Рецепт. 2022; : 96-116
Новые подходы к лечению пациентов с аутоиммунной офтальмопатией (по материалам Клинических практических рекомендаций 2016 и 2021 гг. Европейской группы по изучению орбитопатии Грейвса (EUGOGO) по ведению пациентов с орбитопатией Грейвса, одобренных Европейским обществом эндокринологов (ESE))
https://doi.org/10.34883/PI.2022.25.1.011Аннотация
Лечение аутоиммунной офтальмопатии (АИО) остается непростой задачей для клиницистов, требует пациентоориентированного подхода и анализа эффективности каждого этапа терапии. В обновленных рекомендациях четко прописан алгоритм лечения АИО с выделением терапии первого и второго уровня. Глюкокортикоиды остаются первой линией терапии. Значительный прорыв в понимании патогенеза АИО позволил активно использовать как уже известные, так и новые препараты антипролиферативного действия, биологическую терапию как вторую линию лечения при неудаче применения глюкокортикоидов. Возросло значение лучевой терапии на область орбит. Выделены приоритеты при лечении АИО и тиреотоксикоза в случае болезни Грейвса. Ознакомление эндокринологов и офтальмологов с представленными рекомендациями позволит улучшить результаты лечения пациентов с АИО и качество их жизни. С учетом новых трактовок механизмов развития АИО и практического опыта представляется целесообразным изменение протокола лечения АИО в Республике Беларусь.
Список литературы
1. Danilova L.I. (2005) Autoimmune ophthalmopathy. Thyroid Diseases and Associated Disorders. Ed. NASHIM, Heiwadou offset. Nagasaki, Japan. 137–151 pp.
2. Korolenko G., Dudich O, Bourko I., Dashkevich E., Bourko O. (2019) Experience in treating patients with endocrine ophthalmopathy. Endocrine Abstracts, no 63, pp. 764. doi: 10.1530/endoabs.63.P764
3. Bartalena L., Baldeschi L., Boboridis K., Eckstein A., Kahaly G.J., Marcocci C., Perros P., Salvi M., Wiersinga W.M.and European Group on Graves O. (2016) The 2016 European ThyroidAssociation / European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. Eur Thyroid J., vol. 5, no 1, pp. 9–26. doi: 10.3389/fendo.2020.615993
4. Wiersinga W.M. (2017) Advances in treatment of active, moderate-to-severe Graves’ophthalmopathy. Lancet: Diabetes and Endocrinol., vol. 5, no 2, pp. 134–142. doi: 10.1016/S2213-8587(16)30046-8
5. TaylorP.N., ZhangL., Lee R.W.J., MullerI., Ezra D.G., Dayan C.M., Kahaly G.J., Ludgate M. (2020) New insights into the pathogenesis and nonsurgical management of Gravesorbitopathy. Nat RevEndocrinol., vol. 16, no 2, pp. 104–116. doi: 10.1038/s41574-019-0305-4
6. Bartalena L., Kahaly G.J., Baldeschi L., Dayan C.M., Eckstein A., Marcocci C., Marinò M., Vaidya B. and Wiersinga W.M. on behalf of EUGOGO (2021) The 2021 European Group on Graves’orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathyEurJ Endocrinol., vol. 185, no 4; pp. G43–G67. doi:10.1530/EJE-21-0479
7. Muller-Forell W., Kahaly G.J. (2012) Neuroimaging of Graves’ orbitopathy. Best PractResClin Endocrinol Metab., vol. 26, no 3, pp. 259–271. doi: 10.1016/j.beem.2011.11.009
8. Eckstein A.K., Plicht M., Lax H., Hirche H., Quadbeck B., Mann K., Steuhl K.P., Esser J., Morgenthaler N.G. (2004) Clinical results of antiinflammatory therapy in Graves’ ophthalmopathy and association with thyroidal autoantibodies. Clinical Endocrinology, vol. 61, pp. 612–618. doi: 10.1111/j.1365-2265.2004.02143.x
9. Bartalena L, Wiersinga W.M. (2020) Proposal for standardization of primary andsecondary outcomes in patients with active, moderate-to-severe Graves’ orbitopathy. EurThyroid J., vol. 9, no 1, pp. 3–16. doi: 10.1159/000510700
10. Perros P., Dayan C.M., Dickinson A.J., Ezra D., Estcourt S., Foley P., Hickey J., Lazarus J.H., MacEwen C.J., McLaren J. et al. (2015) Management of patients with Graves’ orbitopathy: initial assessment, management outside specialised centres and referral pathways. Clinical Medicine, vol. 15, pp. 173–178. doi: 10.7861/clinmedicine.15-2-173
11. Bartalena L., Piantanida E, Gallo D., Lai A, Tanda M.L. (2020) Epidemiology, NaturalHistory, Risk Factors, and Prevention of Graves’ Orbitopathy. Front Endocrinol (Lausanne), vol. 11, pp. 615993. doi: 10.3389/fendo.2020.615993
12. Lanzolla G., Vannucchi G., Ionni I., Campi I., Sileo F., Lazzaroni E., Marino M. (2019) Cholesterol Serum Levels and Use of Statins in Graves’ Orbitopathy: A New Starting Pointforthe Therapy. Front Endocrinol (Lausanne), vol. 10, pp. 933. doi: 10.3389/fendo.2019.00933
13. Bartalena L., Marcocci C., Bogazzi F., Panicucci M., Lepri A., Pinchera A. (1989) Use ofcorticosteroids to prevent progression of Graves’ ophthalmopathy after radioiodine therapy for hyperthyroidism. N EnglJMed., vol. 321, no 20, pp. 349–452. doi: 10.1056/NEJM198911163212001
14. Bartalena L., Marcocci C., Tanda M.L., Manetti L., Dell’Unto E., Bartolomei M.P., Nardi M., Martino E., Pinchera A. (1998) Cigarette smoking and treatment outcomes in Gravesophthalmopathy. Ann InternMed., vol. 129, no 8, pp. 632–635. doi: 10.7326/0003-4819-129-8-199810150-00010
15. Uddin J.M., Davies P.D. (2002) Treatment of upper eyelid retraction associated with thyroid eye disease with subconjunctival botulinum toxin injection. Ophthalmology, vol. 109, no 6, pp. 1183–1187. doi: 10.1016/s0161-6420(02)01041-2
16. Negro R., Hegedus L., Attanasio R., Papini E., Winther K.H. (2019) A 2018 European Thyroid Association survey on the use of selenium supplementation in Graves’ hyperthyroidism and Graves’ orbitopathy. Eur Thyroid J., vol. 8, no 1, pp. 7–15. doi: 10.1159/000494837
17. Kahaly G.J. Management of moderate-to-severe-GO. (2017) Graves’ Orbithopathy (eds. W.M. Wiersinga, G.J. Kahaly), Karger, pp. 140–171.
18. Marcocci C., Bartalena L., Tanda M.L., Manetti L., Dell’Unto E., Rocchi R., BarbesinoG., Mazzi B., Bartolomei M.P., Lepri P. et al. (2001) Comparison of the effectiveness andtolerability of intravenous or oral glucocorticoids associated with orbital radiotherapyin the management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J ClinEndocrinol Metab., vol. 86, no 8, pp. 3562–3567. doi: 10.1210/jcem.86.8.7737
19. Kahaly G.J., Pitz S., Hommel G., Dittmar M. (2005) Randomized, single blind trial ofintravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab., vol. 90, no 9, pp. 5234–5240. doi: 10.1210/jc.2005-0148
20. Marcocci C., Watt T., Altea M.A., Rasmussen A.K., Feldt-Rasmussen U., Orgiazzi J., Bartalena L., European Group of Graves O. (2012) Fatal and non-fatal adverse events ofglucocorticoid therapy for Graves’ orbitopathy: a questionnaire survey among members of the European Thyroid Association. Eur J Endocrinol., vol. 166, no 2, pp. 247–253. doi: 10.1530/EJE-11-0779
21. Miskiewicz P., Jankowska A., Brodzinska K., Milczarek-Banach J., Ambroziak U. (2018) Influence of methylprednisolone pulse therapy on liver function in patients withGraves’orbitopathy. IntJ Endocrinol., 2018, 1978590. doi: 10.1155/2018/1978590
22. Bartalena L., Veronesi G., Krassas G.E., Wiersinga W.M., Marcocci C., Marino M., SalviM., Daumerie C., Bournaud C., Stahl M. et al. (2017) Does early response to intravenousglucocorticoids predict the final outcome in patients with moderate-to-severe andactive Graves’ orbitopathy? JEndocrinol Invest., vol. 40, no 5, pp. 547–553. doi: 10.1007/s40618-017-0608-z
23. Wang Y., Sharma A., Padnick-Silver L., Francis-Sedlak M., Holt R.J., Foley C., Massry G., Douglas R.S. (2020) Trends in treatment of active, moderateto-severe thyroid eyediseasein theUnited States. J Endocr Soc., vol. 4, no 12: bvaa 140. doi: 10.1210/jendso/bvaa140
24. Marcocci C., Bartalena L., Panicucci M., Marconcini C., Cartei F., Cavallacci G., Laddaga M., Campobasso G., Baschieri L., Pinchera A. (1987) Orbital cobalt irradiationcombined with retrobulbar or systemic corticosteroids for Graves’ ophthalmopathy: acomparativestudy. ClinEndocrinol (Oxf)., vol. 27, no 1, pp. 33–42. doi: 10.1111/j.1365-2265.1987.tb00836.x
25. Ebner R., Devoto M.H., Weil D., Bordaberry M., Mir C., Martinez H., Bonelli L., Niepomniszcze H. (2004) Treatment of thyroid associated ophthalmopathy with periocularinjectionsoftriamcinolone. BrJ Ophthalmol., vol. 88, no 11, pp. 1380–1386. doi: 10.1136/bjo.2004.046193
26. Lee S.J., Rim T.H., Jang S.Y., Kim C.Y., Shin D.Y., Lee E.J., Lee S.Y., Yoon J.S. (2013) Treatment ofupper eyelid retraction related to thyroid-associated ophthalmopathy usingsubconjunctival triamcinolone injections. Graefes Arch Clin Exp Ophthalmol., vol. 251, no 1, pp. 261–270. doi: 10.1007/s00417-012-2153-y
27. Staatz C.E., Tett S.E. (2014) Pharmacology and toxicology of mycophenolate in organ transplant recipients: anupdate. ArchToxicol., vol. 88, no 7, pp. 1351–1389. doi: 10.1007/s00204-014-1247-1
28. Kahaly G.J., Riedl M., Konig J., Pitz S., Ponto K., Diana T., Kampmann E., Kolbe E., Eckstein A., Moeller L.C. et al. (2018) Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy (MINGO): a randomised, observermasked, multicentre trial. Lancet Diabetes Endocrinol., vol. 6, no 4, pp. 287–298. doi: 10.1016/S2213-8587(18)30020-2
29. Ye X., Bo X., Hu X., Cui H., Lu B., Shao J., Wang J. (2017) Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves’ orbitopathy. ClinEndocrinol(Oxf.), vol. 86, no 2, pp. 247–255. doi: 10.1111/cen.13170
30. Kahaly G., Schrezenmeir J., Krause U., Schweikert B., Meuer S., Muller W., Dennebaum R., Beyer J. (1986) Ciclosporin and prednisone v. prednisone in treatment ofGraves’ ophthalmopathy: a controlled, randomized and prospective study. Eur J ClinInvest., vol. 16, no 5, pp. 415–422. doi: 10.1111/j.1365-2362.1986.tb01016.x
31. Prummel M.F., Mourits M.P., Berghout A., Krenning E.P., van der Gaag R., Koornneef L., Wiersinga W.M. (1989) Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N EnglJ Med., vol. 321, no 20, pp. 1353–1359. doi: 10.1056/NEJM198911163212002
32. Perros P., Weightman D.R., Crombie A.L., Kendall-Taylor P. (1990) Azathioprine in thetreatment of thyroid-associated ophthalmopathy. Acta Endocrinol (Copenh), vol. 122, no 1, pp. 8–12. doi: 10.1530/acta.0.1220008
33. Rajendram R., Taylor P.N., Wilson V.J., Harris N., Morris O.C., Tomlinson M., YarrowS., Garrott H., Herbert H.M., Dick A.D. et al. (2018) Combined immunosuppression andradiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 x 2 factorial, double-blind, randomized controlled trial. Lancet Diabetes Endocrinol., vol. 6, no 4, pp. 299–309. doi: 10.1016/S2213-8587(18)30021-4
34. Oeverhaus M., Witteler T., Lax H., Esser J., Fuhrer D., Eckstein A. (2017) Combinationtherapy of intravenous steroids and orbital irradiation is more effective thanintravenous steroids alone in patients with Graves’ orbitopathy. Horm Metab Res., vol. 49, no 1, pp. 739–747. doi: 10.1055/s-0043-116945
35. Tanda M.L., Bartalena L. (2012) Efficacy and safety of orbital radiotherapy for graves’orbitopathy. J Clin Endocrinol Metab., vol. 97, no 11, pp. 3857–3865. doi: 10.1210/jc.2012-2758
36. Kahaly G.J., Rösler H.P, Pitz S., Hommel G. (2000) Low- versus high-dose radiotherapy forGraves’ ophthalmopathy: a randomized, single blind trial. J Clin Endocrinol Metab., vol. 85, no 1, pp.102–108. doi: 10.1210/jcem.85.1.6257
37. Douglas R.S., Naik V., Hwang C.J., Afifiyan N.F., Gianoukakis A.G., Sand D., Kamat S., Smith T.J. (2008) B cells from patients with Graves’ disease aberrantly express the IGF-1receptor: implications for disease pathogenesis. J Immunol., vol. 181, no 8, pp. 5768–5774. doi: 10.4049/jimmunol.181.8.5768
38. Smith T.J., Kahaly G.J., Ezra D.G., Fleming J.C., Dailey R.A., Tang R.A., Harris G.J., Antonelli A., Salvi M., Goldberg R.A. et al. (2017) Teprotumumab for thyroid-associated ophthalmopathy. N EnglJ Med., vol. 376, no 18, pp. 1748–1761. doi: 10.1056/NEJMoa1614949
39. Douglas R.S., Kahaly G.J., Patel A., Sile S., Thompson E.H.Z., Perdok R., Fleming J.C., Fowler B.T., Marcocci C., Marino M. et al. (2020) Teprotumumab for the treatment of activethyroideyedisease. NEngl J Med., vol. 382, no 4, pp. 341–352.doi: 10.1056/NEJMoa1910434
40. Mitchell A.L., Gan E.H., Morris M., Johnson K., Neoh C., Dickinson A.J., Perros P., Pearce S.H. (2013) The effect of B cell depletion therapy on antiTSH receptor antibodies andclinical outcome in glucocorticoid-refractory Graves’ orbitopathy. Clin Endocrinol(Oxf), vol. 79, no 3, pp. 437–442. doi: 10.1111/cen.12141
41. Khanna D., Chong K.K., Afifiyan N.F., Hwang C.J., Lee D.K., Garneau H.C., Goldberg R.A., Darwin C.H., Smith T.J., Douglas R.S. (2010) Rituximab treatment of patients with severe, corticosteroid-resistant thyroid-associated ophthalmopathy. Ophthalmology, vol. 117, no 1, pp. 133.e2–139. e2. doi: 10.1016/j.ophtha.2009.05.029
42. Stan M.N, Garrity J.A., Carranza Leon B.G., Prabin T., Bradley E.A., Bahn R.S. (2015) Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J Clin Endocrinol Metab., vol. 100, no 2, pp. 432–441. doi: 10.1210/jc.2014-2572
43. Salvi M., Vannucchi G., Curro N., Campi I., Covelli D., Dazzi D., Simonetta S., Guastella C., Pignataro L., Avignone S. et al. (2015) Efficacy of B-cell targeted therapy withrituximab in patients with active moderate to severe Graves’ orbitopathy: arandomizedcontrolledstudy. JClinEndocrinolMetab., vol. 100, no 2, pp. 422–431. doi: 10.1210/jc.2014-3014
44. Vannucchi G., Campi I., Covelli D., Curro N., Lazzaroni E., Palomba A., Soranna D., Zambon A., Fugazzola L., Muller I. et al. (2020) Efficacy profile and safety implications of verylowdoserituximab inpatients withGraves’ orbitopathy. Thyroid, vol. 31, pp. 821–828. doi: 10.1089/thy.2020.0269
45. Perez-Moreiras J.V., Gomez-Reino J.J., Maneiro J.R., Perez-Pampin E., Romo Lopez A., Rodriguez Alvarez F.M., Castillo Laguarta J.M., Del Estad Cabello A., Gessa Sorroche M., Espana Gregori E. et al. (2018) Efficacy of tocilizumab in patients with moderate-to-severecorticosteroid-resistant Graves orbitopathy: A Randomized Clinical Trial. Am J Ophthalmol., vol. 195, pp. 181–190. doi: 10.1016/j.ajo.2018.07.038
46. Dickinson A.J., Vaidya B., Miller M., Coulthard A., Perros P., Baister E., Andrews C.D., Hesse L., Heverhagen J.T., Heufelder A.E. et al. (2004) Doubleblind, placebo-controlled trial ofoctreotide long-acting repeatable (LAR) in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab., vol. 89, no 12, pp. 5910–5915. doi: 10.1210/jc.2004-0697
47. Paridaens D., van den Bosch W.A., van der Loos T.L., Krenning E.P., van Hagen P.M. (2005) The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye (Lond), vol. 19, no 12, pp. 1286–1289. doi: 10.1038/sj.eye.6701768
48. Sipkova Z., Insull E.A., David J., Turner H.E., Keren S., Norris J.H. (2018) Early use of steroid-sparing agents in the inactivation of moderate-tosevere active thyroid eye disease: astep-downapproach. Clin Endocrinol(Oxf), vol. 89, no 6, pp. 834–839. doi: 10.1111/cen.13834
49. Wakelkamp I.M, Baldeschi L., Saeed P., Mourits M.P., Prummel M.F., Wiersinga W.M. (2005) Surgical or medical decompression as a first-line treatment of optic neuropathy inGraves’ ophthalmopathy? A randomized controlled trial. Clin Endocrinol (Oxf), vol. 63, no 3, pp. 323–328. doi: 10.1111/j.1365-2265.2005.02345.x
50. Curro N., Covelli D., Vannucchi G., Campi I., Pirola G., Simonetta S., Dazzi D.,Guastella C., Pignataro L., Beck-Peccoz P. et al. (2014) Therapeutic outcomes of high-doseintravenous steroids in the treatment of dysthyroid optic neuropathy. Thyroid, vol. 24, no 5, pp. 897–905. doi: 10.1089/thy.2013.0445
51. Baldeschi L. (2017) Rehabilitative surgery. Graves’ Orbitopathy A Multidisciplinary Approach – Questions and Answers (eds. W.M. Wiersinga, G.J. Kahaly), 3rd ed., Basel, Switzerland: Karger.
52. Kahaly G.J., Bartalena L., Hegedus L., Leenhardt L., Poppe K., Pearce S.H. (2018) 2018European Thyroid Association Guideline for the management of Graves’hyperthyroidism. EurThyroid J., vol. 7, no 4, pp. 167–186. doi: 10.1159/000490384
53. Diana T., Ponto K.A., Kahaly G.J. (2021) Thyrotropin receptor antibodies and Graves’orbitopathy.J Endocrinol Invest., vol. 44, no 4, pp. 703–712. doi: 10.1007/s40618-020-01380-9
54. Zarkovic M., Wiersinga W., Perros P., Bartalena L., Donati S., Okosieme O., Morris D., Fichter N., Lareida J., Daumerie C. et al. (2021) Antithyroid drugs in Graves’ hyperthyroidism: differences between “block and replace” and “titration” regimes infrequency of euthyroidism and Graves’ orbitopathy during treatment. J Endocrinol Invest., vol. 44, no 2, pp. 371–378. doi: 10.1007/s40618-020-01320-7
55. Bartalena L., Macchia P.E., Marcocci C., Salvi M., Vermiglio F. (2015) Effects of treatmentmodalities for Graves’ hyperthyroidism on Graves’ orbitopathy: a 2015 Italian Society of Endocrinology Consensus Statement. J Endocrinol Invest., vol. 38, no 4, pp. 481–487. doi: 10.1007/s40618-015-0257-z
56. Elbers L., Mourits M., Wiersinga W. (2011) Outcome of very long-term treatment withantithyroid drugs in Graves’ hyperthyroidism associated with Graves’ orbitopathy. Thyroid, vol. 21, no 3, pp. 279–283. doi: 10.1007/s40618-015-0257-z
Recipe. 2022; : 96-116
New Approaches to Treatment of Patients with Autoimmune Ophthalmopathy (the Review of the 2016 and 2021 Clinical Practice Guidelines of the European Group of Graves’ Orbitopathy (EUGOGO) for the Management of Graves’ Orbitopathy Endorsed by the European Society of Endocrinology (ESE))
https://doi.org/10.34883/PI.2022.25.1.011Abstract
The medical management of autoimmune ophthalmopathy (AIO) is a challenge for clinicians requiring a thoughtful analysis of each stage of treatment and considerable skill. Based on the accumulated experience, the AIO mamagement algorithm which provides thefirst- and the second-linetreatmentis clearly defined in the updated Guidelines. Due to their pathogenic validity, effectiveness and widespread availability, glucocorticoids have remained the first-line treatment. A major breakthrough in the understanding of AIO pathogenesis has allowed to actively usewell-establishedand new antiproliferative drugs andbiological agents as a second-line treatment if there is no response to glucocorticoids. The efficacy of orbital radiotherapy has increased. Priorities in the AIO management and treatment of thyrotoxicosis in Graves’ disease are highlighted. Endocrinologists’ and ophthalmologists’awareness of the updated Guidelines will significantly improve the treatment outcomes in patients with AIO and their quality of life. Taking into account the new insights into the pathogenesis of AIO and clinical experience, it seems appropriate to amend the protocol for the medicalmanagement of AIO in the Republic of Belarus.
References
1. Danilova L.I. (2005) Autoimmune ophthalmopathy. Thyroid Diseases and Associated Disorders. Ed. NASHIM, Heiwadou offset. Nagasaki, Japan. 137–151 pp.
2. Korolenko G., Dudich O, Bourko I., Dashkevich E., Bourko O. (2019) Experience in treating patients with endocrine ophthalmopathy. Endocrine Abstracts, no 63, pp. 764. doi: 10.1530/endoabs.63.P764
3. Bartalena L., Baldeschi L., Boboridis K., Eckstein A., Kahaly G.J., Marcocci C., Perros P., Salvi M., Wiersinga W.M.and European Group on Graves O. (2016) The 2016 European ThyroidAssociation / European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. Eur Thyroid J., vol. 5, no 1, pp. 9–26. doi: 10.3389/fendo.2020.615993
4. Wiersinga W.M. (2017) Advances in treatment of active, moderate-to-severe Graves’ophthalmopathy. Lancet: Diabetes and Endocrinol., vol. 5, no 2, pp. 134–142. doi: 10.1016/S2213-8587(16)30046-8
5. TaylorP.N., ZhangL., Lee R.W.J., MullerI., Ezra D.G., Dayan C.M., Kahaly G.J., Ludgate M. (2020) New insights into the pathogenesis and nonsurgical management of Gravesorbitopathy. Nat RevEndocrinol., vol. 16, no 2, pp. 104–116. doi: 10.1038/s41574-019-0305-4
6. Bartalena L., Kahaly G.J., Baldeschi L., Dayan C.M., Eckstein A., Marcocci C., Marinò M., Vaidya B. and Wiersinga W.M. on behalf of EUGOGO (2021) The 2021 European Group on Graves’orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathyEurJ Endocrinol., vol. 185, no 4; pp. G43–G67. doi:10.1530/EJE-21-0479
7. Muller-Forell W., Kahaly G.J. (2012) Neuroimaging of Graves’ orbitopathy. Best PractResClin Endocrinol Metab., vol. 26, no 3, pp. 259–271. doi: 10.1016/j.beem.2011.11.009
8. Eckstein A.K., Plicht M., Lax H., Hirche H., Quadbeck B., Mann K., Steuhl K.P., Esser J., Morgenthaler N.G. (2004) Clinical results of antiinflammatory therapy in Graves’ ophthalmopathy and association with thyroidal autoantibodies. Clinical Endocrinology, vol. 61, pp. 612–618. doi: 10.1111/j.1365-2265.2004.02143.x
9. Bartalena L, Wiersinga W.M. (2020) Proposal for standardization of primary andsecondary outcomes in patients with active, moderate-to-severe Graves’ orbitopathy. EurThyroid J., vol. 9, no 1, pp. 3–16. doi: 10.1159/000510700
10. Perros P., Dayan C.M., Dickinson A.J., Ezra D., Estcourt S., Foley P., Hickey J., Lazarus J.H., MacEwen C.J., McLaren J. et al. (2015) Management of patients with Graves’ orbitopathy: initial assessment, management outside specialised centres and referral pathways. Clinical Medicine, vol. 15, pp. 173–178. doi: 10.7861/clinmedicine.15-2-173
11. Bartalena L., Piantanida E, Gallo D., Lai A, Tanda M.L. (2020) Epidemiology, NaturalHistory, Risk Factors, and Prevention of Graves’ Orbitopathy. Front Endocrinol (Lausanne), vol. 11, pp. 615993. doi: 10.3389/fendo.2020.615993
12. Lanzolla G., Vannucchi G., Ionni I., Campi I., Sileo F., Lazzaroni E., Marino M. (2019) Cholesterol Serum Levels and Use of Statins in Graves’ Orbitopathy: A New Starting Pointforthe Therapy. Front Endocrinol (Lausanne), vol. 10, pp. 933. doi: 10.3389/fendo.2019.00933
13. Bartalena L., Marcocci C., Bogazzi F., Panicucci M., Lepri A., Pinchera A. (1989) Use ofcorticosteroids to prevent progression of Graves’ ophthalmopathy after radioiodine therapy for hyperthyroidism. N EnglJMed., vol. 321, no 20, pp. 349–452. doi: 10.1056/NEJM198911163212001
14. Bartalena L., Marcocci C., Tanda M.L., Manetti L., Dell’Unto E., Bartolomei M.P., Nardi M., Martino E., Pinchera A. (1998) Cigarette smoking and treatment outcomes in Gravesophthalmopathy. Ann InternMed., vol. 129, no 8, pp. 632–635. doi: 10.7326/0003-4819-129-8-199810150-00010
15. Uddin J.M., Davies P.D. (2002) Treatment of upper eyelid retraction associated with thyroid eye disease with subconjunctival botulinum toxin injection. Ophthalmology, vol. 109, no 6, pp. 1183–1187. doi: 10.1016/s0161-6420(02)01041-2
16. Negro R., Hegedus L., Attanasio R., Papini E., Winther K.H. (2019) A 2018 European Thyroid Association survey on the use of selenium supplementation in Graves’ hyperthyroidism and Graves’ orbitopathy. Eur Thyroid J., vol. 8, no 1, pp. 7–15. doi: 10.1159/000494837
17. Kahaly G.J. Management of moderate-to-severe-GO. (2017) Graves’ Orbithopathy (eds. W.M. Wiersinga, G.J. Kahaly), Karger, pp. 140–171.
18. Marcocci C., Bartalena L., Tanda M.L., Manetti L., Dell’Unto E., Rocchi R., BarbesinoG., Mazzi B., Bartolomei M.P., Lepri P. et al. (2001) Comparison of the effectiveness andtolerability of intravenous or oral glucocorticoids associated with orbital radiotherapyin the management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J ClinEndocrinol Metab., vol. 86, no 8, pp. 3562–3567. doi: 10.1210/jcem.86.8.7737
19. Kahaly G.J., Pitz S., Hommel G., Dittmar M. (2005) Randomized, single blind trial ofintravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab., vol. 90, no 9, pp. 5234–5240. doi: 10.1210/jc.2005-0148
20. Marcocci C., Watt T., Altea M.A., Rasmussen A.K., Feldt-Rasmussen U., Orgiazzi J., Bartalena L., European Group of Graves O. (2012) Fatal and non-fatal adverse events ofglucocorticoid therapy for Graves’ orbitopathy: a questionnaire survey among members of the European Thyroid Association. Eur J Endocrinol., vol. 166, no 2, pp. 247–253. doi: 10.1530/EJE-11-0779
21. Miskiewicz P., Jankowska A., Brodzinska K., Milczarek-Banach J., Ambroziak U. (2018) Influence of methylprednisolone pulse therapy on liver function in patients withGraves’orbitopathy. IntJ Endocrinol., 2018, 1978590. doi: 10.1155/2018/1978590
22. Bartalena L., Veronesi G., Krassas G.E., Wiersinga W.M., Marcocci C., Marino M., SalviM., Daumerie C., Bournaud C., Stahl M. et al. (2017) Does early response to intravenousglucocorticoids predict the final outcome in patients with moderate-to-severe andactive Graves’ orbitopathy? JEndocrinol Invest., vol. 40, no 5, pp. 547–553. doi: 10.1007/s40618-017-0608-z
23. Wang Y., Sharma A., Padnick-Silver L., Francis-Sedlak M., Holt R.J., Foley C., Massry G., Douglas R.S. (2020) Trends in treatment of active, moderateto-severe thyroid eyediseasein theUnited States. J Endocr Soc., vol. 4, no 12: bvaa 140. doi: 10.1210/jendso/bvaa140
24. Marcocci C., Bartalena L., Panicucci M., Marconcini C., Cartei F., Cavallacci G., Laddaga M., Campobasso G., Baschieri L., Pinchera A. (1987) Orbital cobalt irradiationcombined with retrobulbar or systemic corticosteroids for Graves’ ophthalmopathy: acomparativestudy. ClinEndocrinol (Oxf)., vol. 27, no 1, pp. 33–42. doi: 10.1111/j.1365-2265.1987.tb00836.x
25. Ebner R., Devoto M.H., Weil D., Bordaberry M., Mir C., Martinez H., Bonelli L., Niepomniszcze H. (2004) Treatment of thyroid associated ophthalmopathy with periocularinjectionsoftriamcinolone. BrJ Ophthalmol., vol. 88, no 11, pp. 1380–1386. doi: 10.1136/bjo.2004.046193
26. Lee S.J., Rim T.H., Jang S.Y., Kim C.Y., Shin D.Y., Lee E.J., Lee S.Y., Yoon J.S. (2013) Treatment ofupper eyelid retraction related to thyroid-associated ophthalmopathy usingsubconjunctival triamcinolone injections. Graefes Arch Clin Exp Ophthalmol., vol. 251, no 1, pp. 261–270. doi: 10.1007/s00417-012-2153-y
27. Staatz C.E., Tett S.E. (2014) Pharmacology and toxicology of mycophenolate in organ transplant recipients: anupdate. ArchToxicol., vol. 88, no 7, pp. 1351–1389. doi: 10.1007/s00204-014-1247-1
28. Kahaly G.J., Riedl M., Konig J., Pitz S., Ponto K., Diana T., Kampmann E., Kolbe E., Eckstein A., Moeller L.C. et al. (2018) Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy (MINGO): a randomised, observermasked, multicentre trial. Lancet Diabetes Endocrinol., vol. 6, no 4, pp. 287–298. doi: 10.1016/S2213-8587(18)30020-2
29. Ye X., Bo X., Hu X., Cui H., Lu B., Shao J., Wang J. (2017) Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves’ orbitopathy. ClinEndocrinol(Oxf.), vol. 86, no 2, pp. 247–255. doi: 10.1111/cen.13170
30. Kahaly G., Schrezenmeir J., Krause U., Schweikert B., Meuer S., Muller W., Dennebaum R., Beyer J. (1986) Ciclosporin and prednisone v. prednisone in treatment ofGraves’ ophthalmopathy: a controlled, randomized and prospective study. Eur J ClinInvest., vol. 16, no 5, pp. 415–422. doi: 10.1111/j.1365-2362.1986.tb01016.x
31. Prummel M.F., Mourits M.P., Berghout A., Krenning E.P., van der Gaag R., Koornneef L., Wiersinga W.M. (1989) Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N EnglJ Med., vol. 321, no 20, pp. 1353–1359. doi: 10.1056/NEJM198911163212002
32. Perros P., Weightman D.R., Crombie A.L., Kendall-Taylor P. (1990) Azathioprine in thetreatment of thyroid-associated ophthalmopathy. Acta Endocrinol (Copenh), vol. 122, no 1, pp. 8–12. doi: 10.1530/acta.0.1220008
33. Rajendram R., Taylor P.N., Wilson V.J., Harris N., Morris O.C., Tomlinson M., YarrowS., Garrott H., Herbert H.M., Dick A.D. et al. (2018) Combined immunosuppression andradiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 x 2 factorial, double-blind, randomized controlled trial. Lancet Diabetes Endocrinol., vol. 6, no 4, pp. 299–309. doi: 10.1016/S2213-8587(18)30021-4
34. Oeverhaus M., Witteler T., Lax H., Esser J., Fuhrer D., Eckstein A. (2017) Combinationtherapy of intravenous steroids and orbital irradiation is more effective thanintravenous steroids alone in patients with Graves’ orbitopathy. Horm Metab Res., vol. 49, no 1, pp. 739–747. doi: 10.1055/s-0043-116945
35. Tanda M.L., Bartalena L. (2012) Efficacy and safety of orbital radiotherapy for graves’orbitopathy. J Clin Endocrinol Metab., vol. 97, no 11, pp. 3857–3865. doi: 10.1210/jc.2012-2758
36. Kahaly G.J., Rösler H.P, Pitz S., Hommel G. (2000) Low- versus high-dose radiotherapy forGraves’ ophthalmopathy: a randomized, single blind trial. J Clin Endocrinol Metab., vol. 85, no 1, pp.102–108. doi: 10.1210/jcem.85.1.6257
37. Douglas R.S., Naik V., Hwang C.J., Afifiyan N.F., Gianoukakis A.G., Sand D., Kamat S., Smith T.J. (2008) B cells from patients with Graves’ disease aberrantly express the IGF-1receptor: implications for disease pathogenesis. J Immunol., vol. 181, no 8, pp. 5768–5774. doi: 10.4049/jimmunol.181.8.5768
38. Smith T.J., Kahaly G.J., Ezra D.G., Fleming J.C., Dailey R.A., Tang R.A., Harris G.J., Antonelli A., Salvi M., Goldberg R.A. et al. (2017) Teprotumumab for thyroid-associated ophthalmopathy. N EnglJ Med., vol. 376, no 18, pp. 1748–1761. doi: 10.1056/NEJMoa1614949
39. Douglas R.S., Kahaly G.J., Patel A., Sile S., Thompson E.H.Z., Perdok R., Fleming J.C., Fowler B.T., Marcocci C., Marino M. et al. (2020) Teprotumumab for the treatment of activethyroideyedisease. NEngl J Med., vol. 382, no 4, pp. 341–352.doi: 10.1056/NEJMoa1910434
40. Mitchell A.L., Gan E.H., Morris M., Johnson K., Neoh C., Dickinson A.J., Perros P., Pearce S.H. (2013) The effect of B cell depletion therapy on antiTSH receptor antibodies andclinical outcome in glucocorticoid-refractory Graves’ orbitopathy. Clin Endocrinol(Oxf), vol. 79, no 3, pp. 437–442. doi: 10.1111/cen.12141
41. Khanna D., Chong K.K., Afifiyan N.F., Hwang C.J., Lee D.K., Garneau H.C., Goldberg R.A., Darwin C.H., Smith T.J., Douglas R.S. (2010) Rituximab treatment of patients with severe, corticosteroid-resistant thyroid-associated ophthalmopathy. Ophthalmology, vol. 117, no 1, pp. 133.e2–139. e2. doi: 10.1016/j.ophtha.2009.05.029
42. Stan M.N, Garrity J.A., Carranza Leon B.G., Prabin T., Bradley E.A., Bahn R.S. (2015) Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J Clin Endocrinol Metab., vol. 100, no 2, pp. 432–441. doi: 10.1210/jc.2014-2572
43. Salvi M., Vannucchi G., Curro N., Campi I., Covelli D., Dazzi D., Simonetta S., Guastella C., Pignataro L., Avignone S. et al. (2015) Efficacy of B-cell targeted therapy withrituximab in patients with active moderate to severe Graves’ orbitopathy: arandomizedcontrolledstudy. JClinEndocrinolMetab., vol. 100, no 2, pp. 422–431. doi: 10.1210/jc.2014-3014
44. Vannucchi G., Campi I., Covelli D., Curro N., Lazzaroni E., Palomba A., Soranna D., Zambon A., Fugazzola L., Muller I. et al. (2020) Efficacy profile and safety implications of verylowdoserituximab inpatients withGraves’ orbitopathy. Thyroid, vol. 31, pp. 821–828. doi: 10.1089/thy.2020.0269
45. Perez-Moreiras J.V., Gomez-Reino J.J., Maneiro J.R., Perez-Pampin E., Romo Lopez A., Rodriguez Alvarez F.M., Castillo Laguarta J.M., Del Estad Cabello A., Gessa Sorroche M., Espana Gregori E. et al. (2018) Efficacy of tocilizumab in patients with moderate-to-severecorticosteroid-resistant Graves orbitopathy: A Randomized Clinical Trial. Am J Ophthalmol., vol. 195, pp. 181–190. doi: 10.1016/j.ajo.2018.07.038
46. Dickinson A.J., Vaidya B., Miller M., Coulthard A., Perros P., Baister E., Andrews C.D., Hesse L., Heverhagen J.T., Heufelder A.E. et al. (2004) Doubleblind, placebo-controlled trial ofoctreotide long-acting repeatable (LAR) in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab., vol. 89, no 12, pp. 5910–5915. doi: 10.1210/jc.2004-0697
47. Paridaens D., van den Bosch W.A., van der Loos T.L., Krenning E.P., van Hagen P.M. (2005) The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye (Lond), vol. 19, no 12, pp. 1286–1289. doi: 10.1038/sj.eye.6701768
48. Sipkova Z., Insull E.A., David J., Turner H.E., Keren S., Norris J.H. (2018) Early use of steroid-sparing agents in the inactivation of moderate-tosevere active thyroid eye disease: astep-downapproach. Clin Endocrinol(Oxf), vol. 89, no 6, pp. 834–839. doi: 10.1111/cen.13834
49. Wakelkamp I.M, Baldeschi L., Saeed P., Mourits M.P., Prummel M.F., Wiersinga W.M. (2005) Surgical or medical decompression as a first-line treatment of optic neuropathy inGraves’ ophthalmopathy? A randomized controlled trial. Clin Endocrinol (Oxf), vol. 63, no 3, pp. 323–328. doi: 10.1111/j.1365-2265.2005.02345.x
50. Curro N., Covelli D., Vannucchi G., Campi I., Pirola G., Simonetta S., Dazzi D.,Guastella C., Pignataro L., Beck-Peccoz P. et al. (2014) Therapeutic outcomes of high-doseintravenous steroids in the treatment of dysthyroid optic neuropathy. Thyroid, vol. 24, no 5, pp. 897–905. doi: 10.1089/thy.2013.0445
51. Baldeschi L. (2017) Rehabilitative surgery. Graves’ Orbitopathy A Multidisciplinary Approach – Questions and Answers (eds. W.M. Wiersinga, G.J. Kahaly), 3rd ed., Basel, Switzerland: Karger.
52. Kahaly G.J., Bartalena L., Hegedus L., Leenhardt L., Poppe K., Pearce S.H. (2018) 2018European Thyroid Association Guideline for the management of Graves’hyperthyroidism. EurThyroid J., vol. 7, no 4, pp. 167–186. doi: 10.1159/000490384
53. Diana T., Ponto K.A., Kahaly G.J. (2021) Thyrotropin receptor antibodies and Graves’orbitopathy.J Endocrinol Invest., vol. 44, no 4, pp. 703–712. doi: 10.1007/s40618-020-01380-9
54. Zarkovic M., Wiersinga W., Perros P., Bartalena L., Donati S., Okosieme O., Morris D., Fichter N., Lareida J., Daumerie C. et al. (2021) Antithyroid drugs in Graves’ hyperthyroidism: differences between “block and replace” and “titration” regimes infrequency of euthyroidism and Graves’ orbitopathy during treatment. J Endocrinol Invest., vol. 44, no 2, pp. 371–378. doi: 10.1007/s40618-020-01320-7
55. Bartalena L., Macchia P.E., Marcocci C., Salvi M., Vermiglio F. (2015) Effects of treatmentmodalities for Graves’ hyperthyroidism on Graves’ orbitopathy: a 2015 Italian Society of Endocrinology Consensus Statement. J Endocrinol Invest., vol. 38, no 4, pp. 481–487. doi: 10.1007/s40618-015-0257-z
56. Elbers L., Mourits M., Wiersinga W. (2011) Outcome of very long-term treatment withantithyroid drugs in Graves’ hyperthyroidism associated with Graves’ orbitopathy. Thyroid, vol. 21, no 3, pp. 279–283. doi: 10.1007/s40618-015-0257-z
