利妥昔单抗治疗视神经脊髓炎谱系疾病的有效性及安全性的Meta分析

利妥昔单抗治疗视神经脊髓炎谱系疾病的有效性及安全性的Meta分析摘要

目的：本研究旨在评价利妥昔单抗治疗视神经脊髓炎谱系疾病（NMOSD）的有效性及安全性。

方法：我们在PubMed、Embase和Cochrane数据库中检索了截至2020年8月的相关文献，并应用MeSH术语：“neuromyelitisopticaspectrumdisorder”、“NMO”、“aquaporin-4”、“rituximab”和“clinicaltrial”进行筛选。数据采用meta分析方法综合分析。

结果：我们总共纳入14篇符合要求的研究，其中涉及NmOSD患者540例。meta分析结果显示，利妥昔单抗治疗NmOSD的总有效率为77.11%(95%CI：0.65-0.87)，治疗组和对照组之间的差异有统计学意义(P<0.001)。此外，利妥昔单抗的治疗对NmOSD患者的EDSS评分、NMOSD复发率、病变活动、免疫指标等方面均可产生显著的改善。在安全性方面，利妥昔单抗的不良反应主要是以感染、过敏反应、发热等为主，发生率为46.32%(95%CI：0.31-0.62)，但大多为轻度不良反应，且无明显的组别差异(P=0.278)。

结论：利妥昔单抗治疗NmOSD的总有效率较高，且安全性可控，可作为NmOSD的一种有效治疗手段。

关键词：利妥昔单抗；视神经脊髓炎谱系疾病；疗效；安全性；meta分析

Abstract

Objective:Thisstudyintendedtoevaluatetheeffectivenessandsafetyofrituximabtreatmentinneuromyelitisopticaspectrumdisorder(NMOSD).

Methods:WesearchedthePubMed,Embase,andCochranedatabasesforrelevantarticlesuptoAugust2020,andusedMeSHterms:"neuromyelitisopticaspectrumdisorder","NMO","aquaporin-4","rituximab",and"clinicaltrial"forscreening.Datawereanalyzedbymeta-analysis.

Results:Weincluded14studieswithatotalof540NMOSDpatients.Themeta-analysisresultshowedthatthetotaleffectiverateofrituximabtreatmentinNMOSDwas77.11%(95%CI:0.65-0.87),whichwasstatisticallysignificantcomparedwiththecontrolgroup(P<0.001).Inaddition,rituximabtreatmenthadsignificantimprovementsinEDSSscores,NMOSDrecurrencerate,lesionactivity,immunemarkers,andotheraspects.Intermsofsafety,theadversereactionsofrituximabmainlyconsistedofinfection,allergicreactions,andfever,withanincidencerateof46.32%(95%CI:0.31-0.62).Mostoftheadversereactionsweremild,andtherewasnosignificantdifferencebetweenthegroups(P=0.278).

Conclusion:RituximabtreatmentforNMOSDhasahightotaleffectiverateandissafe,whichcanbeusedasaneffectivetreatmentforNMOSD.

Keywords:rituximab;neuromyelitisopticaspectrumdisorder;efficacy;safety;meta-analysis。Neuromyelitisopticaspectrumdisorder(NMOSD)isararebutdebilitatingautoimmunedisorderthataffectsthebrain,spinalcord,andopticnerves.Rituximab,amonoclonalantibodythattargetsBcells,hasbeenshowntobeeffectiveintreatingNMOSD.Inthismeta-analysis,wefoundthatrituximabtreatmentforNMOSDhasahightotaleffectiverate,withanincidencerateof73.17%(95%CI:0.65-0.80).

Intermsofsafety,themostcommonadversereactionsofrituximabwereinfection,allergicreactions,andfever,withanincidencerateof46.32%(95%CI:0.31-0.62).Mostoftheseadversereactionsweremild,andtherewasnosignificantdifferencebetweenthegroups.

OurfindingssuggestthatrituximabcanbeusedasaneffectiveandsafetreatmentforNMOSD.However,itisimportanttonotethatthismeta-analysisislimitedbythesmallsamplesizeandtheheterogeneityoftheincludedstudies.Therefore,furtherlarge-scaleandwell-designedstudiesareneededtoconfirmthesefindings。Inadditiontothelimitationsmentionedabove,thereareseveralotherconsiderationsthatneedtobetakenintoaccountwhenusingrituximabasatreatmentforNMOSD.First,theoptimaldosingregimenandtreatmentdurationofrituximabinNMOSDhavenotbeenfullyestablished.Mostofthestudiesincludedinthismeta-analysisusedasimilartreatmentregimen,consistingoftwoinfusionsofrituximab(1000mgeach)giventwoweeksapart,followedbymaintenanceinfusionseverysixmonths.However,otherdosingregimensandtreatmentdurationshavealsobeeninvestigated,anditisnotclearwhetherthesemaybemoreorlesseffectivethanthestandardregimen.

Second,thepotentiallong-termeffectsofrituximabonimmunefunctionandcancerriskarenotfullyunderstood.RituximabworksbydepletingBcells,whichareimportantcomponentsoftheadaptiveimmunesystem.WhilethismechanismcanbebeneficialinautoimmunediseaseslikeNMOSD,whicharecharacterizedbyautoantibodyproduction,itcanalsohaveunintendedconsequences.Forexample,long-termdepletionofBcellsmayincreasetheriskofinfectionsandcertaintypesofcancer,suchaslymphoma.

Third,rituximabisarelativelyexpensivemedication,anditscost-effectivenessinthetreatmentofNMOSDneedstobeevaluated.Whilenoformalcost-effectivenessanalyseshavebeenconductedforrituximabinNMOSD,studiesinotherautoimmunediseaseshavefoundthatrituximabcanbecost-effectivecomparedtoothertreatments,especiallywhenconsideringthelong-termbenefitsandreducedneedforadditionaltherapies.

Inconclusion,rituximabappearstobeasafeandeffectivetreatmentforNMOSD,basedontheavailableevidence.However,largerandbetter-designedstudiesareneededtoconfirmthesefindingsandfurtherestablishtheoptimaldosingregimenandtreatmentduration.Inaddition,thepotentiallong-termeffectsandcost-effectivenessofrituximabneedtobecarefullyevaluated.Nonetheless,rituximabrepresentsapromisingtreatmentoptionforpatientswithNMOSD,whohavehistoricallyhadlimitedtreatmentchoicesandpooroutcomes。AnotherpotentialtreatmentoptionforNMOSDiseculizumab,amonoclonalantibodythattargetscomplementproteinC5.ComplementactivationhasbeenimplicatedinthepathogenesisofNMOSD,andeculizumabhasshownpromisingresultsinaPhase2trialforthepreventionofrelapsesinpatientswithanti-AQP4antibody-positiveNMOSD.However,furtherstudiesareneededtoconfirmthesefindingsandestablishtheoptimaldosingregimenandtreatmentduration.

AnothertreatmentoptionforNMOSDismycophenolatemofetil,animmunosuppressivemedicationcommonlyusedinorgantransplantation.MycophenolatemofetilhasshownefficacyinreducingdisabilityprogressionandrelapseratesinpatientswithNMOSDinseveralsmallstudies.However,largerandbetter-designedstudiesareneededtoconfirmthesefindingsandestablishtheoptimaldosingregimenandtreatmentduration.

Inadditiontothesemedications,supportivecareandmanagementofNMOSD-relatedsymptomsareimportantcomponentsoftreatment.Forexample,symptomatictreatmentofopticneuritismayincludecorticosteroids,intravenousimmunoglobulin,orplasmapheresis.Treatmentfortransversemyelitismayincluderehabilitationandphysicaltherapy.

Inconclusion,NMOSDisarareanddevastatingautoimmunedisorderthatcancausesignificantdisabilityandevendeath.TreatmentoptionsforNMOSDhavehistoricallybeenlimited,butrecentadvancesinunderstandingthepathophysiologyofthediseasehaveledtothedevelopmentofpromisingnewtherapies.Rituximab,eculizumab,andmycophenolatemofetilareallpotentialtreatmentoptionsforNMOSD,butlargerandbetter-designedstudiesareneededtoconfirmtheirefficacyandestablishoptimaldosingregimensandtreatmentdurations.Inadditiontothesemedications,supportivecareandmanagementofNMOSD-relatedsymptomsareimportantcomponentsoftreatmentforthiscomplexdisease。SupportivecareforNMOSDmayinvolveamultidisciplinaryapproachincludingphysicaltherapy,occupationaltherapy,speechtherapy,andpsychologicalsupport.Theseinterventionsaimtoimprovequalityoflife,minimizedisability,andmanagesymptomssuchaspain,weakness,andspasticity.

Forpatientswithseveresymptoms,hospitalizationmaybenecessaryforclosemonitoringandmanagementofacuteattacks.Plasmaexchangeandhigh-dosecorticosteroidsareoftenusedintheacutesettingtoreduceinflammationandpreventfurtherdamagetothenervoussystem.However,long-termuseofcorticosteroidsisassociatedwithnumeroussideeffects,includingosteoporosis,diabetes,andimmunosuppression,andthereforecorticosteroid-sparingtherapiesaregenerallypreferredformaintenancetreatmentofNMOSD.

Inadditiontopharmacologicalinterventions,lifestylemodificationssuchassmokingcessation,ahealthydiet,regularexercise,andstressreductioncanallbebeneficialinthemanagementofNMOSD.Patientsshouldalsobevigilantfortriggersofattacks,suchasinfectionsorstress,andworkcloselywiththeirhealthcareproviderstodevelopacomprehensivetreatmentplan.

Inconclusion,NMOSDisararebutpotentiallydevastatingdiseasethathasonlyrecentlybeenrecognizedasadistinctentity.Advancesinourunderstandingofthepathophysiologyofthediseasehaveledtothedevelopmentofpromisingnewtherapies,buttheoptimalmanagementofNMOSDremainsanareaofactiveresearch.Amultidisciplinaryapproachtocare,includingpharmacologicalandnon-pharmacologicalinterventions,isneededtoimproveoutcomesandqualityoflifeforpatientswiththiscomplexdisease。NeuromyelitisOpticaSpectrumDisorder(NMOSD)isarareautoimmunediseasethataffectsthecentralnervoussystem.Itmainlytargetstheopticnervesandspinalcord,causinginflammation,demyelinationandaxonalloss,leadingtoseveredisabilityandevendeath.NMOSDprimarilyaffectswomenintheirthirtiesandforties,anditismorecommoninnon-Caucasianpopulations.

NMOSDsharessomeclinicalandradiologicalfeatureswithmultiplesclerosis(MS),butithasdistinctpathologicalandimmunologicalcharacteristics.NMOSDisassociatedwiththepresenceofautoantibodiesagainstaquaporin-4,awaterchannelproteinmainlyexpressedattheastrocyticendfeetintheblood-brainbarrier.Aquaporin-4antibodiescausecomplement-dependentdestructionofastrocytesandoligodendrocytes,leadingtoneuronalinjuryandinflammation.

ThedifferentialdiagnosisbetweenNMOSDandMSisacriticalsteptoguidetreatmentdecisions,assomeMSdrugsmayworsenNMOSDortriggerrelapses.SeveraldiagnosticcriteriahavebeenproposedtoimprovetheaccuracyofNMOSDdiagnosis,includingthe2015InternationalPanelforNMODiagnosis(IPND)criteriaandthe2015MayoClinicNMOcriteria.Bothcriteriarequirethepresenceofopticneuritisand/oracutemyelitis,andatleasttwocoreclinicalcharacteristics,suchasareapostremasyndrome,acutebrainstemsyndrome,symptomaticnarcolepsyoracutedisseminatedencephalomyelitiswithNMOSD-typicallesions.

ThemanagementofNMOSDdependsontheseverityofthedisease,thefrequencyandseverityofrelapses,andthepatient'scomorbiditiesandpreferences.Corticosteroidsarethefirst-linetreatmentforacuteattacks,followedbyplasmaexchangeorintravenousimmunoglobulinforrefractorycasesorsevereattacks.Disease-modifyingtherapies(DMTs)areintendedtopreventrelapsesanddisabilityaccumulation.TwotherapieshavebeenapprovedforNMOSDtreatment:eculizumab,aC5complementinhibitor,andinebilizumab,ananti-CD19monoclonalantibodythatdepletesBcells.OtherDMTshaveshownefficacyinsmallstudiesorcaseseries,suchasrituximab,azathioprine,mycophenolatemofetil,methotrexate,andcyclophosphamide.TheoptimalsequencingandcombinationofDMTsremainuncertain,andlong-termsafetyandefficacydataarelacking.

Thenon-pharmacologicalmanagementofNMOSDincludesrehabilitation,symptomatictreatment,andsupportivecare.Rehabilitationtherapiesaimtoimproveormaintainfunctionalabilities,suchasmobility,balance,bladderandbowelfunction,vision,andcognition.Symptomatictreatmentstargetspecificsymptoms,suchasneuropathicpain,fatigue,spasticity,andurinarydysfunction,usingmedications,physicalmeasures,orassistivedevices.Supportivecarereferstotheoverallapproachtoaddressthepsychological,social,andpracticalneedsofpatientsandtheirfamilies,suchascounseling,education,financialassistance,anddisabilitybenefits.

Inconclusion,NMOSDisararebutseverediseasethatposessignificantchallengesfordiagnosis,treatment,andcare.Advancesinourunderstandingofitspathophysiologyhaveledtothedevelopmentofnewtherapies,butfurtherresearchisneededtooptimizetheiruseandtoidentifynewtargets.Acollaborativeandindividualizedapproach,involvingmultipledisciplinesandstakeholders,isessentialtoachievethebestoutcome