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When should antithyroid drug therapy to reduce the relapse rate of hyperthyroidism in Graves’ disease be discontinued?

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Abstract

Objective

The use of antithyroid drug (ATD) therapy in patients with Graves’ disease (GD) hyperthyroidism has been increasing, but ATD therapy is associated with a higher relapse rate. We aimed to evaluate clinical factors for predicting relapse of GD after ATD therapy.

Methods

Patients (n = 149) with newly diagnosed GD who achieved remission of hyperthyroidism after ATD therapy (≥6 months) were followed up for >18 months after ATD withdrawal. We evaluated the predictive factors of relapse during a median of 6.9 years of follow-up.

Results

Disease relapse occurred in 52 patients (34.9%). By multivariate analyses, a duration of the minimum maintenance dose therapy (MMDT) of <6 months was a significant factor in disease relapse (hazard ratio [HR], 2.58; 95% confidence interval [CI], 1.47–4.52; p < 0.001), and a T3/free T4 (fT4) ratio > 120 at ATD withdrawal was significantly more frequent in patients with relapse (HR 2.43; 95% CI, 1.36–4.34; p = 0.002). In the prediction-of-relapse model, the likelihood of relapse was greater in the high-risk group, which had a short MMDT duration and a T3/fT4 ratio ≥120 (HR, 5.81; 95% CI, 2.52–13.39; p < 0.001) and the intermediate-risk group, which had a short MMDT duration or a T3/fT4 ratio < 120 (HR, 2.77; 95% CI, 1.26–6.13; p < 0.001), than in the low-risk group, which had a long MMDT duration and a T3/fT4 ratio < 120.

Conclusion

An MMDT longer than 6 months and a high T3/fT4 ratio at ATD withdrawal were independent predictors of relapse in patients who achieved initial remission after ATD for GD. These factors could be used to determine the optimal time to withdraw ATD during the treatment of GD hyperthyroidism.

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References

  1. D.S. Ross, H.B. Burch, D.S. Cooper, M.C. Greenlee, P. Laurberg, A.L. Maia, S.A. Rivkees, M. Samuels, J.A. Sosa, M.N. Stan, 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 26(10), 1343–1421 (2016)

    Article  Google Scholar 

  2. J.P. Brito, S. Schilz, N. Singh Ospina, R. Rodriguez-Gutierrez, S. Maraka, L.R. Sangaralingham, V.M. Montori, Antithyroid drugs—the most common treatment for Graves’ disease in the United States: a nationwide population-based study. Thyroid 26(8), 1144–1145 (2016)

    Article  Google Scholar 

  3. E. Mohlin, H.F. Nyström, M. Eliasson, Long-term prognosis after medical treatment of Graves’ disease in a northern Swedish population 2000-2010. Eur. J. Endocrinol. 170, 419–427 (2013)

    Article  Google Scholar 

  4. H.B. Burch, K.D. Burman, D.S. Cooper, A 2011 survey of clinical practice patterns in the management of Graves’ disease. J. Clin. Endocrinol. Metab. 97(12), 4549–4558 (2012)

    Article  CAS  Google Scholar 

  5. D. Villagelin, J.H. Romaldini, R.B. Santos, A.B. Milkos, L.S. Ward, Outcomes in relapsed Graves’ disease patients following radioiodine or prolonged low dose of methimazole treatment. Thyroid 25(12), 1282–1290 (2015)

    Article  CAS  Google Scholar 

  6. K.H. Yi, J.H. Moon, I.-J. Kim, H.-S. Bom, J. Lee, W.Y. Chung, J.H. Chung, Y.K. Shong, The diagnosis and management of hyperthyroidism consensus-report of the Korean Thyroid Association. J. Korean Thyroid Assoc. 6(1), 1–11 (2013)

    Article  Google Scholar 

  7. S. Yamashita, N. Amino, Y.K. Shong. The American Thyroid Association and American Association of Clinical Endocrinologists hyperthyroidism and other causes of thyrotoxicosis guidelines: viewpoints from Japan and Korea. (Mary Ann Liebert, Inc, 140 Huguenot Street, 3rd Floor New Rochelle, NY 10801 USA), 2011)

    Book  Google Scholar 

  8. E. Mohlin, H. Filipsson Nystrom, M. Eliasson, Long-term prognosis after medical treatment of Graves’ disease in a northern Swedish population 2000-2010. Eur. J. Endocrinol. 170(3), 419–427 (2014). https://doi.org/10.1530/eje-13-0811

    Article  CAS  PubMed  Google Scholar 

  9. F. Azizi, L. Ataie, M. Hedayati, Y. Mehrabi, F. Sheikholeslami, Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine. Eur. J. Endocrinol. 152(5), 695–701 (2005)

    Article  CAS  Google Scholar 

  10. P. Abraham, A. Avenell, S. McGeoch, L.F. Clark, J.S. Bevan, Antithyroid drug regimen for treating Graves’ hyperthyroidism. Cochrane Database Syst. Rev. CD003420 (2010)

  11. A. Allahabadia, J. Daykin, R.L. Holder, M.C. Sheppard, S.C. Gough, J.A. Franklyn, Age and gender predict the outcome of treatment for Graves’ hyperthyroidism. The. J. Clin. Endocrinol. Metab. 85(3), 1038–1042 (2000)

    CAS  PubMed  Google Scholar 

  12. P. Vitti, T. Rago, L. Chiovato, S. Pallini, F. Santini, E. Fiore, R. Rocchi, E. Martino, A. Pinchera, Clinical features of patients with Graves’ disease undergoing remission after antithyroid drug treatment. Thyroid 7(3), 369–375 (1997)

    Article  CAS  Google Scholar 

  13. T. Chowdhury, P. Dyer, Clinical, biochemical and immunological characteristics of relapsers and non‐relapsers of thyrotoxicosis treated with anti‐thyroid drugs. J. Intern. Med. 244(4), 293–297 (1998)

    Article  CAS  Google Scholar 

  14. D. Glinoer, P. De Nayer, M. Bex, Effects of l-thyroxine administration, TSH-receptor antibodies and smoking on the risk of recurrence in Graves’ hyperthyroidism treated with antithyroid drugs: a double-blind prospective randomized study. Eur. J. Endocrinol. 144(5), 475–483 (2001)

    Article  CAS  Google Scholar 

  15. B. Nedrebo, P.I. Holm, S. Uhlving, J. Sorheim, S. Skeie, G.E. Eide, E.S. Husebye, E.A. Lien, S. Aanderud, Predictors of outcome and comparison of different drug regimens for the prevention of relapse in patients with Graves’ disease. Eur. J. Endocrinol. 147(5), 583–589 (2002)

    Article  CAS  Google Scholar 

  16. A.K. Eckstein, H. Lax, C. Lösch, D. Glowacka, M. Plicht, K. Mann, J. Esser, N.G. Morgenthaler, Patients with severe Graves’ ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission. Clin. Endocrinol. 67(4), 607–612 (2007)

    Google Scholar 

  17. C. Cappelli, E. Gandossi, M. Castellano, C. Pizzocaro, B. Agosti, A. Delbarba, I. Pirola, E. De Martino, E.A. Rosei, Prognostic value of thyrotropin receptor antibodies (TRAb) in Graves’ disease: a 120 months prospective study. Endocr. J. 54(5), 713–720 (2007)

    Article  CAS  Google Scholar 

  18. P. Laurberg, G. Wallin, L. Tallstedt, M. Abraham-Nordling, G. Lundell, O. Tørring, TSH-receptor autoimmunity in Graves’ disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur. J. Endocrinol. 158(1), 69–75 (2008)

    Article  CAS  Google Scholar 

  19. C. Carella, G. Mazziotti, F. Sorvillo, M. Piscopo, M. Cioffi, P. Pilla, R. Nersita, S. Iorio, G. Amato, L. Braverman, 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 16(3), 295–302 (2006)

    Article  CAS  Google Scholar 

  20. H.S. Choi, W.S. Yoo, Free thyroxine, anti-thyroid stimulating hormone receptor antibody titers, and absence of goiter were associated with responsiveness to methimazole in patients with new onset Graves’ disease. Endocrinol. Metab. 32(2), 281–287 (2017)

    Article  CAS  Google Scholar 

  21. M. Rotondi, C. Cappelli, B. Pirali, I. Pirola, F. Magri, R. Fonte, M. Castellano, E.A. Rosei, L. Chiovato, The effect of pregnancy on subsequent relapse from Graves’ disease after a successful course of antithyroid drug therapy. J. Clin. Endocrinol. Metab. 93(10), 3985–3988 (2008). https://doi.org/10.1210/jc.2008-0966

    Article  CAS  PubMed  Google Scholar 

  22. Y.A. Kim, S.W. Cho, H.S. Choi, S. Moon, J.H. Moon, K.W. Kim, D.J. Park, K.H. Yi, Y.J. Park, B.Y. Cho, The second antithyroid drug treatment is effective in relapsed Graves’ disease patients: a median 11-year follow-up study. Thyroid 27(4), 491–496 (2017)

    Article  CAS  Google Scholar 

  23. U. Feldt-Rasmussen, H. Schleusener, P. Carayon, Meta-analysis evaluation of the impact of thyrotropin receptor antibodies on long term remission after medical therapy of Graves’ disease. J. Clin. Endocrinol. Metab. 78(1), 98–102 (1994)

    CAS  PubMed  Google Scholar 

  24. D. Strich, G. Karavani, S. Edri, D. Gillis, TSH enhancement of FT4 to FT3 conversion is age dependent. Eur. J. Endocrinol. 175, 49–54 (2016). EJE-16-0007

    Article  CAS  Google Scholar 

  25. H. Kwon, W.G. Kim, E.K. Jang, M. Kim, S. Park, M.J. Jeon, T.Y. Kim, J.-S. Ryu, Y.K. Shong, W.B. Kim, Usefulness of measuring thyroid stimulating antibody at the time of antithyroid drug withdrawal for predicting relapse of Graves disease. Endocrinol. Metab. 31(2), 300–310 (2016)

    Article  CAS  Google Scholar 

  26. E. Peterson, P. De, R. Nuttall, BMI, diet and female reproductive factors as risks for thyroid cancer: a systematic review. PLoS ONE 7(1), e29177 (2012). https://doi.org/10.1371/journal.pone.0029177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. M.P. Mourits, M.F. Prummel, W.M. Wiersinga, L. Koornneef, Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin. Endocrinol. 47(1), 9–14 (1997)

    Article  CAS  Google Scholar 

  28. L. Bartalena, L. Baldeschi, A.J. Dickinson, A. Eckstein, P. Kendall-Taylor, C. Marcocci, M.P. Mourits, P. Perros, K. Boboridis, A. Boschi, Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 18(3), 333–346 (2008)

    Article  Google Scholar 

  29. World Health Organization, Assessment of Iodine Deficiency Disorders and Monitoring Their Elimination: A Guide for Programme Managers (Geneva: World Health Organization, 2007).

  30. S.M. ChoBY, L. YiKH, M.H. KohCS, Evaluationofserum basalthyrotropinlevelsand thyrotopinreceptorantibodyactivitiesasprognostic markers for discontinuation of antithyroid drug treatmentinpatientswithGraves’ disease. Clin. Endocrinol. 36, 585–590 (1992)

    Article  Google Scholar 

  31. T. Konishi, Y. Okamoto, M. Ueda, Y. Fukuda, I. Harusato, Y. Tsukamoto, N. Hamada, Drug discontinuation after treatment with minimum maintenance dose of an antithyroid drug in Graves’ disease: a retrospective study on effects of treatment duration with minimum maintenance dose on lasting remission. Endocr. J. 58(2), 95–100 (2011)

    Article  CAS  Google Scholar 

  32. M.J. Jeon, W.G. Kim, E.K. Jang, Y.M. Choi, Y.-M. Lee, T.-Y. Sung, J.H. Yoon, K.-W. Chung, S.J. Hong, J.H. Baek, Thyroglobulin level in fine-needle aspirates for preoperative diagnosis of cervical lymph node metastasis in patients with papillary thyroid carcinoma: two different cutoff values according to serum thyroglobulin level. Thyroid 25(4), 410–416 (2015)

    Article  CAS  Google Scholar 

  33. W.B. Kim, Clinical applications of thyrotropin binding inhibitor immunoglobulin (TBII) assays. J. Korean Endocr. Soc. 23(3), 174–178 (2008)

    Article  Google Scholar 

  34. R.V. García-Mayor, C. Paramo, R.L. Cano, L.P. Mendez, J. Galofre, A. Andrade, Antithyroid drug and Graves’ hyperthyroidism. Significance of treatment duration and TRAb determination on lasting remission. J. Endocrinol. Investig. 15(11), 815–820 (1992)

    Article  Google Scholar 

  35. P. Laurberg, Remission of Graves’ disease during anti-thyroid drug therapy. Time to reconsider the mechanism? Eur. J. Endocrinol. 155(6), 783–786 (2006)

    Article  CAS  Google Scholar 

  36. T. Ando, R. Latif, T.F. Davies, Concentration-dependent regulation of thyrotropin receptor function by thyroid-stimulating antibody. J. Clin. Investig. 113(11), 1589–1595 (2004)

    Article  CAS  Google Scholar 

  37. S. Costagliola, N.G. Morgenthaler, R. Hoermann, K. Badenhoop, J. Struck, D. Freitag, S. Poertl, W. Weglöhner, Jr.M. Hollidt, B: Quadbeck, Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves’ disease. J. Clin. Endocrinol. Metab. 84(1), 90–997 (1999)

    CAS  PubMed  Google Scholar 

  38. X.G. Vos, N. Smit, E. Endert, J.G. Tijssen, W.M. Wiersinga, Frequency and characteristics of TBII-seronegative patients in a population with untreated Graves’ hyperthyroidism: a prospective study. Clin. Endocrinol. 69(2), 311–317 (2008). https://doi.org/10.1111/j.1365-2265.2008.03192.x

    Article  CAS  Google Scholar 

  39. A.C. Bianco, D. Salvatore, B. Gereben, M.J. Berry, P.R. Larsen, Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr. Rev. 23(1), 38–89 (2002)

    Article  CAS  Google Scholar 

  40. P. Laurberg, Mechanisms governing the relative proportions of thyroxine and 3, 5, 3′-triiodothyronine in thyroid secretion. Metabolism 33(4), 379–392 (1984)

    Article  CAS  Google Scholar 

  41. P. Laurberg, Thyroxine and 3, 5, 3′-triiodothyronine content of thyroglobulin in thyroid needle aspirates in hyperthyroidism and hypothyroidism. J. Clin. Endocrinol. Metab. 64(5), 969–974 (1987).

    Article  CAS  Google Scholar 

  42. P. Laurberg, H. Vestergaard, S. Nielsen, S.E. Christensen, T. Seefeldt, K. Helleberg, K.M. Pedersen, Sources of circulating 3, 5, 3′-triiodothyronine in hyperthyroidism estimated after blocking of type 1 and type 2 iodothyronine deiodinases. J. Clin. Endocrinol. Metab. 92(6), 2149–2156 (2007)

    Article  CAS  Google Scholar 

  43. A. Carlé, N. Knudsen, I.B. Pedersen, H. Perrild, L. Ovesen, L.B. Rasmussen, P. Laurberg, Determinants of serum T4 and T3 at the time of diagnosis in nosological types of thyrotoxicosis: a population-based study. Eur. J. Endocrinol. 169(5), 537–545 (2013)

    Article  Google Scholar 

  44. J. Takamatsu, K. Kuma, T. Mozai, Serum triiodothyronine to thyroxine ratio: a newly recognized predictor of the outcome of hyperthyroidism due to Graves’ disease. J. Clin. Endocrinol. Metab. 62(5), 980–983 (1986).

    Article  CAS  Google Scholar 

  45. B.L. Solomon, J.E. Evaul, K.D. Burman, L. Wartofsky, Remission rates with antithyroid drug therapy: continuing influence of iodine intake?. Ann. Intern. Med. 107(4), 510–512 (1987).

    Article  CAS  Google Scholar 

  46. F. Azizi, Environmental iodine intake affects the response to methimazole in patients with diffuse toxic goiter. J. Clin. Endocrinol. Metab. 61(2), 374–377 (1985).

    Article  CAS  Google Scholar 

  47. S.M. Park, Y.Y. Cho, J.Y. Joung, S.Y. Sohn, S.W. Kim, J.H. Chung, Excessive iodine intake does not increase the recurrence rate of Graves’ disease after withdrawal of the antithyroid drug in an iodine-replete area. Eur. thyroid J. 4(1), 36–42 (2015)

    Article  CAS  Google Scholar 

  48. T. Hiraiwa, M. Ito, A. Imagawa, J. Takamatsu, K. Kuma, A. Miyauchi, T. Hanafusa, Restriction of dietary Iodine does not ameliorate the early effect of anti-thyroid drug therapy for Graves’ disease in an area of excessive iodine intake. J. Endocrinol. Investig. 29(4), 380–384 (2006)

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea

    Suyeon Park & Doo Man Kim

  2. Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

    Eyun Song, Hye-Seon Oh, Min Ji Jeon, Won Gu Kim, Tae Yong Kim, Young Kee Shong & Won Bae Kim

  3. Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, Korea

    Mijin Kim

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  1. Suyeon Park
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Park, S., Song, E., Oh, HS. et al. When should antithyroid drug therapy to reduce the relapse rate of hyperthyroidism in Graves’ disease be discontinued?. Endocrine 65, 348–356 (2019). https://doi.org/10.1007/s12020-019-01987-w

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