Skip to main content
SpringerLink
Log in

Antithyroid drugs in Graves’ hyperthyroidism: differences between “block and replace” and “titration” regimes in frequency of euthyroidism and Graves’ orbitopathy during treatment

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

Whereas antithyroid drugs (ATD) are the preferred treatment modality for Graves’ hyperthyroidism (GH), there is still controversy about the optimal regimen for delivering ATD.

To evaluate whether ‘Block and Replace’ (B + R) and ‘Titration’ (T) regimes are equivalent in terms of frequency of euthyroidism and Graves’ Orbitopathy (GO) during ATD therapy.

Methods

A prospective multicentre observational cohort study of 344 patients with GH but no GO at baseline. Patients were treated with ATD for 18 months according to B + R or T regimen in line with their institution’s policy.

Results

Baseline characteristics were similar in both groups. In the treatment period between 6 and 18 months thyrotropin (TSH) slightly increased in both groups, but TSH was on average 0.59 mU/L (95% CI 0.27–0.85) lower in the B + R group at all time points (p = 0.026). Serum free thyroxine (FT4) remained stable during the same interval, with a tendency to higher values in the B + R group. The point-prevalence of euthyroidism (TSH and FT4 within their reference ranges) increased with longer duration of ATD in both groups; it was always higher in the T group than in the B + R group: 48 and 24%, respectively, at 6 months, 81 and 58% at 12 months, and 87 and 63% at 18 months (p < 0.002). There were no significant differences between the B + R and T regimens with respect to the fall in thyrotropin binding inhibiting immunoglobulins (TBII) or thyroid peroxidase antibodies (TPO-Ab). GO developed in 15.9% of all patients: 9.1 and 17.8% in B + R group and T group, respectively, (p = 0.096). GO was mild in 13% and moderate-to-severe in 2%.

Conclusion

The prevalence of biochemical euthyroidism during treatment with antithyroid drugs is higher during T compared to B + R regimen. De novo development of GO did not differ significantly between the two regimens, although it tended to be higher in the T group. Whether one regimen is clinically more advantageous than the other remains unclear.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Because of the privacy protection laws data are not available.

References

  1. Wartofsky L, Glinoer D, Solomon B, Nagataki S, Lagasse R, Nagayama Y, Izumi M (1991) Differences and similarities in the diagnosis and treatment of Graves’ disease in Europe, Japan, and the United States. Thyroid 1:129–135. https://doi.org/10.1089/thy.1991.1.129

    Article  CAS  PubMed  Google Scholar 

  2. Burch HB, Burman KD, Cooper DS (2012) A 2011 survey of clinical practice patterns in the management of Graves’ disease. J Clin Endocrinol Metab 97:4549–4558. https://doi.org/10.1210/jc.2012-2802

    Article  CAS  PubMed  Google Scholar 

  3. Brito JP, Schilz S, Singh Ospina N, Rodriguez-Gutierrez R, Maraka S, Sangaralingham LR, Montori VM (2016) Antithyroid drugs-the most common treatment for Graves’ disease in the united states: a nationwide population-based study. Thyroid 26:1144–1145. https://doi.org/10.1089/thy.2016.0222

    Article  PubMed  Google Scholar 

  4. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA (2016) 2016 American thyroid association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 26:1343–1421. https://doi.org/10.1089/thy.2016.0229

    Article  PubMed  Google Scholar 

  5. Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce SH (2018) 2018 European thyroid association guideline for the management of Graves’ hyperthyroidism. ETJ 7:167–186. https://doi.org/10.1159/000490384

    Article  CAS  Google Scholar 

  6. Brix TH, Lund LC, Henriksen DP, Folkestad L, Bonnema SJ, Hallas J, Hegedüs L (2020) Methimazole and risk of acute pancreatitis. Lancet Diabetes Endocrinol 8:187–189. https://doi.org/10.1016/S2213-8587(20)30025-5

    Article  CAS  PubMed  Google Scholar 

  7. Tonacchera M, Chiovato L, Bartalena L, Cavaliere AF, Vitti P (2020) Treatment of Graves’ hyperthyroidism with thionamides: a position paper on indications and safety in pregnancy. J Endocrinol Invest 43:257–265. https://doi.org/10.1007/s40618-019-01148-w

    Article  CAS  PubMed  Google Scholar 

  8. Abraham P, Avenell A, McGeoch SC, Clark LF, Bevan JS (2010) Antithyroid drug regimen for treating Graves’ hyperthyroidism. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD003420.pub4

    Article  PubMed  PubMed Central  Google Scholar 

  9. Smith TJ, Hegedüs L (2016) Graves’ disease. N Engl J Med 375:1552–1565. https://doi.org/10.1056/NEJMra1510030

    Article  Google Scholar 

  10. Vaidya B, Wright A, Shuttleworth J, Donohoe M, Warren R, Brooke A, Gericke CA, Ukoumunne OC (2014) Block & replace regime versus titration regime of antithyroid drugs for the treatment of Graves’ disease: a retrospective observational study. Clin Endocrinol (Oxf) 81:610–613. https://doi.org/10.1111/cen.12478

    Article  CAS  Google Scholar 

  11. Vaidya B, Williams GR, Abraham P, Pearce SHS (2008) Radioiodine treatment for benign thyroid disorders: results of a nationwide survey of UK endocrinologists. Clin Endocrinol (Oxf) 68:814–820. https://doi.org/10.1111/j.1365-2265.2007.03097.x

    Article  Google Scholar 

  12. Wiersinga W, Žarković M, Bartalena L, Donati S, Perros P, Okosieme O, Morris D, Fichter N, Lareida J, von Arx G, Daumerie C, Burlacu M-C, Kahaly G, Pitz S, Beleslin B, Ćirić J, Ayvaz G, Konuk O, Törüner FB, Salvi M, Covelli D, Curro N, Hegedüs L, Brix T, EUGOGO (European Group on Graves’ Orbitopathy) (2018) Predictive score for the development or progression of Graves’ orbitopathy in patients with newly diagnosed Graves’ hyperthyroidism. Eur J Endocrinol 178:635–643. https://doi.org/10.1530/EJE-18-0039

    Article  CAS  PubMed  Google Scholar 

  13. Dickinson AJ, Perros P (2001) Controversies in the clinical evaluation of active thyroid-associated orbitopathy: use of a detailed protocol with comparative photographs for objective assessment. Clin Endocrinol 55:283–303. https://doi.org/10.1046/j.1365-2265.2001.01349.x

    Article  CAS  Google Scholar 

  14. Karvanen J (2003) The statistical basis of laboratory data normalization. Drug Inf J 37:101–107. https://doi.org/10.1177/009286150303700112

    Article  Google Scholar 

  15. Spencer C Assay of thyroid hormones and related substances. In: Thyroid Disease Manager. https://www.thyroidmanager.org/chapter/assay-of-thyroid-hormones-and-related-substances3/#toc-tsh-receptor-autoantibodies-trab. Accessed 4 Mar 2020

  16. Core Team R (2019) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna

    Google Scholar 

  17. Bates D, Mächler M, Bolker B, Walker S (2015) Fitting linear mixed-effects models using lme4. J Stat Softw 67:1–48. https://doi.org/10.18637/jss.v067.i01

    Article  Google Scholar 

  18. Hoffman JI (2019) Multiple comparisons. Basic biostatistics for medical and biomedical practitioners, 2nd edn. Academic Press, London, pp 375–390

    Chapter  Google Scholar 

  19. Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R (2011) Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS ONE 6:e22552. https://doi.org/10.1371/journal.pone.0022552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lytton SD, Ponto KA, Kanitz M, Matheis N, Kohn LD, Kahaly GJ (2010) A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves’ orbitopathy. J Clin Endocrinol Metab 95:2123–2131. https://doi.org/10.1210/jc.2009-2470

    Article  CAS  PubMed  Google Scholar 

  21. Azizi F, Malboosbaf R (2019) Safety of long-term antithyroid drug treatment? A systematic review. J Endocrinol Invest 42:1273–1283. https://doi.org/10.1007/s40618-019-01054-1

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

In memoriam George von Arx: On November 25, 2017, Dr. Georg von Arx, an outstanding physician, clinical researcher and tutor, passed away. He established the Joint Thyroid Eye Clinics in Switzerland and shaped the multidisciplinary collaboration like no other.

Funding

This research did not receive any specific Grant from any funding agency in the public, commercial or not-for-profit sector.

Author information

Author notes

  1. Miloš Žarković and Wilmar Wiersinga contributed equally to this work.

Authors and Affiliations

  1. School of Medicine, University of Belgrade, Belgrade, Serbia

    M. Žarković, B. Beleslin & J. Ćirić

  2. Clinic of Endocrinology Clinical Centre of Serbia, Belgrade, Serbia

    M. Žarković, B. Beleslin & J. Ćirić

  3. Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands

    W. Wiersinga

  4. Department of Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK

    P. Perros

  5. School of Medicine, University of Insubria, Varese, Italy

    L. Bartalena & S. Donati

  6. Department of Endocrinology, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK

    O. Okosieme

  7. Cardiff Eye Unit, University Hospital of Wales, Cardiff, UK

    D. Morris

  8. Interdisciplinary Centre for Graves’ Orbitopathy, Olten and University Eye Hospital, Basel, Switzerland

    N. Fichter & J. Lareida

  9. Department of Endocrinology, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    C. Daumerie & M-C. Burlacu

  10. Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany

    G. J. Kahaly

  11. Orbital Center, Ophthalmic Clinic, Buergerhospital, Frankfurt, Germany

    S. Pitz

  12. Department of Endocrinology and Metabolism, Faculty of Medicine, Gazi University, Ankara, Turkey

    G. Ayvaz & F. B. Törüner

  13. Department of Ophthalmology, Faculty of Medicine, Gazi University, Ankara, Turkey

    O. Konuk

  14. Graves’ Orbitopathy Unit, Department of Clinical Science and Community Health, Fondazione Ca’Granda IRCCS, University of Milan, Milan, Italy

    M. Salvi & D. Covelli

  15. Department of Ophthalmology, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Milan, Italy

    N. Curro

  16. Department of Endocrinology and Metabolism, Odense University Hospital, University of Southern Denmark, Odense, Denmark

    L. Hegedüs & T. Brix

Authors
  1. M. Žarković
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Wiersinga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Perros
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Bartalena
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Donati
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O. Okosieme
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N. Fichter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. Lareida
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C. Daumerie
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M-C. Burlacu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. G. J. Kahaly
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S. Pitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. B. Beleslin
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J. Ćirić
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. G. Ayvaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. O. Konuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. F. B. Törüner
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. M. Salvi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. D. Covelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. N. Curro
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. L. Hegedüs
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. T. Brix
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

EUGOGO (European Group on Graves’ Orbitopathy)

Corresponding author

Correspondence to M. Žarković.

Ethics declarations

Conflict of interest

Authors declare that there were no conflict or competing interests.

Ethical approval

Approval of institutional review boards or local ethical committees was not deemed necessary because the study protocol did not require additional procedures beyond those done in the delivery of usual care. Decisions of the Ethical committee of the Academisch Medisch Centrum, Universiteit van Amsterdam and Ethical committee of the Clinical Centre of Serbia were obtained. Also, HRA-decision tool (https://www.hra-decisiontools.org.uk/ethics/) was used to confirm that ethical committee approval for UK was not required.

Informed consent

Consent has been obtained from each patient after full explanation of the purpose and nature of all procedures.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Žarković, M., Wiersinga, W., Perros, P. et al. Antithyroid drugs in Graves’ hyperthyroidism: differences between “block and replace” and “titration” regimes in frequency of euthyroidism and Graves’ orbitopathy during treatment. J Endocrinol Invest 44, 371–378 (2021). https://doi.org/10.1007/s40618-020-01320-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-020-01320-7

Keywords

Search

Navigation