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

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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).