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

格雷夫斯甲亢是一种免疫系统产生抗体的情况，这种抗体会刺激甲状腺产生过量的甲状腺激素。在英国，每年约有700名青少年受到这种疾病的影响。过量的甲状腺激素(甲状腺机能亢进症)会导致一系列症状，包括注意力难以集中、焦虑、心悸、体重减轻、腹泻和体温不耐受。治疗格雷夫斯甲亢在年轻人中尤其困难，因为这个年龄段的情况更严重，而且最常用的抗甲状腺药物(ATD)(卡比唑，CBZ)与成年人相比不太可能导致疾病消失。只有1/4的患者(25%)发现甲状腺功能亢进症在ATD治疗2-3年后没有复发。让事情进一步复杂化的是，ATD更有可能与年轻人的副作用有关。大约20%的年轻人会经历这种副作用，有时甚至会危及生命。用于年轻人而不是ATD的其他治疗方案是手术(全甲状腺切除术)和放射性碘(RI)。这些治疗导致患者甲状腺功能低下，因此终生依赖甲状腺激素替代。甲状腺切除和RI也有很大的风险，年轻人的风险更大。被诊断为格雷夫斯甲亢的年轻人患有一种可能需要终身监测的疾病，这将影响长期的生活质量。在过去的15年里，一种名为利妥昔单抗(RTX)的药物已被用于成人和儿童的血液和免疫状况。RTX是一种人工制造的抗体，它能将产生抗体的免疫细胞(B淋巴细胞)从体内移除。格雷夫斯的甲状腺功能亢进症是一种免疫疾病，我们相信RTX将通过暂时从血液中移除产生抗体的细胞来发挥作用，但也因为RTX似乎重新设置了免疫系统，使其在未来的表现有所不同。对成年人的小规模研究显示出了希望，但如果这种药物有效，年轻人将获得更多好处，因为传统疗法太令人失望了。RTX的服用与“流感样”症状有关，这种症状可以通过在服用时给予一定剂量的类固醇来控制。RTX的长期安全性非常好，出现感染风险增加等问题的可能性很小。这项探索性试验将检验RTX对人体免疫系统的影响是否会增加格雷夫斯甲状腺功能亢进症在年轻人中解决的可能性。参与这项研究的受试者将接受为期12个月的ATD治疗，剂量相对较小，将使甲状腺激素水平降至正常。参与者还将在确诊后的第一周接受单剂RTX。RTX的剂量相对较小(500毫克)，因为最近的研究表明，这个剂量对成年人的免疫系统有预期的效果。ATD将在RTX治疗12个月后停止，然后我们将观察有多少患者在12个月后(首次出现ATD后2年)仍能很好地接受所有ATD治疗。如果这个数字为40%或更高，那么这表明RTX对结果有有益的影响，并表明我们的新治疗策略(RTX和短程ATD)的作用需要作为更大规模对照试验的一部分进行更详细的研究。虽然试验的主要结果是两年后接受良好治疗的患者的比例，但我们也将在试验期间定期评估身体的免疫反应，看看这表明患者的反应如何。60多年来，对于患有格雷夫斯甲亢的年轻人，没有新的明显有效的治疗方法，扩大可用选择的数量是内分泌学领域的一个关键优先事项(5)。

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).