Horm Metab Res 2017; 49(10): 739-747
DOI: 10.1055/s-0043-116945
Endocrine Care

Combination Therapy of Intravenous Steroids and Orbital Irradiation is More Effective Than Intravenous Steroids Alone in Patients with Graves’ Orbitopathy

Michael Oeverhaus
1   Department of Ophthalmology, University Hospital Essen (EUGOGO Center Essen), Essen, Germany
,
Tobias Witteler
1   Department of Ophthalmology, University Hospital Essen (EUGOGO Center Essen), Essen, Germany
2   Department of Medical Oncology, Kliniken Essen-Mitte, Essen, Germany
,
Hildegard Lax
3   Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany
,
Joachim Esser
1   Department of Ophthalmology, University Hospital Essen (EUGOGO Center Essen), Essen, Germany
,
4   Department of Endocrinology and Metabolism, University Hospital Essen, (EUGOGO Center Essen) University Duisburg-Essen, Essen, Germany
,
Anja Eckstein
1   Department of Ophthalmology, University Hospital Essen (EUGOGO Center Essen), Essen, Germany
› Institutsangaben

Abstract

The aim of this study was to evaluate and compare the efficacy of intravenous (iv) glucocorticoids (GCs) with and without orbital radiotherapy (ORT) in a retrospective analysis of patients with active, moderate-to-severe Graves’ orbitopathy (GO). Since diplopia has the strongest impact on quality of life, a careful work up of motility and binocular single vision (BSV) has been performed. The Essen-EUGOGO-Center database (n=3655) was screened for patients with untreated moderate-to-severe, active GO, onset ≤12 months. The inclusion criteria were met by 148 patients (n=76 ivGC, n=72 ivGC + ORT). We analyzed CAS (inactivation: ≤2), NOSPECS, lid-width, proptosis, motility, and field of BSV. To score the overall ophthalmic outcome, a severity-weighted-score (SOS) was compared with an established EUGOGO inflammation-weighted-score (IOS). Cumulative ivGCs dosages and duration of GO did not differ between the groups. Patients with combination therapy had a significantly more severe GO at baseline. Therefore, a subgroup with matched severity was additionally compared. In the IOS, both groups reached similar improvement rates (55.2 vs. 63.9%; p=0.31). However, in the SOS, the rates differed significantly (46.1 vs. 61.1%; p=0.03- unmatched and p=0.03 matched), despite similar rates of inactivation (65.8 vs. 63.8%). Impaired motility improved significantly more often after combination therapy (p=0.01 matched, p=0.004 unmatched). Treatment responders showed only partial improvement (proptosis: 2.5±0.5 mm; motility: 11.3±10.9°). In our retrospective analysis, combination therapy (ivGCs + ORT) was significantly more effective in reduction of severity and should therefore always be considered in moderate-to-severe GO stages, especially in the presence of motility disorders. However, the limited improvement in clinical parameters, despite the promising effect on inactivation of inflammation, has to be outlined to the patients.

Supplementary Material



Publikationsverlauf

Eingereicht: 20. April 2017

Angenommen: 12. Juli 2017

Artikel online veröffentlicht:
18. September 2017

© Georg Thieme Verlag KG
Stuttgart · New York

 
  • References

  • 1 Shan SJ, Douglas RS. The pathophysiology of thyroid eye disease. J Neuroophthalmol 2014; 34: 177-185
  • 2 Bahn RS. Current Insights into the Pathogenesis of Graves’ Ophthalmopathy. Horm Metab Res 2015; 47: 773-778
  • 3 Banga JP, Moshkelgosha S, Berchner-Pfannschmidt U, Eckstein A. Modeling Graves’ Orbitopathy in Experimental Graves’ Disease. Horm Metab Res 2015; 47: 797-803
  • 4 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
  • 5 Morshed SA, Davies TF. Graves’ disease mechanisms: The role of stimulating, blocking, and cleavage region tsh receptor antibodies. Horm Metab Res 2015; 47: 727-734
  • 6 Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, Gianoukakis AG, Douglas RS, Smith TJ. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease. J Immunol 2008; 181: 4397-4405
  • 7 Krieger CC, Neumann S, Place RF, Marcus-Samuels B, Gershengorn MC. Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by Graves’ disease immunoglobins. J Clin Endocrinol Metab 2015; 100: 1071-1077
  • 8 Gerding MN, Terwee CB, Dekker FW, Koornneef L, Prummel MF, Wiersinga WM. Quality of life in patients with Graves’ ophthalmopathy is markedly decreased: Measurement by the medical outcomes study instrument. Thyroid 1997; 7: 885-889
  • 9 Burch HB, Wartofsky L. Graves’ ophthalmopathy: current concepts regarding pathogenesis and management. Endocr Rev 1993; 14: 747-793
  • 10 Ponto KA, Hommel G, Pitz S, Elflein H, Pfeiffer N, Kahaly GJ. Quality of life in a german graves orbitopathy population. Am J Ophthalmol 2011; 152: 483-490 e481
  • 11 Kahaly GJ, Petrak F, Hardt J, Pitz S, Egle UT. Psychosocial morbidity of Graves' orbitopathy. Clin Endocrinol (Oxf) 2005; 63: 395-402
  • 12 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 Engl J Med 2017; 376: 1748-1761
  • 13 Neumann S, Place RF, Krieger CC, Gershengorn MC. Future prospects for the treatment of graves’ hyperthyroidism and eye disease. Horm Metab Res 2015; 47: 789-796
  • 14 Salvi M, Campi I. Medical treatment of graves' orbitopathy. Horm Metab Res 2015; 47: 779-788
  • 15 Mourits MP, van Kempen-Harteveld ML, Garcia MB, Koppeschaar HP, Tick L, Terwee CB. Radiotherapy for Graves’ orbitopathy: Randomised placebo-controlled study. Lancet 2000; 355: 1505-1509
  • 16 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
  • 17 Johnson KT, Wittig A, Loesch C, Esser J, Sauerwein W, Eckstein AK. A retrospective study on the efficacy of total absorbed orbital doses of 12, 16 and 20 Gy combined with systemic steroid treatment in patients with Graves’ orbitopathy. Graefes Arch Clin Exp Ophthalmol 2010; 248: 103-109
  • 18 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: 853860
  • 19 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
  • 20 Kahaly GJ, Rosler HP, Pitz S, Hommel G. Low- versus high-dose radiotherapy for Graves' ophthalmopathy: A randomized, single blind trial. J Clin Endocrinol Metab 2000; 85: 102-108
  • 21 Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Curro N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marino M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM. European Group on Graves O . Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 2008; 158: 273-285
  • 22 Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM. European Group on Graves O . The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy. Eur Thyroid J 2016; 5: 9-26
  • 23 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
  • 24 Ng CM, Yuen HK, Choi KL, Chan MK, Yuen KT, Ng YW, Tiu SC. Combined orbital irradiation and systemic steroids compared with systemic steroids alone in the management of moderate-to-severe Graves' ophthalmopathy: A preliminary study. Hong Kong Med J 2005; 11: 322-330
  • 25 Kim JW, Han SH, Son BJ, Rim TH, Keum KC, Yoon JS. Efficacy of combined orbital radiation and systemic steroids in the management of Graves' orbitopathy. Graefes Arch Clin Exp Ophthalmol 2016; 254: 991-998
  • 26 Tanda ML, Bartalena L. Efficacy and safety of orbital radiotherapy for graves' orbitopathy. J Clin Endocrinol Metab 2012; 97: 3857-3865
  • 27 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. European Group on Graves O . 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
  • 28 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
  • 29 Roy A, Dutta D, Ghosh S, Mukhopadhyay P, Mukhopadhyay S, Chowdhury S. Efficacy and safety of low dose oral prednisolone as compared to pulse intravenous methylprednisolone in managing moderate severe Graves' orbitopathy: A randomized controlled trial. Indian J Endocrinol Metab 2015; 19: 351-358
  • 30 Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R. Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: A novel approach. Br J Ophthalmol 1989; 73: 639-644
  • 31 Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf) 1997; 47: 9-14
  • 32 Eckstein AK, Plicht M, Lax H, Hirche H, Quadbeck B, Mann K, Steuhl KP, Esser J, Morgenthaler NG. Clinical results of anti-inflammatory therapy in Graves' ophthalmopathy and association with thyroidal autoantibodies. Clin Endocrinol (Oxf) 2004; 61: 612-618
  • 33 Prummel 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
  • 34 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 O . Selenium and the course of mild Graves' orbitopathy. N Engl J Med 2011; 364: 1920-1931
  • 35 Zang S, Ponto KA, Kahaly GJ. Clinical review: Intravenous glucocorticoids for Graves' orbitopathy: Efficacy and morbidity. J Clin Endocrinol Metab 2011; 96: 320-332
  • 36 Sullivan TJ, Kraft SP, Burack C, O'Reilly C. A functional scoring method for the field of binocular single vision. Ophthalmology 1992; 99: 575-581
  • 37 Salvi M, Vannucchi G, Curro 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
  • 38 Kim JW, Han SH, Son BJ, Rim TH, Keum KC, Yoon JS. Efficacy of combined orbital radiation and systemic steroids in the management of Graves' orbitopathy. Graefes Arch Clin Exp Ophthalmol 2016; 254: 991-998
  • 39 Prummel MF, Mourits MP, Blank L, Berghout A, Koornneef L, Wiersinga WM. Randomized double-blind trial of prednisone versus radiotherapy in Graves' ophthalmopathy. Lancet 1993; 342: 949-954
  • 40 Meyer Zu HM, 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
  • 41 Miccoli P, Vitti P, Rago T, Iacconi P, Bartalena L, Bogazzi F, Fiore E, Valeriano R, Chiovato L, Rocchi R, Pinchera A. Surgical treatment of Graves' disease: Subtotal or total thyroidectomy?. Surgery 1996; 120: 1020-1024 discussion 1024–1025
  • 42 Marcocci C, Bartalena L, Tanda ML, Manetti L, Dell'Unto E, Mazzi B, Rocchi R, Barbesino G, Pinchera A. Graves' ophthalmopathy and 131I therapy. Q J Nucl Med 1999; 43: 307-312
  • 43 Wakelkamp IM, Tan H, Saeed P, Schlingemann RO, Verbraak FD, Blank LE, Prummel MF, Wiersinga WM. Orbital irradiation for Graves' ophthalmopathy: Is it safe? A long-term follow-up study. Ophthalmology 2004; 111: 1557-1562
  • 44 Bartalena L, Marcocci C, Manetti L, Tanda ML, Dell'Unto E, Rocchi R, Cartei F, Pinchera A. Orbital radiotherapy for Graves' ophthalmopathy. Thyroid 1998; 8: 439-441
  • 45 Sterker I, Tegetmeyer H, Papsdorf K, Fuhrer-Sakel D. Effect of combined intravenous glucocorticoids and orbital radiotherapy in restoring driving competency in patients with Graves' orbitopathy. Horm Metab Res 2009; 41: 391-396