Advertisement

Journal of Endocrinological Investigation

, Volume 42, Issue 11, pp 1273–1283 | Cite as

Safety of long-term antithyroid drug treatment? A systematic review

  • F. AziziEmail author
  • R. Malboosbaf
Review
  • 205 Downloads

Abstract

Continued low-dose MMI treatment for longer than 12–18 months may be considered in patients not in remission. However, ATDs are not free from adverse effects. We undertook a systematic review to clarify safety of long-term ATD treatment. Medline and the Cochrane Library for trials published between 1950 and Nov 2018 were systematically searched. We included original studies containing data for long-term (> 18 months) ATD treatment. Two reviewers independently extracted data from included trials and any disagreement was adjudicated by consensus. Of 615 related articles found, 12 fulfilled the criteria. Six articles had data for adults, five for non-adults and one article had data for both groups. The sample sizes ranged between 20 and 249 individuals, and the mean duration of ATD treatment ranged between 2.1 and 14.2 years. Considering all data from 1660 patients treated with ATD for a mean duration of 5.8 years (around 10,000 patient-years), major complications occurred only in 14 patients: 7 severe agranulocytosis, 5 severe liver damage, one ANCA-associated glomerulonephritis and one vasculitis with small cutaneous ulcerations. Minor complications rates were between 2 and 36%, while more complications were in higher doses and in the children. The most reported AE was cutaneous reaction; the other adverse events were elevated liver enzymes, leukocytopenia, arthritis, arthralgia, myalgia, thrombocytopenia, fever, nausea and oral aphthous. Long-term ATD treatment is safe, especially in low dose and in adults, indicating that it should be considered as an earnest alternative treatment for GD.

Keywords

Graves’ disease Long-term therapy Continuous therapy Antithyroid drugs Methimazole Propylthiouracil 

Notes

Acknowledgements

The authors wish to acknowledge Ms. Niloofar Shiva for critical editing of English grammar and syntax of the manuscript.

Compliance with ethical statement

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article is a systematic review, so does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.

References

  1. 1.
    Mazza E et al (2008) Long-term follow-up of patients with hyperthyroidism due to Graves’ disease treated with methimazole. Comparison of usual treatment schedule with drug discontinuation vs continuous treatment with low methimazole doses: a retrospective study. J Endocrinol Invest 31:866–872PubMedGoogle Scholar
  2. 2.
    Marino M et al (2014) An update on the medical treatment of Graves’ hyperthyroidism. J Endocrinol Invest 37:1041–1048PubMedGoogle Scholar
  3. 3.
    Rivkees SA, Dinauer C (2007) An optimal treatment for pediatric Graves’ disease is radioiodine. J Clin Endocrinol Metab 92:797–800PubMedGoogle Scholar
  4. 4.
    Lee JA et al (2007) The optimal treatment for pediatric Graves’ disease is surgery. J Clin Endocrinol Metab 92:801–803PubMedGoogle Scholar
  5. 5.
    Nakamura H et al (2007) Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease. J Clin Endocrinol Metab 92:2157–2162PubMedGoogle Scholar
  6. 6.
    Rivkees SA, Szarfman A (2010) Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children. J Clin Endocrinol Metab 95:3260–3267PubMedGoogle Scholar
  7. 7.
    Brito JP et al (2016) Antithyroid drugs-the most common treatment for Graves’ disease in the United States: a nationwide population-based study. Thyroid 26:1144–1145PubMedGoogle Scholar
  8. 8.
    Ross DS et al (2016) American thyroid association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 26:1343–1421PubMedGoogle Scholar
  9. 9.
    Wartofsky L et al (1991) Differences and similarities in the diagnosis and treatment of Graves’ disease in Europe, Japan and the United States. Thyroid 1:129–135PubMedGoogle Scholar
  10. 10.
    Burch HB et al (2012) A 2011 survey of clinical practice patterns in the management of Graves’ disease. J Clin Endocrinol Metab 97:4549–4558PubMedGoogle Scholar
  11. 11.
    Vaidya B et al (2008) Radioiodine treatment for benign thyroid disorders: results of a nationwide survey of UK endocrinologists. Clin Endocrinol (Oxf) 68:814–820Google Scholar
  12. 12.
    Escobar-Jimenez F et al (2000) Trends in diagnostic and therapeutic criteria in Graves’ disease in the last 10 years. Postgrad Med J 76:340–344PubMedPubMedCentralGoogle Scholar
  13. 13.
    Yamashita S et al (2011) The American Thyroid Association and American Association of Clinical Endocrinologists hyperthyroidism and other causes of thyrotoxicosis guidelines: viewpoints from Japan and Korea. Thyroid 21:577–580PubMedGoogle Scholar
  14. 14.
    Moon JH, Yi KH (2013) The diagnosis and management of hyperthyroidism in Korea: consensus report of the Korean thyroid association. Endocrinol Metab (Seoul) 28:275–279Google Scholar
  15. 15.
    Anagnostis P et al (2013) Predictors of long-term remission in patients with Graves’ disease: a single center experience. Endocrine 44:448–453PubMedGoogle Scholar
  16. 16.
    Orgiazzi J (2015) Should protracted treatment with antithyroid drug (ATD) be considered as a routine strategy in patients with graves’ disease who had a relapse after a first course of ATD? Clin Thyroidol 27:302–305Google Scholar
  17. 17.
    Léger J, Carel JC (2017) Management of endocrine disease: arguments for the prolonged use of antithyroid drugs in children with Graves’ disease. Eur J Endocrinol 177:R59–R67PubMedGoogle Scholar
  18. 18.
    Azizi F, Malboosbaf R (2017) Long-term antithyroid drug treatment: a systematic review and meta-analysis. Thyroid 27:1223–1231PubMedGoogle Scholar
  19. 19.
    Liberati A et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 21:339b2700.  https://doi.org/10.1371/journal.pmed.1000100 CrossRefGoogle Scholar
  20. 20.
    Wells GA (2001) The Newcastle-Ottawa scale (NOS) for assessing the quality of non randomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
  21. 21.
    Egger M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedPubMedCentralGoogle Scholar
  22. 22.
    Centre for Reviews and Dissemination (2009) CRD's guidance for undertaking reviews in healthcare. York Publishing Services. www.york.ac.uk
  23. 23.
    Yasuda K et al (2017) Relationship between dose of antithyroid drugs and adverse events in pediatric patients with Graves’ disease. Clin Pediatr Endocrinol 26:1–7PubMedPubMedCentralGoogle Scholar
  24. 24.
    Azizi F et al (2012) Long-term continuous methimazole or radioiodine treatment for hyperthyroidism. Arch Iran Med 15:477–484PubMedGoogle Scholar
  25. 25.
    Le´ger J et al (2012) Positive impact of long-term antithyroid drug treatment on the outcome of children with Graves’ disease: national long-term cohort study. J Clin Endocrinol Metab 97:110–119Google Scholar
  26. 26.
    Laurberg P et al (2011) Sustained control of Graves’ hyperthyroidism during long-term low-dose antithyroid drug therapy of patients with severe Graves’ orbitopathy. Thyroid 21:951–956PubMedGoogle Scholar
  27. 27.
    Sato H et al (2011) Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves’ disease: efficacy and adverse reactions during initial treatment and long-term outcome. J Pediatr Endocrinol Metab 24:257–263PubMedGoogle Scholar
  28. 28.
    Chen DY et al (2009) Comparison of the long-term efficacy of low dose 131I versus antithyroid drugs in the treatment of hyperthyroidism. Nucl Med Commun 30:160–168PubMedGoogle Scholar
  29. 29.
    Kaguelidou F, French Childhood Graves’ Disease Study Group et al (2008) Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of antithyroid drug treatment. J Clin Endocrinol Metab 93:3817–3826PubMedGoogle Scholar
  30. 30.
    Azizi F et al (2005) Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine. Eur J Endocrinol 152:695–701PubMedGoogle Scholar
  31. 31.
    Barrio R et al (2005) Graves’ disease in children and adolescents: response to long-term treatment. Acta Paediatr 94:1583–1589PubMedGoogle Scholar
  32. 32.
    Mashio Y et al (1997) Treatment of hyperthyroidism with a small single daily dose of methimazole: a prospective long-term follow-up study. Endocr J 44:553–558PubMedGoogle Scholar
  33. 33.
    Rivkees SA et al (2010) Adverse events associated with methimazole therapy of graves’ disease in children. Int J Pediatr Endocrinol 2010:1–4Google Scholar
  34. 34.
    Watanabe N et al (2012) Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves’ disease. J Clin Endocrinol Metab 97:E49–53PubMedGoogle Scholar
  35. 35.
    Wartofsky L (1993) Has the use of antithyroid drugs for Graves’ disease become obsolete? Thyroid 3:335–344PubMedGoogle Scholar
  36. 36.
    Franklyn JA et al (1991) Long-term follow up of treatment of hyperthyroidism by three different methods. Clin Endocrinol 34:71–76Google Scholar
  37. 37.
    Astwood EB (1967) Use of antithyroid drugs. In: Irvine WJ (ed) Hyperthyroidism. Williams & Wilkins, Baltimore, pp 85–98Google Scholar
  38. 38.
    Abraham P et al (2010) Antithyroid drug regimen for treating Graves’ hyperthyroidism. Cochrane Database Syst Rev 20:CD003420Google Scholar
  39. 39.
    Masiello E et al (2018) Antithyroid drug treatment for Graves’ disease: baseline predictive models of relapse after treatment for a patient-tailored management. J Endocrinol Invest 41:1425–1432PubMedGoogle Scholar
  40. 40.
    Laurberg P (2006) Remission of Graves’ disease during anti-thyroid drug therapy. Time to reconsider the mechanism? Eur J Endocrinol 155:783–786PubMedGoogle Scholar
  41. 41.
    Montani V et al (1998) Regulation of major histocompatibility class II gene expression in FRTL-5 thyrocytes: opposite effects of interferon and methimazole. Endocrinology 139:290–302PubMedGoogle Scholar
  42. 42.
    Mozes E et al (1998) Spontaneous autoimmune disease in (NZB x NZW) F1 mice is ameliorated by treatment with methimazole. J Clin Immunol 18:106–113PubMedGoogle Scholar
  43. 43.
    Volpe R (1994) Evidence that the immunosuppressive effects of antithyroid drugs are mediated through actions on the thyroid cell, modulating thyrocyte-immunocyte signaling: a review. Thyroid 4:217–223PubMedGoogle Scholar
  44. 44.
    Calissendorff J et al (2015) A prospective investigation of graves’ disease and selenium: thyroid hormones, auto-antibodies and self-rated symptoms. Eur Thyroid J 2:93–98Google Scholar
  45. 45.
    Leo M et al (2017) Effects of selenium on short-term control of hyperthyroidism due to Graves’ disease treated with methimazole: results of a randomized clinical trial. J Endocrinol Invest 40:281–287PubMedGoogle Scholar
  46. 46.
    Marinò M et al (2017) Selenium in the treatment of thyroid diseases. Eur Thyroid J 2:113–114Google Scholar
  47. 47.
    Rayman MP (2012) Selenium and human health. Lancet 379:1256–1268PubMedGoogle Scholar
  48. 48.
    Rotondi M et al (2007) Role of chemokines in endocrine autoimmune diseases. Endocr Rev 28:492–520PubMedGoogle Scholar
  49. 49.
    Slingerland DW, Burrows BA (1979) Long-term antithyroid treatment in hyperthyroidism. JAMA 242:2408–2410PubMedGoogle Scholar
  50. 50.
    Lippe BM et al (1987) Hyperthyroidism in children treated with Long term medical therapy: twenty-five percent remission every two years. J Clin Endocrinol Metab 64:1241–1245PubMedGoogle Scholar
  51. 51.
    Elbers L et al (2011) Outcome of very long-term treatment with antithyroid drugs in Graves’ hyperthyroidism associated with Graves’ orbitopathy. Thyroid 21:279–383PubMedGoogle Scholar
  52. 52.
    Villagelin D et al (2015) Outcomes in relapsed graves’ disease patients following radioiodine or prolonged low dose of methimazole treatment. Thyroid 25:1282–1290PubMedGoogle Scholar
  53. 53.
    Hieu TT et al (2012) Cancer risk after medical exposure to radioactive iodine in benign thyroid diseases: a meta-analysis. Endocr Relat Cancer 19:645–655PubMedGoogle Scholar
  54. 54.
    Sato H et al (2012) Higher dose of methimazole causes frequent adverse effects in the management of Graves’ disease in children and adolescents. J Pediatr Endocrinol Metab 25:863–867PubMedGoogle Scholar
  55. 55.
    Sato S et al (2015) Comparison of efficacy and adverse effects between methimazole 15 mg + inorganic iodine 38 mg/day and methimazole 30 mg/day as initial therapy for Graves’ disease patients with moderate to severe hyperthyroidism. Thyroid 25:43–50PubMedGoogle Scholar
  56. 56.
    Reinwein D et al (1993) A prospective randomized trial of antithyroid drug dose in Graves’ disease therapy. European Multicenter Study Group on Antithyroid Drug Treatment. J Clin Endocrinol Metab 76:1516–1521PubMedGoogle Scholar
  57. 57.
    Takata K et al (2009) Methimazole-induced agranulocytosis in patients with Graves’ disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily. Thyroid 19:559–563PubMedGoogle Scholar
  58. 58.
    Romaldim JH et al (1983) Comparison of effects of high and low dosage regimens of antithyroid drugs in the management of Graves’ hyperthyroidism. J Clin Endocrinol Metab 57:563–570Google Scholar
  59. 59.
    Wilberg JJ, Nuttall FQ (1972) Methimazole toxicity from high doses. Ann Intern Med 77:414–416Google Scholar
  60. 60.
    Nakamura H et al (2013) Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan. J Clin Endocrinol Metab 98:4776–4783PubMedGoogle Scholar
  61. 61.
    Wang MT et al (2014) Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study. Br J Clin Pharmacol 78:619–629PubMedPubMedCentralGoogle Scholar
  62. 62.
    Yang J et al (2015) Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China. Thyroid 25:278–283PubMedGoogle Scholar
  63. 63.
    Ohye H et al (2014) Antithyroid drug treatment for Graves ‘disease in children: a long-term retrospective study at a single institution. Thyroid 24:200–207PubMedGoogle Scholar
  64. 64.
    Minamitani K et al (2011) A report of three girls with antithyroid drug-induced agranulocytosis; retrospective analysis of 18 cases aged 15 years or younger reported between 1995 and 2009. Clin Pediatr Endocrinol 20:39–46PubMedPubMedCentralGoogle Scholar
  65. 65.
    Tamai H et al (1989) Methimazole-induced agranulocytosis in Japanese patients with Graves’ disease. Clin Endocrinol 30:525–530Google Scholar
  66. 66.
    He Y et al (2017) Emphasis on the early diagnosis of antithyroid drug-induced agranulocytosis: retrospective analysis over 16 years at one Chinese center. J Endocrinol Invest 40:733–740PubMedGoogle Scholar
  67. 67.
    Balavoine AS et al (2015) Antineutrophil cytoplasmic antibody-positive small-vessel vasculitis associated with antithyroid drug therapy: how significant is the clinical problem? Thyroid 25:1273–1281PubMedGoogle Scholar
  68. 68.
    Abhayaratna S, Somasundaram N (2013) The role of long term use of antithyroid drugs in Graves’ disease. Sri Lanka J Diabetes Endocrinol Metabol 3:41–44Google Scholar
  69. 69.
    Howard JE (1967) Treatment of thyrotoxicosis. JAMA 202:706–709PubMedGoogle Scholar
  70. 70.
    Sattler H (1952) Basedow’s disease. In: Marchand GW, Marchland JF (trans-ed). Grune & Stratton Inc, New York, pp 367–403Google Scholar
  71. 71.
    McLarty DG et al (1973) Remission of thyrotoxicosis during treatment with propranolol. Br Med J 2:332–334PubMedPubMedCentralGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  1. 1.Internal Medicine and Endocrinology, Endocrine Research Center of Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIslamic Republic of Iran
  2. 2.Internal Medicine and Endocrinology, Endocrine Research Center, Institute of Endocrinology and MetabolismIran University of Medical SciencesTehranIslamic Republic of Iran

Personalised recommendations