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项目总结(见说明)： 自身免疫性自主神经节病(AAG)是一种罕见的以自主神经存在为特征的疾病。 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。患者通常在几周到几个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、眼干。有症状的 自主神经衰竭的治疗只对轻度痛苦的患者有效。许多患者仍留在 因自主神经症状而丧失行为能力，需要疾病修正疗法，但目前还没有确定的 治疗方案。 有几个AAG免疫调节治疗的病例报告和病例系列，但这些都不是 治疗是随机或盲法进行的。此外，未经治疗的AAG的自然病史尚不清楚。 血浆置换和静脉注射免疫球蛋白通常是第一个干预措施，但在所有报告中 反应是短暂的，需要后续的免疫抑制(通常使用几种药物)。它 自身反应性B细胞和自身抗体可能在AAG中起中心致病作用，但到目前为止 靶向B细胞的药物还没有被用于治疗这种疾病。 该项目的长期目标是为AAG找到一种有效、安全和持久的治疗方法。 这项建议的具体目的是：(1)确定静脉注射免疫球蛋白(IVIG)的效果 AAG患者直立性低血压的治疗及生活质量评分 靶向免疫调节联合抗CD20免疫抑制剂利妥昔单抗治疗慢性粒细胞白血病 治疗试验失败的AAG患者的直立性低血压和生活质量评分 静脉注射免疫球蛋白和其他免疫抑制剂。我们预计IVIG将产生具有临床意义的 一过性改善，而利妥昔单抗将是治疗AAG的有效方法。