Current and Future Treatments for Graves’ Disease and Graves’ Ophthalmopathy

Abstract

The course and pathogenesis of Graves’ disease and Graves’ ophthalmopathy are interdependent, influencing each other’s therapeutic choices. Multiple factors including geographic location, access to medical services, patient and physician preferences influence the management of these conditions. Graves’ disease is classically managed with one of three treatment options – antithyroid drugs, radioactive iodine, and thyroidectomy. In recent years, there has been a shift towards antithyroid drugs, including long term therapy with these agents, given the advantage of avoiding hypothyroidism and the apparent safety of this approach. In addition, new therapies are (slowly) emerging, focusing on immunomodulation. Technological advances are opening doors to non-pharmaceutical interventions that aim to deal with both structural thyroid abnormalities as well as biochemical abnormalities of hyperthyroidism. Graves’ ophthalmopathy management is guided by its activity and severity status, with treatment options including smoking cessation, control of hyperthyroidism, local eye measures, glucocorticoids, selenium, orbital radiotherapy, and surgery. In addition to these established treatment choices, new immunotherapy-based approaches are being tested. Some of them (tocilizumab and teprotumumab) are very promising but further evaluation is needed before we can establish their role in clinical care. Agents identified as beneficial in Graves’ disease management will likely be tested in Graves’ ophthalmopathy as well. In the coming years, our main clinical responsibility will be to find the proper balance between the benefits and potential risks of these incoming therapies, and to identify the subgroups of patients where this ratio is most likely to favor a safe and successful therapeutic outcome.

Key words

autoimmunity - thyroid function - hyperthyroidism - immunotherapy

• References

• 1 Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc 1994; 92: 477-588
• 2 Wiersinga WM, Smit T, van der Gaag R, Koornneef L. Temporal relationship between onset of Graves' ophthalmopathy and onset of thyroidal Graves' disease. J Endocrinol Invest 1988; 11: 615-619
• 3 Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid 2016; 26: 1343-1421
• 4 Burch HB, Burman KD, Cooper DS. A 2011 survey of clinical practice patterns in the management of Graves' disease. J Clin Endocrinol Metab 2012; 97: 4549-4558
• 5 Bartalena L, Burch HB, Burman KD, Kahaly GJ. A 2013 European survey of clinical practice patterns in the management of Graves' disease. Clin Endocrinol 2016; 84: 115-120
• 6 Brito JP, Schilz S, Singh Ospina N, Rodriguez-Gutierrez R, Maraka S, Sangaralingham LR, Montori VM. Antithyroid Drugs—The most common treatment for graves' disease in the United States: A nationwide population-based study. Thyroid 2016; 26: 1144-1145
• 7 Sundaresh V, Brito JP, Thapa P, Bahn RS, Stan MN. Comparative effectiveness of treatment choices for graves' hyperthyroidism: A historical cohort study. Thyroid 2017; 27: 497-505
• 8 Laurberg P, Wallin G, Tallstedt L, Abraham-Nordling M, Lundell G, Torring O. TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: A 5-year prospective randomized study. Eur J Endocrinol 2008; 158: 69-75
• 9 Burch HB, Solomon BL, Cooper DS, Ferguson P, Walpert N, Howard R. The effect of antithyroid drug pretreatment on acute changes in thyroid hormone levels after (131)I ablation for Graves' disease. J Clin Endocrinol Metab 2001; 86: 3016-3021
• 10 Akamizu T, Satoh T, Isozaki O, Suzuki A, Wakino S, Iburi T, Tsuboi K, Monden T, Kouki T, Otani H, Teramukai S, Uehara R, Nakamura Y, Nagai M, Mori M. Diagnostic criteria, clinical features, and incidence of thyroid storm based on nationwide surveys. Thyroid 2012; 22: 661-679
• 11 de Rooij A, Vandenbroucke JP, Smit JW, Stokkel MP, Dekkers OM. Clinical outcomes after estimated versus calculated activity of radioiodine for the treatment of hyperthyroidism: Systematic review and meta-analysis. Eur J Endocrinol 2009; 161: 771-777
• 12 Canto AU, Dominguez PN, Jimeno CA, Obaldo JM, Ogbac RV. Comparison of fixed versus calculated activity of radioiodine for the treatment of graves disease in adults. Endocrinol Metab 2016; 31: 168-173
• 13 Bonnema SJ, Bennedbaek FN, Gram J, Veje A, Marving J, Hegedus L. Resumption of methimazole after 131I therapy of hyperthyroid diseases: Effect on thyroid function and volume evaluated by a randomized clinical trial. Eur J Endocrinol 2003; 149: 485-492
• 14 Hieu TT, Russell AW, Cuneo R, Clark J, Kron T, Hall P, Doi SA. Cancer risk after medical exposure to radioactive iodine in benign thyroid diseases: A meta-analysis. Endocr Relat Cancer 2012; 19: 645-655
• 15 Stan MN, Durski JM, Brito JP, Bhagra S, Thapa P, Bahn RS. Cohort study on radioactive iodine-induced hypothyroidism: Implications for Graves' ophthalmopathy and optimal timing for thyroid hormone assessment. Thyroid 2013; 23: 620-625
• 16 Erbil Y, Ozluk Y, Giris M, Salmaslioglu A, Issever H, Barbaros U, Kapran Y, Ozarmagan S, Tezelman S. Effect of lugol solution on thyroid gland blood flow and microvessel density in the patients with Graves' disease. J Clin Endocrinol Metab 2007; 92: 2182-2189
• 17 Yang Y, Hwang S, Kim M, Lim Y, Kim MH, Lee S, Lim DJ, Kang MI, Cha BY. Refractory graves' disease successfully cured by adjunctive cholestyramine and subsequent total thyroidectomy. Endocrinol Metab (Seoul, Korea) 2015; 30: 620-625
• 18 Edafe O, Antakia R, Laskar N, Uttley L, Balasubramanian SP. Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br J Surg 2014; 101: 307-320
• 19 Adam MA, Thomas S, Youngwirth L, Hyslop T, Reed SD, Scheri RP, Roman SA, Sosa JA. Is There a Minimum Number of Thyroidectomies a Surgeon Should Perform to Optimize Patient Outcomes?. Ann Surg 2017; 265: 402-407
• 20 Rubio GA, Koru-Sengul T, Vaghaiwalla TM, Parikh PP, Farra JC, Lew JI. Postoperative Outcomes in Graves' Disease Patients: Results from the Nationwide Inpatient Sample Database. Thyroid 2017; 27: 825-831
• 21 Noordzij JP, Lee SL, Bernet VJ, Payne RJ, Cohen SM, McLeod IK, Hier MP, Black MJ, Kerr PD, Richards ML, Lo CY, Raffaelli M, Bellantone R, Lombardi CP, Cohen JI, Dietrich MS. Early prediction of hypocalcemia after thyroidectomy using parathyroid hormone: an analysis of pooled individual patient data from nine observational studies. J Am Coll Surg 2007; 205: 748-754
• 22 Promberger R, Ott J, Kober F, Karik M, Freissmuth M, Hermann M. Normal parathyroid hormone levels do not exclude permanent hypoparathyroidism after thyroidectomy. Thyroid 2011; 21: 145-150
• 23 Annerbo M, Hultin H, Stalberg P, Hellman P. Left-shifted relation between calcium and parathyroid hormone in Graves' disease. J Clin Endocrinol Metab 2014; 99: 545-551
• 24 Shah M, Bancos I, Thompson GB, Richards ML, Kasperbauer JL, Clarke BL, Drake MT, Stan MN. Teriparatide therapy and reduced postoperative hospitalization for postsurgical hypoparathyroidism. JAMA Otolaryngol Head Neck Surg 2015; 141: 822-827
• 25 Cooper DS. Antithyroid drugs. N Eng J Med 2005; 352: 905-917
• 26 Laurberg P. Remission of Graves' disease during anti-thyroid drug therapy. Time to reconsider the mechanism?. Eur J Endocrinol 2006; 155: 783-786
• 27 Vaidya B, Wright A, Shuttleworth J, Donohoe M, Warren R, Brooke A, Gericke CA, Ukoumunne OC. Block & replace regime versus titration regime of antithyroid drugs for the treatment of Graves' disease: A retrospective observational study. Clin Endocrinol (Oxf) 2014; 81: 610-613
• 28 Carella C, Mazziotti G, Sorvillo F, Piscopo M, Cioffi M, Pilla P, Nersita R, Iorio S, Amato G, Braverman LE, Roti E. Serum thyrotropin receptor antibodies concentrations in patients with Graves' disease before, at the end of methimazole treatment, and after drug withdrawal: evidence that the activity of thyrotropin receptor antibody and/or thyroid response modify during the observation period. Thyroid 2006; 16: 295-302
• 29 Schott M, Eckstein A, Willenberg HS, Nguyen TB, Morgenthaler NG, Scherbaum WA. Improved prediction of relapse of Graves' thyrotoxicosis by combined determination of TSH receptor and thyroperoxidase antibodies. Horm Metab Res 2007; 39: 56-61
• 30 Mazza E, Carlini M, Flecchia D, Blatto A, Zuccarini O, Gamba S, Beninati S, Messina M. Long-term follow-up of patients with hyperthyroidism due to Graves' disease treated with methimazole. Comparison of usual treatment schedule with drug discontinuation vs continuous treatment with low methimazole doses: a retrospective study. J Endocrinol Invest 2008; 31: 866-872
• 31 Konishi T, Okamoto Y, Ueda M, Fukuda Y, Harusato I, Tsukamoto Y, Hamada N. Drug discontinuation after treatment with minimum maintenance dose of an antithyroid drug in Graves' disease: A retrospective study on effects of treatment duration with minimum maintenance dose on lasting remission. Endocr J 2011; 58: 95-100
• 32 Eckstein AK, Lax H, Losch C, Glowacka D, Plicht M, Mann K, Esser J, Morgenthaler NG. Patients with severe Graves' ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission. Clin Endocrinol (Oxf) 2007; 67: 607-612
• 33 Azizi F, Ataie L, Hedayati M, Mehrabi Y, Sheikholeslami F. Effect of long-term continuous methimazole treatment of hyperthyroidism: Comparison with radioiodine. Eur J Endocrinol 2005; 152: 695-701
• 34 Azizi F, Malboosbaf R. Long-term antithyroid drug treatment: A systematic review and meta-analysis. Thyroid 2017; 27: 1223-1231
• 35 Villagelin D, Romaldini JH, Santos RB, Milkos AB, Ward LS. Outcomes in relapsed graves' disease patients following radioiodine or prolonged low dose of methimazole treatment. Thyroid 2015; 25: 1282-1290
• 36 Kim YA, Cho SW, Choi HS, Moon S, Moon JH, Kim KW, Park DJ, Yi KH, Park YJ, Cho BY. The Second Antithyroid Drug Treatment Is Effective in Relapsed Graves' Disease Patients: A Median 11-Year Follow-Up Study. Thyroid 2017; 27: 491-496
• 37 Andersohn F, Konzen C, Garbe E. Systematic review: Agranulocytosis induced by nonchemotherapy drugs. Ann Int Med 2007; 146: 657-665
• 38 Takata K, Kubota S, Fukata S, Kudo T, Nishihara E, Ito M, Amino N, Miyauchi A. Methimazole-induced agranulocytosis in patients with Graves' disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily. Thyroid 2009; 19: 559-563
• 39 Chen PL, Shih SR, Wang PW, Lin YC, Chu CC, Lin JH, Chen SC, Chang CC, Huang TS, Tsai KS, Tseng FY, Wang CY, Lu JY, Chiu WY, Chang CC, Chen YH, Chen YT, Fann CS, Yang WS, Chang TC. Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study. Nat Commun 2015; 6: 7633
• 40 Hallberg P, Eriksson N, Ibanez L, Bondon-Guitton E, Kreutz R, Carvajal A, Lucena MI, Ponce ES, Molokhia M, Martin J, Axelsson T, Yue QY, Magnusson PK, Wadelius M. Genetic variants associated with antithyroid drug-induced agranulocytosis: A genome-wide association study in a European population. Lancet Diabetes Endocrinol 2016; 4: 507-516
• 41 Vilchez FJ, Torres I, Garcia-Valero A, Lopez-Tinoco C, de Los Santos A, Aguilar-Diosdado M. Concomitant agranulocytosis and hepatotoxicity after treatment with carbimazole. Ann Pharmacother 2006; 40: 2059-2063
• 42 Ruiz JK, Rossi GV, Vallejos HA, Brenet RW, Lopez IB, Escribano AA. Fulminant hepatic failure associated with propylthiouracil. Ann Pharmacother 2003; 37: 224-228
• 43 Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein IL, Laurberg P, McDougall IR, Rivkees SA, Ross D, Sosa JA, Stan MN. The role of propylthiouracil in the management of graves' disease in adults: Report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid 2009; 19: 673-674
• 44 Yang J, Li LF, Xu Q, Zhang J, Weng WW, Zhu YJ, Dong MJ. Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China. Thyroid 2015; 25: 278-283
• 45 Andersen SL, Olsen J, Laurberg P. Antithyroid Drug Side Effects in the Population and in Pregnancy. The Journal of clinical endocrinology and metabolism 2016; 101: 1606-1614
• 46 Wang R, Tan J, Zhang G, Zheng W, Li C. Risk factors of hepatic dysfunction in patients with Graves' hyperthyroidism and the efficacy of 131iodine treatment. Medicine 2017; 96: e6035
• 47 Gunton JE, Stiel J, Clifton-Bligh P, Wilmshurst E, McElduff A. Prevalence of positive anti-neutrophil cytoplasmic antibody (ANCA) in patients receiving anti-thyroid medication. Eur J Endocrinol 2000; 142: 587
• 48 Yang J, Yao LP, Dong MJ, Xu Q, Zhang J, Weng WW, Chen F. Clinical characteristics and outcomes of propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis in patients with graves' disease: A median 38-month retrospective cohort study from a single institution in China. Thyroid 2017; 27: 1469-1474
• 49 Kubota S. Successful Re-administration of Low-dose of Methimazole (MMI) in Graves' Disease Patients Who Experienced Allergic Cutaneous Reactions to MMI at Initial Treatment and Had Received Long-term Propylthiouracil (PTU). Int Med (Tokyo, Japan) 2016; 55: 3235-3237
• 50 Vrca VB, Mayer L, Skreb F, Rahelic D, Marusic S. Antioxidant supplementation and serum lipids in patients with Graves' disease: Effect on LDL-cholesterol. Acta Pharm (Zagreb, Croatia) 2012; 62: 115-122
• 51 Wang L, Wang B, Chen SR, Hou X, Wang XF, Zhao SH, Song JQ, Wang YG. Effect of Selenium Supplementation on Recurrent Hyperthyroidism Caused by Graves' Disease: A prospective pilot study. Horm Metab Res 2016; 48: 559-564
• 52 Leo M, Bartalena L, Rotondo Dottore G, Piantanida E, Premoli P, Ionni I, Di Cera M, Masiello E, Sassi L, Tanda ML, Latrofa F, Vitti P, Marcocci C, Marino M. Effects of selenium on short-term control of hyperthyroidism due to Graves' disease treated with methimazole: results of a randomized clinical trial. J Endocrinol Invest 2017; 40: 281-287
• 53 Calissendorff J, Mikulski E, Larsen EH, Moller M. A Prospective Investigation of Graves' Disease and Selenium: Thyroid Hormones, Auto-Antibodies and Self-Rated Symptoms. Eur Thyroid J 2015; 4: 93-98
• 54 Kahaly GJ, Riedl M, Konig J, Diana T, Schomburg L. Double-Blind, Placebo-Controlled, Randomized Trial of Selenium in Graves Hyperthyroidism. J Clin Endocrinol Metab 2017; 102: 4333-4341
• 55 Bogazzi F, Bartalena L, Campomori A, Brogioni S, Traino C, De Martino F, Rossi G, Lippi F, Pinchera A, Martino E. Treatment with lithium prevents serum thyroid hormone increase after thionamide withdrawal and radioiodine therapy in patients with Graves' disease. J Clin Endocrinol Metab 2002; 87: 4490-4495
• 56 Hammond EN, Vangu MD. Effect of adjuvant lithium on thyroxine (T4) concentration after radioactive iodine therapy. Eur J Nucl Med Mol Imag 2016; 43: 1980-1987
• 57 Prakash I, Nylen ES, Sen S. Lithium as an alternative option in Graves thyrotoxicosis. Case Rep Endocrinol 2015; 2015: 86934
• 58 Sato S, Noh JY, Sato S, Suzuki M, Yasuda S, Matsumoto M, Kunii Y, Mukasa K, Sugino K, Ito K, Nagataki S, Taniyama M. Comparison of efficacy and adverse effects between methimazole 15 mg+inorganic iodine 38 mg/day and methimazole 30 mg/day as initial therapy for Graves' disease patients with moderate to severe hyperthyroidism. Thyroid 2015; 25: 43-50
• 59 Okamura K, Sato K, Fujikawa M, Bandai S, Ikenoue H, Kitazono T. Remission after potassium iodide therapy in patients with Graves' hyperthyroidism exhibiting thionamide-associated side effects. J Clin Endocrinol Metab 2014; 99: 3995-4002
• 60 Jha S, Waghdhare S, Reddi R, Bhattacharya P. Thyroid storm due to inappropriate administration of a compounded thyroid hormone preparation successfully treated with plasmapheresis. Thyroid 2012; 22: 1283-1286
• 61 Muller C, Perrin P, Faller B, Richter S, Chantrel F. Role of plasma exchange in the thyroid storm. Therap Apheresis Dial 2011; 15: 522-531
• 62 Chopra IJ, Williams DE, Orgiazzi J, Solomon DH. Opposite effects of dexamethasone on serum concentrations of 3,3',5'-triiodothyronine (reverse T3) and 3,3'5-triiodothyronine (T3). J Clin Endocrinol Metab 1975; 41: 911-920
• 63 Cooper DS, Laurberg P. Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol 2013; 1: 238-249
• 64 Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, Grobman WA, Laurberg P, Lazarus JH, Mandel SJ, Peeters RP, Sullivan S. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid 2017; 27: 315-389
• 65 Andersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregnancy use of antithyroid drugs: A Danish nationwide study. J Clin Endocrinol Metab 2013; 98: 4373-4381
• 66 Laurberg P, Andersen SL. Therapy of endocrine disease: antithyroid drug use in early pregnancy and birth defects: Time windows of relative safety and high risk?. Eur J Endocrinol 2014; 171: R13-R20
• 67 Rotondi M, Capelli V, Coperchini F, Pinto S, Croce L, Tonacchera M, Chiovato L. Post partum and non-post partum relapsing Graves' hyperthyroidism display different response to anti-thyroid drugs. Eur J Endocrinol 2018; 178: 589-594
• 68 El Fassi D, Nielsen CH, Bonnema SJ, Hasselbalch HC, Hegedus L. B lymphocyte depletion with the monoclonal antibody rituximab in Graves' disease: A controlled pilot study. J Clin Endocrinol Metab 2007; 92: 1769-1772
• 69 Nielsen CH, El Fassi D, Hasselbalch HC, Bendtzen K, Hegedus L. B-cell depletion with rituximab in the treatment of autoimmune diseases. Graves' ophthalmopathy the latest addition to an expanding family. Expert Opin Biol Ther 2007; 7: 1061-1078
• 70 Dawson NAJ, Vent-Schmidt J, Levings MK. Engineered Tolerance: Tailoring Development, Function, and Antigen-Specificity of Regulatory T Cells. Front Immunol 2017; 8: 1460
• 71 Sanders P, Young S, Sanders J, Kabelis K, Baker S, Sullivan A, Evans M, Clark J, Wilmot J, Hu X, Roberts E, Powell M, Nunez Miguel R, Furmaniak J, Rees Smith B. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol 2011; 46: 81-99
• 72 Furmaniak J, Sanders J, Young S, Kabelis K, Sanders P, Evans M, Clark J, Wilmot J, Rees Smith B. In vivo effects of a human thyroid-stimulating monoclonal autoantibody (M22) and a human thyroid-blocking autoantibody (K1-70). Auto Immun Highlights 2012; 3: 19-25
• 73 Lang BH, Wu ALH. The efficacy and safety of high-intensity focused ultrasound ablation of benign thyroid nodules. Ultrasonography (Seoul, Korea) 2018; 37: 89-97
• 74 Spiezia S, Garberoglio R, Milone F, Ramundo V, Caiazzo C, Assanti AP, Deandrea M, Limone PP, Macchia PE, Lombardi G, Colao A, Faggiano A. Thyroid nodules and related symptoms are stably controlled two years after radiofrequency thermal ablation. Thyroid 2009; 19: 219-225
• 75 Faggiano A, Ramundo V, Assanti AP, Fonderico F, Macchia PE, Misso C, Marciello F, Marotta V, Del Prete M, Papini E, Lombardi G, Colao A, Spiezia S. Thyroid Nodules Treated with Percutaneous Radiofrequency Thermal Ablation: A Comparative Study. J Clin Endocrinol Metab 2012; 97: 4439-4445
• 76 Baek JH, Moon WJ, Kim YS, Lee JH, Lee D. Radiofrequency ablation for the treatment of autonomously functioning thyroid nodules. World J Surg 2009; 33: 1971-1977
• 77 Hamidi O, Callstrom MR, Lee RA, Dean D, Castro MR, Morris JC, Stan M. Outcomes of radiofrequency ablation therapy for large benign thyroid nodules: A mayo clinic case series. Mayo Clin Proc 2018; 93: 1018-1025
• 78 Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM. The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy. Eur Thyroid J 2016; 5: 9-26
• 79 Stan MN, Garrity JA, Bahn RS. The evaluation and treatment of graves ophthalmopathy. Med Clin North Am 2012; 96: 311-328
• 80 Prummel MF, Wiersinga WM. Smoking and risk of Graves' disease. JAMA 1993; 269: 479-482
• 81 Eckstein A, Quadbeck B, Mueller G, Rettenmeier AW, Hoermann R, Mann K, Steuhl P, Esser J. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br J Ophthalmol 2003; 87: 773-776
• 82 Pfeilschifter J, Ziegler R. Smoking and endocrine ophthalmopathy: Impact of smoking severity and current vs lifetime cigarette consumption. Clin Endocrinol (Oxf) 1996; 45: 477-481
• 83 Tallstedt L, Lundell G, Torring O, Wallin G, Ljunggren JG, Blomgren H, Taube A. Occurrence of ophthalmopathy after treatment for Graves' hyperthyroidism. The Thyroid Study Group. N Eng J Med 1992; 326: 1733-1738
• 84 Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell'Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E, Pinchera A. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Eng J Med 1998; 338: 73-78
• 85 Traisk F, Tallstedt L, Abraham-Nordling M, Andersson T, Berg G, Calissendorff J, Hallengren B, Hedner P, Lantz M, Nystrom E, Ponjavic V, Taube A, Torring O, Wallin G, Asman P, Lundell G. Thyroid-associated ophthalmopathy after treatment for Graves' hyperthyroidism with antithyroid drugs or iodine-131. J Clin Endocrinol Metab 2009; 94: 3700-3707
• 86 Shiber S, Stiebel-Kalish H, Shimon I, Grossman A, Robenshtok E. Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis. Thyroid 2014; 24: 1515-1523
• 87 De Bellis A, Conzo G, Cennamo G, Pane E, Bellastella G, Colella C, Iacovo AD, Paglionico VA, Sinisi AA, Wall JR, Bizzarro A, Bellastella A. Time course of Graves' ophthalmopathy after total thyroidectomy alone or followed by radioiodine therapy: A 2-year longitudinal study. Endocrine 2012; 41: 320-326
• 88 Laurberg P, Berman DC, Andersen S, Pedersen IB. Sustained control of graves' hyperthyroidism during long-term low-dose antithyroid drug therapy of patients with severe graves' orbitopathy. Thyroid 2011; 21: 951-956
• 89 Elbers L, Mourits M, Wiersinga W. Outcome of very long-term treatment with antithyroid drugs in Graves' hyperthyroidism associated with Graves' orbitopathy. Thyroid 2011; 21: 279-283
• 90 Baudouin C, Cochener B, Pisella PJ, Girard B, Pouliquen P, Cooper H, Creuzot-Garcher C. Randomized, phase III study comparing osmoprotective carboxymethylcellulose with sodium hyaluronate in dry eye disease. Eur J Ophthalmol 2012; 22: 751-761
• 91 Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, Altea MA, Nardi M, Pitz S, Boboridis K, Sivelli P, von Arx G, Mourits MP, Baldeschi L, Bencivelli W, Wiersinga W. Selenium and the course of mild Graves' orbitopathy. N Eng J Med 2011; 364: 1920-1931
• 92 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: 5234-5240
• 93 Zhu W, Ye L, Shen L, Jiao Q, Huang F, Han R, Zhang X, Wang S, Wang W, Ning G. A prospective, randomized trial of intravenous glucocorticoids therapy with different protocols for patients with graves' ophthalmopathy. J Clin Endocrinol Metab 2014; 99: 1999-2007
• 94 Bartalena L, Krassas GE, Wiersinga W, Marcocci C, Salvi M, Daumerie C, Bournaud C, Stahl M, Sassi L, Veronesi G, Azzolini C, Boboridis KG, Mourits MP, Soeters MR, Baldeschi L, Nardi M, Curro N, Boschi A, Bernard M, von Arx G. 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: 4454-4463
• 95 Bartalena L, Veronesi G, Krassas GE, Wiersinga WM, Marcocci C, Marino M, Salvi M, Daumerie C, Bournaud C, Stahl M, Sassi L, Azzolini C, Boboridis KG, Mourits MP, Soeters MR, Baldeschi L, Nardi M, Curro N, Boschi A, Bernard M, von Arx G, Perros P, Kahaly GJ. Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves' orbitopathy?. J Endocrinol Invest 2017; 40: 547-553
• 96 Marcocci C, Watt T, Altea MA, Rasmussen AK, Feldt-Rasmussen U, Orgiazzi J, Bartalena L. Fatal and non-fatal adverse events of glucocorticoid therapy for Graves' orbitopathy: A questionnaire survey among members of the European Thyroid Association. Eur J Endocrinol 2012; 166: 247-253
• 97 Zang S, Ponto KA, Pitz S, Kahaly GJ. Dose of intravenous steroids and therapy outcome in Graves' orbitopathy. J Endocrinol Invest 2011; 34: 876-880
• 98 Bradley EA, Gower EW, Bradley DJ, Meyer DR, Cahill KV, Custer PL, Holck DE, Woog JJ. Orbital radiation for graves ophthalmopathy: A report by the American Academy of Ophthalmology. Ophthalmology 2008; 115: 398-409
• 99 Prummel MF, Terwee CB, Gerding MN, Baldeschi L, Mourits MP, Blank L, Dekker FW, Wiersinga WM. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy. J Clin Endocrinol Metab 2004; 89: 15-20
• 100 Oeverhaus M, Witteler T, Lax H, Esser J, Führer D, Eckstein A. Combination Therapy of Intravenous Steroids and Orbital Irradiation is More Effective Than Intravenous Steroids Alone in Patients with Graves’ Orbitopathy. Horm Metab Res 2017; 49: 739-747
• 101 Marcocci C, Bartalena L, Bogazzi F, Bruno-Bossio G, Lepri A, Pinchera A. Orbital radiotherapy combined with high dose systemic glucocorticoids for Graves' ophthalmopathy is more effective than radiotherapy alone: Results of a prospective randomized study. J Endocrinol Invest 1991; 14: 853-860
• 102 Tanda ML, Bartalena L. Efficacy and safety of orbital radiotherapy for graves' orbitopathy. J Clin Endocrinol Metab 2012; 97: 3857-3865
• 103 Hahn E, Laperriere N, Millar BA, Oestreicher J, McGowan H, Krema H, Gill H, DeAngelis D, Hurwitz J, Tucker N, Simpson R, Chung C. Orbital radiation therapy for Graves' ophthalmopathy: measuring clinical efficacy and impact. Pract Radiation. Oncol 2014; 4: 233-239
• 104 Matthiesen C, Thompson JS, Thompson D, Farris B, Wilkes B, Ahmad S, Herman T, Bogardus Jr. C. The efficacy of radiation therapy in the treatment of Graves' orbitopathy. Int J Radiation Oncol Biol Phys 2012; 82: 117-123
• 105 Prummel MF, Mourits MP, Berghout A, Krenning EP, van der Gaag R, Koornneef L, Wiersinga WM. Prednisone and cyclosporine in the treatment of severe Graves' ophthalmopathy. N Eng J Med 1989; 321: 1353-1359
• 106 Kahaly G, Schrezenmeir J, Krause U, Schweikert B, Meuer S, Muller W, Dennebaum R, Beyer J. Ciclosporin and prednisone v. prednisone in treatment of Graves' ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest 1986; 16: 415-422
• 107 Görtz G-E, Horstmann M, Aniol B, Reyes BD, Fandrey J, Eckstein A, Berchner-Pfannschmidt U. Hypoxia-Dependent HIF-1 Activation Impacts on Tissue Remodeling in Graves’ Ophthalmopathy–Implications for Smoking. J Clin Endocrinol Metab 2016; 101: 4834-4842
• 108 Garrity JA. Preoperative Assessment and Orbital Decompression Surgery in Patients with Graves’ Ophthalmopathy. In: Bahn RS. (ed). Graves' Disease: A Comprehensive Guide for Clinicians. Berlin: Springer; 2015: 277-285
• 109 Eckstein A, Joachim E. Surgical Management of Extraocular Muscle Dysfunction in Patients with GO. In: Bahn RS. (ed) Graves' Disease: A Comprehensive Guide for Clinicians. Berlin: Springer; 2016: 287-299
• 110 Baldeschi L. Rehabilitative Surgery. In: Wiersinga WM, Kahaly GJ. (eds) Graves' Orbitopathy: A Multidisciplinary Approach – Questions and Answers. 2 ed Basel: Karger; 2010: 167-170
• 111 Baldeschi L. Orbital Decompression. In: Wiersinga WM, Kahaly GJ. (eds). Graves’ Orbitopathy: A Multidisciplinary Approach – Questions and Answers. 2 ed Basel: Karger; 2010: 171-185
• 112 Perros P, Weightman DR, Crombie AL, Kendall-Taylor P. Azathioprine in the treatment of thyroid-associated ophthalmopathy. Acta Endocrinol 1990; 122: 8-12
• 113 Rajendram R, Taylor PN, Wilson VJ, Harris N, Morris OC, Tomlinson M, Yarrow S, Garrott H, Herbert HM, Dick AD, Cook A, Gattamaneni R, Jain R, Olver J, Hurel SJ, Bremner F, Drummond SR, Kemp E, Ritchie DM, Rumsey N, Morris D, Lane C, Palaniappan N, Li C, Pell J, Hills R, Ezra DG, Potts MJ, Jackson S, Rose GE, Plowman N, Bunce C, Uddin JM, Lee RWJ, Dayan CM. 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
• 114 Grisolia ABD, Couso RC, Matayoshi S, Douglas RS, Briceno CA. Non-surgical treatment for eyelid retraction in thyroid eye disease (TED). Br J Ophthalmol 2017; DOI: 10.1136/bjophthalmol-2017-310695. [Epub ahead of print]
• 115 Uddin JM, Davies PD. Treatment of upper eyelid retraction associated with thyroid eye disease with subconjunctival botulinum toxin injection. Ophthalmology 2002; 109: 1183-1187
• 116 Morgenstern KE, Evanchan J, Foster JA, Cahill KV, Burns JA, Holck DE, Perry JD, Wulc AE. Botulinum toxin type a for dysthyroid upper eyelid retraction. Ophthal Plastic Reconstruct Surg 2004; 20: 181-185
• 117 Laurberg P, Berman DC, Bulow Pedersen I, Andersen S, Carle A. Incidence and clinical presentation of moderate to severe graves' orbitopathy in a Danish population before and after iodine fortification of salt. J Clin Endocrinol Metab 2012; 97: 2325-2332
• 118 Salvi M, Vannucchi G, Beck-Peccoz P. Potential utility of rituximab for Graves' orbitopathy. J Clin Endocrinol Metab 2013; 98: 4291-4299
• 119 Salvi M, Vannucchi G, Currò N, Campi I, Covelli D, Dazzi D, Simonetta S, Guastella C, Pignataro L, Avignone S, Beck-Peccoz P. 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: 422-431
• 120 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: 432-441
• 121 Stan MN, Salvi M. Management of Endocrine Disease: Rituximab therapy for Graves' orbitopathy - lessons from randomized control trials. Eur J Endocrinol 2017; 176: R101-R109
• 122 Perez-Moreiras JV, Alvarez-Lopez A, Gomez EC. Treatment of active corticosteroid-resistant graves' orbitopathy. Ophthal Plast Reconstr Surg 2014; 30: 162-167
• 123 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. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Eng J Med 2017; 376: 1748-1761
• 124 Krieger CC, Place RF, Bevilacqua C, Marcus-Samuels B, Abel BS, Skarulis MC, Kahaly GJ, Neumann S, Gershengorn MC. TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis. J Clin Endocrinol Metab 2016; 101: 2340-2347
• 125 Minich WB, Dehina N, Welsink T, Schwiebert C, Morgenthaler NG, Köhrle J, Eckstein A, Schomburg L. Autoantibodies to the IGF1 Receptor in Graves' Orbitopathy. J Clin Endocrinol Metab 2013; 98: 752-760
• 126 Chen H, Mester T, Raychaudhuri N, Kauh CY, Gupta S, Smith TJ, Douglas RS. Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. J Clin Endocrinol Metab 2014; 99: E1635-E1640
• 127 Wu CY, Niziol LM, Musch DC, Kahana A. Thyroid-Related Orbital Decompression Surgery: A Multivariate Analysis of Risk Factors and Outcomes. Ophthal Plast Reconstr Surg 2017; 33: 189-195
• 128 Baschieri L, Antonelli A, Nardi S, Alberti B, Lepri A, Canapicchi R, Fallahi P. Intravenous immunoglobulin versus corticosteroid in treatment of Graves' ophthalmopathy. Thyroid 1997; 7: 579-585
• 129 Kahaly G, Pitz S, Muller-Forell W, Hommel G. Randomized trial of intravenous immunoglobulins versus prednisolone in Graves' ophthalmopathy. Clin Exp Immunol 1996; 106: 197-202
• 130 Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM. The effect of etanercept on Graves' ophthalmopathy: A pilot study. Eye (Lond) 2005; 19: 1286-1289
• 131 Ayabe R, Rootman DB, Hwang CJ, Ben-Artzi A, Goldberg R. Adalimumab as steroid-sparing treatment of inflammatory-stage thyroid eye disease. Ophthal Plast Reconstr Surg 2014; 30: 415-419
• 132 Ye X, Bo X, Hu X, Cui H, Lu B, Shao J, Wang J. Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves' orbitopathy. Clin Endocrinol (Oxf) 2017; 86: 247-255
• 133 Kahaly GJ, Riedl M, Konig J, Pitz S, Ponto K, Diana T, Kampmann E, Kolbe E, Eckstein A, Moeller LC, Fuhrer D, Salvi M, Curro N, Campi I, Covelli D, Leo M, Marino M, Menconi F, Marcocci C, Bartalena L, Perros P, Wiersinga WM. 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: 287-298
• 134 Liu ZW, Masterson L, Fish B, Jani P, Chatterjee K. Thyroid surgery for Graves' disease and Graves' ophthalmopathy. Cochrane Database System Rev 2015; CD010576
• 135 Marcocci C, Bruno-Bossio G, Manetti L, Tanda ML, Miccoli P, Iacconi P, Bartolomei MP, Nardi M, Pinchera A, Bartalena L. The course of Graves' ophthalmopathy is not influenced by near total thyroidectomy: A case-control study. Clin Endocrinol (Oxf) 1999; 51: 503-508
• 136 Meyer zu Horste M, Pateronis K, Walz MK, Alesina P, Mann K, Schott M, Esser J, Eckstein AK. The Effect of Early Thyroidectomy on the Course of Active Graves’ Orbitopathy (GO): A Retrospective Case Study. Horm Metab Res 2016; 48: 433-439
• 137 Leo M, Marcocci C, Pinchera A, Nardi M, Megna L, Rocchi R, Latrofa F, Altea MA, Mazzi B, Sisti E, Profilo MA, Marino M. Outcome of Graves' orbitopathy after total thyroid ablation and glucocorticoid treatment: Follow-up of a randomized clinical trial. J Clin Endocrinol Metab 2012; 97: E44-E48
• 138 Durrani OM, Reuser TQ, Murray PI. Infliximab: a novel treatment for sight-threatening thyroid associated ophthalmopathy. Orbit 2005; 24: 117-119
• 139 Pascual-Camps I, Molina-Pallete R, Bort-Marti MA, Todoli J, Espana-Gregori E. Tocilizumab as first treatment option in optic neuropathy secondary to Graves' orbitopathy. Orbit 2018; 1-4 doi:10.1080/01676830.2018.1435694 [Epub ahead of print]
• 140 Liu C, Dalm V, van Hagen PM, Croon-de Boer F, Paridaens D. Chemotherapy-induced exacerbations of thyroid orbitopathy in a patient with B-cell lymphoma. Orbit 2018; 37: 299-302
• 141 Krassas GE, Stafilidou A, Boboridis KG. Failure of rituximab treatment in a case of severe thyroid ophthalmopathy unresponsive to steroids. Clin Endocrinol (Oxf) 2010; 72: 853-855