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Graves’ disease remains a challenge for a young person, their family and the healthcare team. There have been no new treatment options for the newly presenting patient for over 55 years1 and the reality is that most young people will ultimately become adults who take long-term thyroid hormone replacement. This is because most young people will relapse after a course of antithyroid drug (ATD)—irrespective of whether this is of 2, 4 or 6 years’ duration. Patients who relapse and who do not want to return to ATD treatment have no option but to undergo definitive thyroid gland surgical removal or destruction by radioiodine. A small minority of patients will develop potentially dangerous early side effects of ATD and are forced in the direction of surgery or radioiodine sooner rather than later. The most notable of these side effects is agranulocytosis which resolves when the ATD is stopped. Thyroid hormone replacement is simple at one level but is not a cure, and data suggest that individuals on thyroxine treatment with normal thyroid-stimulating hormone (TSH) levels have impaired psychological well-being in comparison to controls of similar age and sex.2
The child or adolescent presenting with Graves’ disease tends to have more severe disease than an older person, is more likely to develop adverse effects when treated with ATD, is more likely to relapse when ATD is stopped and will require thyroid hormone replacement for longer following definitive therapy.
Many of the frustrations associated with standard ATD treatment are apparent in the article by Kourime et al. 3 An important part of assessing the hyperthyroid patient, highlighted by the authors, is to establish which patients have Graves’ disease as opposed to a ‘toxic’ phase of autoimmune thyroiditis (Hashimoto’s disease) or viral thyroiditis. The key hallmark of Graves’ disease is the presence of antibodies to the TSH receptor (TSHR antibodies; TRAb) while autoimmune thyroiditis will typically have thyroid peroxidase antibodies present but not TRAb. If TRAb is present then the hyperthyroidism is unlikely to remit in the short to medium term, whereas thyroid hormone excess in the absence of TRAb may be self-limiting. In many patients, there is an argument for only starting ATD once the result of the TRAb assay confirms a diagnosis of Graves’ disease (available after a few days in many units). Patients can be managed symptomatically with beta blockers in the interim. The suspicion is that some paediatric patients who have ‘remitted’ after a course of ATD in the literature have not had Graves’ disease but have actually had thyrotoxicosis in association with autoimmune thyroiditis instead. The article by Kourime et al highlights the medication concordance issues that are seen in young people required to take daily tablets. Reduced attention span is one of the earliest mental changes found in thyrotoxicosis, and another advantage of waiting a short while until TRAb antibody results are available is to provide an additional opportunity for the young person to ask questions and to be more meaningfully involved in the decision-making process. Patients and parents should be warned that unwanted weight gain can be associated with Graves’ disease therapy4 and may complicate the treatment of some young people.
In contrast to the monophasic destructive pathophysiology of type 1 diabetes, a minority of young patients with Graves' disease will get a prolonged remission of their autoimmune disease. This is important because it highlights the fact that the immune system can adapt—or be made to adapt—with time. Unfortunately, this ‘retraining’ only happens in around 25% of children and adolescents after a 2 to 3-year course of ATD and perhaps up to 50% of patients after many years of ATD therapy. Furthermore, many patients with Graves’ disease will ultimately become hypothyroid because of a persistent destructive immune response (probably mediated by cytotoxic effector lymphocytes).
In the same way that diabetologists and rheumatologists have become interested in agents that can modify the immune response, so thyroidologists are becoming interested in interventions that can ameliorate or modify the immune response in Graves’ disease. Kourime et al argue for long-term ATD therapy in young people with Graves’ disease despite their concerns about patient adherence. However, an ideal way forward would be to increase the proportion of patients who remit in the short term or when ATD is stopped. Graves’ disease is seen as a paradigm condition with the abnormal biochemistry the direct consequence of specific antibodies to the TSHR produced by the B lymphocyte-derived plasma cells. Therefore, a reasonable question is whether targeting B cell activity could ameliorate the immune response leading to increased longer term remission rates. Physicians have used rituximab (a chimeric monoclonal antibody against the protein CD20 on the B cell surface) in adults with Graves’ disease although this has not been in the context of well-designed trials. Its potential role in the young patient is currently unclear. One randomised controlled trial has shown that rituximab improves active thyroid ophthalmopathy in adults, suggesting that immune system modification with this particular biologic can have a beneficial impact on this manifestation of the autoimmune process.5 However, a second similarly sized study found no benefit.6 Other novel approaches that aim to ameliorate the immune dysfunction seen in Graves’ disease include administration of small amounts of ‘immunodominant’ TSHR-specific peptides in a trial funded by Apitope International and the European Commission through a Framework 7 grant (NCT02973802) or use of monoclonal blocking TSHR antibodies (NCT02904330). We await the outcomes of these novel approaches with interest because young people may have more to gain from new therapeutic strategies than adults as they are faced with more years on ATD or thyroxine replacement.
For the time being, the paediatrician needs to continue to discuss the advantages and disadvantages of the traditional treatment modalities with the patient and family, highlighting the fact that this can be a frustrating condition that for many is best ultimately managed by definitive treatment with surgery or radioiodine and accepting the need for subsequent long-term thyroid hormone replacement. Planning should include a discussion about the timing of any trial off ATD, avoiding important educational milestones. With regular thyroid function tests and rapid clinic access, a young person who relapses can quickly restart ATD before they become significantly unwell. Factors that may make relapse more likely—for example, young age, severe disease at presentation and persistence of TRAb—can be highlighted in advance although even patients with supposed risk factors for early relapse can still surprise and enter remission.
Acknowledgments
We thank Simon Pearce for his helpful comments on an earlier version of this manuscript.
Footnotes
Contributors TC wrote the first draft of this article which was then edited and refined by LL.
Funding None declared.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.