Graves' Disease in the Young: Could We Change the Weather?

Graves’ disease is a distressing disease for patients. They are told that doctors understand the mechanisms but not the origin of the disease, that it is usually not a life-threatening disease but a long-lasting unpredictable one, that they will have to be on medication for months with no guarantee they will be cured, that the medication may cause some side effects, and that in the rare event of side effects or, more frequently, in case of relapse, they will be offered a definitive treatment leading to hypothyroidism, another disease requiring lifelong treatment (1-3).

Graves’ disease is a vexing disease for doctors. They have only poorly grounded guidelines and consensus (2, 3) to address simple questions that deserve simple and clear answers: How come? How long? Are you sure it will work? Is there a risk of complications? What about my eyes? Can I become pregnant? The poor performance of our therapeutic approach to Graves’ disease is even worse in the case of children and adolescents.

Several years ago, French pediatric endocrinologists conducted a large prospective observational study of medically treated Graves’ disease in children and teenagers (4). This provided important and practical information. The risk of relapse of hyperthyroidism after 24 months of carbimazole was higher in younger, non-Caucasian patients presenting with severe disease (high free thyroxine and high thyrotropin receptor antibodies), whereas a longer duration of antithyroid drug (ATD) treatment was associated with a higher probability of remission. Quite deceptive was the near 60% and 70% relapse rate, 1 and 2 years, respectively, after carbimazole withdrawal. The study was prolonged with 2 to 3 rounds of treatment if a relapse had occurred (5). Repeating long periods of treatment improved the estimated remission rate from 20% at 4 years to a near 50% plateau after 10 years, solid but disappointing results. Who can be satisfied and expect a teenager to be compliant and happy with treatment for 4 years to get an 80% relapse risk, and up to 10 years for a 50% risk? Young patients would rather have a definitive treatment recommended (6).

Tim Cheetham and colleagues report in the Journal of Clinical Endocrinology and Metabolism the results of an exploratory trial in teens and young adults, up to 20 years, of 1 dose of rituximab at the initiation of thionamide ATDs (7). The objective was to evaluate the improvement in the Graves’ disease remission rate such a treatment may bring. Since this was an exploratory study, there was no control group, no randomization, rather 2 opposed working hypotheses. Either the remission rate is lower than 20% and the immunosuppressive treatment is of no help, or the remission rate exceeds 40% and it is worth exploring this therapeutic approach further. Winning bet! One year after ATD withdrawal, 48% of patients were in remission. Interestingly, this was after only 12 months of ATD treatment and a single dose of rituximab. The tolerance was acceptable, though not perfect. The size of the trial does not allow the identification of clear-cut pre- or per-treatment predictive factor of remission or for in-depth analysis of immunological parameters. The short follow-up precludes any strong conclusions on long-term efficiency and safety. Nevertheless, these preliminary results suggest that a larger, comparative, and randomized trial, either with rituximab or other drugs with acceptable safety profile, could be proposed, keeping the benefit–risk balance in mind, especially in young patients.

Although trials in children/adolescents first should not become a trend, the burden of repeated relapses of Graves’ hyperthyroidism in the young legitimates seeking very cautious alternatives for them. If we can draw lessons for adults, fine; but the priority, here, is the care of young patients as the severity of their Graves’ disease does not exactly mimic that of adults.

As a training resident I was taught by one of my mentors that, besides definitive treatments, our only effective action in Graves’ hyperthyroidism (ATD treatment) compares to opening an umbrella when caught in a shower. There is no way to change the weather, just try to keep yourself dry while waiting for the rain to stop. To date, rituximab trials in adults with Graves’ hyperthyroidism has not shown very impressive results. We are still waiting for new therapeutics that would unquestionably surpass conservative ATD treatment (8). This study (7), in a population where relapse is the rule (4, 5), shows it may be worth continuing to attempt to change the course of the disease, at least in severe cases, provided we can identify them in a predictive manner. Reducing the duration of treatment, lowering the rate of relapse, avoiding definitive iatrogenic hypothyroidism, and preventing eye disease may hopefully greatly improve the quality of life of patients that has still not been satisfied today (1, 6).

And for the weather? Randomized trials challenging the umbrella are greatly needed.