Graves disease in children

TOPIC: Predictors of relapse in pediatric Graves’ disease

Title: Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of antithyroid drug treatment.

Authors: Kaguelidou F, Alberti C, Castanet M, Guitteny M-A, Czernichow P, Léger J (the French childhood Graves’ disease study group)

Reference: Journal of Clinical Endocrinology & Metabolism93: 3817–3826, 2008

There is debate about how Graves’ disease (GD) should be treated in children.

Objective

Aim of study was to identify predictors of relapse after antithyroid drug (ATD) treatment in children with GD.

Study Design and Setting

The authors conducted a prospective, multicenter cohort study of children (n = 154) with GD treated with carbimazole for an intended duration of 24 ± 3 months. After the end of treatment, patients were followed up for at least 2 years. The primary outcome was hyperthyroidism relapse. Cox’s regression analysis was used and a prognostic score was constructed.

Results

The overall estimated relapse rate for hyperthyroidism was 59% (95% confidence interval: 52-67%) at 1 year and 68% (95% confidence interval: 60-76%) at 2 years after the end of treatment. Multivariate survival analysis showed that the risk of relapse was higher for patients of non-Caucasian origin [hazard ratio (HR): 2.54, P< 0.001], with high serum thyroid-stimulating hormone receptor antibodies (HR: 1.21 by 10 U, P< 0.03) and free T4 (HR: 1.18 by 10 pM/L, P< 0.001) levels at diagnosis. Conversely, relapse risk decreased with increasing age at onset (HR: 0.74 per 5 yr, P< 0.03) and duration of first course of ATD (HR: 0.57 per 12 months, P< 0.005). A prognostic score was constructed, allowing the identification of three different risk groups, with 2-yr relapse rates of 46, 77, and 98%, respectively.

Conclusions

A longer initial duration of euthyroid state with ATD seems to be the only variable related to the risk of hyperthyroidism relapse in children that can be manipulated. Ethnic origin, age, and severity of the disease at diagnosis may guide long-term disease management decisions.

Commentary

Optimal treatment of pediatric Graves’ disease (GD) remains controversial, though all are in agreement that the disease is more persistent in children & adolescents than in adults. Whereas some authors have espoused earlier more aggressive treatment with radioactive iodine, many if not most pediatric endocrinologists prefer to initiate therapy with antithyroid drugs (ATD) because of the known or potential risks of permanent forms of thyroid ablation in the young. Clearly, the ability to predict which patients are most likely to respond to therapy would be advantageous.

The strength of the present study is its prospective nature and also the relatively large patient population (N = 154), 95% of whom completed a 24 months, standardized initial course of ATD (carbimazole). Although non compliance (a frequent problem in such studies) was encountered in 64 children (44%), patient data were corrected for treatment duration. Overall, the study confirms the results of numerous previous retrospective studies, namely that severity of initial thyrotoxicosis, TSH receptor antibody levels (TRAbs), age of onset (<5 years) and duration of therapy are independent predictors of relapse. A novel finding was the 2.5-fold increased relapse risk in non Caucasian patients. In addition, the authors have taken advantage of the large data set to construct a prognostic score for low (46%), moderate (77%), and high (98%) risk of relapse. Of interest, side effects of therapy were observed in only 9 patients, not much different from the adult literature.

As the authors themselves point out, the high relapse rate (59%, 1 year and 68%, 2 years after discontinuation of ATD) indicates once again that we have a long way to go in improving therapy for GD in the young. A point that is not commented on is the fact that TRAbs remained elevated at the end of ATD therapy in 36% of the patients in whom they were measured, providing further evidence that 2 years of therapy is insufficient for a large proportion of children & adolescents with GD. Data from several retrospective studies have demonstrated an improvement in the relapse rate when therapy is continued for more than 2 years. However, we know from other studies that TRAbs normalize in some patients much earlier, indicating that the course of GD is highly variable and ‘one size does not fit all’. It would seem that, until more specific immunotherapy becomes available, further research should focus on the optimal duration of ATD therapy in individual patients and on better indicators of when therapy can be safely withdrawn rather than focusing on the “Holy Grail” of defining an optimal treatment duration for all patients.

Summary and Commentary prepared by Rosalind Brown (Related to Chapters 10 & 15 of TDM)