Diagnosis and Differential Diagnosis of Systemic Lupus Erythematosus in Adults
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Official reprint from UpToDate www.uptodate.com ©2015 UpToDate Author Daniel J Wallace, MD Section Editor David S Pisetsky, MD, PhD Deputy Editor Monica Ramirez Curtis, MD, MPH Diagnosis and differential diagnosis of systemic lupus erythematosus in adults All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2015. | This topic last updated: Jul 01, 2014. INTRODUCTION — Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause that can affect virtually any organ of the body. Immunologic abnormalities, especially the production of a number of antinuclear antibodies (ANA), are a prominent feature of the disease. Patients present with variable clinical features ranging from mild joint and skin involvement to lifethreatening renal, hematologic, or central nervous system involvement. The clinical heterogeneity of SLE and the lack of pathognomonic features or tests pose a diagnostic challenge for the clinician. To complicate matters, patients may present with only a few clinical features of SLE, which can resemble other autoimmune, infectious, or hematologic diseases. The diagnosis of SLE is generally based on clinical judgment, after excluding alternative diagnoses. In the absence of SLE diagnostic criteria, SLE classification criteria are often used by clinicians as guidance to help identify some of the salient clinical features when making the diagnosis. Serological findings are important to suggesting the possibility of SLE, with some antibodies (eg, antidoublestranded DNA [dsDNA] and antiSmith [Sm]) highly associated with this condition. The approach to the diagnosis and differential diagnosis of SLE will be reviewed here. An overview of the symptoms and signs that can occur in SLE, discussions of particular sites of involvement (eg, skin, kidneys, central nervous system), and the treatment and prognosis of SLE are presented separately. (See "Overview of the clinical manifestations of systemic lupus erythematosus in adults" and "Overview of the management and prognosis of systemic lupus erythematosus in adults" .) EVALUATION FOR SUSPECTED SLE — The initial diagnosis of systemic lupus erythematosus (SLE) depends on the manner of presentation and the exclusion of alternative diagnoses. Given the heterogeneity of clinical presentations, there are some patients for whom the constellation of presenting clinical features and supportive laboratory studies make the diagnosis of SLE relatively straightforward. By contrast, there are others who present with isolated complaints or infrequent disease characteristics and represent more of a diagnostic challenge. Demographics should also be taken into account when evaluating a patient for SLE, since it occurs primarily in young women of childbearing age. In addition, SLE occurs more commonly in certain racial and ethnic groups. (See "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Epidemiology' .) As an example, the diagnosis of SLE is more likely in a young woman who presents with complaints of fatigue, arthralgia, and pleuritic chest pain and who is found to have hypertension, a malar rash, a pleural friction rub, several tender and swollen joints, and mild peripheral edema. Laboratory testing may reveal leukopenia, anemia, an elevated serum creatinine, hypoalbuminemia, proteinuria, an active urinary sediment, hypocomplementemia, and positive tests for antinuclear antibodies (ANA), including those to doublestranded DNA (dsDNA) and the Smith (Sm) antigen. By contrast, another patient may present with leukopenia or singleorgan involvement (eg, nephritis or pericarditis). Such patients may subsequently develop the characteristic multisystem features of SLE over a period of months or years. (See "Overview of the clinical manifestations of systemic lupus erythematosus in adults" .) Thus, the initial evaluation requires a careful history and physical exam, along with selected laboratory testing to identify features that are characteristic of SLE or that suggest an alternative diagnosis. Patients presenting with symptoms for a shorter duration of time will need close followup, as the frequency with which various features of ® ®
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Diferenciales diagnosticos de LES según uptodate
Transcript of Diagnosis and Differential Diagnosis of Systemic Lupus Erythematosus in Adults
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OfficialreprintfromUpToDate www.uptodate.com2015UpToDate
AuthorDanielJWallace,MD
SectionEditorDavidSPisetsky,MD,PhD
DeputyEditorMonicaRamirezCurtis,MD,MPH
Diagnosisanddifferentialdiagnosisofsystemiclupuserythematosusinadults
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Jul01,2014.
INTRODUCTIONSystemiclupuserythematosus(SLE)isachronicinflammatorydiseaseofunknowncausethatcanaffectvirtuallyanyorganofthebody.Immunologicabnormalities,especiallytheproductionofanumberofantinuclearantibodies(ANA),areaprominentfeatureofthedisease.
Patientspresentwithvariableclinicalfeaturesrangingfrommildjointandskininvolvementtolifethreateningrenal,hematologic,orcentralnervoussysteminvolvement.TheclinicalheterogeneityofSLEandthelackofpathognomonicfeaturesortestsposeadiagnosticchallengefortheclinician.Tocomplicatematters,patientsmaypresentwithonlyafewclinicalfeaturesofSLE,whichcanresembleotherautoimmune,infectious,orhematologicdiseases.
ThediagnosisofSLEisgenerallybasedonclinicaljudgment,afterexcludingalternativediagnoses.IntheabsenceofSLEdiagnosticcriteria,SLEclassificationcriteriaareoftenusedbycliniciansasguidancetohelpidentifysomeofthesalientclinicalfeatureswhenmakingthediagnosis.SerologicalfindingsareimportanttosuggestingthepossibilityofSLE,withsomeantibodies(eg,antidoublestrandedDNA[dsDNA]andantiSmith[Sm])highlyassociatedwiththiscondition.
TheapproachtothediagnosisanddifferentialdiagnosisofSLEwillbereviewedhere.AnoverviewofthesymptomsandsignsthatcanoccurinSLE,discussionsofparticularsitesofinvolvement(eg,skin,kidneys,centralnervoussystem),andthetreatmentandprognosisofSLEarepresentedseparately.(See"Overviewoftheclinicalmanifestationsofsystemiclupuserythematosusinadults"and"Overviewofthemanagementandprognosisofsystemiclupuserythematosusinadults".)
EVALUATIONFORSUSPECTEDSLETheinitialdiagnosisofsystemiclupuserythematosus(SLE)dependsonthemannerofpresentationandtheexclusionofalternativediagnoses.Giventheheterogeneityofclinicalpresentations,therearesomepatientsforwhomtheconstellationofpresentingclinicalfeaturesandsupportivelaboratorystudiesmakethediagnosisofSLErelativelystraightforward.Bycontrast,thereareotherswhopresentwithisolatedcomplaintsorinfrequentdiseasecharacteristicsandrepresentmoreofadiagnosticchallenge.DemographicsshouldalsobetakenintoaccountwhenevaluatingapatientforSLE,sinceitoccursprimarilyinyoungwomenofchildbearingage.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)andtheSmith(Sm)antigen.Bycontrast,anotherpatientmaypresentwithleukopeniaorsingleorganinvolvement(eg,nephritisorpericarditis).SuchpatientsmaysubsequentlydevelopthecharacteristicmultisystemfeaturesofSLEoveraperiodofmonthsoryears.(See"Overviewoftheclinicalmanifestationsofsystemiclupuserythematosusinadults".)
Thus,theinitialevaluationrequiresacarefulhistoryandphysicalexam,alongwithselectedlaboratorytestingtoidentifyfeaturesthatarecharacteristicofSLEorthatsuggestanalternativediagnosis.Patientspresentingwithsymptomsforashorterdurationoftimewillneedclosefollowup,asthefrequencywithwhichvariousfeaturesof
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SLEobserveddifferaccordingtostageofdisease[15].
ClinicalmanifestationsGiventhebroadrangeofclinicalmanifestationsofSLE,itishelpfultoconsiderthevariousfeaturesaccordingtofrequencyatdiseaseonset(table1).OurgeneralapproachtothehistoryandphysicalexaminationforpatientswithsuspectedSLEisdescribedbelow.
Weperformathoroughmedicalhistory,withparticularattentiontothefollowingsymptomsandsigns:
Wealsoaskaboutexposuretomedicationsassociatedwithdruginducedlupus(eg,hydralazineandothers)(see"Druginducedlupus").Acompletephysicalexaminationisindicated,sinceanyorgansystemcanbeinvolvedinSLE.
Pertinentphysicalexaminationfindingsincludethefollowing:
DetaileddiscussionsofthevariousphysicalfindingsassociatedwithSLEarediscussedindetailseparately.(See"Mucocutaneousmanifestationsofsystemiclupuserythematosus"and"Musculoskeletalmanifestationsofsystemiclupuserythematosus"and"Pulmonarymanifestationsofsystemiclupuserythematosusinadults"and"Diagnosisandclassificationofrenaldiseaseinsystemiclupuserythematosus"and"Neurologicmanifestationsofsystemiclupuserythematosus"and"Neuropsychiatricmanifestationsofsystemiclupuserythematosus"and"Noncoronarycardiacmanifestationsofsystemiclupuserythematosusinadults"and"Coronaryheartdiseaseinsystemiclupuserythematosus".)
LaboratorytestingWeobtainthefollowingroutinelaboratorytests,whichmayprovidediagnosticallyusefulinformation:
Inadditiontotheroutinelaboratoriesdescribedabove,weperformthefollowinglaboratorytestswhichsupportthediagnosisofSLEifabnormal:
Constitutionalsymptomssuchasfever,fatigue,lymphadenopathy,orweightlossPhotosensitiveskinlesionssuchasamalarrashPainlessoralornasalulcersHairlossthatispatchyorfrontal/peripheralRaynaudphenomenonJointpainorswellingwhichcanbemigratoryorsymmetricalDyspneaorpleuriticchestpainsuggestiveofserositisChestpainsuggestiveofpericarditisLowerextremityedemaNeurologicsymptomssuchasseizuresorpsychosisRecurrentmiscarriages(see"Pregnancyinwomenwithsystemiclupuserythematosus")
SkinlesionsconsistentwithamalarrashordiscoidlesionsScarringornonscarringpatchyalopeciaOralornasopharyngealulcersPolyarticulararthritiswhichisoftensymmetricSubluxationatthemetacarpalphalangeal(MCP)jointsandrheumatoidlikeswanneckdeformitiesinthehandsmaybeobserved,whichareusuallynotreducible
Decreasedorabnormalbreathsoundsmayindicateapleuraleffusion,pneumonitis,orinterstitiallungdisease
Lowerextremityedemaandhypertensionmaybeduetorenalinvolvement
Completebloodcountanddifferentialmayrevealleukopenia,mildanemia,and/orthrombocytopeniaElevatedserumcreatininemaybesuggestiveofrenaldysfunctionUrinalysiswithurinesedimentmayrevealhematuria,pyuria,proteinuria,and/orcellularcasts
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TheANAtestispositiveinvirtuallyallpatientswithSLEatsometimeinthecourseoftheirdisease(see"Measurementandclinicalsignificanceofantinuclearantibodies").IftheANAispositive,oneshouldtestforotherspecificantibodiessuchasdsDNA,antiSm,Ro/SSA,La/SSB,andU1ribonucleoprotein(RNP).Insomelabs,apositiveANAtestbyindirectimmunofluorescencewillautomaticallyresultintestingforsuchadditionalantinuclearantibodiesthatareoftenpresentinpatientsSLE.
IftheANAtestisnegative,buttheclinicalsuspicionofSLEishigh,thenadditionalantibodytestingmaystillbeappropriate.ThisispartlyrelatedtothedifferencesinthesensitivityandspecificityamongthemethodsusedtodetectANA.Thesolidphaseassaysaremoresensitivethanindirectimmunofluorescenceandmaybemorelikelytodetecttheantibodies.AmoredetaileddiscussiononthetechniquesusedtodetectANAispresentedseparately.(See"Measurementandclinicalsignificanceofantinuclearantibodies".)
Weperformthefollowinglaboratorytestsinselectedpatients:
ANAAntiphospholipidantibodies(lupusanticoagulant[LA],IgGandIgManticardiolipin[aCL]antibodiesandIgGandIgMantibeta2glycoprotein[GP]I)
C3andC4orCH50complementlevelsErythrocytesedimentationrate(ESR)and/orCreactiveprotein(CRP)levelsUrineproteintocreatinineratio
AntidsDNAandantiSmantibodiesarehighlyspecificforSLE,butantiSmantibodieslacksensitivity[6,7].AntidsDNAandantiSmantibodiesareseeninapproximately70and30percentofpatientswithSLE,respectively.(See"Antibodiestodoublestranded(ds)DNA,Sm,andU1RNP".)
AntiRo/SSAandantiLa/SSBantibodiesarepresentinapproximately30and20percentofpatientswithSLE,respectivelyhowever,bothantibodiesaremorecommonlyassociatedwithSjgrenssyndrome[6].(See"TheantiRo/SSAandantiLa/SSBantigenantibodysystems".)
AntiU1RNPantibodiesareobservedinapproximately25percentofpatientswithSLE,buttheyalsooccurinpatientswithotherconditionsandhighlevelsarealmostalwayspresentinpatientswithmixedconnectivetissuedisease(MCTD)[6,7].(See"Antibodiestodoublestranded(ds)DNA,Sm,andU1RNP".)
AntiribosomalPproteinantibodieshaveahighspecificityforSLE,buthavelowsensitivityforSLE.Theyalsolackspecificityforinvolvementofaparticularorgansystemordiseasemanifestation.(See"AntiribosomalPproteinantibodies",sectionon'ClinicalutilityofantiribosomalPantibodies'.)
Rheumatoidfactor(RF)andanticycliccitrullinatedpeptide(CCP)antibodiesInpatientswithpredominantarthralgiasorarthritis,RFandantiCCPantibodiesmayhelpexcludeadiagnosisofrheumatoidarthritis(RA).RFhaslessdiagnosticutilitysince20to30percentofpeoplewithSLEhaveapositiveRF.AntiCCPantibodies,however,haveamuchhigherspecificityforRAandmaybemoreusefulfordistinguishingthearthritisassociatedwithRA.(See"Clinicallyusefulbiologicmarkersinthediagnosisandassessmentofoutcomeinrheumatoidarthritis",sectionon'Rheumatoidfactors'and"Clinicallyusefulbiologicmarkersinthediagnosisandassessmentofoutcomeinrheumatoidarthritis",sectionon'Anticitrullinatedpeptideantibodies'.)
SerologicalstudiesforinfectionInpatientswithabriefhistory(forexample,lessthansixweeks)ofpredominantarthralgiasorarthritis,weperformserologictestingforhumanparvovirusB19.WealsoperformserologictestingforhepatitisBvirus(HBV)andhepatitisCvirus(HCV)inpatientswithmultisystemicclinicalfindings.InareasendemicforLymedisease,wemayconsiderserologicstudiesforBorreliaaswell.TestingforEpsteinBarrvirus(EBV)infectionmayalsobeindicatedintheappropriateclinicalsetting.(See"Diagnosisanddifferentialdiagnosisofrheumatoidarthritis",sectionon'Viralpolyarthritis'and"Specificvirusesthatcausearthritis"and"DiagnosisofLymedisease",sectionon'Indicationsforserologictesting'.)
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ImagingDiagnosticimagingmaybevaluable,butisnotroutinelyobtainedunlessindicatedbythepresenceofsymptoms,clinicalfindings,orlaboratoryabnormalities.Examplesinclude:
BiopsyBiopsyofaninvolvedorgan(eg,skinorkidney)isnecessaryinsomecases.TypicalhistologicfindingsinvariousorgansinSLEarediscussedintopicreviewsdevotedtotheparticularsitesofinvolvement.(See"Diagnosisandclassificationofrenaldiseaseinsystemiclupuserythematosus"and"Mucocutaneousmanifestationsofsystemiclupuserythematosus".)
AdditionalstudiesinselectedpatientsOtherteststhatmaybenecessaryaretypicallydictatedbytheclinicalpresentationandassociateddifferentialdiagnosticpossibilities.Examplesinclude:
CLASSIFICATIONCRITERIAClassificationcriteriahavebeendevelopedforsystemiclupuserythematosus(SLE)asameansofcategorizingpatientsforstudypurposes.Thesecriteriacanbeusefulforcliniciansinsystematicallydocumentingkeydiseasefeatures,buttheirimperfectsensitivityandspecificitylimitstheirusefordiagnosticpurposes.
In2012,theSystemicLupusInternationalCollaboratingClinics(SLICC)proposedrevisedclassificationcriteriathatweredevelopedtoaddressinherentweaknessesofthe1997AmericanCollegeofRheumatology(ACR)classificationcriteria[9].Asanexample,oneofthemajorlimitationsofthe1997ACRcriteriaisthatpatientswithbiopsyconfirmedlupusnephritiscouldstillfailtofulfillcriteria.OtherconcernsregardingtheACRcriteriaincludedthepossibleduplicationofhighlycorrelatedcutaneousfeatures(suchasmalarrashandphotosensitivity),thelackofinclusionofothercutaneousmanifestations(suchasmaculopapularorpolycyclicrash),andtheomissionofmanyneurologicmanifestationsofSLE(suchasmyelitis).TheACRcriteriaalsodidnotincluderelevantimmunologicinformationsuchaslowserumlevelsofcomplementcomponents.
2012SLICCcriteriaAconsensusgroupofexpertsonSLE,theSLICC,hasproposedrevisedcriteriaforSLE(table2)[9].ClassificationashavingSLEbytheSLICCcriteriarequireseitherthatapatientsatisfyatleast4of17criteria,includingatleast1ofthe11clinicalcriteriaandoneofthesiximmunologiccriteria,orthatthepatienthasbiopsyprovennephritiscompatiblewithSLEinthepresenceofantinuclearantibodies(ANA)orantidoublestrandedDNA(dsDNA)antibodies.
Creatinekinase(CK)AnelevatedCKmayreflectmyositis,whichisrelativelyuncommoninpatientswithSLE.MyositismayalsosuggestanalternativediagnosissuchasMCTD,polymyositis(PM),ordermatomyositis(DM).
Plainradiographsofswollenjoints.UnlikeaffectedjointsinRA,erosionsareobservedinfrequentlyinSLE[8].Dependingonthestageofdisease,deformitiesmaybepresentonradiograph.
Renalultrasonographytoassesskidneysizeandtoruleouturinarytractobstructionwhenthereisevidenceofrenalimpairment
Chestradiography(eg,forsuspectedpleuraleffusion,interstitiallungdisease,cardiomegaly).
Echocardiography(eg,forsuspectedpericardialinvolvement,toassessforasourceofemboli,ornoninvasiveestimationofpulmonaryarterypressureandforevaluationofsuspectedvalvularlesions,suchasverrucae).
Computedtomography(CT)(eg,forabdominalpain,suspectedpancreatitis,interstitiallungdisease).
Magneticresonanceimaging(MRI)(eg,forfocalneurologicdeficitsorcognitivedysfunction).
Electrocardiographyintheassessmentofchestpainthatmaybeduetopericarditisortomyocardialischemia
TeststoassessforpulmonaryembolisminapatientwithpleuriticchestpainanddyspneaDiffusingcapacityforcarbonmonoxide(DLCO)toassessforsuspectedpulmonaryhemorrhageandtoestimatetheseverityofinterstitiallungdisease
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TheSLICCcriteriawerevalidatedbyanalysisof690patientswithSLEorotherrheumaticdiseases.Inthisinitialvalidationtesting,theSLICCrevisedcriteriahadgreatersensitivitybutlowerspecificitythanthe1997ACRclassificationcriteria(sensitivityof97versus83percentandspecificityof84versus96percent,respectively).
However,despitetheimprovedsensitivitycomparedwiththeACRcriteria,theSLICCcriteriamightdelaythediagnosisofSLEinasignificantnumberofpatients,andsomepatientsmightnotbeclassifiedatall.ThesesituationsweredemonstratedinastudyinwhichpatientsweregroupedaccordingtowhethertheSLICCcriteriaweremetbefore,atthesametimeas,oraftertheACRcriteria,andthegroupswerethencompared.Outof622patients,319(50percent)wereclassifiedatthesametimeusingeithercriteriaset,78(12percent)earlierand225(35percent)later(mean4.4years)withtheSLICCcriteriathanwiththeACRcriteria[10].AmongthepatientsdiagnosedlaterwiththeSLICCcriteria,inthemajorityofcasesthedelaywasduetothecombinationofmalarrashandphotosensitivityintotheacutecutaneousSLEcriterion.
1997ACRcriteriaPreviously,mostcliniciansreliedforthediagnosisoflupusupontheclassificationcriteriathatweredevelopedbytheAmericanRheumatismAssociation(ARA,nowtheACR)(table3)[1113].Thecriteriawereestablishedbyclusteranalyses,primarilyinacademiccentersandprimarilyinCaucasianpatients.
ThepatientisclassifiedwithSLEusingtheACRcriteriaiffourormoreofthemanifestationsarepresent,eitherseriallyorsimultaneously,duringanyintervalofobservations[11,12].ApositiveLEcelltest,usedinoldercriteria,wasreplacedbythepresenceofantiphospholipidantibodies[11].Whentestedagainstotherrheumaticdiseases,thesecriteriahaveasensitivityandspecificityofapproximately96percent.
DIAGNOSISThediagnosisofsystemiclupuserythematosus(SLE)isbaseduponthejudgmentofanexperiencedclinicianwhorecognizescharacteristicconstellationsofsymptomsandsignsinthesettingofsupportiveserologicstudies,afterexcludingalternativediagnoses.ThisisoftenchallengingduetothegreatvariabilityintheexpressionandseverityofSLE.Althoughtheclassificationcriteriaweredesignedforresearchpurposes,manycliniciansrefertoaspectsofthesecriteriawhenmakingthediagnosisofSLE.(See'Classificationcriteria'above.)
Intheabsenceofexistingdiagnosticcriteria,wedescribeourgeneralapproachtothediagnosisthattakesintoconsiderationthestrengthsofbothclassificationsystemsdescribedabove.However,ourgeneralguidelinesdonotadequatelyaddressthemyriadmanifestationsorsubtletiesofsomeclinicalfeatures,nordotheysubstituteforclinicaljudgment.Thus,itisoftenappropriatetoreferpatientinwhomthediagnosisofSLEissuspectedtoarheumatologistwithexperienceinthisdisease[14].
Ourdiagnosticcriteria
DefiniteSLEAfterexcludingalternativediagnoses,wediagnoseSLEinthepatientwhofulfillsthe1997AmericanCollegeofRheumatology(ACR)criteriaorthe2012SystemicLupusInternationalCollaboratingClinics(SLICC)criteria(table2).Aspreviouslymentioned,theACRcriteriarequirethatapatientsatisfyatleast4of11criteria.TheSLICCcriteriarequireeitherthatapatientsatisfyatleast4of17criteria,includingatleast1ofthe11clinicalcriteriaandoneofthesiximmunologiccriteria,orthatthepatienthasbiopsyprovennephritiscompatiblewithSLEinthepresenceofantinuclearantibodies(ANA)orantidoublestrandedDNA(dsDNA)antibodies.
ProbableSLETherearepatientswhodonotfulfilltheclassificationcriteriaforSLE,butinwhomwestilldiagnosethedisorder.ThesepatientsincludethosepresentingwithaninadequatenumberofACRorSLICCcriteria,orthosewhohaveotherSLEmanifestationsnotincludedineitherclassificationcriteria.
Asalooseguide,wediagnoseSLEinpatientswhohavetwoorthreeoftheACRorSLICCcriteria,alongwithatleastoneotherfeaturethatmaybeassociatedwith,butisnotspecificfor,SLE.Someofthesefeaturesincludethefollowing[15]:
Opticneuritis,asepticmeningitisGlomerularhematuriaPneumonitis,pulmonaryhemorrhage,orpulmonaryhypertension,interstitiallungdisease
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PossibleSLEWeconsiderSLEapossiblediagnosisinindividualswhohaveonlyoneoftheACR/SLICCcriteria,inadditiontoatleastoneortwooftheotherfeatureslistedabove.
Ingeneral,patientswitheitherprobableorpossibleSLEaremanagedsimilarlytopatientswithSLEandtreatedaccordingtotheirpredominantsymptomsandmanifestations.Overtime,thesymptomsinthesepatientsmaypersist,evolveintoSLEorarelatedconnectivetissuedisorder,orevenresolve.
UndifferentiatedconnectivetissuediseaseOtherpatientswhohaveevenfewerfeaturessuggestiveofSLEmaybeclassifiedashavingundifferentiatedconnectivetissuedisease(UCTD).ThistermisusedtodescribepatientswithsignsandsymptomssuggestiveofasystemicautoimmunediseasebutdonotmeettheACRcriteriaforSLEoranotherdefinedconnectivetissuesdisease[16].(See"Undifferentiatedsystemicrheumatic(connectivetissue)diseasesandoverlapsyndromes".)
CaseserieshavebeenpublishedthatsummarizetheoutcomeofpatientswhohaveUCTDatpresentation[1721].Uptoonethirdhaveallsymptomsandsignsdisappearovera10yearfollowupperiod.Anywherefrom40to60percentofpatientscontinuetoexhibittheirinitialclinicalfeatures,while5to30percentevolveandmeetclassificationcriteriaforadefinitedisease,suchasSLE,rheumatoidarthritis(RA),scleroderma,oraninflammatorymyopathy(myositis)[1721](see"Undifferentiatedsystemicrheumatic(connectivetissue)diseasesandoverlapsyndromes").Thus,patientswithUCTDshouldbefollowedcarefully,encouragedtoreportnewsymptoms,andhaveperiodiclaboratorytestingtoassessfortheemergenceofnewclinicalfeaturesorlaboratoryfindings.
ANAnegativelupusANAnegativeSLEhasbeenrecognizedsincethe1970s,butwaslatershowntobeinfluencedbythetestingmethodsusedtodetectANA.Atthattimeitwasestimatedthatabout5percentofpatientswithSLEwereANAnegativebyindirectimmunofluorescence[22].However,thisnegativefindingoccurredbecauseseraweretestedusingrodentandnothumantissuesasthesubstratefortheindirectimmunofluorescencetestforANA[23].Bycomparison,antiRoantibodieswerefoundinmanyofthesepatientswhenahumancelllineextractwasusedassubstrateforantiRoantibodytesting.
ThesubsequentsubstitutionofHEp2cells(ahumancellline)forrodenttissuesectionsintheindirectimmunofluorescenceANAassayhasresultedinevenfewerSLEpatientswithnegativeANAbyindirectimmunofluorescence.Nevertheless,onrareoccasions,thepresenceofantiRoantibodiesmaysuggestasystemicautoimmunedisease,despitethepresenceofanegativeANAindirectimmunofluorescence.Asanexample,inonestudyinSweden,among4025seratestedforANA,64patientswithnegativeANAbyindirectimmunofluorescencehadantiRoantibodies[24].Ofthese64patients,12hadSLEandfivehadcutaneousLE.
TheclinicianshouldunderstandthetechniqueusedtodetecttheANAsincethiscaninfluencetheresult.Asanexample,anegativeANAbyindirectimmunofluorescenceisalsoclinicallyusefulasitdramaticallydecreasesthelikelihoodofSLE.Ontheotherhand,inapatientwithastrongclinicalsuspicionforSLEandanegativeANAresultbyasolidphaseassay,thetestshouldberepeatedusingindirectimmunofluorescencemethodwithHep2cellsgiventheincreasedfalsenegativebysolidphaseassay.AdetaileddiscussionofthemethodsusedtodetectANAispresentedseparately.(See"Measurementandclinicalsignificanceofantinuclearantibodies".)
OtherfactorsthatmayalsoinfluenceANAnegativityinSLEpatientsincludediseasedurationandtreatmentexposure[25].Inourexperience,thefrequencyofANAnegativeSLEislowerinpatientspresentingatanearlystageoftheirdisease.Inaddition,SLEpatientswhohavelongstandingdiseaseand/orhaveundergonetreatmentmayloseANAreactivityandbecomeserologicallynegativeovertime.
DIFFERENTIALDIAGNOSISGiventheproteanmanifestationsofsystemiclupuserythematosus(SLE),the
Myocarditis,verrucousendocarditis(LibmanSacksendocarditis)AbdominalvasculitisRaynaudphenomenon
Elevatedacutephasereactants(eg,erythrocytesedimentationrate[ESR]andCreactiveprotein[CRP])
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differentialdiagnosisiscorrespondinglybroad.Whileitisbeyondthescopeofthisreviewtoprovideacomprehensivelistofallpossiblealternativediagnoses,wepresentseveralhere.
Rheumatoidarthritis(RA)EarlyRAmaybedifficulttodistinguishfromthearthritisofSLEsincebothconditionscausejointtendernessandswelling(table4).Featuressuchasswanneckdeformities,ulnardeviation,andsofttissuelaxity,whichareobservedinlaterstagesofRAinpatientswithmoredestructivedisease,canalsobeseeninsomepatientswithSLE.However,importantdistinguishingfeaturesarethatthejointdeformitiesinSLEareoftenreducible,andinfrequentlyerosiveonplainradiographs.
SomeextraarticularRAmanifestations,includingserositis,siccasymptoms,subcutaneousnodules,anemia,andfatigue,areotherfeaturesthatmayalsobeobservedinSLE.ThesefeaturesaremorecommoninRApatientswithmoresevereoradvanceddisease.Serologicabnormalitiessuchasthepresenceofanticycliccitrullinatedpeptides(CCP)aremoresupportiveofthediagnosisofRA,andcanhelpdistinguishthediseases.Itshouldberecognizedthattheantinuclearantibodies(ANA)maybepositiveinuptoonehalfofpatientswithRA.Conversely,rheumatoidfactor(RF)maybepresentinapproximatelyonethirdofSLEpatients.(See"Diagnosisanddifferentialdiagnosisofrheumatoidarthritis".).
RhupusThetermrhupushasbeenusedtodescribepatientswithoverlappingfeaturesofbothSLEandRA.Whetherrhupusisclinicallyandimmunologicallyadistinctentity,atrueoverlapofSLEandRA,orasubsetofpatientswithSLEremainsamatterofdebate.InadditiontohavingserologiesconsistentwithbothSLEandRA,somepatientsclassifiedasrhupusmayhaveanerosivearthropathythatisatypicalforSLE.(See"Undifferentiatedsystemicrheumatic(connectivetissue)diseasesandoverlapsyndromes",sectionon'Earlyundifferentiatedsystemicrheumaticdisease'.)
Mixedconnectivetissuedisease(MCTD)MCTDischaracterizedbyoverlappingfeaturesofSLE,systemicsclerosis(SSc),andpolymyositis(PM),andbythepresenceofhightitersofantibodiesagainstU1ribonucleoprotein(RNP).However,thediagnosisofMCTDisoftencomplicatedsincemanyofitscharacteristicfeaturesoccursequentially,oftenoveraperiodofyears.Inaddition,somepatientswithMCTDmayevolveintoanotherconnectivetissuedisease,includingSLE,duringtheclinicalcourse[26].(See"Definitionanddiagnosisofmixedconnectivetissuedisease".)
Undifferentiatedconnectivetissuedisease(UCTD)Asmentionedabove,patientswithUCTDhavesignsandsymptomssuggestiveofasystemicautoimmunediseasebutdonotsatisfytheclassificationcriteriaforadefinedconnectivetissuediseasesuchasSLEorMCTD.Thesepatientsmayhavesymptomssuchasarthritisandarthralgias,Raynaudphenomenon,andserologicalfindingsthataredifficulttodistinguishfromearlyphasesofSLE.ThemajorityofpatientswithUCTDmaintainanundefinedprofileandhaveamilddiseasecourse[27].(See"Undifferentiatedsystemicrheumatic(connectivetissue)diseasesandoverlapsyndromes".)
Systemicsclerosis(SSc)ThecoexistenceofRaynaudphenomenonandgastroesophagealrefluxistypicallyobservedinSSchowever,thesefindingsarenonspecificandmaybeseeninpatientswithSLEorhealthyindividuals.Bycontrast,sclerodactyly,telangiectasias,calcinosis,andmalignanthypertensionwithacuterenalfailurearemoreconsistentwithSScratherthanSLE.Further,apositiveANAispresentinmostpatientswithSSc,whileotherserologiessuchasantidoublestrandedDNA(dsDNA)andantiSmith(Sm)antibodieswhicharemorespecificforSLE,arenotcommonlyobservedinSSc.Correspondingly,patientswithSSccommonlyexpressantibodiestoanantigencalledScl70(topoisomeraseI)orantibodiestocentromereproteins.DistinguishingSScfromSLEcanbeparticularlydifficultincaseswherethereisoverlapofthesediseases,suchasinMCTD.(See"Diagnosisanddifferentialdiagnosisofsystemicsclerosis(scleroderma)inadults".)
SjgrenssyndromePatientswithSjgrenssyndromemayhaveextraglandularmanifestationsthatcanbeobservedinSLE,suchasneurologicandpulmonaryabnormalities.However,patientswithSjgrenssyndromeshouldhaveobjectivesignsofkeratoconjunctivitissiccaandxerostomia,andcharacteristic
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findingsonsalivaryglandbiopsywhicharenottypicalofSLE.Also,patientswithSjgrenssyndromecommonlyexpressantibodiestoRoandLaantigens.(See"DiagnosisandclassificationofSjgren'ssyndrome".)
VasculitisPatientswithmediumandsmallvesselvasculitidessuchaspolyarteritisnodosa(PAN),granulomatosiswithpolyangiitis(GPA)(Wegeners),ormicroscopicpolyangiitis(MPA)maypresentwithoverlappingfeaturesofSLEincludingconstitutionalsymptoms,skinlesions,neuropathyandrenaldysfunction.However,patientswiththesetypesofvasculitidesareusuallyANAnegative.(See"Clinicalmanifestationsanddiagnosisofgranulomatosiswithpolyangiitisandmicroscopicpolyangiitis"and"Clinicalmanifestationsanddiagnosisofpolyarteritisnodosainadults".)
BehetsdiseaseOralaphthaearepresentinalmostallpatientswithBehetsdisease,andmaybeobservedinpatientswithSLE.Otheroverlappingfeaturesincludeinflammatoryeyedisease,neurologicdisease,vasculardisease,andarthritis.However,patientswithBehetsaremorecommonlymaleandANAnegative.Also,vascularinvolvementofanysize(small,medium,large)ismorecommonlyafeatureofBehetsdiseaseratherthanSLE.(See"ClinicalmanifestationsanddiagnosisofBehetsdisease".)
Dermatomyositis(DM)andpolymyositis(PM)PatientswithSLEcanpresentwithalowgrademyositis,whereaspatientswithDMandPMgenerallydemonstratemoreovertproximalmuscleweakness.ApositiveANAisobservedinapproximately30percentofpatientswithDMandPM,comparedwithalmostallpatientsinSLE.PatientswithDMmayhavecharacteristicskinfindingsincludingGottronspapules,aheliotropeeruptionandphotodistributedpoikiloderma(includingtheshawlandVsigns).ClinicalfindingscharacteristicofSLEsuchasoralulcers,arthritis,nephritis,andhematologicabnormalitiesareabsentinDMandPM.PatientswithDMorPMmayalsoexpressmyositisspecificantibodiessuchasantiJo1.(See"Clinicalmanifestationsofdermatomyositisandpolymyositisinadults".)
AdultStillsdisease(ASD)SomeoftheclinicalmanifestationsobservedinASDsuchasfever,arthritisorarthralgias,andlymphadenopathy,arenotunusualforpatientswithSLE.However,patientswithASDoftenpresentwithaleukocytosisratherthantheleukopeniaobservedinSLE,andtheytypicallyarenegativeforANA.(See"ClinicalmanifestationsanddiagnosisofadultStill'sdisease".)
KikuchisdiseaseKikuchisdiseaseisabenignandusuallyselflimitedformofhistiocyticnecrotizinglymphadenitis.Clinicalfeaturesatpresentationincludelymphadenopathyaswellasfever,myalgias,arthralgias,and,lesscommonly,hepatosplenomegaly.AssociationswithSLEhavebeenreported,buttheclinicalcourseisusuallyfavorablewithspontaneousremissionoftenoccurringwithinfourmonths.ThediagnosisofKikuchisdiseaseisbasedonalymphnodebiopsy,whichrevealsahistiocyticcellularinfiltrate.(See"Kikuchidisease".)
SerumsicknessManyoftheclinicalfeaturesobservedinserumsicknesssuchasfever,lymphadenopathy,cutaneouseruptions,andarthralgiasareoftenobservedinSLE.Furthermore,duringsevereepisodes,complementmeasurementsincludingC3andC4canbedepressed,asinSLE.UnlikeSLE,however,ANAsaretypicallynegativeandthecoursetendstobeselflimited.(See"Serumsicknessandserumsicknesslikereactions".)
FibromyalgiaPatientswithSLEmaypresentwithgeneralizedarthralgias,myalgias,andfatigue,muchlikepatientswithfibromyalgia.However,othercharacteristicfeaturesofSLEsuchasaphotosensitiverash,arthritis,andmultisystemorganinvolvementareabsent.However,fibromyalgiaoccursmorecommonlyinpatientswithsystemicrheumaticdiseasesthaninthegeneralpopulationthus,patientswithSLEmayhaveconcomitantfibromyalgia.(See"Clinicalmanifestationsanddiagnosisoffibromyalgiainadults".)
InfectionsSeveralviralinfectionscanproducesignsandsymptomspresentinSLE,includingcytomegalovirus(CMV)andEpsteinBarrvirus(EBV).Inaddition,EBVinfectionmayleadtoapositiveANA[28,29].HumanparvovirusB19cancauseflulikesymptomsandhematologicabnormalitiessuchasleukopeniaandthrombocytopenia,whichcanbeobservedinSLE,andpatientsmaypresentwitharthralgias
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INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsandBeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5 to6 gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10 to12 gradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingonpatientinfoandthekeyword(s)ofinterest.)
SUMMARYANDRECOMMENDATIONS
orarthritis.
Otherviralinfectionsthatmaypresentwithmultisysteminvolvementincludehumanimmunodeficiencyvirus(HIV),hepatitisBvirus(HBV),hepatitisCvirus(HCV).However,serologicassayscanbediagnosticformanyoftheseviruses.SomebacterialinfectionssuchasSalmonellaortuberculosisshouldalsobeconsideredifappropriate.
Multiplesclerosis(MS)Althoughrare,patientswithSLEcanpresentwithcranialneuropathiesthatmustbedistinguishedfromMS.Unilateralopticneuritisandpyramidalsyndrome,withlesionsdetectedbymagneticresonanceimaging(MRI)suggestingdisseminationinspaceandtimearecharacteristicofMS.(See"Diagnosisofmultiplesclerosisinadults".)
MalignanciesLeukemiaormyelodysplasticsyndromesmaypresentwithhematologicandconstitutionalsymptomssimilartothoseobservedinSLE.However,monoclonalexpansionofBandTcells(asassessedbyimmunophenotyping),monocytosis,ormacrocytosiscandistinguishthesemalignanciesfromSLE.Patientswithlymphomaalsotypicallyhaveadditionalfindingssuchassplenomegaly,lymphadenopathy,orincreasedlactatedehydrogenase(LDH)levels.PatientswithangioimmunoblasticTcelllymphoma(AITL)maybedistinguishedbyfindingsonanexcisionaltissuebiopsy,mostcommonlyalymphnode.
Thromboticthrombocytopenicpurpura(TTP)AlthoughpatientswithSLEmayhavefeverandthrombocytopenia,patientswithTTPalsohavemicroangiopathichemolyticanemia,acuterenalinsufficiency,fluctuatingneurologicalmanifestations,and/orlowlevelsofADAMSTS13.(See"Diagnosisofthromboticthrombocytopenicpurpurahemolyticuremicsyndromeinadults".)
th th
th th
Basicstopics(see"Patientinformation:Lupus(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Antinuclearantibodies(ANA)(BeyondtheBasics)"and"Patientinformation:Systemiclupuserythematosus(SLE)(BeyondtheBasics)")
Theinitialevaluationforsystemiclupuserythematosus(SLE)requiresacarefulhistoryandphysicalexam,alongwithselectedlaboratorytestingtoidentifyfeaturesthatarecharacteristicofSLEorthatsuggestanalternativediagnosis.Aspartofthemedicalhistoryandphysicalexamination,wepayparticularattentiontothefollowingsymptomsandsigns(see'EvaluationforsuspectedSLE'above):
PhotosensitiveskinlesionssuchasamalarrashordiscoidlesionsPainlessoralornasalulcersHairlossthatispatchyorfrontal/peripheralRaynaudphenomenonJointpainorswellingwhichcanbemigratoryorsymmetricalSymptomsofserositis/pericarditis
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Wealsoaskaboutexposuretomedicationsassociatedwithdruginducedlupus(eg,hydralazine).(See"Druginducedlupus".)
WeobtainacompletebloodcountanddifferentialaswellasserumcreatininelevelandurinalysisinallpatientssuspectedofhavingSLE(see'Laboratorytesting'above).Inadditiontotheseroutinelaboratorystudies,weperformselectedlaboratorytestswhichsupportthediagnosisofSLEifabnormal.Theseincludeantinuclearantibodies(ANA)(andifpositive,otherspecificautoantibodiessuchasantidoublestrandedDNA[dsDNA],antiSmith[Sm]),antiphospholipidantibodies,C3andC4orCH50complementlevels,erythrocytesedimentationrate(ESR)and/orCreactiveprotein(CRP)levels,andtheurineproteintocreatinineratio.
Additionalstudiessuchasdiagnosticimagingorbiopsyofaninvolvedorganmaybenecessarysuchtestingisdictatedbytheclinicalpresentationandassociateddifferentialdiagnosticpossibilities.(See'Imaging'aboveand'Biopsy'aboveand'Additionalstudiesinselectedpatients'above.)
ClassificationcriteriahavebeendevelopedforSLEasameansofcategorizingpatientsforstudypurposes.Thesecriteriacanbeusefulforcliniciansinsystematicallydocumentingkeydiseasefeatures.(See'Classificationcriteria'above.)
ThediagnosisofSLEisbaseduponthejudgmentofanexperiencedclinicianwhorecognizescharacteristicconstellationsofsymptomsandsignsinthesettingofsupportiveserologicstudies,afterexcludingalternativediagnoses.GiventhegreatvariabilityintheexpressionandseverityofSLE,thediagnosisofSLEissometimeschallengingandreferraltoarheumatologistwithexperienceinthisdiseaseisoftenappropriate.(See'Ourdiagnosticcriteria'above.)
Intheabsenceofexistingdiagnosticcriteria,ourgeneralapproachtothediagnosisofSLEisasfollows(see'Ourdiagnosticcriteria'above):
DefiniteSLEAfterexcludingalternativediagnoses,wediagnoseSLEinthepatientwhofulfillsthe1997AmericanCollegeofRheumatology(ACR)criteriaorthe2012SystemicLupusInternationalCollaboratingClinics(SLICC)classificationcriteria(table2).(See'DefiniteSLE'above.)
ProbableSLETherearepatientswhodonotfulfilltheclassificationcriteriaforSLE,butinwhomwestilldiagnosethedisorder.ThesepatientsincludethosepresentingwithaninadequatenumberofACRorSLICCcriteria,orthosewhohaveotherSLEmanifestationsnotincludedineitherclassificationcriteria.(See'ProbableSLE'above.)
Asalooseguide,wediagnoseSLEinpatientswhohavetwoorthreeoftheACRorSLICCcriteria,alongwithatleastoneotherfeaturethatmaybeassociatedwith,butisnotspecificfor,SLE.Someofthesefeaturesincludethefollowing:
Opticneuritis,asepticmeningitisGlomerularhematuriaPneumonitis,pulmonaryhemorrhage,orpulmonaryhypertension,interstitiallungdiseaseMyocarditis,verrucousendocarditis(LibmanSacksendocarditis)AbdominalvasculitisRaynaudphenomenonElevatedacutephasereactants(eg,ESRandCRP)
PossibleSLEWeconsiderSLEapossiblediagnosisinindividualswhohaveonlyoneoftheACR/SLICCcriteria,inadditiontoatleastoneortwooftheuncommonfeatureslistedabove.(See'PossibleSLE'above.)
Undifferentiatedconnectivetissuedisease(UCTD)OtherpatientswhohaveevenfewerfeaturessuggestiveofSLEmaybeclassifiedasUCTD.ThistermisusedtodescribepatientswithsignsandsymptomssuggestiveofasystemicautoimmunediseasebutdonotmeettheACRcriteriaforSLEor
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ACKNOWLEDGMENTTheeditorialstaffatUpToDatewouldliketoacknowledgePeterSchur,MD,whocontributedtoanearlierversionofthistopicreview.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1. CerveraR,KhamashtaMA,FontJ,etal.Systemiclupuserythematosus:clinicalandimmunologicpatternsofdiseaseexpressioninacohortof1,000patients.TheEuropeanWorkingPartyonSystemicLupusErythematosus.Medicine(Baltimore)199372:113.
2. EstesD,ChristianCL.Thenaturalhistoryofsystemiclupuserythematosusbyprospectiveanalysis.Medicine(Baltimore)197150:85.
3. FontJ,CerveraR,RamosCasalsM,etal.Clustersofclinicalandimmunologicfeaturesinsystemiclupuserythematosus:analysisof600patientsfromasinglecenter.SeminArthritisRheum200433:217.
4. PonsEstelBA,CatoggioLJ,CardielMH,etal.TheGLADELmultinationalLatinAmericanprospectiveinceptioncohortof1,214patientswithsystemiclupuserythematosus:ethnicanddiseaseheterogeneityamong"Hispanics".Medicine(Baltimore)200483:1.
5. NossentJ,KissE,RozmanB,etal.Diseaseactivityanddamageaccrualduringtheearlydiseasecourseinamultinationalinceptioncohortofpatientswithsystemiclupuserythematosus.Lupus201019:949.
6. RiemakastenGandHiepeF.Autoantibodies.In:Dubois'LupusErythematosusandRelatedSyndromes,8,WallaceDJandHahnBH.(Ed),ElsevierSaunders,Philadelphia2013.p.282.
7. BenitoGarciaE,SchurPH,LahitaR,AmericanCollegeofRheumatologyAdHocCommitteeonImmunologicTestingGuidelines.Guidelinesforimmunologiclaboratorytestingintherheumaticdiseases:antiSmandantiRNPantibodytests.ArthritisRheum200451:1030.
8. WeissmanBN,RappoportAS,SosmanJL,SchurPH.Radiographicfindingsinthehandsinpatientswithsystemiclupuserythematosus.Radiology1978126:313.
9. PetriM,OrbaiAM,AlarcnGS,etal.DerivationandvalidationoftheSystemicLupusInternationalCollaboratingClinicsclassificationcriteriaforsystemiclupuserythematosus.ArthritisRheum201264:2677.
10. PonsEstelGJ,WojdylaD,McGwinGJr,etal.TheAmericanCollegeofRheumatologyandtheSystemicLupusInternationalCollaboratingClinicsclassificationcriteriaforsystemiclupuserythematosusintwomultiethniccohorts:acommentary.Lupus201423:3.
11. HochbergMC.UpdatingtheAmericanCollegeofRheumatologyrevisedcriteriafortheclassificationofsystemiclupuserythematosus.ArthritisRheum199740:1725.
12. TanEM,CohenAS,FriesJF,etal.The1982revisedcriteriafortheclassificationofsystemiclupuserythematosus.ArthritisRheum198225:1271.
13. PetriM,MagderL.Classificationcriteriaforsystemiclupuserythematosus:areview.Lupus200413:829.14. Guidelinesforreferralandmanagementofsystemiclupuserythematosusinadults.AmericanCollegeof
RheumatologyAdHocCommitteeonSystemicLupusErythematosusGuidelines.ArthritisRheum199942:1785.
15. BertsiasGK,PamfilC,FanouriakisA,BoumpasDT.Diagnosticcriteriaforsystemiclupuserythematosus:hasthetimecome?NatRevRheumatol20139:687.
anotherdefinedconnectivetissuesdisease.(See'Undifferentiatedconnectivetissuedisease'above.)
ANAnegativeSLELessthan5percentofpatientswithSLEarenegativeforANAasdetectedbyindirectimmunofluorescence.ThefrequencyofANAnegativeSLEisevenlowerinpatientspresentingatanearlystageoftheirdisease.Inaddition,SLEpatientswhohavelongstandingdiseaseand/orhaveundergonetreatmentmayloseANAreactivityandbecomeserologicallynegativeovertime.
ThedifferentialdiagnosisofSLEisbroad.Itincludesmanysystemicconnectivediseasesaswellasotherautoimmunedisorders.(See'Differentialdiagnosis'above.)
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16. AlarcnGS,WilliamsGV,SingerJZ,etal.Earlyundifferentiatedconnectivetissuedisease.I.Earlyclinicalmanifestationinalargecohortofpatientswithundifferentiatedconnectivetissuediseasescomparedwithcohortsofwellestablishedconnectivetissuedisease.JRheumatol199118:1332.
17. GreerJM,PanushRS.Incompletelupuserythematosus.ArchInternMed1989149:2473.18. LomOrtaH,AlarconSegoviaD,DiazJouanenE.Systemiclupuserythematosus.Differencesbetween
patientswhodo,andwhodonot,fulfillclassificationcriteriaatthetimeofdiagnosis.JRheumatol19807:831.
19. BodolayE,CsikiZ,SzekaneczZ,etal.Fiveyearfollowupof665Hungarianpatientswithundifferentiatedconnectivetissuedisease(UCTD).ClinExpRheumatol200321:313.
20. SthlHallengrenC,NivedO,SturfeltG.Outcomeofincompletesystemiclupuserythematosusafter10years.Lupus200413:85.
21. MoscaM,TaniC,BombardieriS.Acaseofundifferentiatedconnectivetissuedisease:isitadistinctclinicalentity?NatClinPractRheumatol20084:328.
22. MaddisonPJ,ProvostTT,ReichlinM.Serologicalfindingsinpatientswith"ANAnegative"systemiclupuserythematosus.Medicine(Baltimore)198160:87.
23. CrossLS,AslamA,MisbahSA.Antinuclearantibodynegativelupusasadistinctdiagnosticentitydoesitnolongerexist?QJM200497:303.
24. BlombergS,RonnblomL,WallgrenAC,etal.AntiSSA/Roantibodydeterminationbyenzymelinkedimmunosorbentassayasasupplementtostandardimmunofluorescenceinantinuclearantibodyscreening.ScandJImmunol200051:612.
25. HellerCA,SchurPH.Serologicalandclinicalremissioninsystemiclupuserythematosus.JRheumatol198512:916.
26. CappelliS,BellandoRandoneS,MartinoviD,etal."Tobeornottobe,"tenyearsafter:evidenceformixedconnectivetissuediseaseasadistinctentity.SeminArthritisRheum201241:589.
27. MoscaM,TaniC,NeriC,etal.Undifferentiatedconnectivetissuediseases(UCTD).AutoimmunRev20066:1.
28. SculleyDG,SculleyTB,PopeJH.Reactionsofserafrompatientswithrheumatoidarthritis,systemiclupuserythematosusandinfectiousmononucleosistoEpsteinBarrvirusinducedpolypeptides.JGenVirol198667(Pt10):2253.
29. AlJitawiSA,HakoozBA,KazimiSM.FalsepositiveMonospottestinsystemiclupuserythematosus.BrJRheumatol198726:71.
Topic4668Version21.0
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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 1 4to8
Renal 16to38 34to73
Nephrosis 5 11to18
Gastrointestinal 18 38to44
Pulmonary 2to12 24to98
Pleurisy 17 30to45
Effusion 24
Pneumonia 29
Cardiac 15 20to46
Pericarditis 8 8to48
Murmurs 23
ECGchanges 34to70
Lymphadenopathy 7to16 21to50
Splenomegaly 5 9to20
Hepatomegaly 2 7to25
Centralnervoussystem 12to21 25to75
Functional Most
Psychosis 1 5to52
Convulsions 0.5 2to20
Adaptedfrom:VonFeldtJM,PostgradMed199597:79.
Graphic70386Version4.0
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Classificationcriteriaforsystemiclupuserythematosus
ACRcriteriafortheclassificationofsystemiclupuserythematosus
SLICCcriteriafortheclassificationofsystemiclupuserythematosus
(4of11criteria)* (4of17criteria,includingatleastoneclinicalcriterionandoneimmunologiccriterion OR
biopsyprovenlupusnephritis )
Criterion Definition Criterion Definition
Clinicalcriteria
Malarrash Fixederythema,flatorraised,overthemalareminences,tendingtosparethenasolabialfolds
Acutecutaneouslupus
Lupusmalarrash(donotcountifmalardiscoid)bullouslupustoxicepidermalnecrolysisvariantofSLEmaculopapularlupusrashphotosensitivelupusrash(intheabsenceofdermatomyositis)ORsubacutecutaneouslupus(noninduratedpsoriaformand/orannularpolycycliclesionsthatresolvewithoutscarring,althoughoccasionallywithpostinflammatorydyspigmentationortelangiectasias)
Photosensitivity Skinrashasaresultofunusualreactiontosunlight,bypatienthistoryorclinicianobservation
Discoidrash Erythematosusraisedpatcheswithadherentkeratoticscalingandfollicularpluggingatrophicscarringmayoccurinolderlesions
Chroniccutaneouslupus
Classicdiscoidrashlocalized(abovetheneck)generalized(aboveandbelowtheneck)hypertrophic(verrucous)lupuslupuspanniculitis(profundus)mucosallupuslupuserythematosustumiduschilblainslupusORdiscoidlupus/lichenplanusoverlap
Nonscarringalopecia
Diffusethinningorhairfragilitywithvisiblebrokenhairs(intheabsenceofothercauses,suchasalopeciaareata,drugs,irondeficiency,andandrogenic
[1,2][3]
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alopecia)
Oralulcers Oralornasopharyngealulceration,usuallypainless,observedbyaclinician
Oralornasalulcers
Palate,buccal,tongue,ORnasalulcers(intheabsenceofothercauses,suchasvasculitis,Behet'sdisease,infection[herpesvirus],inflammatoryboweldisease,reactivearthritis,andacidicfoods)
Arthritis Nonerosivearthritisinvolvingtwoormoreperipheraljoints,characterizedbytenderness,swelling,oreffusion
Jointdisease Synovitisinvolvingtwoormorejoints,characterizedbyswellingoreffusionOR
Tendernessintwoormorejointsandatleast30minutesofmorningstiffness
Serositis PleuritisConvincinghistoryofpleuriticpainorrubbingheardbyaclinicianorevidenceofpleuraleffusionOR
Serositis Typicalpleurisyformorethanoneday,pleuraleffusions,orpleuralrub,OR
PericarditisDocumentedbyEKG,rub,orevidenceofpericardialeffusion
Typicalpericardialpain(painwithrecumbencyimprovedbysittingforward)formorethanoneday,pericardialeffusion,pericardialrub,orpericarditisbyelectrocardiographyintheabsenceofothercauses,suchasinfection,uremia,andDressler'ssyndrome
Renaldisorder Persistentproteinuriagreaterthan500mg/24hoursorgreaterthan3+ifquantitationnotperformedOR
Renal Urineproteintocreatinineratio(or24hoururineprotein)representing500mgprotein/24hours,OR
CellularcastsMayberedcell,hemoglobin,granular,tubular,ormixed
Redbloodcellcasts
Neurologicdisorder
SeizuresORpsychosisIntheabsenceofoffendingdrugsorknownmetabolicderangements(uremia,ketoacidosis,orelectrolyteimbalance)
Neurologic Seizurespsychosismononeuritismultiplex(intheabsenceofotherknowncauses,suchasprimaryvasculitis)myelitisperipheralor
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cranialneuropathy(intheabsenceofotherknowncauses,suchasprimaryvasculitis,infection,anddiabetesmellitus)ORacuteconfusionalstate(intheabsenceofothercauses,includingtoxic/metabolic,uremia,drugs)
Hematologicdisorder
HemolyticanemiaWithreticulocytosisOR
LeukopeniaLessthan4000/mm totalontwoormoreoccasionsOR
LymphopeniaLessthan1500/mm ontwoormoreoccasionsOR
ThrombocytopeniaLessthan100,000/mm (intheabsenceofoffendingdrugs)
Hemolyticanemia Hemolyticanemia
Leukopeniaorlymphopenia
Leukopenia(
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PositivefindingofantiphospholipidantibodybasedonanabnormalserumlevelofIgGorIgManticardiolipinantibodies,onapositivetestresultforlupusanticoagulantusingastandardmethod,oronafalsepositiveserologictestforsyphilisknowntobepositiveforatleastsixmonthsandconfirmedbyTreponemapallidumimmobilizationorfluorescenttreponemalantibodyabsorptiontest
AntiSm PresenceofantibodytoSmnuclearantigen
Antiphospholipid Antiphospholipidantibodypositivityasdeterminedbyanyofthefollowing:Positivetestresultforlupusanticoagulantfalsepositivetestresultforrapidplasmareaginmediumorhightiteranticardiolipinantibodylevel(IgA,IgG,orIgM)orpositivetestresultforantibeta2glycoproteinI(IgA,IgG,orIgM)
Lowcomplement LowC3lowC4ORlowCH50
DirectCoombs'test
DirectCoombs'testintheabsenceofhemolyticanemia
ACR:AmericanCollegeofRheumatologySLICC:SystemicLupusInternationalCollaboratingClinicsSLE:systemiclupuserythematosusEKG:electrocardiogramANA:antinuclearantibodiesAntiSm:antiSmithantibodyIgG:immunoglobulinGIgM:immunoglobulinMAntidsDNA:antidoublestrandedDNAELISA:enzymelinkedimmunosorbentassayIgA:immunoglobulinA.*FortheACRcriteria,nodistinctionismadebetweenclinicalandimmunologiccriteriaindeterminingwhethertherequirednumberhasbeenmet.Theclassificationisbasedupon11criteria.Forthepurposeofidentifyingpatientsinclinicalstudies,apersonissaidtohaveSLEifany4ormoreofthe11criteriaarepresent,seriallyorsimultaneously,duringanyintervalofobservation.FortheSLICCcriteria,criteriaarecumulativeandneednotbepresentlyconcurrently.ApatientisclassifiedashavingSLEifheorshesatisfiesfouroftheclinicalandimmunologiccriteriausedintheSLICCclassificationcriteria,includingatleastoneclinicalcriterionandoneimmunologiccriterion.Alternatively,accordingtotheSLICCcriteria,apatientisclassifiedashavingSLEifheorshehasbiopsyprovennephritiscompatiblewithSLEinthepresenceofANAsorantidsDNAantibodies.
References:1. TanEM,CohenAS,FriesJF,etal.The1982revisedcriteriafortheclassificationofsystemiclupus
erythematosus.ArthritisRheum198225:1271.2. HochbergMC.UpdatingtheAmericanCollegeofRheumatologyrevisedcriteriafortheclassification
ofsystemiclupuserythematosus(letter).ArthritisRheum199740:1725.3. PetriM,OrbaiAM,AlarcnGS,etal.DerivationandvalidationoftheSystemicLupusInternational
CollaboratingClinicsclassificationcriteriaforsystemiclupuserythematosus.ArthritisRheum201264:2677.
Graphic86633Version5.0
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ACRcriteriafortheclassificationofsystemiclupuserythematosus
Criterion Definition
Malarrash Fixederythema,flatorraised,overthemalareminences,tendingtosparethenasolabialfolds
Discoidrash Erythematosusraisedpatcheswithadherentkeratoticscalingandfollicularpluggingatrophicscarringmayoccurinolderlesions
Photosensitivity Skinrashasaresultofunusualreactiontosunlight,bypatienthistoryorclinicianobservation
Oralulcers Oralornasopharyngealulceration,usuallypainless,observedbyaclinician
Arthritis Nonerosivearthritisinvolvingtwoormoreperipheraljoints,characterizedbytenderness,swelling,oreffusion
Serositis PleuritisConvincinghistoryofpleuriticpainorrubheardbyaclinicianorevidenceofpleuraleffusionOR
PericarditisDocumentedbyEKG,rub,orevidenceofpericardialeffusion
Renaldisorder Persistentproteinuriagreaterthan0.5gramsperdayorgreaterthan3+ifquantitationnotperformedOR
CellularcastsMayberedcell,hemoglobin,granular,tubular,ormixed
Neurologicdisorder
SeizuresORpsychosisIntheabsenceofoffendingdrugsorknownmetabolicderangements(uremia,ketoacidosis,orelectrolyteimbalance)
Hematologicdisorder
HemolyticanemiaWithreticulocytosisOR
LeukopeniaLessthan4000/mm totalontwoormoreoccasionsOR
LymphopeniaLessthan1500/mm ontwoormoreoccasionsOR
ThrombocytopeniaLessthan100,000/mm intheabsenceofoffendingdrugs
Immunologicdisorders
AntiDNAAntibodytonativeDNAinabnormaltiterOR
AntiSmPresenceofantibodytoSmnuclearantigenOR
Positiveantiphospholipidantibodyon:
1.AnabnormalserumlevelofIgGorIgManticardiolipinantibodies,or
2.Apositivetestresultforlupusanticoagulantusingastandardmethod,or
3.AfalsepositivetestresultforatleastsixmonthsconfirmedbyTreponemapallidumimmobilizationorfluorescenttreponemalantibodyabsorptiontest
Antinuclearantibody
Anabnormaltiterofantinuclearantibodybyimmunofluorescenceoranequivalentassayatanypointintimeandintheabsenceofdrugsknowntobeassociatedwith"druginducedlupus"syndrome
ACR:AmericanCollegeofRheumatologyEKG:electrocardiogramIgG:immunoglobulinGIgM:immunoglobulinM.
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Comparisonoffeaturesofmusculoskeletaldiseaseinsystemiclupuserythematosusorrheumatoidarthritis
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:DanielJWallace,MDNothingtodisclose.DavidSPisetsky,MD,PhDConsultant/AdvisoryBoards:Merck[Autoimmunity(Xelganz,Enbrel)]Lilly[Lupus]Celgene[Psoriaticarthritis(apremilast)]Immunoarray[Lupus(SLEtest)].RamirezCurtis,MD,MPHNothingtodisclose.Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.Conflictofinterestpolicy
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