Myasthenia Gravis Treated With Autologous Hematopoietic Stem Cell Transplantation
Myasthenia Gravis Treated With Autologous Hematopoietic Stem Cell Transplantation
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DOI：
10.1001/jamaneurol.2016.0113
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发表时间：
2016-06-01
期刊：
影响因子：
29
通讯作者：
Bredeson, Christopher
中科院分区：
文献类型：
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作者：
Bryant, Adam;Atkins, Harold;Bredeson, Christopher
重要：一些重症肌无力(MG)患者对常规治疗没有反应，并有严重或危及生命的症状。替代疗法和新兴疗法尚未被证明始终如一或持久有效。自体造血干细胞移植(HSCT)已经在治疗其他严重的自身免疫性神经系统疾病方面取得了有效的效果，并可能在MG中有类似的应用。目的报道自体造血干细胞移植治疗重症重症肌无力7例，获得一致、持久、无症状和无治疗的缓解。设计、设置和参与者这项回顾性队列研究报告了2001年1月1日至2014年12月31日在渥太华医院进行的结果。渥太华医院是一家大型的加拿大三级护理转诊中心，在神经科和造血干细胞移植方面具有专业知识，平均随访时间为40个月(范围29-149个月)。数据收集和分析是从2015年2月1日到8月31日进行的。所有在渥太华医院接受自体造血干细胞移植治疗的MG患者都包括在内。尽管继续使用强化免疫抑制治疗，所有患者都有持续的严重或危及生命的MG相关症状。干预：用环磷酰胺和粒细胞集落刺激因子动员自体造血干细胞移植，通过外周血白细胞分离法收集，并使用CD34免疫磁选从污染的淋巴细胞中纯化。患者接受强化条件化疗以破坏自身反应性免疫系统，然后进行移植物输血和免疫重建。主要结果和指标是自体造血干细胞移植后的MG疾病活动性，通过急诊科就诊和住院频率以及美国重症肌无力基金会(MGFA)的临床分类、MGFA治疗状态和干预后MGFA状态来衡量。安全结果包括所有严重的自体造血干细胞移植相关并发症。结果7例患者接受了自体HSCT，6例为MG，1例为滤泡性淋巴瘤合并MG。MG确诊时的平均年龄(SD)为37(11)岁，自体HSCT时的平均年龄为44(10)岁。5名患者(71%)同时患有与免疫调节失调有关的自身免疫性或淋巴增生性疾病。所有患者均有明显的临床和肌电证据(MGFA临床分类IIIb-V)。所有患者都获得了持久的MGFA完全稳定缓解，没有残留的MG症状，也没有任何正在进行的MG治疗(MGFA干预后完全稳定缓解状态)。3名患者(43%)经历了短暂的病毒重新激活，1名患者(14%)在自体造血干细胞移植后发展为继发性自身免疫性疾病，所有这些都通过治疗得以缓解或稳定。没有与治疗或MG相关的死亡。结论在重症MG患者中，自体造血干细胞移植可导致长期无症状和无治疗缓解。应用自体造血干细胞移植治疗这种和其他自身免疫性神经疾病值得进行前瞻性研究。
IMPORTANCE Some patients with myasthenia gravis (MG) do not respond to conventional treatment and have severe or life-threatening symptoms. Alternate and emerging therapies have not yet proved consistently or durably effective. Autologous hematopoietic stem cell transplant (HSCT) has been effective in treating other severe autoimmune neurologic conditions and may have similar application in MG. OBJECTIVE To report 7 cases of severe MG treated with autologous HSCT in which consistent, durable, symptom-free, and treatment-free remission was achieved.DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study reports outcomes at The Ottawa Hospital, a large, Canadian, tertiary care referral center with expertise in neurology and HSCT, from January 1, 2001, through December 31, 2014, with a median follow-up of 40 months (range, 29-149 months). Data collection and analysis were performed from February 1 through August 31, 2015. All patients with MG treated with autologous HSCT at The Ottawa Hospital were included. All had persistent severe or life-threatening MG-related symptoms despite continued use of intensive immunosuppressive therapies.INTERVENTIONS Autologous hematopoietic stem cell grafts were mobilized with cyclophosphamide and granulocyte colony-stimulating factor, collected by peripheral blood leukapheresis, and purified away from contaminating lymphocytes using CD34 immunomagnetic selection. Patients were treated with intensive conditioning chemotherapy regimens to destroy the autoreactive immune system followed by graft reinfusion for blood and immune reconstitution.MAIN OUTCOMES AND MEASURES The primary outcome was MG disease activity after autologous HSCT measured by frequency of emergency department visits and hospitalizations and Myasthenia Gravis Foundation of America (MGFA) clinical classification, MGFA therapy status, and MGFA post intervention status. Safety outcomes included all severe autologous HSCT-related complications. RESULTS Seven patients underwent autologous HSCT, 6 for MG and 1 for follicular lymphoma with coincident active MG. Mean (SD) ages at MG diagnosis and at autologous HSCT were 37 (11) and 44 (10) years, respectively. Five patients (71%) had concurrent autoimmune or lymphoproliferative illnesses related to immune dysregulation. All patients had distinct clinical and electromyographic evidence of MG (MGFA clinical classification IIIb-V). All patients achieved durable MGFA complete stable remission with no residual MG symptoms and freedom from any ongoing MG therapy (MGFA postintervention status of complete stable remission). Three patients (43%) experienced transient viral reactivations, and 1 (14%) developed a secondary autoimmune disease after autologous HSCT, all of which resolved or stabilized with treatment. There were no treatment-or MG-related deaths.CONCLUSIONS AND RELEVANCE Autologous HSCT results in long-term symptom-and treatment-free remission in patients with severe MG. The application of autologous HSCT for this and other autoimmune neurologic conditions warrants prospective study.