project 3 - Autonomic Rare Diseases Clinical Research Consortium

项目3 BIDMC项目总结（见说明）： 自身免疫性自主神经节病（AAG）是一种罕见的疾病，其特征是存在自主神经元， 与针对神经元乙酰胆碱受体（AChR）的特异性抗体相关的失败 自主神经节患者通常在数周至数月内出现严重的直立性低血压， 晕厥、便秘、尿潴留、瞳孔固定和扩大、口干和眼干。症状性 自主神经衰竭的治疗仅在轻度患病的患者中是足够的。许多患者仍然 因自主症状而丧失能力，需要疾病改善治疗，但没有确定的 治疗方案 存在几个AAG免疫调节治疗的病例报告和病例系列，但没有一个是 治疗设盲或随机化。此外，未经治疗的AAG的自然史尚不清楚。 血浆置换和静脉注射免疫球蛋白通常是第一种干预措施，但在所有报告中， 反应似乎是短暂的，需要后续的免疫抑制（通常用几种药物）。它 自身反应性B细胞和自身抗体可能在AAG中发挥重要的致病作用，但迄今为止， 靶向B细胞的药物尚未用于治疗这种疾病。 该项目的长期目标是为AAG找到有效，安全和持久的治疗方法。 本建议的具体目的是：（1）确定静脉注射免疫球蛋白（IVIG）的效果 治疗对AAG患者的体位性低血压和生活质量评分的影响， 抗CD20免疫抑制剂利妥昔单抗治疗对靶向免疫调节的作用 AAG治疗试验失败患者的体位性低血压和生活质量评分 IVIG和其他免疫抑制剂。我们预计IVIG将产生临床上显著的， 短暂的改善，而利妥昔单抗将是AAG患者的有效治疗。

PROJECT 3 BIDMC PROJECT SUMMARY (See instructions): Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by the presence of autonomic failure in association with specific antibodies directed against the neuronal acetylcholine receptor (AChR) of the autonomic ganglia. Patients typically present over weeks to months with severe orthostatic hypotension, syncope, constipation, urinary retention, fixed and dilated pupils, dry mouth and dry eyes. Symptomatic treatment of autonomic failure is sufficient in only mildly afflicted patients. Many patients remain incapacitated by autonomic symptoms and require disease modifying therapy but there is no established therapeutic regimen. Several case reports and case series of immunomodulatory treatments for AAG exist but in none of these is the treatment blinded or randomized. Furthermore, the natural history of untreated AAG is not known. Plasma exchange and intravenous immunoglobulin are usually the first interventions but in all reports the response appears transient and follow-up immunosuppression (typically with several agents) is required. It is likely that autoreactive B-cells and autoantibodies play a central pathogenetic role in AAG but to date agents targeting B-cells have not been used in the treatment of this disorder. The long term goals of the project are to find an effective, safe and durable treatment for AAG. The specific aims of this proposal are: (1) To determine the effect of intravenous immunoglobulin (IVIG) treatment on orthostatic hypotension and quality of life scores in patients with AAG and to determine the effect of targeted immunomodulatory, with the anti-CD20 immunosuppressive agent, rituximab, treatment on orthostatic hypotension and quality of life scores in patients with AAG who have failed therapeutic trials with IVIG and other immunosuppressant agents. We anticipate that IVIG will produce a clinically significant but transient improvement whereas rituximab will be an efficacious treatment for patients with AAG.