Perfil epidemiológico da espondiloartrite de início juvenil comparada com a espondiloartrite de início na vida adulta em uma grande coorte brasileira

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REVISTA

BRASILEIRA

DE

REUMATOLOGIA

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

Original

article

Epidemiologic

profile

of

juvenile-onset

compared

to

adult-onset

spondyloarthritis

in

a

large

Brazilian

cohort

Angela

P. Duarte

a

_,

_Cláudia

_D.L.

_Marques

a

_,

_Adriana

_B.

_Bortoluzzo

b

_,

_Célio

_R.

_Gonc¸alves

c

_,

José

Antonio

Braga

da

Silva

d

_,

_Antonio

_Carlos

_Ximenes

e

_,

_Manoel

_B.

_Bértolo

f

_,

Sandra

Lúcia

E. Ribeiro

g

_,

_Mauro

_Keiserman

h

_,

_Thelma

_L.

_Skare

i

_,

_Sueli

_Carneiro

j,k

,

Rita

Menin

l

_,

_Valderilio

_F.

_Azevedo

m

_,

_Walber

_P.

_Vieira

n

_,

_Elisa

_N.

_Albuquerque

k

_,

Washington

A. Bianchi

o

_,

_Rubens

_Bonfiglioli

p

_,

_Cristiano

_Campanholo

q

_,

Hellen

M.S.

Carvalho

r

_,

_Izaias

_P.

_Costa

s

_,

_Charles

_L.

_Kohem

t

_,

_Nocy

_Leite

u

_,

Sonia

A.L.

Lima

v

_,

_Eduardo

_S.

_Meirelles

w

_,

_Ivânio

_A.

_Pereira

x

_,

_Marcelo

_M.

_Pinheiro

y

_,

Elizandra

Polito

z

_,

_Gustavo

_G.

_Resende

aa

_,

_Francisco

_Airton

_C.

_Rocha

bb

_,

Mittermayer

B. Santiago

cc

_,

_Maria

_de

_Fátima

_L.C.

_Sauma

dd

_,

_Valéria

_Valim

ee

_,

Percival

D. Sampaio

Barros

c,∗

a_Universidade_Federal_de_Pernambuco,_Recife,_PE,_Brazil

b_Insper_Institute_of_Education_and_Research,_São_Paulo,_SP,_Brazil

c_Division_of_{Rheumatology,}_Universidade_de_São_Paulo,_São_Paulo,_SP,_Brazil

d_Universidade_de_Brasília,_Brasília,_DF,_Brazil

e_Hospital_Geral_de_Goiânia,_Goiânia,_GO,_Brazil

f_Universidade_de_Campinas,_Campinas,_SP,_Brazil

g_Universidade_Federal_do_Amazonas,_Manaus,_AM,_Brazil

h_Pontifícia_Universidade_Católica,_Porto_Alegre,_RS,_Brazil

i_Hospital_Evangélico_de_Curitiba,_Curitiba,_PR,_Brazil

j_Universidade_Federal_do_Rio_de_Janeiro,_Rio_de_Janeiro,_RJ,_Brazil

k_Universidade_Estadual_do_Rio_de_Janeiro,_Rio_de_Janeiro,_RJ,_Brazil

l_Faculdade_de_Medicina_de_São_José_do_Rio_Preto,_São_José_do_Rio_Preto,_SP,_Brazil

m_Universidade_Federal_do_Paraná,_Curitiba,_PR,_Brazil

n_Hospital_Geral_de_Fortaleza,_Fortaleza,_CE,_Brazil

o_Santa_Casa_do_Rio_de_Janeiro,_Rio_de_Janeiro,_RJ,_Brazil

p_Pontifícia_Universidade_Católica,_Campinas,_SP,_Brazil

q_Santa_Casa_de_São_Paulo,_São_Paulo,_SP,_Brazil

r_Hospital_de_Base,_Brasília,_DF,_Brazil

s_Universidade_Federal_do_Mato_Grosso_do_Sul,_Campo_Grande,_MS,_Brazil

t_Universidade_Federal_do_Rio_Grande_do_Sul,_Porto_Alegre,_RS,_Brazil

u_Faculdade_de_Medicina_Souza_Marques,_Rio_de_Janeiro,_RJ,_Brazil

v_Hospital_do_Servidor_Público_Estadual,_São_Paulo,_SP,_Brazil

∗ _{Corresponding}_author.

E-mail:pdsampaiobarros@uol.com.br(P.D.S.Barros).

http://dx.doi.org/10.1016/j.rbre.2014.06.001

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w_Instituto_de_Ortopedia_e_{Traumatologia,}_Universidade_de_São_Paulo,_São_Paulo,_SP,_Brazil

x_Universidade_Federal_de_Santa_Catarina,_{Florianópolis,}_SC,_Brazil

y_Universidade_Federal_de_São_Paulo,_São_Paulo,_SP,_Brazil

z_Santa_Casa_de_Belo_Horizonte,_Belo_Horizonte,_MG,_Brazil

aa_Universidade_Federal_de_Minas_Gerais,_Belo_Horizonte,_MG,_Brazil

bb_Universidade_Federal_do_Ceará,_Fortaleza,_CE,_Brazil

cc_Escola_de_Medicina_e_Saúde_Pública,_Salvador,_BA,_Brazil

dd_Universidade_Federal_do_Pará,_Belém,_PA,_Brazil

ee_Universidade_Federal_do_Espírito_Santo,_Vitória,_ES,_Brazil

a

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t

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Articlehistory:

Received15December2013 Accepted2June2014

Availableonline26October2014

Keywords:

Juvenile-onsetspondyloarthritis Brazilianpopulation

Epidemiology

Chronicarthritisinchildhood Enthesitis-relatedarthritis

a

b

s

t

r

a

c

t

Objective:Toanalyzetheclinicalandepidemiologiccharacteristicsofjuvenile-onset spondy-loarthritis(SpA)(<16years)andcomparethemwithagroupofadult-onset(≥16years)SpA patients.

Patientsandmethods:Prospective,observationalandmulticentriccohortwith1,424patients withthediagnosisofSpAaccordingtotheEuropeanSpondyloarthropathyStudyGroup (ESSG)submittedtoacommonprotocolofinvestigationandrecruitedin29reference cen-tersparticipantsoftheBrazilianRegistryofSpondyloarthritis(RBE–RegistroBrasileirode Espondiloartrites).Patientsweredividedintwogroups:ageatonset<16years(JOSpAgroup) andageatonset≥16years(AOSpAgroup).

Results:Amongthe1,424patients,235presenteddiseaseonsetbefore16years(16.5%).The clinicalandepidemiologicvariablesassociatedwithJOSpAweremalegender(p<0.001), lower limbarthritis(p=0.001),enthesitis(p=0.008),anterioruveitis(p=0.041)and posi-tiveHLA-B27(p=0.017),associatedwithlowerscoresofdiseaseactivity(BathAnkylosing SpondylitisDiseaseActivityIndex–BASDAI;p=0.007)andfunctionality(BathAnkylosing SpondylitisFunctionalIndex–BASFI;p=0.036).Cutaneouspsoriasis(p<0.001), inflamma-toryboweldisease(p=0.023),dactylitis(p=0.024)andnailinvolvement(p=0.004)weremore frequentinpatientswithadult-onsetSpA.

Conclusions: PatientswithJOSpAinthislargeBraziliancohortwerecharacterized predomi-nantlybymalegender,peripheralinvolvement(arthritisandenthesitis),positiveHLA-B27 andlowerdiseasescores.

Perfil

epidemiológico

da

espondiloartrite

de

início

juvenil

comparada

com

a

espondiloartrite

de

início

na

vida

adulta

em

uma

grande

coorte

brasileira

Palavras-chave:

Espondiloartritedeiníciojuvenil Populac¸ãobrasileira

Epidemiologia

Artritecrônicanainfância Artriterelacionadaàentesite

r

e

s

u

m

o

Objetivo:Analisarascaracterísticasclínicaseepidemiológicasdaespondiloartrite(EspA)de iníciojuvenil(<16anos)ecompará-lascomumgrupodepacientescomEspAdeiníciona vidaadulta(≥16anos).

Pacientesemétodos:Coorteprospectiva,observacionalemulticêntricacom1.424pacientes comdiagnósticodeEspAdeacordocomoEuropeanSpondyloarthropathyStudyGroup(ESSG) submetidosaumprotocolocomumdeinvestigac¸ãoerecrutadosem29centrosdereferência participantesdoRegistroBrasileirodeEspondiloartrites(RBE).Ospacientesforamdivididos emdoisgrupos:idadenoinício<16anos(grupoEspAiJ)eidadenoinício≥16anos.

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Conclusões:Nessa grande coorte brasileira, os pacientes comEspAiJ se caracterizavam predominantementepelogêneromasculino, envolvimentoperiférico(artriteeentesite), HLA-B27positivoeescoresdedoenc¸amaisbaixos.

Introduction

MostpatientswithSpAstartdiseaseintheadultage. Recog-nizingjuvenile-onsetSpA(JOSpA)canbeachallenge,asmany patientspresenttheclassicmanifestationsofthediseasein the3rdto4thdecadesoflife.Nevertheless,asSpAcanstartata pediatricage,itisimportanttheearlydiagnosisofthedisease, contributingtoavoidstructuraldamageandtheconsequent functionalincapacityinadultage.1

MostpatientswithJOSpAcanpresentanundifferentiated formofdisease,characterizedbythepresenceofperipheral arthritis,enthesitisandhipinvolvement,onthecontrastof adult-onsetpatients,whopresentmorefrequentlytheaxial complaintscharacteristicofSpA.Asaconsequenceofthis presentation,JOSpAcanbeconfoundedwithotherformsof juvenilearthritis.2

Nowadays,classificationcriteriaforJOSpAareincludedin theInternationalLeagueAgainstRheumatism(ILAR)criteria forjuvenileidiopathicarthritis.ManycasesofJOSpAcanbe consideredasenthesitis-relatedarthritis(ERA)iftheypresent arthritisand/orenthesitisassociatedwithatleasttwoofthese variables:(1)presenceorahistoryofsacroiliacjoint tender-nessand/orinflammatorylumbosacralpain;(2)presenceof HLA-B27antigen;(3)onsetofarthritisinamaleover6years ofage;(4)acutesymptomaticanterioruveitis;(5)historyof ankylosingspondylitis,enthesitisrelatedarthritis,sacroilitis withinflammatoryboweldisease,reactivearthritisoracute anterior uveitis in afirst-degree relative. Exclusion criteria includepsoriasisorhistory ofpsoriasisinthe patientorin afirst-degreerelative;presenceofpositiverheumatoidfactor inatleasttwooccasionsinathreemonthinterval;orsystemic juvenileidiopathicarthritis.3_Patients_classified_as enthesitis-relatedarthritisunderthecurrentILARclassificationcriteria forjuvenile idiopathic arthritiscan infact representearly casesofJOSpA.

Recently,thepropositionoftheclassificationcriteriaforthe peripheralSpAcanincludemanyjuvenilepatientswith undif-ferentiatedarthritisorERAinthegroupofSpA.4_The_modern conceptofperipheralSpAconsiderthatpatientswith arthri-tisorenthesitisordactylitiswithatleastone(anterioruveitis; psoriasis;Crohn’sdiseaseorulcerativecolitis;preceding infec-tion;positiveHLA-B27;sacroilitisbyimaging)ortwo(arthritis; enthesitis;dactilitis;inflammatorylowbackpainsomehow; familyhistoryofSpA)characteristicsshouldbeconsideredas aSpA.

Themainobjectivesofthisarticlearetoanalyzetheclinic andepidemiologiccharacteristics ofpatientswithJOSpAin alargecohortofpatientswithSpA,andcomparethemwith

thosepresentedbypatientswithadult-onsetSpAinthesame cohort.

Methods

Thisisaprospective,observationalandmulticentriccohort ofconsecutive SpA patientsrecruited from29 referral cen-ters participantsintheRBE(RBE–). AlltheseSpA patients, from all the five major geographic areas in Brazil, were classified according to the ESSG,5 _with _the _data _collected from June 2006 to December 2009. The Brazilian Reg-istry ofSpondyloartrhritisispartofthe RESPONDIAgroup, constituted by nine Latin-American countries (Argentina, Brazil,CostaRica,Chile,Ecuador,Mexico,Peru,Uruguayand Venezuela)andthetwoIberianPeninsulacountries(Spainand Portugal).

In this study, a common protocol of investigation was applied to 1,424 SpA patients. The diagnosis of ankylos-ing spondylitiswas considered if the patients fulfilled the New York modified criteria,6 _and _as _psoriatic _arthritis _in casetheyfulfilledMollandWrightcriteria;7_reactive_arthritis wasconsideredwhenasymmetricinflammatoryoligoarthritis of lower limbs was present associated with enthesopa-thy and/or inflammatory low back pain following enteric or urogenital infections,8 _and _enteropathic _arthritis _when the patientpresentedinflammatoryaxialand/orperipheral joint involvement associated with confirmed inflamma-tory bowel disease (IBD) (Crohn’s disease or ulcerative colitis).

Patientsweredividedintwogroups:JOSpAwasconsidered whenthepatientstartedSpAsymptoms<16yearsofage,and adult-onsetSpAwasconsideredwhendiseaseonsetwas≥16 years.

Demographic and clinical data were collected includ-ingtimeofdiseaseduration,extra-articularmanifestations, and treatment.Erythrocytesedimentationrate(ESR)and C-reactiveprotein(CRP)valueswerealsoregistered.

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BASFI 4.23

0 1 2 3 4 5 6 7 8 9 10

4.67

P=0.036 _P=0.007

P=0.000

P=0.088

3.82 4.29

8.63

6.82 6.85

5.8

1.81

1.06

7.24 7.9

BASDAI BASRI

Index

≤16 Years >16 Years

BASRI-SPINE BASRI-HIP ASQoL

Figure1–Meanscoresofthediseaseactivity(BASDAI),functional(BASFI),andqualityoflife(ASQoL)indexesinthe juvenile-onsetSpAgroup(JOSpA)comparedwiththeadult-onsetSpAgroup(AOSpA).

ASQoL,AnkylosingSpondylitisQualityofLife;BASDAI,BathAnkylosingSpondylitisDiseaseActivityIndex;BASFI,Bath AnkylosingSpondylitisFunctionalIndex.

Statistical Analysis: Categorical variables were compared by2_and _Fisher’s_exact _test,_and _continuous_variables _were comparedbyANOVAtest.AvalueofP<0.05wasconsidered significant,and0.05 >P> 0.10was consideredastatistical trend.

Results

Amongthe 1,424 SpA patients, 235 referred disease onset before16years(16.5%).Atthemoment,theywereevaluated forthe SpA protocol, just3.0% ofthe patients were below 16years.PatientsconsideredasJOSpApresentedsignificant delayinthediagnosis(10.02±9.28yearsvs.5.84±7.27years;P <0.001)comparedtotheadult-onsetpatients.Atthemoment oftheclinicalinvestigation,JOSpApatientsweresignificantly younger(32.53± 11.78years)thanthe adult-onsetpatients (44.51±11.94years)(P<0.001).

Theclinical andepidemiologicvariables associatedwith JOSpA were male gender (P < 0.001), lower limb arthri-tis (P=0.001), enthesitis (P=0.008), and positive HLA-B27 (P=0.017).Inflammatorybackpain(P=0.006),cervicalpain(P= 0.034)anddactylitis(P=0.024)weremorefrequentinpatients withadult-onsetSpA(Table1).Ethnicitywassimilarinboth age-onsetgroups.

Whenwestudiedtheextra-articularmanifestations, ante-rior uveitis (P=0.041) was associated with JOSpA, while cutaneouspsoriasis(P<0.001),inflammatoryboweldisease

(P=0.023),andnailinvolvement(P=0.004)wereassociatedto adult-onsetSpA(Table1).

Theanalysisofthephysicalexaminationshowedthatthe mean numberofpainfuljoints (3.40± 6.99vs.3.83 ±7.52; P = 0.423),mean number of swollenjoints (1.19 ± 3.73 vs. 1.58 ± 4.62;P = 0.183),as well asthe mean MASES scores (2.04±2.89vs.2.17±3.02;P=0.548)weresimilarinthetwo groups.

Diseaseindicesindicatedthatdiseaseactivity(BASDAI;P =0.007)andfunctionality(BASFI;P=0.036)werebetterinthe JOSpAgroup,whileASQoL(P=0.088)didnotreachstatistical significance(Fig.1).

Discussion

Theclinicalcharacteristicsofthiscohorthaveshown concor-dancewiththeclassicdescriptionofJOSpA:3_predominance ofmalegender,positiveHLA-B27,andperipheralinvolvement characterizedby lower limbarthritis and enthesitis. These characteristicsalsoagreewiththeconceptoftheperipheral SpA.4

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Table1–Associationsbetweenclinic-epidemiologicvariablesandageatonset(beforeandafter16years-old)in1,424 patients.

Variables Ageatonsetofsymptoms pa

<16years ≥16years

n=235 % n=1189 %

Gender <0.001

Male 202 86.0 839 70.6

Female 33 14.0 350 29.4

Ethnicity 0.621

White 121 51.5 686 57.7

Non-white 114 48.5 503 42.3

Inflammatorylowbackpain 142 60.4 827 69.6 0.006

Buttockpain 81 34.5 396 33.3 0.730

Cervicalpain 60 25.5 387 32.5 0.034

Hippain 71 30.2 294 24.7 0.078

Lowerlimbarthritis 140 59.6 563 47.4 0.001

Upperlimbarthritis 47 20.0 274 23.0 0.307

Enthesitis 137 58.3 581 48.9 0.008

Dactilitis 17 7.2 147 12.4 0.024

HLA-B27b ₈₂ _79.6 ₃₉₆ _67.9 _0.024

Anterioruveitis 59 25.1 229 19.3 0.041

Inflammatoryboweldisease 4 1.7 61 5.1 0.021

Psoriasis 9 3.8 245 20.6 <0.001

Nailinvolvement 11 4.7 129 10.8 0.004

Balanitis 11 4.7 37 3.1 0.223

a _Qui-square.

b _Calculated_for₁₀₃_(<₁₆_years)_and₅₈₃_patients₍_≥₁₆_years).

JOSpA and adult-onset SpA, particularly ankylosing spondylitis,candifferinsomeclinicalaspects,butthereisno evidencethattheycouldbeconsideredasdifferentdiseases. Themaindifferencesareinthediseasepresentation.Different fromwhathappensintheadult-onsetpatients,childrenand adolescents withJOSpA frequentlystart diseasesymptoms withperipheralcomplaints(lower limbarthritisand enthe-sitis),andwilldevelopaxialsymptomsafterfiveto10yearsof follow-up.14–20_In_the_present_study,_the_authors_found_a signif-icantfrequencyoflowerlimbarthritisandenthesitisinJOSpA. Thisstudyalsoshowedthattherewasasignificantdelayin thediagnosisofJOSpAcomparedtoadult-onsetSpApatients; wesupposethatthisdelayisassociatedwiththemanytimes undifferentiatedclinicalpresentationofSpAinchildrenand teenagers.

Regarding extra-articular manifestations, the present studyfoundthatanterior uveitiswasmorefrequentinthe JOSpAgroup,whilepsoriasis, nailinvolvementand inflam-matoryboweldiseaseweremorefrequentintheadult-onset group.Thesefindingsare similartotheresultsobservedin othercohorts.14,19,21_In_a_Turkish_study,_uveitis_was_observed_in 11.6%ofthepatientswithjuvenileidiopathicarthritisandwas relatedtotheclinicalform,associatedwiththeoligoarticular (extendedandpersistent)andpsoriaticforms.21

ThefrequencyofpositiveHLA-B27intheJOSpAgroupwas significantlyhigherthanthatobservedintheadult-onsetSpA group.Theseresultsweresimilartootherstudiesincluding EuropeanandAsiaticpopulations,21–23_and_confirm_that HLA-B27shouldbedoneinallthepatientssuspectedtohaveSpA,

accordingtoitselevatedpositivityandassociationwithmore severedisease.23

Theseverityofankylosingspondylitisisfrequentlyhigh in juvenile cases as there are many patients with juve-nile ankylosing spondylitis who require hip arthroplasty. TheresultsoffunctionalincapacityinpatientswithJOSpA can be discordant. While Stone et al.24 _have _found _a worsefunctionalcapacityinjuvenileankylosingspondylitis patients,Gensleretal.16_showed_similar_results_compared_to adult-onsetpatients.Inthepresentstudy,BASDAIandBASFI meanscoresweresignificantlylowerintheJOSpApatients, whileASQoLscoresweresimilarinthetwogroups.These find-ingscansuggestthattheimpactofSpAinthequalityoflifein thejuvenilegroupishigh,despitebetterdiseaseactivityand functionalindices.

Despite thelower frequencyofaxialinvolvementinthe JOSpA,studieshavedemonstrated40%offunctional incapac-ity after10 to 15 years of disease duration issignificantly associatedwithhipinvolvement.16,25 _In_another_study_with 326JOSpApatients,mean BASFIwas5.1±1.5,significantly higher than theBASFI oftheadult-onset SpAgroup (4.6 ±

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Concluding,thepresentstudy,analyzingalargeBrazilian cohortofpatientswithSpA,attendedinuniversitycentersin allthemaingeographicregionsinthecountry,showedthat JOSpAwasassociatedwithmalegender,HLA-B27positivity, anterioruveitisandperipheralinvolvement.This character-ization will help to understand the characteristics of the JOSpA patients and their needs in the long-term follow up.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

Theelectronicversion ofthe Brazilian Registry of Spondy-loarthritis is maintained by an unrestricted grant of Wyeth/PfizerBrazil,whichdoesnotinfluenceinthe statisti-calanalysisandinthewritingofthemanuscripts.Dr.Sampaio BarrosisarecipientofaresearchgrantfromFederico Foun-dation.

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