Relevance of TSH Receptor Stimulating and Blocking Autoantibody Measurement for the Prediction of Relapse in Graves’ Disease

Abstract

Recently, we demonstrated that higher levels of autoantibodies to the human TSH receptor (TBII) predict relapse of hyperthyroidism in Graves’ disease (GD). The aim of this study was to extend this outcome prediction by dividing TBII into stimulating (TSAb) and blocking (TBAb) TSH receptor autoantibodies. Altogether, ninety patients (81 female, 9 male) were retrospectively analyzed; sixty-four patients (71 %) did not go into remission or relapsed, whereas twenty-six patients (29 %) went into remission (median follow-up: 17.5 months). TSAb and TBAb measurement was performed in a CHO cell bioassay with cAMP readout at the time of their first visit in our outpatient clinic (single point measurement in median 6.5 months after initial diagnosis). In the remission group, eighteen of twenty-six patients (69 %) were TSAb-positive, whereas fifty-three of sixty-four patients (83 %) were TSAb-positive in the relapse group (p = ns). The mean stimulation indices (SI) were 4.1 in the remission group and 12.9 in the relapse group, respectively (p = 0.015). By using a threshold of 10 SI, the specificity for relapse was 96.0 %, as only one in twenty patients with an SI above 10 went into remission during follow-up (PPV 95 %). Most TSAb-positive patients also had high levels of TBII. Neither group showed any difference with respect to blocking type autoantibodies, which were mostly negative in both groups. In summary, high TSAb levels are similar but not superior to TBII for predicting relapse in GD patients. In contrast, TBAb measurement does not add any valuable information in this context. In the clinical routine, TSAb/TBAb measurement may not play an important role for diagnosis or outcome prediction of GD, since sensitive 2^nd generation TBII assays are easier to perform and offer similar information to the clinician. Bioassays should be reserved for special clinical questions such as Graves’ disease in pregnancy.

Graves’ disease - remission - relapse - TSH-receptor antibodies - stimulating autoantibodies - blocking autoantibodies

References

• 1 Weetman A P. Graves’ disease.  N Engl J Med. 2000;  343 1236-1248
• 2 Rapoport B, Chazenbalk G D, Jaume J C, McLachlan S M. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies.  Endocr Rev. 1998;  19 673-716
• 3 Morgenthaler N G. New assay systems for thyrotropin receptor antibodies.  Curr Opin Endocrinol Diabetes. 1999;  6 251-260
• 4 Smith B R, Hall R. Thyroid-stimulating immunoglobulins in Graves’ disease.  Lancet. 1974;  2 427-431
• 5 Costagliola S, Morgenthaler N G, Hoermann R, Badenhoop K, Struck J, Freitag D. et al . Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves’ disease.  J Clin Endocrinol Metab. 1999;  84 90-97
• 6 Schott M, Feldkamp J, Bathan C, Fritzen R, Scherbaum W A, Seissler J. Detecting TSH-receptor antibodies with the recombinant TBII assay: technical and clinical evaluation.  Horm Metab Res. 2000;  32 429-435
• 7 Massart C, Orgiazzi J, Maugendre D. Clinical validity of a new commercial method for detection of TSH-receptor binding antibodies in sera from patients with Graves’ disease treated with antithyroid drugs.  Clin Chim Acta. 2001;  304 39-47
• 8 Maugendre D, Massart C. Clinical value of a new TSH binding inihibitory activity assay using human TSH receptors in the follow-up of antithyroid drug treated Graves’ disease. Comparison with thyroid stimulating antibody bioassay.  Clin Endocrinol (Oxf). 2001;  54 89-96
• 9 Giovanella L, Ceriani L, Garancini S. Clinical applications of the 2nd generation assay for anti-TSH receptor antibodies in Graves’ disease. Evaluation in patients with negative 1st generation test.  Clin Chem Lab Med. 2001;  39 25-28
• 10 Zimmermann-Belsing T, Nygaard B, Rasmussen A K, Feldt-Rasmussen U. 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
• 11 Pedersen I B, Knudsen N, Perrild H, Ovesen L, Laurberg P. TSH-receptor antibody measurement for differentiation of hyperthyroidism into Graves’ disease and multinodular toxic goitre: a comparison of two competitive binding assays.  Clin Endocrinol (Oxf). 2001;  55 381-390
• 12 Wallaschofski H, Orda C, Georgi P, Miehle K, Paschke R. Distinction between autoimmune and non-autoimmune hyperthyroidism by determination of TSH-receptor antibodies in patients with the initial diagnosis of toxic multinodular goiter.  Horm Metab Res. 2001;  33 504-507
• 13 Morgenthaler N G, Nagata A, Katayama S, Bergmann A, Iitaka M. Detection of low titre TBII in patients with Graves’ disease using recombinant human TSH receptor.  Clin Endocrinol (Oxf). 2002;  57 193-198
• 14 Schleusener H, Schwander J, Fischer C, Holle R, Holl G, Badenhoop K. et al . Prospective multicentre study on the prediction of relapse after antithyroid drug treatment in patients with Graves’ disease.  Acta Endocrinol (Copenh). 1989;  120 689-701
• 15 Feldt-Rasmussen U, Schleusener H, Carayon P. Meta-analysis evaluation of the impact of thyrotropin receptor antibodies on long term remission after medical therapy of Graves’ disease.  J Clin Endocrinol Metab. 1994;  78 98-102
• 16 Davies T F, Roti E, Braverman L E, DeGroot L J. Thyroid controversy-stimulating antibodies.  J Clin Endocrinol Metab. 1998;  83 (11) 3777-3785
• 17 Wallaschofski H, Miehle K, Mayer A, Tuschy U, Hentschel B, Paschke R. Prediction of remission or relapse for Graves’ hyperthyroidism by the combined determination of stimulating, blocking and binding TSH-receptor antibodies after the withdrawal of antithyroid drug treatment.  Horm Metab Res. 2002;  34 383-388
• 18 Morgenthaler N G, Pampel I, Aust G, Seissler J, Scherbaum W A. Application of a bioassay with CHO cells for the routine detection of stimulating and blocking autoantibodies to the TSH-receptor.  Horm Metab Res. 1998;  30 162-168
• 19 Lenzner C, Morgenthaler N G. The effect of thyrotropin-receptor blocking antibodies on stimulating autoantibodies from patients with Graves’ disease.  Thyroid. 2003;  13 1153-1161
• 20 Schott M, Morgenthaler N G, Fritzen R, Feldkamp J, Willenberg H S, Scherbaum W A. et al . Levels of autoantibodies against human TSH receptor predict relapse of hyperthyroidism in Graves’ disease.  Horm Metab Res. 2004;  36 92-96
• 21 Quadbeck B, Hoermann B, Roggenbuck U, Hahn S, Mann K, Janssen O E. 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
• 22 Morgenthaler N G, Minich W B, Willnich M, Bogusch T, Hollidt J M, Weglohner W. et al . Affinity purification and diagnostic use of TSH receptor autoantibodies from human serum.  Mol Cell Endocrinol. 2003;  212 73-79
• 23 Schott M, Scherbaum W A, Morgenthaler N G. TSH-receptor autoantibodies in Graves’ disease: recent developments in the diagnosis and therapy monitoring.  Trends Endocrinol Metab. 2005;  16 243-248
• 24 McIver B, Rae P, Beckett G, Wilkinson E, Gold A, Toft A. 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
• 25 Vitti P, Rago T, Chiovato L, Pallini S, Santini F, Fiore E. et al . Clinical features of patients with Graves’ disease undergoing remission after antithyroid drug treatment.  Thyroid. 1997;  7 369-375
• 26 Michelangeli V, Poon C, Taft J, Newnham H, Topliss D, Colman P. The prognostic value of thyrotropin receptor antibody measurement in the early stages of treatment of Graves’ disease with antithyroid drugs.  Thyroid. 1998;  8 119-124
• 27 Kasagi K, Konishi J, Iida Y, Ikekubo K, Mori T, Kuma K. et al . A new in vitro assay for human thyroid stimulator using cultured thyroid cells: effect of sodium chloride on adenosine 3',5'-monophosphate increase.  J Clin Endocrinol Metab. 1982;  54 108-114
• 28 Wallaschofski H, Paschke R. Detection of thyroid stimulating (TSAB)- and thyrotropin stimulation blocking (TSBAB) antibodies with CHO cell lines expressing different TSH-receptor numbers.  Clin Endocrinol (Oxf). 1999;  50 365-372
• 29 Allannic H, Fauchet R, Orgiazzi J, Madec A M, Genetet B, Lorcy Y. et al . Antithyroid drugs and Graves’ disease: a prospective randomized evaluation of the efficacy of treatment duration.  J Clin Endocrinol Metab. 1990;  70 675-679
• 30 Garcia-Mayor R V, Paramo C, Luna C R, Perez Mendez L F, Galofre J C, Andrade A. Antithyroid drug and Graves’ hyperthyroidism. Significance of treatment duration and TRAb determination on lasting remission.  J Endocrinol Invest. 1992;  15 815-820
• 31 Maugendre D, Gatel A, Campion L, Massart C, Guilhem I, Lorcy Y. et al . Antithyroid drugs and Graves’ disease - prospective randomized assessment of long-term treatment.  Clin Endocrinol (Oxf). 1999;  50 127-132