利妥昔单抗治疗难治性重症肌无力有效性和安全性的Meta分析
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摘要
目的评价利妥昔单抗治疗难治性重症肌无力的有效性和安全性。方法以rituximab、myasthenia gravis等英文检索词计算机检索2000年1月1日-2018年4月30日美国国立医学图书馆生物医学信息检索系统(Pub Med)、荷兰医学文摘(EMBASE/SCOPUS)、Cochrane图书馆,并辅助手工检索获得回顾性病例分析和病例观察研究,采用Newcastle-Ottawa量表和Stata 12.0统计软件进行文献质量评价和Meta分析。结果共1772篇英文文献,经剔除重复和不符合纳入标准者,最终纳入11篇文献(包括回顾性病例分析10篇和病例观察研究1篇)共160例利妥昔单抗治疗的难治性重症肌无力患者[包括血清抗乙酰胆碱受体(ACh R)抗体阳性88例、抗肌肉特异性受体酪氨酸激酶(Mu SK)抗体阳性65例、抗ACh R和Mu SK抗体阴性7例]。Meta分析显示,利妥昔单抗治疗血清抗ACh R抗体阳性的难治性重症肌无力的临床症状改善率为77%(95%CI:0.642~0.899,P=0.030),治疗血清抗Mu SK抗体阳性或抗ACh R和Mu SK抗体阴性的难治性重症肌无力的临床症状改善率为73%(95%CI:0.631~0.829,P=0.048),且可以显著减少激素日剂量[治疗前31.80(20.00,45.90)mg/d、治疗后6.81(3.44,8.00)mg/d,减量21.70(15.50,42.46)mg/d;Z=2.366,P=0.018];利妥昔单抗不良反应主要包括白细胞减少症、阵发性心房颤动、感染性肺炎、进行性多灶性白质脑病、口腔带状疱疹等。结论循证医学方法对评价利妥昔单抗治疗难治性重症肌无力的有效性和安全性具有重要意义。利妥昔单抗治疗难治性重症肌无力安全、有效,并可以显著减少激素日剂量。
Objective To evaluate the efficacy and safety of rituximab(RTX) in the treatment ofrefractory myasthenia gravis(MG). Methods Retrieve relevant retrospective case analysis andobservational studies that reported RTX therapy in patients with refractory MG from online databases(January 1, 2000-April 30, 2018) in Pub Med, EMBASE/SCOPUS and Cochrane Online Library with keywords: rituximab, myasthenia gravis. Quality of studies was evaluated by using Newcastle-Ottawa Scale(NOS). All data were pooled by Stata 12.0 software for Meta-analysis. Results A total of 1772 articleswere enrolled, and 10 retrospective case analysis and one observational study with 160 eligible participantstaking RTX were finally included after excluding duplicates and those not meeting the inclusion criteria.Among 160 patients, 88 were tested positive for acetylcholine receptor antibody(ACh R-Ab +), 65 weretested positive for muscle-specific receptor tyrosine kinase antibody(Mu SK-Ab +), and 7 were testednegative for two antibodies. Meta-analysis showed the overall effective rate of RTX treating refractory MGpatients with serum ACh R-Ab + was 77%(95%CI: 0.642-0.899, P = 0.030); the overall effective rate ofRTX treating refractory MG patients with serum Mu SK-Ab + was 73%(95%CI: 0.631-0.829, P = 0.048);RTX significantly reduced average daily dose of corticosteroids [before treatment 31.81(20.00, 45.90) mg/d,after treatment 6.81(3.44, 8.00) mg/d, decrement 21.70(15.50, 42.46) mg/d; Z = 2.366, P = 0.018]; the mainside effects of RTX were leukopenia, paroxysmal atrial fibrillation, infectious pneumonia, progressivemultifocal leukoencephalopathy(PML), oral herpes zoster, et al. Conclusions Critical findings have beendemonstrated in the evidence-based evaluation on efficacy and safety of RTX in the treatment of refractoryMG. The effect of RTX on refractory MG is remarkable, and can significantly reduce the average dailydosage of corticosteroids.
Objective To evaluate the efficacy and safety of rituximab(RTX) in the treatment ofrefractory myasthenia gravis(MG). Methods Retrieve relevant retrospective case analysis andobservational studies that reported RTX therapy in patients with refractory MG from online databases(January 1, 2000-April 30, 2018) in Pub Med, EMBASE/SCOPUS and Cochrane Online Library with keywords: rituximab, myasthenia gravis. Quality of studies was evaluated by using Newcastle-Ottawa Scale(NOS). All data were pooled by Stata 12.0 software for Meta-analysis. Results A total of 1772 articleswere enrolled, and 10 retrospective case analysis and one observational study with 160 eligible participantstaking RTX were finally included after excluding duplicates and those not meeting the inclusion criteria.Among 160 patients, 88 were tested positive for acetylcholine receptor antibody(ACh R-Ab +), 65 weretested positive for muscle-specific receptor tyrosine kinase antibody(Mu SK-Ab +), and 7 were testednegative for two antibodies. Meta-analysis showed the overall effective rate of RTX treating refractory MGpatients with serum ACh R-Ab + was 77%(95%CI: 0.642-0.899, P = 0.030); the overall effective rate ofRTX treating refractory MG patients with serum Mu SK-Ab + was 73%(95%CI: 0.631-0.829, P = 0.048);RTX significantly reduced average daily dose of corticosteroids [before treatment 31.81(20.00, 45.90) mg/d,after treatment 6.81(3.44, 8.00) mg/d, decrement 21.70(15.50, 42.46) mg/d; Z = 2.366, P = 0.018]; the mainside effects of RTX were leukopenia, paroxysmal atrial fibrillation, infectious pneumonia, progressivemultifocal leukoencephalopathy(PML), oral herpes zoster, et al. Conclusions Critical findings have beendemonstrated in the evidence-based evaluation on efficacy and safety of RTX in the treatment of refractoryMG. The effect of RTX on refractory MG is remarkable, and can significantly reduce the average dailydosage of corticosteroids.
引文
[1]Hehir MK,Silvestri NJ.Generalized myasthenia gravis:classification,clinical presentation,natural history,and epidemiology[J].Neurol Clin,2018,36:253-260.
[2]Guptill JT,Sanders DB.Update on muscle-specific tyrosine kinase antibody positive my asthenia gravis[J].Curr Opin Neurol,2010,23:530-535.
[3]Li HF,Xie Y,Hong Y.Letter re:International consensus guidance for management of myasthenia gravis[J].Neurology,2017,88:505.
[4]Boye J,Elter T,Engert A.An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab[J].Ann Oncol,2003,14:520-535.
[5]Iorio R,Damato V,Alboini PE,Evoli A.Efficacy and safety of rituximab for myasthenia gravis:a systematic review and metaanalysis[J].J Neurol,2015,262:1115-1119.
[6]Jaretzki A 3rd,Barohn RJ,Ernstoff RM,Kaminski HJ,Keesey JC,Penn AS,Sanders DB.Myasthenia gravis:recommendations for clinical research standards.Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America[J].Neurology,2000,55:16-23.
[7]Liberati A,Altman DG,Tetzlaff J,Mulrow C,Gtzsche PC,Ioannidis JP,Clarke M,Devereaux PJ,Kleijnen J,Moher D.The prisma statement for reporting systematic reviews and metaanalyses of studies that evaluate health care interventions[J].Ann Intern Med,2009,151:65-94.
[8]Wells GA,Shea B,O'Connell D,Peterson J,Welch V.The Newcastle-Ottawa Scale(NOS)for assessing the quality of nonrandomized studies in meta-analysis[J].Appl Eng Agriculture,18:727-734.
[9]Higgins JP,Thompson SG,Deeks JJ,Altman DG.Measuring inconsisency in meta-analyses[J].BMJ,2003,327:557-560.
[10]Robeson KR,Kumar A,Keung B,DiCapua DB,Grodinsky E,Patwa HS,Stathopoulos PA,Goldstein JM,O'Connor KC,Nowak RJ.Durability of the rituximab response in acetylcholine receptor autoantibody-positive myasthenia gravis[J].JAMA Neurol,2017,74:60-66.
[11]Diaz-Manera J,Martinez-Hernandez E,Querol L,Klooster R,Rojas-Garcia R,Suarez-Calvet X,Munoz-Blanco JL,Mazia C.,Straasheijm KR,Gallardo E,Juarez C,Verschuuren JJ,Illa I.Long-lasting treatment effect of rituximab in MuSK myasthenia[J].Neurology,2012,78:189-193.
[12]Keung B,Robeson KR,DiCapua DB,Rosen JB,O'Connor KC,Goldstein JM,Nowak RJ.Long-term benefit of rituximab in MuSK autoantibody myasthenia gravis patients[J].J NeurolNeurosurg Psychiatry,2013,84:1407-1409.
[13]Afanasiev V,Demeret S,Bolgert F,Eymard B,Laforet P,Benveniste O.Resistant myasthenia gravis and rituximab:a monocentric retrospective study of 28 patients[J].Neuromuscul Disord,2017,27:251-258.
[14]Nowak RJ,Dicapua DB,Zebardast N,Goldstein JM.Response of patients with refractory myasthenia gravis to rituximab:a retrospective study[J].Ther Adv Neurol Disord,2011,4:259-266.
[15]Jing S,Song Y,Song J,Pang S,Quan C,Zhou L,Huang Y,Lu J,Xi J,Zhao C.Responsiveness to low-dose rituximab in refractory generalized myasthenia gravis[J].J Neuroimmunol,2017,311:14-21.
[16]Hehir MK,Hobson-Webb LD,Benatar M,Barnett C,Silvestri NJ,Howard JF Jr,Howard D,Visser A,Crum BA,Nowak R,Beekman R,Kumar A,Ruzhansky K,Chen IA,Pulley MT,LaBoy SM,Fellman MA,Greene SM,Pasnoor M,Burns TM.Rituximab in refractory myasthenia gravis:a prospective,openlabel study with long-term follow-up[J].Ann Clin Transl Neurol,2016,3:552-555.
[17]Hehir MK,Hobson-Webb LD,Benatar M,Barnett C,Silvestri NJ,Howard JF Jr,Howard D,Visser A,Crum BA,Nowak R,Beekman R,Kumar A,Ruzhansky K,Chen IA,Pulley MT,LaBoy SM,Fellman MA,Greene SM,Pasnoor M,Burns TM.Rituximab as treatment for anti-MuSK myasthenia gravis:multicenter blinded prospective review[J].Neurology,2017,89:1069-1077.
[18]Illa I,Diaz-Mainera J,Rojas-Garcia R,Pradas J,Rey A,Blesa R,Juarez C,Gallardo E.Sustained response to rituximab in antiAChR and anti-MuSK positive myasthenia gravis patients[J].J Neuroimmunol,2008,202:90-94.
[19]Maddison P,McConville J,Farrugia ME,Davies N,Rose M,Norwood F,Jungbluth H,Robb S,Hilton-Jones D.The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome[J].J Neurol Neurosurg Psychiatry,2011,82:671-673.
[20]Blum S,Gillis D,Brown H,Boyle R,Henderson R,HeyworthSmith D,Hogan P,Kubler P,Lander C,Limberg N,Pillans P,Prain K,Staples C,Walsh M,McCombe P,Wong R.Use and monitoring of low dose rituximab in myasthenia gravis[J].J Neurol Neurosurg Psychiatry,2011,82:659-663.
[2]Guptill JT,Sanders DB.Update on muscle-specific tyrosine kinase antibody positive my asthenia gravis[J].Curr Opin Neurol,2010,23:530-535.
[3]Li HF,Xie Y,Hong Y.Letter re:International consensus guidance for management of myasthenia gravis[J].Neurology,2017,88:505.
[4]Boye J,Elter T,Engert A.An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab[J].Ann Oncol,2003,14:520-535.
[5]Iorio R,Damato V,Alboini PE,Evoli A.Efficacy and safety of rituximab for myasthenia gravis:a systematic review and metaanalysis[J].J Neurol,2015,262:1115-1119.
[6]Jaretzki A 3rd,Barohn RJ,Ernstoff RM,Kaminski HJ,Keesey JC,Penn AS,Sanders DB.Myasthenia gravis:recommendations for clinical research standards.Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America[J].Neurology,2000,55:16-23.
[7]Liberati A,Altman DG,Tetzlaff J,Mulrow C,Gtzsche PC,Ioannidis JP,Clarke M,Devereaux PJ,Kleijnen J,Moher D.The prisma statement for reporting systematic reviews and metaanalyses of studies that evaluate health care interventions[J].Ann Intern Med,2009,151:65-94.
[8]Wells GA,Shea B,O'Connell D,Peterson J,Welch V.The Newcastle-Ottawa Scale(NOS)for assessing the quality of nonrandomized studies in meta-analysis[J].Appl Eng Agriculture,18:727-734.
[9]Higgins JP,Thompson SG,Deeks JJ,Altman DG.Measuring inconsisency in meta-analyses[J].BMJ,2003,327:557-560.
[10]Robeson KR,Kumar A,Keung B,DiCapua DB,Grodinsky E,Patwa HS,Stathopoulos PA,Goldstein JM,O'Connor KC,Nowak RJ.Durability of the rituximab response in acetylcholine receptor autoantibody-positive myasthenia gravis[J].JAMA Neurol,2017,74:60-66.
[11]Diaz-Manera J,Martinez-Hernandez E,Querol L,Klooster R,Rojas-Garcia R,Suarez-Calvet X,Munoz-Blanco JL,Mazia C.,Straasheijm KR,Gallardo E,Juarez C,Verschuuren JJ,Illa I.Long-lasting treatment effect of rituximab in MuSK myasthenia[J].Neurology,2012,78:189-193.
[12]Keung B,Robeson KR,DiCapua DB,Rosen JB,O'Connor KC,Goldstein JM,Nowak RJ.Long-term benefit of rituximab in MuSK autoantibody myasthenia gravis patients[J].J NeurolNeurosurg Psychiatry,2013,84:1407-1409.
[13]Afanasiev V,Demeret S,Bolgert F,Eymard B,Laforet P,Benveniste O.Resistant myasthenia gravis and rituximab:a monocentric retrospective study of 28 patients[J].Neuromuscul Disord,2017,27:251-258.
[14]Nowak RJ,Dicapua DB,Zebardast N,Goldstein JM.Response of patients with refractory myasthenia gravis to rituximab:a retrospective study[J].Ther Adv Neurol Disord,2011,4:259-266.
[15]Jing S,Song Y,Song J,Pang S,Quan C,Zhou L,Huang Y,Lu J,Xi J,Zhao C.Responsiveness to low-dose rituximab in refractory generalized myasthenia gravis[J].J Neuroimmunol,2017,311:14-21.
[16]Hehir MK,Hobson-Webb LD,Benatar M,Barnett C,Silvestri NJ,Howard JF Jr,Howard D,Visser A,Crum BA,Nowak R,Beekman R,Kumar A,Ruzhansky K,Chen IA,Pulley MT,LaBoy SM,Fellman MA,Greene SM,Pasnoor M,Burns TM.Rituximab in refractory myasthenia gravis:a prospective,openlabel study with long-term follow-up[J].Ann Clin Transl Neurol,2016,3:552-555.
[17]Hehir MK,Hobson-Webb LD,Benatar M,Barnett C,Silvestri NJ,Howard JF Jr,Howard D,Visser A,Crum BA,Nowak R,Beekman R,Kumar A,Ruzhansky K,Chen IA,Pulley MT,LaBoy SM,Fellman MA,Greene SM,Pasnoor M,Burns TM.Rituximab as treatment for anti-MuSK myasthenia gravis:multicenter blinded prospective review[J].Neurology,2017,89:1069-1077.
[18]Illa I,Diaz-Mainera J,Rojas-Garcia R,Pradas J,Rey A,Blesa R,Juarez C,Gallardo E.Sustained response to rituximab in antiAChR and anti-MuSK positive myasthenia gravis patients[J].J Neuroimmunol,2008,202:90-94.
[19]Maddison P,McConville J,Farrugia ME,Davies N,Rose M,Norwood F,Jungbluth H,Robb S,Hilton-Jones D.The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome[J].J Neurol Neurosurg Psychiatry,2011,82:671-673.
[20]Blum S,Gillis D,Brown H,Boyle R,Henderson R,HeyworthSmith D,Hogan P,Kubler P,Lander C,Limberg N,Pillans P,Prain K,Staples C,Walsh M,McCombe P,Wong R.Use and monitoring of low dose rituximab in myasthenia gravis[J].J Neurol Neurosurg Psychiatry,2011,82:659-663.