类风湿性关节炎英语.docx
- 文档编号:23936585
- 上传时间:2023-05-22
- 格式:DOCX
- 页数:15
- 大小:28.03KB
类风湿性关节炎英语.docx
《类风湿性关节炎英语.docx》由会员分享,可在线阅读,更多相关《类风湿性关节炎英语.docx(15页珍藏版)》请在冰豆网上搜索。
类风湿性关节炎英语
Chapter286 RHEUMATOIDARTHRITIS
FrankC.Arnett
Rheumatoidarthritis(RA)isachronicsystemicinflammatorydiseasepredominantlyaffectingdiarthrodialjointsandfrequentlyavarietyofotherorgans.TheAmericanCollegeofRheumatologyrevisedtheclassificationcriteriaforRAtoguaranteeuniformityininvestigativeandepidemiologicstudies(Table286-1).AlthoughthesesevenitemsincludethemostcharacteristicclinicalfeaturesofRA,avarietyofotherdisordersmaymimicthedisease(seeDifferentialDiagnosisandTable286-3).
RAoccursworldwideinallethnicgroups.Prevalenceratesrangefrom0.3to1.5%inmostpopulations,butfrequenciesof3.5to5.3%havebeenfoundinseveralNativeAmericantribes(Yakima,Chippewa,Inuit).Thepeakincidenceofonsetisbetweenthe4thand6thdecades,butRAmaybeginatanytimefromchildhood(seeJuvenileChronicArthritis)tolaterlife.Femalesaretwotothreetimesmorelikelytobeaffectedthanmales.
ETIOLOGY.
Despiteintensiveresearchovermanydecades,thecauseofRAremainsunknown.Threeareasofinterrelatedresearcharecurrentlymostpromising:
(1)hostgeneticfactors,
(2)immunoregulatoryabnormalitiesandautoimmunity,and(3)atriggeringorpersistingmicrobialinfection.
GeneticsusceptibilitytoRAhasbeenclearlydemonstrated.Thediseaseclustersinfamiliesandismoreconcordantinmonozygotic(30%)thandizygotic(5%)twins.Certainmajorhistocompatibilitycomplex(MHC)classIIalleles(andtheirencodedHLA,orhumanleukocyteantigens)occurwithincreasedfrequencyinaffectedindividuals.AmongwhitepeopleofwesternEuropeanorigin,HLA-DR4occursin60to70%ofseropositivepatientswithRAascomparedwith25to30%ofnormalindividuals.HLA-DR1isfoundinthemajorityofHLA-DR4-negativepatientsandismoststronglyassociatedwiththediseaseinseveralotherethnicgroups(Israelis,AsianIndians).SeveralsubtypesofHLA-DR4wereinitiallydefinedbymixedlymphocytecultureandmorerecentlyby DNA sequencing(Table286-2).OnlycertainHLA-DR4subtypespredisposetoRA(Dw4orDRB1*0401,Dw14orDRB1*0404,andDw15orDRB1*0405),whereasothersdonot(Dw10orDRB1*0402andDw13orDRB1*0403).HLA-DR4subtypesresultfromonlyafewaminoaciddifferencesinthe3rdhypervariableregionoftheHLA-DRbeta-chain.HLA-DR1sharesthissameaminoacidsequence,asdoseveralotherHLAallelesthathavemorerecentlybeenassociatedwithRAinsomepopulations(seeTable286-2).Thusa"sharedepitope"amongseveralMHCclassIImoleculesappearstopredisposetoRA.Moreover,homozygosityfortheaminoacidsequence,especiallyifcarriedonHLA-DR4molecules,hasbeenshowntocorrelatewithdiseaseseverity,includingmoredestructivejointdisease,subcutaneousnodules,andextra-articularmanifestations,especiallyrheumatoidlungdiseaseandFelty'ssyndrome.ThecrucialregionforthesharedepitopeonHLA-DRmoleculesappearstobeacombiningsitefortheT-cellantigenreceptor(TCR).BecauseMHCclassIImoleculespresentprocessedantigentotheTCRonhelper(CD4+)Tlymphocytes(seeChapter270)itappearslikelythatanabnormalantigen-specificcellularand/orhumoralimmuneresponseisinherenttothe
RAappearstobean"autoimmune"disease,similartootherMHCclassII-associateddisorders(see Chapter278) .AutoantibodiestotheFcportionofIgGmolecules,orrheumatoidfactorsarepresentinthebloodandsynovialtissuesof80%ofRApatients.Suchcasesaretermed"seropositive."HightitersofserumrheumatoidfactortypicallyoftheIgMisotype,areassociatedwithmoreseverejointdiseaseandwithextra-articularmanifestations,especiallysubcutaneousnodules.
DespitetheextremelystrongassociationofrheumatoidfactorswithRA,theyclearlydonotcausethedisease.Productionofrheumatoidfactorcommonlyoccursinotherdisorderscharacterizedbychronicantigenicstimulation,suchasbacterialendocarditis,tuberculosis,syphilis,kala-azar,viralinfections,intravenousdrugabuse,andcirrhosis.Normalindividualsoccassionallyproducerheumatoidfactor,especiallywithincreasingage.
AninfectiousoriginforRAhasbeenacontinuinghypothesis.Avarietyofbacterialandviralcandidateshavebeenproposedandlaterdiscardedbecauseoflackofdefinitiveevidence.Viralinfectionssuchasrubella, Ross River virus,andparvovirusB19havebeenshowntoproduceanacutepolyarthritis,butnoevidenceexiststhattheyinitiatechronicRA.Epstein-Barrvirus(EBV)remainsaviablebutunprovencandidateforapathogeneticrolebecauseseveralunusualimmuneresponsestoitarefoundinpatientswithRA.AnEBVproteinhasalsobeenshowntosharethesamefiveaminoacidsastheHLA-DR4(Dw14)andHLA-DR1molecules,whichareimplicatedinsusceptibilitytoRA,thusraisingthepossibilityof"molecularmimicry"asamechanism.Asimilarhomologywithan Escherichiacoli heatshockproteinhasalsobeenfound.
PATHOLOGYANDPATHOGENESIS.
ThepathologichallmarkofRAissynovialmembran
Theeventsinitiatingtheprocessareunknown (Fig.286-1) .Theearliestfindingsincludemicrovascularinjuryandproliferationofsynovialcells,accompaniedbyinterstitialedemaandperivascularinfiltrationbymononuclearcells,predominantlyTlymphocytes.Continuationoftheprocessleadstofurtherhyperplasiaofliningcells,bothDR-positivetypeA(macrophage-like)andDR-negativetypeB(fibroblast-like),andthenormallyacellularsubsynovialstromabecomesengorgedwithmononuclearinflammatorycells,whichmaycollectintoaggregatesorfollicles,especiallyaroundpost-capillaryvenules.Thecompositionofcellularinfiltratesvaries,withsomebeingpredominantlyTcells,usuallyCD4+(helper/inducer),andothershavingamixedpopulationoflymphocytes(oftenCD8+cytotoxicTcells),plasmacells,macrophages,andinterdigitating(dendritic)cells.Occasionally,germinalcentersrichinBlymphocytescanbeseen.Theproliferatingsynovium(pannus)becomesvillousandisvascularizedbyarterioles,capillaries,andvenules.
Rolesforboth cellular and humoral immunemechanismsintherheumatoidsynoviumaresupportedbymolecularandimmunopathologicfindings.Tlymphocytes,chieflyoftheTH 1type,appeartobeactivated,presumablybysomeunknownantigen(s)presentedbyDR-positivecells(typeAsynoviocytes,macrophages,dendriticcells,Blymphocytes).StudiesofTCRgeneexpressionsuggestrestrictedVbetausageandoligoclonality,butthisareaiscontroversial.Collectively,theseinteractingimmunecellsproduceavarietyofcytokinesthatpromotefurthersynovialproliferationandinflammation,aswellasboneandcartilagedestruction.
Important pro-inflammatorycytokines appeartobelinkedinacascade,withtumornecrosisfactoralpha(TNF-alpha)attheapexpromotingthesubsequentelaborationofinterleukin-1(IL-1),IL-6,IL-8,andgranulocyte-macrophagecolony-stimulatingfactor(GM-CSF).IL-1inducestheproductionofmetalloproteinases(collagenaseandstromelysin)andprostaglandinE2 bysynoviocytes.Thiscytokinealsopromotesthedegradationandinhibitsthesynthesisofproteoglycanbychondrocytes,aswellasenhancesresorptionofcalciumfrombone.Atthesame time,thereappearstobeanattemptbyunregulated anti-inflammatorycytokines, suchassolubleTNFreceptor,transforming-growthfactorbeta(TGF-beta),IL-10,andIL-1receptorantagonist,tocounterbalancethesedestructiveeffects.
Theultimatedestructionofcartilage,bone,tendons,andligamentsprobablyresultsfromacombinationofproteolyticenzymes,metalloproteinases,andsolublemediators.Collagenase,producedattheinterfaceofpannusandcartilage,isprobablylargelyresponsibleforthetypicalbonyerosions.
CLINICALFEATURES.
ThemodeofonsetofRAishighlyvariable.Inthemajorityofcases,jointpainand/orstiffnessdevelopsinsidiouslyoverseveralweekstomonths.Oneormoresmalljointsofthehands,wrists,shoulders,orkneesand/orthemetatarsophalangeal(MTP)jointsarefrequentlythe1stsymptomaticareas.Malaiseandfatigue,occasionallywithlow-gradefever,mayaccompanymusculoskeletaldiscomfort.Asthediseaseprogresses,jointswelling,tenderness,andaredorbluishdiscolorationbecomeapparent (Fig.286-2) .Thepatternofjointinvolvementistypicallypolyarticularandsymmetricalandinvolvestheproximalinterphalangeal(PIP),metacarpophalangeal(MCP),wrist,elbow,shoulder,knee,ankle,andMTPjoints.Thedistalinterphalangeal(DIP)jointsofthefingersareusuallyspared.Jointstiffness,especiallyiflastingmorethan1hourinthemorningandafterinactivity,isprominent.Socharacteristicisthissymptomthatthedurationofmorningstiffnessisoftenusedasaquantitativeguidetotheactivityoftheinflammatoryprocessinbothclinicalpracticeandresearchstudies.Overtimethepatientmayexperienceincreasingdifficultywithpainandstiffness,aswellasimpairedjointfunction.Thesimpleactivitiesofdailylivingmaybeseverelycompromised,andthe
abilitytocontinueaproductiveoccupationisthreatened.Sleephabitsbecomedisturbed,andthepatientmayexperiencedepressionandweightloss.
An"acute"onsetoccurringover1orseveraldaysisseeninabout20%ofpatients.Occasionally,anindividualretiresintheeveningwithnosymptomsandawakenswithacute,generalizedRA.Sucharapidonsetofpaininvolvingthejoints,surroundingsofttissue,andmusclecanmimicandmustbedifferentiatedfromacutemyositis,viralsyndromes,oriffocal,evensepticorcrystal-inducedarthritides.Rarepatientsexperiencerecurrent(palindromic)episodesofacutemonarthritis,oftensosevereastomimicgout,yetlastingonly24to48hours.Suchpatients,especiallyifseropo
- 配套讲稿:
如PPT文件的首页显示word图标,表示该PPT已包含配套word讲稿。双击word图标可打开word文档。
- 特殊限制:
部分文档作品中含有的国旗、国徽等图片,仅作为作品整体效果示例展示,禁止商用。设计者仅对作品中独创性部分享有著作权。
- 关 键 词:
- 类风湿性关节炎 英语