Medical Treatment of Graves’ Orbitopathy

 

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Abstract

The medical treatment of Graves’ orbitopathy (GO) is usually reserved to moderate to severe disease. Steroids have been widely employed and possess anti-inflammatory activity, but about 20–30% of patients are not responsive and about 20% present with disease recurrence. Immunosuppressive therapy alternative to corticosteroids may target the different antigens involved in pathogenic mechanisms of GO. Some have already been employed in clinical studies and showed interesting results, although the lack of randomized and controlled trials suggests caution for their use in clinical practice. Potential targets for therapy in GO are the TSH receptor and the IGF-1 receptor on the fibroblasts, inflammatory cytokines, B and T cells. Most promising results are obtained by interacting with the PIK3/mTORC1 signaling cascades for adipogenesis and the anti-IGF-1R with the monoclonal antibody teprotumumab. A recent open study has shown that tocilizumab, an anti-sIL-6R antibody, inactivates GO. Consistent reports on the efficacy of rituximab have recently been challenged by randomized controlled trials. Clinical practice will greatly benefit from the use of disease modifying agents in GO, as compared to steroids, currently standard treatment for GO. Among these, rituximab may be useful, especially in patients resistant to steroid or with contraindications to steroids. However, larger randomized controlled trials are needed for definitive data on the potential disease-modifying role of rituximab in GO. Direct targeting of the orbital fibroblast via immunosuppression or nonimmunosuppressive drugs is emerging as a promising alternative.

• References

• 1 Prummel 1 MF, Bakker A, Wiersinga WM, Baldeschi L, Mourits MP, Kendall-Taylor P, Perros P, Neoh C, Dickinson AJ, Lazarus JH, Lane CM, Heufelder AE, Kahaly GJ, Pitz S, Orgiazzi J, Hullo A, Pinchera A, Marcocci C, Sartini MS, Rocchi R, Nardi M, Krassas GE, Halkias A. Multi-center study on the characteristics and treatment strategies of patients with Graves’ orbitopathy: the first European Group on Graves’ Orbitopathy experience. Eur J Endocrinol 2003; 148: 491-495
  CrossrefPubMedGoogle Scholar
• 2 Perros P, Žarković M, Azzolini C, Ayvaz G, Baldeschi L, Bartalena L, Boschi A, Bournaud C, Brix TH, Covelli D, Ćirić S, Daumerie C, Eckstein A, Fichter N, Führer D, Hegedüs L, Kahaly GJ, Konuk O, Lareida J, Lazarus J, Leo M, Mathiopoulou L, Menconi F, Morris D, Okosieme O, Orgiazzi J, Pitz S, Salvi M, Vardanian-Vartin C, Wiersinga W, Bernard M, Clarke L, Currò N, Dayan C, Dickinson J, Knežević M, Lane C, Marcocci C, Marinò M, Möller L, Nardi M, Neoh C, Pearce S, von Arx G, Törüner FB. PREGO (presentation of Graves’ orbitopathy) study: changes in referral patterns to European Group On Graves’ Orbitopathy (EUGOGO) centres over the period from 2000 to 2012. Br J Ophthalmol 2015; May 7. pii: bjophthalmol-2015-306733 DOI: doi: 10.1136/bjophthalmol-2015-306733. [Epub ahead of print]
  CrossrefPubMedGoogle Scholar
• 3 Menconi F, Profilo MA, Leo M, Sisti E, Altea MA, Rocchi R, Latrofa F, Nardi M, Vitti P, Marcocci C, Marinò M. Spontaneous improvement of untreated mild Graves’ ophthalmopathy: Rundle’s curve revisited. Thyroid 2014; 24: 60-66
  CrossrefPubMedGoogle Scholar
• 4 Marcocci C, Marinò M. Treatment of mild, moderate-to-severe and very severe Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab 2012; 26: 325-337
  CrossrefPubMedGoogle Scholar
• 5 Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin Endocrinol 1995; 42: 45-50
  CrossrefPubMedGoogle Scholar
• 6 Streeten DH, Anderson Jr. GH, Reed GF, Woo P. Prevalence, natural history and surgical treatment of exophthalmos. Clin Endocrinol 1987; 27: 125-133
  CrossrefPubMedGoogle Scholar
• 7 Noth D, Gebauer M, Muller B, Burgi U, Diem P. Graves’ ophthalmopathy: natural history and treatment outcomes. Swiss Med Wkly 2001; 131: 603-609
  PubMedGoogle Scholar
• 8 Tanda ML, Piantanida E, Liparulo L, Veronesi G, Lai A, Sassi L, Pariani N, Gallo D, Azzolini C, Ferrario M, Bartalena L. Prevalence and natural history of Graves’ orbitopathy in a large series of patients with newly diagnosed Graves’ hyperthyroidism seen at a single center. J Clin Endocrinol Metab 2013; 98: 1443-1449
  Google Scholar
• 9 Hegedüs L, Bonnema SJ, Smith TJ, Brix TH. Treating the thyroid in the presence of Graves’ ophthalmopathy. Best Pract Res Clin Endocrinol Metab 2012; 26: 313-324
  CrossrefPubMedGoogle Scholar
• 10 Terwee C, Wakelkamp I, Tan S, Dekker F, Prummel MF, Wiersinga W. Long-term effects of Graves’ ophthalmopathy on health-related quality of life. Eur J Endocrinol 2002; 146: 751-717
  CrossrefPubMedGoogle Scholar
• 11 Wiersinga WM, Prummel MF, Terwee CB. Effects of Graves’ ophthalmopathy on quality of life. J Endocrinol Invest 2004; 27: 259-264
  CrossrefPubMedGoogle Scholar
• 12 Lai A, Sassi L, Compri E, Marino F, Sivelli P, Piantanida E, Tanda ML, Bartalena L. Lower dose prednisone prevents radioiodine-associated exacerbation of initially mild or absent Graves’ orbitopathy: a retrospective cohort study. J Clin Endocrinol Metab 2010; 95: 1333-1337
  CrossrefPubMedGoogle Scholar
• 13 Dederichs B, Dietlein M, Jenniches-Kloth B, Schmidt M, Theissen P, Moka D, Schicha H. Radioiodine therapy of Graves’ hyperthyroidism in patients without pre-existing ophthalmopathy: can glucocorticoids prevent the development of new ophthalmopathy?. Exp Clin Endocrinol Diabetes 2006; 114: 366-370
  Article in Thieme ConnectPubMedGoogle Scholar
• 14 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
  CrossrefPubMedGoogle Scholar
• 15 Leo M, Marcocci C, Pinchera A, Nardi M, Megna L, Rocchi R, Latrofa F, Altea MA, Mazzi B, Sisti E, Profilo MA, Marinò 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
  CrossrefPubMedGoogle Scholar
• 16 Menconi F, Marinò M, Pinchera A, Rocchi R, Mazzi B, Nardi M, Bartalena L, Marcocci C. Effects of total thyroid ablation vs. near-total thyroidectomy alone on mild to moderate Graves’ orbitopathy treated with intravenous glucocorticoids. J Clin Endocrinol Metab 2007; 92: 1653-1658
  CrossrefPubMedGoogle Scholar
• 17 Moleti M, Violi MA, Montanini D, Trombetta C, Di Bella B, Sturniolo G, Presti S, Alibrandi A, Campennì A, Baldari S, Trimarchi F, Vermiglio F. Radioiodine ablation of postsurgical thyroid remnants after treatment with recombinant human TSH (rhTSH) in patients with moderate-to-severe Graves’ orbitopathy (GO): a prospective, randomized, single-blind clinical trial. J Clin Endocrinol Metab 2014; 99: 1783-1789
  CrossrefPubMedGoogle Scholar
• 18 Catania A, Guaitoli E, Carbotta G, Bianchini M, Di Matteo FM, Carbotta S, Nardi M, Fabiani E, Grani G, D’Andrea V, Fumarola A. Total thyroidectomy for Graves’ disease treatment. Clin Ter 2013; 164: 193-196
  PubMedGoogle Scholar
• 19 Bartalena L. The dilemma of how to manage Graves’ hyperthyroidism in patients with associated orbitopathy. J Clin Endocrinol Metab 2011; 96: 592-599
  CrossrefPubMedGoogle Scholar
• 20 Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM. Consensus statement of the European Group on Graves’ Orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 2008; 158: 273-285
  CrossrefPubMedGoogle Scholar
• 21 Kendall-Taylor P, Perros P. Clinical presentation of thyroid associated orbitopathy. Thyroid 1998; 8: 427-428
  CrossrefPubMedGoogle Scholar
• 22 Piantanida E, Tanda ML, Lai A, Sassi L, Bartalena L. Prevalence and natural history of Graves’ orbitopathy in the XXI century. J Endocrinol Invest 2013; 36: 444-449
  Google Scholar
• 23 Salvi M, Currò N. Management of mild Graves’ orbitopathy. In Wiersinga WM, Kahaly GJ. (eds.) Graves’ orbitopathy. A multidisciplinary approach – questions and answers. 2^nd, revised version. Basel: Karger; 2010: 111-119
  CrossrefGoogle Scholar
• 24 Bartalena L. Graves’ Disease Complications. In: De Groot LJ. Thyroid Disease Manager. Chapter 12 http://www.thyroidmanager.org/
  Google Scholar
• 25 Altiparmak UE, Acar DE, Ozer PA, Emec SD, Kasim R, Ustun H, Duman S. Topical cyclosporine A for the dry eye findings of thyroid orbitopathy patients. Eye 2010; 24: 1044-1050
  CrossrefPubMedGoogle Scholar
• 26 Gürdal C, Genç I, Saraç O, Gönül I, Takmaz T, Can I. Topical cyclosporine in thyroid orbitopathy-related dry eye: clinical findings, conjunctival epithelial apoptosis, and MMP-9 expression. Curr Eye Res 2010; 35: 771-777
  CrossrefPubMedGoogle Scholar
• 27 Uddin JM, Davies PD. Treatment of upper eyelid retraction associated with thyroid eye disease with subconjunctival botulinum toxin injection. Ophthalmology 2002; 109: 1183-1187
  CrossrefPubMedGoogle Scholar
• 28 Pfeilschifter J, Ziegler R. Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs lifetime cigarette consumption. Clin Endocrinol 1996; 45: 477-481
  Google Scholar
• 29 Bartalena L, Bogazzi F, Tanda ML, Manetti L, Dell’Unto E, Martino E. Cigarette smoking and the thyroid. Eur J Endocrinol 1995; 133: 507-512
  CrossrefPubMedGoogle Scholar
• 30 OECD Health Data 2012 Eurostat Statistics Database; WHO Global Infobase
  PubMed
• 31 Marcocci C, Bartalena L. Role of oxidative stress and selenium in Graves’ hyperthyroidism and orbitopathy. J Endocrinol Invest 2013; 36: 15-20
  PubMedGoogle Scholar
• 32 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. European Group on Graves’ Orbitopathy . Selenium and the course of mild Graves’ orbitopathy. N Engl J Med 2011; 364: 1920-1931
  Google Scholar
• 33 Bahn RS, Heufelder AE. Pathogenesis of Graves ophthalmopathy. Engl J Med 1993; 329: 1468-1475
  CrossrefPubMedGoogle Scholar
• 34 Dolman PJ. Evaluating Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab 2012; 26: 229-248
  CrossrefPubMedGoogle Scholar
• 35 Heufelder AE, Wenzel BE, Bahn RS. Glucocorticoids modulate the synthesis and expression of a 72 kDa heat shock protein in cultured Graves’ retroocular fibroblasts. Acta Endocrinol 1993; 128: 41-50
  PubMedGoogle Scholar
• 36 Goldberg RA. Orbital steroid injections. Br J Ophthalmol 2004; 88: 1359-1360
  CrossrefPubMedGoogle Scholar
• 37 Marcocci C, Bartalena L, Tanda ML, Manetti L, Dell’Unto E, Rocchi R, Barbesino G, Mazzi B, Bartolomei MP, Lepri P, Cartei F, Nardi M, Pinchera A. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab 2001; 86: 3562-3567
  CrossrefPubMedGoogle Scholar
• 38 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
  CrossrefPubMedGoogle Scholar
• 39 Kahaly GJ. Management of moderately severe Graves’ orbitopathy. In: Wiersinga WM, Kahaly GJ. (eds.) Graves’ orbitopathy. A multidisciplinary approach – Questions and answers. 2^nd, revised version. Basel: Karger; 2010: 120-158
  CrossrefGoogle Scholar
• 40 Bartalena L, Marcocci C, Chiovato L, Laddaga M, Lepri G, Andreani D, Cavallacci G, Baschieri L, Pinchera A. Orbital cobalt irradiation combined with systemic corticosteroids for Graves’ ophthalmopathy: comparison with systemic corticosteroids alone. J Clin Endocrinol Metab 1983; 56: 1139-1144
  CrossrefPubMedGoogle Scholar
• 41 Kahaly G, Schrezenmeir J, Krause U, Schweikert B, Meuer S, Muller W, Dennebaum R, Beyer J. Cyclosporine and prednisone v. prednisone in treatment of Graves’ ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest 1986; 16: 415-422
  CrossrefPubMedGoogle Scholar
• 42 Kung AW, Michon J, Tai KS, Chan FL. The effect of somatostatin versus corticosteroid in the treatment of Graves’ ophthalmopathy. Thyroid 1996; 6: 381-384
  CrossrefPubMedGoogle Scholar
• 43 Kahaly G, Pitz S, Müller-Forell W, Hommel G. Randomized trial of intravenous immunoglobulins versus prednisolone in Graves’ ophthalmopathy. Clin Exp Immunol 1996; 106: 197-202
  CrossrefPubMedGoogle Scholar
• 44 van Geest RJ, Sasim IV, Koppeschaar HP, Kalmann R, Stravers SN, Bijlsma WR, Mourits MP. Methylprednisolone pulse therapy for patients with moderately severe Graves’ orbitopathy: a prospective, randomized, placebo-controlled study. Eur J Endocrinol 2008; 158: 229-237
  CrossrefPubMedGoogle Scholar
• 45 Matejka G, Vergès B, Vaillant G, Petit JM, Brun-Pacaud A, Rudoni S, Brun JM. Intravenous methylprednisolone pulse therapy in the treatment of Graves’ ophthalmopathy. Horm Metab Res 1998; 30: 93-98
  Article in Thieme ConnectPubMedGoogle Scholar
• 46 Kendall-Taylor P, Crombie AL, Stephenson AM, Hardwick M, Hall K. Intravenous methylprednisolone in the treatment of Graves’ ophthalmopathy. BMJ 1988; 297: 1574-1578
  CrossrefPubMedGoogle Scholar
• 47 Aktaran S, Akarsu E, Erbağci I, Araz M, Okumuş S, Kartal M. Comparison of intravenous methylprednisolone therapy vs. oral methylprednisolone therapy in patients with Graves’ ophthalmopathy. Int J Clin Pract 2007; 61: 45-51
  PubMedGoogle Scholar
• 48 Kauppinen-Mäkelin R, Karma A, Leinonen E, Löyttyniemi E, Salonen O, Sane T, Setälä K, Viikari J, Heufelder A, Välimäki M. High dose intravenous methylprednisolone pulse therapy versus oral prednisone for thyroid-associated ophthalmopathy. Acta Ophthalmol Scand 2002; 80: 316-321
  CrossrefPubMedGoogle Scholar
• 49 Macchia PE, Bagattini M, Lupoli G, Vitale M, Vitale G, Fenzi G. High-dose intravenous corticosteroid therapy for Graves’ ophthalmopathy. J Endocrinol Invest 2001; 24: 152-158
  CrossrefPubMedGoogle Scholar
• 50 Zang S, Ponto KA, Kahaly GJ. Intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab 2011; 96: 320-332
  CrossrefPubMedGoogle Scholar
• 51 Gao G, Dai J, Qian Y, Ma F. Meta-analysis of methylprednisolone pulse therapy for Graves’ ophthalmopathy. Clin Experiment Ophthalmol 2014; 42: 769-777
  CrossrefPubMedGoogle Scholar
• 52 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, Currò N, Boschi A, Bernard M, von Arx G. and the European Group on Graves’ Orbitopathy . 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
  CrossrefPubMedGoogle Scholar
• 53 Vannucchi G, Covelli D, Campi I, Origo D, Currò N, Cirello V, Dazzi D, Beck-Peccoz P, Salvi M. The therapeutic outcome to intravenous steroid therapy for active Graves’ orbitopathy is influenced by the time of response but not polymorphisms of the glucocorticoid receptor. Eur J Endocrinol 2013; 22; 170: 55-61
  PubMedGoogle Scholar
• 54 Weissel M, Hauff W. Fatal liver failure after high-dose glucocorticoid pulse therapy in a patient with severe thyroid eye disease. Thyroid 2000; 10: 521
  PubMedGoogle Scholar
• 55 Marinò M, Morabito E, Brunetto MR, Bartalena L, Pinchera A, Marcocci C. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy. Thyroid 2004; 14: 403-406
  CrossrefPubMedGoogle Scholar
• 56 Lendorf ME, Rasmussen AK, Fledelius HC, Feldt-Rasmussen U. Cardiovascular and cerebrovascular events in temporal relationship to intravenous glucocorticoid pulse therapy in patients with severe endocrine ophthalmopathy. Thyroid 2009; 19: 1431-1432
  CrossrefPubMedGoogle Scholar
• 57 Gursoy A, Cesur M, Erdogan MF, Corapcioglu D, Kamel N. New-onset acute heart failure after intravenous glucocorticoid pulse therapy in a patient with Graves’ ophthalmopathy. Endocrine 2006; 29: 513-516
  CrossrefPubMedGoogle Scholar
• 58 Owecki M, Sowinski J. Acute myocardial infarction during high-dose methylprednisolone therapy for Graves’ ophthalmopathy. Pharm World Sci 2006; 28: 73-75
  CrossrefPubMedGoogle Scholar
• 59 Marcocci C, Watt T, Altea MA, Rasmussen AK, Feldt-Rasmussen U, Orgiazzi J, Bartalena L. European Group of Graves’ Orbitopathy . 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 2011; 166: 247-253
  PubMedGoogle Scholar
• 60 Le Moli R, Baldeschi L, Saeed P, Regenburg N, Mourits MP, Wiersinga WM. Determinants of liver damage associated woth intravenous methylprednisolone pulse therapy in Graves’ ophthalmopathy. Thyroid 2007; 17: 357-362
  CrossrefPubMedGoogle Scholar
• 61 Marinò M, Morabito E, Altea MA, Ambrogini E, Oliveri F, Brunetto MR, Pollina LE, Campani D, Vitti P, Bartalena L, Pincheral A, Marcocci C. Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves’ ophthalmopathy treated successfully with glucocorticoids themselves. J Endocrinol Invest 2005; 28: 280-284
  CrossrefPubMedGoogle Scholar
• 62 Salvi M, Vannucchi G, Sbrozzi F, Del Castello AB, Carnevali A, Fargion S, Beck-Peccoz P. Onset of autoimmune hepatitis during intravenous steroid therapy for thyroid associated ophthalmopathy in a patient with Hashimoto’s thyroiditis: case report. Thyroid 2004; 14: 631-634
  CrossrefPubMedGoogle Scholar
• 63 Bahn RS. Current insights into the pathogenesis of Graves’ ophthalmopathy. Horm Metab Res 2015; 47: - in press
  PubMedGoogle Scholar
• 64 Salvi M. Immunotherapy for Graves’ ophthalmopathy. Curr Opin Endocrinol Diabetes Obes 2014; 21: 409-414
  CrossrefPubMedGoogle Scholar
• 65 Neumann S, Place RF, Krieger CC, Gershengorn MC. Future prospects for the treatment of Graves’ hyperthyroidism and eye disease. Horm Metab Res 2015; 47: - in press
  PubMedGoogle Scholar
• 66 Gershengorn MC, Neumann S. Update in TSH receptor agonists and antagonists. J Clin Endocrinol Metab 2012; 97: 4287-4292
  Google Scholar
• 67 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
  CrossrefPubMedGoogle Scholar
• 68 Zhang L, Grennan-Jones F, Draman MS, Lane C, Morris D, Dayan CM, Tee AR, Ludgate M. Author information Possible targets for nonimmunosuppressive therapy of Graves’ orbitopathy. J Clin Endocrinol Metab 2014; 99: E1183-E1190
  CrossrefPubMedGoogle Scholar
• 69 Jerusalem G, Rorive A, Collignon J. Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes. Breast Cancer 2014; 17 6: 43-57
  PubMedGoogle Scholar
• 70 van Steensel L, Paridaens D, van Meurs M, van Hagen PM, van den Bosch WA, Kuijpers RW, Drexhage HA, Hooijkaas H, Dik WA. Orbit-infiltrating mast cells, monocytes, and macrophages produce PDGF isoforms that orchestrate orbital fibroblast activation in Graves’ ophthalmopathy. J Clin Endocrinol Metab 2012; 97: E400-E408
  CrossrefPubMedGoogle Scholar
• 71 van Steensel L, van Hagen PM, Paridaens D, Kuijpers RW, van den Bosch WA, Drexhage HA, Hooijkaas H, Dik WA. Whole orbital tissue culture identifies imatinib mesylate and adalimumab as potential therapeutics for Graves’ ophthalmopathy. Br J Ophthalmol 2011; 95: 735-738
  CrossrefPubMedGoogle Scholar
• 72 Virakul S, Dalm VA, Paridaens D, van den Bosch WA, Hirankarn N, van Hagen PM, Dik WA. The tyrosine kinase inhibitor dasatinib effectively blocks PDGF-induced orbital fibroblast activation. Graefes Arch Clin Exp Ophthalmol 2014; 252: 1101-1109
  CrossrefPubMedGoogle Scholar
• 73 Distler JH, Distler O. Intracellular tyrosine kinases as novel targets for anti-fibrotic therapy in systemic sclerosis. Rheumatology 2008; 47 (Suppl. 05) v10-v11
  CrossrefPubMedGoogle Scholar
• 74 Li H, Fitchett C, Kozdon K, Jayaram H, Rose GE, Bailly M, Ezra DG. Independent adipogenic and contractile properties of fibroblasts in Graves’ orbitopathy: an in vitro model for the evaluation of treatments. PLoS One 2014; 21; 9: e95586
  CrossrefPubMedGoogle Scholar
• 75 Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM, Prummel MF. TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves’ ophthalmopathy patients. Clin Endocrinol 2003; 58: 280-287
  Google Scholar
• 76 Li B, Smith TJ. Regulation of IL-1 receptor antagonist by TSH in fibrocytes and orbital fibroblasts. J Clin Endocrinol Metab 2014; 99: E625-E633
  CrossrefPubMedGoogle Scholar
• 77 Pasi S, Kant R, Gupta S, Surolia A. Novel multimeric IL-1 receptor antagonist for the treatment of rheumatoid arthritis. Biomaterials 2015; 42: 121-133
  CrossrefPubMedGoogle Scholar
• 78 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 2005; 19: 1286-1289
  CrossrefPubMedGoogle Scholar
• 79 Slowik M, Urbaniak-Kujda D, Bohdanowicz-Pawlak A, Kapelko-Slowik K, Dybko J, Wolowiec D, Jazwiec B, Daroszewski J. CD8+CD28-lymphocytes in peripheral blood and serum concentrations of soluble interleukin 6 receptor are increased in patients with Graves’ orbitopathy and correlate with disease activity. Endocr Res 2012; 37: 89-95
  CrossrefPubMedGoogle Scholar
• 80 Pérez-Moreiras JV, Alvarez-López A, Gómez EC. Treatment of active corticosteroid-resistant Graves’ orbitopathy. Ophthal Plast Reconstr Surg 2014; 30: 162-167
  CrossrefPubMedGoogle Scholar
• 81 Fabris M, Grimaldi F, Villalta D, Picierno A, Fabro C, Bolzan M, De Vita S, Tonutti E. BLyS and April serum levels in patients with autoimmune thyroid diseases. Autoimmun Rev 2010; 9: 165-169
  CrossrefPubMedGoogle Scholar
• 82 Vannucchi G, Covelli D, Currò N, Dazzi D, Maffini A, Campi I, Bonara P, Guastella C, Pignataro L, Ratiglia R, Beck-Peccoz P, Salvi M. Serum BAFF concentrations in patients with Graves’ disease and orbitopathy before and after immunosuppressive therapy. J Clin Endocrinol Metab 2012; 97: E755-E759
  CrossrefPubMedGoogle Scholar
• 83 Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006; 9: 341-349
  CrossrefPubMedGoogle Scholar
• 84 Kurtz J-E, Ray-Coquard I. PI3 kinase inhibitors in the clinic: an update. Anticancer Res 2012; 32: 2463-2470
  PubMedGoogle Scholar
• 85 Gong Q, Ou Q, Ye S, Lee WP, Cornelius J, Diehl L, Lin WY, Hu Z, Lu Y, Chen Y, Wu Y, Meng YG, Gribling P, Lin Z, Nguyen K, Tran T, Zhang Y, Rosen H, Martin F, Chan AC. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol 2005; 174: 817-826
  CrossrefPubMedGoogle Scholar
• 86 Mélet J, Mulleman D, Goupille P, Ribourtout B, Watier H, Thibault G. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheum 2013; 65: 2783-2790
  CrossrefPubMedGoogle Scholar
• 87 Salvi M, Vannucchi G, Campi I, Rossi S, Bonara P, Sbrozzi F, Guastella C, Avignone S, Pirola G, Ratiglia R, Beck-Peccoz P. Efficacy of rituximab treatment for thyroid-associated ophthalmopathy as a result of intraorbital B-cell depletion in one patient unresponsive to steroid immunosuppression. Eur J Endocrinol 2006; 154: 511-517
  Google Scholar
• 88 El Fassi D, Nielsen CH, Hasselbalch HC, Hegedüs L. Treatment-resistant severe, active Graves’ ophthalmopathy successfully treated with B lymphocyte depletion. Thyroid 2006; 16: 709-710
  CrossrefPubMedGoogle Scholar
• 89 Salvi M, Vannucchi G, Campi I, Currò N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P. Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol 2007; 156: 33-40
  CrossrefPubMedGoogle Scholar
• 90 Erdei A, Paragh G, Kovacs P, Karanyi Z, Berenyi E, Galuska L, Lenkey A, Szabados L, Gyory F, Ujhelyi B, Berta A, Boda J, Berta E, Bodor M, Gazdag A, Nagy EV. Rapid response to and long-term effectiveness of anti-CD20 antibody in conventional therapy resistant Graves’ orbitopathy: A five-year follow-up study. Autoimmunity 2014; 47: 548-555
  CrossrefPubMedGoogle Scholar
• 91 Mitchell AL, Gan EH, Morris M, Johnson K, Neoh C, Dickinson AJ, Perros P, Pearce SH. The effect of B cell depletion therapy on anti-TSH receptor antibodies and clinical outcome in glucocorticoid-refractory Graves’ orbitopathy. Clin Endocrinol 2013; 79: 437-442
  CrossrefPubMedGoogle Scholar
• 92 Salvi M, Vannucchi G, Currò N, Introna M, Rossi S, Bonara P, Covelli D, Dazzi D, Guastella C, Pignataro L, Ratiglia R, Golay J, Beck-Peccoz P. Small dose of rituximab for Graves’ orbitopathy: new insights into the mechanism of action. Arch Ophthalmol 2012; 130: 122-124
  CrossrefPubMedGoogle Scholar
• 93 Khanna D, Chong KK, Afifiyan NF, Hwang CJ, Lee DK, Garneau HC, Goldberg RA, Darwin CH, Smith TJ, Douglas RS. Rituximab treatment of patients with severe, corticosteroid-resistant thyroid-associated ophthalmopathy. Ophthalmology 2010; 117: 133-139
  CrossrefPubMedGoogle Scholar
• 94 Edwards JC, Leandro MJ, Cambridge G. B lymphocyte depletion therapy with rituximab in rheumatoid arthritis. Rheum Dis Clin North Am 2004; 30: 393-403
  CrossrefPubMedGoogle Scholar
• 95 Bredemeier M, de Oliveira FK, Rocha CM. Low- versus high dose rituximab for rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res 2014; 66: 228-235
  CrossrefPubMedGoogle Scholar
• 96 Descotes J. Immunotoxicity of monoclonal antibodies. MAbs 2009; 1: 104-111
  CrossrefPubMedGoogle Scholar
• 97 van der Kolk LE, Grillo-López AJ, Baars JW, Hack CE, van Oers MH. Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol 2001; 115: 807-811
  CrossrefPubMedGoogle Scholar
• 98 van Vollenhoven RF, Emery P, Bingham 3rd CO, Keystone EC, Fleischmann RM, Furst DE, Tyson N, Collinson N, Lehane PB. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 2013; 72: 1496-502
  CrossrefPubMedGoogle Scholar
• 99 Food and Drug Administration . FDA Public Health Advisory: life-threatening brain infection in patients with systemic lupus erythematosus after Rituxan (rituximab) treatment. http://www.fda.gov/cder/drug/ 2006
  PubMedGoogle Scholar
• 100 Salvi M, Vannucchi G, Beck-Peccoz P. Potential utility of rituximab for Graves’ orbitopathy. J Clin Endocrinol Metab 2013; 98: 4291-4299
  CrossrefPubMedGoogle Scholar
• 101 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 2014; 24 jc20142572
  PubMedGoogle Scholar
• 102 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
  Google Scholar
• 103 El Fassi D, Banga JP, Gilbert JA, Padoa C, Hegedüs L, Nielsen CH. Treatment of Graves’ disease with rituximab specifically reduces the production of thyroid stimulating autoantibodies. Clin Immunol 2009; 130: 252-258
  Google Scholar
• 104 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-severe Graves’ orbitopathy: a randomized controlled study. J Clin Endocrinol Metab 2015; 100: 422-431
  Google Scholar
• 105 Krassas GE, Stafilidou A, Boboridis KG. Failure of rituximab treatment in a case of severe thyroid ophthalmopathy unresponsive to steroids. Clin Endocrinol 2010; 72: 853-855
  PubMedGoogle Scholar
• 106 Salvi M, Vannucchi G, Campi I, Currò N, Simonetta S, Covelli D, Pignataro L, Guastella C, Rossi S, Bonara P, Dazzi D, Ratiglia R, Beck-Peccoz P. Rituximab treatment in a patient with severe thyroid-associated ophthalmopathy: effects on orbital lymphocytic infiltrates. Clin Immunol 2009; 131: 360-365
  CrossrefPubMedGoogle Scholar
• 107 Madaschi S, Rossini A, Formenti I, Lampasona V, Bianchi Marzoli S, Cammarata G, Politi L, Martinelli V, Bazzigaluppi E, Scavini M, Bosi E, Lanzi R. Endocr Pract 2010; 16: 677-685
  CrossrefPubMed
• 108 Salvi M, Vannucchi G, Currò N, Introna M, Rossi S, Bonara P, Covelli D, Dazzi D, Guastella C, Pignataro L, Ratiglia R, Golay J, Beck-Peccoz P. A small dose of rituximab may be sufficient to treat Graves’ orbitopathy: new insights into the mechanism of action. Arch Ophthalmol 2012; 130: 122-124
  CrossrefPubMedGoogle Scholar
• 109 Pasquali D, Vassallo P, Esposito D, Bonavolontà G, Bellastella A, Sinisi AA. Somatostatin receptor gene expression and inhibitory effects of octreotide on primary cultures of orbital fibroblasts from Graves’ ophthalmopathy. J Mol Endocrinol 2000; 25: 63-71
  CrossrefPubMedGoogle Scholar
• 110 Pasquali D, Notaro A, Bonavolontà G, Vassallo P, Bellastella A, Sinisi AA. Somatostatin receptor genes are expressed in lymphocytes from retroorbital tissues in Graves’ disease. J Clin Endocrinol Metab 2002; 87: 5125-5129
  CrossrefPubMedGoogle Scholar
• 111 Kahaly GJ. Recent developments in Graves’ ophthalmopathy imaging. J Endocrinol Invest 2004; 27: 254-258
  CrossrefPubMedGoogle Scholar
• 112 Dickinson AJ, Vaidya B, Miller M, Coulthard A, Perros P, Baister E, Andrews CD, Hesse L, Heverhagen JT, Heufelder AE, Kendall-Taylor P. Double-blind placebo-controlled trial of octreotide long-acting repeatable (LAR) in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2004; 89: 5910-5915
  CrossrefPubMedGoogle Scholar
• 113 Wemeau JL, Caron P, Beckers A, Rohmer V, Orgiazzi J, Borson-Chazot F, Nocuadie M, Perimenis P, Bisot-Locard S, Bourdeix I, Dejager S. Octreotide (long-acting release formulation) treatment in patients with Graves’ orbitopathy: clinical results of a four-month, randomized, placebocontrolled, double-blind study. J Clin Endocrinol Metab 2005; 90: 841-848
  CrossrefPubMedGoogle Scholar
• 114 Chang T-C, Liao S-L. Slow-release lanreotide in Graves’ ophthalmopathy: a double-blind randomized, placebo-controlled clinical trial. J Endocrinol Invest 2006; 29: 413-422
  CrossrefPubMedGoogle Scholar
• 115 Stan MN, Garrity JA, Bradley EA, Woog JJ, Bahn MM, Brennan MD, Bryant SC, Achenbach SJ, Bahn RS. Randomized, placebo-controlled, double-blind trial of long-acting release octreotide for treatment of Graves’ ophthalmopathy. J Clin Endocrinol Metab 2006; 91: 4817-4824
  CrossrefPubMedGoogle Scholar
• 116 Bartalena L, Marcocci C, Pinchera A. Somatostatin analogs for Graves’ ophthalmopathy: do they bounce off like a rubber bullet?. J Clin Endocrinol Metab 2004; 89: 5908-5909
  CrossrefPubMedGoogle Scholar
• 117 Tanda ML, Bartalena L. Currently available somatostatin analogs are not good for Graves’ orbitopathy. J Endocrinol Invest 2006; 29: 389-390
  CrossrefPubMedGoogle Scholar
• 118 Cozma I, Zhang L, Uddin J, Lane C, Rees A, Ludgate M. Modulation of expression of somatostatin receptor subtypes in Graves’ ophthalmopathy orbits: Relevance to novel analogs. Am J Physiol Endocrinol Metab 2007; 293: E1630-E1635
  CrossrefPubMedGoogle Scholar
• 119 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 Engl J Med 1989; 321: 1353-1359
  CrossrefPubMedGoogle Scholar
• 120 Bartalena L, Pinchera A, Marcocci C. Management of Graves’ ophthalmopathy: reality and perspectives. Endocr Rev 2000; 21: 168-199
  CrossrefPubMedGoogle Scholar
• 121 Wakelkamp IM, Baldeschi L, Saeed P, Mourits MP, Prummel MF, Wiersinga WM. Surgical or medical decompression as a first-line treatment of optic neuropathy in Graves’ ophthalmopathy? A randomized controlled trial. Clin Endocrinol 2005; 63: 323-328
  CrossrefPubMedGoogle Scholar
• 122 Currò N, Covelli D, Vannucchi G, Campi I, Pirola G, Simonetta S, Dazzi D, Guastella C, Pignataro L, Beck-Peccoz P, Ratiglia R, Salvi M. Therapeutic outcomes of high-dose intravenous steroids in the treatment of dysthyroid optic neuropathy. Thyroid 2014; 24: 897-905
  Google Scholar
• 123 Al-Bakri M, Rasmussen 2 AK, Thomsen 3 C, Toft PB. Orbital Volumetry in Graves’ Orbitopathy: Muscle and Fat Involvement in relation to Dysthyroid Optic Neuropathy. ISRN Ophthalmol 2014; 435276
  PubMedGoogle Scholar
• 124 McKeag D, Lane C, Lazarus JH, Baldeschi L, Boboridis K, Dickinson AJ, Hullo AI, Kahaly G, Krassas G, Marcocci C, Marinò M, Mourits MP, Nardi M, Neoh C, Orgiazzi J, Perros P, Pinchera A, Pitz S, Prummel MF, Sartini MS, Wiersinga WM. European Group on Graves’ Orbitopathy (EUGOGO) Clinical features of dysthyroid optic neuropathy: a European Group on Graves’ Orbitopathy (EUGOGO) survey. Br J Ophthalmol 2007; 91: 455-458
  CrossrefPubMedGoogle Scholar