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w w w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Original

article

18

F-Fluorodeoxyglucose

positron

emission

tomography

and

serum

cytokines

and

matrix

metalloproteinases

in

the

assessment

of

disease

activity

in

Takayasu’s

arteritis

Anne

E.

D.

Arraes

a

,

Alexandre

W.

S.

de

Souza

a

,

Henrique

A.

Mariz

a

,

Neusa

P.

Silva

a

,

Ivone

C.

G.

Torres

b

,

Paula

N.

V.

Pinto

b

,

Eduardo

N.

P.

Lima

b

,

Emilia

I.

Sato

a,∗

aRheumatologyDivision,EscolaPaulistadeMedicina,UniversidadeFederaldeSãoPaulo(Unifesp),SãoPaulo,SP,Brazil bRadiologyDivision,HospitalA.C.Camargo,SãoPaulo,SP,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received7August2014 Accepted1March2015

Availableonline9September2015

Keywords:

Cytokines

Matrixmetalloproteinases

Positronemissiontomographyscan Takayasu’sarteritis

a

b

s

t

r

a

c

t

Objective:To evaluate 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission

tomography–computedtomography(PET–CT)andserumlevelsofdifferentcytokinesand matrixmetalloproteinases(MMPs)inpatientswithTakayasuarteritis(TA)andassociations withdiseaseactivity.

Methods:Serumlevelsoftumornecrosisfactor-␣(TNF-␣),interleukin(IL)-2,IL-6,IL-8,

IL-12,IL-18,MMP-3andMMP-9weremeasuredin36TApatientsand36controls.Maximum standarduptakevalue(SUVmax)of18F-FDGinarterialwallswasdeterminedbyPET–CTscans.

TApatientswereclassifiedasactivedisease,inactivediseaseandpossibleactivedisease.

Results:SerumIL-6andMMP-3levelswerehigherinTApatientsthanincontrols(p<0.001). SerumIL-6washigherinpatientswithactivediseaseandinpatientswithpossibleactive diseasethanininactivedisease(p<0.0001).Patientswithactivediseasehadhigherserum TNF␣levelsthanpatientswithinactivedisease(p=0.049)whilepatientswithpossibleactive

diseasepresentedhigherIL-18levelsthanpatientswithinactivedisease(p=0.046).Patients withactivediseasehadhigherSUVmaxvaluesthanthosewithinactivedisease(p=0.042).By

receiveroperatingcharacteristic(ROC)curveSUVmaxwaspredictiveofactivediseaseinTA

andvalues≥1.3wereassociatedwithdiseaseactivity(p=0.039).SerumTNF-␣levelswere

higherinpatientswithSUVmax≥1.3than<1.3(p=0.045)andcontrols(p=0.012).SerumIL-6

levelswerehigherinpatientswithSUVmax≥1.3thanincontrols(p<0.001).Nodifferences regardingotherbiomarkerswerefoundbetweenTApatientsandcontrols.

Conclusions: HigherserumIL-6andTNF␣levelsaswellashigher18F-FDGuptakeinarterial

wallareassociatedwithactiveTA.

©2015ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Correspondingauthor.

E-mail:eisato@unifesp.br(E.I.Sato).

http://dx.doi.org/10.1016/j.rbre.2015.08.007

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Tomografia

por

emissão

de

pósitrons

com

18F-fluordesoxiglicose

e

citocinas

séricas

e

metaloproteinases

da

matriz

na

avaliac¸ão

da

atividade

da

doenc¸a

na

arterite

de

Takayasu

Palavras-chave:

Citocinas

Metaloproteinasesdamatriz Tomografiacomputadorizada ArteritedeTakayasu

r

e

s

u

m

o

Objetivo: Avaliaracaptac¸ãode18F-fluordesoxiglicose(18F-FDG)natomografiaporemissão depósitrons–tomografiacomputadorizada(PET–CT)eosníveisséricosdediferentes citoci-nasedametaloproteinasesdamatriz(MMP)empacientescomarteritedeTakayasu(AT)e associac¸õescomaatividadedadoenc¸a.

Métodos: Forammensuradososníveisséricosdofatordenecrosetumoral-␣(TNF-␣),

inter-leucina(IL)-2,IL-6,IL-8,IL-12,IL-18,MMP-3eMMP-9em36pacientescomATe36controles. Ovalorpadronizadodecaptac¸ãomáximo(SUVmax)de18F-FDGnasparedesarteriaisfoi

determinadoporexamesdePET–CT.OspacientescomATforamclassificadoscomotendo doenc¸aativa,doenc¸ainativaepossíveldoenc¸aativa.

Resultados: OsníveisséricosdeIL-6eMMP-3forammaisaltosempacientescomATdoque noscontroles(p<0,001).OsníveisséricosdeIL-6erammaiselevadosempacientescom doenc¸aativaeempacientescompossíveldoenc¸aativadoquenaquelescomdoenc¸a ina-tiva(p<0,0001).Ospacientescomdoenc¸aativaapresentaramníveisséricosmaiselevados deTNF-␣doqueospacientescomdoenc¸ainativa(p=0,049),enquantoosindivíduoscom

possíveldoenc¸aativaapresentarammaioresníveisséricosdeIL-18doqueospacientes comdoenc¸ainativa(p=0,046).Aquelescomdoenc¸aativaapresentarammaioresvaloresde SUVmaxdoqueaquelescomdoenc¸ainativa(p=0,042).DeacordocomacurvaROC,oSUVmax

eracapazdepredizeradoenc¸aativanaATevalores≥1,3estavamassociadosàatividadeda doenc¸a(p=0,039).OsníveisséricosdeTNF-␣forammaioresempacientescomSUVmax≥1,3

doquenaquelescomvalor<1,3(p=0,045)econtroles(p=0,012).OsníveisséricosdeIL-6 forammaiselevadosempacientescomSUVmax≥1,3doquenoscontroles(p<0,001).Não

foramencontradasdiferenc¸asemrelac¸ãoaoutrosbiomarcadoresentrepacientescomAT econtroles.

Conclusões: NíveisséricoselevadosdeIL-6eTNF-␣,bemcomoumamaiorcaptac¸ãode

18F-FDGnaparedearterial,estãoassociadosaATativa.

©2015ElsevierEditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCC BY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Takayasu arteritis (TA) is a primary systemic vasculitis of unknownetiologythataffectslargearteries,mainlytheaorta and its mainbranches and less frequently pulmonaryand coronaryarteries.Thechronicgranulomatousinflammation occursinalllayersofthevesselwallandmayleadtostenosis, occlusion,dilationoraneurysmformation.1,2

Cell-mediatedautoimmunityplaysakeyroleinthe patho-genesisofTA.Immunohistochemicalstudiesoftheinfiltrating cellsintheaortictissuehaveshownmainlygamma-delta T-cells,CD4+andCD8+T-cells,NKcellsandmacrophages.3The

presenceofgranulomatousinflammationintheinternal elas-ticlayeristhemostcharacteristicpathologicfindingofTA. Theinflammatoryprocessbeginsinthevasavasorumanditis believedtobetriggeredbytheactivationofdendriticcellsand dendriticcell/T-cellinteractioninthevascular microenviron-mentoftheadventitiaoflargearteriesleadingtotheinduction ofaTh1response.4

ThedetectionofvascularinflammationinTApatientsis a major challenge in clinical practice, since up to 60% of asymptomaticpatientsdevelopednewangiographiclesions onsequentialarteriographicevaluation,and44%ofpatients

consideredtobeinremissionbyclinicalevaluationshowed histopathologicalevidenceofactiveinflammationonsurgical specimens.1 Duetotheevidenceofprogressionofvascular

damageinasymptomaticTApatients,additionalevaluation isnecessarytoguidetherapeuticdecisions.Nevertheless,to datethereisnoreliablesurrogateparametertodetect subclini-caldiseaseactivityinTApatients.Potentialbiologicalmarkers of inflammationand tissuedegradation,such ascytokines and metalloproteinases (MMPs) have been evaluated sepa-rately indifferent studies but some resultshave not been reproduced.5–7 Differentimagingtechniqueshavebeenused

toassesstheextentofarterialinvolvementinTA,amongthem

18F-fluorodeoxyglucose(18F-FDG)positronemission

tomogra-phy with computed tomography (PET–CT) scan can detect active arterial wallinflammation. Some studies have been promising8–10 whereasothershavefoundconflictingresults

withtheuseofPET–CTscanstoevaluatediseaseactivityin TA.11,12

Theaimsofthis studywere toevaluatetheintensityof

18F-FDGuptakeonPET–CTscansonarterialwallsand

quan-tifyserumlevelsofinterleukin-2(IL-2),IL-6,IL-8,IL-12,IL-18, tumornecrosisfactor-␣(TNF-␣),MMP-3andMMP-9inpatients

(3)

Materials

and

methods

Patientsandcontrols

Patients under regular follow-up at the Vasculitis Unit of theuniversityhospitalofUniversidadeFederaldeSãoPaulo (Unifesp)oratprivateofficesofrheumatologistswhoworkat Unifespwereconsecutivelyinvitedtoparticipateinthis cross-sectional study. They underwent clinical, laboratorial and imagingevaluationwithina20-dayperiod.Inclusioncriteria were the fulfillment of the American College of Rheuma-tology (ACR) classification criteria for TA,13 age above 18

years and the absence of malignancy,active infection and pregnancy.Thecontrolgroupscomprisedlaboratorycontrols (lab-controls)and PET–CTscan controls(PET-controls). The formergroupincluded36age-andgender-matchedsubjects withoutchronicinflammatoryorinfectiousdiseaseandthe lattergroupconsistedofsixhealthyindividualswho under-went a PET–CT scan, using the same protocol used by TA patients.Allsubjectssignedinformedconsentformapproved bytheInstitutionalEthicsCommitteesfromUnifespandAC CamargoHospital.

Clinicalandlaboratoryassessment

TheclinicalassessmentofTApatientswasperformedbytwo physiciansexperiencedinTAmanagement(AWSSandHAM) atroutinemedicalvisits.Diseaseactivitywasdefinedwhether theonsetorworseningofatleasttwoofthefollowingfeatures waspresent: (a)systemic featureswith noother identified cause;(b)theonsetoffeaturesofvascularischemiaor inflam-mation,suchaslimbclaudication,unequalorabsentpulse, bruit,vascularpain(carotidynia)orasymmetricblood pres-sure;(c)elevatedacutephasereactantsincludingerythrocyte sedimentationrate(ESR);(d)developmentofnewlesionsin previouslyunaffectedvascularterritories onserialvascular imagingevaluation.1TApatientspresentingabnormallevels

ofacutephasereactants(i.e.ESR≥40mm/hand/orserumCRP levels≥10mg/dL)withoutsignsandsymptomsofactiveTAor newangiographiclesionswereconsideredadistinctsubgroup namedaspossibleactivedisease.

Blood samples were collected from patients and lab-controls for cytokines, MMPs, ESR (Westergren) and CRP measurements. Serumsamples were separated and stored at −70◦C until tests were performed. The enzyme-linked

immunosorbentassay(ELISA)techniquewasusedtoquantify CRP(DiagnosticsSystemsLaboratories,EUA),IL-18(KitMed &BiologicLabCo,Japan),MMP-3andMMP-9(R&DSystems, EUA).Alltestswereperformedinduplicate.Themeasurement ofIL-2,IL-6,IL-8,IL-12andTNF-␣wasperformedbyLUMINEX

Millipexkits.

Imageassessment

PET–CTscans were acquired usinga GeminiPET–CT scan-ner (Philips) after at least a 6-h fasting period. Capillary glucose levels were checkedbefore scans and no one pre-sentedlevelsabove200mg/dLpriorto18F-FDGadministration.

Imageacquisition wasperformed 60minafterthe infusion

of0.154millicurie(mCi)/kgof18F-FDGandparticipantswere

scannedfromtheskulltoproximalthighs.Firstly,CTimages were obtainedwithoutthe infusionofintravenouscontrast using the following parameters: 120kV,120mAs, 0.75s per rotation, pitch1.5,5mmslicethicknessanda3mm recon-structioninterval.ThenPETscanwasacquiredduring2min and15sateachbedpositioninatotalof11bedpositions. PET-controlsubjectshadundergonethesameprotocolandtheir scanswereretrievedfromthearchive.AllPET–CTscanswere performedatACCamargoHospitalandimageswere evalu-atedbyaradiologist(PNVP)andanuclearmedicinephysician (ICGT)who wereunawareofclinical andlaboratory assess-mentsofTApatients.

A semi-quantitative assessment of 18F-FDG uptake was

done at using the standard uptake value (SUV). The SUV wascalculated dividingthemaximumtissueconcentration bythe totalinjecteddose of18F-FDGperbody weight.The

regionofinterest(ROI)wasmanuallyplacedonarterywallsof thefollowingsites:vertebral,internalcarotid,subclavianand commoncarotidarteries,pulmonaryartery,brachiocephalic trunk, aortic arch, ascending, descending and abdominal aorta,celiactrunk,superiorandinferiormesentericarteries, renalandiliacarteries.ThehighestvalueofSUVfoundineach arterywasrecordedandonlythehighestvalueonthewhole PET–CTscan(SUVmax)wasusedforstatisticalanalysis.

Statisticalanalysis

Statisticalanalysiswasperformedwiththesoftware Statisti-calPackagefortheSocialSciences(SPSS)version17.0(Chicago, IL).Categoricaldatawaspresentedastotalnumberand per-centage, and numerical data as median (range) or mean (standard deviation) as appropriate. The Shapiro–Wilk test wasusedtotestthenormalityofcontinuousvariables. Com-parisonsregardingnumericalvariableswereperformedwith Mann–WhitneyUtestorStudent’sttestfortwogroupsorwith Kruskal–Wallistestorone-wayANOVAtestforthreeormore groups.TheMann–WhitneyUtestwithBonferroni’scorrection wasusedasaposthoc test.Valuesofp<0.05were consid-eredsignificant whilepvaluesbetween0.10and 0.05were consideredasstatisticaltendency.

SUVmax valuesforthe diagnosis of disease activity was

evaluatedbytheROC(receiveroperatingcharacteristic)curve andtheYoudenindexwasusedtoassessthebestcutoff val-ues.ResultsoftheROCcurvewereexpressedinareaunder thecurve,95%confidenceinterval(95%CI),positive predic-tivevalue,negativepredictivevalue,accuracy,sensitivityand specificityforcutoffpointsofSUVmax.Correlationsbetween

numericalvariableswereperformedbySpearman’stest.The presenceofactivediseaseinTAdeterminedbythecutoffof SUVmaxwascomparedtodiseaseactivitydeterminedby

clini-calevaluationusingFisher’sexacttest.Statisticalsignificance wasconsideredforp<0.05.

Results

Patientsandcontrols

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Table1–DemographicanddiseasefeaturesofTApatientsevaluatedinthisstudy.

Variables Activedisease(n=14) Inactivedisease(n=11) Possibleactivedisease(n=11) p

Age,years 35.0(22.0–54.0) 32.0(24.0–68.0) 32.0(21.0–56.0) 0.818

Females,n(%) 14(100.0) 9(81.8) 10(90.9) 0.262

TimesincefirstTAsymptoms,months 72.0(24.0–216.0) 85.0(23.0–372.0) 118.0(9.0–207.0) 0.800 Timesincediagnosis,months 45.5(2.0–216.0) 66.0(17.0–292.0) 58.0(1.0–240.0) 0.628 ESR,mm/h 20.00(5.00–115.00) 11.00(1.00–26.00) 26.00(7.00–70.00) 0.059 SerumCRPlevels,mg/dL 18.17(0.10–99.05) 1.53(0.17–7.77) 78.13(8.16–91.89) <0.0001

CRP,C-reactiveprotein;ESR,erythrocytesedimentationrate.

Dataarepresentedasmeanandstandarddeviationorasmedianandrange.

considered withinactive disease and11 (30.6%)had possi-ble activedisease.Table 1describes demographicfeatures, timesincethe onset ofsymptoms attributabletoTA,time sincediagnosis and acutephase reactantsin subgroupsof TApatients.PatientswithactivediseasehadhigherESRand serum CRP levels than patients with inactive disease. TA patientswithpossibleactivediseasehadsignificantlyhigher serumCRPlevelsthan patientsinremissionandatrendto havehigherESRthanpatientsinremission(Table1).Atthe timeofassessment,21patientswereonsteroidsand immu-nosuppressive agents, three patients only on steroids, six weretreatedonlywithanimmunosuppressiveagentandsix other patients were not receiving any therapy for TA. The medianprednisonedailydosewas12.5mg(5.62–27.50).The followingimmunosuppressiveagentswereusedbypatients: methotrexate (50.0%), mycophenolate sodium (11.1%), aza-thioprine (8.3%), and cyclophosphamide (5.6%). Only one patientusedetanercept.

Thelab-controlgroupcomprised33 womenand 3men, withamedianageof34.0(20–68)years.Alllab-controlsdidnot presentanymedicalconditionandwerenotunderany med-icaltherapy.ThePET-controlgroupconsistedofsixhealthy individuals(fourwomen,twomen)withmedianageof32.5 (28–45)years.

Cytokinesandmetalloproteinases

Table 2 shows serum levels ofcytokines and MMPs in TA

patientsandlab-controls.TApatientspresentedhigherIL-6 levels(p<0.001)andhigherserumMMP-3levels(p<0.001)and atendencyforhigherTNF-␣levels(p=0.069)thanlab-controls.

No significant differences were found regarding serum

levelsofIL-2,IL-8,IL-12,IL-18andMMP-9whencomparing TApatientsandlab-controls(Table2).

SerumcytokineandMMPslevelsinTApatientswithactive disease,patientswithinactivediseaseandpatientswith pos-sibleactivediseaseare showninTable3.SerumIL-6levels were higherinpatientswithactivedisease andinpatients withpossibleactivediseasecomparedtowithpatientswith inactivedisease(p<0.0001)(Fig.1).Althoughatendencyfor differenceswasfoundregardingserumTNF␣andIL-18levels

amongTAsubgroups,whenthosesubgroupswereanalyzed separately,TApatientswithactivediseasehadsignificantly higherserumTNF␣levelsthanpatientswithinactivedisease

(p=0.049) while patients with possible active disease pre-sentedhigherserumIL-18levelsthanpatientswithinactive disease(p=0.046).

CorrelationsamonginflammatorymarkersinTApatients

IL-6levelscorrelatedwithESR(rho=0.475;p=0.005)andwith CRPlevels (rho=0.673;p<0.001).CRPlevels andESRvalues (rho=0.585; p<0.001) were significantly correlated as well. TNF-␣ levelscorrelatedwithIL-6 (rho=0.365;p=0.029),IL-8

(rho=0.346;p=0.039),aswellaswithCRPlevels(rho=0.370;

p=0.026).Furthermore,serumIL-2andIL-12levelswere corre-lated(rho=0.529,p=0.001).Nocorrelationswerefoundamong othercytokinesandMMPs.

Medicaltherapy,cytokines,metalloproteinasesandacute

phasereactants

MMP-3 levels were higher in TA patients using steroids than in those without steroids (45.05±26.96ng/mL vs.

Table2–SerumlevelsofcytokinesandmetalloproteasesinTApatientsandcontrols.

Markers TApatients(n=36) Lab-controls(n=36) p

IL-2,pg/mL 0.36(0.00–23.38) 0.25(0.00–21.87) 0.710

IL-6,pg/mL 7.55(0.17–76.22) 1.74(0.17–16.21) <0.0001a

IL-8,pg/mL 4.83(1.88–17.92) 4.49(2.02–22.02) 0.327

IL-12,pg/mL 0.00(0.00–46.39) 0.00(0.00–11.97) 0.908

IL-18,pg/mL 151.71(0.00–463.26) 121.63(0.00–745.22) 0.130

TNF-␣,pg/mL 5.64(1.91–15.28) 4.26(1.41–12.89) 0.056

MMP-3,ng/mL 27.00(6.00–102.70) 12.05(4.30–75.50) <0.0001a

MMP-9,ng/mL 495.55(183.70–2338.80) 452.15(221.20–2044.00) 0.457

IL,interleukin;MMP,matrixmetalloproteinase;TNF,tumornecrosisfactor.

(5)

Table3–SerumlevelsofcytokinesandmetalloproteasesinTApatientswithactivedisease,inactivediseaseandwith possibleactivedisease.

Variables Activedisease(n=14) Inactivedisease(n=11) Possibleactivedisease(n=11) p

TNF␣,pg/mL 5.93(3.84–10.71) 4.16(1.91–15.28) 6.76(3.69–9.23) 0.079

IL-2,pg/mL 0.19(0.00–1.57) 1.12(0.00–12.04) 0.44(0.00–23.38) 0.354 IL-6,pg/mL 9.15(0.65–76.22) 2.48(0.17–10.80) 8.48(1.25–37.56) 0.003a

IL-8,pg/mL 5.47(2.83–17.92) 4.53(1.88–10.56) 4.61(2.74–8.82) 0.368

IL-12,pg/mL 0.00(0.00–2.22) 0.00(0.00–12.56) 0.00(0.00–46.39) 0.587

IL-18,pg/mL 183.58±129.05 119.96±57.98 246.20±147.29 0.059

MMP3,ng/mL 22.40(6.00–94.90) 26.30(9.30–102.70) 31.10(7.10–84.90) 0.682

MMP9,ng/mL 515.10(208.40–2338.80) 424.20(183.70–1422.50) 491.30(274.40–1160.40) 0.547

IL,interleukin;MMP,matrixmetalloproteinase;TNF,tumornecrosisfactor.

Continuousdataarepresentedasmedianandrangeorasmeanandstandarddeviation. a Statisticallysignificantvalues.

13.11±6.36ng/mL; p<0.001)and apositive correlation was observedbetweenMMP-3levels and dailyprednisonedose (rho=0.463; p=0.023) (Fig. 2). No associations were found amongsteroidsuse,dailyprednisonedose, immunosuppress-ivetherapy and levels ofMMP-9,cytokines or acutephase reactants(datanotshown).

PET–CTscanandbiomarkers

MedianSUVmaxvalueswerehigherinTApatientsthanin

PET-controls[1.57(0.87–3.04)vs.0.99(0.67–1.23);p=0.001]andin patientswithactivediseasecomparedwiththoseinremission [1.97(1.19–3.04)vs.1.19(0.87–2.59);p=0.015].However,no sig-nificantdifferencesregardingSUVmaxcouldbefoundbetween

TA patients with active disease and those with possible activedisease[1.97(1.19–3.04)vs.1.58(1.00–2.72);p=0.324]or betweenpatientswithpossibleactivediseaseandthosewith inactivedisease[1.58(1.00–2.72)vs.1.19(0.87–2.59);p=0.212]. Furthermore,patientswithinactivediseasepresentedhigher

Possible active disease Inactive disease

Active disease .00

20.00 40.00

p=0.001

p=0.584 o

o

o o

p=0.008

pg/ml

60.00 80.00

Fig.1–IL-6levelsinpatientswithactivedisease,inactive diseaseandpossibleactivedisease.SerumIL-6levelswere significantlyhigherinpatientswithactivediseaseandin patientswithpossiblediseaseactivitythaninpatients withinactivedisease.Nosignificantdifferencescouldbe foundbetweenTApatientswithactivediseaseandpatients withpossibleactivedisease.

SUVmax values than PET-controls [1.19 (0.87–2.59) vs. 0.99

(0.67–1.23);p=0.049].Fig.3illustratesthePET–CTfindingsina TApatientwithactivedisease.

TA patients on immunosuppressive therapy presented lower median SUVmax values than patients without those

agents [1.41 (0.87–3.04) vs. 2.57 (0.96–3.00); p=0.044]. How-ever, no differences in median SUVmax values were found

in patients with and without steroids [1.48 (0.87–3.04) vs. 2.14(0.96–3.00);p=0.127]aswellasnocorrelationwasfound between SUVmax and daily prednisone dose (rho=0.233;

p=0.274). Moreover, no correlations were found between SUVmax valuesand ESR(rho=0.081; p=0.647)orCRP levels

(rho=0.139; p=0.419)and betweenSUVmax valuesand

lev-elsofanycytokineorMMPsevaluatedinthisstudy(datanot shown).

ROCcurveanalysisshowedthevalueofSUVmaxasa

pre-dictorofactivediseaseinTA(AUC=0.703;95%CI=0.534–0.832;

p=0.043). The best cutoff points obtained for SUVmax

val-ues (withtheir respective sensitivity and specificity) were:

Daliy prednisone dose, mg

MMP-3, ng/ml

0 0 10 20 30 40 50 60

120 100 80

60 40 20

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Fig.3–RepresentativePET–CTscanimagesfromapatientwithTakayasuarteritisandactivedisease.

PET–CTscanimagesofa32-years-oldfemalepatientwithclinicallyactivedisease:(A)fusionimageincoronal

reconstructionwith18F-FDGuptakeinascendingaorta,(B)imagesofPETscanincoronalplanewith18F-FDGuptakeinthe

abdominalandascendingaorta;(C)fusionimageinaxialsectionshowing18F-FDGuptakeinascendingaortaandright

pulmonaryartery,(D)fusionimageinaxialsectionwith18F-FDGuptakeintheabdominalaorta.

1.23,(93%and 45%),1.29 (86%and50%) and1.83 (57%and 73%).MoreTApatientspresentingactivediseasebasedonNIH criteriahadSUVmax≥1.3onarterialwallswhencomparedto

thosewithSUVmax<1.3(p=0.039)(Table4).Thiscutoffvalue

yieldedapositivepredictivevalueof52.0%,anegative predic-tivevalueof78%andanaccuracyof63.8%foractivediseasein TA.PatientswithSUVmax values≥1.3presentedhigher

TNF-␣(p=0.015)andIL-6levels(p=0.036)incomparisontothose

withSUVmaxvalue<1.3andlab-controls(Fig.4AandB).No

sig-nificantdifferenceswerefoundregardinglevelsofIL-2,IL-8,

IL-12,IL-18,MMP-3,MMP-9,ESRandCRPregardingtheSUVmax

cutoffvalueof1.3(Table4).

Discussion

Thisisthefirststudyevaluatingthemajorityofbiomarkers of inflammatoryactivity already reported inthe literature, including several cytokines and MMPs as well as 18F-FDG

uptakeinlargearteriesonPET–CTscan inTApatients.TA

Table4–Comparisonofdiseaseactivityparameters,cytokinesandmatrixmetalloproteinasesinTApatientsbasedon SUVmaxcutoffvalueof1.3.

Variables SUVmax≥1.3(n=23) SUVmax<1.3(n=13) p

Activedisease,n(%) 12(52.2) 2(15.4) 0.039a

ESR,mm/h 19.00(5.00–115.00) 14.00(1.00–70.00) 0.139

CRP,mg/dL 24.56(0.10–99.05) 5.23(0.17–82.34) 0.096

TNF␣,pg/mL 6.76(3.56–15.28) 4.37(1.91–9.23) 0.015a

IL-2,pg/mL 0.44(0.00–23.38) 0.05(0.00–8.50) 0.484

IL-6,pg/mL 8.48(0.43–76.22) 4.46(0.17–37.56) 0.036a

IL-8,pg/mL 5.15(1.88–17.92) 4.53(2.16–10.56) 0.553

IL-12,pg/mL 0.00(0.00–46.39) 0.00(0.00–5.06) 0.130

IL18,pg/mL 164.60(0.00–424.01) 132.05(60.95–463.26) 0.987

MMP-3,ng/mL 26.90(6.00–94.90) 27.10(7.10–102-70) 0.542

MMP-9,ng/mL 499.80(183.70–2338.80) 461.60(283.20–1442.40) 0.564

CRP,C-reactiveprotein,ESR,erythrocytesedimentationrate;IL,interleukin;MMP,matrixmetalloproteinase;SUV,standarduptakevalue;TNF, tumornecrosisfactor.

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TNFα, pg/mL

IL-6, pg/mL

SUV≥1.3

SUV≥1.3

SUV<1.3

SUV<1.3

Lab-controls

Lab-controls 15

A

B

10

p=0.015

p<0.0001

p=0.036 p=0.075 p=0.002

p=0.802

5

0

80

60

40

20

0

Fig.4–SerumTNF␣andIL-6levelsinpatientswith

SUVmax≥1.3,patientswithSUVmax<1.3andlab-controls. SerumTNF␣(A)andIL-6(B)levelsweresignificantlyhigher

inTApatientspresentingSUVmax≥ 1.3comparedto patientswithSUVmax<1.3andlab-controls.Nodifference

couldbefoundregardingserumTNF␣andIL-6levels

betweenpatientswithSUVmax<1.3andlab-controls.

patientspresentedhigherSUVmax valuesof18F-FDGuptake

onlargearteries byPET–CTscansand higherserum levels ofIL-6andMMP-3thancontrols.Moreover,SUVmaxvaluesof 18F-FDGuptakeonlargearteries,serum IL-6andTNF

lev-elswerehigherinTApatientspresentingactivediseasewhen comparedtothoseconsideredwithinactivedisease.Patients withpossibleactivedisease(i.e.onlyhighacutephase reac-tantswithoutsignsandsymptomsofactiveTA)presenthigher serumIL-6andIL-18levelsthanpatientswithinactivedisease. However,nosignificantdifferenceswereobservedregarding SUVmaxvaluesinpatientswithpossibleactivedisease

com-paredtothosewith activediseaseand those withinactive disease.

Althoughbeingararedisorder,TAoftencauseshigh mor-bidity due to the progression of vascular lesions, and to thelackofreliableparameters todetectdisease activity to allowanefficaciousintervention.Studiesevaluatingsurrogate

markersandimagingmethodstoassessdiseaseactivityinTA patientshaveprovidedinconsistentresults.Thereasonsfor thisincludethelackofagoldstandardtodetectdisease activ-ityandtheinclusionofsmallnumberofTApatientsinvarious studies.

Corroboratingpreviousstudies5,6wefoundassociationof

serum IL-6 levelswithboththe disease statusand disease activityinTA.DifferentlyfromtheresultsofParketal.,6serum

TNF␣levelswerehigherinpatientswithactivediseasethan

thoseinremissionbutthedifferenceshowedonlyatendency tobehigheramongTApatientsthaninlab-controls(p=0.056). Serumlevelsofothercytokineswere notdifferentbetween TApatientsandcontrolsandtheywerenotusefulto differen-tiateTApatientswithactiveandinactivedisease.Although, apreviousstudyhadfoundanassociationbetweendisease activity andserumlevelsofIL-18inTApatients,6 wecould

notfindsignificantdifferencesinIL-18levelsbetweenpatients and controls,orbetweenTApatientswithactiveand inac-tivedisease.Indeed,wefoundhigherserumIL-18levelsinTA patientswithpossibleactivediseasecomparedtocontrolsand thismayindicatethatthosepatientsmaypresentsubclinical inflammation.SimilarlytoTrypathyetal.,wefoundno differ-encesinserumIL-2levelsbetweenTApatientsandcontrols. Nevertheless,theyobservedalowerpercentageofIL-2 produc-ingCD3+T-cellsinpatientswithactivediseaseincomparison topatientswithinactivediseaseandcontrols.14Theroleof

IL-12asasurrogatemarkerofdisease activityinTAisstill controversial.Inonestudy,similarlevelsofserumIL-12were foundbetweenpatientsandcontrolswhileinanotherstudy, plasmaIL-12levelswerehigherinpatientswithactivedisease incomparisontothosewithinactivediseaseandcontrols.6,15

Inthepresentstudy,IL-12levelsweresimilarinTApatients and controlsandnoassociationwithdiseaseactivity could befound.AlthoughIL-8levelswerehigherinTApatientsthan incontrolsandassociatedwithdiseaseactivityinonestudy,16

wecouldnotfindanydifferencesregardingIL-8levelsbetween patientsandcontrols.

In asinglestudy,higher MMP-3and MMP-9levelswere associatedwithactivediseaseinTApatients,witha subse-quentdecreasefollowingdiseasecontrol.7Inourstudy,only

MMP-3 levels were higher inpatients than in controlsbut no difference related to disease activity was found. MMP-3 levelswere higheramong patientsusing steroids witha positive correlation betweenMMP-3 levels and daily pred-nisonedose.Theassociationbetweensteroiddailydoseand MMP-3levelswasalsoreportedinpatientswithrheumatic diseases,17 including a recent study in patientswith TA.18

Sharif etal.19 founda53% increaseinpro-MMP-3levelsin

patients with rheumatoid arthritis using prednisone, even amongstpatientspresentingadecreaseinother inflamma-toryparameters.However,themechanisminvolvedinMMP-3 elevationassociatedwithsteroidsuseisstillunclear.

Initial studies with PET–CT scans evaluating disease activity inTAshowed promisingresults.10,20 Morerecently,

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to detect active disease in TA.21 However, another study

hasraised questions about the usefulness ofthis method, sincethereisno SUVvaluedefinedasnormalforthe ves-selwall.11Ameta-analysisincludingsixstudiesfoundthat

PET–CTscanhadamoderatevaluetoevaluatedisease activ-ityinTA.Thepooledsensitivityandspecificity were70.1% (95%CI:58.6–80.0)and77.2%(95%CI:64.2–87.3),respectively. Authors considered that PET–CT scan was not suitable to beused asthe sole methodto evaluatedisease activity in TAbutitmaybeadditionalvaluetocurrentclinical assess-ment. Heterogeneityamong studies is a limitation of this meta-analysis.22

Several studies have considered the SUV values useful in the diagnosis and prognosis for cancers.23–25

Neverthe-less, this imaging technique is still a matter of debate as longasalargevariabilityofSUVvalueshasbeen observed amongseveral institutes,thus raisingthe needtocalibrate equipments and standardize parameters for data acquisi-tionandprocessinginordertoobtaincomparableresults.26

SUVmax valuesbecomemorereliablewhenusedas

param-eters withinthe same institute, under the same technical conditions, especially in the comparison of serial imaging studies.

Inthisstudy,PET–CTscanswereperformedunderfasting conditionsandcapillarybloodglucosewascheckedbefore18

F-FDGadministrationtoexcludethepossibilityoffalse-negative resultsdue tohyperglycemia. Although,the 18F-FDGin TA

might betaken up mostly byinflammatory cells in vessel walls,theinfluenceofbloodglucoselevelshasnotbeenstill establishedinthiscontext.27Rabkin etal.28havedescribed

false-negativeresultsinpatientswithdifferenttypesofcancer whenbloodglucoseexceeded180mg/dL,butnotinpatients withinfectiousorinflammatoryconditions.

Henesetal.studiedtheuseofPET–CTinpatientswithlarge vesselvasculitis,includingthreepatientswithTAandfound SUVmaxvaluesbetween1.6and6.8withinarterialwalls.Inthis

study,SUVmaxvaluesrangedfrom2.5to5.8inTApatientswith

activedisease.Amongeightpatientswithsurgicallytreated solidtumorsusedascontrols,SUVmaxvaluesrangedfrom1.4

to2.3.8

AnotherstudyevaluatedPET–CTscansin20patientswith large vessel vasculitis including 3 patients with TA. The SUVmaxcutoffvalueof1.78hadthebestperformanceforthe

diagnosisofalargevesselvasculitiswithsensitivityand speci-ficityof,respectively,65%and80%byvisualscale,and90% and45%bytheSUVmax.Thecontrolgroupwasconstitutedby

patientstreatedforthyroidcancer.12

SUVmax values in the above-mentioned studies were

slightlyhigherthanwhatwefoundforTApatients. Techni-caldifferencesinPET–CTscanprotocolsmaybeahurdleto compareourresultswithdifferentstudies.Furthermore,our studyincludedonlyTApatientswithameanageof36years whereas inthe above-mentioned studies,8,12 mostpatients

had giant cell arteritis witha higher mean age (62 years). Ourcontrolgroup consistedofhealthysubjects, instead of cancerpatients.Theinfluenceofageintheincreaseof18

F-FDGhasbeendemonstratedinoneretrospectivestudy29and

itmayoccurinpartduetoatherosclerosis.Indeed,thisfact mightreducePET–CTscansspecificityinTApatients,sincethe prevalenceofatherosclerosisisincreasedinthosepatients.30

Arnaudetal.foundlowsensitivityandspecificityofPET–CT scantodetect diseaseactivityinTApatients.Theydidnot findanyassociationwitheitherinflammatorymarkersornew lesions onserialMRIangiographies.Theyusedvisualscale and quantitative evaluation to assess 18F-FDG uptake and

foundastrongcorrelationbetweenbothmethods.11 In

con-trast,Leeetal.havealsoevaluatedthePET–CTscansinTA patientsusingthevisualscaleandSUV.Theyfoundan asso-ciation between18F-FDGuptakein vesselwalland disease

activityinbothassessments.31

Using theSUVmax tomeasure18F-FDGuptake,wefound

higher valuesofSUVmax inTApatientswithactivedisease

comparedtothosewithinactivedisease.Henceinourstudy, SUVmax seemed to be predictive of disease activity in TA.

Patientsusingimmunosuppressiveagentshadlowerarterial SUVmaxvaluescomparingwiththosewithoutthese

medica-tions.Thisfindingindicatesasuppressiveeffectonvascular inflammationbroughtbythe useoftheseagentsandadds anotherargumentinfavoroftheusefulnessofPET–CTscans forthedetectionofthevascularinflammationinTA.Inline with thisfinding, Leeet al.31 havedescribed adecrease in

18F-FDGuptakeduringthe follow-upofeightpatientsafter

controlling disease activity with immunosuppressive treat-ment.

We found SUVmax values similar to those found by

Kobayashiet al.,despitetechnicaldifferencesinstudy pro-tocols.Thecutoffvalueof1.3wasthesameinbothstudies andwasbasedonthehighestSUVmaxvaluefoundincontrols.

However,thesensitivityandspecificityfordetectionofdisease activitywere86%and50%,respectively,inourstudy,which arelowerthanthosefoundbytheseauthors.Thisremarkable difference maybeduetodifferent criteriausedforclinical evaluationinbothstudies.Theyconsideredclinicalremission onlywhenpatientswereatleast2yearswithoutsteroid.10

Ourstudyalsoanalyzedtheassociationbetweenacutoff value ofSUVmax and serum levelsofcytokines and MMPs.

PatientswithSUVmax≥1.3hadhigherlevelsofTNF-␣andIL-6.

WealsofoundanassociationbetweenSUVmax≥1.3and dis-easeactivity.TheanalysisofbiomarkersusingthisSUVmax

cutoffvaluehighlightstheconsistentresultsachievedfrom clinical evaluationofdisease activity inTA.Thesignificant correlationbetweenserumIL-6levelsandotherinflammatory markersindicatestheconsistencyofthesefindings.

Main limitations of this study include the sample size, thecross-sectionaldesignandthelackofagoldstandardto evaluateinflammatoryactivityinTA,sinceeventhewidely usedNIHcriteriahavenotbeenvalidatedyet.Moreover,the weakness oftheNIHcriteriaishighlightedbythefactthat TApatientswithhighacutephasereactantswhodonot ful-filltheNIHcriteriaforactivediseaseactuallypresenthigher serumlevelsofIL-6andIL-18thanTApatientsconsideredwith inactive disease.Suchpatientsshouldbefollowedupmore carefullyinordertodetectclinicallysignificantactivedisease early.However,thelownumberofpatientsinthesubgroups ofinactivepatientsandpatientswithpossibleactivedisease mayhaveimpairedcomparisonsamonggroupsand assump-tions,especiallyregardingIL-18levelsshouldbetakenwith caution.

Ourresultssuggestthat theintensityof18F-FDGuptake

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processandthatPET–CTscanseemstobeausefulmethod todetectdisease activityinTA,especiallytoexcludeactive disease indoubtful cases.A prospectivestudy witha long termfollow-upwouldbenecessarytoobservechangesinthe SUVmax valuesaftertreatmentoreventodetectthe

devel-opment of new vascular lesions (e.g. vascular stenosis or aneurysms)insitespresentinghigh18F-FDGuptake.IL-6also

appearstobeapromisingparameterofdiseaseactivityinTA thatshouldbeassessedinalongitudinalstudyaswell.The rel-evanceofIL-6residesinthefactthatitcanalsobeapotential therapeutictargetinTA.32

Funding

TheresearchhadfinancialsupportbyFAPESP(São PauloRe-searchFoundation),grantnumber2008/54787-3toSatoEI.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

TheauthorsthankACCamargoHospital.

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Imagem

Table 1 – Demographic and disease features of TA patients evaluated in this study.
Table 3 – Serum levels of cytokines and metalloproteases in TA patients with active disease, inactive disease and with possible active disease.
Fig. 3 – Representative PET–CT scan images from a patient with Takayasu arteritis and active disease.
Fig. 4 – Serum TNF ␣ and IL-6 levels in patients with SUV max ≥ 1.3, patients with SUV max &lt; 1.3 and lab-controls.

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