中等剂量利妥昔单抗治疗视神经脊髓炎谱系疾病疗效分析

科研成果详情

题名	中等剂量利妥昔单抗治疗视神经脊髓炎谱系疾病疗效分析
其他题名	Effects of moderate dosage of Rituximab treatment on Neuromyeliti Optica Spectrum Disorder
作者	林杰
学位类型	硕士
导师	夏君慧
答辩日期	2017-05-31
学位授予单位	温州医科大学
学位专业	神经病学
关键词	视神经脊髓炎谱系疾病利妥昔单抗平均年复发率缓解期 EDSS CD19+B细胞
摘要	研究背景及目的：视神经脊髓炎谱系疾病（Neuromyelitis optica spectrum disorder, NMOSD）是一种累及中枢神经系统的自身免疫性炎性脱髓鞘疾病，病变部位以中枢神经系统水通道蛋白4(Aquaporin4, AQP4)分布区域为主。以脊髓、视神经和极后区受累最为常见，临床上典型的表现为肢体乏力、麻木、顽固性呃逆、恶心、呕吐、视力障碍等。NMOSD表现为复发缓解病程，反复的发作给患者带来不良预后，在首次发作的5年后多数患者会出现肢体瘫痪、视力障碍，严重者四肢全瘫，视力丧失，甚至死亡。因此减少NMOSD的复发尤其重要。目前一线免疫抑制剂，如糖皮质激素、硫唑嘌呤等广泛应用于NMOSD患者，但是不良反应如骨髓抑制、代谢紊乱、骨质疏松、股骨头坏死等往往又限制了临床应用。随着NMOSD发病机制研究的进展，明确了B细胞参与的体液免疫在其中发挥了关键作用。B细胞产生的致病性抗体与AQP4通道结合，致使中枢神经系统水通道异常，继而出现一系列病理变化，导致一系列症状。前体B细胞和成熟B细胞表面表达有CD20分子，而病理性抗体正是来源于以上两种细胞。利妥昔单抗（Rituximab, RTX）是CD20细胞的特异性单克隆抗体，其通过抗体依赖的细胞毒作用（antibody dependent cellular cytotoxicity， ADCC）和补体依赖的细胞毒作用（complement dependent cellular cytotoxicity，CDC）破坏B细胞，从而减少病理性抗体的生成。国内外研究发现RTX对于减少NMOSD复发及改善其残疾程度都有良好的疗效。然而由于国外研究使用的剂量大，其不良反应发生率相对较高，并结合我国国情，其高昂的经济负担会限制其使用。本研究旨在探讨中等剂量利妥昔单抗对于NMOSD的疗效及安全性。方法：收集在我院就诊的符合2015年NMOSD诊断标准的患者，经知情同意，排除禁忌症后收住入院，接受中等剂量即375mg/m2（体表面积）利妥昔单抗治疗。治疗前1天无菌条件下采集患者的静脉血，利用流式细胞仪进行CD19+B细胞测定，治疗后同样采集患者静脉血进行CD19+B细胞测定。定期随访，检测CD19+B细胞，符合1：CD19+B>1%外周血淋巴细胞；2：治疗6个月者，再次进行利妥昔单抗治疗。收集患者临床资料，计算平均年复发率，治疗前后残疾程度评分（Expanded disability scale score, EDSS），及缓解期时间等。结果：本研究共纳入14名患者，均为女性，平均首发年龄为（33.71±7.36）岁，治疗后平均随访时间为（14.71±7.20）月（4-23月），14名患者接受利妥昔单抗治疗的总次数为23次，平均次数为（1.64±0.74）次（1-3次）。治疗过程中，4名患者出现共4次复发。平均年复发率由治疗前的（2.01±1.79）次/年降至治疗后的（0.29±0.59）次/年（p<0.01）。与采用其他免疫抑制剂患者比较，其缓解期显著延长（17.95±2.11m Vs 10.08±1.00m， Log Rank test: p<0.001）。平均EDSS评分有治疗前的（3.68±2.05）分（1.5-9分）降至治疗后的平均EDSS为（2.79±2.58）分（1-9分）（p<0.01）。其中12名患者EDSS评分改善，1名患者保持平稳，1名患者在复发后出现评分增加。首次治疗后CD19+B细胞显著下降（p<0.001）。COX风险回归模型发现利妥昔单抗是预防NMOSD复发的保护因素[HR=4.452，95%(confidence interval) CI: 1.580-12.546, p=0.005]。结论：我们的研究结果提示中等剂量利妥昔单抗能减少NMOSD患者的平均年复发率，延长治疗后的缓解期，改善患者的残障程度，且副作用发生少。
其他摘要	Background and purpose:Neuromyelitis optica spectrum disorder (NMOSD) has been defined as an inflammatory demyelination disorder of central nervous system (CNS). Areas of aquaporin 4 (AQP4) abundantly distributed which are the main water channel in CNS are the primary targets, such as spinal cord, optic nerves, postarea. Symptoms of paralysis, numbness, disability of vision, intractable hiccup, nausea, vomit are most frequent manifestations occurred in NMOSD patients. NMOSD patients had a poor prognosis because of the course of relapse-remission, about 50% patients had the outcome of paralysis, partial or complete visual loss, even death. Hence, therapies of prevention are vital for NMOSD patients. Glucocorticoids (GCs) and azathioprine(AZA) have been recommended as the first line of suppressions for NMOSD, while a large number of NMOSD patients had been stopped treatments because of severe side effects. More evidences were found that humoral immunity plays important role in the pathogenesis of NMOSD, pathogenic antibodies produced by pre-B cells and mature B cells combined with AQP4 which causes lesions. Molecule CD20 was expressed on the surface of pre-B cells and mature B cells. Rituximab (RTX)-CD20 monoclonal antibody specifically combined with CD20 which causes apoptosis by ADCC and CDC. Researchers reported that the reduced annual relapsed rate (ARR) and disability score after the treatments of RTX. However, Chinese patients will be restricted to the high expenditure based on the European and American protocols which also brings more frequent side effects. The purpose of this study was to evaluate the effects of low dosage of RTX treatment on NMOSD patients.Methods:NMOSD patients from the First hospital of Wenzhou Medical University were enrolled in our study after informed consent. Clinical characteristics were also collected, such as annual relapse rate (ARR), time to next relapse, disability scale via Expanded disability scale score (EDSS), previous used drugs, CD19+B cells, serostatus of AQP4-ab, brain and spinal cord magnetic resonance imaging (MRI). Contraindications must be eliminated before induced RTX treatment. Peripheral venous blood samples were collected at 1 day before treatment, after treatment and monthly interval. CD19+B cells were analyzed by flow-cytometry. Maintain treatments were based on CD19+B cells more than 1% of peripheral blood lymphocyte or every 6 months. Results:Forteen females were enrolled in our study, mean age of onset was 33.71±7.36 years old，and mean time of follow-up was 14.71±7.20 months（4-23 months）. There were 23 infusions totally conducted for 14 patients, with an average times of 1.64±0.74（1-3 time/ times）. Four relapse attacks were happened in 4 patients. ARR was reduced from 2.01±1.79 times per year to 0.29±0.59（p<0.01）. And patients treated with RTX had a longer time to next relapse compared with those who were treated with other immunosuppressive drugs（17.95±2.11m Vs 10.08±1.00m， Log Rank test: p<0.001）。Meantime a reduced mean EDSS score was detected after RTX treatments (3.68±2.05- 2.79±2.58, p<0.01).One patient had an increased EDSS score when relapsed, while the remains kept disability improvement or stable. A significantly decreased level of CD19+B cells was detected (p<0.001) after the first therapy. Therapy of RTX was a protective factor for NMOSD patients (HR=4.452，95%(confidence interval) CI: 1.580-12.546, p=0.005) from COX hazard model. Tuberculosis was reported in one patient after RTX treatment, while there were no side effects reported.Conclusion:Rituximab with a dosage of 375mg/m2 (body surface area) per time might reduce the ARR and prolong the remission of NMOSD patients. Meantime neurological disability evaluated by EDSS could be improved by the treatment of RTX.
语种	中文
学号	141001130
发布年限	2020-09-01
毕业论文分类号	0R7401
原始专题	第一临床学院
参考文献	参考文献 1 Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015,85(2):177-189. 2 Matiello M, Jacob A, Wingerchuk DM, et al. Neuromyelitis optica. Curr Opin Neurol 2007,20(3):255-260. 3 中国视神经脊髓炎谱系疾病诊断与治疗指南. 中国神经免疫学和神经病学杂志 2016,03):155-166. 4 Cree BA, Lamb S, Morgan K, et al. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 2005,64(7):1270-1272. 5 Annovazzi P, Capobianco M, Moiola L, et al. Rituximab in the treatment of Neuromyelitis optica: a multicentre Italian observational study. J Neurol 2016,263(9):1727-1735. 6 Nosadini M, Alper G, Riney CJ, et al. Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2016,3(1):e188. 7 Rommer PS, D?rner T, Freivogel K, et al. Safety and Clinical Outcomes of Rituximab Treatment in Patients with Multiple Sclerosis and Neuromyelitis Optica: Experience from a National Online Registry (GRAID). J Neuroimmune Pharmacol 2016,11(1):1-8. 8 Yang CS, Yang L, Li T, et al. Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis optica. Neurology 2013,81(8):710-713. 9 Evangelopoulos ME, Andreadou E, Koutsis G, et al. Treatment of neuromyelitis optica and neuromyelitis optica spectrum disorders with rituximab using a maintenance treatment regimen and close CD19 B cell monitoring. A six-year follow-up. J Neurol Sci 2017,372:92-96. 10 Kim SH, Huh SY, Lee SJ, et al. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol 2013,70(9):1110-1117. 11 Ringelstein M, Ayzenberg I, Harmel J, et al. Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder. JAMA Neurol 2015,72(7):756-763. 12 Araki M, Matsuoka T, Miyamoto K, et al. Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology 2014,82(15):1302-1306. 13 Pittock SJ, Lennon VA, McKeon A, et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol 2013,12(6):554-562. 14 Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004,364(9451):2106-2112. 15 Saadoun S, Waters P, Bell BA, et al. Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice. Brain 2010,133(Pt 2):349-361. 16 Ju EJ, Yeon SK, Park JH, et al. Screening, Synthesis, and In Vitro Evaluation of Vinyl Sulfones as Inhibitors of Complement-Dependent Cytotoxicity in Neuromyelitis Optica. ChemMedChem 2016,11(4):377-381. 17 Kira J. Neuromyelitis optica and opticospinal multiple sclerosis: Mechanisms and pathogenesis. Pathophysiology 2011,18(1):69-79. 18 Argyriou AA and Makris N. Neuromyelitis optica: a distinct demyelinating disease of the central nervous system. Acta Neurol Scand 2008,118(4):209-217. 19 Kim HJ and Kim SH. Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis optica. Neurology 2014,82(6):546-547. 20 Kitley J, Leite MI, Elsone L, et al. Time to next relapse as a primary endpoint in neuromyelitis optica clinical trials. J Neurol Neurosurg Psychiatry 2014,85(5):589-590. 21 Kim SM, Park J, Kim SH, et al. Factors associated with the time to next attack in neuromyelitis optica: accelerated failure time models with random effects. PLoS One 2013,8(12):e82325. 22 Elsone L, Kitley J, Luppe S, et al. Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK. Mult Scler 2014,20(11):1533-1540. 23 Huh SY, Kim SH, Hyun JW, et al. Mycophenolate mofetil in the treatment of neuromyelitis optica spectrum disorder. JAMA Neurol 2014,71(11):1372-1378. 24 Hlavaty T, Batovsky M, Balakova D, et al. The impact of thiopurine-S-methyltransferase genotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases. Bratisl Lek Listy 2013,114(4):199-205. 25 Jabin D, Kumar S, and Gow PJ. Outcome of patients on azathioprine: a need for a better pre-treatment assessment and dosing guideline. N Z Med J 2010,123(1324):67-73. 26 Jeong IH, Park B, Kim SH, et al. Comparative analysis of treatment outcomes in patients with neuromyelitis optica spectrum disorder using multifaceted endpoints. Mult Scler 2016,22(3):329-339. 27 Simonetta F, Allali D, Roux-Lombard P, et al. Successful treatment of refractory lupus nephritis by the sequential use of rituximab and belimumab. Joint Bone Spine 2016. 28 McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998,16(8):2825-2833. 29 Lindsey JW, Meulmester KM, Brod SA, et al. Variable results after rituximab in neuromyelitis optica. J Neurol Sci 2012,317(1-2):103-105. 30 Kim SH, Jeong IH, Hyun JW, et al. Treatment Outcomes With Rituximab in 100 Patients With Neuromyelitis Optica: Influence of FCGR3A Polymorphisms on the Therapeutic Response to Rituximab. JAMA Neurol 2015,72(9):989-995. 31 Damato V, Evoli A, and Iorio R. Efficacy and Safety of Rituximab Therapy in Neuromyelitis Optica Spectrum Disorders: A Systematic Review and Meta-analysis. JAMA Neurol 2016,73(11):1342-1348. 32 Jacob A, Weinshenker BG, Violich I, et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol 2008,65(11):1443-1448. 33 Vaknin-Dembinsky A, Charbit H, Brill L, et al. Circulating microRNAs as biomarkers for rituximab therapy, in neuromyelitis optica (NMO). J Neuroinflammation 2016,13(1):179. 34 Quan C, ZhangBao J, Lu J, et al. The immune balance between memory and regulatory B cells in NMO and the changes of the balance after methylprednisolone or rituximab therapy. J Neuroimmunol 2015,282:45-53. 35 Wang HH, Dai YQ, Qiu W, et al. Interleukin-17-secreting T cells in neuromyelitis optica and multiple sclerosis during relapse. J Clin Neurosci 2011,18(10):1313-1317. 36 Li Y, Wang H, Long Y, et al. Increased memory Th17 cells in patients with neuromyelitis optica and multiple sclerosis. J Neuroimmunol 2011,234(1-2):155-160.
全文文件名	141001130林杰2016神经病学.pdf\|141001130林杰2016神经病学.pdf
文献类型	学位论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/113656
专题	温州医科大学
作者单位	溫州医科大学第一临床学院
推荐引用方式 GB/T 7714	林杰. 中等剂量利妥昔单抗治疗视神经脊髓炎谱系疾病疗效分析[D]. 温州医科大学,2017.