Perspectives on Antibody-Based Thyroid-Associated Orbitopathy Treatments
Main Article Content
Abstract
Thyroid-associated orbitopathy (TAO) is a disfiguring and in severe cases debilitating autoimmune disease that has been the subject of much recent drug development and investigation. This condition is characterized by an acute inflammatory phase followed by a resolving, cicatricial phase. There has been a search to find an effective agent to address the acute inflammatory phase of this disease, which would hopefully minimize end stage disfigurement, overall morbidity, and the need for surgery. The advent of antibody-based immunologic therapies has shown promise in this regard. Herein we discuss the current biologic therapeutic landscape, including agents targeting the insulin-like growth factor-1 receptor (IGF-1R, teprotumumab) and the interleukin-6 receptor (IL-6R, tocilizumab), and provide additional insight and opinion from our group practice that is highly experienced in treating a large number of TAO patients. Notably, though teprotumumab is effective, and we regularly prescribe this agent with good success, we feel that tocilizumab should be regarded as another first-line therapy that may be a more appropriate choice for certain patients with active inflammatory TAO.
Article Details
How to Cite
JENSEN, Adrianna D.; SEIFF, Stuart R..
Perspectives on Antibody-Based Thyroid-Associated Orbitopathy Treatments.
Medical Research Archives, [S.l.], v. 11, n. 4, apr. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3788>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i4.3788.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2. Rundle FF. Management of exophthalmos and related ocular changes in Graves’ disease. Metabolism. 1957;6(1):36-48.
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6. Burch HB, Wartofsky L. Graves’ ophthalmopathy: current concepts regarding pathogenesis and management. Endocr Rev. 1993;14(6):747-793. doi:10.1210/edrv-14-6-747
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8. Mourits MPh, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol (Oxf). 1997;47(1):9-14. doi:10.1046/j.1365-2265.1997.2331047.x
9. Smith LD, Moscato EE, Seiff SR. Tocilizumab for the Management of Thyroid-Associated Orbitopathy. Ophthal Plast Reconstr Surg. 2022;38(2):188-192. doi:10.1097/IOP.0000000000002027
10. Men CJ, Kossler AL, Wester ST. Updates on the understanding and management of thyroid eye disease. Ther Adv Ophthalmol. 2021;13:251584142110277. doi:10.1177/25158414211027760
11. Limone PP, Bianco L, Mellano M, et al. Is concomitant treatment with steroids and radiotherapy more favorable than sequential treatment in moderate-to-severe graves orbitopathy? Radiol Med (Torino). 2021;126(2):334-342. doi:10.1007/s11547-020-01244-5
12. Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, Single Blind Trial of Intravenous versus Oral Steroid Monotherapy in Graves’ Orbitopathy. J Clin Endocrinol Metab. 2005;90(9):5234-5240. doi:10.1210/jc.2005-0148
13. 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 Graves’ Orbitopathy. J Clin Endocrinol Metab. 2012;97(12):4454-4463. doi:10.1210/jc.2012-2389
14. Marinó M, Morabito E, Brunetto MR, Bartalena L, Pinchera A, Marocci C. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy. Thyroid Off J Am Thyroid Assoc. 2004;14(5):403-406. doi:10.1089/105072504774193276
15. Bagheri A, Abbaszadeh M, Yazdani S. Intraorbital Steroid Injection for Active Thyroid Ophthalmopathy. J Ophthalmic Vis Res. Published online February 3, 2020. doi:10.18502/jovr.v15i1.5948
16. Kahaly GJ, Riedl M, König 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. 2018;6(4):287-298. doi:10.1016/S2213-8587(18)30020-2
17. Douglas RS, Naik V, Hwang CJ, et al. B Cells from Patients with Graves’ Disease Aberrantly Express the IGF-1 Receptor: Implications for Disease Pathogenesis. J Immunol. 2008;181(8):5768-5774. doi:10.4049/jimmunol.181.8.5768
18. Douglas RS, Afifiyan NF, Hwang CJ, et al. Increased Generation of Fibrocytes in Thyroid-Associated Ophthalmopathy. J Clin Endocrinol Metab. 2010;95(1):430-438. doi:10.1210/jc.2009-1614
19. Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. 2017;376(18):1748-1761. doi:10.1056/NEJMoa1614949
20. 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. doi:10.1056/NEJMoa1910434
21. Kahaly GJ, Douglas RS, Holt RJ, Sile S, Smith TJ. Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials. Lancet Diabetes Endocrinol. 2021;9(6):360-372. doi:10.1016/S2213-8587(21)00056-5
22. Douglas RS, Kahaly GJ, Ugradar S, et al. Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment. Ophthalmology. 2022;129(4):438-449. doi:10.1016/j.ophtha.2021.10.017
23. Ashraf DC, Jankovic I, El-Nachef N, Winn BJ, Kim GE, Kersten RC. New-Onset of Inflammatory Bowel Disease in a Patient Treated With Teprotumumab for Thyroid Associated Ophthalmopathy. Ophthal Plast Reconstr Surg. 2021;37(5):e160-e164. doi:10.1097/IOP.0000000000001943
24. Diniz SB, Cohen LM, Roelofs KA, Rootman DB. Early Experience With the Clinical Use of Teprotumumab in a Heterogenous Thyroid Eye Disease Population. Ophthal Plast Reconstr Surg. 2021;37(6):583-591. doi:10.1097/IOP.0000000000001959
25. Zhao Y, Tsai J, Newell R, Bedian V. VRDN-001, a Full Antagonist Antibody to the Insulin-Like Growth Factor-1 Receptor (IGF-1R) for Thyroid Eye Disease (TED), Binds to a Distinct Epitope from Teprotumumab. Presented at: American Thyroid Association 2022 Annual Meeting; October 19, 2022; Montreal, Quebec, Canada.
26. Ugradar S, Katz B, O’Shaughnessy D, Summerfelt R, She A, Douglas R. VRDN-001, A Full Antagonist Antibody to the Insulin-Like Growth Factor-1 Receptor (IGF-1R) for Thyroid Eye Disease (TED): Phase 1/2 Proof of Concept in Patients with TED. Poster presented at: 91st Annual Meeting of the American Thyroid Association; October 19, 2022; Montreal, Quebec, Canada.
27. Dickinson B, Claussen C, Pestano L, Bedian V. VRDN-002, A Second-Generation Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody for TED: Preclinical PK Profile and Clinical Promise. Poster presented at: American Thyroid Association (ATA) 2021 Annual Meeting; September 30, 2021; Virtual.
28. Rajaii F, McCoy AN, Smith TJ. Cytokines as villains and potential therapeutic targets in thyroid-associated ophthalmopathy: from bench to bedside. Expert Rev Ophthalmol. 2014;9(3):227-234. doi:10.1586/17469899.2014.917960
29. Jyonouchi SC, Valyasevi RW, Harteneck DA, Dutton CM, Bahn RS. Interleukin-6 Stimulates Thyrotropin Receptor Expression in Human Orbital Preadipocyte Fibroblasts from Patients with Graves’ Ophthalmopathy. Thyroid. 2001;11(10):929-934. doi:10.1089/105072501753210984
30. Pérez-Moreiras JV, Álvarez-López A, Gómez EC. Treatment of Active Corticosteroid-Resistant Graves’ Orbitopathy. Ophthal Plast Reconstr Surg. 2014;30(2):162-167. doi:10.1097/IOP.0000000000000037
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. doi:10.1016/j.ajo.2018.07.038
32. Pérez-Moreiras JV, Varela-Agra M, Prada-Sánchez MC, Prada-Ramallal G. Steroid-Resistant Graves’ Orbitopathy Treated with Tocilizumab in Real-World Clinical Practice: A 9-Year Single-Center Experience. J Clin Med. 2021;10(4):706. doi:10.3390/jcm10040706
33. Sánchez-Bilbao L, Martínez-López D, Revenga M, et al. Anti-IL-6 Receptor Tocilizumab in Refractory Graves’ Orbitopathy: National Multicenter Observational Study of 48 Patients. J Clin Med. 2020;9(9):2816. doi:10.3390/jcm9092816
34. Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS. Randomized Controlled Trial of Rituximab in Patients With Graves’ Orbitopathy. J Clin Endocrinol Metab. 2015;100(2):432-441. doi:10.1210/jc.2014-2572
35. 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. doi:10.1210/jc.2014-3014
36. Deltour JB, d’Assigny Flamen M, Ladsous M, et al. Efficacy of rituximab in patients with Graves’ orbitopathy: a retrospective multicenter nationwide study. Graefes Arch Clin Exp Ophthalmol. 2020;258(9):2013-2021. doi:10.1007/s00417-020-04651-6
37. Zhang C, Yan K, Diao Q, et al. A multicenter, randomized, double-blinded, placebo-controlled, dose-ranging study evaluating the efficacy and safety of vunakizumab in patients with moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2022;87(1):95-102. doi:10.1016/j.jaad.2022.01.005
38. Lane LC, Cheetham TD, Perros P, Pearce SHS. New Therapeutic Horizons for Graves’ Hyperthyroidism. Endocr Rev. 2020;41(6):873-884. doi:10.1210/endrev/bnaa022
2. Rundle FF. Management of exophthalmos and related ocular changes in Graves’ disease. Metabolism. 1957;6(1):36-48.
3. Hales IB, Rundle FF. Ocular changes in Graves’ disease. A long-term follow-up study. Q J Med. 1960;29:113-126.
4. Hales IB, Myhill J, Rundle FF, Mackay IR, Perry B. Relation of eye signs in Graves’ disease to circulating antibodies to thyroglobulin. Lancet Lond Engl. 1961;1(7175):468-469. doi:10.1016/s0140-6736(61)90056-3
5. Menconi F, Profilo MA, Leo M, et al. Spontaneous improvement of untreated mild Graves’ ophthalmopathy: Rundle’s curve revisited. Thyroid Off J Am Thyroid Assoc. 2014;24(1):60-66. doi:10.1089/thy.2013.0240
6. Burch HB, Wartofsky L. Graves’ ophthalmopathy: current concepts regarding pathogenesis and management. Endocr Rev. 1993;14(6):747-793. doi:10.1210/edrv-14-6-747
7. Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R. Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: a novel approach. Br J Ophthalmol. 1989;73(8):639-644. doi:10.1136/bjo.73.8.639
8. Mourits MPh, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol (Oxf). 1997;47(1):9-14. doi:10.1046/j.1365-2265.1997.2331047.x
9. Smith LD, Moscato EE, Seiff SR. Tocilizumab for the Management of Thyroid-Associated Orbitopathy. Ophthal Plast Reconstr Surg. 2022;38(2):188-192. doi:10.1097/IOP.0000000000002027
10. Men CJ, Kossler AL, Wester ST. Updates on the understanding and management of thyroid eye disease. Ther Adv Ophthalmol. 2021;13:251584142110277. doi:10.1177/25158414211027760
11. Limone PP, Bianco L, Mellano M, et al. Is concomitant treatment with steroids and radiotherapy more favorable than sequential treatment in moderate-to-severe graves orbitopathy? Radiol Med (Torino). 2021;126(2):334-342. doi:10.1007/s11547-020-01244-5
12. Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, Single Blind Trial of Intravenous versus Oral Steroid Monotherapy in Graves’ Orbitopathy. J Clin Endocrinol Metab. 2005;90(9):5234-5240. doi:10.1210/jc.2005-0148
13. 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 Graves’ Orbitopathy. J Clin Endocrinol Metab. 2012;97(12):4454-4463. doi:10.1210/jc.2012-2389
14. Marinó M, Morabito E, Brunetto MR, Bartalena L, Pinchera A, Marocci C. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy. Thyroid Off J Am Thyroid Assoc. 2004;14(5):403-406. doi:10.1089/105072504774193276
15. Bagheri A, Abbaszadeh M, Yazdani S. Intraorbital Steroid Injection for Active Thyroid Ophthalmopathy. J Ophthalmic Vis Res. Published online February 3, 2020. doi:10.18502/jovr.v15i1.5948
16. Kahaly GJ, Riedl M, König 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. 2018;6(4):287-298. doi:10.1016/S2213-8587(18)30020-2
17. Douglas RS, Naik V, Hwang CJ, et al. B Cells from Patients with Graves’ Disease Aberrantly Express the IGF-1 Receptor: Implications for Disease Pathogenesis. J Immunol. 2008;181(8):5768-5774. doi:10.4049/jimmunol.181.8.5768
18. Douglas RS, Afifiyan NF, Hwang CJ, et al. Increased Generation of Fibrocytes in Thyroid-Associated Ophthalmopathy. J Clin Endocrinol Metab. 2010;95(1):430-438. doi:10.1210/jc.2009-1614
19. Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. 2017;376(18):1748-1761. doi:10.1056/NEJMoa1614949
20. 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. doi:10.1056/NEJMoa1910434
21. Kahaly GJ, Douglas RS, Holt RJ, Sile S, Smith TJ. Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials. Lancet Diabetes Endocrinol. 2021;9(6):360-372. doi:10.1016/S2213-8587(21)00056-5
22. Douglas RS, Kahaly GJ, Ugradar S, et al. Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment. Ophthalmology. 2022;129(4):438-449. doi:10.1016/j.ophtha.2021.10.017
23. Ashraf DC, Jankovic I, El-Nachef N, Winn BJ, Kim GE, Kersten RC. New-Onset of Inflammatory Bowel Disease in a Patient Treated With Teprotumumab for Thyroid Associated Ophthalmopathy. Ophthal Plast Reconstr Surg. 2021;37(5):e160-e164. doi:10.1097/IOP.0000000000001943
24. Diniz SB, Cohen LM, Roelofs KA, Rootman DB. Early Experience With the Clinical Use of Teprotumumab in a Heterogenous Thyroid Eye Disease Population. Ophthal Plast Reconstr Surg. 2021;37(6):583-591. doi:10.1097/IOP.0000000000001959
25. Zhao Y, Tsai J, Newell R, Bedian V. VRDN-001, a Full Antagonist Antibody to the Insulin-Like Growth Factor-1 Receptor (IGF-1R) for Thyroid Eye Disease (TED), Binds to a Distinct Epitope from Teprotumumab. Presented at: American Thyroid Association 2022 Annual Meeting; October 19, 2022; Montreal, Quebec, Canada.
26. Ugradar S, Katz B, O’Shaughnessy D, Summerfelt R, She A, Douglas R. VRDN-001, A Full Antagonist Antibody to the Insulin-Like Growth Factor-1 Receptor (IGF-1R) for Thyroid Eye Disease (TED): Phase 1/2 Proof of Concept in Patients with TED. Poster presented at: 91st Annual Meeting of the American Thyroid Association; October 19, 2022; Montreal, Quebec, Canada.
27. Dickinson B, Claussen C, Pestano L, Bedian V. VRDN-002, A Second-Generation Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody for TED: Preclinical PK Profile and Clinical Promise. Poster presented at: American Thyroid Association (ATA) 2021 Annual Meeting; September 30, 2021; Virtual.
28. Rajaii F, McCoy AN, Smith TJ. Cytokines as villains and potential therapeutic targets in thyroid-associated ophthalmopathy: from bench to bedside. Expert Rev Ophthalmol. 2014;9(3):227-234. doi:10.1586/17469899.2014.917960
29. Jyonouchi SC, Valyasevi RW, Harteneck DA, Dutton CM, Bahn RS. Interleukin-6 Stimulates Thyrotropin Receptor Expression in Human Orbital Preadipocyte Fibroblasts from Patients with Graves’ Ophthalmopathy. Thyroid. 2001;11(10):929-934. doi:10.1089/105072501753210984
30. Pérez-Moreiras JV, Álvarez-López A, Gómez EC. Treatment of Active Corticosteroid-Resistant Graves’ Orbitopathy. Ophthal Plast Reconstr Surg. 2014;30(2):162-167. doi:10.1097/IOP.0000000000000037
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. doi:10.1016/j.ajo.2018.07.038
32. Pérez-Moreiras JV, Varela-Agra M, Prada-Sánchez MC, Prada-Ramallal G. Steroid-Resistant Graves’ Orbitopathy Treated with Tocilizumab in Real-World Clinical Practice: A 9-Year Single-Center Experience. J Clin Med. 2021;10(4):706. doi:10.3390/jcm10040706
33. Sánchez-Bilbao L, Martínez-López D, Revenga M, et al. Anti-IL-6 Receptor Tocilizumab in Refractory Graves’ Orbitopathy: National Multicenter Observational Study of 48 Patients. J Clin Med. 2020;9(9):2816. doi:10.3390/jcm9092816
34. Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS. Randomized Controlled Trial of Rituximab in Patients With Graves’ Orbitopathy. J Clin Endocrinol Metab. 2015;100(2):432-441. doi:10.1210/jc.2014-2572
35. 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. doi:10.1210/jc.2014-3014
36. Deltour JB, d’Assigny Flamen M, Ladsous M, et al. Efficacy of rituximab in patients with Graves’ orbitopathy: a retrospective multicenter nationwide study. Graefes Arch Clin Exp Ophthalmol. 2020;258(9):2013-2021. doi:10.1007/s00417-020-04651-6
37. Zhang C, Yan K, Diao Q, et al. A multicenter, randomized, double-blinded, placebo-controlled, dose-ranging study evaluating the efficacy and safety of vunakizumab in patients with moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2022;87(1):95-102. doi:10.1016/j.jaad.2022.01.005
38. Lane LC, Cheetham TD, Perros P, Pearce SHS. New Therapeutic Horizons for Graves’ Hyperthyroidism. Endocr Rev. 2020;41(6):873-884. doi:10.1210/endrev/bnaa022