Adjuvant Rituximab - a potential cure for the young patient with Graves' hyperthyroidism

Graves' hyperthyroidism is a condition where the immune system produces antibodies that stimulate the thyroid gland to produce excess thyroid hormone. Around 700 adolescents are affected by this condition in the UK each year. Excess thyroid hormone (hyperthyroidism) results in a range of symptoms including difficulty concentrating, anxiety, palpitations, weight loss, diarrhoea and temperature intolerance.

Treating Graves' hyperthyroidism is particularly difficult in young people because the condition is more severe in this age group and because the anti-thyroid drug (ATD) that is used most often (carbimazole, CBZ) is less likely to result in the disease resolving when compared to adults. Only 1 in 4 patients (25%) find that the hyperthyroidism does not return after 2 to 3 years of ATD therapy. To complicate matters further, ATD is more likely to be associated with side-effects in the young. The side-effects are experienced by around 20% of young people and can occasionally be life-threatening. The other treatment options that are used in young people instead of ATD are surgery (total thyroidectomy) and radioactive iodine (RI). These treatments render the person hypothyroid (underactive) and hence dependent on thyroid hormone replacement for life. Thyroidectomy and RI also have significant risks that are more substantial in the young. Young people diagnosed with Graves' hyperthyroidism have a condition that is likely to require life-long surveillance and that will impact on long term quality of life.

Over the last 15 years a medication called rituximab (RTX) has been used in blood and immune conditions in adults and children. RTX is an artificially-made antibody that removes the antibody-generating immune cells (B lymphocytes) from the body. Graves' hyperthyroidism is an immune condition and we believe that RTX will work by removing the antibody-producing cells from the blood temporarily but also because RTX appears to 're-set' the immune system so that it behaves differently in future. Small studies in adults have shown promise but the young person stands to gain much more if this drug is efficacious because conventional therapy is so disappointing. RTX administration is associated with 'flu-like' symptoms that can be controlled by a dose of steroid given at the time of administration. The long-term safety of RTX is excellent and the likelihood of problems such as an increased risk of infection are small.

This exploratory trial will examine whether the effects of RTX on the body's immune system will increase the likelihood of Graves' hyperthyroidism resolving in young people. Subjects taking part in the study will be treated with ATD for 12 months using a relatively low dose that will reduce thyroid hormone levels to normal. Participants will also receive a single dose of RTX in the first weeks after diagnosis. A relatively low dose of RTX will be used (500mg) because it has recently been shown that this amount has the desired effect on the immune system in adults. ATD will be stopped 12 months after the RTX and we will then look to see how many patients remain well off all ATD treatment 12 months later (2 years after initial presentation). If this figure is 40% or more then this suggests that RTX has had a beneficial effect on outcome and indicate that the role of our novel treatment strategy (RTX and a short course of ATD) needs to be studied in much more detail as part of a larger controlled trial. Although the main outcome of the trial is the proportion of patients who are well off treatment 2 years after presentation, we shall also assess the body's immune response on a regular basis during the trial to see how well this indicates how patients are going to respond.

There have been no new demonstrably effective treatments for young people with Graves' hyperthyroidism for more than 60 years and expanding the number of options available is a key priority in the field of endocrinology (5).

Young people with Graves' hyperthyroidism can be managed with anti-thyroid drugs (ATD), surgery (total thyroidectomy) or radioiodine (RI). None of these interventions provides a realistic prospect of cure in the short term and all have disadvantages that are particularly pertinent in the young patient. Only 25% of young patients with Graves' hyperthyroidism remit after a 2 year course of ATD and this will be a chronic condition for most patients with a requirement for long-term thyroxine replacement and a significant impact on quality of life. Novel approaches to management are needed and B lymphocyte depletion with rituximab (RTX) has shown promise in adults with Graves' hyperthyroidism. RTX has disease-modifying properties and is standard care for some paediatric autoimmune conditions. The aim of this proposed single-arm 'proof of concept' trial is to establish whether a single dose of RTX, administered with a short course of ATD therapy, is likely to improve remission rates in young people with Graves' hyperthyroidism. 27 subjects with newly-diagnosed Graves' hyperthyroidism aged 12 to 20 years will receive a single dose of 500mg RTX 2 to 6 weeks post-diagnosis. Subjects will have commenced ATD and this will be stopped 12 months post RTX. In the interim the dose of ATD will be adjusted to maintain a euthyroid state. Thyroid function tests, immunological markers including thyroid stimulating hormone receptor (TSHR) and peroxidase antibodies, serum immunoglobulin levels and peripheral blood lymphocyte subset analysis (including CD19+ and CD27+) will be measured throughout the trial. The primary end-point will be the proportion of patients who are in remission off ATD 2 years post RTX. 40% or more patients in remission at 2 years following a single dose of RTX and a 12 month course of ATD would constitute a clinically meaningful improvement in outcome, above that normally observed, that would provide the foundation for a definitive trial.

This could be the first significant advance in care of Graves' hyperthyroid patients for over 60 years.

HEALTH AND WELLBEING
The individuals who stand to benefit most from this research are young people with Graves' hyperthyroidism. The proposed strategy may:

1. Cure Graves' hyperthyroidism by rendering patients euthyroid who would not have responded to ATD or who are unable to tolerate long term ATD.
2. Reduce the duration of ATD treatment in patients who would ultimately be rendered euthyroid by ATD.
3. Stop patients from becoming hypothyroid in the longer term when ATD is stopped.

Successful treatment of Graves' hyperthyroidism will improve long term well-being because patients with Graves' hyperthyroidism and patients on thyroid hormone replacement are known to have a suboptimal quality of life with a significant identifiable impact on their education and subsequent career opportunities and economic output. Adolescents and their families have the added complication of transitioning between NHS provision for children and for adults.

NHS AND CLINICAL PROFESSION
There will also be economic benefit for the NHS with reduced need for surgical interventions, radio-iodine therapy and life-long monitoring in primary care. Other beneficiaries include endocrinologists (nationally and internationally) who manage young people with Graves' hyperthyroidism, general practitioners who manage patients on thyroid hormone replacement and support groups such as the BTF.

DISSEMINATION
The results of this trial will be profiled at the European Society for Paediatric Endocrinology meeting in 2020, the annual American Endocrine Society meeting and the European Thyroid Association meeting. The results will also be presented at the annual meetings of UK endocrinologists (BSPED, BES, BTF) - some of whom will have helped to recruit patients to the trial.

EXPLOITATION
It is possible that there may be commercially exploitable opportunities for the use of immune modulating agents (in this instance RTX) in the management of this autoimmune disorder. We will work with our Business Development Manager during the course of the trial to identify potential pharma partners with which to develop any intellectual property and commercialisation opportunities. This will be particularly important during the trial as the medication comes off patent in Europe in 2018.

NEXT STEPS
The proposed trial will last approximately 4 years. If the combination of RTX and ATD shows promise then we will liaise closely with the BTF and the NIHR/Children/British Society for Paediatric Endocrinology and Diabetes (BSPED) Clinical Studies Group and the BES as we move to the next stage which will be a UK randomised trial. A UK multi-centre trial would need to be planned and discussed carefully with paediatric and adult endocrinologists and user groups. We would continue to rely on the expertise of the BTF when planning recruitment of a much larger number of patients at a substantial number of UK sites.

A positive outcome to this and subsequent trials would raise questions about whether younger (below 12) or older (above 20 years) patients would also benefit from this therapeutic strategy. The risk / benefit assessment would require careful consideration and input from families of younger children with Graves' hyperthyroidism and adults. This treatment strategy will be of great interest to adolescents with thyroid disorders and Cheetham is a member of the Transition Collaboration Group (NIHR funded).

Once efficacy is fully established, we will work towards the implementation of this approach in tertiary paediatric endocrine units around the UK and in tertiary adult endocrine units.