Diagnosis and Differential Diagnosis of Systemic Lupus Erythematosus in Adults

10/13/2015
Diagnosisanddifferentialdiagnosisofsystemiclupuserythematosusinadults
OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate
Author
DanielJWallace,MD
SectionEditor
DavidSPisetsky,MD,
PhD
DeputyEditor
MonicaRamirezCurtis,
MD,MPH
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Sep2015.|Thistopiclastupdated:May04,2015.
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
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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
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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"Biologicmarkersinthediagnosisandassessmentofrheumatoid
arthritis",sectionon'Rheumatoidfactors'and"Biologicmarkersinthediagnosisandassessmentof
rheumatoidarthritis",sectionon'Anticitrullinatedpeptideantibodies'.)
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'.)
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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.
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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
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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
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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
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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".)
BehetssyndromeOralaphthaearepresentinalmostallpatientswithBehetssyndrome,andmaybe
observedinpatientswithSLE.Otheroverlappingfeaturesincludeinflammatoryeyedisease,neurologic
disease,vasculardisease,andarthritis.However,patientswithBehetsaremorecommonlymaleand
ANAnegative.Also,vascularinvolvementofanysize(small,medium,large)ismorecommonlyafeatureof
BehetssyndromeratherthanSLE.(See"ClinicalmanifestationsanddiagnosisofBehetssyndrome".)
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
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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"Acquired
TTP:Clinicalmanifestationsanddiagnosis".)
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
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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
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anotherdefinedconnectivetissuesdisease.(See'Undifferentiatedconnectivetissuedisease'above.)
ANAnegativeSLELessthan5percentofpatientswithSLEarenegativeforANAasdetectedby
indirectimmunofluorescence.ThefrequencyofANAnegativeSLEisevenlowerinpatientspresenting
atanearlystageoftheirdisease.Inaddition,SLEpatientswhohavelongstandingdiseaseand/orhave
undergonetreatmentmayloseANAreactivityandbecomeserologicallynegativeovertime.
ThedifferentialdiagnosisofSLEisbroad.Itincludesmanysystemicconnectivediseasesaswellasother
autoimmunedisorders.(See'Differentialdiagnosis'above.)
ACKNOWLEDGMENTTheeditorialstaffatUpToDatewouldliketoacknowledgePeterSchur,MD,who
contributedtoanearlierversionofthistopicreview.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
Topic4668Version23.0
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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.
Graphic70386Version5.0
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Classificationcriteriaforsystemiclupuserythematosus
ACRcriteriafortheclassificationof
systemiclupuserythematosus [1,2]
(4of11criteria)*
Criterion
Definition
SLICCcriteriafortheclassification
ofsystemiclupus
erythematosus [3]
(4of17criteria,includingatleastoneclinical
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
follicularpluggingatrophic
scarringmayoccurinolder
Chronic
cutaneouslupus
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)
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Oralulcers
Oralornasopharyngeal
ulceration,usuallypainless,
observedbyaclinician
Oralornasal
ulcers
Palate,buccal,tongue,OR
nasalulcers(inthe
absenceofothercauses,
suchasvasculitis,Behet's
disease,infection
[herpesvirus],
inflammatorybowel
disease,reactivearthritis,
andacidicfoods)
Arthritis
Nonerosivearthritis
Jointdisease
involvingtwoormore
peripheraljoints,
characterizedby
tenderness,swelling,or
effusion
Serositis
PleuritisConvincing
Synovitisinvolvingtwoor
morejoints,characterized
byswellingoreffusionOR
Tendernessintwoormore
jointsandatleast30
minutesofmorning
stiffness
Serositis
Typicalpleurisyformore
historyofpleuriticpainor
rubbingheardbyaclinician
orevidenceofpleural
effusionOR
thanoneday,pleural
effusions,orpleuralrub,
OR
PericarditisDocumented
byEKG,rub,orevidenceof
pericardialeffusion
Typicalpericardialpain
(painwithrecumbency
improvedbysitting
forward)formorethan
oneday,pericardial
effusion,pericardialrub,or
pericarditisby
electrocardiographyinthe
absenceofothercauses,
suchasinfection,uremia,
andDressler'ssyndrome
Renaldisorder
Persistentproteinuria
greaterthan500mg/24
hoursorgreaterthan3+if
Renal
Urineproteintocreatinine
ratio(or24hoururine
protein)representing500
quantitationnotperformed
OR
mgprotein/24hours,OR
CellularcastsMaybered
cell,hemoglobin,granular,
Redbloodcellcasts
tubular,ormixed
Neurologic
disorder
SeizuresORpsychosisIn
theabsenceofoffending
drugsorknownmetabolic
derangements(uremia,
ketoacidosis,orelectrolyte
imbalance)
Neurologic
Seizurespsychosis
mononeuritismultiplex(in
theabsenceofother
knowncauses,suchas
primaryvasculitis)
myelitisperipheralor
cranialneuropathy(inthe
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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
once)(intheabsenceof
ThrombocytopeniaLess
than100,000/mm 3(in
theabsenceofoffending
drugs)
otherknowncauses,such
asglucocorticoids,drugs,
andinfection)
Thrombocytopenia
Thrombocytopenia
(<100,000/mm 3)atleast
onceintheabsenceof
otherknowncauses,such
asdrugs,portal
hypertension,and
thrombotic
thrombocytopenicpurpura
ANA
AnabnormaltiterofANA
Immunologiccriteria
ANA
byimmunofluorescenceor
anequivalentassayatany
pointintimeandinthe
absenceofdrugsknownto
beassociatedwith"drug
inducedlupus"syndrome
Immunologic
disorders
AntiDNAAntibodyto
nativeDNAinabnormal
titerOR
AntiSmPresenceof
antibodytoSmnuclear
antigenOR
Positivefindingof
antiphospholipidantibody
basedonanabnormal
ANAlevelabovelaboratory
referencerange
AntidsDNA
AntidsDNAantibodylevel
abovelaboratoryreference
range(or>twofoldthe
referencerangeiftested
byELISA)
AntiSm
Presenceofantibodyto
Smnuclearantigen
Antiphospholipid
Antiphospholipidantibody
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positivityasdeterminedby
serumlevelofIgGorIgM
anticardiolipinantibodies,
anyofthefollowing:
Positivetestresultfor
lupusanticoagulantfalse
positivetestresultfor
onapositivetestresultfor
lupusanticoagulantusinga
standardmethod,orona
falsepositiveserologictest
forsyphilisknowntobe
rapidplasmareagin
mediumorhightiter
anticardiolipinantibody
level(IgA,IgG,orIgM)or
positivetestresultforanti
beta2glycoproteinI(IgA,
positiveforatleastsix
monthsandconfirmedby
Treponemapallidum
immobilizationor
fluorescenttreponemal
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.
16/19
10/13/2015
ACRcriteriafortheclassificationofsystemiclupuserythematosus
Criterion
Malarrash
Definition
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
disorder
SeizuresORpsychosisIntheabsenceofoffendingdrugsorknownmetabolic
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
Anabnormaltiterofantinuclearantibodybyimmunofluorescenceoran
antibody
equivalentassayatanypointintimeandintheabsenceofdrugsknowntobe
associatedwith"druginducedlupus"syndrome
ACR:AmericanCollegeofRheumatologyEKG:electrocardiogramIgG:immunoglobulinGIgM:
immunoglobulinM.
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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
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Disclosures
Disclosures:DanielJWallace,MDNothingtodisclose.DavidSPisetsky,MD,PhD
Consultant/AdvisoryBoards:Merck[Autoimmunity(Xelganz,Enbrel)]Lilly[Lupus]Celgene[Psoriatic
arthritis(apremilast)]Immunoarray[Lupus(SLEtest)].MonicaRamirezCurtis,MD,MPHNothingto
disclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmust
conformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy
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