肿瘤坏死因子的产生和有自身免疫性疾病住院抗感染治疗的危险性的关系.docx
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肿瘤坏死因子的产生和有自身免疫性疾病住院抗感染治疗的危险性的关系.docx
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肿瘤坏死因子的产生和有自身免疫性疾病住院抗感染治疗的危险性的关系
InitiationofTumorNecrosisFactor-αAntagonistsandtheRiskofHospitalizationforInfectioninPatientsWithAutoimmuneDiseases
OriginalContribution
ONLINEFIRST
JAMA.2011;306(21):
2331-2339.PublishedonlineNovember6,2011.doi:
10.1001/jama.2011.1692
CarlosG.Grijalva,MD,MPH;
LangChen,PhD;
ElizabethDelzell,ScD;
JohnW.Baddley,MD,MSPH;
TimothyBeukelman,MD,MSCE;
KevinL.Winthrop,MD,MPH;
MarieR.Griffin,MD,MPH;
LisaJ.Herrinton,PhD;
LiyanLiu,MD,MSc;
RitaOuellet-Hellstrom,PhD,MPH;
NiveditaM.Patkar,MD,MSPH;
DanielH.Solomon,MD,MPH;
JamesD.Lewis,MD,MSCE;
FenglongXie,MS;
KennethG.Saag,MD,MSc;
JeffreyR.Curtis,MD,MS,MPH
[+]AuthorAffiliations
AuthorAffiliations:
DepartmentofPreventiveMedicine,VanderbiltUniversity,Nashville,Tennessee(DrsGrijalvaandGriffin);UniversityofAlabamaatBirmingham(DrsChen,Delzell,Baddley,Beukelman,Patkar,Saag,andCurtisandMsXie);BirminghamVAMedicalCenter(DrsBaddley);OregonHealth&ScienceUniversity,Portland(DrWinthrop);KaiserPermanenteNorthernCalifornia,Oakland(DrsHerrintonandLiu);FoodandDrugAdministration,SilverSpring,Maryland(DrOuellet-Hellstrom);BrighamandWomen'sHospitalandHarvardUniversity,Boston,Massachusetts(DrSolomon);andCenterforClinicalEpidemiologyandBiostatistics,DepartmentsofMedicineandBiostatisticsandEpidemiology,UniversityofPennsylvania,Philadelphia(DrLewis).
CorrespondingAuthor:
CarlosG.Grijalva,MD,MPH,DivisionofPharmacoepidemiology,DepartmentofPreventiveMedicine,VanderbiltUniversitySchoolofMedicine,150021stAveS,Ste2600,TheVillageatVanderbilt,Nashville,TN37212(carlos.grijalva@vanderbilt.edu)
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Abstract
ContextAlthoughtumornecrosisfactor(TNF)-αantagonistsareincreasinglyusedinplaceofnonbiologiccomparatormedications,theirsafetyprofileremainsincomplete.
ObjectivesTodeterminewhetherinitiationofTNF-αantagonistscomparedwithnonbiologiccomparatorsisassociatedwithanincreasedriskofseriousinfectionsrequiringhospitalization.
Design,Setting,andPatientsWithinaUSmulti-institutionalcollaboration,weassembledretrospectivecohorts(1998-2007)ofpatientswithrheumatoidarthritis(RA),inflammatoryboweldisease(IBD),andpsoriasis,psoriaticarthritis,orankylosingspondylitis(psoriasisandspondyloarthropathies)combiningdatafromKaiserPermanenteNorthernCalifornia,NewJerseyandPennsylvaniaPharmaceuticalAssistanceprograms,TennesseeMedicaid,andnationalMedicaid/Medicare.TNF-αantagonistsandnonbiologicregimenswerecomparedindisease-specificpropensityscore(PS)–matchedcohortsusingCoxregressionmodelswithnonbiologicsasthereference.Baselineglucocorticoidusewasevaluatedasaseparatecovariate.
MainOutcomeMeasureInfectionsrequiringhospitalization(seriousinfections)duringthefirst12monthsafterinitiationofTNF-αantagonistsornonbiologicregimens.
ResultsStudycohortsincluded10 484RA,2323IBD,and3215psoriasisandspondyloarthropathiesmatchedpairsusingTNF-αantagonistsandcomparatormedications.Overall,weidentified1172seriousinfections,mostofwhich(53%)werepneumoniaandskinandsofttissueinfections.AmongpatientswithRA,seriousinfectionhospitalizationrateswere8.16(TNF-αantagonists)and7.78(comparatorregimens)per100person-years(adjustedhazardratio[aHR],1.05[95%CI,0.91-1.21]).AmongpatientswithIBD,rateswere10.91(TNF-αantagonists)and9.60(comparator)per100person-years(aHR,1.10[95%CI,0.83-1.46]).Amongpatientswithpsoriasisandspondyloarthropathies,rateswere5.41(TNF-αantagonists)and5.37(comparator)per100person-years(aHR,1.05[95%CI,0.76-1.45]).AmongpatientswithRA,infliximabwasassociatedwithasignificantincreaseinseriousinfectionscomparedwithetanercept(aHR,1.26[95%CI,1.07-1.47])andadalimumab(aHR,1.23[95%CI,1.02-1.48]).Baselineglucocorticoidusewasassociatedwithadose-dependentincreaseininfections.
ConclusionAmongpatientswithautoimmunediseases,comparedwithtreatmentwithnonbiologicregimens,initiationofTNF-αantagonistswasnotassociatedwithanincreasedriskofhospitalizationsforseriousinfections.
KEYWORDS:
ARTHRITIS,RHEUMATOID,
AUTOIMMUNEDISEASES,
COMMUNICABLEDISEASES,
DRUGREACTION,ADVERSE,
GLUCOCORTICOIDS,
HOSPITALIZATION,
INFLAMMATORYBOWELDISEASES,
INFLIXIMAB,
PATIENTSAFETY,
PSORIASIS,
RISKASSESSMENT,
SPONDYLITIS,ANKYLOSING,
TUMORNECROSISFACTORANTAGONISTS,
TUMORNECROSISFACTOR-ALPHA.
Althoughtheintroductionoftumornecrosisfactor(TNF)-αantagonistsrevolutionizedthetreatmentofautoimmunediseases,concernsaboutthesafetyofthesebiologicdrugsremain.1,2SeveralstudiesreportedseriousinfectionsinusersofTNF-αantagonists.1,2,3However,whethertheriskofseriousinfectionswithTNF-αantagonistsisgreaterthanthatwithcomparatornonbiologicmedicationsisunclear.
AvailableinformationfromrandomizedclinicaltrialsofTNF-αantagonistsislimitedbecauseofinsufficientpowertoassesssafetyoutcomesconclusively.4Moreover,theselectedpopulationsparticipatinginthetrialswarrantcautioninextrapolatingresultstothebroaderpopulationofpatientswhoreceivetheseagents.4Furthermore,manyefficacytrialsofbiologicswereplacebocontrolled,whichlimitsinferenceaboutalternativetreatmentoptionsforautoimmunediseases.1,2,4,5,6,7
Althoughobservationalstudieshavetriedtofillthisknowledgegap,severalpublishedreportshadimportantlimitations.2,3,8,9,10,11,12,13SomestudiesaggregatedTNF-αantagonistsintoasinglecategory,precludingtheassessmentofindividualmedications.Similarly,seriousinfectionswereaggregated,buttheeffectofTNF-αantagonistsonspecificinfections,suchaspneumonia,remainsunknown.Furthermore,methodologicaldifferencesmayhavecontributedtodissimilarandsometimesconflictingresults.Largerstudies,addressingspecificmethodologicalconcerns,14,15areneededtoquantifytheriskofseriousinfectionsinusersofspecificTNF-αantagonists.
AspartofalargeUSfederallyfundedmulti-institutionalinitiative,theSafetyAssessmentofBiologicTherapy(SABER)project,16weevaluatedwhetherinitiationofTNF-αantagonistswasassociatedwithanincreasedriskofseriousinfectionsamongpatientswithautoimmunediseases,andwhetherriskvariedbyspecificTNF-αantagonist.
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METHODS
Thisretrospectivecohortstudycombineddatafrom4largeUSautomateddatabases.16ExposuretoTNF-αantagonistsandothermedicationswasdeterminedusingpharmacyandproceduresdata,andseriousinfectionsresultinginhospitalizationwereidentifiedusingdischargediagnosesandvalidateddefinitions.Theincidenceofseriousinfectionsbetweendisease-specificpropensityscore(PS)–matchedexposuregroupswascomparedusingCoxproportionalhazardregressionmodels.Plannedsensitivityandsubgroupanalysesevaluatedtherobustnessofthemainfindingsandkeystudyassumptions.
CohortAssembly
Studydatabasesincludedthefollowing:
nationalUSMedicaidandMedicaredatabases,excludingTennessee(MedicaidAnalyticeXtract,2000-2005;Medicare,2000-2006;andMedicarePartD,2006);TennesseeMedicaid(TennCare,1998-2005);NewJersey'sPharmaceuticalAssistancetotheAgedandDisabledandPennsylvania'sPharmaceuticalAssistanceContractfortheElderly(PAAD/PACE,1998-2006);andKaiserPermanenteNorthernCalifornia(KPNC,1998-2007).Weusedthesedataandacommonprogrammingalgorithmtoassembleretrospectivecohortsofpatientswithautoimmunediseaseswhowereinitiatingselectedmedications.
Foreachdatabase,weidentifiedpatientswithstudy-definedautoimmunediseases,usingtheearliestInternationalClassificationofDiseases,NinthRevision(ICD-9)–codedhealthcareencounter,whosubsequentlyfilledaprescriptionorreceivedaninfusionforaTNF-αantagonistorcomparatormedication(see“Exposures”formedicationdetails).16,17,18Werequiredabaselineperiodof365dayswithcontinuousenrollmentintherespectivedatabaseprecedingthefirstinfusionorprescriptionfilltoascertainotherselectioncriteriaandstudycovariates.Usingbaselineinformation,patientswerecategorizedinto3mutuallyexclusivegroups:
rheumatoidarthritis(RA);inflammatoryboweldisease(IBD);andpsoriasis,psoriaticarthritis,orankylosingspondylitis(herein,psoriasisandspondyloarthropathiesgroup).Patientswithdiagnosesformorethan1autoimmunediseasewereexcluded(Figure1).
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Figure1.AssemblyofRetrospectiveCohortsofPatientsWithAutoimmuneDiseases,SABER(1998-2007)
Anepisodereferstotheobservationtimefrominitiationofuseofastudyregimenthroughtheendoffollow-up.NationalMedicare/MedicaiddatadonotincludeTennessee.TennCareistheMedicaidprograminTennessee;PAAD/PACEindicatesNewJersey'sPharmaceuticalAssistancetotheAgedandDisabledandPennsylvania'sPharmaceuticalAssistanceContractfortheElderly;andKPNC,KaiserPermanenteNorthernCalifornia.SABERindicatesSafetyAssessmentofBiologicTherapy;TNF,tumornecrosisfactor.Eligiblepatientshadadiagnosisofautoimmunedisease,usedstudymedications,andhad365daysofavailablebaselinedata.
Amongpotentialcohortmembers,weidentifiednewusersofstudymedications,19definedbyafilledprescriptionforastudymedicationafter365baselinedayswithoutprescriptionsfilledforthespecificstudymedicationorothersinthesamegroup.This“first”fillingdate(t0)markedth
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- 肿瘤 坏死 因子 产生 自身免疫 性疾病 住院 感染 治疗 危险性 关系