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Epitope Heterogeneity of Thyroid-Stimulating Antibodies Predicts Long-Term Outcome in Graves’ Patients Treated with Antithyroid Drugs

Department of Internal Medicine, Seoul National University College of Medicine and Clinical Research Institute, Seoul National University Hospital (T.Y.K., Y.J.P., D.J.P., B.Y.C.), Seoul 110-744, Korea; Department of Internal Medicine, Dankook University College of Medicine (H.C.), Cheonan 330-715, Korea; Department of Internal Medicine, Asan Medical Center, University of Ulsan, College of Medicine (W.B.K.), Seoul 110-744, Korea; and Edison Biotechnology Institute and Ohio University College of Osteopathic Medicine (L.D.K.), Athens, Ohio 45701

Address all correspondence and requests for reprints to: Bo Youn Cho, M.D., Ph.D., Department of Internal Medicine, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea. E-mail: bycho{at}plaza.snu.ac.kr.

Differences in the epitopes of thyroid-stimulating antibodies (TSAbs) from patients with untreated Graves’ disease were compared with long-term response to antithyroid drugs. Epitopes were measured using Chinese hamster ovary cells transfected with wild-type human TSH receptor (TSHR) and two receptor chimeras, wherein TSHR residues 9–165 or 90–165 had been substituted with comparable residues of the LH/chorionic gonadotropin receptor. Of 159 patients studied, 52 (32.7%) exhibited positive TSAb activity with one or both chimera lines (heterogeneous group), and 107 (67.3%) had no activity with either (homogeneous group). Independent of all other parameters, patients with heterogeneous epitopes responded more favorably to oral antithyroid drugs than patients with homogeneous epitopes (65.4% vs. 41.9%, P = 0.011: estimated odds ratio by logistic regression, 2.17). Although most clinical parameters were not different at presentation, significant differences in the size of goiters, total T₃ concentrations, and titers of TSH-binding inhibitory Igs were evident in the successfully treated group (n = 80) by comparison to the group of patients whose treatment failed (n = 79). Alone, these three parameters did not predict outcome; however, when either of these parameters were considered together with epitope heterogeneity, predictability of a positive therapeutic response was increased to nearly 80%. Thus, the presence of TSAbs with a heterogeneous epitope in a patient with Graves’ disease is not only associated with a favorable response to antithyroid drug treatment, it may help predict the response to treatment when the patient is initially seen.

This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (01-PJ1-PG3-20500-0014).

Abbreviations: CG, Chorionic gonadotropin; CHO, Chinese hamster ovary; GD, Graves’ disease; TBII, TSH-binding inhibitory Ig; TSAbs, thyroid-stimulating antibodies; TSHR, TSH receptor.

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