Rev. Bras. Reumatol. vol.55 número4

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

Liver

and

spleen

biometrics

in

childhood-onset

systemic

lupus

erythematosus

patients

Andressa

Guariento

,

Marco

Felipe

C.

Silva

,

Priscilla

S.F.

Tassetano

,

Sílvia

Maria

S.

Rocha

_,

_Lúcia

_M.A.

_Campos

_,

_Marcelo

_Valente

_,

_Clovis

_A.

_Silva

a_{PediatricRheumatologyUnit,FaculdadedeMedicina,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil} b_{PediatricRheumatologyUnit,SantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil}

c_{PediatricRadiologyUnit,FaculdadedeMedicina,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil} d_{DepartmentofRheumatology,FaculdadedeMedicina,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil}

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Articlehistory: Received31July2014 Accepted24December2014 Availableonline16March2015

Keywords: Hepatomegaly Spleenatrophy Ultrasound Biometry

Systemiclupuserythematosus Pediatricrheumatology

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Objective:Toevaluateliverandspleendimensionsinchildhood-onsetsystemiclupus ery-thematosus(c-SLE)patientsandhealthycontrols.

Methods:30c-SLEpatientsand30healthycontrolvolunteersunderwentabdominal ultra-sound. The following two liver measurements were performed in left hepatic lobe: craniocaudalandanteroposterior andthreein righthepaticlobe (RHL):posterior cran-iocaudal(PCC-RHL),anterior craniocaudalandanteroposterior.Threespleendimension measurementswerealsoevaluated:longitudinal,transverseandanteroposterior. Demo-graphic, clinical and laboratorial data, SLEDAI-2K, ECLAM, SLAM and treatment were assessed.

Results:Meancurrentagewassimilarinc-SLEandcontrols(170.31±27.81vs.164.15±39.25 months;p=0.486).ThemeanofPCC-RHLdimensionwassignificantlyhigherinc-SLE com-paredtocontrols(13.30±1.85vs.12.52±0.93,p=0.044).Therewerenodifferencesbetween theother hepaticbiometricsandsplenicparameters(p>0.05).Furtheranalysisinc-SLE patientsaccordingtoPCC-RHLdimension≥13.3cmversus<13.3cmshowedthatthemedian ofSLEDAI-2K[8(0–18)vs.2(0–8),p=0.004],ECLAM[4(0–9)vs.2(0–5),p=0.019]andSLAM [5(1–13)vs.2(0–14),p=0.016]weresignificantlyhigherinpatientswithhigherPCC-RHL dimension,likewisethefrequencieofnephritis(77%vs.29%,p=0.010).Liverenzymeswere similarinbothgroups(p>0.05).PositivecorrelationwasobservedbetweenSLEDAI-2Kand PCC-RHL(p=0.001,r=+0.595).Negativecorrelationwasevidencedbetweendiseaseduration andlongitudinaldimensionofspleen(p=0.031,r=−0.394).

Conclusion:Ourdataraisesthepossibilitythatdiseaseactivitycouldleadtoasubclinical andlocalizedhepatomegalyduringthediseasecourse.Longdiseasedurationresultedto spleenatrophyinc-SLEpatients.

©2015ElsevierEditoraLtda.Allrightsreserved.

∗ _{Correspondingauthor.}

E-mail:[email protected](C.A.Silva).

http://dx.doi.org/10.1016/j.rbre.2014.12.009

Biometria

do

fígado

e

do

bac¸o

em

pacientes

com

lúpus

eritematoso

sistêmico

de

início

na

infância

Palavras-chave: Hepatomegalia Atrofiadobac¸o Ultrassonografia Biometria

Lúpuseritematososistêmico Reumatologiapediátrica

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Objetivo: Avaliarasdimensõesdofígadoedobac¸oempacientescomlúpuseritematoso sistêmicodeiníciopediátrico(LESp)econtrolessaudáveis.

Métodos: 30pacientescomLES-ie30voluntáriossaudáveiscontroleforamsubmetidos a umaultrassonografiadoabdome. Foramrealizadasduas medic¸õesdofígadonolobo hepáticoesquerdo(craniocaudaleanteroposterior)etrêsnolobohepáticodireito(LHD) (craniocaudalposterior[CCP-LHD],craniocaudalanterioreanteroposterior).Foramtambém avaliadastrêsmedidasdasdimensõesdobac¸o:longitudinal,transversaleanteroposterior. Foramavaliadosdadosdemográficos,clínicoselaboratoriais,SLEDAI-2K,ECLAM,SLAMe tratamento.

Resultados:AidademédiafoisemelhantenospacientescomLES-iecontroles(170,31±27,81 vs.164,15±39,25meses;p=0,486).AmédiadadimensãoCCP-LHDfoisignificativamente maiornogrupoLES-iemcomparac¸ãoaoscontroles(13,30±1,85vs.12,52±0,93,p=0,044). Nãohouvediferenc¸asnosoutrosparâmetrosbiométricosdofígadoedobac¸o(p>0,05).Uma análiseespecificarealizadaapenasnospacientescomLESpdeacordocomadimensão CCP-LHD≥13,3cmversus<13,3cmmostrouqueamedianadoSLEDAI-2K[8(0–18)vs.2 (0–8),p=0,004],ECLAM[4(0–9)vs.2(0–5),p=0,019]eSLAM[5(1–13)vs.2(0–14),p=0,016]era significativamentemaiorempacientescommaiordimensãoCCP-LHD,domesmomodoque afrequênciadenefrite(77%vs.29%,p=0,010).Asenzimashepáticasforamsemelhantesnos doisgrupos(p>0,05).Foiobservadaumacorrelac¸ãopositivaentreoSLEDAI-2Keadimensão CCP-LHD(p=0,001,r=+0,595).Evidenciou-seumacorrelac¸ãonegativaentreadurac¸ãoda doenc¸aeadimensãolongitudinaldobac¸o(p=0,031,r=−0,394).

Conclusão: Osdadoslevantamapossibilidadedequeaatividadedadoenc¸apodelevara umahepatomegaliasubclínicaelocalizadaduranteocursodadoenc¸a.Adurac¸ãodadoenc¸a resultouematrofiadobac¸oempacientescomLES-i.

©2015ElsevierEditoraLtda.Todososdireitosreservados.

Introduction

Hepatomegaly and/or splenomegaly occur in 20–50%

childhood-onset systemic lupus erythematosus1 _(c-SLE)

patients at disease onset, usually associated with disease activity.Involvementofthe reticuloendothelialsystemmay alsobeassociatedwithabnormalliverfunctiontests.2,3

Abdominalultrasound can beused to assess liver4 _and

spleen measurements in children and adolescents

with-out risk of radiation.5 _{However, a systematic evaluation}

of these visceral organ dimensions has not been

per-formedinc-SLEpopulation, particularlyduringthedisease course.

Therefore,theobjectivesofourstudyweretoevaluateliver andspleendimensionsinc-SLEpatientsandhealthycontrols andtoassesspossibleassociationsbetweenabnormalitiesin liverandspleensizeswithdemographicdata,clinicalfeatures, diseaseactivity,cumulativedamageandtreatment.

Materials

and

methods

Patientsandcontrols

FromMaytoJune2012,58c-SLEpatientswerefollowedatour PediatricRheumatologyService. All ofthe patientsfulfilled

theAmericanCollegeofRheumatologycriteriaforc-SLE.6_The exclusion criteria were currentacute or chronicinfections, autoimmunehepatitis,otherconcomitantdiseasewith hep-atosplenomegaly, canceror unwillingtoparticipate.Out of them,15wereexcludedduetocurrentacuteinfections,9due tounwillingnesstoparticipateand4duetoautoimmune hep-atitis.Therefore,thecross-sectionalstudywasconductedin 30c-SLEpatients.Thecontrolgroupincluded30healthy con-trolvolunteersrecruitedfromtheprimarycareclinicnearby our tertiary hospital. The control volunteers were submit-ted toclinical evaluation, and liver and spleenbiometrics. Localethics committeeofouruniversity hospitalapproved thisstudy,andinformedconsentwasobtainedfromall par-ticipants.

Liverandspleenbiometrics

Abdominal ultrasound was carried out by an experienced

and trained, specialist(SMS) using a1–6mHz convex mul-tifrequency transducer(LOGIC E9® _{– GeneralElectric, USA).}

The following two liver measurements were performed in

measurementswerealsoevaluated:longitudinal,transverse andanteroposterior.

Demographicdata,clinical,laboratorialandtreatment assessment

Demographic data included current age, disease duration

and gender. Weight and heightwere evaluated. Body mass

index (BMI) was defined by weight in kilograms/height in

meters2_(kg/m2_{).Bodysurfacearea(BSAinm}2_{)wascalculated}

accordingtotheformula:(weightinkilograms0.425_×heightin

centimeters0.725_)×0.007184.

SLEclinicalmanifestationsweredefinedas:hepatomegaly (liveredge>2cmbelowtherightcostalmargin),splenomegaly

(palpable spleen below the left costal margin),

mucocu-taneous lesions (malar or discoid rash, oral ulcers or

photosensitivity),articular involvement(non-erosive arthri-tis), neuropsychiatric disease (seizure or psychosis), renal involvement (proteinuria≥0.5g/24h, presence of cellular casts,and/orpersistenthematuria≥10redbloodcellsperhigh power field), serositis(pleuritis or pericarditis), and hema-tologicabnormalities(hemolyticanemia,leukopeniawitha whitebloodcellcount<4000mm–3_{,lymphopenia<1500mm}–3

on two or more occasions and thrombocytopenia with

platelet count<100,000mm–3 _{in the absence of drugs or}

infection).

Diseaseactivity wasevaluated accordingto SLEDisease ActivityIndex2000(SLEDAI-2K),7_{EuropeanConsensusLupus} ActivityMeasurement(ECLAM),8_{andSystemicLupus}

Activ-ity Measure (SLAM) scores.9 _{Cumulative damageusing the}

SLE International Collaborating Clinics/ACR Damage Index

(SLICC/ACR-DI).10

Erythrocyte sedimentation rate (ESR) was performed

by Westergreen method and C-reactive protein (CRP) by

nephelometry.Anti-double-strandedDNA(anti-dsDNA)was

detectedbyindirectimmunofluorescenceusingCrithidia lucil-iaeassubstrate.Presenceofanticardiolipinantibodies(aCL)

IgG and IgM was analyzed by enzyme-linked

immunosor-bentassay(ELISA). Lupusanticoagulant(LAC)wasdetected accordingto the guidelines ofthe InternationalSociety on ThrombosisandHemostasis.11

Data concerning the cumulative and current dosage of

prednisone,hydroxychloroquine,methotrexate,azathioprine,

intravenouscyclophosphamide,cyclosporineand

mycophe-nolatemofetilweredetermined.

Statisticalanalysis

Resultswerepresentedasthemean±standarddeviation(SD) ormedian(range)forcontinuousandnumber (%)for cate-goricalvariables.DatawerecomparedbyMann–Whitneytest incontinuousvariablestoevaluatedifferencesamongc-SLE andcontrolgroup,andamongSLEsubgroups.For categori-calvariables,differenceswereassessedbyFisher’sexacttest. Spearmanrankcorrelationcoefficientwasusedfor correla-tions between disease activity scores and liver and spleen parameters.Thelevelofsignificanceofindependentvariable wassetat5%(p<0.05).

Results

Table1includesdemographicdata,liverandspleen biomet-ricsinc-SLEpatientsandhealthycontrols.Themeancurrent agewassimilarbetweenthec-SLEandcontrols(170.31±27.81 vs. 164.15±39.25months; p=0.486),likewisethe frequency

of female gender (77% vs. 63%, p=0.398) and median of

BSA (p=0.875). The mean ofPCC-RHL dimension was

sig-nificantly higherinc-SLEcomparedtocontrols(13.30±1.85 vs.12.52±0.93,p=0.044)(Table1).Therewerenodifferences betweentheotherhepaticbiometricsandsplenicparameters (p>0.05). Noneofc-SLEandhealthy controlshadjaundice, ascites,pruritus,bleeding,liverorspleenthrombosisor sono-graphichepaticsteatosis.

Further analysis in c-SLE patients according to

PCC-RHL dimension ≥13.3cm (Table 2) (mean ofthis biometric measurementin30c-SLEpatients)versus<13.3cmshowed thatthemedianofSLEDAI-2K[8(0–18)vs.2(0–8),p=0.004], ECLAM [4 (0–9) vs. 2 (0–5), p=0.019] and SLAM [5 (1–13) vs. 2 (0–14),p=0.016] were significantly higher in patients

withhigher PCC-RHLdimension,likewisethe meanofESR

(33.7±16 vs. 22.0±13mm/h, p=0.038). The frequencies of nephritisweresignificantlyhigherinpatientswithPCC-RHL dimension≥13.3cmversus<13.3cm(77%vs.29%,p=0.010). ThemeanofBSAwasalsosignificantlyhigherintheformer group(1.56±0.23vs.1.37±0.26m2_{,p=0.043).Themedianof}

serumliverenzymesweresimilarinbothgroups(p>0.05). Onlyonec-SLEpatienthadhepatosplenomegaly(liveredge

4cm below the right costal margin and spleen edge 4cm

Table1–Demographicdata,liverandspleenbiometrics inchildhood-onsetsystemiclupuserythematosus (c-SLE)patientsandhealthycontrols.

Variables c-SLE (n=30)

Controls (n=30)

p

Demographicdata

Currentage, months

170.31±27.81 164.15±39.25 0.486

Femalegender 23(77) 19(63) 0.398 BMI,kg/m2 _{21.15(17.4–35.3) 22.1(18.6–29.6) 0.721}

BSA,m2 _{1.56(0.94–2.02) 1.49(1.32–2.03) 0.875}

Liverbiometrics

CC-LHL,cm 7.73±1.48 7.57±1.21 0.648 AP-LHL,cm 5.22±0.79 5.38±0.68 0.405 PCC-RHL,cm 13.30±1.85 12.52±0.93 0.044 ACC-RHL,cm 8.33±1.27 8.25±1.04 0.698 AP-RHL,cm 11.40±1.60 10.74±0.98 0.060

Spleenbiometrics

Longitudinal, cm

9.85(7.0–16.9) 9.50(8.1–11.9) 0.387

Transverse,cm 3.50(2.8–5.8) 3.75(2.0–6.0) 0.524 AP,cm 6.70±1.09 6.64±0.85 0.793

Resultsarepresentedinmedian(range)ormean±standard devia-tionandn(%).

Table2–Demographicdata,diseaseparameters,clinicalandlaboratorialfeaturesandtreatmentinchildhood-onset systemiclupuserythematosus(cSLE)patientsaccordingtoposteriorcraniocaudalofrighthepaticlobe(PCC-RHL) dimension.

PCC-RHL≥13.3cm (n=13)

PCC-RHL<13.3cm (n=17)

p

Demographicdata

Currentage,month 173.49±23.05 167.87±31.45 0.592

Diseaseduration,month 36.0(7.2–104.4) 40.8(4.8–156.0) 0.869

BMI,kg/m2 _{21.1(17.4–35.3) 21.4(16.9–32.9) 0.483}

BSA,m2 _{1.56±0.23 1.37±0.26 0.043}

Femalegender 11(85) 12(71) 0.326

Diseaseparameters

SLEDAI-2K 8(0–18) 2(0–8) 0.004

ECLAM 4(0–9) 2(0–5) 0.019

SLAM 5(1–13) 2(0–14) 0.016

SLICC-ACR-DI 0(0–1) 0(0–1) 0.242

Clinicalandlaboratorialfeatures

Hepatosplenomegaly 0(0) 1(6) 1.0

Articular 2(15) 3(18) 0.633

Mucocutaneous 6(46) 6(35) 0.547

Hematological 5(38) 4(23) 0.314

Serositis 1(8) 1(6) 0.687

Neuropsychiatric 2(15) 0(0) 0.179

Nephritis 10(77) 5(29) 0.010

ESR,mm/h 33.7±16 22.0±13 0.038

CRP,mg/dL 7.4(0.1–20.8) 0.8(0.1–12.9) 0.094

AST,IU/L 20(11–55) 21(11–63) 0.322

ALT,IU/L 31(11–47) 33(7–61) 0.622

Anti-dsDNA 3(23) 0(0) 0.070

IgMACL 3(23) 1(6) 0.204

IgGACL 3(23) 2(12) 0.367

LAC 0(0) 2(12) 0.313

Treatment

Currentprednisone 12(92) 12(71) 0.156

Dose,mg/day 20(10–50) 15(3–30) 0.089

Cumulativedose,g 24.85(7.1–54.5) 19.72(6.1–451.3) 0.477

Currentazathioprine 4(31) 7(41) 0.421

Currentmycophenolatemofetil 7(54) 4(23) 0.093

Currentmethotrexate 2(15) 2(12) 0.591

Currenthydroxychloroquine 11(85) 17(100) 0.179

Resultsarepresentedinmedian(range)ormean±standarddeviationandn(%).

BMI,bodymassindex;BSA,bodysurfacearea;SLEDAI-2K,SystemicLupusErythematosusDiseaseActivityIndex2000;ECLAM,European ConsensusLupusActivityMeasurement;SLAM,SystemicLupusActivityMeasure;SLICC/ACR-DI,SystemicLupusInternational Collaborat-ingClinics/ACRDamageIndex;AST,alanineaminotransferase;ALT,aspartateaminotransferase;ACL,anticardiolipinantibody;LAC,lupus anticoagulant.

below the left costal margin), however the PCC-RHL was <13.3cm.

CorrelationswereevidencedbetweenSLEDAI-2Kand PCC-RHL (p=0.001, r=+0.595), SLEDAI-2K and CC-LHL (p=0.015, r=+0.440),SLEDAI-2KandACC-RHL(p=0.017,r=+0.431),and SLEDAI-2Kand AP-RHL dimensions(p=0.029, r=+0.399), as wellasobservedbetweenSLEDAI-2Kandlongitudinalspleen dimension(p=0.042,r=+0.373).Also,itwasfoundapositive correlationbetweenSLAMandPCC-RHL(p=0.020,r=+0.422), SLAMandCC-LHL(p=0.047,r=+0.365),ECLAMandPCC-RHL (p=0.018,r=+0.430),ECLAMandCC-LHL(p=0.008,r=+0.475), as well as found between ECLAMand longitudinal spleen dimension(p=0.047,r=+0.365).

Negative correlation was evidenced between disease duration and longitudinal dimension of spleen (p=0.031, r=−0.394).

Discussion

Toour knowledge,this wasthe first studythat specifically addressedliverandspleenbiometricsinpediatriclupus popu-lation,andshowedsubclinicalhepatomegalyinpatientswith diseaseactivityassociatedwithBSA.Moreover,longperiodof diseaseduration mayberelatedtosplenicatrophyinc-SLE patient.

concomitantchronicdiseaseswithhepatosplenomegalyare importantsincetheseabnormalitiesmayalsoinfluencethe dimensions.However,themainlimitationsofthisstudywere thesmallnumber ofpatients, thelackoflaboratoryexams evaluationincontrolgroupand thelackofassessementof splenicfunction,sincec-SLEpatientscouldpresentfunctional asplenia.14

Hepatomegaly is acommon finding atdisease onset in

c-SLE patients and adult SLE.2,3,15 _{During disease course,} liverenlargementinlupuspatients,eitherchildrenoradults, maybeassociatedwithhepaticcongestion,fattyinfiltration, autoimmuneandviralhepatitis,metabolicdisorders, throm-bosisorhepatotoxicdrugsusage.2,15,16

Ourpatients had localized right-liverhypertrophy asso-ciatedwith disease activity, suggesting the same systemic

pathogenesismechanism.Thesepatientshadmildand

sub-clinical liverenlargementprobablydue tolivercongestion, liverchronicinflammationandhypervascularization.Ofnote,

this enlargement was associated with severe disease and

correlatedwithvariousclinicalandlaboratorydisease param-eters.Indeed,theautopsyregistrydataofthe livershowed that hepatic congestion, liver chronicinflammationand/or liverarteritiswereobservedin77%ofadultandc-SLEpatients andmaybereflectinglupusactivity.15_{Positivecorrelationwas} alsofoundbetweendiseaseactivityparametersand longitu-dinalspleendimension,despitetheabsence ofclinicaland

sonographysplenomegaly.

Damagetohepatocytecellseemsnottoberelevantherein, sincenoneofourpatientshadelevatedlevelsofliverenzymes. Moreover,corticosteroiduse,aknowncauseofhepatomegaly andfattyliverdisease,mayhavenotcontributedto enlarge-mentofthisorganinthepresentstudy.2,15

BothpediatricandadultSLEpatientsmaypresentsplenic atrophy.14,17_{Importantly,ourchildrenandadolescentlupus} patients with long disease duration presented spleen size reduction, thus indicating splenic atrophy during the dis-easecourse.Apreviousstudy evaluatingadultSLEpatients foundthatsplenicatrophyhad nocorrelationwithdisease duration.17_{However,themechanismsofspleenatrophyand} functionalaspleniaarestillnotclearinpediatricandadultSLE populationsandfurtherstudieswillbenecessary.

Inconclusion,ourdataraisesthepossibilitythatdisease activitycouldleadtosubclinicalandlocalizedhepatomegaly. We hypothesize that liver is a potential target organ for activelupusduringthediseasecourse.Longdiseaseduration resultedtospleenatrophyinc-SLEpatients.

Funding

ThisstudywassupportedbygrantsfromFundac¸ãodeAmparo àPesquisadoEstadodeSãoPaulo (FAPESP2011/12471-2to CAS),ConselhoNacionaldeDesenvolvimentoCientíficoe Tec-nológico(CNPQ302724/2011-7toCAS),FedericoFoundation(to CAS),andNúcleodeApoioàPesquisa“SaúdedaCrianc¸aedo Adolescente”ofUSP(NAP-CriAd)toCAS.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgement

OurgratitudetoUlyssesDoria-Filhoforthestatisticalanalysis.

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