Developmental Clinical Studies- Combined Immunotherapy and Trophic Adrenocortical Stimulation in New Onset Autoimmune Addison's Disease

自身免疫性Addison病是由免疫系统攻击和破坏肾上腺皮质引起的，由于缺乏肾上腺类固醇激素而给人们带来了危及生命的问题。典型的症状包括疲惫、头晕、呕吐、体重减轻、食欲不振、肌肉无力和痉挛。此外，爱迪生的人容易发生不可预测的严重疾病，称为肾上腺危机。这意味着患有爱迪生病的人终生依赖类固醇药物，并可能在错过剂量后的几个小时内生病。六十年来，爱迪生病的治疗一直没有重大进展。然而，肾上腺皮质是体内最具可塑性的组织之一，这项研究的目的是利用这种与生俱来的再生能力来治愈刚刚被诊断为阿迪森氏病的人。这项研究的想法是将一种激素疗法与一种抑制免疫系统对肾上腺皮质的攻击的疗法结合起来。这种激素疗法是人体天然肾上腺刺激素的合成版，称为ACTH(促肾上腺皮质激素)。在之前的一项研究中，我们发现隔日注射合成ACTH可以有效地刺激肾上腺再生，但我们不知道哪种治疗方法会有效地抑制免疫反应。这对于确保肾上腺再生不会再次被免疫攻击迅速摧毁是很重要的。这项研究将分3个阶段进行，每个阶段涉及4名新诊断为爱迪生病的患者。在研究的每个阶段，参与者将接受相同剂量的隔日ACTH。然而，研究的第一部分将使用一种名为利妥昔单抗的药物，这种药物可以在大约6个月的时间内从血液和组织中移除产生抗体的B淋巴细胞，看看这是否会阻止对肾上腺的免疫攻击，并允许永久再生。如果这不起作用，我们将尝试一种不同的免疫疗法，称为abatacept，它会影响T淋巴细胞的功能，T淋巴细胞既是免疫系统的雷达，也是刺杀团队。这两种疗法都是短期(2或5剂)的抗体疗法，但对免疫系统功能产生长期持久的影响，持续几个月。如果这两种免疫系统疗法都不起作用，那么我们将使用3次大剂量类固醇注射的组合，然后每天服用一种名为霉酚酸酯的免疫抑制药片，服用12周。在每一次治疗后，参与者的肾上腺功能将定期重新测试一年，看看肾上腺的激素功能是否得到了改善。我们相信，这种治疗方法将抑制免疫系统对肾上腺的攻击的药物与促进肾上腺再生的激素刺激相结合，为治愈这种慢性病提供了真正的希望。

Autoimmune Addison's disease is caused by the immune system attacking and destroying the cortex of the adrenal glands, which gives people a life-threatening problem owing to lack of the adrenal steroid hormones. Symptoms typically include exhaustion, light-headedness, vomiting, weight loss, poor appetite, muscle weakness and cramps. In addition, Addison's people are prone to unpredictable episodes of severe illness, termed adrenal crisis. This means that people with Addison's disease have a life-long dependency on steroid medications, and may become ill within hours of a missed dose. There have been no significant advances in therapy for Addison's disease for sixty years. However, the adrenal cortex is one of the most plastic tissues in the body and this study aims to exploit this innate regenerative capacity to produce a cure for people who have just been diagnosed with Addison's disease.The idea of this study is to combine a hormone therapy that is a synthetic version of the body's natural adrenal stimulating hormone, termed ACTH (adrenocorticotropic hormone), with a treatment to dampen down the immune system's attack on the adrenal cortex. In a previous study, we have found that alternate day injections with synthetic ACTH is effective in stimulating adrenal gland regeneration, but we do not know what sort of treatment will be effective in dampening down the immune response. This will be important to make sure any adrenal regeneration isn't just rapidly destroyed again by the immune attack. The study will take place in 3 stages, each involving 4 people with newly-diagnosed Addison's disease. In each stage of the study, the participants will receive the same dose of alternate day ACTH. However, the first part of the study will use a drug called rituximab, that removes the antibody-producing B lymphocytes from the blood and tissues for about 6 months, to see if this stops the immune attack on the adrenals and allows permanent regeneration. If this doesn't work, we will try a different sort of immunotherapy called abatacept, that affects the function of the T lymphocytes, which act both as the immune system's radar and assassination team. Both these treatments are antibody therapies that are administered for a short period of time (either 2 or 5 doses), but produce long lasting effects on immune system function, for several months. If neither of these immune system treatments work, we will then use a combination of 3 high-dose steroid infusions followed by a daily immunosuppressive tablet called mycophenolate which will be taken for 12 weeks. After each of these treatments adrenal function will be retested in participants at regular intervals for a year to see if the hormonal function of the adrenal gland had been improved. We believe that this therapeutic approach, combining both a drug to quash the immune system attack on the adrenal glands with hormonal stimulation to promote adrenal regeneration, holds genuine promise for cure of this chronic condition.