系统性红斑狼疮——英语.docx

系统性红斑狼疮——英语.docx

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Chapter289 SYSTEMICLUPUSERYTHEMATOSUS

PeterH.Schur

Systemiclupuserythematosus（SLE）isadiseaseofunknowncausethatmayproducevariablecombinationsoffever,rash,hairloss,arthritis,pleuritis,pericarditis,nephritis,anemia,leukopenia,thrombocytopenia,andcentralnervoussystem（CNS）disease.Theclinicalcourseischaracterizedbyperiodsofremissionsandacuteorchronicrelapses.Characteristicimmuneabnormalities,especiallyantibodiestoanumberofnuclearandothercellularantigens,developinpatientswithSLE.Thediagnosisisfacilitatedbydeterminingwhetherthepatienthas4ofthe11clinicaland/orlaboratorycriteriadevelopedfortheclassificationofSLE（Table289-1）.

EPIDEMIOLOGY.

SLEcanoccuratanyagebuthasitsonsetprimarilybetweenages16and55.Itoccursmorefrequentlyinwomen.Inchildren,thefemale-maleratiois1.4to5.8:

1;inadults,itrangesfrom8:

1to13:

1;andinolderindividuals,theratiois2:

1.TheprevalenceofSLEisestimatedtobebetween4and250casesper100,000population.IntheUnitedStates,thehighestincidenceisamongAsiansinHawaii,blacks,andcertainNativeAmericans（Sioux,Crow,Arapahoe）.TheriskofSLEdevelopinginablackAmericanfemalehasbeenestimatedtobe1:

250.Theprevalenceisaboutthesameworldwide;thediseaseappearstobecommoninChina,inSoutheastAsia,andamongblacksintheCaribbean,butisseeninfrequentlyinblacksinAfrica.LimitedobservationssuggestthattheincidenceofdiscoidlupuserythematosusisthesameasthatforSLE.

ETIOLOGY.

ThecauseofSLEremainsunknown,althoughmanyobservationssuggestaroleforgenetic,hormonal,immune,andenvironmentalfactors.TheevidenceforageneticroleissummarizedinTable289-2.SomeofthesegeneticmarkerassociationsarefoundmorefrequentlyinSLEpatientsofdifferentracesandethnicities.IthasbeencalculatedthatatleastfourgenesareinvolvedinpredisposingindividualstoSLE.Eachgenepresumablyaffectssomeaspectofimmuneregulation,proteindegradation,peptidetransportacrosscellmembranes,immuneresponse,complement,thereticuloendothelialsystem（includingphagocytosis）,immunoglobulins,apoptosis,andsexhormones.Thuscombinationsofdissimilargenedefectsmayresultindistinctabnormalresponsesandproduceseparatepathologicprocessesanddifferentclinicalexpression.

TheevidenceforhormonalabnormalitiesisbasedprimarilyontheobservationthatSLEismuchmorecommonamongwomenintheirchildbearingyears.Inaddition,SLEhasbeenobservedinsomemaleswithKlinefelter'ssyndrome,andsomeabnormalitiesofestrogenmetabolismhavebeennotedinbothmenandwomenwithSLE.However,theclinicalexpressionofSLEisthesameinmenandwomen.Furthermore,alupus-likediseaseofNewZealandmiceismorecommonandmoresevereandhasanearlieronsetinfemales--andisamelioratedbyoophorectomyortreatmentwithmalehormones.However,inotherstrainsofmicewithalupus-likedisease,thisgenderdifferenceisnotnoted.

NumerousimmuneabnormalitiesoccurinpatientswithSLE,theetiologyofwhichremainsunclear;nordoweknowwhichareprimaryandwhicharesecondary.Someoftheseimmunedefectsareepisodic,andsomecorrelatewithdiseaseactivity.SLEisprimarily

PATHOGENESIS.

Manymanifestationsaremediatedbyantibodies.Theclassicexampleisthatofdiffuseproliferativeglomerulonephritis.Immunecomplexes,whichconsistofnuclearantigens（especially DNA）andhigh-affinitycomplement-fixingIgG（especiallyIgG1andIgG3）andANAs（especiallyantibodiestoDNA）,forminthecirculationandaredepositedintheglomerularbasementmembrane（GBM）orforminsitu;histonemayfacilitateimmunecomplexdeposition.Thecomplementsystemisthenactivatedandchemotacticfactorsaregenerated.Thesefactorsinducetheattractionandinfiltrationofleukocytes,whichthenphagocytoseimmunecomplexesandcausethereleaseofmediators（suchasactivatorsoftheclottingsystem）,whichfurtherperpetuatetheglomerularinflammation.Withcontinuingimmunecomplexdeposition,chronicinflammationmayensue,ultimatelyleadingtofibrinoidnecrosisandscarring（crescents）andlossofrenalfunction.Inlupusmembranousglomerulonephritis,similarmechanismsoccur,althoughimmunecomplex-containing,poorlycomplement-fixingIgG2andIgG4formprimarilyinsituontheGBM;thereisnocellularinfiltrate.ThemechanismfortheGBMproteinleakage,whichresultsinthenephroticsyndrome,isnotclear.Inlupusmesangialglomerulonephritis,mesangialcells（macrophage-like

PATHOLOGY.

Fewuniquepathologicfeaturesareassociatedwith SLE.Inpatientswitharthritis,thesynovialhistopathologytendstobenon-specific,withsuperficialfibrin-likematerialandlocalordiffusecellliningproliferation.Vascularchangesincludeperivascularmononuclearcells,lumenobliteration,enlargedendothelialcells,andthrombi,butfibrinoidnecrosisisuncommon.Biopsiesofthemalarerythemamayrevealsomeminorbasallayerabnormalities,aswellasimmunecomplexdepositsatthedermal-epidermaljunction.Discoidskinlesionsarecharacterizedbyhyperkeratosis,follicularplugging,andmorebasalcelllayerchanges,includingimmunecomplexesatthedermal-epidermaljunction.Pleuraandpericardiumareinfiltratedbymononuclearcells.Lupuspneumonitisischaracterizedbyalveolarwallinjury,hemorrhage,andedema;hyalinemembraneformation;andimmunecomplexdeposits.Coronaryarteriesoftendemonstratepremature-onsetatherosclerosis.Libman-Sacksendocarditisischaracterizedbytheaccumulationofimmunecomplexes,mononuclearcells,hematoxylinbodies,andfibrinandplateletthrombi.Pathologicexaminationofthespleenoftenrevealsan"onionskin"appearanceofthesplenicarteries,whichisthoughttorepresenthealedarteritis.

RENALDISEASE.

Minimaldisease（typeIIAmesangialdisease）ofglomerulihasimmunecomplexdepositsonlyinmesangialcells.TypeIIbmesangialnephritisalsohasmesangialhypercellularity.Focalproliferativenephritis（typeIII）hassegmentalproliferationinglomerulartuftsandinthemesangiumandimmunecomplexdepositsinthemesangiumandscatteredgranulardepositsinthesubendothelial,subepithelial,andintrabasementGBM.Activediffuseproliferativeglomerulonephritis（typeIV）affectsmorethan50%ofglomeruliwithcellularproliferation,necrosis,"wireloops,"subendothelialdeposits,andhematoxylinbodies.Whenchronic,theprocessinvolvessclerosis,adhesions,crescents,and（tubular）atrophy.Extensive"lumpyandbumpy"depositsofimmunecomplexesarepresent.Inmembranousnephritis（typeV）diffuse,uniformthickeningoftheGBMisseen,withafinegranulardepositionofimmunecomplexesinthesubendothelialregionbeneathfusedfootprocesses.Tubulardegenerativechangeswithinterstitialmononuclearcellsarenotuncommon.Extensivecrescentformation,representingscarring,indicatesapoorprognosis.

Thebrainisnotableforthepaucityofpathologicchanges.Someminorbloodvesselabnormalities,anoccasionalmicroinfarct,andsomeperivascularinfiltrationhavebeennoted.

CLINICALMANIFESTATIONS.

SLEishighlyvariableinonsetaswellascourse.Theinitialsymptomsmaybenon-specific（Table289-4）andincludemyalgia,nausea,vomiting,headaches,depression,easybruising,ormorespecificsymptomsoranycombinationthereof.Thesesymptomsmaybemildorsevere,fleetingorpersistent.

GENERALSYMPTOMS.

FatigueoccursinvirtuallyallpatientswithSLE.FatiguemayparalleltheonsetofSLEoritsrelapsebutshouldbedistinguishedfromthefatigueassociatedwithotherfactorssuchasincreasedworkload,sleepdisturbance,depression,unhealthfulhabits,stress,deconditioning,anemia,theuseofcertain

medications（includingprednisone）,andanyintercurrentdisease.Feverisseenin80%ofpatients;itisusuallyepisodic.Infections,whichoccurcommonlyinSLEpatients,mustalwaysbeconsidered.

MUSCULOSKELETALMANIFESTATIONS.

Arthralgiaandarthritishavebeennotedin95%ofpatientswithSLE.Symptomstendtobeasymmetricalandmigratory,withcomplaintsinaparticularjointoftengonein1to3days.Fingers,hands,wrists,knees,andlessfrequently,ankles,elbows,shoulders,andhipsareaffected.Morningstiffnessisgenerallymeasuredinminutes,incontrasttohoursinrheumatoidarthritis.Althoughjointdeformitiesareconsideredtobemoreafeatureofrheumatoidarthritis,damagetoperiarticula

PULMONARYMANIFESTATIONS.

Pulmonaryinvolvementoccursinmostpatientsandismanifestedaspleurisy,coughing,dyspnea,abnormalpulmonaryfunctiontests,orchestradiographicabnormalities.Pleurisyoccursinover50%ofpatients;themostcommoncauseischestwallpainonlocalpressureand/ormovement.Pleuritis（inflammationofthepleura）alsocausespleurisy.Itisdiagnosedbythepresenceofapleuralfrictionruband/ortheradiographicpresenceofapleuraleffusion.Effusionstypicallyhavelowcomplementandproteinlevels,fewWBCs（thepleurahasmononuclearcells）,glucoselevelsapproximatingplasmalevels（bycontrast,theyarelowinrheumatoidarthritis）,andLEcells.Coughusuallyrepresentsaninfection,butpulmonaryedemasecondarytocardiacorrenalfailureorfluidoverloadinapatientreceivingcorticosteroidsshouldbeconsidered.

Acutelupuspneumonitisoccursin5to12%andischaracterizedbyfever,cough（evenhemoptysis）,pleurisy,anddyspnea.Radiographyshowsdiffuseacinarinfiltrates,especiallyinthelowerlobes.Subsequently,interstitialinfiltratesandfibrosismaydevelop,withpulmonaryfunctionabnormalities.Theprognosisispoor.

Pulmonaryhypertensionmaycomplicate SLE butismorefrequentwithsclerodermao