahaly GJ, Stan MN, Frommer L, et al. A novel anti-CD40 monoclonal antibody, iscalimab, for control of Graves hyperthyroidism-a proof-of-concept trial. J Clin Endocrinol Metab, 2020, 105(3): dgz013.

1. Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med, 2016, 375(16): 1552-1565.
2. Hai YP, Lee ACH, Frommer L, et al. Immunohistochemical analysis of human orbital tissue in Graves’ orbitopathy. J Endocrinol Invest, 2020, 43(2): 123-137.
3. Bahn RS. Graves’ ophthalmopathy. N Engl J Med, 2010, 362(8): 726-738.
4. 李凯军, 何剑峰. 甲状腺相关眼病的治疗进展. 眼科学报, 2019, 34(1): 52-56.
5. 马超, 刘薇, 李凯军, 等. 甲状腺相关眼病免疫相关发病机制的研究现状与进展. 眼科新进展, 2019, 39(8): 790-794.
6. Huang Y, Fang S, Li D, et al. The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy. Eye (Lond), 2019, 33(2): 176-182.
7. Khong JJ, McNab AA, Ebeling PR, et al. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol, 2016, 100(1): 142-150.
8. Fang S, Huang Y, Wang S, et al. IL-17A exacerbates fbrosis by promoting the proinfammatory and profibrotic function of orbital fibroblasts in TAO. J Clin Endocrinol Metab, 2016, 101(8): 2955-2965.
9. 陆燕, 张鹏, 魏锐利. CD40-CD40配体共刺激通路在甲状腺相关性眼病发病中作用研究进展. 眼科新进展, 2011, 31(7): 695-697.
10. Salvi M, Covelli D. B cells in Graves’ Orbitopathy: more than just a source of antibodies?. Eye (Lond), 2019, 33(2): 230-234.
11. 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(2): 183-190.
12. Piantanida E, Bartalena L. Teprotumumab: a new avenue for the management of moderate-to-severe and active Graves’ orbitopathy?. J Endocrinol Invest, 2017, 40(8): 885-887.
13. Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med, 2017, 376(18): 1748-1761.
14. Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med, 2020, 382(4): 341-352.
15. Markham A. Teprotumumab: first approval. Drugs, 2020, 80(5): 509-512.
16. Smith TJ. Teprotumumab in thyroid-associated ophthalmopathy: rationale for therapeutic insulin-like growth factor-i receptor inhibition. J Neuroophthalmol, 2020, 40(1): 74-83.
17. Stan MN, Salvi M. Management of endocrine disease: rituximab therapy for Graves’ orbitopathy-lessons from randomized control trials. Eur J Endocrinol, 2017, 176(2): R101-R109.
18. Strianese D, Rossi F. Interruption of autoimmunity for thyroid eye disease: B-cell and T-cell strategy. Eye (Lond), 2019, 33(2): 191-199.
19. Salvi M, Vannucchi G, Currò N, et al. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves’ orbitopathy: a randomized controlled study. J Clin Endocrinol Metab, 2015, 100(2): 422-431.
20. Stan MN, Garrity JA, Carranza Leon BG, et al. Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J Clin Endocrinol Metab, 2015, 100(2): 432-441.
21. Wiersinga WM. Advances in treatment of active, moderate-to-severe Graves’ ophthalmopathy. Lancet Diabetes Endocrinol, 2017, 5(2): 134-142.
22. Genere N, Stan MN. Current and emerging treatment strategies for Graves’ orbitopathy. Drugs, 2019, 79(2): 109-124.
23. Bartalena L, Baldeschi L, Boboridis K, et al. The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. Eur Thyroid J, 2016, 5(1): 9-26.
24. Li J, Xiao Z, Hu X, et al. The efficacy of rituximab combined with 131I for ophthalmic outcomes of Graves’ ophthalmopathy patients. Pharmacology, 2017, 99(3-4): 144-152.
25. Shen WC, Lee CH, Loh EW, et al. Efficacy and safety of rituximab for the treatment of Graves’ orbitopathy: a meta-analysis of randomized controlled trials. Pharmacotherapy, 2018, 38(5): 503-510.
26. Hamed Azzam S, Kang S, Salvi M, et al. Tocilizumab for thyroid eye disease. Cochrane Database Syst Rev, 2018, 11(11): CD012984.
27. Reiner SL. Development in motion: helper T cells at work. Cell, 2007, 129(1): 33-36.
28. Pérez-Moreiras JV, Alvarez-López A, Gómez EC. Treatment of active corticosteroid-resistant Graves’ orbitopathy. Ophthalmic Plast Reconstr Surg, 2014, 30(2): 162-167.
29. Sy A, Eliasieh K, Silkiss RZ. Clinical response to tocilizumab in severe thyroid eye disease. Ophthalmic Plast Reconstr Surg, 2017, 33(3): e55-e57.
30. Canas CA, Bonilla-Abadia F, Vallejo K, et al. Successful treatment for severe thyroid-associated ophthalmopathy with tocilizumab. Endocr Metab Immune Disord Drug Targets, 2018, 18(6): 665-667.
31. 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.
32. Leszczynska A, Molins B, Fernández E, et al. Cytokine production in thyroid eye disease: in vitro effects of dexamethasone and IL-6 blockade with tocilizumab. Graefes Arch Clin Exp Ophthalmol, 2019, 257(10): 2307-2314.
33. Tang F, Chen X, Mao Y, et al. Orbital fibroblasts of Graves’ orbitopathy stimulated with proinflammatory cytokines promote B cell survival by secreting BAFF. Mol Cell Endocrinol, 2017(446): 1-11.
34. Paridaens D, van den Bosch WA, van der Loos TL, et al. The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye (Lond), 2005, 19(12): 1286-1289.
35. Ayabe R, Rootman DB, Hwang CJ, et al. Adalimumab as steroid-sparing treatment of inflammatory-stage thyroid eye disease. Ophthalmic Plast Reconstr Surg, 2014, 30(5): 415-419.
36. Beringer A, Noack M, Miossec P. IL-17 in chronic inflammation: from discovery to targeting. Trends Mol Med, 2016, 22(3): 230-241.
37. Zheng L, Ye P, Liu C. The role of the IL-23/IL-17 axis in the pathogenesis of Graves’ disease. Endocr J, 2013, 60(5): 591-597.
38. Rajaii F, McCoy AN, Smith TJ. Cytokines are both villains and potential therapeutic targets in thyroid-associated ophthalmopathy: from bench to bedside. Expert Rev Ophthalmol, 2014, 9(3): 227-234.
39. 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(5): 2153-2159.
40. Sanders P, Young S, Sanders J, et al. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol, 2011, 46(2): 81-99.
41. Kahaly GJ, Stan MN, Frommer L, et al. A novel anti-CD40 monoclonal antibody, iscalimab, for control of Graves hyperthyroidism-a proof-of-concept trial. J Clin Endocrinol Metab, 2020, 105(3): dgz013.

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