Download PDF
Horm Metab Res 2021; 53(04): 235-244
DOI: 10.1055/a-1373-5523
Endocrine Care

Predicting the Relapse of Hyperthyroidism in Treated Graves’ Disease with Orbitopathy by Serial Measurements of TSH-Receptor Autoantibodies

Mareile Stöhr 
1   Department of Ophthalmology, University Hospital Essen, Essen, Germany
,
Michael Oeverhaus
1   Department of Ophthalmology, University Hospital Essen, Essen, Germany
,
Simon D. Lytton
2   SeraDiaLogistics, Munich, Germany
,
Mareike Horstmann
1   Department of Ophthalmology, University Hospital Essen, Essen, Germany
,
Denise Zwanziger
3   Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany
,
Lars Möller
3   Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany
,
Achim Stark
4   Practice for General Medicine, Essen, Germany
,
Dagmar Führer-Sakel 
3   Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany
,
Nikolaos Bechrakis
1   Department of Ophthalmology, University Hospital Essen, Essen, Germany
,
Utta Berchner-Pfannschmidt
3   Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany
,
J. Paul Banga
5   Emeritus, King’s College London, London, UK
,
Svenja Philipp
3   Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany
,
Anja Eckstein
1   Department of Ophthalmology, University Hospital Essen, Essen, Germany
› Author Affiliations Funding Information: This study was supported by the Junior Clinician Scientist Program of the University Medicine Essen Clinician Scientist Academy (UMEA).
› Further Information
Also available at
   Permissions and Reprints

Abstract

The aim of this study was to investigate the potential of the new TSH-receptor antibody (TRAb) assays to predict remission or relapse of hyperthyroidism in patients with Graves’ disease (GD) and Graves’ orbitopathy (GO). TRAbs were measured retrospectively in sera from a cohort of GD patients with GO (n=117; remission n=38 and relapse n=79–Essen GO biobank) with automated binding immunoassays: TRAb Elecsys (Cobas Roche) and TRAb bridge assay (IMMULITE, Siemens), and the TSAb (thyroid stimulating Ab) cell-based bioassay (Thyretain, Quidel Corp.). To identify relapse risk/remission of hyperthyroidism patients were followed up at least 10 months after the end of antithyroid drug therapy (ATD) therapy. ROC plot analysis was performed to calculate cut-off levels of TRAb and TSAb for prediction of relapse and remission of hyperthyroidism. Cut-off serum levels are provided for timepoints around 3, 6, 10, and 15 months after the beginning of ATD. Repeated measurements of TRAb increase the rate of relapses predictions to 60% (Elecsys), 70% (IMMULITE), and 55% (Thyretain). Patients with remission have consistently TRAb levels below the cut off for relapse in repeated measurements. The cell-based bioassay was the most sensitive – and continued to be positive during follow up [at 15 months: 90% vs. 70% (IMMULITE) and 65% (Elecsys)]. Identification of relapsing hyperthyroidism is possible with automated immunoassays and cell-based bioassay especially with serial TRAb measurements during the course of ATD therapy. Patient who need eye surgery may profit from an early decision towards definitive treatment.

Key words

binding assays - bioassays - TSH receptor antibodies - TRAb - Graves’ disease - Graves’ orbitopathy


Publication History

Received: 03 September 2020

Accepted after revision: 18 January 2021

Article published online:
22 February 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Kahaly GJ, Bartalena L, Hegedüs L. et al. 2018; European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. Eur Thyroid J 2018: 167-186
    CrossrefPubMedGoogle Scholar
  • 2 Orgiazzi J, Madec AM. Reduction of the risk of relapse after withdrawal of medical therapy for Graves’ disease. Thyroid 2002; 12: 849-853
    CrossrefPubMedGoogle Scholar
  • 3 Schott M, Morgenthaler NG, Fritzen R. et al. Levels of autoantibodies against human TSH receptor predict relapse of hyperthyroidism in Graves’ disease. Horm Metab Res 2004; 36: 92-96
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Quadbeck B, Hoermann R, Roggenbuck U. et al. Sensitive thyrotropin and thyrotropin-receptor antibody determinations one month after discontinuation of antithyroid drug treatment as predictors of relapse in Graves’ disease. Thyroid 2005; 15: 1047-1054
    CrossrefPubMedGoogle Scholar
  • 5 Carella C, Mazziotti G, Sorvillo F. et al. 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
    CrossrefPubMedGoogle Scholar
  • 6 Eckstein AK, Lax H, Losch C. et al. 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
    CrossrefPubMedGoogle Scholar
  • 7 Masiello E, Veronesi G, Gallo D. et al. Antithyroid drug treatment for Graves’ disease: baseline predictive models of relapse after treatment for a patient-tailored management. J Endocrinol Invest 2018; 41: 1425-1432
    CrossrefPubMedGoogle Scholar
  • 8 Zimmermann-Belsing T, Nygaard B, Rasmussen AK. et al. Use of the 2nd generation TRAK human assay did not improve prediction of relapse after antithyroid medical therapy of Graves’ disease. Eur J Endocrinol 2002; 146: 173-177
    CrossrefPubMedGoogle Scholar
  • 9 McIver B, Rae P, Beckett G. et al. Lack of effect of thyroxine in patients with Graves’ hyperthyroidism who are treated with an antithyroid drug. N Engl J Med 1996; 334: 220-224
    CrossrefPubMedGoogle Scholar
  • 10 Schott M, Eckstein A, Willenberg HS. et al. Improved prediction of relapse of Graves’ thyrotoxicosis by combined determination of TSH receptor and thyroperoxidase antibodies. Horm Metab Res 2007; 39: 56-61
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Schott M, Hermsen D, Broecker-Preuss M, Casati M. et al. Clinical value of the first automated TSH receptor autoantibody assay for the diagnosis of Graves’ disease (GD): An international multicentre trial. Clin Endocrinol (Oxf) 2009; 71: 566-573
    CrossrefPubMedGoogle Scholar
  • 12 Hermsen D, Eckstein A, Schinner S. et al. Reproducibility of Elecsys Anti-TSHR test results in a lot-to-lot comparison. Horm Metab Res 2010; 42: 295-297
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Allelein S, Ehlers M, Goretzki S. et al. Clinical evaluation of the first automated assay for the detection of stimulating TSH receptor autoantibodies. Horm Metab Res 2016; 48: 795-801
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Allelein S, Diana T, Ehlers M. et al. Comparison of a bridge immunoassay with two bioassays for thyrotropin receptor antibody detection and differentiation. Horm Metab Res 2019; 51: 341-346
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Lytton S, Li Y, Olivo P. et al. Novel chimeric thyroid-stimulating hormone-receptor bioassay for thyroid-stimulating immunoglobulin. Clin Exp Immunol 2010; 162: 438-446
    CrossrefPubMedGoogle Scholar
  • 16 Giuliani C, Cerrone D, Harii N. et al. A TSHr-LH/CGr chimera that measures functional TSAb in Graves’ disease. J Clin Endocrinol Metab 2012; 97: E1106-E1115
    CrossrefPubMedGoogle Scholar
  • 17 Giuliani C, Cerrone D, Harii N, Thornton M. et al. A TSHR-LH/CGR chimera that measures functional thyroid-stimulating autoantibodies (TSAb) can predict remission or recurrence in Graves’ patients undergoing antithyroid drug (ATD) treatment. J Clin Endocrinol Metab 2012; 97: E1080-E1087
    CrossrefPubMedGoogle Scholar
  • 18 Struja T, Jutzi R, Imahorn N. et al. Comparison of Five TSH-receptor antibody assays in Graves’ disease: results from an observational pilot study. BMC Endocr Disord 2019; 19: 38
    CrossrefPubMedGoogle Scholar
  • 19 Autilio C, Morelli R, Locantore P. et al. Stimulating TSH receptor autoantibodies immunoassay: Analytical evaluation and clinical performance in Graves’ disease. Ann Clin Biochem 2018; 55: 172-177
    CrossrefPubMedGoogle Scholar
  • 20 Smith BR, Bolton J, Young S. et al. A new assay for thyrotropin receptor autoantibodies. Thyroid 2004; 14: 830-835
    CrossrefPubMedGoogle Scholar
  • 21 Hermsen D, Broecker-Preuss M, Casati M. et al. Technical evaluation of the first fully automated assay for the detection of TSH receptor autoantibodies. Clin Chim Acta 2009; 401: 84-89
    CrossrefPubMedGoogle Scholar
  • 22 Frank CU, Braeth S, Dietrich JW. et al. Bridge Technology with TSH receptor chimera for sensitive direct detection of TSH receptor antibodies causing Graves’ disease: Analytical and Clinical Evaluation. Horm Metab Res 2015; 47: 880-888
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Tozzoli R, D’Aurizio F, Villalta D. et al. Evaluation of the first fully automated immunoassay method for the measurement of stimulating TSH receptor autoantibodies in Graves’ disease. Clin Chem Lab Med 2017; 55: 58-64
    CrossrefPubMedGoogle Scholar
  • 24 Tun NN, Beckett G, Zammitt NN. et al. Thyrotropin receptor antibody levels at diagnosis and after thionamide course predict Graves’ disease relapse. Thyroid 2016; 26: 1004-1009
    CrossrefPubMedGoogle Scholar
  • 25 Massart C, Gibassier J, d’Herbomez M. Clinical value of M22-based assays for TSH-receptor antibody (TRAb) in the follow-up of antithyroid drug treated Graves’ disease: Comparison with the second generation human TRAb assay. Clin Chim Acta 2009; 407: 62-66
    CrossrefPubMedGoogle Scholar
  • 26 Diana T, Wuster C, Kanitz M. et al. Highly variable sensitivity of five binding and two bio-assays for TSH-receptor antibodies. J Endocrinol Invest 2016; 39: 1159-1165
    CrossrefPubMedGoogle Scholar
  • 27 Schott M, Feldkamp J, Bathan C. et al. Detecting TSH-receptor antibodies with the recombinant TBII assay: Technical and clinical evaluation. Horm Metab Res 2000; 32: 429-435
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Diana T, Kanitz M, Lehmann M. et al. Standardization of a bioassay for thyrotropin receptor stimulating autoantibodies. Thyroid 2015; 25: 169-175
    CrossrefPubMedGoogle Scholar
  • 29 Diana T, Krause J, Olivo PD. et al. Prevalence and clinical relevance of thyroid stimulating hormone receptor-blocking antibodies in autoimmune thyroid disease. Clin Exp Immunol 2017; 189: 304-309
    CrossrefPubMedGoogle Scholar
  • 30 Laurberg P, Wallin G, Tallstedt L. et al. 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
    CrossrefPubMedGoogle Scholar
  • 31 Hwang S, Shin DY, Song MK. et al. High cut-off value of a chimeric TSH receptor (Mc4)-based bioassay may improve prediction of relapse in Graves’ disease for 12 months. Endocrine 2015; 48: 89-95
    CrossrefPubMedGoogle Scholar
  • 32 Diana T, Wüster C, Olivo PD. et al. Performance and specificity of 6 immunoassays for TSH receptor antibodies: A multicenter study. Eur Thyroid J 2017; 6: 243-249
    CrossrefPubMedGoogle Scholar
  • 33 Plohn S, Hose M, Schluter A. et al. Fingolimod improves the outcome of experimental Graves’ Disease and Associated orbitopathy by modulating the autoimmune response to the thyroid-stimulating hormone receptor. Thyroid : Official Journal of the American Thyroid Association 2019; 29: 1286-1301
    CrossrefPubMedGoogle Scholar
  • 34 Meyer Zu Horste M, Pateronis K, Walz MK. et al. The effect of early thyroidectomy on the course of active Graves’ Orbitopathy (GO): A retrospective case study. Horm Metab Res 2016; 48: 433-439
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 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
    CrossrefPubMedGoogle Scholar
  • 36 Vitti P, Rago T, Chiovato L. et al. Clinical features of patients with Graves’ disease undergoing remission after antithyroid drug treatment. Thyroid 1997; 7: 369-375
    CrossrefPubMedGoogle Scholar
  • 37 Eckstein AK, Plicht M, Lax H. et al. Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab 2006; 91: 3464-3470
    CrossrefPubMedGoogle Scholar
  • 38 Perros P, Crombie AL, Matthews JN. et al. Age and gender influence the severity of thyroid-associated ophthalmopathy: A study of 101 patients attending a combined thyroid-eye clinic. Clin Endocrinol (Oxf) 1993; 38: 367-372
    CrossrefPubMedGoogle Scholar