内科学教学课件：Systemic Lupus Erythematosus

SystemicLupusErythematosus

SystemicLupuserythematosus(SLE)isasyndromeofunknownaetiologymostcommonlyaffectingyoungwomen.Virtuallyanyorganofthebodymaybeinvolved.Typicallythecourseofthediseaseisaseriesofremissionsandexacerbations.Withgoodmanagement,thetenyearssurvivalmaybeover90%.INTRODUCTIONEtiologyandPathogenesisofSLE1.GeneticfactorManystudieshavedescribedfamilialaggregationofSLE.5-13%oflupushaveatleastonefirstorseconddegreerelativewithlupusItwasfounda24-58%concordanceinmonozygotictwins.2-5%concordanceindizygotictwinsorsiblings..Theriskofachilddevelopinglupusbornfromamother(orfather)withlupusiscalculatedtobe3-4%atworst.

WhatarethereasonsofGeneticsusceptibility?ItseemslikelythatmostofthegenespredisposingtoSLEarenormal.Anindividualinheritsanunluckycombinationofnormalgeneticpolymorphisms,eachofwhichpermitalittleimmuneoverreponse,orpresentationofhighquantitiesoftargetantigensincertaintissues.ThecombinationofwhichisjustenoughtopermitSLEtoevolveaftersomeenvironmentalstimulus.C2,C4,C1qdeficiencies,DR2,DR3,1q41-42region,Fc-rRIIA,IL10andBclpolymorphisms.2.EnvironmentalfactorsUVlight,especiallyUVB,flaresSLEinmostpatients.ItisunclearwhetherexposuretoUVlightcaninitiatethelupus,butonsetafterasunburnisnotunusual.ThereisgoodevidencethatexposureofskintoUVlightaltersthelocationandchemistryofDNAaswellastheavailabilityofRoandRNPantigens.Drug-inducedlupus.Drugs(hydralazine,procainamide,beta-blokers,isoniazid,penicillamine)caninducelupus.Drug-inducelupusmayresembleSLEbothclinicallyandserologically.Usuallythediseaseismild,andrenalandneurologicalcomplicationsarerare.Generally,lupusthatiscausedbyadrugexposuregoesawayoncethedrugisstopped.Allergy.Doesitinducelupusflare?Nodirectevidence.Infection.TherehasbeencontinuinginterestinthepossibilitythatinfectiousagentsmightinitiateorflareSLE.MechanismmightincludemolecularmimicrybetweenexternalAgandaself-Ag,epitopespreading,nonspecificactivationofTorBcells.TherehasbeenrecentinterestinEB,CMVandothervirus.3.SexhormonesFemale:Male=9:1Thesexdifferenceismostprominentduringthefemalereproductiveyears.Inmice,castratingfemalesand/orprovidingandrogensorantiestrogensprotectsfromdisease,whereascastratingmalesandprovidingestrogensacceleratesandworsensSLE.Themetabolishofsexhormoneisabnormalinsomelupuspatients.Menandwomenwithlupusmetabolizedtestosteronemorerapidlythannormal,andestrogenicmetabolitesofestradialpersistlongerinwomen.Neuroendocrinesystem.Hyperprolactinemia,abnormalitiesinhypothalamicand/orpituitaryfunction.4.AbnormalimmunesystemSustainedpresenceofautoantigens:increasedapoptosis,impairedclearanceofapoptosisHyperactivityinBandTlymphocyte.IncreasedexpressionofsurfacemoleculesparticipatingincellactivationinbothB-andT-cell.OverproductionofIL-6andIL-10Defectiveregulatorymechanism.AutoantibodiestoDNA,RNA,andahostofothercellnucleusantigens.Circulatingimmunecomplexesarefrequentlyobservedandthesemaydepositinthekidney,skin,brain,lung,andothertissues.Itcausesinflammationandtissuedamagebyanumberofmechanism,notablyfixationandactivationofthecomplementsystem.OverviewofthepathogenesisofSLE

SkincellTcellTcellBcellAPCAPCDefectiveICclearanceUVlightInfectionExternalAgSelfAgAbICTargetGeneticsusceptibilityClinicalmanifestationsofSLETheclinicalspectrumofSLEisverybroadItmakeSLEbothfascinatingbutpotentiallydifficulttodiagnoseandmanage.Generalsymptoms

Themostcommonsymptomslistedasinitialcomplaintsarefatigue,fever,andweightloss.

Fever:feversecondarytoactivediseasewasrecordedfrom50%to86%.Nofevercurveorpatternischaracteristic.Fatigue

iscommoninpatientswithSLE,especiallyduringperiodsofdiseaseactivity.Itisalsooftentheonlysymptomthatremainsaftertreatmentofacuteflares.Lowgradefever,anemia,oranysourceofinflammationcanresultinfatigue.Raynaud’sphenomenon

iscommonlyfoundinlupus.Itlackspecificity.(atriphasicreactionofdistaldigitstocoldoremotion,inwhichtheskincolourchangesfromwhitetobluetored)DermatologicalinvolvementUpto85%ofSLEButterflyrashMaculopapulareruptionDiscoidlupusRelapsingnodularnon-suppurativepanniculitisVasculiticskinlesinLivedoreticularisPurpuriclesionsAlopeciaOralulcerMalarrash:Thisisa"butterfly-shaped"redrashoverthecheeksbelowtheeyesandacrossthebridgeofthenose.Itmaybeaflatoraraisedrash.

Therashesaremadeworsebysunexposure.MaculopapulareruptionDiscoidlupus

Thesearered,raisedpatcheswithscalingoftheoverlyingskin.VasculiticskinlesinAlopecia

Oralulcer:Painlesssoresinthenoseormouthneedtobeobservedanddocumentedbyadoctor.MusculoskeletalsystemThearthritisoflupusisusuallyfoundonbothsidesofthebodyanddoesnotcausedeformityofthejoints.Swellingandtendernessmustbepresent.Themostfrequentlyinvolvedjointsarethoseofthehand,knees,andwrists.Peoplewithlupuscansufferfromacertaintypeoflowbloodflowinjurytoajointcausingdeathoftheboneinthejoint.Themuscleinvolvementwasreportedin30-50%oflupuspatientsAvacularnecrosisofbone.

ItmaybecausedbyprednisonetherapyKidneysystemHaematuriaProteinure

(>0.5gprotein/dor3+)Cast

NervoussystemThebrain,nerveproblemsandpsychiatricsyndromesarecommoninlupusaffectinguptotwo-thirdsofpeople.Potentialdisordersincludeseizures,nerveparalysis,severedepression,andevenpsychosis.Spinalcordinvolvementinlupusisrareandoccursprimarilywhenthereisclotformationinacriticalvesselthatsuppliesbloodtothespinalcord.Hematologicalabnormalities

Redbloodcellsanormochromic,normocyticanemiaisfrequentlyfoundinSLE.Theyappearstoberelatedtochronicinflammation,drug-relatedhaemorrhage.haemolyticanemiaasdetectedbytheCoombs’testisthefeatureofSLE.onrareoccasion,aserumantibodymaybeproducedwhichimpairsredcellproduction.Platelets.thrombocytopenia(<100*109/L)appearstobemediatedbyanti-plateletantibodiesor/andanti-phospholipidantibodies.Whitebloodcell

leucopenia(<4.0*109/L),itscauseisprobablyacombinationofdestructionofwhitecellsbyautoantibodies,decreasedmarrowproduction,increasedormarginalsplenicpooling,andcomplementactivation.PulmonarymanifestationsPleurisy

itisthemostcommonmanifestationofpulmonaryinvolvementofSLE.Thevolumeofpleuraleffusionsusuallyissmalltomoderateandmaybeunilateralorbilateral.Largepleuraleffusionareuncommon.Itusuallyexudativeincharacter.

PleuraleffusionsmayalsooccurinSLEpatientswithnephroticsyndrome,infection,cardiacfailure.Lung1)acutelupuspneumonitis:fever,dyspnea,coughwithscantysputum,hemoptysis,tachypneaandpleuriticchestpain.2)pulmonaryhemorrhage3)chronicdiffuseinterstitiallungdisease.

thediagnosisshouldnotbemadeuntilinfectiousprocessessuchasviralpneumonia,tuberculosis,andotherbacterial,fungalandpneumocystiscariniiinfectionhavebeencompletelyexcluded.CardiovascularmanifestationsPericarditisisthemostcommoncardiacmanifestationofSLE.Myocarditis(theclinicalfeaturesoflupusmyocarditisresemblesthatofviralmyocarditis)Libman-SacksendocarditisandvalvulardiseaseHypertension,cardiacfailure

PericarditisSLEcanbeassociatedwithendocarditis.ShownhereisLibman-Sacksendocarditisinwhichtherearemanyflat,reddish-tanvegetationsspreadingoverthemitralvalveandchordae.GastrointestinalandhepaticmanifestationEsophagitis,dysphagia,nausea,vomiting:(drugrelatedinmostcases)Chronicintestinalpseudo-obstruction,mesentericvasculitis,protein-losingenteropathyPancreatitisLupushepatitis

EyesTheeyesarerarelyinvolvedinlupusexceptfortheretina.PeoplewithlupusoftenhavetobescreenedbyanophthalmologistiftheyaretakingtheantimalarialdrugschloroquineorhydroxychloroquineSecondarysjogren’ssyndromeDryeyesDrymouth

exocrineglandswereinfiltratedwithlymphocytesSecondaryAntiphospholipidsyndromeAntiphospholipidsyndrome(APS)ischaracterizedbyrecurrentarterialand/orvenousthrombosis,fetallossandthrombocytopenia.HightiterofAntiphospholipidantibodycanbefoundinAPSpatients.Laboratoryinvestigation

AutoantibodiesinSLEAntibodiestocellnucleuscomponentANA,anti-dsDNA,antibodiestoextracellularnuclearantigen(ENA,anti-Sm,anti-RNP,anti-Jo1)Antibodiestocytoplasmicantigensanti-SSA,anti-SSBCell-specificautoantibodieslymphocytotoxicantibodies,anti-neuroneantibodies,anti-erythrocyteantibodies,anti-plateletantibodiesAntibodiestoserumcomponentsantiphospholipidantibodyanticoagulantsantiglobulin(rheumatoidfactor)

Anti-nuclearantibodiesThelupuserythematosus(LE)

cellithasbeensupersededbytheANAandanti-dsDNAtechniques.ANAisascreeningtestanti-Sm,anti-dsDNAantibodiesarelupusspecificantoantibodies.ThishomogenouspatternofdiffusebrightgreenstainingofnucleiseenbyimmunofluorescencemicroscopywithaHep2cellsubstrateiscalledhomogenous,andisthemostcommonpatternwithautoimmunediseasesoverall.Thisrim(peripheral)patternoflinearbrightgreenstainingaroundtheperipheralofnucleiseenbyimmunofluorescencemicroscopywithaHep2cellsubstrate.dsDNANucleolarpatternSpeckledpatternScl70,SSA,SSB,SmTheselittleCrithidiaorganismshaveasmallkinetoplastbetweenthenucleusandtheflagellawhichglowsbrightgreenunderimmunofluorescencemicroscopy,andisindicativeofanti-nativeDNAantibodythatisveryspecificforSLE.Immu-blottingmethodtodetectanti-Sm,RNP,SSA,SSB,Jo1,Scl70andribosomalP.LupusbandtestImmunofluorescenceofskinwithantibodytoIgGdemonstratesaband-likedepositionofimmunecomplexesthatisbrightgreenatthedermalepidermaljunctioninthisskinbiopsytakenfromanareawithavisiblerash.WithSLEsuchdepositioncanbefoundinskinuninvolvedbyarash,whereaswithDLEtheimmunecomplexesarefoundonlyininvolvedskin.Vasculitis

Vasculitisinarteriesthroughoutthebodycanaccountforsignsandsymptomsfromavarietyoforganinvolvements.Seenhereisanarterywithextensivevasculitiswithchronicinflammatorycells.SLEisassociatedwithapeculiarperiarteriolarfibrosisinthespleen,asshownhere.

KidneybiopsyWHOclassificationoflupusnephritisisbasedonlight,immunofluorescence,andelectronmicroscopicfindings.WHOclassificationoflupusnephritis

immunofluorence

electronmicroscopyPattern

mesangialperipheralmesangialsubendothelialsubepithelialⅠnormal00000ⅡAmesangialdeposit+0+00ⅡBmesangialhypercellularity+0+00ⅢfocalsegmentalGN+++++++ⅣdiffuseGN+++++++++ⅤmembranousGN+++++++SemiquantitativeassessmentofactivityandchronicityActiveindicatorscellularproliferation,necrosis,karyorrhexis,cellularcrescents,wireloops,hyalinethrombi,leukocyticinfiltration,interstitialinfiltration.Chronicityindicatorsglomerularsclerosis,fibrouscrescents,interstitialfibrosis,tubularatrophyIndicatorsarescoredonascaleof0to3,withnecrosis,karyorrhexis,andcellularcrescentsweightedtwotimes.Themaximumofactivityis24,andthemaximumofchronicityis12.

DiagnosisCriteriafordiagnosinglupusThediagnosisoflupusisaclinicalonemadebyobservingsymptoms.Labtestsprovideonlyapartofthepicture.TheAmericanCollegeofRheumatologyhasdesignated11criteriafordiagnosis.Toreceivethediagnosisoflupus,apersonmusthave4ormoreofthesecriteria:1.Malarrash:Fixederythemaovermalarareas,sparingnasolabialfolds2.Discoidrash:Erythematousraisedpatcheswithkeratoticscalingandfollicularplugging3.Photosensitivity:Skinrashafterexposuretosunlight,historyorphysicalexam4.Oralulcers:Oralornasopharyngeal,painless,byphysicalexam5.Arthritis:Tenderness,swelling,effusionin2ormoreperipheraljoints6.Serositis:A)pleuritisorB)pericarditis7.RenaldisorderA)proteinuria>0.5g/24houror3+orB)cellularcasts8.Neurologicaldisorder:A)seizuresorB)psychiatricdisorder(havingexcludedothercauses,e.g.drigs)9.Haematologicaldisorder:A)haemolyticanaemiaorB)leucopeniaorC)thrombocytopenia10.Immunologicdisorder:A)positiveLEcellsorB)raisedanti-nativeDNAantibdybindingorC)anti-SmantibodyorD)falsepositiveserologicaltestforsyphilis.11.Positiveantinuclearantibody:CriteriaoftheARAfortheclassificationofSLEManagementandtreatment1.MonitoringthelupuspatientsItcannotbeemphasizedtoostronglythatlupusisadiseaserequiringregularandcarefulfollow-up.ImportantinitialadviceshouldbegivenaboutavoidingUVlight,infections,extremestressorfatigueLaboratorytest—bloodtest,ESR,C3,IC,liverfunctiontestsandanti-dsDNA.2.GradingclinicalactivityThehighlyvariablenatureofthesyndromeEvaluationoflupusactivityisthebaseorbeginningoftherapy.Non-life-threateningfeaturessuchasarthralgia,skinrash,RP,alopeciaSeverecomplicationsuchasrenal,cerebralandheartinvolvement.SLEdiseaseactivityindex(SLEDAI)Clinicalfeature

scoreseizure,psychosis,organbrainsyndrome8visualdisturbance,cranialnervedisorder8lupusheadache,cerebrovascularaccidents,8vasculitis8arthritis4myositis4urinarycasts,hematuria,proteinure,pyuria4rash,alopecia,mucosalulcers,2pleurisy,pericarditis2lowcomplement,increasedDNAbinding2fever1thrombocytopenia,leucopenia13.ClinicaltherapyTherearefourmaingroupsdrugsusefulinthetreatmentoflupus:thenon-steroidanti-inflammatorydrugs,anti-malarials,corticosteroidandcytotoxicdrugs.Howtotreatlupusisakindofart.Whichandthedosageofdrugswillbeusedtotreatthepatientdependonlupusactivity.MildlyactivelupusItcanbemanagedwithcombinationofNSAIDand/oranti-malarials.Prednisoloneremainthedrugsoffirstchoicetocontrollupusactivity.Lowdosage<=10mg/dcanbeusedUseofcorticosteriodtotreatvariouslupusmanifestationClinicalfeatureinitialdoseofprenisoloneArthritis(poorlyrespondingtoNSAIDs)