Hematologic Manifestations of Systemic Lupus Erythematosus in Adults

10/13/2015
Hematologicmanifestationsofsystemiclupuserythematosusinadults
OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate
Authors
PeterHSchur,MD
NancyBerliner,MD
SectionEditor
DavidSPisetsky,MD,
PhD
DeputyEditor
MonicaRamirezCurtis,
MD,MPH
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Sep2015.|Thistopiclastupdated:Aug06,2015.
INTRODUCTIONAbnormalitiesoftheformedelementsoftheblood,andoftheclotting,fibrinolytic,andrelated
systems,areverycommoninsystemiclupuserythematosus(SLE).ThemajorhematologicmanifestationsofSLE
areanemia,leukopenia,thrombocytopenia,andtheantiphospholipidsyndrome(APS).Thesehematologic
abnormalitiesmaybeapresentingmanifestationofSLE,andcanbeasignofdiseaseactivityifotherpossible
causesareexcluded.Thistopicreviewwillprovideanoverviewoftheseproblems.
ANEMIAAnemiaisafrequentoccurrenceinsystemiclupuserythematosus(SLE),affectingmostpatientsat
sometimeinthecourseoftheirdisease.Multiplemechanismscontributetothedevelopmentofanemia,including
inflammation,renalinsufficiency,bloodloss,dietaryinsufficiency,medications,hemolysis,infection,
hypersplenism,myelofibrosis,myelodysplasia,andaplasticanemiathatissuspectedtohaveanautoimmune
pathogenesis[18].
AnemiaofchronicinflammationAfrequentcauseofanemiainSLEissuppressederythropoiesisfrom
chronicinflammation(anemiaofchronicdiseaseoranemiaofchronicinflammation)[4].Theanemiaisnormocytic
andnormochromicwitharelativelylowreticulocytecount.Althoughserumironlevelsmaybereduced,bone
marrowironstoresareadequate,andtheserumferritinconcentrationiselevated.Themajormediatorofthe
anemiaofchronicinflammationishepcidin,acentralregulatorofironhomeostasisthatinhibitsthereleaseofiron
frommacrophagesandironabsorptioninthesmallintestine.Thisresultsinironlimitedhematopoiesis.The
mechanismsbywhichthisanemiaisproducedbychronicinflammatorydiseasesarefurtherdiscussedindetail
elsewhere.(See"Anemiaofchronicdisease/inflammation".)
Asinotherchronicillnesses,serumerythropoietinlevelsmaybeinappropriatelylowforthedegreeofanemia.
However,someoftheapparentreductioninserumerythropoietinmaybespuriousautoantibodiestoerythropoietin
mayinterferewithcommerciallaboratorytesting[9].
RecommendationsIntheabsenceofeithersymptomsattributabletoanemia(eg,dyspneaonexertion,
easyfatigability)orrenalinsufficiency(see'Renalinsufficiency'below),anemiaofchronicinflammationdoesnot
requirespecifictreatment.
Patientswithsymptomsduetoanemiaofchronicinflammationandwithoutanotherdefiniteindicationfor
glucocorticoidorotherimmunosuppressivetherapymaybegivenatrialofanagentthatpromoteserythropoiesis.
TwosuchagentsareavailableintheUnitedStates:
Epoetinalfa(recombinanthumanerythropoietin).Treatmentshouldbestartedat80to120units/kgperweek
(usuallyastwotothreeinjectionsperweek).Thepatientshouldbereassessedafteronemonth,andthe
doseshouldbeincreasedmonthlyuntilthehemoglobinlevelismaintainedat11g/dL.
Darbepoetinalfa,auniquemoleculethatstimulateserythropoiesiswithalongerhalflifethanrecombinant
humanerythropoietin.Atypicaldoseofdarbepoetinalfaforadultsis0.45mcg/kgonceaweek.
InonestudythatassessedtheresponsetoerythropoietininpatientswithSLEandanemiaofchronic
inflammation,58percenthadanadequateresponsetoerythropoietinsupplementation[7].
Patientswhoaresymptomaticallyanemichavesignsofactiveinflammation,anddonotrespondtoanagentthat
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promoteserythropoiesis,oftenimprovewhenglucocorticoidsareusedinhighdoses(1mg/kgperdayof
prednisoneoritsequivalentindivideddoses).If,afterapproximatelyonemonthoftreatment,theresponseis
unsatisfactory(eg,hemoglobinstill<11g/dL),thedoseofglucocorticoidsshouldberapidlyreducedand
discontinuedifthereisnootherindicationfortheiruse.Ifthereisaresponse,thedoseshouldbetaperedas
rapidlyastopossibletothelowestdosethatmaintainstheimprovement.Immunosuppressiveagentsalsomay
help,butcarryariskoffurtherbonemarrowsuppression.
RenalinsufficiencyAninappropriatelylowleveloferythropoietinisahallmarkofanemiaduetorenal
insufficiency.Theprimarycauseofanemiainthissettingistypicallydeficientproductionoferythropoietinbythe
diseasedkidneys.InthepatientwithSLE,anemia,andrenalinsufficiencywhodoesnothaveotherevidenceof
activeinflammation,administrationoferythropoiesisstimulatingagentsmaybeindicatedwhentheanemiais
causingsymptomsorthehemoglobinconcentrationis<11g/dL.
Therationalefortreatinganemiaduetochronicrenaldiseasepriortoinitiationofrenalreplacementtherapy
(dialysisortransplantation)isdiscussedindetailseparately.(See"Erythropoietinfortheanemiaofchronickidney
diseaseamongpredialysisandperitonealdialysispatients"and"Erythropoietinfortheanemiaofchronickidney
diseaseinhemodialysispatients"and"Darbepoetinalfaforthemanagementofanemiainchronickidney
disease".)
IrondeficiencyanemiaAnemiamayreflectacuteorchronicbloodlossfromthegastrointestinaltract,usually
secondarytomedications(nonsteroidalantiinflammatorydrugs[NSAIDs]orsteroids),ormaybeduetoexcessive
menstrualbleeding(see"NSAIDs(includingaspirin):Pathogenesisofgastroduodenaltoxicity").Irondeficiency
anemiaisnotuncommon,especiallyamongteenagersoryoungwomen.Longtermanemiaofchronic
inflammationcanalsoleadtoirondeficiency,since,asmentionedearlier(see'Anemiaofchronicinflammation'
above),hepcidin,thekeyinduceroftheanemiaofchronicinflammation,inhibitsironabsorptionfromthe
gastrointestinaltract.
PulmonaryhemorrhageisararecauseofanemiainSLE.Notallpatientshavehemoptysis.Othersymptomsof
alveolarhemorrhagearedyspneaandcough.Thepresenceofalveolarinfiltratesonachestradiographorground
glassopacitiesonchestcomputedtomography(CT)aresuggestiveofalveolarhemorrhage.(See"Pulmonary
manifestationsofsystemiclupuserythematosusinadults".)
RedcellaplasiaRedcellaplasia,probablyduetoantibodiesdirectedagainsteithererythropoietinorbone
marrowerythroblasts,hasbeenobserved,althoughitisrare[5,6,10].Thisformofanemiausuallyrespondsto
steroids,althoughcyclophosphamideandcyclosporinehavebeensuccessfullyemployed.(See"Acquiredpurered
cellaplasiaintheadult".)
Evenrarerareisolatedcasereportsofaplasticanemia,presumablymediatedbyautoantibodiesagainstbone
marrowprecursorsimmunosuppressivetherapyalsomaybeeffectiveinthissetting[1113].
Inaddition,bonemarrowsuppressioncanalsobeinducedbymedications,includingantimalarialsand
immunosuppressivedrugs.
AutoimmunehemolyticanemiaOvertautoimmunehemolyticanemia(AIHA),characterizedbyanelevated
reticulocytecount,lowhaptoglobinlevels,increasedindirectbilirubinconcentration,increasedlevelsoflactate
dehydrogenase(LDH),andapositivedirectCoombs'test,hasbeennotedinupto10percentofpatientswithSLE
[24,8,14].Thepresenceofhemolyticanemiamaybeassociatedwithothermanifestationsofseverediseasesuch
asrenaldisease,seizures,andserositis[14].
OtherpatientshaveapositiveCoombs'testwithoutevidenceofoverthemolysis.Thepresenceofboth
immunoglobulinandcomplementontheredcellisusuallyassociatedwithsomedegreeofhemolysis,whilethe
presenceofcomplementalone(eg,C3and/orC4)isoftennotassociatedwithhemolysis[14].Theantibodiesare
"warm,"IgG,anddirectedagainstRhdeterminants(see"Pathogenesisofautoimmunehemolyticanemia:Warm
agglutininsanddrugs").IgMmediatedcoldagglutininhemolysisisuncommon.
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RecommendationsAIHArespondstosteroids(1mg/kgperdayofprednisoneoritsequivalentindivided
doses)in75to96percentofpatients[15,16].Oncethehematocritbeginstoriseandthereticulocytecountfalls,
steroidscanberapidlytapered.Ifthereisnoresponse,onecanconsiderintermittentintravenouspulsesofhigh
dosesteroids(eg,1000mgmethylprednisoloneintravenouslydailyforthreedays)[15],azathioprine(upto2mg/kg
perday)[17],cyclophosphamide(upto2mg/kg)[18],orsplenectomy.Successratesforsplenectomyashighas
60percenthavebeenreported[19],althoughothershavefoundnobenefit[20].
OtheranecdotallydescribedapproachestopatientswithrefractoryAIHAincludeintravenousimmuneglobulin[18],
danazol(indosesof600to800mg/day)[2123],mycophenolatemofetil[24],andrituximab[25].
MicroangiopathichemolyticanemiaLupushasalsobeenassociatedwithathromboticmicroangiopathic
hemolyticanemia(TMA)[26],asmanifestedbyaperipheralbloodsmearshowingschistocytesandelevated
serumlevelsofLDHandbilirubin(picture1).Manyaffectedpatientsalsohavethrombocytopenia,kidney
involvement,fever,andneurologicsymptoms.Thispentadoffeaturesiscompatiblewithadiagnosisofthrombotic
thrombocytopenicpurpura(TTP).However,thepathogenesisofthromboticmicroangiopathyinthesepatientsis
likelyheterogeneous,asitmayreflectvasculitisorantiphospholipidsyndromeaswell[27,28].
WhethertheoccurrenceofbothSLEandTTPinanindividualpatientisacoincidenceorrepresentsatrue
associationisanunsettledquestion.
Ina1998reviewoftheworldliterature,only40suchcaseswerefound[29].
Asubsequentretrospectivestudyofrenalbiopsiesof257patientswithSLEidentifiedfourcaseswith
compatibleclinicalfeaturesandhistologicevidenceofTTP[30].
AlargestudyofpatientswithTMAinassociationwithconnectivetissuediseaseexaminedclinical
parametersofthediseaseinthecontextofassessmentofADAMTS13activity[27].Mostofthe127patients
withTMAandaconnectivetissuediseasehaddepressedADAMTS13activity.Severedeficiency(eg,
activity<10percent),whichisconsistentwithacquired(autoimmune)TTP,wasfoundinonly16percentof
thosewithassociatedconnectivetissuedisease,ascomparedwith70percentofthe64patientswithTTPin
theabsenceofconnectivetissuedisease.VerylowADAMTS13levelswereassociatedwithinhibitory
antibodiesdirectedagainsttheenzyme.ClinicalresponseratesinpatientswithSLEwerecomparableto
otherpatientswithacquiredTTP.
Otherpatientswithmicroangiopathicredcelldestructiondonothavefeverorneurologicdisease,producinga
patternofhemolyticuremicsyndrome.Thepathogenesisofthissyndromeisnotcompletelyunderstood.Inone
reportoffourpatientsplus24othersidentifiedfromaliteraturereview,antiphospholipidantibodies(aPL)were
searchedforineightandfoundinfive[26].(See"AcquiredTTP:Clinicalmanifestationsanddiagnosis".)
ThepresenceofaPLinSLEpatientswithseverehemolyticanemia,renaldysfunction,andcentralnervous
systeminvolvementhasalsobeenreported[31].(See"Clinicalmanifestationsoftheantiphospholipidsyndrome",
sectionon'Hematologicmanifestations'.)
TreatmentInareviewof28reportedpatients,thosetreatedwithplasmainfusionsorplasmaexchange,
glucocorticoidsalone,ornotherapyhadmortalityratesof25,50,and100percent,respectively[26].However,in
anotherseriesof15patientswithSLEandmicroangiopathichemolyticanemia,allrespondedtotreatmentwith
highdoseglucocorticoids,andnoneweretreatedwithplasmaexchange[32].Inaretrospectivestudycitedabove
[27]inwhich70percentofpatientswithSLEandTMAunderwentplasmaexchange,theresponserateof74
percentwascomparabletothatobservedinpatientswithidiopathicTTP.
RecommendationsPatientswithSLE,severemicroangiopathichemolyticanemia,andothermajor
organdysfunctionshouldbetreatedwithplasmaexchangeasinothercasesofthromboticthrombocytopenic
purpuraorthehemolyticuremicsyndrome.(See"AcquiredTTP:Initialtreatment".)
AvailabletestingforADAMTS13activityhasaturnaroundtimethatistoolongtobeusefulininitialtreatment
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decisionmaking.IfthediagnosisofTTPisunclear,itmaybeappropriatetotreatwithplasmaexchangewhile
awaitingADAMSTS13activitylevelresults.(See"ApproachtothepatientwithsuspectedTTP,HUS,orother
thromboticmicroangiopathy(TMA)".)
LEUKOPENIALeukopeniaiscommoninsystemiclupuserythematosus(SLE)andusuallyreflectsdisease
activity.Awhitebloodcellcountoflessthan4500/microLhasbeennotedinapproximately50percentofpatients,
especiallythosewithactivedisease[3,4],whilelymphocytopeniaoccursinapproximately20percent[3].In
comparison,awhitebloodcellcountbelow4000/microL(anAmericanCollegeofRheumatologycriterionforSLE)
occursinonly15to20percentofpatients[3,33].Neutropenia,lymphocytopenia,anddecreasedcirculating
eosinophilsandbasophilsmayallcontributetoleukopenia.
NeutropeniaNeutropeniainpatientswithSLEcanresultfromimmunemechanisms,medications(eg,
cyclophosphamideorazathioprine),bonemarrowdysfunction,orhypersplenism[3,4,33,34].Otherclinicalfeatures
thatmaybeassociatedwithmoderatetosevereneutropenia(absoluteneutrophils<1000/microL)includeinfection,
anemia,thrombocytopenia,andahistoryofneuropsychiatricinvolvement[34].
Functionaldefectsofneutrophilshavealsobeennoted.Theyarethoughttobeinducedbyimmuneabnormalities
(eg,immunecomplexes,inhibitionofcomplementderivedchemotacticfactors)and/ormedications(eg,
glucocorticoids)[35,36].
LymphocytopeniaLymphocytopenia(lymphocyteslessthan1500/microL),especiallyinvolvingsuppressorT
cells,hasbeenobservedin20to75percentofpatients,particularlyduringactivedisease[13,37,38].Thisfinding
isstronglyassociatedwithIgM,coldreactive,complementfixing,andpresumablycytotoxicantilymphocyte
antibodiessuchantibodieswerenotedin26of29patientswithSLE,andtheantibodytitercorrelateddirectlywith
thedegreeoflymphopenia[39].
AnotherpotentialmechanismoflymphopeniaisincreasedapoptosisasreflectedbyincreasedexpressionofFas
antigenonTcells[40].
DecreasedeosinophilsandbasophilsSteroidtherapymayresultinlowabsoluteeosinophilandmonocyte
counts[41].
ThenumberofbasophilsmayalsobedecreasedinSLE,particularlyduringactivedisease[42].Basophil
degranulationwithreleaseofplateletactivatingfactorandothermediatorsmayplayaroleinimmunecomplex
depositionandvascularpermeability.
RecommendationsLeukopeniainSLErarelyneedstreatment.Anexceptionisthepatientwithneutropenia
andrecurrentpyogenicinfections.Oneproblemisthetoxicityoftheusualtherapies.Prednisone(10to60mg/day)
canraisethewhitebloodcellcountbutcanalsoresultinanincreasedriskofinfectionsimmunosuppressive
agentssuchasazathioprineorcyclophosphamidehavethepotentialtocauseworseningoftheleukopeniavia
bonemarrowsuppression[43].
Cautioususeofazathioprine,withcarefulmonitoringofthewhitebloodcellcount,maybeconsideredinthis
setting.
Therapiesforleukopeniausedinothersettingsmayresultinsignificantadverseresultswhenappliedtopatients
withSLE.Asanexample,onestudyofninepatientswithneutropeniaandrefractoryinfectionsfoundthat
treatmentwithrecombinantgranulocytecolonystimulatingfactor(GCSF)increasedthepolymorphonuclearcell
countbutalsocausedadiseaseflareinthreepatients[44].Leukocytoclasticvasculitishasalsodevelopedin
somepatientsthus,itisrecommendedthattheminimumamountofGCSFbeusedinordertomaintainthe
peripheralneutrophilcount1000/microL[45,46].
LEUKOCYTOSISLeukocytosis(mostlygranulocytes)canoccurinsystemiclupuserythematosus(SLE).
Whenpresent,itisusuallyduetoinfectionortheuseofhighdosesofglucocorticoids[43],butitmayoccurduring
acuteexacerbationsofSLE.Ashiftofgranulocytestomoreimmatureforms(a"left"shift)suggestsinfection.
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THROMBOCYTOPENIAMildthrombocytopenia(plateletcountsbetween100,000and150,000/microL)has
beennotedin25to50percentofpatients,whilecountsoflessthan50,000/microLoccurinonly10percent
[1,3,4,33].Thereareseveralpotentialcausesofthrombocytopeniainpatientswithsystemiclupuserythematosus
(SLE).Immunemediatedplateletdestructionismostoftenthecause,butplateletconsumptionmayalsooccurin
associationwithmicroangiopathichemolyticanemia(see'Microangiopathichemolyticanemia'above)ormaybe
duetoimpairedplateletproductionasaresultoftheuseofcytotoxic,immunosuppressive,orotherdrugs(table1).
PathogenesisThemajormechanismisimmunoglobulinbindingtoplateletsfollowedbyphagocytosisinthe
spleen,asinimmunethrombocytopenia(ITP)[47].Membraneglycoproteins(GP)aremostoftenthetargetofsuch
antibodies(eg,GPIIb/IIIa),butantiHLAspecificityalsooccurs[48].
AntigendependentBcelldevelopmentinlymphoidtissuesisinfluencedbybindingofCD40onBcellstoCD40
ligandonactivatedTcells(see"Thehumoralimmuneresponse").ThefindingofautoantibodiestoCD40ligandin
patientswithSLE,antiphospholipidsyndrome(APS),andITP,butnotintheserumofhealthyblooddonors,
suggeststhatinterferencewithTcellandBcellinteractionmayplayaroleinthedevelopmentof
thrombocytopenia[49].
Otherimportantmechanismsinselectedpatientsincludebonemarrowsuppressionbyimmunosuppressivedrugs
(otherthanglucocorticoids),increasedconsumptionduetoathromboticmicroangiopathy(thrombotic
thrombocytopenicpurpura[TTP])[26],theAPS,orantibodiesthatblockthethrombopoietinreceptoron
megakaryocytesortheirprecursors.(See'Antibodiestoclottingfactorsandphospholipids'belowand"Approachto
theadultwithunexplainedthrombocytopenia",sectionon'Hematologistreferral/consultation'.)
ITPmaybethefirstsignofSLE,followedbyothersymptomsasdistantasmanyyearslater.Ithasbeen
estimatedthat3to15percentofpatientswithapparentlyisolatedITPgoontodevelopSLE[50].Evanssyndrome
(ie,bothautoimmunethrombocytopeniaandautoimmunehemolyticanemia)alsomayprecedetheonsetofSLE.
Severebleedingfromthrombocytopeniaisonlyexperiencedbyaminorityofpatientshowever,SLEpatientswith
thrombocytopeniaaremorelikelytohaveassociatedsignificantorgandamage,suchasthatoftheheart,the
kidneys,ortheCNS[51].
SplenectomyinITPwasoriginallythoughttopredisposetothedevelopmentofSLE[52].However,this
hypothesiswasrefutedinsubsequentstudies[53].
TreatmentPlateletcountsbetween50,000/microLand20,000/microLrarelycausesymptomsorsigns,while
countsoflessthan20,000/microLmaybeassociatedwith(andmayaccountfor)petechiae,purpura,
ecchymoses,epistaxis,gingival,andotherclinicalbleeding.(See"Immunethrombocytopenia(ITP)inadults:
Clinicalmanifestationsanddiagnosis".)
TheindicationsforandthetreatmentofITPinSLEaregenerallythesameasthatinpatientswithoutlupus,and
arediscussedindetailelsewhere.(See"Immunethrombocytopenia(ITP)inadults:Initialtreatmentandprognosis"
and"Immunethrombocytopenia(ITP)inadults:Secondlineandsubsequenttherapies".)
OnepracticedifferenceisthatphysiciansarelesslikelytousesplenectomyinSLEpatientsduetoconcerns
aboutalessdurableresponsetothistherapeuticintervention.Instead,rituximabisoftenpreferredbecauseitmay
alsobeusedtotreatothermanifestationsofSLE.However,usingcurrentsurgicaltechniques,weconsider
splenectomytobeagenerallysafeandareasonablesecondlinetherapeuticoptionforSLEpatientswith
refractoryITP.Thisviewissupportedbydatafromthelargestobservationalseriesinwhichsplenectomywas
performedin25patientswithSLEseenfrom1975to2001attheMayoClinic[54].Afteramedianfollowupof6.6
years,16patientshadacompleteorpartialresponseeightofthesesubsequentlyrequiredmedicaltherapy.Nine
patientsrelapsed,butfivesubsequentlyrespondedtomedicaltherapy.Afteramedianfollowupof9.5years,9of
the25patientshaddied,withonlyonedeathbeingaresultofbleedingcomplications.
THROMBOCYTOSISThrombocytosisisalessfrequentfindinginthosewithsystemiclupuserythematosus
(SLE).Asanexample,among465patientswithSLE,17(3.7percent)werefoundtohavethrombocytosis(platelet
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400,000/mm3).Threeofthesepatientshadoneormoreofthefollowingfeaturesonperipheralbloodsmear:
HowellJollybodies,spherocytes,andtargetcells.Ultrasound,computedtomography(CT),andliverspleen
scintigraphyfailedtodemonstrateaspleen.Allthreepatientshadantiphospholipidantibodies(aPL)[55].These
observationssuggestthatautosplenectomymayoccurinpatientswithSLE,perhapsmediatedbyaPL.
PANCYTOPENIAAlthoughperipheraldestructionofredcells,leukocytes,andplateletsmayoccurtogether
andleadtoclinicallysignificantpancytopenia,depressionofallthreecelllinesalsosuggestsbonemarrowfailure,
asinthecaseinaplasticanemia.Thus,bonemarrowexaminationisthemostimportantdiagnostictestto
perform.(See"Aplasticanemia:Pathogenesisclinicalmanifestationsanddiagnosis".)
Causesofmarrowfailureincludedrugsandcoincidentaldiseasesincludingtheacuteleukemias,largegranular
lymphocyteleukemia,themyelodysplasticsyndromes,marrowreplacementbyfibrosisortumor,severe
megaloblasticanemia,paroxysmalnocturnalhemoglobinuria(PNH),andoverwhelminginfection.Inaddition,
unexplainedcytopeniacanbeassociatedwithbonemarrownecrosis,dysplasia,anddistortionofthebonemarrow
architecture[56,57].(See"Clinicalmanifestationsanddiagnosisofprimarymyelofibrosis",sectionon'Secondary
formsofmyelofibrosis'.)
Amongpatientswithsystemiclupuserythematosus(SLE),anunusualcauseofpancytopeniaisthemacrophage
activationsyndrome.(See"Clinicalfeaturesanddiagnosisofhemophagocyticlymphohistiocytosis",sectionon
'Rheumatologicdisorders/MAS'.)
Theclinicalcharacteristicsof12patientswithSLEassociatedmacrophageactivationsyndromeincluded[58]:
Fever100percent
Weightloss80percent
Arthritis50percent
Pericarditis42percent
Rash66percent
Myocarditis33percent
Nephritis33percent
Splenomegaly27percent
Hepatomegaly13percent
Lymphadenopathy73percent
Anemia100percent
Leukopenia87percent
Hyperferritinemia100percent
AntiDNAantibodies80percent
LowCreactiveprotein(CRP)(<30mg/L)90percent
Hypocomplementemia60percent
Thedemonstrationofhemophagocytosisinthebonemarroworinmaterialobtainedfromperipherallymphnodesis
acharacteristicfinding.
ThefewreportedcasesofmacrophageactivationsyndromeinpatientswithSLEhaveusuallyrespondedto
treatmentwithglucocorticoidsandimmunosuppressiveagents.Optimaltreatmentisuncertain.(See"Treatment
andprognosisofhemophagocyticlymphohistiocytosis",sectionon'MAS/rheumatologicconditions'.)
LYMPHADENOPATHYANDSPLENOMEGALYEnlargementoflymphnodesoccursinapproximately50
percentofpatientswithsystemiclupuserythematosus(SLE).Thenodesaretypicallysoft,nontender,discrete,
varyinginsizefrom0.5toseveralcentimeters,andusuallydetectedinthecervical,axillary,andinguinalareas.
Lymphadenopathyismorefrequentlynotedattheonsetofdiseaseorinassociationwithanexacerbation.
Biopsiesrevealareasoffollicularhyperplasiaandnecrosistheappearanceofhematoxylinbodiesishighly
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suggestiveofSLE,althoughunusual[1].
LymphnodeenlargementcanalsobeduetoinfectionoralymphoproliferativediseaseinSLE.Wheninfectionsare
present,theenlargednodesaremorelikelytobetender.
ProminentlymphadenopathymayalsobeamanifestationofangioimmunoblasticTcelllymphoma.Thisdisorder
hasotherclinicalfeatures(arthritis,Coombspositivehemolyticanemia,skinrash,fever,andweightloss)thatare
suggestiveofsystemiclupuserythematosusorsystemicjuvenileidiopathicarthritis(Still'sdisease).Thistypeof
Tcelllymphomaisdiscussedindetailelsewhere.(See"Clinicalmanifestations,pathologicfeatures,and
diagnosisofangioimmunoblasticTcelllymphoma".)
Enlargementofthespleenoccursin10to46percentofpatients,particularlyduringactivedisease.Splenomegaly
isnotnecessarilyassociatedwithacytopenia.Pathologicexaminationofthespleenrevealsanonionskin
appearanceofthesplenicarteries,alesionthatisthoughttorepresenthealedvasculitis.
InviewofthefrequentpresenceoflymphadenopathyandsplenomegalyinSLE,thepossibilityofa
lymphoproliferativemalignancymaybeconsidered.TheriskofnonHodgkinlymphomaappearstobeincreased
fourtofivefoldinpatientswithlupus.Thestudiesthatprovidethisestimateoftherelativeriskoflymphomaand
issuesrelatedtotheriskofothermalignanciesarediscussedindetailelsewhere.(See"Overviewofthe
managementandprognosisofsystemiclupuserythematosusinadults",sectionon'Iscancerriskincreased?'.)
Anothergroupatriskforlymphoproliferativedisordersispatientstreatedwithprolongedoralcyclophosphamide
therapy(whichisunusualinSLE)whoarealsoatincreasedriskforbladderandothermalignancies.Pulse
intravenouscyclophosphamideappearstohaveeliminatedtheriskofbladdercancer.Thelongtermriskofnon
bladdermalignancywithintravenouspulsedosingisuncertain,butnoassociationhasyetbeenreported.(See
"Generaltoxicityofcyclophosphamideininflammatorydiseases".)
Alymphnodebiopsymaybewarrantedwhenthedegreeoflymphadenopathyisoutofproportiontotheactivityof
thelupus.
ANTIBODIESTOCLOTTINGFACTORSANDPHOSPHOLIPIDSAntibodiestoanumberofclottingfactors,
includingVIII,IX,XI,XII,andXIII,havebeennotedinpatientswithSLE[1,2,33].Theseantibodiesmaynotonly
causeabnormalitiesofinvitrocoagulationtests,butmayalsocausebleeding.(See"Acquiredinhibitorsof
coagulation".)
Muchmorecommonareantiphospholipidantibodies(aPL),thepresenceofwhichhasbeenassociatedwitha
prolongationofthepartialthromboplastintime(lupusanticoagulantactivity)andanincreasedriskofarterialand
venousthrombosis,thrombocytopenia,andfetalloss[59,60].Antibodiestootherphospholipidsandto
phospholipidbindingproteins(eg,anticardiolipinantibodies)inmoderateorhighlevelsmayalsobeassociatedwith
theseclinicalphenomena.WhenaPLoccurinassociationwithoneormoreoftheseclinicalfeaturesinapatient
withSLE,itsuggeststhepresenceoftheAPS.Amoredetaileddiscussionofthisdisorderispresented
separately.(See"Clinicalmanifestationsoftheantiphospholipidsyndrome".)
AnincreasedprevalenceofaPLinpatientswithSLEfollowingtreatmentwithcyclophosphamidewasnotedina
singleretrospectivestudythatcompared177cyclophosphamidetreatedSLEpatientswith203SLEpatientsnever
treatedwiththisalkylatingagent[61].Seroconversionoccurredatahigherrateinthecyclophosphamidetreated
patients(19versus1percent,respectively).
ERYTHROCYTESEDIMENTATIONRATEAlthoughacutephasereactants,suchastheerythrocyte
sedimentationrate(ESR)andserumCreactiveproteinlevels,arelessreliablemarkersofdiseaseactivityinlupus
thantheyareinmanyotherinflammatoryconditions,includingrheumatoidarthritisandpolymyalgiarheumatica
[62],elevatedlevelsoftheESRmaybeassociatedwithactivityandaccumulateddamage[63].
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topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Anemiaofchronicdisease(TheBasics)")
SUMMARYANDRECOMMENDATIONS
Anemiaisafrequentoccurrenceinsystemiclupuserythematosus(SLE),affectingmostpatientsatsome
timeinthecourseoftheirdisease.Multiplemechanismscontributetothedevelopmentofanemia,including
inflammation,renalinsufficiency,bloodloss,dietaryinsufficiency,medications,hemolysis,infection,
hypersplenism,myelofibrosis,myelodysplasia,andaplasticanemiathatissuspectedtohavean
autoimmunepathogenesis.Treatmentofanemiadiffersdependinguponthemechanism.(See'Anemiaof
chronicinflammation'aboveand'Renalinsufficiency'aboveand'Irondeficiencyanemia'aboveand'Redcell
aplasia'aboveand'Autoimmunehemolyticanemia'aboveand'Microangiopathichemolyticanemia'above.)
LeukopeniaiscommoninSLEandusuallyreflectsdiseaseactivity,althoughitmayalsoresultfromcertain
medications,particularlyimmunosuppressivedrugs.Decreasesindifferentcelllinesmayoccur
independentlyofeachotherandmayresultfromdifferentmechanisms.LeukopeniainSLErarelyneeds
treatment,exceptwhenneutropeniaresultsinrecurrentpyogenicinfections.Leukocytosis(mostly
granulocytes)isusuallyduetoinfectionortheuseofhighdosesofglucocorticoids.(See'Leukopenia'above
and'Neutropenia'aboveand'Lymphocytopenia'aboveand'Decreasedeosinophilsandbasophils'aboveand
'Recommendations'aboveand'Leukocytosis'above.)
MildthrombocytopeniaiscommoninSLEmoreseverethrombocytopeniaoccursinonly10percent.Immune
thrombocytopenia(ITP)maybethefirstsignofSLE,followedbyothersymptomsasdistantasmanyyears
later.PotentialcausesofthrombocytopeniainSLEincludeimmunemediatedplateletdestruction,whichis
themostcommon,andplateletconsumption,associatedwithmicroangiopathichemolyticanemiaordueto
impairedplateletproductionfrommedications(table1).(See'Thrombocytopenia'aboveand'Pathogenesis'
above.)
Plateletcountsbetween50,000/microLand20,000/microLrarelycausesymptomsorsigns,whilecountsof
lessthan20,000/microLmaybeassociatedwith(andmayaccountfor)petechiae,purpura,ecchymoses,
epistaxis,gingival,andotherclinicalbleeding.TheindicationsforandthetreatmentofITPinSLEare
generallythesameasthatinpatientswithoutlupus.(See'Treatment'above.)
Pancytopeniamayresulteitherfromperipheraldestructionofredcells,leukocytes,andplateletstogetheror
frombonemarrowfailure.Thus,inpatientswithpancytopenia,bonemarrowexaminationisthemost
importantdiagnostictest.Thereareanumberofpotentialcausestoconsidersuchasdrugs,variousother
diseases,andbonemarrowabnormalitiesanuncommoncauseisthemacrophageactivationsyndrome.
(See'Pancytopenia'above.)
Lymphadenopathyoccursinapproximately50percentofpatientswithSLE,morefrequentlyattheonsetof
diseaseorinassociationwithanexacerbation.Splenomegalymayalsobepresent,particularlyduringactive
disease.Alymphnodebiopsymaybewarrantedwhenthedegreeoflymphadenopathyisoutofproportionto
theactivityofthelupus.Othercausesincludeinfectionoralymphoproliferativedisorder,suchasnon
HodgkinlymphomaorangioimmunoblasticTcelllymphoma(see'Lymphadenopathyandsplenomegaly'
above).LymphadenopathyduetoSLEdoesnotrequiretreatment,butenlargednodestypicallymeltawayon
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steroids.Lymphadenopathyinapatientonmoderateorgreaterdosesofglucocorticoidsshouldincrease
suspicionregardinginfectionormalignancy.
Antibodiestoanumberofclottingfactors,includingVIII,IX,XI,XII,andXIII,havebeennotedinrare
patientswithSLE,whichmaycauseabnormalitiesofinvitrocoagulationtestsandsometimesbleeding.
Muchmorecommonareantiphospholipidantibodies,thepresenceofwhichhasbeenassociatedwitha
prolongationofthepartialthromboplastintime(lupusanticoagulantactivity)andanincreasedriskofarterial
andvenousthrombosis,thrombocytopenia,andfetalloss.(See'Antibodiestoclottingfactorsand
phospholipids'above.)
Elevatedlevelsoftheerythrocytesedimentationrate(ESR)maybeassociatedwithdiseaseactivity,butthe
ESRisalessreliablemarkerofdiseaseactivityinlupusthaninmanyotherinflammatoryconditions.(See
'Erythrocytesedimentationrate'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
Topic4670Version22.0
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GRAPHICS
Peripheralsmearinmicroangiopathichemolytic
anemiashowingpresenceofschistocytes
Peripheralbloodsmearfromapatientwithamicroangiopathic
hemolyticanemiawithmarkedredcellfragmentation.Thesmear
showsmultiplehelmetcells(smallblackarrows),otherfragmented
redcells(largeblackarrow)microspherocytesarealsoseen(blue
arrows).Theplateletnumberisreducedthelargeplateletinthe
center(redarrow)suggeststhatthethrombocytopeniaisdueto
enhanceddestruction.
CourtesyofCarolavonKapff,SH(ASCP).
Graphic70851Version5.0
Normalperipheralbloodsmear
Highpowerviewofanormalperipheralbloodsmear.Several
platelets(blackarrows)andanormallymphocyte(bluearrow)can
alsobeseen.Theredcellsareofrelativelyuniformsizeand
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shape.Thediameterofthenormalredcellshouldapproximatethat
ofthenucleusofthesmalllymphocytecentralpallor(redarrow)
shouldequalonethirdofitsdiameter.
CourtesyofCarolavonKapff,SH(ASCP).
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Drugsassociatedwithisolatedthrombocytopenia
Drug
Mechanism(s)
Abciximab
DITP
Acetaminophen
DITPwithantibodiestoadrugmetabolitetheantibodiesdonot
reactwiththeunmodifiedparentcompound
Alemtuzumab
ITPlikesyndrome*
Amiodarone
DITP
Betalactamantibiotics
(eg,penicillins,
cephalosporins)
DITP
Carbamazepine
DITP
Eptifibatide
DITP
Ethambutol
DITP
Furosemide
DITP
Goldcompounds
Bonemarrowsuppression
Haloperidol
DITP
Heparin
Drugdependentantibodiesthatalsoactivateplateletsandcause
endothelialinjury
Ibuprofen
DITPinsomepatientsinotherpatientsonlyantibodiestoadrug
metabolitethatdonotreactwiththeunmodifiedparent
compound
Irinotecan
DITP
Levofloxacin
DITP
Linezolid
Bonemarrowsuppression(dosedependent)
Measlesmumpsrubella
(MMR)vaccine
ITPlikesyndrome
Naproxen
DITPwithaantibodiestoadrugmetabolitetheantibodiesdonot
reactwiththeunmodifiedparentcompound
Oxaliplatin
DITP
Phenytoin
DITP
Piperacillin
DITP
Quinidine
DITP
Quinine
DITP
Ranitidine
DITP
Rifampin
DITP
Simvastatin
DITP
Sulfonamides
DITP
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Tirofiban
DITP
Trimethoprim
DITP
sulfamethoxazole
Valproicacid
Bonemarrowsuppression(dosedependent)
Vancomycin
DITP
Thistablelistsdrugswithevidenceforacausalassociationwithisolatedthrombocytopenia,
fromclinicaldatainpublishedcasereports,identificationofdrugdependent,plateletreactive
antibodies,orbothitalsoliststheirmechanisms.Drugsinboldarethemostcommonly
implicatedinacausalrelationshipbasedonclinicalcriteria(eg,temporalrelationship,
absenceofanalternateexplanationforthrombocytopenia).Drugdependentantibodieshave
beenshownforallagentsassociatedwithDITP.RefertoothercontentinUpToDateondrugs
thatcancausethromboticmicroangiopathy(TMA).
DITP:druginducedimmunethrombocytopenia(ie,thrombocytopeniacausedbydrugdependent
antibodies)ITP:immunethrombocytopenia,whichiscausedbyanautoimmunemechanismthatno
longerrequiresthepresenceofthedrugTMA:thromboticmicroangiopathy,whichisassociated
withmicroangiopathichemolyticanemiaandthrombocytopenia,withanimmuneordosedependent
mechanism.
*Arareadversereactiontoalemtuzumabresultsinprolonged,severethrombocytopeniathatresponds
toITPtherapywithsustainedremission.
QuininecanalsocauseaTMA.
ResearchleadingtothiscompilationofdrugswasoriginallypublishedinBloodandhasbeenmodifiedfor
useinthispublication.ReeseJA,LiX,HaubenM,etal.Identifyingdrugsthatcauseacute
thrombocytopenia:ananalysisusing3distinctmethods.Blood2010116:2127.
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Disclosures
Disclosures:PeterHSchur,MDNothingtodisclose.NancyBerliner,MDNothingtodisclose.DavidS
Pisetsky,MD,PhDConsultant/AdvisoryBoards:Merck[Autoimmunity(Xelganz,Enbrel)]Lilly[Lupus]
Celgene[Psoriaticarthritis(apremilast)]Immunoarray[Lupus(SLEtest)].MonicaRamirezCurtis,MD,
MPHNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmust
conformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy
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