Plasma-cell depletion therapy for severe Graves' disease

格雷夫斯病(自身免疫性甲状腺功能亢进症)影响了约3%的女性一生，并会出现心悸、热耐受、体重意外下降、甲状腺肿大、眼皮红肿、眼球突出和复视等症状。这些症状是由异常的免疫反应导致循环抗体(称为TRAb)引起的，这种抗体刺激甲状腺，导致眼睛周围组织的炎症和生长。虽然许多患者可以成功地用抗甲状腺药物治疗，但这些药物并不能改善眼睛问题。相当大一部分患者患有严重的Graves病，有更强烈的甲状腺功能亢进和更严重的眼部炎症，这与血液TRAb水平高于正常水平10倍有关。这些人不能通过药物治愈，经常患有致残眼病，偶尔还会失明。目前，这些严重的Graves病患者接受了手术切除甲状腺，然后进行了几次眼部手术，以纠正眼睛的视觉功能和外观。这些都是昂贵的手术，总体而言，只有50%的NHS患者感到这种治疗的结果令人满意。我们迫切需要更好的治疗方法。导致甲状腺和眼睛症状的TRAb抗体是由一种名为浆细胞的白细胞产生的，其唯一目的是制造大量抗体。该项目将发现一种名为daratumumab的新疗法是否也可以用于治疗重症Graves病患者的良性浆细胞，这种疗法已经被开发用于治疗浆细胞癌。通过去除Graves病的浆细胞，我们预计会降低致病TRAb抗体浓度，并迅速改善甲状腺功能亢进和眼睛症状。这项研究将在30名重症Graves病患者中进行Daratumumab的两阶段临床试验。由于Daratumumab以前从未用于治疗Graves病，我们研究的第一部分将给一小群参与者服用4种不同的剂量，看看哪种剂量效果最好，副作用最少。然后，我们将使用这些最佳的Daratumumab剂量和安慰剂来治疗更多的患者。每个参与者静脉滴注两次Daratumumab，随后将对每个人的甲状腺和眼睛状态进行为期6个月的跟踪。我们的研究可能会改变许多重症Graves病患者的生活，他们未来可能会接受注射Daratumumab的治疗，而不是几次手术。此外，我们的研究可能会打开一扇门，使daratumumab可以用于治疗其他几种自身免疫性疾病，在这些疾病中，异常抗体也会推动疾病的发展。

Graves' disease (autoimmune thyroid overactivity) affects around 3% of women over their life-time and gives symptoms such as heart palpitations, heat intolerance, unintended weight loss, enlarged thyroid, red and swollen eyelids, protuberant eyeballs and double vision. These symptoms are caused by an abnormal immune response leading to a circulating antibody (known as TRAb) that stimulates the thyroid gland and causes inflammation and growth of the tissues around the eyes. While many patients can be successfully treated with anti-thyroid drugs, these do not improve the eye problems. A sizeable minority of patients have severe Graves' disease, with more intense thyroid overactivity and worse eye inflammation, which is associated with blood TRAb levels that are ten times higher than normal. These people are not cured by medication and frequently have disabling eye disease and occasionally loss of vision. Currently these severe Graves' disease patients have their thyroid gland removed surgically, followed by several eye operations to correct the visual function and appearance of the eyes. These are expensive operations and overall, only 50% of NHS patients feel that the outcomes of such treatment are satisfactory. Better treatments are sorely needed.The TRAb antibodies that drive the thyroid and eye symptoms are produced by a type of white blood cell called a plasma cell, whose sole purpose is to make large quantities of antibodies. This project will find out whether a new treatment called daratumumab that has been developed to treat plasma cell cancer, could also be used to target the benign plasma cells in patients with severe Graves' disease. By removing plasma cells in Graves' disease, we would expect a reduction in the disease-causing TRAb antibody concentration and a rapid improvement in the thyroid overactivity and eye symptoms. This study will perform a 2-stage clinical trial of daratumumab in 30 patients with severe Graves' disease. Because daratumumab has not been used in Graves' disease before, the first part of our study will administer 4 different doses to small groups of participants to see which of the doses works best and has least side-effects. Then we will use these optimal daratumumab doses and a placebo to treat larger groups of patients. The daratumumab is given twice by intravenous infusion to each participant, and the thyroid and eye state of each person will be followed for 6 months afterwards. Our study could change the lives of many people with severe Graves' disease, who in the future might be able to have treatment with infusions of daratumumab, rather than several surgical operations. In addition, our study might open a door whereby daratumumab might be used to treat several other autoimmune conditions where abnormal antibodies also drive the disease process.