Update endokrine Orbitopathie

Zusammenfassung

Die endokrine Orbitopathie ist eine Autoimmunerkrankung, die am häufigsten zusammen mit einer Schilddrüsenüberfunktion vom Typ Basedow auftritt. Die Patienten weisen spezifisch TSH-Rezeptor-Autoantikörper auf. Diese stimulieren die Schilddrüse und führen zu einer von der Hypophyse nicht mehr kontrollierten Schilddrüsenüberfunktion. Die TSH-Rezeptor-Autoantikörper und vornehmlich infiltrierende T-Zellen und Makrophagen verursachen krankhafte Veränderungen der Orbitafibroblasten mit dem Endresultat einer Fettvermehrung in der Orbita, Entzündungsreaktion und Fibrose. Die Folge sind Lidretraktion, Augenbewegungsstörung, Exophthalmus und eine mehr oder weniger ausgeprägte entzündliche Weichteilsymptomatik. Die chronische Entzündungsreaktion verläuft in drei Phasen: aktive Phase, Plateauphase und inaktive Phase. In der aktiven Phase kann man mit einer antientzündlichen Therapie (i. v. Steroide und Orbitaspitzenbestrahlung – bei ausbleibenden Erfolg Kombination mit einer immunmodulatorischen Therapie) die endokrine Orbitopathie bessern. Eine Vollheilung ist jedoch mit den aktuell verfügbaren Therapieoptionen selten. Dies ändert sich möglicherweise in der Zukunft, wenn neue zielgerichtete Therapien zum Einsatz kommen, die aktuell in Studien getestet werden. Meist müssen bleibende Defekte chirurgisch in folgender Reihenfolge korrigiert werden: 1. Orbitadekompression, 2. Augenmuskelchirurgie und 3. Lidchirurgie. Eine schlechte Kontrolle der Schilddrüsenfunktion, Nikotinkonsum und hohe TSH-Rezeptor-Autoantikörper-Spiegel sind die stärksten Risikofaktoren für einen schweren Verlauf der Erkrankung. Seltenere Formen wie die endokrine Orbitopathie ohne begleitende Schilddrüsenerkrankung und die endokrine Orbitopathie assoziiert mit einer Autoimmunthyreoiditis vom Typ Hashimoto verlaufen meist mild und häufig asymmetrisch.

Die endokrine Orbitopathie (EO) ist die häufigste extrathyreoidale Manifestation des Morbus Basedow. Für Therapieentscheidungen wird die Erkrankung in eine aktive und eine inaktive Phase eingeteilt sowie eine Unterscheidung zwischen einer milden, moderaten und schweren visusbedrohenden Manifestation vorgenommen, wobei die Lebensqualität der Patienten bei den beiden letzteren erheblich eingeschränkt ist.

Abstract

Gravesʼ orbitopathy (GO) is an autoimmune disease which is most often associated with autoimmune hyperthyroidism (Gravesʼ hyperthyroidism). Most of the patients have Anti TSH receptor autoantibodies (TRAb). TRAK stimulate the thyroid and cause an uncontrolled hyperthyroidism. TRAb and infiltrating T-cells and macrophages can pathologically stimulate the orbital fibroblasts, which results in increased adipogenesis, inflammation and fibrosis in the orbita. The consequence are clinical symptoms like lid retraction, impaired eye movement, exophthalmus and variable amounts of soft tissue inflammation. The chronical inflammatory reaction follows three phases: active increasing phase, plateau phase and inactive phase. Patients in the active phase are treated with i. v. glucocorticoids and orbital irradiation. If these therapies are not effective, additional immunomodulatory therapies are given in addition. A complete remission in response to the anti-inflammatory therapy is rare. This might change in the future since several targeted therapies are currently tested in randomized clinical trials. Today persistent defects have to be corrected surgically in the following order: 1. orbital decompression, 2. squint surgery and 3. lid corrections. Poor control of thyroid function, smoking and high TRAb levels are the most important risk factors for a severe course of GO. Rare conditions like GO without thyroid disease (euthyroid GO) or GO associated with autoimmune thyroiditis type Hashimoto do mostly have a mild course and do manifest much more asymmetrically.

Kernaussagen

• Die endokrine Orbitopathie (EO) ist die häufigste extrathyreoidale Manifestation des Morbus Basedow.

• Für Therapieentscheidungen wird die Erkrankung in eine aktive und eine inaktive Phase eingeteilt und eine Unterscheidung zwischen einer milden, moderaten und schweren visusbedrohenden Manifestation vorgenommen.

• Milde Form:

  • Bei der milden Form der Erkrankung kann der Spontanverlauf unter Selen-Supplementation abgewartet werden.

• Moderate und schwere Manifestationen:

  • Die Lebensqualität der Patienten ist erheblich beeinträchtigt.

  • In der aktiven Phase der Erkrankung ist bei diesen Patienten eine antientzündliche Therapie angezeigt.

    • Die Primärtherapie besteht aktuell noch aus einer i. v. Steroidstoßtherapie (kumulativ 4 – 5 g) in Kombination mit einer Orbitaspitzenbestrahlung bei Motilitätsstörungen.

    • 6 Wochen nach Beginn der i. v. Steroidtherapie sollte bei ungenügendem Ansprechen eine immunsuppressive Therapie hinzugefügt werden.

    • Bei schwerer visusbedrohender Manifestation ist meist eine knöcherne Orbitadekompression die Therapie der Wahl.

  • Im inaktiven Krankheitsstadium kann Patienten mit bleibenden Defekten mit einer Reihe von ophthalmochirurgischen Maßnahmen sehr gut geholfen werden.

Schlüsselwörter

Morbus Basedow - immunologisch bedingte Entzündung - Orbita - Pathogenese - Klassifikation - Risikofaktoren - antientzündliche Therapie - chirurgische Therapie

• Literatur

• 1 Bahn RS. Current Insights into the Pathogenesis of Gravesʼ Ophthalmopathy. Horm Metab Res 2015; 47: 773-778
• 2 Davies TF, Ando T, Lin RY. et al. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest 2005; 115: 1972-1983
• 3 Bahn RS. Thyrotropin receptor expression in orbital adipose/connective tissues from patients with thyroid-associated ophthalmopathy. Thyroid 2002; 12: 193-195
• 4 Kumar S, Iyer S, Bauer H. et al. A stimulatory thyrotropin receptor antibody enhances hyaluronic acid synthesis in Gravesʼ orbital fibroblasts: inhibition by an IGF-I receptor blocking antibody. J Clin Endocrinol Metab 2012; 97: 1681-1687
• 5 Kumar S, Nadeem S, Stan MN. et al. A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Gravesʼ ophthalmopathy. J Mol Endocrinol 2011; 46: 155-163
• 6 Kumar S, Schiefer R, Coenen MJ. et al. A stimulatory thyrotropin receptor antibody (M22) and thyrotropin increase interleukin-6 expression and secretion in Gravesʼ orbital preadipocyte fibroblasts. Thyroid 2010; 20: 59-65
• 7 Krieger CC, Neumann S, Marcus-Samuels B. et al. TSHR/IGF-1R Cross-Talk, Not IGF-1R Stimulating Antibodies, Mediates Gravesʼ Ophthalmopathy Pathogenesis. Thyroid 2017; 27: 746-747
• 8 Krieger CC, Place RF, Bevilacqua C. et al. Thyrotropin/IGF-1 receptor crosstalk in Gravesʼ ophthalmopathy pathogenesis. J Clin Endocrinol Metab 2016; 10: 2340-2347
• 9 Hiromatsu Y, Yang D, Bednarczuk T. et al. Cytokine profiles in eye muscle tissue and orbital fat tissue from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2000; 85: 1194-1199
• 10 Shan SJ, Douglas RS. The pathophysiology of thyroid eye disease. J Neuroophthalmol 2014; 34: 177-185
• 11 Plohn S, Edelmann B, Japtok L. et al. CD40 enhances sphingolipids in orbital fibroblasts: potential role of sphingosine-1-phosphate in inflammatory T-cell migration in Gravesʼ orbitopathy. Invest Ophthalmol Vis Sci 2018; 59: 5391-5397
• 12 Gortz GE, Horstmann M, Aniol B. et al. Hypoxia-dependent HIF-1 activation impacts on tissue remodeling in Gravesʼ ophthalmopathy-implications for smoking. J Clin Endocrinol Metab 2016; 101: 4834-4842
• 13 Banga JP, Moshkelgosha S, Berchner-Pfannschmidt U. et al. Modeling Gravesʼ orbitopathy in experimental Gravesʼ disease. Horm Metab Res 2015; 47: 797-803
• 14 Bartley GB, Fatourechi V, Kadrmas EF. et al. Long-term follow-up of Graves ophthalmopathy in an incidence cohort. Ophthalmology 1996; 103: 958-962
• 15 Dederichs B, Dietlein M, Jenniches-Kloth B. et al. Radioiodine therapy of Gravesʼ hyperthyroidism in patients without preexisting ophthalmopathy: can glucocorticoids prevent the development of new ophthalmopathy?. Exp Clin Endocrinol Diabetes 2006; 114: 366-370
• 16 Uddin JM, Rubinstein T, Hamed-Azzam S. Phenotypes of thyroid eye disease. Ophthalmic Plast Reconstr Surg 2018; 34: S28-S33
• 17 Wiersinga WM. Quality of life in Gravesʼ ophthalmopathy. Best Pract Res Clin Endocrinol Metab 2012; 26: 359-370
• 18 Eckstein AK, Losch C, Glowacka D. et al. Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy. Br J Ophthalmol 2009; 93: 1052-1056
• 19 McKeag D, Lane C, Lazarus JH. et al. Clinical features of dysthyroid optic neuropathy: a European Group on Gravesʼ Orbitopathy (EUGOGO) survey. Br J Ophthalmol 2007; 91: 455-458
• 20 Saeed P, Tavakoli Rad S, Bisschop P. Dysthyroid optic neuropathy. Ophthalmic Plast Reconstr Surg 2018; 34 (Suppl. 01) S60-S67
• 21 Regensburg NI, Wiersinga WM, Berendschot TT. et al. Do subtypes of Gravesʼ orbitopathy exist?. Ophthalmology 2011; 118: 191-196
• 22 Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin Endocrinol (Oxf) 1995; 42: 45-50
• 23 Mourits MP, Koornneef L, Wiersinga WM. et al. Clinical criteria for the assessment of disease activity in Gravesʼ ophthalmopathy: a novel approach. Br J Ophthalmol 1989; 73: 639-644
• 24 Bartalena L, Baldeschi L, Boboridis K. et al. The 2016 European Thyroid Association/European Group on Gravesʼ Orbitopathy Guidelines for the Management of Gravesʼ Orbitopathy. Eur Thyroid J 2016; 5: 9-26
• 25 Bartalena L, Baldeschi L, Dickinson A. et al. Consensus statement of the European Group on Gravesʼ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 2008; 158: 273-285
• 26 Dolman PJ, Rootman J. VISA Classification for Gravesʼ orbitopathy. Ophthal Plast Reconstr Surg 2006; 22: 319-324
• 27 Wiersinga WM. Combined thyroid eye clinic: the importance of a multidisciplinary health care in patients with Gravesʼ orbitopathy. Pediatr Endocrinol Rev 2010; 7 (Suppl. 02) 250-253
• 28 Bartalena L, Martino E, Marcocci C. et al. More on smoking habits and Gravesʼ ophthalmopathy. J Endocrinol Invest 1989; 12: 733-737
• 29 Prummel MF, Wiersinga WM. Smoking and risk of Gravesʼ disease. JAMA 1993; 269: 479-482
• 30 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
• 31 Träisk F, Tallstedt L, Abraham-Nordling M. et al. Thyroid-associated ophthalmopathy after treatment for Gravesʼ hyperthyroidism with antithyroid drugs or iodine-131. J Clin Endocrinol Metab 2009; 94: 3700-3707
• 32 Bartalena L, Marcocci C, Bogazzi F. et al. Relation between therapy for hyperthyroidism and the course of Gravesʼ ophthalmopathy. N Engl J Med 1998; 338: 73-78
• 33 Bartalena L, Marcocci C, Tanda ML. et al. Cigarette smoking and treatment outcomes in Graves ophthalmopathy. Ann Intern Med 1998; 129: 632-635
• 34 Eckstein A, Quadbeck B, Mueller G. et al. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br J Ophthalmol 2003; 87: 773-776
• 35 Tallstedt L, Lundell G, Torring O. et al. Occurrence of ophthalmopathy after treatment for Gravesʼ hyperthyroidism. The Thyroid Study Group. N Engl J Med 1992; 326: 1733-1738
• 36 Meyer Zu Horste M, Pateronis K, Walz MK. et al. The effect of early thyroidectomy on the course of active Gravesʼ orbitopathy (GO): A retrospective case study. Horm Metab Res 2016; 48: 433-439
• 37 Vannucchi G, Campi I, Covelli D. et al. Gravesʼ orbitopathy activation after radioactive iodine therapy with and without steroid prophylaxis. J Clin Endocrinol Metab 2009; 94: 3381-3386
• 38 Lai A, Sassi L, Compri E. et al. Lower dose prednisone prevents radioiodine-associated exacerbation of initially mild or absent Gravesʼ orbitopathy: a retrospective cohort study. J Clin Endocrinol Metab 2010; 95: 1333-1337
• 39 Kahaly GJ, Bartalena L, Hegedus L. et al. 2018 European Thyroid Association Guideline for the management of Gravesʼ hyperthyroidism. Eur Thyroid J 2018; 7: 167-186
• 40 Perros P, Kendall-Taylor P, Neoh C. et al. A prospective study of the effects of radioiodine therapy for hyperthyroidism in patients with minimally active Gravesʼ ophthalmopathy. J Clin Endocrinol Metab 2005; 90: 5321-5323
• 41 Menconi F, Marino M, Pinchera A. et al. Effects of total thyroid ablation vs. near-total thyroidectomy alone on mild to moderate Gravesʼ orbitopathy treated with intravenous glucocorticoids. J Clin Endocrinol Metab 2007; 92: 1653-1658
• 42 Menconi F, Leo M, Vitti P. et al. Total thyroid ablation in Gravesʼ orbitopathy. J Endocrinol Invest 2015; 38: 809-815
• 43 Marcocci C, Kahaly GJ, Krassas GE. et al. Selenium and the course of mild Gravesʼ orbitopathy. N Engl J Med 2011; 364: 1920-1931
• 44 Kahaly GJ, Pitz S, Hommel G. et al. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Gravesʼ orbitopathy. J Clin Endocrinol Metab 2005; 90: 5234-5240
• 45 Bartalena L, Krassas GE, Wiersinga W. et al. Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Gravesʼ orbitopathy. J Clin Endocrinol Metab 2012; 97: 4454-4463
• 46 Zhu W, Ye L, Shen L. et al. A prospective, randomized trial of intravenous glucocorticoids therapy with different protocols for patients with Gravesʼ ophthalmopathy. J Clin Endocrinol Metab 2014; 99: 1999-2007
• 47 Oeverhaus M, Witteler T, Lax H. et al. Combination therapy of intravenous steroids and orbital irradiation is more effective than intravenous steroids alone in patients with Gravesʼ orbitopathy. Horm Metab Res 2017; 49: 739-747
• 48 Mourits MP, van Kempen-Harteveld ML, Garcia MB. et al. Radiotherapy for Gravesʼ orbitopathy: randomised placebo-controlled study. Lancet 2000; 355: 1505-1509
• 49 Johnson KT, Wittig A, Loesch C. et al. 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 Gravesʼ orbitopathy. Graefes Arch Clin Exp Ophthalmol 2010; 248: 103-109
• 50 Bartalena L, Veronesi G, Krassas GE. et al. Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Gravesʼ orbitopathy?. J Endocrinol Invest 2017; 40: 547-553
• 51 Salvi M, Vannucchi G, Curro N. et al. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Gravesʼ orbitopathy: a randomized controlled study. J Clin Endocrinol Metab 2015; 100: 422-431
• 52 Rajendram R, Taylor PN, Wilson VJ. et al. Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 × 2 factorial, double-blind, randomised controlled trial. Lancet Diabet Endocrinol 2018; 6: 299-309
• 53 Kahaly GJ, Riedl M, Konig J. et al. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Gravesʼ orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. Lancet Diabet Endocrinol 2018; 6: 287-298
• 54 Stan MN, Garrity JA, Carranza Leon BG. et al. Randomized controlled trial of rituximab in patients with Gravesʼ orbitopathy. J Clin Endocrinol Metab 2015; 100: 432-441
• 55 Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR. et al. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant graves orbitopathy: a randomized clinical trial. Am J Ophthalmol 2018; 195: 181-190
• 56 Kahaly G, Schrezenmeir J, Krause U. et al. Ciclosporin and prednisone v. prednisone in treatment of Gravesʼ ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest 1986; 16: 415-422
• 57 Ghadiri N. The management of thyroid eye disease by immunomodulation. The Cambridge regime. International Thyroid Eye Disease Society Symposium. 2016
• 58 Prummel MF, Mourits MP, Berghout A. et al. Prednisone and cyclosporine in the treatment of severe Gravesʼ ophthalmopathy. N Engl J Med 1989; 321: 1353-1359
• 59 Wakelkamp I, Baldeschi L, Saeed P. et al. Surgical or medical decompression as a first-line treatment of optic neuropathy in Gravesʼ ophthalmopathy? A randomized controlled trial. Clin Endocrinol (Oxf) 2005; 63: 323-328
• 60 Curro N, Covelli D, Vannucchi G. et al. Therapeutic outcomes of high-dose intravenous steroids in the treatment of dysthyroid optic neuropathy. Thyroid 2014; 24: 897-905
• 61 Smith TJ, Kahaly GJ, Ezra DG. et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 2017; 376: 1748-1761
• 62 Douglas RS, Kahaly GJ, Patel A. et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med 2020; 382: 341-352
• 63 Pearce S, Perros P, Razvi P. et al. Antigen-specific immune modulation using TEH receptor peptides (ATX-GD-59) for Gravesʼ hyperthyroidism: Results of a first in human study. ETA abstracts 2018; 4: 11-26
• 64 Furmaniak J, Ryder MR, Castro MR. et al. Blocking the TSH receptor with the human monoclonal autoantibody K1 – 70 improves Gravesʼ ophthalmopathy and aids control of advanced follicular thyroid carcinoma – results of long term treatment under the first in human single patient expended use therapy. European Thyroid Association meeting 2018 in Newcastle OP-08 – 57.
• 65 Neumann S, Nir EA, Eliseeva E. et al. A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology 2014; 155: 310-314
• 66 Wabbels B, Forl M. Botulinumtoxin bei Überfunktion der Tränendrüse, spastischem Entropium und Oberlidretraktion bei endokriner Orbitopathie. Ophthalmologe 2007; 104: 771-776
• 67 Chee E, Chee SP. Subconjunctival injection of triamcinolone in the treatment of lid retraction of patients with thyroid eye disease: a case series. Eye (Lond) 2008; 22: 311-315
• 68 Lee SJ, Rim TH, Jang SY. et al. Treatment of upper eyelid retraction related to thyroid-associated ophthalmopathy using subconjunctival triamcinolone injections. Graefes Arch Clin Exp Ophthalmol 2013; 251: 261-270
• 69 Oeverhaus M, Copei A, Mattheis S. et al. Influence of orbital morphology on proptosis reduction and ocular motility after decompression surgery in patients with Gravesʼ orbitopathy. PLoS One 2019; 14: e0218701
• 70 Eckstein A, Esser J, Oeverhaus M. et al. Surgical Treatment of Diplopia in Graves Orbitopathy Patients. Ophthalmic Plast Reconstr Surg 2018; 34: S75-S84
• 71 Eckstein A, Esser J. Surgical Management of extraocular Muscle Dysfunction in Patients with GO. In: Gravesʼ Disease. Berlin, New York: Springer; 2015: 287-299
• 72 Eckstein A, Esser J, Oeverhaus M. et al. Surgical Treatment of Diplopia in Graves Orbitopathy Patients. Ophthalmic Plast Reconstr Surg 2018; 34: S75-S84
• 73 Prummel MF, Wiersinga WM, Mourits MP. et al. Effect of abnormal thyroid function on the severity of Gravesʼ ophthalmopathy. Arch Intern Med 1990; 150: 1098-1101
• 74 Eckstein AK, Lax H, Losch C. et al. Patients with severe Gravesʼ ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission. Clin Endocrinol (Oxf) 2007; 67: 607-612
• 75 Masiello E, Veronesi G, Gallo D. et al. Antithyroid drug treatment for Gravesʼ disease: baseline predictive models of relapse after treatment for a patient-tailored management. J Endocrinol Invest 2018; 41: 1425-1432
• 76 Ehlers M, Allelein S, Schott M. TSH-receptor autoantibodies: pathophysiology, assay methods, and clinical applications. Minerva Endocrinol 2018; 43: 323-332
• 77 Costagliola S, Morgenthaler NG, Hoermann R. et al. Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Gravesʼ disease. J Clin Endocrinol Metab 1999; 84: 90-97
• 78 Schott M, Hermsen D, Broecker-Preuss M. et al. Clinical value of the first automated TSH receptor autoantibody assay for the diagnosis of Gravesʼ disease (GD): an international multicentre trial. Clin Endocrinol (Oxf) 2009; 71: 566-573
• 79 Giuliani C, Cerrone D, Harii N. et al. A TSHr-LH/CGr chimera that measures functional TSAb in Gravesʼ disease. The Journal of clinical endocrinology and metabolism 2012; 97: E1106-E1115
• 80 Frank CU, Braeth S, Dietrich JW. et al. Bridge technology with tsh receptor chimera for sensitive direct detection of TSH receptor antibodies causing Gravesʼ disease: analytical and clinical evaluation. Horm Metab Res 2015; 47: 880-888
• 81 Quadbeck B, Hoermann R, Hahn S. et al. Binding, stimulating and blocking TSH receptor antibodies to the thyrotropin receptor as predictors of relapse of Gravesʼ disease after withdrawal of antithyroid treatment. Horm Metab Res 2005; 37: 745-750
• 82 Carella C, Mazziotti G, Sorvillo F. et al. Serum thyrotropin receptor antibodies concentrations in patients with Gravesʼ 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
• 83 Perros P, Zarkovic M, Azzolini C. et al. PREGO (presentation of Gravesʼ orbitopathy) study: changes in referral patterns to European Group On Gravesʼ Orbitopathy (EUGOGO) centres over the period from 2000 to 2012. Br J Ophthalmol 2015; 99: 1531-1535
• 84 Eckstein AK, Plicht M, Lax H. et al. Thyrotropin receptor autoantibodies are independent risk factors for Gravesʼ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab 2006; 91: 3464-3470
• 85 Eckstein A, Stöhr M, Oeverhaus M. et al. Predicting potential of Anti-TSH-Receptor-autoantibodies (TRAb) measurements for the course of Gravesʼ hyperthyroidism (GD) and Gravesʼ orbitopathy (GO) depending on the assay technology. Abstract of the 2019 ETA meeting in Budapest 2019.