Role of inflammatory markers in Takayasu arteritis disease monitoring

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Role of inflammatory markers in Takayasu arteritis disease monitoring
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O'Connor, Timothy E.
Carpenter, Haley E.
Bidari, Sharatchandra
Waters, Michael F.
Hedna, Vishnumurthy Shushrutha
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Background: Takayasu arteritis (TA) is an idiopathic large-vessel vasculitis that can result in significant morbidity and mortality secondary to progressive stenosis and occlusion. Monitoring disease progression is crucial to preventing relapse, but is often complicated by the lack of clinical symptoms in the setting of active disease. Although acute phase reactants such as ESR and CRP are generally used as an indicator of inflammation and disease activity, mounting evidence suggests that these markers cannot reliably distinguish active from inactive TA. Case presentation: We report a 24-year-old Hispanic female with a 5-year history of TA who presented with stroke-like symptoms and evidence of left MCA occlusion on imaging, despite a history of decreasing inflammatory markers. CTA revealed complete occlusion of the left common carotid artery, left subclavian, and left MCA from their origins. It also revealed a striking compensatory circulation supplying the left anterior circulation as well as the left subclavian as a response to progressive stenosis. Conclusion: Monitoring ESR and CRP levels alone may not be a reliable method to evaluate disease progression in patients with TA, and should be taken in context with both patient’s clinical picture and the imaging. We recommend that serial imaging be performed regularly in the setting of active disease to monitor progression and allow for immediate therapy in response to evidence of disease advancement, with a relaxation of the imaging interval once the disease is presumed inactive. Keywords: Takayasu arteritis, ESR, CRP, Compensatory circulation, Subclavian steal
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O’Connor et al. BMC Neurology 2014, 14:62 http://www.biomedcentral.com/1471-2377/14/62; Pages 1-9
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doi:10.1186/1471-2377-14-62 Cite this article as: O’Connor et al.: Role of inflammatory markers in Takayasu arteritis disease monitoring. BMC Neurology 2014 14:62.

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CASEREPORTOpenAccessRoleofinflammatorymarkersinTakayasuarteritis diseasemonitoringTimothyEO ’ Connor1,HaleyECarpenter2,SharatchandraBidari4,MichaelFWaters2,3andVishnumurthyShushruthaHedna3*AbstractBackground: Takayasuarteritis(TA)isanidiopathiclarge-vesselvasculitisthatcanresultinsignificantmorbidityand mortalitysecondarytoprogressivestenosisandocclusion.Monitoringdiseaseprogressioniscrucialtopreventing relapse,butisoftencomplicatedbythelackofclinicalsymptomsinthesettingofactivedisease.Althoughacutephase reactantssuchasESRandCRParegenerallyusedasanindicatorofinflammationanddiseaseactivity,mounting evidencesuggeststhatthesemarkerscannotreliablydistinguishactivefrominactiveTA. Casepresentation: Wereporta24-year-oldHispanicfemalewitha5-yearhistoryofTAwhopresentedwithstroke-like symptomsandevidenceofleftMCAocclusiononimaging,despiteahistoryofdecreasinginflammatorymarkers.CTA revealedcompleteocclusionoftheleftcommoncarotidartery,leftsubclavian,andleftMCAfromtheirorigins.Italso revealedastrikingcompensatorycirculationsupplyingtheleftanteriorcirculationaswellastheleftsubclavianasa responsetoprogressivestenosis. Conclusion: MonitoringESRandCRPlevelsalonemaynotbeareliablemethodtoevaluatediseaseprogressionin patientswithTA,andshouldbetakenincontextwithbothpatient ’ sclinicalpictureandtheimaging.Werecommend thatserialimagingbeperformedregularlyinthesettingofactivediseasetomonitorprogressionandallowfor immediatetherapyinresponsetoevidenceofdiseaseadvancement,witharelaxationoftheimagingintervaloncethe diseaseispresumedinactive. Keywords: Takayasuarteritis,ESR,CRP,Compensatorycirculation,SubclavianstealBackgroundTakayasuarteritis(TA)isanidiopathiclargevesselvasculitisthatprimarilyaffectstheaortaanditsmain branches.Althoughtheprevalenceandclinicaloutcome ofTAvariesglobally,theannualincidenceofTAinthe UnitedStatesisreportedly2.6permillionwitha5-year survivalrateashighas94%[1,2].Thediseasepredominantlyaffectswomenandtypicallypresentsduringthe secondtothirddecadeoflife[3].Signsandsymptoms ofTAarediverseandreflectboththestageofthediseaseandtheaffectedvasculature.EarlystageTAcan presentwithnonspecificsymptomssuchasfatigue, weightloss,andlowgradefever,butasthediseaseprogressesitcanmanifestasvascularbruits,claudication, retinopathy,andischemiaduetoarterialocclusion[4]. Theevolutionofthesesymptomsisduetoprogressing vascularlesionssecondarytoinflammatoryprocesses[5]. TAisgenerallymonitoredcloselybecauserelapsesare oftenunpredictableanddangerous.Inflammatorymarkers suchaserythrocytesedimentationrate(ESR)andC-reactiveprotein(CRP)arecommonlyusedtomonitordisease progressionduringremissionduetotheirnoninvasivenatureandaffordablecost,whiletheradiationdiagnostic techniqueCTangiography(CTA)isreservedforpatients presentingwithactivedisease.Despitethesemonitoring techniques,assessmentofdiseaseactivityandprogression inTAremainsachallenge[6].However,relyingontheinflammatorymarkerESRtodistinguishactivefrominactive TAyieldsonlya72%sensitivityanda56%specificitypredictorvalue[7].Asaresult,relyingonthesemarkersduringasymptomaticperiodscanpotentiallyleadtothefalse assumptionthatthepatientisinremissionwhilethereis ongoingactivefibrosisandprogressiveocclusion.Infact, onestudyfoundhistologicallyactivediseasein44%of *Correspondence: vhedna@mail.ufl.edu3DepartmentofNeurology,UniversityofFlorida,RoomL3-100,McKnight BrainInstitute1149NewellDrive,Gainesville,FL32611,USA Fulllistofauthorinformationisavailableattheendofthearticle 2014OConnoretal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycredited.TheCreativeCommonsPublicDomain Dedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle, unlessotherwisestated.O ’ Connor etal.BMCNeurology 2014, 14 :62 http://www.biomedcentral.com/1471-2377/14/62

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cardiacbiopsyspecimensandangiographicevidenceof progressionin61%ofpatientspreviouslybelievedtobein remission[7].Asaresult,mountingevidencesuggestsit maybenecessarytousemoreinvasiveimagingtoaccuratelydetermineactivedisease. Wepresentapatientwhosufferedanischemicstroke inspiteofimprovinginflammatorymarkerssuggestive ofdiseaseremission.Thispatient ’ sclinicalcoursesupportsthehypothesisthatinflammatorymarkersalone maynotbesufficienttotracktheprogressionofTA, andreaffirmstheneedtomonitordiseaseprogression withmoreextensivescreening.Inaddition,thispatient demonstratedaremarkablecapacityviacollateralsto compensateinthesettingofprogressiveocclusion.In responsetoactivedisease,utilizationofvascularreserve throughcollateralcirculationeventuallyresultedin retrogradeflowthroughthevertebralarterytoperfuse tissuedistaltoseverestenosisofthecommoncarotidartery(CCA).CasepresentationA24year-oldwomanwithTakayasu ’ sarteritis(TA)anda recenthistoryofprogressivediffuseheadachespresented toanoutsidehospitalwithalteredmentalstatusfollowing lossofconsciousness.Fiveyearspreviouslythepatient wasdiagnosedwithanti-myeloperoxidase(MPO)andpANCAvasculitiswithanESRof57mm/hrandaCRPof 75mg/L(Figure1,initialdiagnosis).Thepatientwasprescribedcellceptandaprednisonetaper,butwaslosttofollowupuntiltwoyearslaterwhenshedevelopedhand numbness,headaches,andpostprandialabdominalpain. CTArevealed90%stenosisofthesuperiormesentericartery,andESRandCRPwereelevatedat33mm/hrand 32mg/L,respectively(Figure1,2ndpresentation).The patientwastreatedwithcellceptandhigh-doseprednisone butwasagainlosttofollowup. Attheageof23thepatientpresentedtotheemergencydepartmentwithpostprandialabdominalpain, andCTAindicatedprogressionofherdiseasewithluminalnarrowingduetointimalthickeningoftheaortic arch,descendingaorta,andleftsubclavianarterythat wascharacteristicoflargevesseldiseaseconsistentwith Takayasu ’ sarteritis.HerESRandCRPwere28mm/hr and7.1mg/L,respectively,andthefollowingday,her ESRwas15mm/hr(Figure1,3rdpresentation).Imuran 50mg/dwasstartedwithplanstotitratethedose;howevershediscontinuedhertreatmentafter3weeksdue topersistentnauseaandvomiting. Fourmonthslaterthepatientcomplainedofprogressive,persistent,diffusepoundingheadachesthatwereassociatedwithdizzinessandblurryvision,andshewas admittedtothehospitalforfurtherevaluation.Atthat timeshewasnotonanyimmunosuppressanttherapy. ESRwaswithinnormallimitsat19mm/hrandCRPwas onlymildlyelevatedat8.9mg/L(Figure1,4thpresentation).ButCTAofthehead,neck,chest,abdomen,and pelvisdemonstratedfurtherprogressionofherdisease withcircumferentialthickeningoftheaorticarchandsignificantnarrowingoftheproximaldescendingthoracic aorta,alongwithaseverestenosisoftheleftcommoncarotidarteryatitsorigin,1centimeterinlength(Figure2A). Therewascompleteocclusionoftheleftproximalsubclavianarteryatitsoriginfromtheaorticarch,withflow inthedistalleftsubclavianarteryprovidedbytheleftvertebralartery,suggestiveofsubclaviansteal(Figure2B), andwithreconstitutionofflowatthebifurcationofthe vertebralarterysuggestingcollateralflowwasarisingfrom theposteriorcirculation.Carotidultrasoundindicatedthe leftvertebralarterywaspatentwithretrogradeflow. Imuranwasstoppedandcellceptwasrestartedwitha 60mgprednisonetaper;however,sherefusedpulsesteroidsduetoconcernsweightgainandalsorefusedcytoxan again.Overthenextseveralweeksthepatientcontinued toexperienceworseningheadachesunrelievedbyoverthe counterpainmedications.Shealsobecamenoncompliant withcellcept. Onemonthlater,thepatientpresentedtoanoutside hospitalwithrightsidedweaknessandspeechdifficultly. AfterCTruledouthemorrhage,recombinanttissueplasminogenactivator(t-PA)wasadministeredwithinthe therapeuticwindowandthepatientwastransferredtoour hospitalforfurtherworkup.Onadmission,thepatient waslimitedtofollowingonestepcommands.Neurologic examdemonstratedanomia,dysarthria,arightlowerfacial droop,andsevereweaknessontherightupperandlower extremity.Thestrengthinleftupperandlowerextremities wasintact,andtherestofthephysicalexamwas unremarkable. 2.0 4.0 4.5 5.0 5.5 6.0 0 10 20 30 40 50 60 -0.50 0.0 0 10 20 30 40 50 60 70 80 Laboratory Values and Patient's Clinical Coursenormal ESR ESRESR (mm/hr) 2nd presentation 3rd presentation 4th presentation Stroke Post-CVA 6 months Post-CVAnormal CRP Time (years)CRP (mg/L) CRPInitial diagnosis Figure1 ESRandCRPvaluesovertimespanoftreatment. O ’ Connor etal.BMCNeurology 2014, 14 :62 Page2of9 http://www.biomedcentral.com/1471-2377/14/62

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CTAoftheheadandneckdemonstratedmuralthickeningoftheaorticarchthatwasconsistentwithprevious images.Therewasalsocompleteocclusionoftheleft commoncarotidarteryatitsorigin(Figure3)andleftinternalcarotidartery,withcollateralflowarisingfromthe rightanteriorcirculationviathecircleofWillisandleptomeningealcollaterals.Inaddition,thereiscompleteocclusionofashortsegmentoftheMCA,justpastits bifurcation(Figure4A)andevidenceofflowthroughthe anteriorandposteriorcommunicatingarteriesisabsent uponimaging(Figure4).Thesefindingswouldexplainthe CTperfusionabnormalitiesofdelayintransittimewith decreasedcerebralbloodflowandcerebralbloodvolume, consistentwiththeleftMCAinfarct,includingtheleft basalganglia(Figure5). Initially,thepatient ’ sESRwaselevatedat54mm/hr (Figure1,stroke).Thepatientwasstartedonpulsesteroidsthedayfollowingherstroke.OnthefifthdayofadmissionrepeatESRwas6mm/hrandCRPwaswithin normallimitsat3.4mg/L(Figure1,Post-CVA).Strength intherightupperandlowerextremityimprovedwhilefacialdroopandspeechdeficitpersisted.After8daysthe patientwasdischargedtoaninpatientrehabilitationfacility,whereshecontinuedtoimproveandcannowwalk unassistedandperformallofheractivitiesofdailyliving. Sixmonthsfollowingthepatient ’ scerebrovascularattack(CVA),thepatient ’ sESRreturnedtothenormal rangeat10mm/hrandherCRPvalueremainedelevated at19.5mg/L(Figure1,6monthspost-CVA).CTAofthe headandneckshowedencephalomalaciarelatedtothe LSA LCCA LCCA Distal LSAABC Figure2 CTAsthreemonthsbeforeCVA. ObliquelateralMPRviewCTangiogramoftheneckshowingathrombosedleftcommoncarotid artery(LCCA)withahigh-gradestenosisattheoriginofthecommoncarotid,1cminlength (A) .TransverseCTAjustabovetheoriginofthe greatvesselsrevealingcompleteocclusionoftheleftproximalsubclavianartery(LSA) (B) ,withflowtothedistalleftsubclavianarteryprovided bytheleftvertebralartery,indicativeofsubclaviansteal (C) AB Figure3 CTAoftheneckimmediatelyfollowingCVA. Anterior (A) andlateral (B) viewsofaCTangiogramoftheneckdemonstrating thrombosisoftheproximalandmidleftcommoncarotidartery(arrows). O ’ Connor etal.BMCNeurology 2014, 14 :62 Page3of9 http://www.biomedcentral.com/1471-2377/14/62

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previousinfarct,completeocclusionoftheleftcommon carotidartery,andastrikingcompletelackofflowinthe leftinternalcarotidartery(Figure6).DiscussionWepresentedapatientwhoexperiencedprogressive vascularlesionsduetoTAculminatinginanischemic strokedespitenormalizinglevelsofinflammatorymarkers. TAisalarge-vesselpan-arteritisaffectingpredominantlytheaortaanditsmajorbranches.Itsetiologyis unknown,butitspathogenesisissuggestiveofanautoimmuneprocessandislikelymultifactorial[5].The pathophysiologyofthisdiseasecanbedividedinto early,intermediateandchronicstages[3].Earlyinthe diseaseprocess,lymphocytesinfiltratetheadventitia throughactivatedvasa-vas orumendothelialcells.The lymphocytesarestimulatedbycirculatingcytokinesto producematrixmetalloproteinases(MMP),leadingtothe destructionoftheelasticfibersinthearterialwall.Increasedadventitialneovascularizationandup-regulation ofadhesionmoleculesresultsinincreasedrecruitmentof inflammatorycells.Intheintermediatestage,thereis secondarydepositionofmucopolysaccharidesandfibroblastsandsmoothmusclecellproliferation,encouraged byTNF-alpha.Eventuallytheintimabecomeshypertrophiedduetofibrocellularthickening.Thepathological changesoccurringinalllayersleadtothenarrowingof thevascularlumen,whichresultinstenosisandocclusion. Inthechronicphase,inflammatorylesionsprogressto scarsandthevesselsbecomefibroticandcalcified[8]. Whenfibrosisisinsufficient,aswhenlesionsprogressrapidly,thearterialwallisthinnedanddilationandaneurysmsoccur.InadditiontotheprimarylesionsofTAthat occurintheelasticarteries,affectingboththemediaand adventitiathroughthevasa-vasorum,peripheralbranches ofaffectedarteriesaredisruptedaswell.Intheseperipheralbranches,intimalthickeningoccursintheabsenceof associatedchangesinthemediaandadventitia,leadingto occlusionandsecondaryischemiclesionstothekidneys, heart,andbrain[9].ThespreadofvascularlesionsinTA isthoughttodevelopsystemicallyratherthanfromadjacentvascularbeds[5]. Althoughourpatientwasmanagedusingcellceptand prednisone,hernoncompliancemadeitdifficultto BNo Acom ANo Pcom MCA occlusion/highGrade stenosis Figure4 Subtracted3DCTangiogramfollowingCVA. Obliqueviewshowinghigh-gradestenosisofleftMCAwithM2M3branchesopacified byretrogradeflowthroughleptomeningealcollaterals (A) .Neitherposteriorcommunicatingartery (A) noranteriorcommunicatingartery (B) visibleuponimaginginobliqueandAPviews,respectively. Figure5 BrainCTimagingpostCVA. BrainCTshowingcompletedinfarctinleftmiddlecerebralarteryterritoryaffectingtheleftbasalganglia andleftinsularcortex.Cytotoxicedemapresent (A) .CTperfusionshowsincreasedtimetopeak (B) ,reducedcerebralbloodvolume (C) and reducedcerebralbloodflow (D) inthecoreleftMCAterritory. O ’ Connor etal.BMCNeurology 2014, 14 :62 Page4of9 http://www.biomedcentral.com/1471-2377/14/62

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maintainremission.TraditionaltherapyforTAconsistsof corticosteroids,withimmunosuppressantsandcytotoxic agentsprescribedintreatment-resistantandrefractory cases.Reportsindicatethathalfofallpatientswhoachieve remissionthroughtreatmentwilleventuallyrelapse,and onefourthofpatientsareunabletoachieveremissionwith eitherglucocorticoidsorglucocorticoidsincombination withcytotoxicagents[7].Alte rnativetherapiesthathave beenusedwithsuccessinrefractorycasesofTAinclude infliximab,tocilizumab,rituximab,tacrolimus,methotrexate,azathioprine,cyclophos phamide,mycophenolatemofetil,andleflunomide[10 – 14].Giventhehighprobabilityof relapseandpotentialdisastrousconsequences,itisnecessarytofrequentlyandreliablymonitorprogression. IneveryphaseofTAmanagement,fromtheinitial diagnosistothemonitoringofquiescentperiods,flares andremission,clinicalexamination,biomarkerdata,and imagingareallcriticalcomponentsTAevaluation.None oftheseassessmenttechniquescanbeusedinisolation tosufficientlyevaluatediseasestate[15]. FortheclinicalassessmentofTA,severalindexeshave beendeveloped.ForTAdiagnosis,the1990American CollegeofRheumatology(ACR)criteriaforTAclassificationwasdeveloped.Thisindexcontainsofsixcriteria:1) Ageofonset<40years;2)Claudicationofextremities;3) Decreasedbrachialarterypulse;4)Asystolicbloodpressuredifferenceof>10mmHgbetweenarms;5)Abruitof thesubclavianarteriesoraorta;and6)Anarteriogramabnormality.Ifthreeormoreofthesecriteriaaremet,aTA diagnosiscanbemadewithasensitivityof90.5%anda specificityof97.8%[16].TAdiseaseactivitycanbe assessedwiththeNationalInstitutesofHealth(NIH)criteriaforactivedisease,withactivediseasedefinedasthe newonsetorworseningoftwoofthefollowingfourcriteria:1)Systemicfeatures,suchasfeverandmalaise,with noothercauseidentified;2)Elevatederythrocytesedimentationrate;3)featuresofvascularischemiaorinflammation(claudication,diminishedorabsentpulses,bruit, vascularpain,asymmetricbloodpressure);and4)Typicalangiographicfeatures[7].TheDiseaseExtent Index-Takayasu(DEI-Tak)isanindexconsistingof71 itemsdesignedforthefollow-upofTAbasedsolelyon clinicalfindings,eliminatingtherequirementofimaging.Thoughtime-consumingtoadminister,theDEITakshowsgoodagreementwiththeNIHcriteria[17]. TheIndianTakayasu ’ sArteritisScore(ITAS)wasdevelopedfromtheDEI-Takandmodifiedtooptimizeinterraterreliabilityandreflectionofdiseaseactivity.The ITASconsistsof44items,33ofwhichpertaintothecardiovascularsystem,and7ofwhichareweightedmore heavily.TheITASissensitivetoeffectivemedicalinterventions,andahighITASscoredenotespoorcontrolof diseaseactivity[18]. Thispatient ’ scaseisuniquebecauseinflammatory markersweredecreasingoverseveralyearsdespiteactivediseaseandprogressivelesions.Acute-phasereactantssuchasESRandCRParecommonlyusedto monitordiseaseprogressioninTA.Despitetheirusage, neitherESRnorCRPcandistinguishactivefrominactivediseasewiththenecessaryclinicalaccuracy [19,20].ESRhasasensitivity andspecificityforactive TAof72%and56%,whileCRPhasasensitivityof 71.4%andspecificityupto100%foractivedisease [7,21](Table1).However,TAcanrelapseandactivediseasecanpersistintheabsenceofelevatedCRPandESR [21].NeitherESRnorCRPcorrelatewithMRfindings ofvascularedemaidentifiedwithelectrocardiogramgatededema-weightedMR[22].Inaddition,bothESR andCRParesuppressedbyfactorsotherthandisease remission.ESRcanbeinfluencedbyextraneousfactors suchasmedicationusageandbloodviscosityandCRPexhibitsnonspecificelevationinresponsetotissueinflammationandinfection.Additionally,CRPisproducedinthe liverinresponsetothecirculatingcytokineIL-6,rather thanatthesiteofinflammation,whichmayaccountforits lowsensitivity[7,21,23].Rel yingontheseinflammatory C AB Thrombosed LCCA Normal RCCA SupraclinoidICA Figure6 Imagingfrom6monthsfollowinginitialacuteCVA. BrainCTshowingencephalomalaciarelatedtothepreviousinfarctoftheleft basalgangliaandleftinsularcortex(leftMCAterritory). (A) Transverseslicethroughneckshowingcompleteocclusionofleftcommoncarotid artery (B) .Subtracted3DCTangiogramshowingacompletelackofflowinleftinternalcarotidarteryaswellasarecanalizationoftheprevious areaofleftMCAthrombosis (C) O ’ Connor etal.BMCNeurology 2014, 14 :62 Page5of9 http://www.biomedcentral.com/1471-2377/14/62

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markersalonetomonitordiseaseprogressioncanhavesevereandevenlethalconsequencesforpatients[8,10]. Therefore,ESRandCRPshouldbeviewedinthecontext ofthepatient ’ sclinicalcourseandimaging. TheunreliabilityofESRandCRPhaspromptedthe searchforamorereliableserologicalmarkerofdiseaseactivity.Manybiomarkercandidateshavebeenidentified. Parketal.examinedtheserumprofilesofinflammatory cytokinesandfoundthatTNF-alpha,IL-6andIL-18were elevatedinTA,andofthese,IL-18correlatedbestwithremission[24].DeSouzaetal.foundthathigherhomocysteinelevelsinTAisariskfactorforcardiovascularevents [25].InevaluatingserumghrelinandleptinlevelsaspotentialbiomarkersforTA,Yilmazetal.foundthatghrelin levelswerenegativelycorrelatedwithdiseaseactivityand thattheleptin/ghrelinratiowashigherinTA[26].RegulatedandnormalTcell-expressedandsecreted(RANTES) levelsareincreasedinactiveTAandcorrelatewithdisease activity[5].Dagnaetal.foundthatPentraxin-3(PTX-3) levelsarepositivelycorrelatedwithdiseasestateanddeterminedPTX-3tobemorepredictiveofTAdiseasestate thanESRorCRP,withasensitivityof89%andspecificity of87%.AnadditionalbenefitofPTX-3overconventional markersisthatPTX-3didnotshownonspecificelevationinhealthycontrolsorinresponsetoinfection[23]. Thoughallrequirefurthervalidation,theseserological markersshowpromiseasfuturebiomarkersforTA. Inadditiontobiomarkers,imagingisindispensablefor thediagnosisandmonitoringofTA.Imagingmethods usefulforTAincludedigitalsubtractionangiography (DSA),computedtomographyangiography(CTA),magneticresonanceimaging(MRI),ultrasonography,and positronemissiontomographywithradiolabelledglucose (FDG-PET).Angiographycanbeusedforbothscreening andtreatment.Ithasahighsensitivityandspecificityfor TAdiagnosis,ashortstudytime,isminimallyinvasive, andallowsforeasycomparisonofstudiesperformed throughoutdiseaseprogression.Incomparisontostandardangiography,CTAhasahighsensitivityandspecificity forassessingstenoticlesions,93%and98%,respectively, withanoverallsensitivityandspecificityof95%and100% indiagnosis[27].CTAallowsevaluationofthevesselwall andlumenintheaortaandlargevesselsandcanprovide informationconcerningendorganischemia.However,itis costly,exposesthepatienttohigherradiationthanother imagingmodalities,andisimpracticalforfrequentmonitoring[8,28]. MRIisnoninvasive,lacksradiation,andcandetect anatomicandpathophysiologicchangessuchasvascular lesions,sitesofinflammation,andwallthickening[26]. T2imagingcanvisualizevesseledema,asignofinflammation,andaspecializedT2weightedtechnique,short tauinversionrecovery(STIR),isidealforimagingsofttissueinflammation[22,29].MRangiography(MRA)with gadoliniumcontrastfacilitatesvisualizationofpathological wallenhancementandhasdemonstratedasensitivityand specificityofupto100%indiagnosingTA[30,31].However,MRIistimeconsuming,expensive,canbeaffected bymovementartifact,cannotbeperformedinpatients withferromagneticimplants,andmayrequire3Tesla strengthinordertovisualizesmallervessels[8]. Ultrasonography(US)isnon-invasive,cheap,painless, andavoidsionizingradiation,makingitexcellenttoolfor frequentmonitoringofTA.Itcanbeusedtoidentifythe presenceofstenosis,estimatebloodflow,andassessvessel anatomy,thelumen,andvesselwallalterations.Additionally,UShasahighresolutionofapproximately0.1mm, providing10xtheresolutionofMRI[32,33]. FDG-PETcanassessmetabolicactivityofthevascular wall,highlightingregionsofinflammation.Asinflammationbeginsbeforemorpholo gicalchangesinthearterial wallmanifest,FDG-PETcanf acilitateearlierdiagnosis. FDG-PEThasshownasensitivityof92%andaspecificityof100%indiagnosingTAandismoresensitive thanMRAindetectingvascularinvolvementinearlyTA [34,35].PETfindingsofinflammationnormalizeafter treatmentwithimmunosuppressants,mirroringclinical improvement,makingPETareliableindicatorofdisease Table1EfficacyofserologicalmarkersandimagingmodalitiesinthediagnosisofTAModalitySensitivity(%)Specificity(%)Citation ESR72*56*Kerr,Hallahan,Giordano,etal.,1994† ‡[ 7 ] CRP71.4*100*Ishihara,Haraguchi,Tezuka,etal.,2012† ,§,[ 21 ] FDG-PET92*100*Webb,Chambers,AL-Nahhas,etal.,2004† ‡ ,§[ 34 ] MRA100*100*Yamada,Nakagawa,Himeno,etal.,2000‡[ 31 ] CTA95*100*Yamada,Nakagawa,Himeno,etal.,1998‡[ 27 ] PTX-382.1-89**87-94.1**Ishihara,Haraguchi,Tezuka,etal.,2012† ,§,,[ 21 ]Dagna,Salvo,Tiraboschi,etal.,2011† ‡ ,§[ 23 ]*IndiagnosingTA. **Indistinguishingactivefrominactivedisease. TAdiagnosisordiseaseactivitystatedeterminedby;†Clinicalassessment.‡Typicalfindingsonconventionalangiography.§Patientsmet1990AmericanCollegeofRheumatologycriteriaforTAdiagnosis.MRA.O ’ Connor etal.BMCNeurology 2014, 14 :62 Page6of9 http://www.biomedcentral.com/1471-2377/14/62

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activity[32].FDG-PETisusefulforscreeningpatientswith systemicdiseasesanddiagnosingTA[36].However,itisexpensive,notwidelyavailable,exposesthepatienttoradiation,islimitedtovesselsgreaterthan4mmindiameter, andcannotbeusedtoexaminethevesselwall[28,32]. Inourpatient,itispossiblethatcomplicationsfromher diseasecouldhavebeenpreventedifserialimagingallowed fortreatmenttobeimplementedbeforemanifestationsoccurred.However,theliteratureguidinghowTAshouldbe managedandhowoftenimagingshouldbeperformedin thesepatientsislimited,lackingplacebo-controlled,randomizedcontrolledtrialsandconsistingprimarilyofcase series,openstudies,andexpertopinion[15].Additionally, localconsiderations,suchastechniqueavailabilityandproviderexpertise,willalsoimpactwhichimagingmodalityis implemented,furthercomplicatingtheconceptofauniversalimagingalgorithmforTA[28].Threecasereportsprovideinsightonfeasibleimagingintervals.Inthefirstcase, improvementinvascularlesionsonCTAwasseenwithin 6monthsofinitialpresentationwithanischemicstroke [3].ThesecondreportwasaninstanceofTAcausingpulmonarystenosisandocclusion.Improvementoflesions wasshownonfourimagingmodalities,gadoliniumenhancedMRI,twodimensionaltransesophagealechocardiography(TEE),pulmonaryangiography,andFDG-PET. Remarkably,improvementswereseenafteronly6weeks ofsteroidtherapy[37].Inathirdreport,TAdiagnosiswas madewithFDG-PET,whichshowedF-18FDGuptakein theaorta,subclavian,andbrachiocephalicarteries.Followingtwomonthsofsuccessfulimmunosuppressanttherapy, withremissionofclinicalsymptoms,thepatientwasagain imagedwithFDG-PET,revealingadramaticdecreasein F-18FDGuptakeintheaffectedvessels[38].SerialimagingisimportantformonitoringTApatientsbothforremissionandrelapse,togaugetheeffectivenessofcurrent therapiesandtodetectsubclinicalprogressionofvascular lesions.Werecommendconservativeimagingintervalsfor bothoftheseperiods,withmorefrequentimagingduring activediseaseandregularimagingevenintheabsenceof clinicalsymptomsduringremission. Anotherremarkablefeatureofthiscasewasthelabyrinthinesupplyofcerebralbloodflow,withcollateraland retrogradeflowcompensatingforseverestenosisand eventualcompleteocclusionofseveralvessels.Inourpatient,bothherleftcommoncarotidarteryandleftsubclavianarteryprogressedfromseverestenosistocomplete occlusion.Despitecompleteocclusionatitsorigin,theleft commoncarotidwaspatent.CTAimagingrevealedthe occipitalarterywasthepredominantcollateralsupplyto theleftanteriorcirculation,supplyingretrogradeflow throughtheexternalcarotid.Additionally,Transcranial Dopplerrevealedstenosisofherleftsubclavianarterywas compensatedbyretrogradeflowthroughherleftvertebral artery.Ithasbeenreportedthattheslowprogressionof stenosiscanallowforthedevelopmentofcollateralcirculation,delayingorminimizingsymptomsofvascularcompromise[4].Ourpatient ’ scompensatorycirculationwas protectiveagainstlefthemisphereischemiaanddelayed theonsetofneurologicalsymptoms.Thiscasedemonstratestheincrediblecompensatorycapacityofthesevesselsinthesettingofongoingstenosis. Thispatientsufferedanischemicstrokeduetotheprogressiveocclusionofhercerebralarteriessecondarytoher TA.Insomecases,whenthethreatfromstenosisbecomes severe,endovascularorsurgicalrevascularizationproceduresmayberequired.Theseproceduresshouldbereservedfortheinactivephaseofthedisease,andforstents, diseaseflareupscancausere-occlusionofboththeaffectedarteryandthestent.Balloonangioplastyandstent graftreplacementscanbeusedinthesettingofshortsegmentarterialstenosis,whereaslong-segmentstenosis requiresacompletesurgicalbypass[15].Itispossiblethat thecurrentpatientcouldhavebenefittedfromrevascularizationprocedures,especiallyaroundthetimeofher fourthpresentation,whencriticalstenosisofseveralextracraniallargevesselswasbecomingapparentandbothher ESRandCRPwerewithinnormallimits.ConclusionsThiscasesuggeststhatinflammatorymarkersaloneare notsufficienttomonitordiseaseactivity,highlightingthe needforfrequentfollowupimaging.Werecommendthat serialimagingbeperformedregularlyinthesettingofactivediseaseuntilpatientdemonstratesevidenceofremission,withanextendedimagingintervalinthecontextof inactivedisease.Thiscaseisalsoservesasareminderof theimportanceofregularvisitsandcomplianceinTA management.Thispatienthadextendedperiodsbetween visits,presentingonlywhensymptomsreemerged,and frequentlybecamenoncompliantwithmedication.Itis likelythatherdiseasecoursewouldhavebeenlesssevere withmorerobustpatienteducation,continuedcommunicationwithproviders,regularfollowup,andmedication compliance. Thesetimeintervalsprovideameanstoassesstreatmentefficacyandallowforimmediateinterventioninresponsetodiseaseexacerbation.Furthermore,thiscase providesastrikingexampleofhowcollateralandretrogradecirculationcancompensatefortheprogressivestenosisassociatedwithTA.ConsentWritteninformedconsentwasobtainedfromthepatient forpublicationofthiscasereportandanyaccompanying images.AcopyofthewrittenconsentisavailableforreviewbytheEditor-in-Chiefofthisjournal.O ’ Connor etal.BMCNeurology 2014, 14 :62 Page7of9 http://www.biomedcentral.com/1471-2377/14/62

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Abbreviations ESR: Erythrocytesedimentationrate;CRP:C-reactiveprotein;MCA:Middle cerebralartery;CTA:CTangiogram;MRA:Magneticresonanceangiogram; CCA:Commoncarotidartery;CVA:Cerebrovascularattack;MMP:Matrix metalloproteinase;TNF-alpha:Tumornecrosisfactoralpha;PTX:Pentraxin; TEE:Transeophagealechocardiogram. Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. Authors ’ contributions Studyconceptanddesign:TEO,HEC,VSH.Acquisitionofdata:TEO,HEC. Analysisandinterpretationofdata:TEO,HEC,VSH.Draftingandcritical revisionofmanuscript:TEO,HEC,VSH.Statisticalanalysis:TEO,HEC,VSH. Administrative,technical,andmaterialsupport:SB,MFW,VSH.Study supervision:SB,MFW,VSH.Allauthorsreadandapprovedthefinal manuscript. Acknowledgement PublicationofthisarticlewasfundedinpartbytheUniversityofFlorida Open-AccessPublishingFund. Authordetails1CollegeofMedicine,UniversityofFlorida,Gainesville,FL,USA.2Department ofNeuroscience,UniversityofFlorida,Gainesville,FL,USA.3Departmentof Neurology,UniversityofFlorida,RoomL3-100,McKnightBrainInstitute1149 NewellDrive,Gainesville,FL32611,USA.4DepartmentofRadiology, UniversityofFlorida,Gainesville,FL,USA. Received:9October2013Accepted:21March2014 Published:28March2014 References1.HallS,BarrW,LieJT,StansonAW,KazmierFJ,HunderGG: Takayasu arteritis.Astudyof32NorthAmericanpatients. Medicine(Baltimore) 1985, 64: 89 – 99. 2.SadurskaE,JawniakR,MajewskiM,Czekajska-ChehabE: Takayasuarteritis asacauseofarterialhypertension.Casereportandliteraturereview. EurJPediatr 2012, 171: 863 – 869. 3.HednaVS,PatelA,BidariS,ElderM,HohBL,YachnisA,WatersMF: Takayasu ’ sArteritis:isitareversibledisease?Casereportandliterature review. SurgNeurolInt 2012, 3: 132. 4.CastanerE,AlguersuariA,AndreuM,GallardoX,SpinuC,MataJM: Imagingfindingsinpulmonaryvasculitis. SeminUltrasoundCTMR 2012, 33: 567 – 579. 5.ArnaudL,HarocheJ,MathianA,GorochovG,AmouraZ: Pathogenesisof Takayasu ’ sarteritis:a2011update. AutoimmunRev 2011, 11: 61 – 67. 6.DireskeneliH,AydinSZ,MerkelPA: Assessmentofdiseaseactivityand progressioninTakayasu ’ sarteritis. ClinExpRheumatol 2011, 29: S86 – S91. 7.KerrGS,HallahanCW,GiordanoJ,LeavittRY,FauciAS,RottemM,HoffmanGS: Takayasuarteritis. AnnInternMed 1994, 120: 919 – 929. 8.BrylM,GuzinskiM,RabczynskiM,Waliszewska-ProsolM,GarcarekJ,AdamiecR, SasiadekM: ImagingdifficultiesinTakayasuarteritis-casereportandreview oftheliterature. PolJRadiol 2012, 77: 67 – 71. 9.HotchiM: PathologicalstudiesonTakayasuarteritis. HeartVesselsSuppl 1992, 7: 11 – 17. 10.MahlmannA,PflueckeC,OudaA,SimonisG,WeissN,KappertU: CombinedimmunosuppressivetherapyincludingaTNF-alphablocker inducesremissioninadifficulttotreatpatientwithTakayasuarteriitis andcoronaryinvolvement. Vasa 2012, 41: 451 – 457. 11.BravoManchenoB,PerinF,GuezVazquezDelReyMdelM,Garcia SanchezA,AlcazarRomeroPP: Successfultocilizumabtreatmentina childwithrefractoryTakayasuarteritis. Pediatrics 2012, 130: e1720 – e1724. 12.ErnstD,GreerM,StollM,Meyer-OlsonD,SchmidtRE,WitteT:Remission achievedinrefractoryadvancedtakayasuarteritisusingrituximab. CaseReportRheumatol 2012, 2012: 406963. 13.YamazakiH,NankiT,HarigaiM,MiyasakaN: Successfultreatmentofrefractory Takayasuarteritiswithtacrolimus. JRheumatol 2012, 39: 1487 – 1488. 14.UnizonyS,StoneJH,StoneJR: Newtreatmentstrategiesinlarge-vessel vasculitis. CurrOpinRheumatol 2013, 25: 3 – 9. 15.KeserG,DireskeneliH,AksuK: ManagementofTakayasuarteritis:a systematicreview. Rheumatology 2013[Epubaheadofprint]. 16.ArendWP,MichelBA,BlochDA,HunderGG,CalabreseLH,EdworthySM, FauciAS,LeavittRY,LieJT,LightfootRWJr,MasiAT,McShaneDJ,MillsJA, StevensMB,WallaceSL,ZvaiflerNJ: TheAmericanCollegeof Rheumatology1990criteriafortheclassificationofTakayasuarteritis. ArthritisRheum 1990, 33: 1129 – 34. 17.AydinSZ,YilmazN,AkarS,AksuK,KamaliS,YucelE,KaradagO, BicakcigilM,OzerH,KirazS,OnenF,InancM,KeserG,AkkocN, DireskeneliH: Assessmentofdiseaseactivityandprogressionin Takayasu ’ sarteritiswithDiseaseExtentIndex-Takayasu. Rheumatology(Oxford) 2010, 49: 1889 – 93. 18.MisraR,DandaD,RajappaSM,GhoshA,GuptaR,MahendranathKM, JeyaseelanL,LawrenceA,BaconPA: Developmentandinitialvalidationof theIndianTakayasuClinicalActivityScore(ITAS2010). Rheumatology(Oxford) 2013, 52: 1795 – 801. 19.HoffmanGS,AhmedAE: Surrogatemarkersofdiseaseactivityinpatients withTakayasuarteritis.ApreliminaryreportfromTheInternational NetworkfortheStudyoftheSystemicVasculitides(INSSYS). IntJCardiol 1998, 66 (66Suppl1):S191 – S194.discussionS195. 20.SalvaraniC,CantiniF,BoiardiL,HunderGG: Laboratoryinvestigations usefulingiantcellarteritisandTakayasu ’ sarteritis. ClinExpRheumatol 2003, 21: S23 – 8. 21.IshiharaT,HaraguchiG,TezukaD,KamiishiT,InagakiH,IsobeM: Diagnosis andassessmentofTakayasuarteritisbymultiplebiomarkers. CircJ 2013, 77: 477 – 83. 22.TsoE,FlammSD,WhiteRD,SchvartzmanPR,MaschaE,HoffmanGS: Takayasuarteritis:utilityandlimitationsofmagneticresonanceimaging indiagnosisandtreatment. ArthritisRheum 2002, 46: 1634 – 42. 23.DagnaL,SalvoF,TiraboschiM,BozzoloEP,FranchiniS,DoglioniC,Manfredi AA,BaldisseraE,SabbadiniMG: Pentraxin-3asamarkerofdiseaseactivityinTakayasuarteritis. AnnInternMed 2011, 155: 425 – 33. 24.ParkMC,LeeSW,ParkYB,LeeSK: Serumcytokineprofilesandtheir correlationswithdiseaseactivityinTakayasu ’ sarteritis. Rheumatology (Oxford) 2006, 45: 545 – 8. 25.deSouzaAW,deLimaCS,OliveiraAC,MachadoLS,PinheiroFA,HixS, D ’ AlmeidaV: HomocysteinelevelsinTakayasuarteritis – ariskfactorfor arterialischemicevents. JRheumatol 2013, 40: 303 – 8. 26.YilmazH,GerdanV,KozaciD,SolmazD,AkarS,CanG,GulcuA,GoktayY, SariI,BirlikM,AkkocN,OnenF: Ghrelinandadipokinesascirculating markersofdiseaseactivityinpatientswithTakayasuarteritis. ArthritisRes Ther 2012, 14: R272. 27.YamadaI,NakagawaT,HimenoY,NumanoF,ShibuyaH: Takayasuarteritis: evaluationofthethoracicaortawithCTangiography. Radiology 1998, 209: 103 – 9. 28.MavrogeniS,DimitroulasT,ChatziioannouSN,KitasG: Theroleof multimodalityimagingintheevaluationofTakayasuarteritis. SeminArthritisRheum 2013, 42: 401 – 12. 29.Budtz-LillyJW,PaaskeW,ThrysoeSA,AndersenG: Takayasu ’ sarteritisand theutilityofmagneticresonanceimaging. JVascSurg 2012, 56: 832. 30.SchneeweisC,SchnackenburgB,StuberM,BergerA,SchneiderU,YuJ, GebkerR,WeissRG,FleckE,KelleS: Delayedcontrast-enhancedMRIofthe coronaryarterywallintakayasuarteritis. PLoSOne 2012, 7: e50655. 31.YamadaI,NakagawaT,HimenoY,KobayashiY,NumanoF,ShibuyaH: Takayasuarteritis:diagnosiswit hbreath-holdcontrast-enhanced three-dimensionalMRangiography. JMagnResonImaging 2000, 11: 481 – 7. 32.PipitoneN,VersariA,SalvaraniC: Roleofimagingstudiesinthediagnosis andfollow-upoflarge-vesselvasculitis:anupdate. Rheumatology(Oxford) 2008, 47: 403 – 8. 33.KissinEY,MerkelPA: DiagnosticimaginginTakayasuarteritis. CurrOpin Rheumatol 2004,16: 31 – 7. 34.WebbM,ChambersA,AdilAL-N,MasonJC,MaudlinL,RahmanL,FrankJ: Theroleof18F-FDGPETincharacterisingdiseaseactivityinTakayasu arteritis. EurJNuclMedMolImaging 2004, 31: 627 – 34. 35.MellerJ,GrabbeE,BeckerW,VosshenrichR: ValueofF-18FDGhybrid cameraPETandMRIinearlytakayasuaortitis. EurRadiol 2003, 13: 400 – 5. 36.WengerM,CalamiaKT,SalvaraniC,MoncayoR,SchirmerM: Doweneed 18F-FDG-positronemissiontomographyasafunctionalimaging techniquefordiagnosinglargevesselarteritis? ClinExpRheumatol 2003, 21: S1 – 2.O ’ Connor etal.BMCNeurology 2014, 14 :62 Page8of9 http://www.biomedcentral.com/1471-2377/14/62

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37.KusunoseK,YamadaH,TomitaN,NishioS,NikiT,YamaguchiK,KoshibaK, YagiS,TaketaniY,IwaseT,SoekiT,WakatsukiT,AkaikeM,SataM: Serial imagingchangesduringtreatmentofTakayasuarteritiswithpulmonary arterystenosis. IntJCardiol 2011, 148: e47 – 50. 38.SagerS,YilmazS,OzhanM,HalacM,ErgulN,CiftciH,CermikTF: F-18Fdg PET/CTFindingsofaPatientwithTakayasuArteritisBeforeandAfter Therapy. MolImagingRadionuclTher 2012, 21: 32 – 4.doi:10.1186/1471-2377-14-62 Citethisarticleas: O ’ Connor etal. : Roleofinflammatorymarkersin Takayasuarteritisdiseasemonitoring. BMCNeurology 2014 14 :62. Submit your next manuscript to BioMed Central and take full advantage of: € Convenient online submission € Thorough peer review € No space constraints or color “gure charges € Immediate publication on acceptance € Inclusion in PubMed, CAS, Scopus and Google Scholar € Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit O ’ Connor etal.BMCNeurology 2014, 14 :62 Page9of9 http://www.biomedcentral.com/1471-2377/14/62