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Jelmer M van Lieshout, Christiaan F Mooij, A. S Paul van Trotsenburg, and Nitash Zwaveling-Soonawala

Objective: Comparison of studies on remission rates in pediatric Graves’ disease is complicated by lack of uniformity in treatment protocols, remission definition, and follow-up duration. We performed a systematic review on remission rates in pediatric Graves’ disease and attempted to create uniformity by recalculating remission rates based on an intention-to-treat analysis.

Methods: PubMed and Embase were searched in August 2020 for studies on patients with Graves’ disease (i) 2 to 18 years of age, (ii) initially treated with methimazole or carbimazole for at least 18 months, (iii) with a follow-up duration of at least one year after cessation of methimazole or carbimazole. All reported remission rates were recalculated using an intention-to-treat analysis.

Results: Of 1,890 articles, 29 articles consisting of 24 patient cohorts, were included with a total of 3,057 patients (82.6% female). Methimazole or carbimazole was initially prescribed in 2,864 patients (93.7%). Recalculation based on intention-to-treat analysis resulted in an overall remission rate of 28.8% (829/2,880). Pooled remission rates based on treatment duration were 23.7%, 31.0%, 43.7%, and 75% after respectively 1.5-2.5 years, 2.5-5 years, 5-6 years (two studies), and 9 years (single study) treatment duration. Occurrence of adverse events was 419 in 2,377 patients (17.6%), with major side effects in 25 patients (1.1%).

Conclusions: Using a standardized calculation the overall remission rate in methimazole treated pediatric GD is 28.8%. A few small studies indicate that longer treatment increases the remission rate. However, evidence is limited and further research is necessary to investigate the efficacy of longer treatment durations.

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Nitash Zwaveling-Soonawala, M Emma Witteveen, Jan Pieter Marchal, Femke C C Klouwer, Nadine A Ikelaar, Anne M J B Smets, Rick R van Rijn, Erik Endert, Eric Fliers, and A S Paul van Trotsenburg


The hypothalamus–pituitary–thyroid (HPT) axis set point develops during the fetal period and first two years of life. We hypothesized that thyroxine treatment during these first two years, in the context of a randomized controlled trial (RCT) in children with Down syndrome, may have influenced the HPT axis set point and may also have influenced the development of Down syndrome-associated autoimmune thyroiditis.


We included 123 children with Down syndrome 8.7 years after the end of an RCT comparing thyroxine treatment vs placebo and performed thyroid function tests and thyroid ultrasound. We analyzed TSH and FT4 concentrations in the subgroup of 71 children who were currently not on thyroid medication and had no evidence of autoimmune thyroiditis.


TSH concentrations did not differ, but FT4 was significantly higher in the thyroxine-treated group than that in the placebo group (14.1 vs 13.0 pmol/L; P = 0.02). There was an increase in anti-TPO positivity, from 1% at age 12 months to 6% at age 24 months and 25% at age 10.7 years with a greater percentage of children with anti-TPO positivity in the placebo group (32%) compared with the thyroxine-treated group (18.5%) (P = 0.12). Thyroid volume at age 10.7 years (mean: 3.4 mL; range: 0.5–7.5 mL) was significantly lower (P < 0.01) compared with reference values (5.5 mL; range: 3–9 mL) and was similar in the thyroxine and placebo group.


Thyroxine treatment during the first two years of life led to a mild increase in FT4 almost 9 years later on and may point to an interesting new mechanism influencing the maturing HPT axis set point. Furthermore, there was a trend toward less development of thyroid autoimmunity in the thyroxine treatment group, suggesting a protective effect of the early thyroxine treatment. Lastly, thyroid volume was low possibly reflecting Down-specific thyroid hypoplasia.