Comparação entre o Disease Activity Score-28 e o Juvenile Arthritis Disease Activity Score na artrite idiopática juvenil

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REVISTA

BRASILEIRA

DE

REUMATOLOGIA

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

Original

article

Comparison

of

the

Disease

Activity

Score

and

Juvenile

Arthritis

Disease

Activity

Score

in

the

juvenile

idiopathic

arthritis

Renata

Campos

Capela,

José

Eduardo

Corrente,

Claudia

Saad

Magalhães

∗

UniversidadeEstadualPaulistaJúliodeMesquitaFilho,Botucatu,SP,Brazil

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o

Articlehistory:

Received20February2014 Accepted17August2014

Availableonline27November2014

Keywords:

Juvenileidiopathicarthritis Rheumatoidarthritis DiseaseActivityScore-28 JuvenileArthritisDiseaseActivity Score

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Introduction:Theassessmentoftheactivityofrheumatoidarthritisandjuvenileidiopathic arthritisismadebymeansofthetoolsDAS-28andJADAS,respectively.

Objective:TocompareDAS-28andJADASwithscoresof71,27and10jointcountsinjuvenile idiopathicarthritis.

Method:AsecondaryanalysisofaphaseIII_{placebo-controlled}_trial,_testing_safety_and

effi-cacyofabataceptwasconductedin8patientswith178assessmentvisits.Jointcountscores foractiveandlimitedjoints,physician’sandparents’globalassessmentby0–10cmVisual AnalogScale,anderythrocytesedimentationratenormalizedto0–10scale,inallvisits.The comparisonamongtheactivityindicesindifferentobservationswasmadethroughAnova oradjustedgammamodel.ThepairedobservationsbetweenDAS-28andJADAS71,27and 10,respectively,wereanalyzedbylinearregression.

Results:Thereweresignificantdifferencesamongindividualmeasures,exceptforESR,in thefirst4monthsofbiologicaltreatment,whenfiveoftheeightpatientsreached ACR-Pedi 30, with improvement.The indices of DAS-28, JADAS 71,27 and10 also showed significant differenceduring follow-up.Linearregressionadjustedmodelbetween DAS-28andJADASresultedinmathematicalformulasforconversion:[DAS-28=0.0709(JADAS 71)+1.267](R2₌_0.49); _[DAS-28₌_0.084 _(JADAS ₂₇₎₊_1.7404] ₍_R2₌_0.47) _and _[DAS-28₌_0.1129

(JADAS-10)+1.5748](R2₌_0.50).

Conclusion: TheconversionofscoresofDAS-28andJADAS71,27and10forthismathematical modelwouldallowequivalentapplicationofbothinadolescentswitharthritis.

∗ _{Corresponding}_author_.

E-mail:claudi@fmb.unesp.br(C.S.Magalhães).

http://dx.doi.org/10.1016/j.rbre.2014.08.009

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Comparac¸ão

entre

o

Disease

Activity

Score

e

o

Juvenile

Arthritis

Disease

Activity

Score

na

artrite

idiopática

juvenil

Palavras-chave:

Artriteidiopáticajuvenil Artritereumatoide DiseaseActivityScore-28 JuvenileArthritisDisease ActivityScore

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s

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Introdução: Aavaliaçãodeatividadedaartritereumatoideedaartriteidiopáticajuvenilé feitapormeiodeinstrumentosdistintos,respectivamentepeloDAS-28epeloJADAS. Objetivo: CompararoDAS-28eoJADAScomapontuaçãode71,27e10articulações,na artriteidiopáticajuvenil.

Método: Foramavaliadas178visitasemoitopacientescomartriteidiopáticajuvenil, par-ticipantes deumensaioclínicocontroladode faseIII,testandoeficáciae segurançado abatacepte.Pontuaram-seasarticulaçõesativaselimitadas,aavaliaçãoglobalpelomédico epelospaisemescalaanalógicavisualde0-10cmeavelocidadedehemossedimentação convertidaemescalade0-10,emtodasasvisitas.Acomparaçãoentreosíndicesde ativi-dadeentrediferentesobservaçõesfoiporAnovaoumodeloajustadoGama.Asobservações pareadasentreoDAS-28eoJADAS71,27e10,respectivamente,foramanalisadaspormeio deregressãolinear.

Resultados: Houvediferençasignificativaentreasmedidasindividuais,excetoaVHS,nos primeirosquatromesesdetratamentocombiológico,quandocincoentreosoitopacientes atingiramarespostaACR-Pedi30,commelhoria.OsíndicesDAS-28,JADAS71,27e10 tam-bémapresentaramdiferençarelevanteduranteoperíododeobservação.Oajustamentopor meioderegressãolinearentreoDAS-28eoJADASresultouemfórmulasmatemáticaspara conversão:[DAS-28=0,0709(JADAS71)+1,267](R2₌_0,49);_[DAS-28₌_0,084_(JADAS₂₇₎₊_1,7404]

(R2₌_0,47)_e_[DAS-28₌_0,1129_(JADAS-10)₊_1,5748]_(R2₌_0,50).

Conclusão: Aconversãodapontuac¸ãodoDAS-28edoJadas71,27e10poressemodelo matemáticopermitiriaaaplicac¸ãoequivalentedeambosemadolescentescomartrite.

Introduction

Juvenileidiopathicarthritis(JIA)hasachroniccourseandgreat variabilityofoutcomes,itmayprogresstospontaneous remis-sionor berefractorytoavailabletreatments.1 _JIA_subtypes

representdifferentphenotypes,classifiedasoligoarticular(<5 joints),polyarticular(≥5joints),systemic,arthritisrelatedto

enthesitis,psoriaticarthritis,andundifferentiatedor unclas-sifiedarthritis.2

Inordertoassessarthritisactivity,itisessentialtomeasure theresponsetotreatment,andearlytreatmentiscrucialtothe outcome.Inchildren,theresponsetotreatment,evaluatedin clinicaltrials,involvessixprimaryoutcomemeasures: physi-cian’sglobalassessment,globalassessmentbytheparentsor bythepatient,jointcountinabsolutenumbersofinflamed jointsand joints withlimitedrange ofmotion,erythrocyte sedimentationrate(ESR),andfunctionalcapacityindex.The minimumcriteriaforresponse(ACRPedi30)aredefinedas improvementofatleast30%inthreeofsixmeasures,with notmorethan30%ofworseninginnomorethanoneofthese parameters,representingacutoffofresponsedifferentiation inthetreatedgroupandintheplacebogroupinclinicaltrials.3

Currently,theimprovementsthatareconsideredclinically sig-nificantarethoseinexcessof50,70,90%,oreventheinactive stateofarthritis.4_However,_these_measures_are_related_to_the

responsetotreatment,andarenotsuitableasabsolute meas-uresofarthritisactivity,becausenatureofcalculationdoes

notallowabsolutecomparisonofresponsebetweengroupsof patients.

Themostcommonlyusedinrheumatoidarthritis(RA)are theDAS5₍_Disease_Activity_Score₎_and_DAS286_in_its_simplified

version.JADAS7₍_Juvenile_Arthritis_Disease_Activity_Score_),_with

threeversions ofjointscoring,was developedforJIA.Both use the same components for the absolute assessmentof arthritis activity, including “active” joint count, physician’s andpatient’sorhis/herparents’globalassessment,and labo-ratorytests,whichmaybeESRorC-reactiveprotein(CRP),and isusefulinclinicaltrialsandindailypractice.8

DAS286 _combines_information_on _the_number_of_painful

and swollenjoints,with28jointsbeingselected,aswellas ESRorCRPandpatient’s globalassessmentmeasuredona visualanalogscale(VAS)fromzeroto10cm.DAS28scoreis calculatedusingamathematicalformula,andtheactivityof arthritiscanbeinterpretedincategoricalscale.

JADAS score7 _is _performed _by _adding _the _four

individ-ualmeasurements:globalassessmentofarthritisactivityby the physician, in10-cm VAS, global evaluationbythe par-ents/patientsasmeasuredinthesame10-cmVAS,where0 indicatesnoactivityand10,maximumactivity,ESRandjoint count.Therearethreeversions,scoringfrom0to71,0to27 or0to10joints.

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AssessmentQuestionnaire(HAQ).Both evaluatethe degree ofdifficulty and independence in activities ofdaily life in eightdomainsoffunctionalcapacity,alsoconsideringthepain anddiscomfortthroughaggregatedVAS(0–10cm).Functional capacityisincludedamongtheresponsemeasuresofACRPedi 30.

Thepresentstudy isa secondaryanalysisofa placebo-controlled, phase III clinical trial, to evaluate the efficacy and safety of intravenous abatacept in patients with activepolyarticularJIAand unresponsivetotreatmentwith antirheumatictherapywithmethotrexate(MTX).11,12_Patients

selectedforclinicaltrialshavemoreintenseactivityandare resistanttoconventionaltreatment,showingmoreenhanced differencesofclinicalresponse.Thus,thissamplewas con-sideredoptimaltocomparedifferentcontinuousmeasuresof activity.

TheaimwastoexplorescoreequivalenceofthetoolDAS28 andJADASwithscoresof71,27and10joints,respectively,in childrenandadolescentswithJIA.

Subjects

and

method

Onehundredandseventy-eightvisitswereassessedofeight patients with JIA who participated in a controlled clinical phaseIIItrialtestingtheefficacyandsafetyofabatacept11,12

andusingthesameevaluationsatintervalsoffourto12weeks ofthe original trial, a withdrawal study design,11,12 _which

includedanopen-labelphaseof4months,double-blindphase trialopen-labelextensionphaseofupto5years.Inthe double-blindperiod,assessmentswere monthlyperformed,and in otherperiods,completeassessments,includingmeasuresof activity,wereperformedevery3months.Thesameclinical, laboratoryandfunctionalparametersoftheclinicaltrialfor thecalculationofactivityratesofDAS28andJADAS-71,27,10 wereused.Theprotocolofsecondarystudywasapprovedby theEthicsCommitteeinInstitutionalResearch(no.345/2009) of14September2009.

Datawerecollectedfromfirsttolastvisitwithcomplete jointassessment. Oftheeight subjectsincluded, five com-pleted the open phase of induction and the double-blind phase,extensionopen-labelphase.Ofthefivewhoconcluded thedouble-blindperiod, twowere givenplacebo and three weregiventhestudymedication.Threesubjectsconcluded theopenperiod,butwerenotapprovedforthedouble-blind sincetheydidnotreachACR-Pedi30response,stayinginthe open-labelextensionindicatedbytheprotocol.Foursubjects leftthestudyintheextensionphaseindifferentperiods,due tolackofmedicationefficacy,withchangeoftreatmentbeing necessary.Threesubjectsconcludedthe5yearsofextension phase.

Standardizedjointassessment(itismorespecificforthe technical procedure) was performed bythe same observer throughoutthestudy.Withinthesamejointassessmentof eachvalidvisit,JADAS-71,27and10 werescoredalongside DAS28.TocalculateJADAS71,thescoreincludes71joints,with morecomprehensiveexaminationincludingthejointsofthe lowerandupperextremities,spine,andtemporomandibular joint. In JADAS-27, the following joints are scored: cervi-calspine,elbows,wrists,metacarpophalangealfrom1to3,

proximalinterphalangeal,hips,kneesandankles.Regarding JADAS-10,theupperscoreis10,thatis,ifapatienthas15or 20 activejoints,themaximum scoretobeassignedwillbe 10.

JADASfinalscoreiscalculatedbythesumoffour compo-nents:globalassessmentofarthritisactivitybyaphysician, measuredina10-cmVAS,wherezeroindicatesnoactivityand 10,maximumactivity;globalassessmentbyparents/patients alsomeasuredona10-cmVAS,wherezeroindicatesno activ-ity and 10,the maximum activity perceived byparents or bythepatient; activejointscountofzero-71jointsandESR convertedtoascalefromzero-10=[VHSmm/h− 20)/10]with

valuesover120mm/hbeingconvertedto120.

The following joints were assessed for scoring DAS 28: shoulders(2),elbows(2),wrists(2),metacarpophalangeal(10), proximalinterphalangeal(10)andknees(2).Thejointswith painandedemaareindependentlyscored,inadditiontothe global assessment ofactivity bythe patient, which in this studywasperformedeitherbytheparentsorbythepatient him/herself,accordingtoage,beingmeasuredona10-cmVAS inwhichzeroindicatesnodiseaseactivityand10,maximum activity,accordingtothepatient’sperception.Inthisstudy, scalesscoreswereperformedbytheparentsregardlessofage. DAS28scorewas calculatedusing thefollowingformulain MicrosoftExcel:

DAS28=0.56√numberofjointswithpain(28)

+0.₂₈√_number_of_joints_with_swelling₊₀.₇₀_logn_(ESR)

+0.₀₁₄ _global _VAS.

Functionalcapacity,asanintegralparameterforthe calcula-tionofACR-Pedi-30response,wasassessedbytheCHAQscore withvaluesofzero-3,with3meaningthemaximumdisability scale.

Statisticsanalysis

Adescriptive analysiswascarriedout ofbaselinevariables obtainedduringpatientselectionandwithcalculationof aver-age,standarddeviation,medianandquartilesforquantitative variables,aswellasfrequenciesandpercentagesfor qualita-tivevariables.

Alongitudinalanalysisofvariableswasperformedusing a repeated measure model through analysis of variance (ANOVA) followedbyTukey’smultiplecomparisonstestfor datashowingsymmetricaldistribution.Theadjustmentofa generalizedlinearmodelforrepeatedmeasures,withGamma distribution,wasperformedforthedatathatshowedan asym-metricdistribution.

ForcomparativeevaluationbetweenDAS28andJADASin three versions(71, 27 and 10),a linearregression was per-formed by applying the ANOVA test fordata with normal distribution.AsforthecomparisonbetweenJADAS-71, JADAS-27 and JADAS-10, a model with Gamma distribution was adjusted.

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Table1–Clinical,anthropometric,laboratorial,activityandfunctionalparametersineightpatientsduringthefirst evaluationofselectionfortheclinicaltrial.

Variables Average Standarddeviation Median Q1 Q3

Age(months) 137.6 39.5 136.2 110.8 162.3

Weight(kg) 31.9 11.4 32.4 23.4 39.4

Height(cm) 135.5 18.6 139.7 124 149.5

No.ofactivejoints 24 10.5 20.5 18 30.5

No.oflimitedjoints 20.3 11.6 16.5 15 26

No.ofjointswithedema 19.6 10 20 12.5 28

No.ofjointswithpain 12 13.3 8.5 4.5 11.5

Physician’sVAS(0–10cm) 5.5 1.3 5.8 5.3 6.3

Parents’VAS(0–10cm) 3.6 2.2 3.1 1.8 5.6

PainVAS(0–10cm) 3.2 2.1 2.4 2.2 5.3

CHAQDI(0–3) 1.2 0.5 1.2 0.8 1.8

JADAS-71(0–101) 10.1 12 6.1 0.4 14.1

JADAS-27(0–57) 8.7 10 5.7 0.4 11.5

JADAS-10(0–40) 7.9 7.6 6.1 3.9 13

DAS-28(0–7.8) 4.8 1 4.8 3.9 5.2

ESR(mm/h) 36.2 10.3 35 30 45

Q1,firstquartile;Q3,thirdquartile;VAS,visualanalogicalscale;CHAQ-DI,ChildhoodHealthAssessmentQuestionnaireDisabilityIndex;JADAS,

JuvenileArthritisDiseaseActivityScore;DAS-28,DiseaseActivityScore;ESR,erythrocytesedimentationrate.

Results

Threeboysandfivegirlswereassessed,alldiagnosedwithJIA andaged7–17years,withacaseclassifiedassystemicand sevenaspolyarticular,withtwobeingpositiveforrheumatoid factor (latex test). Clinical, anthropometric, laboratory and activityvariablesofarthritis,includingthefunctionalindices inthefirstevaluation,arepresentedinTable1.

WiththeuseofANOVAasignificantdifferencewasfound inthevisitswhichtookplaceforselectionandthoseafter4 monthsoftreatmentforallindices,whenfivepatientsmetthe criteriaofACRPedi30response,thatis,therewas improve-mentin30%ofatleastthreeofthesixkeyvariables.

Longitudinalcomparisonshowedthattherewas asymmet-ricdistributionofCHAQ,DAS28,JADAS-71,27and10variables, andtheadjustmentofthe modelwithGammadistribution showedstatisticallysignificantdifferencewithinthe assess-ments(p<0.05),withthehighestratesbeinginthefirstandin thesecondevaluation,respectively,attheselectionandafter 4monthsofbiologicaltreatment inopen phase.Theother visitsincludedatotalof30serialevaluations,monthly,within 6monthsofthedouble-blindphase,andquarterlyinthe eval-uationsthatfollowedduringtheopen-labelextension.These evaluationswerecompared,butnosignificantdifferencewas foundinalltheindividualparametersforthecalculationof theindicesanditemsofDAS28andJADAS-71,27and10.No significantdifferencewasobservedwithintherespective ver-sionsofJADAS-71, 27and 10.Forthis comparison,wealso adjustedamodelwithGamma(p=0.5)distribution.

ThelinearregressionanalysisofJADAS-71,27and10and DAS28resultedinconversionformulasamongthescales,the regressionanalysisofwhichisshowninFig.1:

[DAS28=0.₀₇₀₉ _(JADAS-71)₊₁._267] ₍R2₌₀.₄₉₎.

[DAS28=0.₀₈₄ _(JADAS-27)₊₁._7404] ₍R2₌₀.₄₇₎.

[DAS28=0.1129 (JADAS-10)+1.5748] (R2₌0.50).

Discussion

Thepresentedresultssupporttheequivalencebetweenthe DAS-28andJADASinthreeversions,withjointcountsof71, 27or10,respectively,throughlongitudinalobservationmade duringacontrolledclinicaltrialinpolyarticularJIA.Besides DAS28,thereareotherinstrumentsusedforRA,suchasthe ClinicalDiseaseActivityIndex(CDAI),amongothers,13_but_of

limiteduseinpediatricpatients.

ContinuousmeasuressuchasDAS28andJADAShavethe advantageofestablishingabsolutevalues,identifyingchanges inclinicalstatusbyanumberonacontinuousscale.13_The

straightforward calculation makes the method feasible in dailypractice,justasinclinicaltrials.However,therearefew publicationsreportingtheuseofDAS28inJIA.7,8

Measuresinabsolutevaluesprovidebetterconsistencyof assessmentamongphysiciansandallowpatientsto under-standthesignificanceoftheirdiseaseactivityviaanabsolute number. Thecorresponding measuresforJIAwererecently developed,7 _and_three_versions_of_the_tool_JADAS_allowed_to

equatethedifferentpresentationsofJIAaccordingtotheILAR classification.2

OnemustalsoconsiderthatthejointcountsoftheDAS28 omitthelowerlimbjoints,14_but_in_the_JIA_the_involvement_of

thelowerextremitiesispredominant.Measuresofperceived activityofarthritisbythephysician,thepatienthim/herselfor theirparents,aswellasESRorCRP,implementthe compos-itemeasures,weighingupseveralcompetingfactorsforthe activitystatus.

InJADASvalidation study,7 _as_well _as_in_a_recent_study,

whichusedCRPtoreplaceESR,15_results_of_JADAS-71,₂₇_and

10keptthecorrelationamongthemandwiththeotheractivity parameters.Also,McErlaneetal.16_recently_calculated_JADAS

withonlythreevariables,excludingESRforbroader applica-bility,andreportedacorrelationofmeasuresandtheirmetric equivalence.

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8

a

y=0.0709x + 1.7546 R2_=0.4913 7 6 5 4 3 2 1 0

0 10 20 30 40

JADAS71

DAS28

50 60 70

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b

y=0.084x + 1.7404 R2_=0.4745 7 6 5 4 3 2 1 0

0 10 20 30 40

JADAS27

DAS28

50 60

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c

y=0.1129x + 1.5748 R2_=0.5043 7 6 5 4 3 2 1 0

0 5 10 15 20

JADAS10

DAS28

25 30 35

Fig.1–LinearregressionplotswithinvaluesofDAS28and JADAS-71(a),JADAS-27(b)andJADAS-10(c)andtheir respectiveconversionequations(plotsa,b,c).

bythescoreofthescaleperformedbytheparents.Itisalso knownthat,regardlessofage,caregiver’sperceptionmay sub-stantiallydifferfromtheperceptionofthepatientatanyage. Amongtheotherlimitationsofthisanalysiswefindthe smallsamplethatlimitsthepowerofthestudy,andthe selec-tion ofchildrenenrolled inclinical trials. If,on one hand, the populationsample would provide greater variability of activity,strictcontrolofallmeasuresandstandardizedjoint examination,by the same observer at regular intervals, in additiontotheparallelevaluationofresponsemeasures (ACR-Pedi-30)toestablishresponders,theresponsepatterninthe periodofgreatestactivitywhenselectingfortesting,werethe favorablepointstotestthisequivalence.17

Thereispractical applicabilityofthe resultstopatients withJIA,because,besidesthesimpleanddirectscore,the indi-vidualmeasuresofclinicalparameterscanbeconductedin dailypractice.Theuseofmetricconversionmayalsobe use-fulinspecificsituationsoftransitionfromadolescenttoadult condition.Asanexample,apatientdiagnosedwithJIAat15

yearsandanotherdiagnosedwithRAat17couldbeevaluated bycalculatingtheequivalenceoftheinstrumentsused.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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