project 3 - Autonomic Rare Diseases Clinical Research Consortium

项目 3 - 自主神经罕见疾病临床研究联盟

• 批准号: 7901213
• 负责人: ROY FREEMAN
• 金额: $ 27.31万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901213
• 关键词: Address; Antibodies; Antibody Formation; Autoantibodies; Autoimmune Process; Autonomic ganglion; B-Lymphocytes; Blinded; Case Series; Case Study; Cholinergic Receptors; Clinical; Clinical Research; Clinical Trials; Constipation; Disease; Double-Blind Method; Enrollment; Failure; Goals; Hylobates Genus; Immunoglobulins; Immunosuppression; Immunosuppressive Agents; Instruction; Intervention; Intravenous Immunoglobulins; Natural History; Neurons; Orthostatic Hypotension; Patients; Placebos; Plasma Exchange; Play; Pupil; Quality of life; Randomized; Randomized Clinical Trials; Randomized Controlled Clinical Trials; Rare Diseases; Reporting; Role; Symptoms; Syncope; Testing; Therapeutic; Therapy Clinical Trials; Treatment Protocols; Urinary Retention; Xerostomia; autoreactive B cell; clinically significant; effective therapy; eye dryness; follow-up; improved; placebo controlled study; randomized placebo controlled trial; response; rituximab

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.

项目3 BIDMC项目摘要（请参阅说明）： 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 与针对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。患者通常会在数周到数月内患有严重的体性低血压， 晕厥，便秘，尿retention留，固定和扩张的学生，口干和干眼睛。有症状 仅在轻度折磨的患者中，自主衰竭的治疗就足够了。许多患者仍然存在 自主症状无能为力，需要修改疗法，但没有建立 治疗方案。 有几个病例报告和病例系列的AAG免疫调节治疗，但其中没有 治疗盲目或随机。此外，未知未经处理的AAG的自然史。 血浆交换和静脉免疫球蛋白通常是第一批干预措施，但在所有报告中 反应似乎是短暂的，并且需要进行随访（通常与几种药物）。它 自动反应性B细胞和自身抗体可能在AAG中起着核心的致病作用，但迄今为止 靶向B细胞的药物尚未用于治疗该疾病。 该项目的长期目标是为AAG找到一种有效，安全和耐用的治疗方法。 该提案的具体目的是：（1）确定静脉免疫球蛋白（IVIG）的影响 AAG患者的体位低血压和生活质量评分的治疗 靶向免疫调节的作用，抗CD20免疫抑制剂利妥昔单抗治疗对 在治疗试验失败的AAG患者中，体位低血压和生活质量得分 IVIG和其他免疫抑制剂。我们预计IVIG将产生临床意义，但 瞬态改善，而利妥昔单抗将是AAG患者的有效治疗方法。