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www.uptodate.com2015UpToDate

Diagnosisanddifferentialdiagnosisofsystemiclupuserythematosusinadults
Author
DanielJWallace,MD

SectionEditor
DavidSPisetsky,MD,PhD

DeputyEditor
MonicaRamirezCurtis,MD,MPH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Jul01,2014.
INTRODUCTIONSystemiclupuserythematosus(SLE)isachronicinflammatorydiseaseofunknowncause
thatcanaffectvirtuallyanyorganofthebody.Immunologicabnormalities,especiallytheproductionofanumberof
antinuclearantibodies(ANA),areaprominentfeatureofthedisease.
Patientspresentwithvariableclinicalfeaturesrangingfrommildjointandskininvolvementtolifethreateningrenal,
hematologic,orcentralnervoussysteminvolvement.TheclinicalheterogeneityofSLEandthelackof
pathognomonicfeaturesortestsposeadiagnosticchallengefortheclinician.Tocomplicatematters,patientsmay
presentwithonlyafewclinicalfeaturesofSLE,whichcanresembleotherautoimmune,infectious,orhematologic
diseases.
ThediagnosisofSLEisgenerallybasedonclinicaljudgment,afterexcludingalternativediagnoses.Inthe
absenceofSLEdiagnosticcriteria,SLEclassificationcriteriaareoftenusedbycliniciansasguidancetohelp
identifysomeofthesalientclinicalfeatureswhenmakingthediagnosis.Serologicalfindingsareimportantto
suggestingthepossibilityofSLE,withsomeantibodies(eg,antidoublestrandedDNA[dsDNA]andantiSmith
[Sm])highlyassociatedwiththiscondition.
TheapproachtothediagnosisanddifferentialdiagnosisofSLEwillbereviewedhere.Anoverviewofthe
symptomsandsignsthatcanoccurinSLE,discussionsofparticularsitesofinvolvement(eg,skin,kidneys,
centralnervoussystem),andthetreatmentandprognosisofSLEarepresentedseparately.(See"Overviewofthe
clinicalmanifestationsofsystemiclupuserythematosusinadults"and"Overviewofthemanagementand
prognosisofsystemiclupuserythematosusinadults".)
EVALUATIONFORSUSPECTEDSLETheinitialdiagnosisofsystemiclupuserythematosus(SLE)depends
onthemannerofpresentationandtheexclusionofalternativediagnoses.Giventheheterogeneityofclinical
presentations,therearesomepatientsforwhomtheconstellationofpresentingclinicalfeaturesandsupportive
laboratorystudiesmakethediagnosisofSLErelativelystraightforward.Bycontrast,thereareotherswhopresent
withisolatedcomplaintsorinfrequentdiseasecharacteristicsandrepresentmoreofadiagnosticchallenge.
DemographicsshouldalsobetakenintoaccountwhenevaluatingapatientforSLE,sinceitoccursprimarilyin
youngwomenofchildbearingage.Inaddition,SLEoccursmorecommonlyincertainracialandethnicgroups.
(See"Epidemiologyandpathogenesisofsystemiclupuserythematosus",sectionon'Epidemiology'.)
Asanexample,thediagnosisofSLEismorelikelyinayoungwomanwhopresentswithcomplaintsoffatigue,
arthralgia,andpleuriticchestpainandwhoisfoundtohavehypertension,amalarrash,apleuralfrictionrub,
severaltenderandswollenjoints,andmildperipheraledema.Laboratorytestingmayrevealleukopenia,anemia,
anelevatedserumcreatinine,hypoalbuminemia,proteinuria,anactiveurinarysediment,hypocomplementemia,
andpositivetestsforantinuclearantibodies(ANA),includingthosetodoublestrandedDNA(dsDNA)andthe
Smith(Sm)antigen.Bycontrast,anotherpatientmaypresentwithleukopeniaorsingleorganinvolvement(eg,
nephritisorpericarditis).SuchpatientsmaysubsequentlydevelopthecharacteristicmultisystemfeaturesofSLE
overaperiodofmonthsoryears.(See"Overviewoftheclinicalmanifestationsofsystemiclupuserythematosus
inadults".)
Thus,theinitialevaluationrequiresacarefulhistoryandphysicalexam,alongwithselectedlaboratorytestingto
identifyfeaturesthatarecharacteristicofSLEorthatsuggestanalternativediagnosis.Patientspresentingwith
symptomsforashorterdurationoftimewillneedclosefollowup,asthefrequencywithwhichvariousfeaturesof

SLEobserveddifferaccordingtostageofdisease[15].
ClinicalmanifestationsGiventhebroadrangeofclinicalmanifestationsofSLE,itishelpfultoconsiderthe
variousfeaturesaccordingtofrequencyatdiseaseonset(table1).Ourgeneralapproachtothehistoryand
physicalexaminationforpatientswithsuspectedSLEisdescribedbelow.
Weperformathoroughmedicalhistory,withparticularattentiontothefollowingsymptomsandsigns:

Constitutionalsymptomssuchasfever,fatigue,lymphadenopathy,orweightloss
Photosensitiveskinlesionssuchasamalarrash
Painlessoralornasalulcers
Hairlossthatispatchyorfrontal/peripheral
Raynaudphenomenon
Jointpainorswellingwhichcanbemigratoryorsymmetrical
Dyspneaorpleuriticchestpainsuggestiveofserositis
Chestpainsuggestiveofpericarditis
Lowerextremityedema
Neurologicsymptomssuchasseizuresorpsychosis
Recurrentmiscarriages(see"Pregnancyinwomenwithsystemiclupuserythematosus")

Wealsoaskaboutexposuretomedicationsassociatedwithdruginducedlupus(eg,hydralazineandothers)(see
"Druginducedlupus").Acompletephysicalexaminationisindicated,sinceanyorgansystemcanbeinvolvedin
SLE.
Pertinentphysicalexaminationfindingsincludethefollowing:

Skinlesionsconsistentwithamalarrashordiscoidlesions
Scarringornonscarringpatchyalopecia
Oralornasopharyngealulcers
Polyarticulararthritiswhichisoftensymmetric
Subluxationatthemetacarpalphalangeal(MCP)jointsandrheumatoidlikeswanneckdeformitiesinthe
handsmaybeobserved,whichareusuallynotreducible
Decreasedorabnormalbreathsoundsmayindicateapleuraleffusion,pneumonitis,orinterstitiallung
disease
Lowerextremityedemaandhypertensionmaybeduetorenalinvolvement
DetaileddiscussionsofthevariousphysicalfindingsassociatedwithSLEarediscussedindetailseparately.(See
"Mucocutaneousmanifestationsofsystemiclupuserythematosus"and"Musculoskeletalmanifestationsof
systemiclupuserythematosus"and"Pulmonarymanifestationsofsystemiclupuserythematosusinadults"and
"Diagnosisandclassificationofrenaldiseaseinsystemiclupuserythematosus"and"Neurologicmanifestationsof
systemiclupuserythematosus"and"Neuropsychiatricmanifestationsofsystemiclupuserythematosus"and
"Noncoronarycardiacmanifestationsofsystemiclupuserythematosusinadults"and"Coronaryheartdiseasein
systemiclupuserythematosus".)
LaboratorytestingWeobtainthefollowingroutinelaboratorytests,whichmayprovidediagnosticallyuseful
information:
Completebloodcountanddifferentialmayrevealleukopenia,mildanemia,and/orthrombocytopenia
Elevatedserumcreatininemaybesuggestiveofrenaldysfunction
Urinalysiswithurinesedimentmayrevealhematuria,pyuria,proteinuria,and/orcellularcasts
Inadditiontotheroutinelaboratoriesdescribedabove,weperformthefollowinglaboratorytestswhichsupportthe
diagnosisofSLEifabnormal:

ANA
Antiphospholipidantibodies(lupusanticoagulant[LA],IgGandIgManticardiolipin[aCL]antibodiesandIgG
andIgMantibeta2glycoprotein[GP]I)
C3andC4orCH50complementlevels
Erythrocytesedimentationrate(ESR)and/orCreactiveprotein(CRP)levels
Urineproteintocreatinineratio
TheANAtestispositiveinvirtuallyallpatientswithSLEatsometimeinthecourseoftheirdisease(see
"Measurementandclinicalsignificanceofantinuclearantibodies").IftheANAispositive,oneshouldtestforother
specificantibodiessuchasdsDNA,antiSm,Ro/SSA,La/SSB,andU1ribonucleoprotein(RNP).Insomelabs,a
positiveANAtestbyindirectimmunofluorescencewillautomaticallyresultintestingforsuchadditionalantinuclear
antibodiesthatareoftenpresentinpatientsSLE.
AntidsDNAandantiSmantibodiesarehighlyspecificforSLE,butantiSmantibodieslacksensitivity[6,7].
AntidsDNAandantiSmantibodiesareseeninapproximately70and30percentofpatientswithSLE,
respectively.(See"Antibodiestodoublestranded(ds)DNA,Sm,andU1RNP".)
AntiRo/SSAandantiLa/SSBantibodiesarepresentinapproximately30and20percentofpatientswith
SLE,respectivelyhowever,bothantibodiesaremorecommonlyassociatedwithSjgrenssyndrome[6].
(See"TheantiRo/SSAandantiLa/SSBantigenantibodysystems".)
AntiU1RNPantibodiesareobservedinapproximately25percentofpatientswithSLE,buttheyalsooccur
inpatientswithotherconditionsandhighlevelsarealmostalwayspresentinpatientswithmixedconnective
tissuedisease(MCTD)[6,7].(See"Antibodiestodoublestranded(ds)DNA,Sm,andU1RNP".)
AntiribosomalPproteinantibodieshaveahighspecificityforSLE,buthavelowsensitivityforSLE.They
alsolackspecificityforinvolvementofaparticularorgansystemordiseasemanifestation.(See
"AntiribosomalPproteinantibodies",sectionon'ClinicalutilityofantiribosomalPantibodies'.)
IftheANAtestisnegative,buttheclinicalsuspicionofSLEishigh,thenadditionalantibodytestingmaystillbe
appropriate.Thisispartlyrelatedtothedifferencesinthesensitivityandspecificityamongthemethodsusedto
detectANA.Thesolidphaseassaysaremoresensitivethanindirectimmunofluorescenceandmaybemorelikely
todetecttheantibodies.AmoredetaileddiscussiononthetechniquesusedtodetectANAispresented
separately.(See"Measurementandclinicalsignificanceofantinuclearantibodies".)
Weperformthefollowinglaboratorytestsinselectedpatients:
Rheumatoidfactor(RF)andanticycliccitrullinatedpeptide(CCP)antibodiesInpatientswithpredominant
arthralgiasorarthritis,RFandantiCCPantibodiesmayhelpexcludeadiagnosisofrheumatoidarthritis
(RA).RFhaslessdiagnosticutilitysince20to30percentofpeoplewithSLEhaveapositiveRF.AntiCCP
antibodies,however,haveamuchhigherspecificityforRAandmaybemoreusefulfordistinguishingthe
arthritisassociatedwithRA.(See"Clinicallyusefulbiologicmarkersinthediagnosisandassessmentof
outcomeinrheumatoidarthritis",sectionon'Rheumatoidfactors'and"Clinicallyusefulbiologicmarkersin
thediagnosisandassessmentofoutcomeinrheumatoidarthritis",sectionon'Anticitrullinatedpeptide
antibodies'.)
SerologicalstudiesforinfectionInpatientswithabriefhistory(forexample,lessthansixweeks)of
predominantarthralgiasorarthritis,weperformserologictestingforhumanparvovirusB19.Wealsoperform
serologictestingforhepatitisBvirus(HBV)andhepatitisCvirus(HCV)inpatientswithmultisystemic
clinicalfindings.InareasendemicforLymedisease,wemayconsiderserologicstudiesforBorreliaaswell.
TestingforEpsteinBarrvirus(EBV)infectionmayalsobeindicatedintheappropriateclinicalsetting.(See
"Diagnosisanddifferentialdiagnosisofrheumatoidarthritis",sectionon'Viralpolyarthritis'and"Specific
virusesthatcausearthritis"and"DiagnosisofLymedisease",sectionon'Indicationsforserologictesting'.)

Creatinekinase(CK)AnelevatedCKmayreflectmyositis,whichisrelativelyuncommoninpatientswith
SLE.MyositismayalsosuggestanalternativediagnosissuchasMCTD,polymyositis(PM),or
dermatomyositis(DM).
ImagingDiagnosticimagingmaybevaluable,butisnotroutinelyobtainedunlessindicatedbythepresenceof
symptoms,clinicalfindings,orlaboratoryabnormalities.Examplesinclude:
Plainradiographsofswollenjoints.UnlikeaffectedjointsinRA,erosionsareobservedinfrequentlyinSLE
[8].Dependingonthestageofdisease,deformitiesmaybepresentonradiograph.
Renalultrasonographytoassesskidneysizeandtoruleouturinarytractobstructionwhenthereisevidence
ofrenalimpairment
Chestradiography(eg,forsuspectedpleuraleffusion,interstitiallungdisease,cardiomegaly).
Echocardiography(eg,forsuspectedpericardialinvolvement,toassessforasourceofemboli,or
noninvasiveestimationofpulmonaryarterypressureandforevaluationofsuspectedvalvularlesions,such
asverrucae).
Computedtomography(CT)(eg,forabdominalpain,suspectedpancreatitis,interstitiallungdisease).
Magneticresonanceimaging(MRI)(eg,forfocalneurologicdeficitsorcognitivedysfunction).
BiopsyBiopsyofaninvolvedorgan(eg,skinorkidney)isnecessaryinsomecases.Typicalhistologicfindings
invariousorgansinSLEarediscussedintopicreviewsdevotedtotheparticularsitesofinvolvement.(See
"Diagnosisandclassificationofrenaldiseaseinsystemiclupuserythematosus"and"Mucocutaneous
manifestationsofsystemiclupuserythematosus".)
AdditionalstudiesinselectedpatientsOtherteststhatmaybenecessaryaretypicallydictatedbythe
clinicalpresentationandassociateddifferentialdiagnosticpossibilities.Examplesinclude:
Electrocardiographyintheassessmentofchestpainthatmaybeduetopericarditisortomyocardial
ischemia
Teststoassessforpulmonaryembolisminapatientwithpleuriticchestpainanddyspnea
Diffusingcapacityforcarbonmonoxide(DLCO)toassessforsuspectedpulmonaryhemorrhageandto
estimatetheseverityofinterstitiallungdisease
CLASSIFICATIONCRITERIAClassificationcriteriahavebeendevelopedforsystemiclupuserythematosus
(SLE)asameansofcategorizingpatientsforstudypurposes.Thesecriteriacanbeusefulforcliniciansin
systematicallydocumentingkeydiseasefeatures,buttheirimperfectsensitivityandspecificitylimitstheirusefor
diagnosticpurposes.
In2012,theSystemicLupusInternationalCollaboratingClinics(SLICC)proposedrevisedclassificationcriteria
thatweredevelopedtoaddressinherentweaknessesofthe1997AmericanCollegeofRheumatology(ACR)
classificationcriteria[9].Asanexample,oneofthemajorlimitationsofthe1997ACRcriteriaisthatpatientswith
biopsyconfirmedlupusnephritiscouldstillfailtofulfillcriteria.OtherconcernsregardingtheACRcriteriaincluded
thepossibleduplicationofhighlycorrelatedcutaneousfeatures(suchasmalarrashandphotosensitivity),thelack
ofinclusionofothercutaneousmanifestations(suchasmaculopapularorpolycyclicrash),andtheomissionof
manyneurologicmanifestationsofSLE(suchasmyelitis).TheACRcriteriaalsodidnotincluderelevant
immunologicinformationsuchaslowserumlevelsofcomplementcomponents.
2012SLICCcriteriaAconsensusgroupofexpertsonSLE,theSLICC,hasproposedrevisedcriteriaforSLE
(table2)[9].ClassificationashavingSLEbytheSLICCcriteriarequireseitherthatapatientsatisfyatleast4of
17criteria,includingatleast1ofthe11clinicalcriteriaandoneofthesiximmunologiccriteria,orthatthepatient
hasbiopsyprovennephritiscompatiblewithSLEinthepresenceofantinuclearantibodies(ANA)orantidouble
strandedDNA(dsDNA)antibodies.

TheSLICCcriteriawerevalidatedbyanalysisof690patientswithSLEorotherrheumaticdiseases.Inthisinitial
validationtesting,theSLICCrevisedcriteriahadgreatersensitivitybutlowerspecificitythanthe1997ACR
classificationcriteria(sensitivityof97versus83percentandspecificityof84versus96percent,respectively).
However,despitetheimprovedsensitivitycomparedwiththeACRcriteria,theSLICCcriteriamightdelaythe
diagnosisofSLEinasignificantnumberofpatients,andsomepatientsmightnotbeclassifiedatall.These
situationsweredemonstratedinastudyinwhichpatientsweregroupedaccordingtowhethertheSLICCcriteria
weremetbefore,atthesametimeas,oraftertheACRcriteria,andthegroupswerethencompared.Outof622
patients,319(50percent)wereclassifiedatthesametimeusingeithercriteriaset,78(12percent)earlierand225
(35percent)later(mean4.4years)withtheSLICCcriteriathanwiththeACRcriteria[10].Amongthepatients
diagnosedlaterwiththeSLICCcriteria,inthemajorityofcasesthedelaywasduetothecombinationofmalar
rashandphotosensitivityintotheacutecutaneousSLEcriterion.
1997ACRcriteriaPreviously,mostcliniciansreliedforthediagnosisoflupusupontheclassificationcriteria
thatweredevelopedbytheAmericanRheumatismAssociation(ARA,nowtheACR)(table3)[1113].Thecriteria
wereestablishedbyclusteranalyses,primarilyinacademiccentersandprimarilyinCaucasianpatients.
ThepatientisclassifiedwithSLEusingtheACRcriteriaiffourormoreofthemanifestationsarepresent,either
seriallyorsimultaneously,duringanyintervalofobservations[11,12].ApositiveLEcelltest,usedinoldercriteria,
wasreplacedbythepresenceofantiphospholipidantibodies[11].Whentestedagainstotherrheumaticdiseases,
thesecriteriahaveasensitivityandspecificityofapproximately96percent.
DIAGNOSISThediagnosisofsystemiclupuserythematosus(SLE)isbaseduponthejudgmentofan
experiencedclinicianwhorecognizescharacteristicconstellationsofsymptomsandsignsinthesettingof
supportiveserologicstudies,afterexcludingalternativediagnoses.Thisisoftenchallengingduetothegreat
variabilityintheexpressionandseverityofSLE.Althoughtheclassificationcriteriaweredesignedforresearch
purposes,manycliniciansrefertoaspectsofthesecriteriawhenmakingthediagnosisofSLE.(See
'Classificationcriteria'above.)
Intheabsenceofexistingdiagnosticcriteria,wedescribeourgeneralapproachtothediagnosisthattakesinto
considerationthestrengthsofbothclassificationsystemsdescribedabove.However,ourgeneralguidelinesdo
notadequatelyaddressthemyriadmanifestationsorsubtletiesofsomeclinicalfeatures,nordotheysubstitutefor
clinicaljudgment.Thus,itisoftenappropriatetoreferpatientinwhomthediagnosisofSLEissuspectedtoa
rheumatologistwithexperienceinthisdisease[14].
Ourdiagnosticcriteria
DefiniteSLEAfterexcludingalternativediagnoses,wediagnoseSLEinthepatientwhofulfillsthe1997
AmericanCollegeofRheumatology(ACR)criteriaorthe2012SystemicLupusInternationalCollaboratingClinics
(SLICC)criteria(table2).Aspreviouslymentioned,theACRcriteriarequirethatapatientsatisfyatleast4of11
criteria.TheSLICCcriteriarequireeitherthatapatientsatisfyatleast4of17criteria,includingatleast1ofthe11
clinicalcriteriaandoneofthesiximmunologiccriteria,orthatthepatienthasbiopsyprovennephritiscompatible
withSLEinthepresenceofantinuclearantibodies(ANA)orantidoublestrandedDNA(dsDNA)antibodies.
ProbableSLETherearepatientswhodonotfulfilltheclassificationcriteriaforSLE,butinwhomwestill
diagnosethedisorder.ThesepatientsincludethosepresentingwithaninadequatenumberofACRorSLICC
criteria,orthosewhohaveotherSLEmanifestationsnotincludedineitherclassificationcriteria.
Asalooseguide,wediagnoseSLEinpatientswhohavetwoorthreeoftheACRorSLICCcriteria,alongwithat
leastoneotherfeaturethatmaybeassociatedwith,butisnotspecificfor,SLE.Someofthesefeaturesinclude
thefollowing[15]:
Opticneuritis,asepticmeningitis
Glomerularhematuria
Pneumonitis,pulmonaryhemorrhage,orpulmonaryhypertension,interstitiallungdisease

Myocarditis,verrucousendocarditis(LibmanSacksendocarditis)
Abdominalvasculitis
Raynaudphenomenon
Elevatedacutephasereactants(eg,erythrocytesedimentationrate[ESR]andCreactiveprotein[CRP])
PossibleSLEWeconsiderSLEapossiblediagnosisinindividualswhohaveonlyoneoftheACR/SLICC
criteria,inadditiontoatleastoneortwooftheotherfeatureslistedabove.
Ingeneral,patientswitheitherprobableorpossibleSLEaremanagedsimilarlytopatientswithSLEandtreated
accordingtotheirpredominantsymptomsandmanifestations.Overtime,thesymptomsinthesepatientsmay
persist,evolveintoSLEorarelatedconnectivetissuedisorder,orevenresolve.
UndifferentiatedconnectivetissuediseaseOtherpatientswhohaveevenfewerfeaturessuggestiveof
SLEmaybeclassifiedashavingundifferentiatedconnectivetissuedisease(UCTD).Thistermisusedtodescribe
patientswithsignsandsymptomssuggestiveofasystemicautoimmunediseasebutdonotmeettheACRcriteria
forSLEoranotherdefinedconnectivetissuesdisease[16].(See"Undifferentiatedsystemicrheumatic(connective
tissue)diseasesandoverlapsyndromes".)
CaseserieshavebeenpublishedthatsummarizetheoutcomeofpatientswhohaveUCTDatpresentation[17
21].Uptoonethirdhaveallsymptomsandsignsdisappearovera10yearfollowupperiod.Anywherefrom40to
60percentofpatientscontinuetoexhibittheirinitialclinicalfeatures,while5to30percentevolveandmeet
classificationcriteriaforadefinitedisease,suchasSLE,rheumatoidarthritis(RA),scleroderma,oran
inflammatorymyopathy(myositis)[1721](see"Undifferentiatedsystemicrheumatic(connectivetissue)diseases
andoverlapsyndromes").Thus,patientswithUCTDshouldbefollowedcarefully,encouragedtoreportnew
symptoms,andhaveperiodiclaboratorytestingtoassessfortheemergenceofnewclinicalfeaturesorlaboratory
findings.
ANAnegativelupusANAnegativeSLEhasbeenrecognizedsincethe1970s,butwaslatershowntobe
influencedbythetestingmethodsusedtodetectANA.Atthattimeitwasestimatedthatabout5percentof
patientswithSLEwereANAnegativebyindirectimmunofluorescence[22].However,thisnegativefinding
occurredbecauseseraweretestedusingrodentandnothumantissuesasthesubstratefortheindirect
immunofluorescencetestforANA[23].Bycomparison,antiRoantibodieswerefoundinmanyofthesepatients
whenahumancelllineextractwasusedassubstrateforantiRoantibodytesting.
ThesubsequentsubstitutionofHEp2cells(ahumancellline)forrodenttissuesectionsintheindirect
immunofluorescenceANAassayhasresultedinevenfewerSLEpatientswithnegativeANAbyindirect
immunofluorescence.Nevertheless,onrareoccasions,thepresenceofantiRoantibodiesmaysuggesta
systemicautoimmunedisease,despitethepresenceofanegativeANAindirectimmunofluorescence.Asan
example,inonestudyinSweden,among4025seratestedforANA,64patientswithnegativeANAbyindirect
immunofluorescencehadantiRoantibodies[24].Ofthese64patients,12hadSLEandfivehadcutaneousLE.
TheclinicianshouldunderstandthetechniqueusedtodetecttheANAsincethiscaninfluencetheresult.Asan
example,anegativeANAbyindirectimmunofluorescenceisalsoclinicallyusefulasitdramaticallydecreasesthe
likelihoodofSLE.Ontheotherhand,inapatientwithastrongclinicalsuspicionforSLEandanegativeANA
resultbyasolidphaseassay,thetestshouldberepeatedusingindirectimmunofluorescencemethodwithHep2
cellsgiventheincreasedfalsenegativebysolidphaseassay.Adetaileddiscussionofthemethodsusedtodetect
ANAispresentedseparately.(See"Measurementandclinicalsignificanceofantinuclearantibodies".)
OtherfactorsthatmayalsoinfluenceANAnegativityinSLEpatientsincludediseasedurationandtreatment
exposure[25].Inourexperience,thefrequencyofANAnegativeSLEislowerinpatientspresentingatanearly
stageoftheirdisease.Inaddition,SLEpatientswhohavelongstandingdiseaseand/orhaveundergonetreatment
mayloseANAreactivityandbecomeserologicallynegativeovertime.
DIFFERENTIALDIAGNOSISGiventheproteanmanifestationsofsystemiclupuserythematosus(SLE),the

differentialdiagnosisiscorrespondinglybroad.Whileitisbeyondthescopeofthisreviewtoprovidea
comprehensivelistofallpossiblealternativediagnoses,wepresentseveralhere.
Rheumatoidarthritis(RA)EarlyRAmaybedifficulttodistinguishfromthearthritisofSLEsinceboth
conditionscausejointtendernessandswelling(table4).Featuressuchasswanneckdeformities,ulnar
deviation,andsofttissuelaxity,whichareobservedinlaterstagesofRAinpatientswithmoredestructive
disease,canalsobeseeninsomepatientswithSLE.However,importantdistinguishingfeaturesarethat
thejointdeformitiesinSLEareoftenreducible,andinfrequentlyerosiveonplainradiographs.
SomeextraarticularRAmanifestations,includingserositis,siccasymptoms,subcutaneousnodules,anemia,
andfatigue,areotherfeaturesthatmayalsobeobservedinSLE.ThesefeaturesaremorecommoninRA
patientswithmoresevereoradvanceddisease.Serologicabnormalitiessuchasthepresenceofanticyclic
citrullinatedpeptides(CCP)aremoresupportiveofthediagnosisofRA,andcanhelpdistinguishthe
diseases.Itshouldberecognizedthattheantinuclearantibodies(ANA)maybepositiveinuptoonehalfof
patientswithRA.Conversely,rheumatoidfactor(RF)maybepresentinapproximatelyonethirdofSLE
patients.(See"Diagnosisanddifferentialdiagnosisofrheumatoidarthritis".).
RhupusThetermrhupushasbeenusedtodescribepatientswithoverlappingfeaturesofbothSLEand
RA.Whetherrhupusisclinicallyandimmunologicallyadistinctentity,atrueoverlapofSLEandRA,ora
subsetofpatientswithSLEremainsamatterofdebate.Inadditiontohavingserologiesconsistentwithboth
SLEandRA,somepatientsclassifiedasrhupusmayhaveanerosivearthropathythatisatypicalforSLE.
(See"Undifferentiatedsystemicrheumatic(connectivetissue)diseasesandoverlapsyndromes",sectionon
'Earlyundifferentiatedsystemicrheumaticdisease'.)
Mixedconnectivetissuedisease(MCTD)MCTDischaracterizedbyoverlappingfeaturesofSLE,
systemicsclerosis(SSc),andpolymyositis(PM),andbythepresenceofhightitersofantibodiesagainstU1
ribonucleoprotein(RNP).However,thediagnosisofMCTDisoftencomplicatedsincemanyofits
characteristicfeaturesoccursequentially,oftenoveraperiodofyears.Inaddition,somepatientswithMCTD
mayevolveintoanotherconnectivetissuedisease,includingSLE,duringtheclinicalcourse[26].(See
"Definitionanddiagnosisofmixedconnectivetissuedisease".)
Undifferentiatedconnectivetissuedisease(UCTD)Asmentionedabove,patientswithUCTDhave
signsandsymptomssuggestiveofasystemicautoimmunediseasebutdonotsatisfytheclassification
criteriaforadefinedconnectivetissuediseasesuchasSLEorMCTD.Thesepatientsmayhavesymptoms
suchasarthritisandarthralgias,Raynaudphenomenon,andserologicalfindingsthataredifficultto
distinguishfromearlyphasesofSLE.ThemajorityofpatientswithUCTDmaintainanundefinedprofileand
haveamilddiseasecourse[27].(See"Undifferentiatedsystemicrheumatic(connectivetissue)diseasesand
overlapsyndromes".)
Systemicsclerosis(SSc)ThecoexistenceofRaynaudphenomenonandgastroesophagealrefluxis
typicallyobservedinSSchowever,thesefindingsarenonspecificandmaybeseeninpatientswithSLEor
healthyindividuals.Bycontrast,sclerodactyly,telangiectasias,calcinosis,andmalignanthypertensionwith
acuterenalfailurearemoreconsistentwithSScratherthanSLE.Further,apositiveANAispresentinmost
patientswithSSc,whileotherserologiessuchasantidoublestrandedDNA(dsDNA)andantiSmith(Sm)
antibodieswhicharemorespecificforSLE,arenotcommonlyobservedinSSc.Correspondingly,patients
withSSccommonlyexpressantibodiestoanantigencalledScl70(topoisomeraseI)orantibodiesto
centromereproteins.DistinguishingSScfromSLEcanbeparticularlydifficultincaseswherethereisoverlap
ofthesediseases,suchasinMCTD.(See"Diagnosisanddifferentialdiagnosisofsystemicsclerosis
(scleroderma)inadults".)
SjgrenssyndromePatientswithSjgrenssyndromemayhaveextraglandularmanifestationsthatcan
beobservedinSLE,suchasneurologicandpulmonaryabnormalities.However,patientswithSjgrens
syndromeshouldhaveobjectivesignsofkeratoconjunctivitissiccaandxerostomia,andcharacteristic

findingsonsalivaryglandbiopsywhicharenottypicalofSLE.Also,patientswithSjgrenssyndrome
commonlyexpressantibodiestoRoandLaantigens.(See"DiagnosisandclassificationofSjgren's
syndrome".)
VasculitisPatientswithmediumandsmallvesselvasculitidessuchaspolyarteritisnodosa(PAN),
granulomatosiswithpolyangiitis(GPA)(Wegeners),ormicroscopicpolyangiitis(MPA)maypresentwith
overlappingfeaturesofSLEincludingconstitutionalsymptoms,skinlesions,neuropathyandrenal
dysfunction.However,patientswiththesetypesofvasculitidesareusuallyANAnegative.(See"Clinical
manifestationsanddiagnosisofgranulomatosiswithpolyangiitisandmicroscopicpolyangiitis"and"Clinical
manifestationsanddiagnosisofpolyarteritisnodosainadults".)
BehetsdiseaseOralaphthaearepresentinalmostallpatientswithBehetsdisease,andmaybe
observedinpatientswithSLE.Otheroverlappingfeaturesincludeinflammatoryeyedisease,neurologic
disease,vasculardisease,andarthritis.However,patientswithBehetsaremorecommonlymaleand
ANAnegative.Also,vascularinvolvementofanysize(small,medium,large)ismorecommonlyafeatureof
BehetsdiseaseratherthanSLE.(See"ClinicalmanifestationsanddiagnosisofBehetsdisease".)
Dermatomyositis(DM)andpolymyositis(PM)PatientswithSLEcanpresentwithalowgrademyositis,
whereaspatientswithDMandPMgenerallydemonstratemoreovertproximalmuscleweakness.Apositive
ANAisobservedinapproximately30percentofpatientswithDMandPM,comparedwithalmostallpatients
inSLE.PatientswithDMmayhavecharacteristicskinfindingsincludingGottronspapules,aheliotrope
eruptionandphotodistributedpoikiloderma(includingtheshawlandVsigns).Clinicalfindingscharacteristic
ofSLEsuchasoralulcers,arthritis,nephritis,andhematologicabnormalitiesareabsentinDMandPM.
PatientswithDMorPMmayalsoexpressmyositisspecificantibodiessuchasantiJo1.(See"Clinical
manifestationsofdermatomyositisandpolymyositisinadults".)
AdultStillsdisease(ASD)SomeoftheclinicalmanifestationsobservedinASDsuchasfever,arthritis
orarthralgias,andlymphadenopathy,arenotunusualforpatientswithSLE.However,patientswithASD
oftenpresentwithaleukocytosisratherthantheleukopeniaobservedinSLE,andtheytypicallyarenegative
forANA.(See"ClinicalmanifestationsanddiagnosisofadultStill'sdisease".)
KikuchisdiseaseKikuchisdiseaseisabenignandusuallyselflimitedformofhistiocyticnecrotizing
lymphadenitis.Clinicalfeaturesatpresentationincludelymphadenopathyaswellasfever,myalgias,
arthralgias,and,lesscommonly,hepatosplenomegaly.AssociationswithSLEhavebeenreported,butthe
clinicalcourseisusuallyfavorablewithspontaneousremissionoftenoccurringwithinfourmonths.The
diagnosisofKikuchisdiseaseisbasedonalymphnodebiopsy,whichrevealsahistiocyticcellularinfiltrate.
(See"Kikuchidisease".)
SerumsicknessManyoftheclinicalfeaturesobservedinserumsicknesssuchasfever,
lymphadenopathy,cutaneouseruptions,andarthralgiasareoftenobservedinSLE.Furthermore,during
severeepisodes,complementmeasurementsincludingC3andC4canbedepressed,asinSLE.Unlike
SLE,however,ANAsaretypicallynegativeandthecoursetendstobeselflimited.(See"Serumsickness
andserumsicknesslikereactions".)
FibromyalgiaPatientswithSLEmaypresentwithgeneralizedarthralgias,myalgias,andfatigue,much
likepatientswithfibromyalgia.However,othercharacteristicfeaturesofSLEsuchasaphotosensitiverash,
arthritis,andmultisystemorganinvolvementareabsent.However,fibromyalgiaoccursmorecommonlyin
patientswithsystemicrheumaticdiseasesthaninthegeneralpopulationthus,patientswithSLEmayhave
concomitantfibromyalgia.(See"Clinicalmanifestationsanddiagnosisoffibromyalgiainadults".)
InfectionsSeveralviralinfectionscanproducesignsandsymptomspresentinSLE,including
cytomegalovirus(CMV)andEpsteinBarrvirus(EBV).Inaddition,EBVinfectionmayleadtoapositiveANA
[28,29].HumanparvovirusB19cancauseflulikesymptomsandhematologicabnormalitiessuchas
leukopeniaandthrombocytopenia,whichcanbeobservedinSLE,andpatientsmaypresentwitharthralgias

orarthritis.
Otherviralinfectionsthatmaypresentwithmultisysteminvolvementincludehumanimmunodeficiencyvirus
(HIV),hepatitisBvirus(HBV),hepatitisCvirus(HCV).However,serologicassayscanbediagnosticfor
manyoftheseviruses.SomebacterialinfectionssuchasSalmonellaortuberculosisshouldalsobe
consideredifappropriate.
Multiplesclerosis(MS)Althoughrare,patientswithSLEcanpresentwithcranialneuropathiesthatmust
bedistinguishedfromMS.Unilateralopticneuritisandpyramidalsyndrome,withlesionsdetectedby
magneticresonanceimaging(MRI)suggestingdisseminationinspaceandtimearecharacteristicofMS.
(See"Diagnosisofmultiplesclerosisinadults".)
MalignanciesLeukemiaormyelodysplasticsyndromesmaypresentwithhematologicandconstitutional
symptomssimilartothoseobservedinSLE.However,monoclonalexpansionofBandTcells(asassessed
byimmunophenotyping),monocytosis,ormacrocytosiscandistinguishthesemalignanciesfromSLE.
Patientswithlymphomaalsotypicallyhaveadditionalfindingssuchassplenomegaly,lymphadenopathy,or
increasedlactatedehydrogenase(LDH)levels.PatientswithangioimmunoblasticTcelllymphoma(AITL)
maybedistinguishedbyfindingsonanexcisionaltissuebiopsy,mostcommonlyalymphnode.
Thromboticthrombocytopenicpurpura(TTP)AlthoughpatientswithSLEmayhavefeverand
thrombocytopenia,patientswithTTPalsohavemicroangiopathichemolyticanemia,acuterenal
insufficiency,fluctuatingneurologicalmanifestations,and/orlowlevelsofADAMSTS13.(See"Diagnosisof
thromboticthrombocytopenicpurpurahemolyticuremicsyndromeinadults".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Lupus(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Antinuclearantibodies(ANA)(BeyondtheBasics)"and
"Patientinformation:Systemiclupuserythematosus(SLE)(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Theinitialevaluationforsystemiclupuserythematosus(SLE)requiresacarefulhistoryandphysicalexam,
alongwithselectedlaboratorytestingtoidentifyfeaturesthatarecharacteristicofSLEorthatsuggestan
alternativediagnosis.Aspartofthemedicalhistoryandphysicalexamination,wepayparticularattentionto
thefollowingsymptomsandsigns(see'EvaluationforsuspectedSLE'above):

Photosensitiveskinlesionssuchasamalarrashordiscoidlesions
Painlessoralornasalulcers
Hairlossthatispatchyorfrontal/peripheral
Raynaudphenomenon
Jointpainorswellingwhichcanbemigratoryorsymmetrical
Symptomsofserositis/pericarditis

Wealsoaskaboutexposuretomedicationsassociatedwithdruginducedlupus(eg,hydralazine).(See
"Druginducedlupus".)
Weobtainacompletebloodcountanddifferentialaswellasserumcreatininelevelandurinalysisinall
patientssuspectedofhavingSLE(see'Laboratorytesting'above).Inadditiontotheseroutinelaboratory
studies,weperformselectedlaboratorytestswhichsupportthediagnosisofSLEifabnormal.Theseinclude
antinuclearantibodies(ANA)(andifpositive,otherspecificautoantibodiessuchasantidoublestrandedDNA
[dsDNA],antiSmith[Sm]),antiphospholipidantibodies,C3andC4orCH50complementlevels,erythrocyte
sedimentationrate(ESR)and/orCreactiveprotein(CRP)levels,andtheurineproteintocreatinineratio.
Additionalstudiessuchasdiagnosticimagingorbiopsyofaninvolvedorganmaybenecessarysuchtesting
isdictatedbytheclinicalpresentationandassociateddifferentialdiagnosticpossibilities.(See'Imaging'
aboveand'Biopsy'aboveand'Additionalstudiesinselectedpatients'above.)
ClassificationcriteriahavebeendevelopedforSLEasameansofcategorizingpatientsforstudypurposes.
Thesecriteriacanbeusefulforcliniciansinsystematicallydocumentingkeydiseasefeatures.(See
'Classificationcriteria'above.)
ThediagnosisofSLEisbaseduponthejudgmentofanexperiencedclinicianwhorecognizescharacteristic
constellationsofsymptomsandsignsinthesettingofsupportiveserologicstudies,afterexcluding
alternativediagnoses.GiventhegreatvariabilityintheexpressionandseverityofSLE,thediagnosisofSLE
issometimeschallengingandreferraltoarheumatologistwithexperienceinthisdiseaseisoftenappropriate.
(See'Ourdiagnosticcriteria'above.)
Intheabsenceofexistingdiagnosticcriteria,ourgeneralapproachtothediagnosisofSLEisasfollows
(see'Ourdiagnosticcriteria'above):
DefiniteSLEAfterexcludingalternativediagnoses,wediagnoseSLEinthepatientwhofulfillsthe
1997AmericanCollegeofRheumatology(ACR)criteriaorthe2012SystemicLupusInternational
CollaboratingClinics(SLICC)classificationcriteria(table2).(See'DefiniteSLE'above.)
ProbableSLETherearepatientswhodonotfulfilltheclassificationcriteriaforSLE,butinwhomwe
stilldiagnosethedisorder.ThesepatientsincludethosepresentingwithaninadequatenumberofACR
orSLICCcriteria,orthosewhohaveotherSLEmanifestationsnotincludedineitherclassification
criteria.(See'ProbableSLE'above.)
Asalooseguide,wediagnoseSLEinpatientswhohavetwoorthreeoftheACRorSLICCcriteria,
alongwithatleastoneotherfeaturethatmaybeassociatedwith,butisnotspecificfor,SLE.Someof
thesefeaturesincludethefollowing:

Opticneuritis,asepticmeningitis
Glomerularhematuria
Pneumonitis,pulmonaryhemorrhage,orpulmonaryhypertension,interstitiallungdisease
Myocarditis,verrucousendocarditis(LibmanSacksendocarditis)
Abdominalvasculitis
Raynaudphenomenon
Elevatedacutephasereactants(eg,ESRandCRP)

PossibleSLEWeconsiderSLEapossiblediagnosisinindividualswhohaveonlyoneofthe
ACR/SLICCcriteria,inadditiontoatleastoneortwooftheuncommonfeatureslistedabove.(See
'PossibleSLE'above.)
Undifferentiatedconnectivetissuedisease(UCTD)Otherpatientswhohaveevenfewerfeatures
suggestiveofSLEmaybeclassifiedasUCTD.Thistermisusedtodescribepatientswithsignsand
symptomssuggestiveofasystemicautoimmunediseasebutdonotmeettheACRcriteriaforSLEor

anotherdefinedconnectivetissuesdisease.(See'Undifferentiatedconnectivetissuedisease'above.)
ANAnegativeSLELessthan5percentofpatientswithSLEarenegativeforANAasdetectedby
indirectimmunofluorescence.ThefrequencyofANAnegativeSLEisevenlowerinpatientspresenting
atanearlystageoftheirdisease.Inaddition,SLEpatientswhohavelongstandingdiseaseand/orhave
undergonetreatmentmayloseANAreactivityandbecomeserologicallynegativeovertime.
ThedifferentialdiagnosisofSLEisbroad.Itincludesmanysystemicconnectivediseasesaswellasother
autoimmunedisorders.(See'Differentialdiagnosis'above.)
ACKNOWLEDGMENTTheeditorialstaffatUpToDatewouldliketoacknowledgePeterSchur,MD,who
contributedtoanearlierversionofthistopicreview.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1. CerveraR,KhamashtaMA,FontJ,etal.Systemiclupuserythematosus:clinicalandimmunologicpatterns
ofdiseaseexpressioninacohortof1,000patients.TheEuropeanWorkingPartyonSystemicLupus
Erythematosus.Medicine(Baltimore)199372:113.
2. EstesD,ChristianCL.Thenaturalhistoryofsystemiclupuserythematosusbyprospectiveanalysis.
Medicine(Baltimore)197150:85.
3. FontJ,CerveraR,RamosCasalsM,etal.Clustersofclinicalandimmunologicfeaturesinsystemiclupus
erythematosus:analysisof600patientsfromasinglecenter.SeminArthritisRheum200433:217.
4. PonsEstelBA,CatoggioLJ,CardielMH,etal.TheGLADELmultinationalLatinAmericanprospective
inceptioncohortof1,214patientswithsystemiclupuserythematosus:ethnicanddiseaseheterogeneity
among"Hispanics".Medicine(Baltimore)200483:1.
5. NossentJ,KissE,RozmanB,etal.Diseaseactivityanddamageaccrualduringtheearlydiseasecourse
inamultinationalinceptioncohortofpatientswithsystemiclupuserythematosus.Lupus201019:949.
6. RiemakastenGandHiepeF.Autoantibodies.In:Dubois'LupusErythematosusandRelatedSyndromes,8,
WallaceDJandHahnBH.(Ed),ElsevierSaunders,Philadelphia2013.p.282.
7. BenitoGarciaE,SchurPH,LahitaR,AmericanCollegeofRheumatologyAdHocCommitteeon
ImmunologicTestingGuidelines.Guidelinesforimmunologiclaboratorytestingintherheumaticdiseases:
antiSmandantiRNPantibodytests.ArthritisRheum200451:1030.
8. WeissmanBN,RappoportAS,SosmanJL,SchurPH.Radiographicfindingsinthehandsinpatientswith
systemiclupuserythematosus.Radiology1978126:313.
9. PetriM,OrbaiAM,AlarcnGS,etal.DerivationandvalidationoftheSystemicLupusInternational
CollaboratingClinicsclassificationcriteriaforsystemiclupuserythematosus.ArthritisRheum2012
64:2677.
10. PonsEstelGJ,WojdylaD,McGwinGJr,etal.TheAmericanCollegeofRheumatologyandtheSystemic
LupusInternationalCollaboratingClinicsclassificationcriteriaforsystemiclupuserythematosusintwo
multiethniccohorts:acommentary.Lupus201423:3.
11. HochbergMC.UpdatingtheAmericanCollegeofRheumatologyrevisedcriteriafortheclassificationof
systemiclupuserythematosus.ArthritisRheum199740:1725.
12. TanEM,CohenAS,FriesJF,etal.The1982revisedcriteriafortheclassificationofsystemiclupus
erythematosus.ArthritisRheum198225:1271.
13. PetriM,MagderL.Classificationcriteriaforsystemiclupuserythematosus:areview.Lupus200413:829.
14. Guidelinesforreferralandmanagementofsystemiclupuserythematosusinadults.AmericanCollegeof
RheumatologyAdHocCommitteeonSystemicLupusErythematosusGuidelines.ArthritisRheum1999
42:1785.
15. BertsiasGK,PamfilC,FanouriakisA,BoumpasDT.Diagnosticcriteriaforsystemiclupuserythematosus:
hasthetimecome?NatRevRheumatol20139:687.

16. AlarcnGS,WilliamsGV,SingerJZ,etal.Earlyundifferentiatedconnectivetissuedisease.I.Earlyclinical
manifestationinalargecohortofpatientswithundifferentiatedconnectivetissuediseasescomparedwith
cohortsofwellestablishedconnectivetissuedisease.JRheumatol199118:1332.
17. GreerJM,PanushRS.Incompletelupuserythematosus.ArchInternMed1989149:2473.
18. LomOrtaH,AlarconSegoviaD,DiazJouanenE.Systemiclupuserythematosus.Differencesbetween
patientswhodo,andwhodonot,fulfillclassificationcriteriaatthetimeofdiagnosis.JRheumatol1980
7:831.
19. BodolayE,CsikiZ,SzekaneczZ,etal.Fiveyearfollowupof665Hungarianpatientswithundifferentiated
connectivetissuedisease(UCTD).ClinExpRheumatol200321:313.
20. SthlHallengrenC,NivedO,SturfeltG.Outcomeofincompletesystemiclupuserythematosusafter10
years.Lupus200413:85.
21. MoscaM,TaniC,BombardieriS.Acaseofundifferentiatedconnectivetissuedisease:isitadistinct
clinicalentity?NatClinPractRheumatol20084:328.
22. MaddisonPJ,ProvostTT,ReichlinM.Serologicalfindingsinpatientswith"ANAnegative"systemiclupus
erythematosus.Medicine(Baltimore)198160:87.
23. CrossLS,AslamA,MisbahSA.Antinuclearantibodynegativelupusasadistinctdiagnosticentitydoesit
nolongerexist?QJM200497:303.
24. BlombergS,RonnblomL,WallgrenAC,etal.AntiSSA/Roantibodydeterminationbyenzymelinked
immunosorbentassayasasupplementtostandardimmunofluorescenceinantinuclearantibodyscreening.
ScandJImmunol200051:612.
25. HellerCA,SchurPH.Serologicalandclinicalremissioninsystemiclupuserythematosus.JRheumatol
198512:916.
26. CappelliS,BellandoRandoneS,MartinoviD,etal."Tobeornottobe,"tenyearsafter:evidencefor
mixedconnectivetissuediseaseasadistinctentity.SeminArthritisRheum201241:589.
27. MoscaM,TaniC,NeriC,etal.Undifferentiatedconnectivetissuediseases(UCTD).AutoimmunRev2006
6:1.
28. SculleyDG,SculleyTB,PopeJH.Reactionsofserafrompatientswithrheumatoidarthritis,systemiclupus
erythematosusandinfectiousmononucleosistoEpsteinBarrvirusinducedpolypeptides.JGenVirol1986
67(Pt10):2253.
29. AlJitawiSA,HakoozBA,KazimiSM.FalsepositiveMonospottestinsystemiclupuserythematosus.BrJ
Rheumatol198726:71.
Topic4668Version21.0

GRAPHICS
Frequencyofsignsandsymptomsofsystemiclupuserythematosus
Signsandsymptoms

Percentatonset

Percentatanytime

Fatigue

50

74to100

Fever

36

40to80+

Weightloss

21

44to60+

Arthritisorarthralgia

62to67

83to95

Skin

73

80to91

Butterflyrash

28to38

48to54

Photosensitivity

29

41to60

Mucuousmembranelesion

10to21

27to52

Alopecia

32

18to71

Raynaud'sphenomenon

17to33

22to71

Purpura

10

15to34

Urticaria

4to8

16to38

34to73

11to18

Gastrointestinal

18

38to44

Pulmonary

2to12

24to98

Pleurisy

17

30to45

Effusion

24

Pneumonia

29

15

20to46

Pericarditis

8to48

Murmurs

23

ECGchanges

34to70

Lymphadenopathy

7to16

21to50

Splenomegaly

9to20

Hepatomegaly

7to25

Centralnervoussystem

12to21

25to75

Functional

Most

Psychosis

5to52

Convulsions

0.5

2to20

Renal
Nephrosis

Cardiac

Adaptedfrom:VonFeldtJM,PostgradMed199597:79.
Graphic70386Version4.0

Classificationcriteriaforsystemiclupuserythematosus
ACRcriteriafortheclassificationof
systemiclupuserythematosus [1,2]

SLICCcriteriafortheclassification
ofsystemiclupus
erythematosus [3]

(4of11criteria)*

(4of17criteria,includingatleastoneclinical

Criterion

Definition

criterionandoneimmunologiccriterion OR
biopsyprovenlupusnephritis )
Criterion

Malarrash

Fixederythema,flator
raised,overthemalar
eminences,tendingto

Definition
Clinicalcriteria

Acutecutaneous
lupus

sparethenasolabialfolds

Photosensitivity

Lupusmalarrash(donot
countifmalardiscoid)
bullouslupustoxic
epidermalnecrolysis
variantofSLE
maculopapularlupusrash
photosensitivelupusrash
(intheabsenceof
dermatomyositis)OR
subacutecutaneouslupus
(noninduratedpsoriaform
and/orannularpolycyclic
lesionsthatresolve
withoutscarring,although

Skinrashasaresultof
unusualreactionto
sunlight,bypatienthistory
orclinicianobservation

occasionallywith
postinflammatory
dyspigmentationor
telangiectasias)
Discoidrash

Erythematosusraised
patcheswithadherent
keratoticscalingand

Chronic
cutaneouslupus

follicularpluggingatrophic
scarringmayoccurinolder
lesions

Classicdiscoidrash
localized(abovetheneck)
generalized(aboveand
belowtheneck)
hypertrophic(verrucous)
lupuslupuspanniculitis
(profundus)mucosal
lupuslupus
erythematosustumidus
chilblainslupusORdiscoid
lupus/lichenplanusoverlap

Nonscarring
alopecia

Diffusethinningorhair
fragilitywithvisiblebroken
hairs(intheabsenceof
othercauses,suchas
alopeciaareata,drugs,iron
deficiency,andandrogenic

alopecia)
Oralulcers

Oralornasopharyngeal

Oralornasal

Palate,buccal,tongue,OR

ulceration,usuallypainless,
observedbyaclinician

ulcers

nasalulcers(inthe
absenceofothercauses,
suchasvasculitis,Behet's
disease,infection
[herpesvirus],
inflammatorybowel
disease,reactivearthritis,
andacidicfoods)

Arthritis

Nonerosivearthritis
involvingtwoormore
peripheraljoints,
characterizedby

Jointdisease

Tendernessintwoormore
jointsandatleast30
minutesofmorning
stiffness

tenderness,swelling,or
effusion

Serositis

PleuritisConvincing
historyofpleuriticpainor
rubbingheardbyaclinician
orevidenceofpleural
effusionOR

Synovitisinvolvingtwoor
morejoints,characterized
byswellingoreffusionOR

Serositis

PericarditisDocumented
byEKG,rub,orevidenceof
pericardialeffusion

Typicalpleurisyformore
thanoneday,pleural
effusions,orpleuralrub,
OR
Typicalpericardialpain
(painwithrecumbency
improvedbysitting
forward)formore
thanoneday,pericardial
effusion,pericardialrub,or
pericarditisby
electrocardiographyinthe
absenceofothercauses,
suchasinfection,uremia,
andDressler'ssyndrome

Renaldisorder

Persistentproteinuria
greaterthan500mg/24
hoursorgreaterthan3+if
quantitationnotperformed

Renal

Urineproteintocreatinine
ratio(or24hoururine
protein)representing500
mgprotein/24hours,OR

OR
CellularcastsMaybered
cell,hemoglobin,granular,
tubular,ormixed
Neurologic
disorder

SeizuresORpsychosisIn
theabsenceofoffending
drugsorknownmetabolic
derangements(uremia,
ketoacidosis,orelectrolyte
imbalance)

Redbloodcellcasts

Neurologic

Seizurespsychosis
mononeuritismultiplex(in
theabsenceofother
knowncauses,suchas
primaryvasculitis)
myelitisperipheralor

cranialneuropathy(inthe
absenceofotherknown
causes,suchasprimary
vasculitis,infection,and
diabetesmellitus)OR
acuteconfusionalstate(in
theabsenceofother
causes,including
toxic/metabolic,uremia,
drugs)
Hematologic
disorder

HemolyticanemiaWith
reticulocytosisOR
LeukopeniaLessthan
4000/mm 3totalontwoor
moreoccasionsOR

Hemolyticanemia

Hemolyticanemia

Leukopeniaor
lymphopenia

Leukopenia(<4000/mm 3
atleastonce)(inthe
absenceofotherknown
causes,suchasFelty's
syndrome,drugs,and
portalhypertension),OR

LymphopeniaLessthan
1500/mm 3ontwoor
moreoccasionsOR

Lymphopenia
(<1000/mm 3atleast

ThrombocytopeniaLess
3

than100,000/mm (in
theabsenceofoffending
drugs)

once)(intheabsenceof
otherknowncauses,such
asglucocorticoids,drugs,
andinfection)
Thrombocytopenia

Thrombocytopenia

(<100,000/mm 3)atleast
onceintheabsenceof
otherknowncauses,such
asdrugs,portal
hypertension,and
thrombotic
thrombocytopenicpurpura

ANA

Anabnormaltiterof
antinuclearantibodyby

Immunologiccriteria
ANA

ANAlevelabovelaboratory
referencerange

AntidsDNA

AntidsDNAantibodylevel
abovelaboratoryreference
range(or>twofoldthe
referencerangeiftested

immunofluorescenceoran
equivalentassayatany
pointintimeandinthe
absenceofdrugsknownto
beassociatedwith"drug
inducedlupus"syndrome
Immunologic
disorders

AntiDNAAntibodyto
nativeDNAinabnormal
titerOR
AntiSmPresenceof
antibodytoSmnuclear
antigenOR

byELISA)

Positivefindingof
antiphospholipidantibody
basedonanabnormal
serumlevelofIgGorIgM

AntiSm

Presenceofantibodyto
Smnuclearantigen

Antiphospholipid

Antiphospholipidantibody
positivityasdeterminedby
anyofthefollowing:
Positivetestresultfor
lupusanticoagulantfalse
positivetestresultfor

anticardiolipinantibodies,
onapositivetestresultfor
lupusanticoagulantusinga
standardmethod,orona
falsepositiveserologictest
forsyphilisknowntobe

rapidplasmareagin
mediumorhightiter
anticardiolipinantibody
level(IgA,IgG,orIgM)or
positivetestresultforanti

positiveforatleastsix
monthsandconfirmedby
Treponemapallidum
immobilizationor
fluorescenttreponemal

beta2glycoproteinI(IgA,
IgG,orIgM)

antibodyabsorptiontest

Lowcomplement

LowC3lowC4ORlow
CH50

DirectCoombs'
test

DirectCoombs'testinthe
absenceofhemolytic
anemia

ACR:AmericanCollegeofRheumatologySLICC:SystemicLupusInternationalCollaboratingClinicsSLE:
systemiclupuserythematosusEKG:electrocardiogramANA:antinuclearantibodiesAntiSm:anti
SmithantibodyIgG:immunoglobulinGIgM:immunoglobulinMAntidsDNA:antidoublestranded
DNAELISA:enzymelinkedimmunosorbentassayIgA:immunoglobulinA.
*FortheACRcriteria,nodistinctionismadebetweenclinicalandimmunologiccriteriaindetermining
whethertherequirednumberhasbeenmet.Theclassificationisbasedupon11criteria.Forthepurpose
ofidentifyingpatientsinclinicalstudies,apersonissaidtohaveSLEifany4ormoreofthe11criteria
arepresent,seriallyorsimultaneously,duringanyintervalofobservation.
FortheSLICCcriteria,criteriaarecumulativeandneednotbepresentlyconcurrently.Apatientis
classifiedashavingSLEifheorshesatisfiesfouroftheclinicalandimmunologiccriteriausedinthe
SLICCclassificationcriteria,includingatleastoneclinicalcriterionandoneimmunologiccriterion.
Alternatively,accordingtotheSLICCcriteria,apatientisclassifiedashavingSLEifheorshehas
biopsyprovennephritiscompatiblewithSLEinthepresenceofANAsorantidsDNAantibodies.
References:
1. TanEM,CohenAS,FriesJF,etal.The1982revisedcriteriafortheclassificationofsystemiclupus
erythematosus.ArthritisRheum198225:1271.
2. HochbergMC.UpdatingtheAmericanCollegeofRheumatologyrevisedcriteriafortheclassification
ofsystemiclupuserythematosus(letter).ArthritisRheum199740:1725.
3. PetriM,OrbaiAM,AlarcnGS,etal.DerivationandvalidationoftheSystemicLupusInternational
CollaboratingClinicsclassificationcriteriaforsystemiclupuserythematosus.ArthritisRheum
201264:2677.
Graphic86633Version5.0

ACRcriteriafortheclassificationofsystemiclupuserythematosus
Criterion

Definition

Malarrash

Fixederythema,flatorraised,overthemalareminences,tendingtosparethe
nasolabialfolds

Discoidrash

Erythematosusraisedpatcheswithadherentkeratoticscalingandfollicular
pluggingatrophicscarringmayoccurinolderlesions

Photosensitivity

Skinrashasaresultofunusualreactiontosunlight,bypatienthistory
orclinicianobservation

Oralulcers

Oralornasopharyngealulceration,usuallypainless,observedbyaclinician

Arthritis

Nonerosivearthritisinvolvingtwoormoreperipheraljoints,characterizedby
tenderness,swelling,oreffusion

Serositis

PleuritisConvincinghistoryofpleuriticpainorrubheardbyaclinicianor
evidenceofpleuraleffusionOR
PericarditisDocumentedbyEKG,rub,orevidenceofpericardialeffusion

Renaldisorder

Persistentproteinuriagreaterthan0.5gramsperdayorgreaterthan3+if
quantitationnotperformedOR
CellularcastsMayberedcell,hemoglobin,granular,tubular,ormixed

Neurologic

SeizuresORpsychosisIntheabsenceofoffendingdrugsorknownmetabolic

disorder

derangements(uremia,ketoacidosis,orelectrolyteimbalance)

Hematologic
disorder

HemolyticanemiaWithreticulocytosisOR
LeukopeniaLessthan4000/mm 3totalontwoormoreoccasionsOR
LymphopeniaLessthan1500/mm 3ontwoormoreoccasionsOR
ThrombocytopeniaLessthan100,000/mm 3intheabsenceofoffendingdrugs

Immunologic
disorders

AntiDNAAntibodytonativeDNAinabnormaltiterOR
AntiSmPresenceofantibodytoSmnuclearantigenOR
Positiveantiphospholipidantibodyon:
1.AnabnormalserumlevelofIgGorIgManticardiolipinantibodies,or
2.Apositivetestresultforlupusanticoagulantusingastandardmethod,or
3.AfalsepositivetestresultforatleastsixmonthsconfirmedbyTreponema
pallidumimmobilizationorfluorescenttreponemalantibodyabsorptiontest

Antinuclear
antibody

Anabnormaltiterofantinuclearantibodybyimmunofluorescenceoran
equivalentassayatanypointintimeandintheabsenceofdrugsknowntobe
associatedwith"druginducedlupus"syndrome

ACR:AmericanCollegeofRheumatologyEKG:electrocardiogramIgG:immunoglobulinGIgM:
immunoglobulinM.
Graphic73334Version5.0

Comparisonoffeaturesofmusculoskeletaldiseaseinsystemiclupus
erythematosusorrheumatoidarthritis
Feature

Lupus

Rheumatoidarthritis

Arthralgia

Common

Common

Arthritis

Common

Deforming

Symmetry

Yes

Yes

Jointsinvolved

PIP>MCP>wrist>knee

MCP>wrist>knee

Synovialhypertrophy

Rare

Common

Synovialmembraneabnormality

Minimal

Proliferative

Synovialfluid

Transudate

Exudate

Subcutaneousnodules

Rare

35percent

Erosions

Veryrare

Common

Morningstiffness

Minutes

Hours

Myalgia

Common

Common

Myositis

Rare

Uncommon

Osteoporosis

Variable

Common

Avascularnecrosis

5to50percent

Uncommon

Deformingarthritis

Uncommon

Common

Swanneck

10percent,reducible

Common,notreducible

Ulnardeviation

5percent,reducible

Common,notreducible

Graphic54324Version1.0

Disclosures

Disclosures:DanielJWallace,MDNothingtodisclose.DavidSPisetsky,MD,PhDConsultant/AdvisoryBoards:Merck[Autoimmunity(Xelganz,
RamirezCurtis,MD,MPHNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevel
AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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