Can Red Cell Distribution Width Be Used as a Marker of Crohn’s Disease Activity?

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www.elsevier.pt/ge

ORIGINAL ARTICLE

Can Red Cell Distribution Width Be Used as a Marker of Crohn’s Disease Activity?

Ana Maria Oliveira

^∗

, Filipe Sousa Cardoso, Catarina Grac ¸a Rodrigues, Liliana Santos, Alexandra Martins, João Ramos de Deus, Jorge Reis

GastroenterologyDepartment,HospitalProf.DoutorFernandoFonseca,Amadora,Portugal

Received7August2015;accepted11October2015 Availableonline24November2015

KEYWORDS CrohnDisease;

ErythrocyteIndices

Abstract

Introduction:Recently,ithasbeensuggestedanassociationbetweenredcelldistributionwidth (RDW)andCrohn’sdiseaseactivityindex(CDAI),butitsuseisnotyetperformedindailyclinical practice.

Objectives:TodeterminewhetherRDWcanbeusedasamarkerofCrohn’sdisease(CD)activity.

Methods:Thiswasacross-sectionalstudyincludingpatientswithCD,observedconsecutively inanoutpatientsettingbetween January 1standSeptember30th2013. Bloodcellindices, erythrocytesedimentationrate(ESR),andC-reactiveproteinweremeasured.CDactivitywas determinedby CDAI(active diseaseif CDAI≥150).Associationswere analyzedusinglogistic regression(SPSSversion20).

Results:119patients (56%female) wereincludedinthestudy withameanageof47years (SD15.2).Twentypatients(17%)hadactivedisease.ThemedianRDWwas14.0(13---15).There wasanassociationbetweenRDWanddiseaseactivity(p=0.044).Afteradjustmentforageand gender,thisassociationremainedconsistent(OR1.20,95%CI1.03---1.39,p=0.016).Itwasalso foundthattheassociationbetweenRDWanddiseaseactivitywasindependentofhemoglobin andESR(OR1.36,95%CI1.08---1.72,p=0.01)andofbiologictherapy(OR1.19,95%CI1.03---1.37, p=0.017).ARDWcutoffof16%hadaspecificityandnegativepredictivevalueforCDAI≥150 of88%and86%,respectively.

∗Correspondingauthor.

E-mailaddress:[email protected](A.M.Oliveira).

http://dx.doi.org/10.1016/j.jpge.2015.10.003

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Conclusion: Inthisstudy,RDWprovedtobeanindependentandrelativelyspecificmarkerof CDactivity.Theseresultsmaycontributetotheimplementationofthissimpleparameter,in clinicalpractice,aimingtohelptherapeuticdecisions.

ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

PALAVRAS-CHAVE Doenc¸adeCrohn;

ÍndicesdeEritrócitos

AAmplitudedeDistribuic¸ãodosGlóbulosVermelhos(RDW)PodeSerConsiderado ComoumMarcadordaAtividadedaDoenc¸adeCrohn?

Resumo

Introdução: Recentemente,temvindoasersugeridaumaassociaçãoentreovalordeRDWe aatividadedadoençadeCrohn(DC),mas asuautilizaçãonão estáaindaimplementadana práticaclínicadiária.

Objetivos: DeterminarseoRDWpodeserutilizadocomomarcadordeatividadedaDC.

Métodos: Estudotransversal,emdoentescomDC,observadosconsecutivamenteemconsulta deDoençaInflamatóriaIntestinal,entre1dejaneiroe30desetembrode2013.Analisaram-se índicesdohemograma,proteínaCreativaevelocidadedesedimentação.Agravidadedadoença foi avaliadapeloCrohn’sdiseaseactivity index(doença ativaseCDAI≥150). Asassociações foramestudadasusandoaregressãologística(SPSSStatisticsV20).

Resultados: Incluídos119doentes(56%dosexofeminino),comidademédiade47anos(DP15,2 anos).Vintedoentes(17%)tinhamdoenc¸aativa.OvalordoRDWmedianofoi14,0%(13-15).

Verificou-seumaassociaçãoentreRDWeatividadedadoença(p=0,044).Apósajusteparaa idadeeosexo,estaassociaçãomanteve-seconsistente(OR1,20;95%CI1,03-1,39;p=0,016).

Verificou-seaindaqueaassociaçãodovalordoRDWcomaatividadedadoençafoiindependente dovalordahemoglobinaedavelocidadedesedimentação(OR1,36;95%CI1,08-1,72;p=0,01) edaterapêuticabiológica(OR1,19;95%CI1,03-1,37;p=0,017).Paraumvalor decortede RDWde16%,aespecificidadeeovalorpreditivonegativodeCDAI≥150foramde88%e86%, respetivamente.

Conclusão:Nesteestudo,ovalordoRDWdemonstrouserum marcadorindependenteerel- ativamenteespecíficodaatividadedadoenc¸adeCrohn.Estesresultadospoderãocontribuir paraaaplicac¸ãodesteparâmetrosimples,napráticaclinicadiária,visandoauxiliardecisões terapêuticas.

Este éum artigo OpenAccess sob alicençade CCBY-NC-ND(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

1. Introduction

Crohn’sdisease (CD) is achronic inflammatory bowel disease (IBD) characterized by a relapsing-remitting clinical behavior.¹ Forthis reason,the assessment ofthe severity ofIBDandthemonitoringofdiseaseactivityareimportant issues.²

Currently,endoscopywithbiopsyisconsideredthegold standard for the evaluation of mucosal inflammation.^2,4 However, endoscopy is invasive and requires good bowel cleansing,aprocedure thatispoorlyacceptedbypatients and potentially harmful.^1,2 Therefore, CD activity index (CDAI) is still accepted to grade CD activity by inter- national guidelines, namely European Crohn’s and Colitis Organization(ECCO).Despitebeingbasedmainlyinclinical parameters,itremainstheprincipalindexforevaluatingCD patients’outcomesinclinicalstudies.Clinicalremissionis acceptedasaCDAIof<150.³

To improve non-invasive monitoring of CD activity, numerousbiomarkers(e.g.C-reactiveprotein(CRP),erythrocyte sedimentation rate (ESR), leukocyte and platelet counts,albumin, fecalcalprotectin and lactoferrin)⁵ have beenproposedbutfewhaveproventobeclinicallyusefulin IBD.^1,6Nevertheless,CRPhasbeenincludedasanancillary testtomonitorCDactivitybyECCOguidelines.³

Redcelldistributionwidth(RDW)isaquantitativemea- sureofvariabilityinthesizeofcirculatingerythrocytes.^7,8 It is routinely measured by automated hematology ana- lyzers and is usually reported as a component of the completebloodcount(CBC),⁹ thusnotimplyingadditional costs.^10,11 Until recently, it was used mainly to differen- tiate iron deficiency anemia from thalassemia trait.^11,12 However,in the last years,numerous studies have shown that a higher RDW is associated with several patho- logic conditions, including heart failure,⁹ acute coronary syndrome,¹³atherosclerosis,¹⁴pulmonaryimpairment,¹⁵and

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venous thromboembolism.¹⁶ Also, some studies have sug- gestedthatRDWmaybean inflammatorymarkerfor IBD, mainlyinaninpatientsetting.^17,18

Since RDW is easily accessible and relatively cheap, understandingitsprognosticsignificancein thecontextof CD could be useful to optimize clinical decisions. Conse- quently, we hypothesized that RDW may be a surrogate markerofCDactivity,notonlyinan inpatientsetting,but alsoinanoutpatientsetting.Accordingly,thepurposeofthis studywas,firstly,todeterminewhetherRDWisassociated withCDAI;and,secondly,toidentifyapossibleRDWcutoff withclinicalapplicabilityforanoutpatientsetting.

2. Materials and methods

2.1. Design,setting,andparticipants

Thiswasacross-sectionalobservationalstudyperformedat theGastroenterologyDepartmentofalargedistricthospital (Prof.DoutorFernandoFonsecaHospital,Amadora,Portu- gal).

AllCDpatients(ascertainedbystandardclinical,radio- logical,histological,andendoscopiccriteria)³ observedin theIBDoutpatientclinicbetweenJanuary1standSeptem- ber30th2013, withlaboratoryevaluation upto2months beforetheclinic visitwereincluded inthestudy.Patients withfollow-up at our clinic for less than 6 months, with laboratoryevaluationdonemorethan2monthsbeforethe clinicvisit,orwithlackofinformationtoassessCDAIwere excludedfromthestudy.

2.2. Variablesandprimaryoutcome

Specificpatients’ characteristics considered were thefol- lowing:age,sex,MontrealclassificationofCD,²⁰ bloodcell indices (RDW, hemoglobin, mean cellular volume (MCV), leukocyte(WBC)and platelet(PLT)counts), inflammatory biochemical parameters (CRP and ESR), and medication relatedtoCD.InourDepartment,CDmanagementfollows ECCOguidelines.²¹

Primary outcome was defined asCD activity measured byCDAI.Thisindexisanumericalcalculationderivedfrom thesumofeightitems,each consideredafteradjustment with a weighting factor. CDAI items include: number of liquid or very soft stools, abdominal pain score, general wellbeing, symptoms related to CD (arthritis or arthral- gia,iritisoruveitis,mucocutaneouslesions(e.g.erythema nodosum, pyoderma gangrenosum, aphthous stomatitis), anal disease (e.g. fissure, fistula), external fistula (e.g.

skin, bladder,vagina),fever >37.8^◦C), antidiarrhealmed- icationsuse,abdominalmass,47minushematocrit(males) or42minushematocrit(females)and1−x(1−bodyweight dividedbyastandardweight).¹⁹PatientswhohadCDAI≥150 wereaccepted ashaving activedisease, whilst CDAI<150 definedclinicalremission.³

2.3. Statisticalanalysis

Continuousvariableswerereportedasmeanandstandard deviation (SD), if normally distributed, or median and

interquartilerange(IQR),ifnon-normallydistributed.Cate- goricalvariableswerereportedasabsolutenumber(n)and proportion(%).

Group comparisons of continuous variables were performed using Student t-test or Mann---Whitney test, as appropriate. ² test or Fisher’s exact test were used for groupcomparisonsofcategoricalvariables.

Logisticregression wasused tostudy associationswith theprimaryoutcome. Selectionof variablesfor multivari- ateanalysiswasbasedonclinicallyrelevantknowledgeand univariatecomparisonsyieldingap<0.15.Aforwardstep- wiseprocesswasusedfor theselection ofvariablestobe includedinfinalmodels.Collinearbehaviorwasstudiedand corrected where applicable.Models’discriminative ability wasassessedbyc-statistic.

A RDW cutoff point with clinical utility was studied throughanalysisofthecoordinatepointsofROCcurve.Sen- sitivity,specificity, negativepredictivevalue, andpositive predictive value were calculated for the selected cutoff point.

All statistical tests were two-sided and a p<0.05 was consideredtobesignificant.

StatisticalanalyseswereperformedusingSPSS^®,version 20.0(IBM,NewYork).

3. Results

3.1. Baselinecharacteristics

During the study period considered, 119 patients were included. Females comprised56.3% (n=67)andmean age was47years(SD,15.2years).

AccordingtotheMontrealclassification,²⁰thepredomi- nantfeaturespresentfromtheonsetofdiseasewereanage between17and40years(A2)(n=67;56.3%);terminalileal disease location(L1) (n=62; 52%);and non-stenosing and non-penetratingdiseasebehavior(B1)(n=66;56%).Perianal diseasewasdiagnosedin24%(n=28)ofpatients.

Thiopurinesandanti-tumornecrosisfactor-␣(anti-TNF-

␣) drugs were in use by 40.3% (n=48) and 21% (n=25), respectively(with8.4%(n=10)patientstakingbothdrugs).

BaselinecharacteristicsaredepictedinTable1.

Anemia(definedashemoglobin<13g/dLifmalegender;

orhemoglobin<12g/dLiffemalegender)²² waspresent in 29.4%(n=35)ofpatients.

ThemedianRDWwas14.0(13---15);themedianCRPwas 1.0mg/dL(1.0---3.75)andmeanESRwas33mm.

Concerning CD activity measured by CDAI, 17% (n=20) ofCDpatientshadactivedisease(CDAI≥150)whereas83%

(n=99)wereinclinicalremission.

TenpatientswithCDAI≥150hadCRP≥1.0mg/dL.

3.2. Univariateanalysis

Inunivariatecomparisons,RDW(14.5(13---17)vs13(13---14);

p=0.044),andanti-TNF-␣drugs(40%vs17%;p=0.044)were theonlyfactorsassociatedwithCDAI≥150.

AlbeitnotstatisticallysignificantassociatedwithCDAI, there was a trend toward association between age, ileocolic location,perianal diseaseandhemoglobinvalue and activedisease(Table1).Theothervariablesanalyzed,with

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Table1 OverallbaselinecharacteristicsandunivariatecomparisonsbasedondiseaseactivitymeasuredbyCDAI.

n(%),mean(SD),ormedian(IQR) CDAI<150 p-Value

Total CDAI≥150 (n=99)

(n=119) (n=20)

Gender,female 67(56.3%) 13/20(65%) 54/99(54.5%) 0.39

Age,years 47(15.2) 48(15.3) 41(14.2) 0.076

Ageatdiagnosis,years 36.49(14.87) 32.3(11.75) 37.35(15.34) 0.168

<16years 6(5%) 1/20(5%) 19/20(95%) 1.0

17---39 67(56.3%) 13/20(65%) 7/20(35%) 0.39

≥40 46(38.7%) 6/20(30%) 14/20(70%) 0.38

Location,n(%)

Ileal 62(52%) 8/20(40%) 54/99(55%) 0.24

Colonic 15(13%) 2/20(10%) 13/99(13%) 1

Ileocolic 38(32%) 10/20(50%) 28/99(28%) 0.06

Uppergastrointestinaltract 16(13%) 3/20(15%) 13/99(13%) 0.73

Behavior

Non-stenosing,non-penetrating 66(55%) 13/20(65%) 53/99(53%) 0.35

Stenosing 28(24%) 3/20(15%) 25/99(25%) 0.32

Penetrating 25(21%) 4/20(20%) 21/99(21%) 1

Perianaldisease 28(24%) 8/20(40%) 20/99(20%) 0.06

Therapeutic

5-ASAsolely 34(28.6%) 0 34/99(34%) 0.001

Thiopurine 48(40.3%) 10/20(50%) 38/99(38%) 0.33

Anti-TNF-␣drugs 25(21%) 8/20(40%) 17/99(17%) 0.02

Laboratoryvalues

RDW(n=119) 14.0(13---15) 14.5(13---17) 13(13---14) 0.044

RDW≥16(n=119) 18(15.1%) 6/20(30%) 12/99(12%) 0.042

Hgb(g/dL)(n=119) 12.96(1.9) 12.27(1.8) 13.11(1.9) 0.07

Anemia(n=119) 35(29.4%) 8/20(40%) 27/99(27%) 0.26

MCV(fL)(n=117) 89.4(7.8) 88.9(9.5) 89.56(7.44) 0.73

PLT(uL)(n=118) 286200.85(102750.04) 298300.00(91909.6) 283731.63(105087.6) 0.57 WBC(uL)(n=119) 7344.66(2849.9) 7490.35(3636.03) 7315.2(2685.38) 0.80 CRP(mg/dL)(n=60) 1.0(1.0---3.75) 1.0(0---4.75) 1.0(1.0---3.25) 0.69

ESR(mm)(n=75) 33.44(25.82) 33.92(32.46) 33.35(24.68) 0.95

n,frequency;SD,standarddeviation;IQR,inter-quartilerange;CDAI,Crohn’sdiseaseactivityindex;RDW,redcelldistributionwidth;Hgb, hemoglobin;WBC,whitebloodcellcount;PLT,plateletcount;Anti-TNF-␣,anti-tumornecrosisfactor-␣;ESR,erythrocytesedimentation rate;CRP,C-reactiveprotein.

Anemiawasdefinedashemoglobin<13g/dLifmalegender;orhemoglobin<12g/dLiffemalegender.

aspecialfocusonCRPandESR,werenotsignificantlydif- ferentbetweenpatientswithCDAI<150andpatientswith CDAI≥150.

3.3. Multivariateanalysis

Inmultivariateanalysis,afteradjustingforageandgender, RDWwasassociatedwithCDAI≥150.Inthesub-population ofpatientswithoutanemia,RDWwasalsoassociatedwith CDAI,evenafteradjustingforageandgender(Table2).

Subsequently,inordertobetterstudytheassociationof RDWwithCDAI≥150, threefurthermodelswerederived.

AsdepictedinTable3,RDWwasindependentlyandconsis- tentlyassociatedwithCDAIafteradjustingforhemoglobin andESR(Model1),orileocolicandperianaldisease(Model 2),oranti-TNF-␣therapy(Model3).

Finally, through analysis of coordinate points of ROC curve, the cutoff16% was deemed the bestin prognosti- catingactivedisease(AUC0.64:95%CI:0.5---0.78);inherent sensitivity,specificity,negativepredictivevalue,andposi- tivepredictivevalueof30%,88%,86%and33%,respectively (Fig.1).

4. Discussion

Inthistransversalstudy,wefoundthatanincreaseinRDW, asimpleparameter thatis reportedaspart ofa standard completebloodcount,wasassociatedwiththeseverityof Crohn’sdisease,assessedbyCDAI.

This association remained consistent after adjustment for clinical, laboratory parameters and therapy (age, gender,diseaselocation,perianaldisease,hemoglobinand

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Table2 IndependentindicatorsassociationwithactiveCDbymultivariatelogisticregressionanalysis.

Indicator CDpatients CDwithoutanemia

OR(95%CI) p-Value OR(95%CI) p-Value

RDW 1.20(1.03---1.39) 0.016 1.59(1.10---2.31) 0.014

Gender 1.42(0.50---4.05) 0.510 3.06(0.6---15.6) 0.178

Age 0.97(0.93---1.02) 0.065 0.99(0.94---1.04) 0.614

MultivariatelogisticregressionanalysisforRDW,gender,age,andhemoglobin.

RDW,redcelldistributionwidth.

Table3 MultivariatelogisticregressionanalysisfortheassociationbetweenRDWandCDAI.

Model1 Model2 Model3

OR(95%CI) p OR(95%CI) p OR(95%CI) p

RDW 1.36(1.08---1.72) 0.01 1.18(1.03---1.35) 0.017 1.19(1.03---1.37) 0.017

ESR 0.99(0.96---1.02) 0.38

Hemoglobin 1.04(0.70---1.53) 0.85

Ileocolicdisease 2.09(0.74---5.9) 0.165

Perianaldisease 2.27(0.77---6.69) 0.138

Biologictherapy 3.33(1.13---9.78) 0.029

RDW,redcelldistributionwidth;ESR,erythrocytesedimentationrateOR,oddsratio;CI,confidenceinterval.

Model1:2test9(degreesoffreedom:3);p=0.030;areaunderROCcurve:0.73(95%CI:0.58,0.89);n=75patients.

Model2:2test11(degreesoffreedom:3);p=0.012;areaunderROCcurve:0.71(95%CI:0.58,0.84);n=119patients.

Model3:2test10.5(degreesoffreedom:2);p=0.005;areaunderROCcurve:0.70(95%CI:0.55,0.84);n=119patients.

1,0

0,8

0,6

0,4

0,2

0,0

0,0 0,2 0,4 0,6 0,8 1,0

1 - specificity

Sensitivity

Figure1 ROCcurveforRDW(theareaunderthecurveis0.64, p=0.04).ROC,receiveroperatingcharacteristic.

erythrocyte sedimentation rate, and anti-TNF-␣ drugs).

Theseresultsareinlinewithpreviousrecentresults.^9,17,18,23 Themechanismsthatmediatetherelationshipbetween highRDWvaluesandincreasedCDactivityarestillunknown.

An elevated RDW is commonly found when there is a nutritionaldeficiency,such asiron,folate,or vitamin B12 deficiency.²⁴ Also, conditions that cause more immature

cellstobereleasedintothebloodstream(severebloodloss), abnormalhemoglobins(e.g.sicklecellanemia),orhemol- ysiscanalsomodifytheshapeofredbloodcells,resulting froman increased RDW.²⁵ Also,it hasbeen demonstrated thatachronicinflammatorystatemaycontributetoineffec- tiveerythropoiesiscausingimmatureerythrocytestoenter thecirculation,resultinginelevated RDW.Severalmecha- nismsarebelievedtomediatetherelationshipbetweenthe chronic inflammatory state and ineffective erythropoiesis leadingtoelevatedRDW.^26,27Proinflammatorycytokineslike tumor necrosisfactor-␣and interleukin-6mayhinderery- thropoiesis via directsuppression of erythroidprecursors, promotionofapoptosisofprecursorcells,enhancementof erythropoietin resistance in the precursor cell lines and reductionin bioavailabilityof ironforhemoglobinsynthe- sis.Higheroxidativestressmayreduceerythrocytelife-span andthusmayresultinanisocytosisduetoanincreaseinthe proportionofcirculatingprematureerythrocytes.^26---28

ThemajorityofpatientsobservedintheIBDoutpatient clinicwereinclinicalremission,assessedbyCDAI.Only17%

wereconsideredtohaveactivedisease,despitethefactthat 45%ofpatientshadcomplicatedCD,definedasstricturing orpenetratingbehavior.

One interesting finding was that median CRP value was 1mg/dL both in patients in clinical remission and in patientswithactivedisease,whichisnearthenormalvalue (<0.3mg/dL). As CRP is considered an objective marker of inflammation,⁵ the lowvalue may beexplainedby low inflammatoryactivitydespitehavingactivediseaseaccord- ingtoCDAI.

Inthisstudy,weanalyzedtheassociationbetweenhema- tologicalparameters(includinghemoglobin,MCV,RDW,PLT,

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andWBC),CRP,andESRwithCDAI.Throughunivariatecom- parisons, we demonstrated RDW was the only laboratory parameterindependentlyassociatedwithCDAI.

Multivariate logistic regression analysis revealed that RDW was associated with CDAI considering all patients included in the study (anemic and non-anemic patients), evenafteradjustingfordemographicdata(ageandgender).

Theseresultsweresimilarinthesub-populationofpatients without anemia,which is an importantfindingthat is not completelyunderstood.

Song et al.¹⁷ reportedidentical results. In their study, theyshowedRDWwashighlycorrelatedwithdiseaseactivity innon-anemicpatientsaswellasanemicpatientswithIBD.

InthestudyperformedbyCakaletal.,²³itwasalsofound thatRDWwassignificantlyelevatedinpatientshavingactive IBDcomparedwiththosewithoutactivedisease.

Furthermore,hemoglobinandESR,ileocolicandperianal disease,andanti-TNF-␣therapydidnotconsiderablymod- ifytheassociation betweenRDWandCDAI.Itisparticular relevantthefactthattheassociationbetweenRDWandCD activitywasindependentofanti-TNF-␣drugs.Wedothink thisfindingmaybeduetoa moreseverediseasewhichis indeedmoredifficulttocontrol.

TheseresultsareinlinewiththeonesreportedbySong and colleagues.¹⁷ In multivariate analysis, after adjusting forpatientdemographicsandhematologicparameters,the authorsshowedRDWwasassociatedwithCDAI≥150.

Finally,thisstudy revealedRDWcutoffof16%hadhigh specificityandnegativepredictivevaluefordeterminingthe diseaseactivityinCDpatients,albeitwithalowsensitivity.

The low positive predictive value maybe due to thelow prevalenceofprimaryoutcome.

In the study performed by Yesil etal.,¹⁸ a RDWcutoff of14.7hadasensitivityof 45%andaspecificityof96%in detectingactiveCD.However,intheCakaletal.’s²³ study aRDWcutoffof14.1showed78% sensitivityandonly63%

specificitytodetectactiveCD.

4.1. Strengthsandlimitations

Thisstudyhassomelimitationsthatmaybereferred.

First, this is an observational study performed in one hospitalonly. Forthis reason,it ispronetoselection bias andlimitedgeneralization.Second,thesizeofourpopula- tionwithactivediseasewassmallduetothefactthatall patientsincluded werein outpatientsetting.Futurestud- ieswithalargerpopulationofactiveCDpatientswillallow to accurately identify the degree of RDW increase which revealsactivedisease.Third,ironstatuswasnotdetermined (which,asdiscussedabove,mayinfluenceRDWvalues).

Strengthsofthisstudyincludethefactthatallpatients includedwereinoutpatientsettingandassociationbetween RDW and CDAI was adjusted for clinical and laboratory parametersthatarerelevantindailyclinicalpractice.

Second,RDWisroutinelymeasuredbyautomatedhema- tology analysers and is reported as a component of the complete blood. Thus, testing RDW is easy to perform, affordableanddoesnotrequireanyadditionalcosts.

Ifinfutureoflargeprospectivestudies,RDWisconfirmed tobean accurateparameter for diseaseactivitymonitor- ing, this could impact positively outpatient IBP patients’

surveillanceanddecisionmaking.

5. Conclusion

Inconclusion,inthisstudywedemonstratedRDWwasasso- ciated with the severity of Crohn’s disease, assessed by Crohn’sdiseaseactivityindex.TheRDWcutoff16%showed possibleclinicalapplicability.

Conflicts of interest

Theauthorshavenoconflictsofinteresttodeclare.

Ethical disclosures

Protection of human and animal subjects.The authors declarethat the proceduresfollowed were inaccordance withtheregulationsoftherelevantclinicalresearchethics committeeandwiththoseoftheCodeofEthicsoftheWorld MedicalAssociation(DeclarationofHelsinki).

Confidentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthepublica- tionofpatientdata.

Righttoprivacyandinformedconsent.Theauthorshave obtainedthe written informed consentof the patients or subjectsmentionedinthearticle.Thecorrespondingauthor isinpossessionofthisdocument.

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