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Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant thyroid eye disease: a prospective study

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Abstract

Purpose

To evaluate the clinical outcomes of intravenous tocilizumab (TCZ) injection in patients with moderate-to-severe active thyroid eye disease (TED).

Methods

Patients with active and moderate-to-severe TED who did not respond to conventional therapies were treated with TCZ from June 2019 to January 2021. The medical records of the patients were evaluated before the treatment. We analyzed patient demographics, including the duration of Graves’ disease and TED, and assessed subjective symptoms, such as diplopia and ocular movement, clinical activity score (CAS), modified NOSPECS score, and exophthalmos before treatment and at 4, 8, 12, and 16 weeks after the first drug injection. Blood tests, including TSH Rc Ab and TS Ab, were performed before treatment and 24 weeks after the first injection. And orbital computed tomography (CT) was performed and Barrett’s Index was calculated at baseline and after completion of all injections.

Results

Nineteen completed the scheduled treatment. There were no significant side effects, other than herpes zoster in one case and headache and dermatitis in another. Clinical symptoms before and 16 weeks after the treatment showed mean CAS decreased by 2.4 points, mean modified NOSPECS score decreased by 3.7 points, and mean exophthalmos decreased by 0.4 mm. Diplopia and extraocular muscle limitation improved in ten and remained stationary in five of the 15 patients, who presented with extraocular motility abnormalities. Six of 11 patients who underwent orbit CT showed improvement in muscle size. The mean TSH Rc Ab decreased by 7.5 IU/L and TS-Ab decreased by 162.9%.

Conclusion

TCZ can treat active moderate-to-severe TED, showing high drug compliance and reasonable response to inflammation and extraocular motility abnormality.

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References

  1. Woo KI, Kim YD, Lee SL (2008) The clinical characteristics of thyroid orbitopathy in thyroid dysfunction patients in korea. J Korean Ophthalmol Soc 49:1387–1396. https://doi.org/10.3341/jkos.2008.49.9.1387

    Article  Google Scholar 

  2. Perros P, Neoh C, Dickinson J (2009) Thyroid eye disease. BMJ 338:b560. https://doi.org/10.1136/bmj.b560

    Article  PubMed  Google Scholar 

  3. Woo KI, Kim YD, Lee SY (2013) Prevalence and risk factors for thyroid eye disease among Korean dysthyroid patients. Korean J Ophthalmol 27:397–404. https://doi.org/10.3341/kjo.2013.27.6.397

    Article  PubMed  PubMed Central  Google Scholar 

  4. Crisp M, Starkey KJ, Lane C, Ham J, Ludgate M (2000) Adipogenesis in thyroid eye disease. Invest Ophthalmol Vis Sci 41:3249–3255

    CAS  PubMed  Google Scholar 

  5. Khong JJ, McNab AA, Ebeling PR, Craig JE, Selva D (2016) Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol 100:142–150. https://doi.org/10.1136/bjophthalmol-2015-307399

    Article  PubMed  Google Scholar 

  6. Shan SJ, Douglas RS (2014) The pathophysiology of thyroid eye disease. J Neuroophthalmol 34:177–185. https://doi.org/10.1097/WNO.0000000000000132

    Article  PubMed  Google Scholar 

  7. Douglas RS, Gupta S (2011) The pathophysiology of thyroid eye disease: implications for immunotherapy. Curr Opin Ophthalmol 22:385–390. https://doi.org/10.1097/ICU.0b013e3283499446

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM, European Group on Graves Orbitopathy (2016) The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. Eur Thyroid J 5:9–26. https://doi.org/10.1159/000443828

    Article  CAS  Google Scholar 

  9. Kumari R, Chandra Saha B (2018) Advances in the management of thyroid eye diseases: an overview. Int Ophthalmol 38:2247–2255. https://doi.org/10.1007/s10792-017-0694-0

    Article  PubMed  Google Scholar 

  10. Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodriguez Alvarez FM, Castillo Laguarta JM, Del Estad Cabello A, Gessa Sorroche M, Espana Gregori E, Sales-Sanz M, Tocilizumab in Graves Orbitopathy Study Group (2018) Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial. Am J Ophthalmol 195:181–190. https://doi.org/10.1016/j.ajo.2018.07.038

    Article  CAS  Google Scholar 

  11. Naik VM, Naik MN, Goldberg RA, Smith TJ, Douglas RS (2010) Immunopathogenesis of thyroid eye disease: emerging paradigms. Surv Ophthalmol 55:215–226. https://doi.org/10.1016/j.survophthal.2009.06.009

    Article  PubMed  PubMed Central  Google Scholar 

  12. Copperman T, Idowu OO, Kersten RC, Vagefi MR (2019) Subcutaneous tocilizumab for thyroid eye disease: simplified dosing and delivery. Ophthalmic Plast Reconstr Surg 35:e64–e66. https://doi.org/10.1097/IOP.0000000000001346

    Article  PubMed  Google Scholar 

  13. Smith TJ (2020) Thyroid-associated ophthalmopathy: emergence of teprotumumab as a promising medical therapy. Best Pract Res Clin Endocrinol Metab 34:101383. https://doi.org/10.1016/j.beem.2020.101383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Perez-Moreiras JV, Alvarez-Lopez A, Gomez EC (2014) Treatment of active corticosteroid-resistant graves’ orbitopathy. Ophthalmic Plast Reconstr Surg 30:162–167. https://doi.org/10.1097/IOP.0000000000000037

    Article  PubMed  Google Scholar 

  15. Kahaly GJ (2019) Immunotherapies for thyroid eye disease. Curr Opin Endocrinol Diabetes Obes 26:250–255. https://doi.org/10.1097/MED.0000000000000493

    Article  CAS  PubMed  Google Scholar 

  16. Zang S, Ponto KA, Kahaly GJ (2011) Clinical review: intravenous glucocorticoids for graves’ orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab 96:320–332. https://doi.org/10.1210/jc.2010-1962

    Article  CAS  PubMed  Google Scholar 

  17. Ceballos-Macias Jose J, Rivera-Moscoso R, Flores-Real Jorge A, Vargas-Sanchez J, Ortega-Gutierrez G, Madriz-Prado R, Velasco-Ramos PC, Munoz-Monroy Omar E, Meneses-Perez Anna C, Fernandez-Morales Irma N, Hernandez-Moreno A (2020) Tocilizumab in glucocorticoid-resistant graves orbitopathy. A case series report of a mexican population. Ann Endocrinol (Paris) 81:78–82. https://doi.org/10.1016/j.ando.2020.01.003

    Article  PubMed  Google Scholar 

  18. Bothun ED, Scheurer RA, Harrison AR, Lee MS (2009) Update on thyroid eye disease and management. Clin Ophthalmol 3:543–551. https://doi.org/10.2147/opth.s5228

    Article  PubMed  PubMed Central  Google Scholar 

  19. Verity DH, Rose GE (2013) Acute thyroid eye disease (TED): principles of medical and surgical management. Eye (Lond) 27:308–319. https://doi.org/10.1038/eye.2012.284

    Article  CAS  PubMed  Google Scholar 

  20. Sanchez-Bilbao L, Martinez-Lopez D, Revenga M, Lopez-Vazquez A, Valls-Pascual E, Atienza-Mateo B, Valls-Espinosa B, Maiz-Alonso O, Blanco A, Torre-Salaberri I, Rodriguez-Mendez V, Garcia-Aparicio A, Veroz-Gonzalez R, Jovani V, Peiteado D, Sanchez-Orgaz M, Tomero E, Toyos-Saenz de Miera FJ, Pinillos V, Aurrecoechea E, Mora A, Conesa A, Fernandez-Prada M, Troyano JA, Calvo-Rio V, Demetrio-Pablo R, Gonzalez-Mazon I, Hernandez JL, Castaneda S, Gonzalez-Gay MA, Blanco R (2020) Anti-IL-6 receptor tocilizumab in refractory graves’ orbitopathy: national multicenter observational study of 48 patients. J Clin Med 9:2816. https://doi.org/10.3390/jcm9092816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sy A, Eliasieh K, Silkiss RZ (2017) Clinical response to tocilizumab in severe thyroid eye disease. Ophthalmic Plast Reconstr Surg 33:e55–e57. https://doi.org/10.1097/IOP.0000000000000730

    Article  PubMed  Google Scholar 

  22. Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson EHZ, Perdok R, Fleming JC, Fowler BT, Marcocci C, Marino M, Antonelli A, Dailey R, Harris GJ, Eckstein A, Schiffman J, Tang R, Nelson C, Salvi M, Wester S, Sherman JW, Vescio T, Holt RJ, Smith TJ (2020) Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med 382:341–352. https://doi.org/10.1056/NEJMoa1910434

    Article  CAS  PubMed  Google Scholar 

  23. Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, Harris GJ, Antonelli A, Salvi M, Goldberg RA, Gigantelli JW, Couch SM, Shriver EM, Hayek BR, Hink EM, Woodward RM, Gabriel K, Magni G, Douglas RS (2017) Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 376:1748–1761. https://doi.org/10.1056/NEJMoa1614949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sheppard M, Laskou F, Stapleton PP, Hadavi S, Dasgupta B (2017) Tocilizumab (Actemra). Hum Vaccin Immunother 13:1972–1988. https://doi.org/10.1080/21645515.2017.1316909

    Article  PubMed  PubMed Central  Google Scholar 

  25. Singh JA, Beg S, Lopez-Olivo MA (2010) Tocilizumab for rheumatoid arthritis. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD008331.pub2

    Article  PubMed  PubMed Central  Google Scholar 

  26. Biggioggero M, Crotti C, Becciolini A, Favalli EG (2019) Tocilizumab in the treatment of rheumatoid arthritis: an evidence-based review and patient selection. Drug Des Devel Ther 13:57–70. https://doi.org/10.2147/DDDT.S150580

    Article  CAS  PubMed  Google Scholar 

  27. Scott LJ (2017) Tocilizumab: a review in rheumatoid arthritis. Drugs 77:1865–1879. https://doi.org/10.1007/s40265-017-0829-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Toro-Tobon D, Rachmasari KN, Bradley EA, Wagner LH, Tooley AA, Stokken JK, Stan MN (2023) Medical therapy in patients with moderate to severe, steroid-resistant, thyroid eye disease. Thyroid 33:1237–1244. https://doi.org/10.1089/thy.2023.0167

    Article  CAS  PubMed  Google Scholar 

  29. Stan MN, Garrity JA, Bahn RS (2012) The evaluation and treatment of graves ophthalmopathy. Med Clin North Am 96:311–328. https://doi.org/10.1016/j.mcna.2012.01.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Eckstein AK, Plicht M, Lax H, Neuhauser M, Mann K, Lederbogen S, Heckmann C, Esser J, Morgenthaler NG (2006) Thyrotropin receptor autoantibodies are independent risk factors for graves’ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab 91:3464–3470. https://doi.org/10.1210/jc.2005-2813

    Article  CAS  PubMed  Google Scholar 

  31. Monteiro ML, Goncalves AC, Silva CT, Moura JP, Ribeiro CS, Gebrim EM (2008) Diagnostic ability of barrett’s index to detect dysthyroid optic neuropathy using multidetector computed tomography. Clinics (Sao Paulo) 63:301–306. https://doi.org/10.1590/s1807-59322008000300003

    Article  PubMed  Google Scholar 

  32. Barrett L, Glatt HJ, Burde RM, Gado MH (1988) Optic nerve dysfunction in thyroid eye disease: CT. Radiology 167:503–507. https://doi.org/10.1148/radiology.167.2.3357962

    Article  CAS  PubMed  Google Scholar 

  33. Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P (2007) New therapies for treatment of rheumatoid arthritis. Lancet 370:1861–1874. https://doi.org/10.1016/S0140-6736(07)60784-3

    Article  CAS  PubMed  Google Scholar 

  34. Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R, Investigators O (2008) Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371:987–997. https://doi.org/10.1016/S0140-6736(08)60453-5

    Article  CAS  PubMed  Google Scholar 

  35. Yabe Y, Kojima T, Kaneko A, Asai N, Kobayakawa T, Ishiguro N (2013) A review of tocilizumab treatment in 122 rheumatoid arthritis patients included in the tsurumai biologics communication registry (TBCR) study. Mod Rheumatol 23:245–253. https://doi.org/10.1007/s10165-012-0648-3

    Article  CAS  PubMed  Google Scholar 

  36. Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, Franceschini E, Cuomo G, Orlando G, Borghi V, Santoro A, Di Gaetano M, Puzzolante C, Carli F, Bedini A, Corradi L, Fantini R, Castaniere I, Tabbi L, Girardis M, Tedeschi S, Giannella M, Bartoletti M, Pascale R, Dolci G, Brugioni L, Pietrangelo A, Cossarizza A, Pea F, Clini E, Salvarani C, Massari M, Viale PL, Mussini C (2020) Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol 2:e474–e484. https://doi.org/10.1016/S2665-9913(20)30173-9

    Article  PubMed  PubMed Central  Google Scholar 

  37. Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, Woolley AE, Nikiforow S, Lin N, Sagar M, Schrager H, Huckins DS, Axelrod M, Pincus MD, Fleisher J, Sacks CA, Dougan M, North CM, Halvorsen YD, Thurber TK, Dagher Z, Scherer A, Wallwork RS, Kim AY, Schoenfeld S, Sen P, Neilan TG, Perugino CA, Unizony SH, Collier DS, Matza MA, Yinh JM, Bowman KA, Meyerowitz E, Zafar A, Drobni ZD, Bolster MB, Kohler M, D’Silva KM, Dau J, Lockwood MM, Cubbison C, Weber BN, Mansour MK, Investigators BBTT (2020) Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med 383:2333–2344. https://doi.org/10.1056/NEJMoa2028836

    Article  CAS  PubMed  Google Scholar 

  38. Ito M, Takahashi Y, Katsuda E, Oshima Y, Takeuchi A, Mori T, Abe S, Mori Y, Kakizaki H, Suzuki K (2019) Predictive factors of prognosis after radiation and steroid pulse therapy in thyroid eye disease. Sci Rep 9:2027. https://doi.org/10.1038/s41598-019-38640-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hart RH, Kendall-Taylor P, Crombie A, Perros P (2005) Early response to intravenous glucocorticoids for severe thyroid-associated ophthalmopathy predicts treatment outcome. J Ocul Pharmacol Ther 21:328–336. https://doi.org/10.1089/jop.2005.21.328

    Article  CAS  PubMed  Google Scholar 

  40. Wiersinga W, Zarkovic M, Bartalena L, Donati S, Perros P, Okosieme O, Morris D, Fichter N, Lareida J, von Arx G, Daumerie C, Burlacu MC, Kahaly G, Pitz S, Beleslin B, Ciric J, Ayvaz G, Konuk O, Toruner FB, Salvi M, Covelli D, Curro N, Hegedus L, Brix T, Eugogo, (2018) Predictive score for the development or progression of graves’ orbitopathy in patients with newly diagnosed graves’ hyperthyroidism. Eur J Endocrinol 178:635–643. https://doi.org/10.1530/EJE-18-0039

    Article  CAS  PubMed  Google Scholar 

  41. Thornton J, Kelly SP, Harrison RA, Edwards R (2007) Cigarette smoking and thyroid eye disease: a systematic review. Eye (Lond) 21:1135–1145. https://doi.org/10.1038/sj.eye.6702603

    Article  CAS  PubMed  Google Scholar 

  42. Bartalena L, Marcocci C, Tanda ML, Manetti L, Dell’Unto E, Bartolomei MP, Nardi M, Martino E, Pinchera A (1998) Cigarette smoking and treatment outcomes in graves ophthalmopathy. Ann Intern Med 129:632–635. https://doi.org/10.7326/0003-4819-129-8-199810150-00010

    Article  CAS  PubMed  Google Scholar 

  43. Xing L, Ye L, Zhu W, Shen L, Huang F, Jiao Q, Zhou X, Wang S, Wang W, Ning G (2015) Smoking was associated with poor response to intravenous steroids therapy in Graves’ ophthalmopathy. Br J Ophthalmol 99:1686–1691. https://doi.org/10.1136/bjophthalmol-2014-306463

    Article  PubMed  Google Scholar 

  44. Choy EH, Bernasconi C, Aassi M, Molina JF, Epis OM (2017) Treatment of rheumatoid arthritis with anti-tumor necrosis factor or tocilizumab therapy as first biologic agent in a global comparative observational study. Arthritis Care Res (Hoboken) 69:1484–1494. https://doi.org/10.1002/acr.23303

    Article  CAS  PubMed  Google Scholar 

  45. Gabay C, Emery P, van Vollenhoven R, Dikranian A, Alten R, Pavelka K, Klearman M, Musselman D, Agarwal S, Green J, Kavanaugh A, ADACTA Study Investigators (2013) Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 381:1541–1550. https://doi.org/10.1016/S0140-6736(13)60250-0

    Article  CAS  Google Scholar 

  46. Godfrey KJ, Schmuter G, Hu B, Tooley AA, Dunbar KE, Basner RC, Kazim M (2021) Prospective correlation of risk of obstructive sleep apnea with severe clinical features of thyroid eye disease. Ophthalmic Plast Reconstr Surg 37:S58–S61. https://doi.org/10.1097/IOP.0000000000001809

    Article  PubMed  Google Scholar 

  47. Naselli A, Moretti D, Regalbuto C, Arpi ML, Lo Giudice F, Frasca F, Belfiore A, Le Moli R (2020) Evidence that baseline levels of low-density lipoproteins cholesterol affect the clinical response of graves’ ophthalmopathy to parenteral corticosteroids. Front Endocrinol (Lausanne) 11:609895. https://doi.org/10.3389/fendo.2020.609895

    Article  PubMed  Google Scholar 

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CYL and JWP wrote the main manuscript text. KIW and YDK reviewed the manuscript and revised.

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Correspondence to Kyung In Woo.

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Lee, C., Park, J.W., Kim, YD. et al. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant thyroid eye disease: a prospective study. Int Ophthalmol 44, 179 (2024). https://doi.org/10.1007/s10792-024-03117-6

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