类风湿性关节炎英语.docx

类风湿性关节炎英语.docx

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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