r e v b r a s r e u m a t o l . 2017;57(6):616–619
ww w . r e u m a t o l o g i a . c o m . b r
REVISTA
BRASILEIRA
DE
REUMATOLOGIA
Case
report
Reduced
activation
and
CD3
lymphocyte
recruitment
after
TNF-inhibitor
use:
evaluation
of
clinical
and
99mTc-OKT3
scintigraphic
response
in
a
patient
with
juvenile
idiopathic
arthritis
Reduc¸ão
da
ativac¸ão
e
do
recrutamento
de
linfócito
CD3
com
o
uso
de
anticorpo
anti-TNF-alfa:
avaliac¸ão
da
resposta
clínica
e
cintilográfica
com
99mTc-OKT3
em
paciente
com
artrite
idiopática
juvenil
Flavia
Paiva
Proenc¸a
Lobo
Lopes
a,
Sergio
Augusto
Lopes
de
Souza
a,∗,
Blanca
Elena
Rios
Gomes
Bica
b,
Lea
Mirian
Barbosa
da
Fonseca
a,
Mario
Newton
Leitão
de
Azevedo
b,
Bianca
Gutfilen
aaUniversidadeFederaldoRiodeJaneiro(UFRJ),FaculdadedeMedicina,DepartamentodeRadiologia,LaboratóriodeMarcac¸ãodeCélulas
eMoléculas(LMCM),RiodeJaneiro,RJ,Brazil
bUniversidadeFederaldoRiodeJaneiro(UFRJ),HospitalUniversitárioClementinoFragaFilho,Servic¸odeReumatologia,RiodeJaneiro,
RJ,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received5August2014 Accepted1March2015
Availableonline8September2015
Introduction
Theimmuneresponseininflammatoryconnectivetissue dis-eases depends on the antigen presentation by the T cell receptor complex (TCR) and cell Major Histocompatibility Complex(MHC),ofthecytoplasmicsignaltransduction involv-ing CD3 complex leading to activation,of the proliferative responseofTlymphocytesandofcytokineproduction.1
∗ Correspondingauthor.
E-mail:[email protected](S.A.Souza).
TheCD3molecularcomplexiscriticalandmustnecessarily be present onthe surface ofT lymphocytesfor the occur-renceTCRexpressionbythecell,2whiletheabsenceofCD3
chainblocksthedevelopmentofTlymphocytes,preventing TCRexpressionandT-cellactivation.3
CD3 blockage by anti-CD3 monoclonal antibodies pre-ventstheexpressionofTCRandactivationofTlymphocytes, extending transplant survival.4 There is an intrinsic
rela-tionship among antigen presentation, T cell activation,
http://dx.doi.org/10.1016/j.rbre.2015.08.011
rev bras reumatol.2 0 1 7;57(6):616–619
617
transplantedtissuerejection,andproductionofTNF-alpha, dependingonthepresenceofaCD3molecule.5
InJuvenileidiopathicarthritis(JIA),theantigen presenta-tionbydendriticcellsandthelymphocyteactivationdepend ontherelationTCR/MHC,andconsequentlyonCD3complex, actingonTNF-alphaproduction–afactofgreatimportance inthe pathophysiology of the disease and in perpetuating mechanisms of a chronic synovial inflammation process.6
Currently,the treatmentwithanti-TNFinhibitors hasbeen usedtocontrolJIA;theuseofthisantibodyallowsthedecrease oftheinflammatoryprocessandboneinjury,withan effec-tivecontrolofthesignsandsymptomsofthedisease.7This
medicationactsoncirculating moleculesandalsointhose moleculespresentonthesurfaceofthecellmembrane, induc-ingapoptosisofcellsthatproduceTNF-␣.8
Oftenisdifficultto carryout a clinical jointevaluation, making it impossible to verify the disease activity. Thus, thecontinuityoftreatmentproceedsonempirically,andnot based on pathophysiological characteristics. It is notewor-thythatthediseaseusuallyaccompaniesthepatientforlife, with periods of exacerbation and inactivity, and in many cases,onecannotdifferentiatethesestagesonlywithclinical assessment.9
Basedonthespecificbindingabilityofanti-CD3complex monoclonalantibodies present in joint inflammatory reac-tionswhenthediseaseisactive,asinJIA,itwaspossibleto deviseadiagnosticmethodusinggamma-emitting radionu-clide(technetium-99m–99mTc)coupledtothesemolecules.
Theaimofthisstudywastodemonstratethepotentialof 99mTc-OKT3scintigraphytoassessdiseaseactivityandthe therapeuticresponseinafemalepatientwithjuvenile idio-pathicarthritis.
Case
report
FemaleCaucasian patient,16 yearsold,46kg,1.63m, diag-nosedeightyearsagowithseveresystemiconsetpolyarticular courseJIArefractorytomultipleDMARDS,andincontinuous treatmentwithprednisoneandazathioprine.The difficult-to-controldiseasewasactiveandwithanintenseinflammatory reaction: polyarthritis of small and large joints, presence of synovial cysts, fever and deterioration of general con-dition. Laboratory tests: RBC 4.69×106mm−3, hematocrit
37.9%,leukocytes 8.1×103mm−3, platelets 569×103mm−3,
negative serology for hepatitis B and C, CRP 12.1mg/dL (normal<0.5mg/dL), erythrocyte sedimentation rate (ESR) 90mm(normal<10mm).Rheumatoidfactor,ANA,andVDRL were negative. She presented arthritis (pain and swelling) in 21 joints; global assessment by visual analogue scale (VAS): patient8/physician 8;DAS 28 (ESR) 7.94 – (high dis-easeactivity).Duetotheintenseinflammatoryactivity,the patienthadbeentreatedwithintravenousimmunoglobulin plusdeflazacort,prednisone,methotrexate,azathioprine,and leflunomide.Withthissevere condition,treatment withan anti-TNFinhibitoratadoseof5mg/kgevery8weekswas indi-cated.TheinitialevaluationwithchestX-raywasnormaland thePPDtestwasnegative(withBCGscar).Beforetheuseof bio-logicalmedication,abaseline99mTc-OKT3scintigraphywas performed.Theparentssignedaninformedconsentformfor
bothproceduresandthestudywasapprovedbytheResearch EthicsCommitteeofHUCFF/UFRJ(protocol080/03).Theinitial scintigraphy(Fig.1A)withanteriorandposteriorwhole-body scans were obtained 1h and 3h after intravenous admin-istrationof99mTc-OKT3,showednormalbiodistributionof theradiopharmaceuticalintheliverandkidneys,withareas ofincreaseduptakeinhands-phalanges,lowerlimbs,knees and ankles(morepronouncedinwrists,anklesand knees). By comparingearly(1h)andlate(3h)images, asignificant increaseinradiopharmaceuticaluptakewasnoted.This pro-ceduredetectsinflammatorypolyarticularinvolvement,butit isworthmentioningthatitsspecificityforCD3Tcells demon-stratestheintenseactivityandthepresenceofthesecellsin jointtissues.
After a 10-month treatment with anti-TNF blocker at a dose of 5mg/kg every 8 weeks, and with the patient in use of stable doses of azathioprine, prednisone and a non-steroidal anti-inflammatory agent, improvement of the clinical parameters was observed. The fever disap-peared. Laboratory tests: RBC 4.74×106mm−3, hematocrit
36.2%,leukocytes10.1×103mm−3,platelets458×103mm−3,
CRP12.3mg/dL,erythrocytesedimentationrate(ESR)64mm. Arthritis(painandswelling)wasobservedintwojoints;global assessmentscale–patient2/physician2;DAS28(ESR) 3.99 – moderate disease activity. In the post-treatment scintig-raphy (ten monthsafter the use ofanti-TNF-alpha [Fig. 1, lowersegment]),areasofuptakeinfeet,ankles,knees,wrists andhandswereobserved.Inthecomparativeanalysisversus thepretreatmentstudy,thereisintenseinflammatory activ-ity(buttoalesserdegree)infeet,ankles,knees,wristsand hands,showingadecreaseintheinflammatoryprocess,but withpersistentactivediseasedespiteclinicalandlaboratory improvement.
Discussion
618
rev bras reumatol.2 0 1 7;57(6):616–619Fig.1–99mTc-OKT3scintigraphyimagesbefore(A)andafter(B)theuseofanti-TNF-inhibitor,demonstratingankles,knees
andwristsuptake.
possibletodetectactivityofthestillpresentdisease,leading toacontinuationoftreatmentwithanti-TNF-inhibitor,until remissionwasachieved.
Thestudywithanti-CD3monoclonalantibody(OKT3) tar-getedagainsthumanCD3-cell moleculesandlabelled with Technetium-99minJIApatientsshowedmarkedradiotracer uptakeininflamedjoints,secondarilytolymphocyte activa-tionandproliferation,especiallywithrespecttoCD3,related totheseverityofsynovialinflammation.10Thepurposeofthis
observationistoevaluate,using 99mTc-OKT3 scintigraphy, theaggression tojoint andsynovialstructures, theclinical actionofanti-TNF-inhibitor,itseffectsontheinflammatory jointprocess,andtherecruitmentandactivationofCD3 lym-phocytesinthejointsofapatientwithrheumatoiddisease.
Althoughotherstudieshavedescribedtheoccurrenceof sideeffectsafteradministrationof99mTc-OKT3,these draw-backs were not observed after the use of 99mTc-OKT3 in thisstudy.ItisnoteworthythattheOKT3labellingmethods described byother authors11 were different, implying even
differencesintheaccumulationandclearingofradiotracers. These results demonstrate improvement of signs and symptomswithanti-TNFalphamonoclonalantibodytherapy, withmarked decrease ininflammatoryactivity in synovial tissuesoftherheumatoidarthritispatient.The99mTc-OKT3 scintigraphystudywasabletodemonstratesensitivity, indi-catingincreasedpresenceofCD3injointstructures,andits declineafterspecifictreatment,withadecreasein inflamma-toryactivityinsynovialtissues,andalsodemonstratesdisease activity,despite amarked clinical and laboratory improve-ment.Theresultsshowedthatthismethodwasabletocapture therecruitmentrestriction,activation ofCD3moleculeand
decreaseofactivityofinflammatorycellssuchasCD4andCD8 cells,12secondarytotheuseofanti-TNF-inhibitor.Thus,we
presumethatthismethodcouldbecomeanimportant adju-vantinthediagnosisandmonitoringoftreatmentofpatients with rheumatoid arthritis, especially in those difficult-to-evaluatecases;andalso,perhaps,inoptimizingthetherapy forpatientswho,atthetimeoftheexamination,demonstrate inactivityofthedisease(absenceofabnormaluptakeofthe radiopharmaceutical).
Conflict
of
interests
Theauthorsdeclarenoconflictofinterests.
r
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e
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e
s
1.JanewayCA,TravesP,WalportM,SclomchikMJ.
Immunobiology:theimmunesysteminhealthanddisease. 6thed.NewYork:GarlandSciencePublishing;2005.
2.SunZJ,KimKS,WagnerG,ReinherEL.Mechanism contributingtoTcellreceptorsignalingandassembly revealedbythesolutionstructureofanectodomainofthe CD3heterodimer.Cell.2001;105:913–23.
3.deSaintBasileG,GeissmannF,FloriE,Urung-LambertB, SoudaisC,Cavazzana-CalvoM,etal.Severecombined immunedeficiencycausedbydeficiencyineitherthe␦orthe subunitofCD3.JClinInvestig.2004;114:1512–7.
rev bras reumatol.2 0 1 7;57(6):616–619
619
5. SmithJB,HaynesMK.Rheumatoidarthritis–amolecular understanding.AnnInternMed.2002;136:908–22.
6. ThomasR,DavisLS,LipskyPE.Rheumatoidsyniviumis enrichedinmatureantigen-presentingdendriticcells.J Immunol.1994;152:2613–23.
7. SmolenJS,SteinerG.Therapeuticstrategiesforrheumatoid arthritis.NatVerDrugDiscov.2003;2:473–88.
8. HoveTT,vanMontfransC,PeppelenboschMP,vanDeventer SJH.Infliximabtreatmentinducesapoptosisoflaminapropria T.lymphocytesinCrohn’sdisease.Gut.2002;50:206–11.
9. BicaBERG,RuizDG,MagalhãesPA,BarcellosaMG,Azevedo MNL.Associac¸ãoentreartriteidiopáticajuvenile
osteogenesisimperfecta–Relatodecaso.RevBrasReumatol. 2013;53:535–7.
10.LopesFPPL,AzevedoMNL,MarchioriE,FonsecaLMB,Souza SAL,GutfilenB.Useof99m-anti-CD3scintigraphyinthe differentialdiagnosisofrheumaticdiseases.Rheumatology. 2010;49:933–9.
11.MartinsFP,GutfilenB,deSouzaSA,deAzevedoMN,Cardoso LR,FragaR,etal.Monitoringrheumatoidarthritissynovitis with99mTc-anti-CD3.BrJRadiol.2008;81:25–9.
