Translation and initial validation of the Medication Adherence Report Scale (MARS) in Italian patients with Crohn's Disease

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Contents lists available atScienceDirect

Digestive

and

Liver

Disease

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d

Translation

and

initial

validation

of

the

Medication

Adherence

Report

Scale

(MARS)

in

Italian

patients

with

Crohn’s

Disease

Maria

Lia

Scribano

a

_,

_Flavio

_Caprioli

b,c

_,

_Andrea

_Michielan

d

_,

_Antonella

_Contaldo

e

_,

Antonino

Carlo

Privitera

f

_,

_Rosa

_Maria

_Bozzi

g

_,

_Emma

_Calabrese

h

_,

_Fabiana

_Castiglione

i

_,

Antonio

Francesco

Ciccaglione

j

_,

_Gianfranco

_Delle

_Fave

k

_,

_Giorgia

_Bodini

l

_,

Giuseppe

Costantino

m

_,

_Robert

_Horne

n,o

_,

_Silvia

_Saettone

p

_,

_Paolo

_Usai

q

_,

_Piero

_Vernia

r

_,

Sara

Di

Fino

s,∗

_,

_Giuliana

_Gualberti

s

_,

_Michela

_di

_Fonzo

s

_,

_Rocco

_Merolla

s

_,

Ambrogio

Orlando

t

_,

_The

_SOLE

_Study

_Group

a_IBD_Center,_San_{Camillo-Forlanini}_Hospital,_Rome,_Italy

b_{Gastroenterology}_and_Endoscopy_Unit,_Fondazione_IRCCS_Ca`_Granda,_Maggiore_Hospital,_Milan,_Italy c_Department_of_{Pathophysiology}_and_{Transplantation,}_Università_degli_Studi_di_Milano,_Italy

d_Department_of_Surgery,_{Gastroenterology}_and_Digestive_Endoscopy_Unit,_Santa_Chiara_Hospital,_Trento,_Italy e_{Gastroenterology}_Unit_DETO,_Hospital_of_Bari,_Bari,_Italy

f_IBD_UNIT,_Emergency_Hospital_{“Cannizzaro”,}_Catania,_Italy

g_{Gastroenterology}_and_endoscopy_unit,_ASL_Benevento,_Benevento,_Italy

h_{Gastroenterology}_Unit,_Department_of_Systems_Medicine,_Università_degli_Studi_di_Roma_“Tor_Vergata”,_Rome,_Italy i_{Gastroenterology,}_Department_of_Clinical_Medicine_and_Surgery,_Università_“Federico_II”,_Naples,_Italy

j_{Gastroenterology,}_“S._Spirito”_Hospital,_Pescara,_Italy k_{Gastroenterology,}_S._Andrea_Hospital,_Rome,_Italy

l_{Gastroenterology}_unit,_San_Martino_Hospital,_University_of_Genoa,_Genoa,_Italy

m_IBD-Unit,_Clinical_Unit_for_Chronic_Bowel_Disorders,_Department_of_Clinical_and_Experimental_Medicine,_University_of_Messina,_Messina,_Italy n_Centre_for_Behavioural_Medicine,_UCL_School_of_Pharmacy,_University_College,_London,_UK

o_Centre_for_Advancement_of_Sustainable_Medical_Innovation_(CASMI),_London,_UK p_SCDO_{Gastroenterology,}_Hospital_“Maggiore_della_Carità_di_Novara”,_Novara,_Italy q_{Gastroenterology,}_Hospital_of_Cagliari,_Cagliari,_Italy

r_{Gastroenterology,}_Sapienza,_Università_di_Roma,_Rome,_Italy s_AbbVie,_Rome,_Italy

t_Chronic_{Inﬂammatory}_Bowel_Disease_Dept._Unit,_Hospital_”Villa_Soﬁa_–_Cervello”,_Palermo,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received8May2018 Receivedinrevisedform 20September2018 Accepted21September2018 Availableonlinexxx Keywords: Crohndisease MARS-5 Medicationadherence Translationvalidation

a

b

s

t

r

a

c

t

TheMARS-5(MedicationAdherenceReportScale)wasdevelopedinEnglish.Theaimofthisproject wastoanalysetheMARS-5I(©ProfRobHorne)psychometricpropertiesandtoidentifywhetherits ItaliantranslationissuitableforassessingmedicationadherenceinCrohnDisease(CD)Italianpatients. TheMARSwastranslatedandlinguisticallyvalidatedinItalian.TheMARS-5Iwasusedforevaluating medicationadherenceintheSOLEstudy,conductedinItalyon552subjectswithCD.Inorderto un-biasthequestionnaireresultsfromtheeffectsoftreatmentchangeand/oreffectiveness,theanalyses wereperformedonthe277patientswhosediseaseactivityremainedstable,selectedamongthe371 patientswhomaintainedthesametreatmentbetweentwoconsecutivevisits.Internalconsistencywas high(Cronbach’salphaof0.86).Pearson’scorrelationcoefficientwas0.50(p<0.001)and0.86(p< 0.001-outliersremoved),indicatingsatisfactorytest-retest.MARS5IscoreswerenotcorrelatedwithTreatment SatisfactionQuestionnaireforMedicationbutasmallandstatisticallysignificantcorrelationwasshown withphysician-evaluatedmedicationadherence,indicatingconvergentvalidity.MARS-5I,theItalian translationoftheEnglishMARS,showedsatisfactoryinternalconsistencyandtest-retest,andalowbut statisticallysignificantconvergentvalidity.WeconfirmedtheutilityofthistoolinpatientswithCD.

∗ Correspondingauthorat:AbbVieSrl,Vialedell’arte25,00144,Roma,Italy E-mailaddress:sara.diﬁno@abbvie.com(S.DiFino).

https://doi.org/10.1016/j.dld.2018.09.026

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1. Introduction

Crohn’sdisease(CD)isachronicinﬂammatorycondition affect-ingthegastrointestinaltract,characterizedbyperiodsofremission andﬂare-ups[1].Althoughreliableepidemiologicalstudies regard-ingthisclinicalconditionarenotavailableinItaly,CDhasbeen consideredtohaveanationwideincidencerangingfrom2.3to5.8 per100,000inhabitants[2,3].Morerecentlyastudycarriedouton theentirepopulationoftheItalianregionLazioreportedan inci-denceof7.0per100.000inhabitants[4].Thesedatasuggestthat theincidenceofCDinItalymaybehigherthanpreviously antic-ipated.PatientssufferingfromCDareoftenyoung,thereforewill beartheburdenofthediseaseformanyyears,withamajorimpact ontheirdailyactivities,productivityandqualityoflife.

ThemanagementofCDhasbeenprofoundlymodiﬁedbythe introductionofbiologictreatments,inparticularbytheavailability ofTumour-Necrosis-Factor-␣(TNF-␣)inhibitors.TNF-␣inhibitors haveprovenhighlyeffectiveinCD,reducingratesofhospitalization andsurgery[1,5].However,despitetheavailabilityofsucheffective agents,CDtreatmentremainsoftensuboptimalandﬂaresremain partlyuncontrolled[6].

Ithasbeenrecentlydemonstratedthatnon-adherenceto pre-scribedlong-termtreatmentisamajordeterminantoftreatment efficacyininflammatoryboweldisease(IBD)patientsand repre-sentsacommonprobleminIBDmanagementinclinicalpractice. Thefrequencyofnon-adherencerangesfrom18to30%asreported in several recent international trials [7–10]. In a recent study ofpotentialtriggersforIBDflares,whichincludednon-steroidal anti-inflammatorydruguse, antibioticuse, stressful life events, cigarette smoking,infections, travel in thepreceding 3months, andmedicationadherence,onlythelastoneresultedtobe signifi-cantlyassociatedwithflares[11].Thesefindingsareincentivesto improvemedicationadherence,andtosetuptoolsformeasuring thisparametereasilyinreallifeIBDsettings.

Sinceonlyasingletrialregardingtreatmentadherencein Ital-ianCDpopulationhasbeenpublishedsofar[12],weincludedthis evaluationintheSOLEstudy(SurveyonqualityOfLifeinCrohn’s patiEnts)protocol.

Amongthemethodsfor assessingadherencebehaviour, self-reportmeasures are themostcommonly used in research and clinicalcare[13].Theyrepresentthemostpracticaltoolfor mea-suring adherence, with their easy and ﬂexible administration, low-cost,andminimalpatientburden.Self-reportedmeasuresof adherencecan provide valuable estimates of medication dose-takingbehaviourandinformationregardingpsychosocialfactors relatedwithadherence(suchasreasonsfornon-adherenceand attitudes/beliefstowardmedicines)[13].

Nevertheless,self-reportedmeasureofadherencecanbe fre-quentlyinaccurate,becausepatientsoftenfailtorecollectwhether theytookthedrugornot,andtendtoover-reporttheiradherence, duetothesocialdesirabilityofhighadherencelevels.Forthese reasons,self-reportscalesresultscansufferfromaceilingeffect, withthemajorityofrespondentreportinganunrealistic perfect adherence[13].

Beingawareofself-administeredadherencemeasures advan-tagesanddisadvantages,wedecidedtoadoptoneofthesetools in ourprotocol, since weconsidered ease of useand low bur-denforpatientsandinvestigatorsoutweighingtheirdrawbacks. Amongtheavailabletoolswechosethe5itemsMedication Adher-enceReportScale(MARS-5-©ProfessorRobHorne),awidelyused simpleself-administeredquestionnaire[14].

TheMARS-5isaimedtocollectinformationregardingpatient’s levelofadherencetotheprescribedpharmacologicaltherapy.Itis agenerictool,whichcanbeadministeredregardlessofthedisease andtheprescribeddrug.Ithasbeenvalidatedsofarindifferent clinicalsettings,namelystatintherapy[15],rheumatoidarthritis

[16],asthma[17],psychosis[18],andhasbeenusedforassessing adherenceinmanyclinicalstudiesworldwide[19–37].

The MARS-5 consists of 5 items describing non-adherent behaviours (“Iforget totakethe medicine/ I alter thedoseof medicine/Istoptakingthemedicineforawhile /Idecidedto missoutadose/Itakelessthaninstructed”):patientsareasked toevaluatehowoftentheyadopteachbehaviourwitha5point scale,rangingfrom“always”to“never”(1–5points).Thescaletotal score rangesfrom 5(lowest adherence)to 25 points(maximal adherence).

TheMARS-5wasoriginallydevelopedinEnglish[14],andhas beentranslatedinGerman,Swedish,andPortuguese[38–40].Due tothelackofanItalianversionoftheMARS-5(MARS-5I©Prof.Rob Horne),thescalewastranslatedbeforeSOLEstudystartandthe Italiantranslationperformedlinguisticvalidation.Theaimofthis projectwastoanalysetheMARS-5Ipsychometricpropertiesand toidentifywhetheritsItaliantranslationisasuitableinstrument forassessingmedicationadherenceinCDItalianpatients,inorder tobeabletohaveafastandsimpletooltoquantifythepatients’ compliance.

2. Materialsandmethods

2.1. TheMARS-5Ilinguisticvalidation

TheMARSwasoriginallytranslatedintoItalianbytwo indepen-dentprofessionaltranslators.Thetranslationswerethendiscussed duringaconsensusconference,whichboththetranslatorsattended alongwiththreesupervisinggastroenterologists.Duringthe con-ferencethetwotranslationswereevaluated;theoneconsidered moreclearandaccuratewasselectedandconsequentlyamended accordingtosuggestionsmadebythephysicians.

The ﬁnal Italian translation was then back translated into Englishbyamothertongueprofessionaltranslator;theback trans-lationwasapprovedbytheMARSoriginator,ProfessorRobHorne, and then tested in a group of 15 patients. The patients were askedtoanswertheMARS-5Iitemsand toreportanydifﬁculty inunderstandingthem.Followingthiscomprehensionevaluation, nofurtheramendmentstotheMARS-5Iwererequired.

2.2. TheSOLEStudy

ThevalidatedMARS-5Iwasthenusedforevaluatingmedication adherenceintheSOLEstudy,alargemulticentresurvey,conducted inItalyin38referralcentres,onadult(≥18years)subjectswitha diagnosisofactiveCD,prospectivelyrecruited overa12-month observationperiodbetweenSeptember2011andNovember2013 (n=552),withvisitsscheduledatbaseline,3,6and12months.

Patient’s disease activityin SOLEstudy was measured with Harvey-BradshawIndex(HBI),aﬁvequestions,simpliﬁedversion oftheCrohn’s DiseaseActivityIndex[41].HBIindextotalscore rangesfrom0 to>16, withscores<5indicating remission, and scores>16indicatingseveredisease.InSOLEstudyHBIscoreat enrolmenthadtobe≥8(moderate-to-severedisease).

PrimaryobjectiveoftheSOLEstudywastoevaluatethe qual-ityof life (QoL)evolution during thestudyand itsrelationship withthepatients’workingcapabilityandproductivity.Secondary objectivesweretodeterminetherelationshipbetweenQoLand dis-easeactivity,patientsatisfactionandcompliancewithtreatment, toassessthestructuralandorganizationalvariablesoftheinvolved gastroenterologycentres,toestimatethecostofillnessofCDina 12monthsperiod,andtoassessitsrelationshipwithQoL. 2.3. TheMARS-5Ievaluation

HerewepresentsomeadditionalanalysesofSOLEstudyresults conductedtoevaluatetheMARS-5I.

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SincetheSOLEstudywasanepidemiologicalstudy,conducted asperclinicalroutine,withnoobligationstoprovidethepatients withanyparticulartreatmentatanytimepoint,thewhole pop-ulation(552pts) consistedofpatientswithallcombinationsof treatmentsandstartdates.Inordertoeliminatethebiasdueto theeffectsofatreatmentchangeand/ortherelevanteffectiveness onthequestionnaire,weconductedtheseanalysesonasubgroup of277patients,whosediseaseactivity(measuredwithHBIindex) remained quitestable (HBI score _±4), selected among the 371 patientswhomaintainedthesametreatmentbetweentwo con-secutivevisits(visit2andvisit3,at3and6monthsfromstudy startrespectively).Thisisparticularlyimportantforthetest-retest reliabilitythatisameasureofhowmuchtheresultsobtainedwith ascaleareconsistentacrosstime.Itismeasuredbyadministering atesttwice,attwodifferenttimepoints,supposingthemeasured phenomenonhasnotchanged.MARS-5Iwassubjectedto statis-ticalanalysisinordertoevaluateinternalconsistency,test-retest reliability,andconvergentvalidity.

2.3.1. Internalconsistency

Whendifferentitemsareusedtoformascale,suchinthe MARS-5I,theyneedtohaveinternalconsistency.Inotherwords,they shouldbecorrelated withoneanother,allmeasuringthesame thing(adherence).TomeasuretheMARS-5Iinternalconsistency weusedtheCronbach’salphacoefﬁcient,whichrangesfrom0(the itemsareindependent)to1(theitemsareperfectlycorrelated). Valuesof0.7-0.8aregenerallyregardedassatisfactory[42]. 2.3.2. Test-retestreliability

Test-retestreliabilityismeasuredbythecorrelationcoefﬁcient betweentheresultscollectedattwodifferenttimepoints.

ForevaluatingtheMARS-5Itest-retestreliability,wecompared theresultsofSOLEstudyvisits2and3(3monthsintervalbetween the two visits, always on the subpopulation remaining onthe sametreatmentand witha modestHBIchange)and calculated thePearson’scorrelationcoefﬁcient.Pearson’scoefﬁcientvalues rangesfrom−1to1,with1indicatingaperfectcorrespondence betweenthetwotests,and0indicatingnocorrespondence.We usedathresholdof0.8toconsidertheMARS-5Ireliable.

The MARS-5I reproducibility was also evaluated using Bland–Altman plot [43]. This plot is used for comparing two differentmeasuresofthesamenature;itconsistsinadispersion diagramwiththedifferencebetweenthetwomeasuresonY-axis, andthereferencevalueobtainedcalculatingthearithmeticmean ofthetwovaluesonX-axis.Thehorizontallinesrepresentthemean ofdifferences,andthemeanofdifferences±2xSD.Bland–Altman plotconsistsoftheinvestigator’sopinion:ifthemeanvariationin theconﬁdenceinterval isnotrelevant,thetwo methodscanbe consideredinterchangeable.Itisnotbasedoncriticalvalues,but onexpertopinion.

2.3.3. Validity

InordertoevaluatetheMARS-5Iconvergentvaliditywe con-ductedtwodifferentanalyses.

In theﬁrst one we assumed that resultsobtainedwith this scale correlate withthose obtainedwith anotherscale used in SOLEstudy:theTreatmentSatisfactionQuestionnairefor Medica-tion(TSQM,providingaglobaltreatmentsatisfactionscore).We reliedonthehypothesisthatahighleveloftreatmentsatisfaction isdirectlycorrelatedwithahighleveloftreatmentadherence.The hypothesisiswidelyrecognisedandconﬁrmedbytrialsinmany therapeuticsettings[44–47].Forassessingthehypothesisthata correlationexistsbetweenMARSandTSQMwecalculated Spear-man’srhocorrelation.

InthesecondanalysisweusedSpearman’srhoforassessing thecorrelation betweenMARS-5I results and a physician

eval-Table1

Characteristicsofthestudysample.

MARSvalidation samplea_(n₌₂₇₇₎ Totalpopulationb (n=552) N % N % Gender Male 130 46.93 271 49.09 Female 147 53.07 281 50.91 Ageclass 18–25 47 16.97 72 13.04 26–35 71 25.63 139 25.18 36–45 60 21.66 127 23.01 46–55 64 23.10 130 23.55 >55 35 12.64 84 15.22

Livingwithpartner

Yes 145 52.35 307 55.62

No 132 47.65 245 44.38

Education

Primaryschool 16 5.78 35 6.34

Juniorhighschool 66 23.83 146 26.45

Highschool 154 55.70 287 51.99 University 41 14.80 84 15.21 Employment Employed 158 57.04 300 54.35 Unemployed 119 42.96 252 45.66 Treatment

Notbiologicdrugs 95 34.30 263 51.27

Biologicdrugs 182 65.70 260 47.10

Comorbidities

Yes 184 66.43 352 63.77

Concomitantdiseases

Yes 118 42.60 239 43.30

a_At_the_ﬁrst_considered_visit_(visit_2). b_At_the_ﬁnal_analysis.

uated medication adherence score. In fact, during SOLE study investigatorswererequiredtoevaluatetheirpatients’medication adherencewitha5pointscale,rangingfrom1to5(nevertoalways adherent).ForthisanalysisMARS-5Iscoreswerecategorizedin5 classes(“neveradherent:scores5-9”;“seldomadherent:10–14”; “sometimesadherent:15–19”;“oftenadherent:20–24”;“always adherent:25”).

2.3.4. InﬂuenceofpatientcharacteristicsonMARS-5Iscores Weanalysedallthefactorspotentiallyrelatedwithtreatment adherencewitha logisticregressionmodel.A binomialvariable basedonMARS-5Iscoreswascreated:

• MARSscore<25:lowertreatmentadherence • MARSscore=25:perfecttreatmentadherence

Weconsideredasindependentvariables:gender,age, educa-tion,maritalstatus,employmentstatus,treatment,comorbidities andconcomitantdiseases.Estimateswerecorrectedforthe“centre effect”,duetothepossiblecorrelationbetweensubjectsenrolled bythesamecentre.

3. Results

Amongthe277patientsevaluatedthemajoritywerewomen (53%),and about26%wasbetween26and35 yearsold.52%of patients lived with a partner, 56% had a highschool diploma, 57%wasemployed,66%wastreatedwithbiologicdrugs,66%had comorbidities,and43%concomitantdiseases(Table1).

Themeandiseaseactivityscore(HBI)at theﬁrst considered visit(visit2)was4.9(SD2.6;median5.0;range0–12;interquartile

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Table2

DiseaseactivityandMARS-5Iscoreofthestudysampleatvisit2.

N Mean SD Minimum Maximum 25thPctl Median 75thPctl

HBIindex 277 4.90 2.61 0.00a _12.00 _3.00 _5.00 _7.00

MARS-5I 277 23.73 2.41 5.00 25.00 23.00 25.00 25.0

Pctl:percentile.SD:StandardDeviation.HBI:Harvey–BradshawIndex.MARS:MedicationAdherenceReportScale.MARS-5I:ItalianversionoftheMARS.

a₁₁_patients_with_disease_activity₌₀_at_the_ﬁrst_considered_visit_(visit_2).

Table3

Chronbach’salpharesultsforinternalconsistencyevaluation.

Cronbach’salphavalue(N=277) CompleteMARS-5I 0.86

ExcludingsingleitemsofMARS-5I

Item1 0.85

Item2 0.83

Item3 0.84

Item4 0.82

Item5 0.82

MARS:MedicationAdherenceReportScale.MARS-5I:ItalianversionoftheMARS.

range:3.0–7.0);themeanMARS-5Iscorewas23.7(SD2.4;median 25.0;range5–25;interquartilerange23–25)(Table2).

3.1. Internalconsistency

Internalconsistencywassatisfactory,withaCronbach’salphaof 0.86.Thisvalueisverygood,andfallswithintheGermanvalidation studyinterval(0.67-0.90)[38](Table3).Wealsoreportedalpha valuescalculatedafterexcludingsingleMARS-5Iitems.Items4(“I decidetomissouta dose”)and5(“Itakelessthaninstructed”) seemedtohavealittlehigherweight,i.e.whenexcluded,alpha valuewassmaller.

3.2. Test-retestreliability

Retestevaluationincluded275patientsandthecalculated Pear-son’scorrelationcoefﬁcientwas0.50(p<0.001),quiteasuboptimal result.Fig.1AshowsagraphicalrepresentationofMARSresults pairsobtainedatvisits2and3foreachpatientinthesamplegroup. Themajorityofvalueswasequalto25,buttherewerealsooutlier values,witha reallyhighdifferencebetweenvisit2and 3,that couldbeduetoarealchangeinadherence.

BlandAltmanPlot(Fig.1B)showsthatabout95%ofdifferences fellwithin−5and 5;despitethemeanvaluewasclosetozero (whichindicateagoodreproducibility),variationremainedhigh (±5).Excludingvalueswhichfelloutsidethe±2SDinterval,the obtainedcorrelationcoefﬁcientwas0.86(p<0.001).

3.3. Validity

Theﬁrstanalysisforvalidityevaluation,inwhichTSQM ques-tionnairewasusedascomparator(totalscoreandsubscores),is reportedinTable4.Thecorrelationvalues showedtheabsence ofrelationbetweenthetwoquestionnaires.Thesecondanalysis, inwhichweassessedthecorrelationbetweenthephysician eval-uatedmedicationadherencescoreandMARS-5Iscore,showeda weaklevelofcorrelation(rho=0.15,p=0.014),although statisti-callysigniﬁcant(Table4).

3.4. Incidenceofpatientscharacteristicsonreportedadherence Table5showsresultsofthelogisticmodelweusedtoevaluate thepatientscharacteristicsrelatedwithperfectadherence (“per-fectadherencepredictors”).Patientcharacteristicswhichshowed signiﬁcantcorrelation withadherencewere increasingage (OR

Fig.1.A)ScatterplotofMARS-5Ivaluesatvisit2and3.Linerepresentstheﬁtted regressionbetweenMARSvalues.Circleshavediameterdimensionsproportional tothefrequencyofpairedvalues;B)BlandAltmanplotofMARSscoresdifferences andmeansfortest-retestreliabilityevaluation.Circles’diameterisproportionalto frequenciesofpatientspresentingthesamedifferencesandsamemeans. MARS:MedicationAdherenceReportScale.

Table4

CorrelationbetweenMARS-5IscoresandTSQMscoresorphysicianevaluated adher-encescoresforvalidityanalysis,calculatedwithSpearman’srho.

N Spearman’srho Pvalue TSQM

Generalsatisfaction 276 0.05 0.378 Adverseevents 277 0.03 0.650

Efﬁcacy 276 0.03 0.586

Convenience 276 0.04 0.479

Adherenceevaluatedbyphysicians 277 0.15 0.014 MARS:MedicationAdherenceReportScale.MARS-5I:ItalianversionoftheMARS. TSQM:TreatmentSatisfactionQuestionnaireforMedication.

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Table5

Patientcharacteristicspotentiallyrelatedtoperfecttreatmentadherence(MARS-5I=25).

Subgroupanalysis(n=277) SOLEtotalpopulation(n=466)

OR 95%IC pvalue OR 95%IC pvalue

Gender Male 1.00 1.00 Female 1.11 0.67 1.82 0.681 1.11 0.79 1.55 0.536 Classage 18–25 1.00 1.00 26–35 1.47 0.68 3.19 0.322 1.59 0.76 3.34 0.209 36–45 1.54 0.68 3.51 0.291 1.85 0.96 3.56 0.066 46–55 2.25 1.08 4.70 0.032 1.81 0.93 3.52 0.081 >55 3.38 1.59 7.16 0.002 2.65 1.34 5.23 0.006

Livingwithpartner

Yes 1.74 1.08 2.8 0.024 1.60 1.11 2.30 0.013

No 1.00 1.00

Education

Primaryschool 2.14 0.75 6.16 0.152 2.66 1.24 5.70 0.014

Juniorhighschool 1.16 0.67 2.04 0.572 0.87 0.52 1.45 0.575

Highschool 1.00 1.00 University 2.35 0.98 5.65 0.055 1.59 0.92 2.75 0.093 Employment Employed 1.00 1.00 Notemployed 1.12 0.66 1.88 0.669 0.35 0.62 1.47 0.815 Treatment

Notbiologicdrugs 1.00 1.00

Biologicdrugs 3.73 2.02 6.88 <0.001 3.42 2.23 5.27 <0.001 Speciﬁctreatment

Notbiologicdrugs 1.00 1.00

Inﬂiximab 2.24 1.32 7.95 0.012 2.89 1.52 5.49 0.002 Adalimumab 4.17 2.24 7.77 <0.001 3.85 2.34 3.66 <0.001 Comorbidities No 1.00 1.00 Yes 1.77 0.87 3.61 0.114 1.65 0.97 2.83 0.065 Concomitantdiseases No 1.00 1.00 Yes 1.30 0.76 2.23 0.325 1.26 0.63 1.73 0.156

ResultsofalogisticregressionmodelbasedonabinomialvariablederivedfromMARS-5Iscores:MARSscore<25,lowertreatmentadherence;MARSscore=25,perfect treatmentadherence.Independentvariables:gender,age,education,maritalstatus,employmentstatus,treatment,comorbiditiesandconcomitantdiseases.Estimateswere correctedforthe“centereffect”.MARS:MedicationAdherenceReportScale.MARS-5I:ItalianversionoftheMARS.

forpatients>55years old3.38,95%CI1.59–7.16p=.002),living withapartner(OR:1.74, 95%CI1.08-2.08, p=0.024),and treat-mentwithbiologicdrugsbothconsideringthewholedrugcategory (OR: 3.73, 95% CI 2.02–6.88, p<0.001), and the two different activeingredients[ORforinﬂiximabandadalimumab2.24(95%CI 1.32–7.95,p=0.012)and4.17(95%CI2.24–7.77,p<0.001) respec-tively].Thesefactorswerealsofoundtobesigniﬁcantpredictors forperfectadherenceinthetotalpopulation.

4. Discussion

InouranalysistheItalianversionofthewidelyusedMARSscale showedasatisfactoryinternalconsistency,andthelevelof test-retestreliability wasgood whenexcludingoutlier patients(out of±2SD).Asforvalidityevaluation,alowcorrelationwasshown betweenMARS-5Iandphysicianevaluatedmedicationadherence scores,probablyduetoadifferentperceptionofthepatient’s adher-encefromthephysicianpointofview,whilewefailedtoshowany correlationbetweenMARS-5IandTSQMresults.

It is important to recognise that our study was not origi-nallydesignedforevaluatingtheMARS-5Iscale.Consequentlyour analysespresentseveralimportantlimitationsandarenota com-prehensive evaluation of validity and test-retest reliability. For instance,theselectionofoursamplegroup(n=277),basedonlyon stabilityofdiseaseactivity,couldbebiased.Infact,comparedwith thetotalpopulationofSOLEstudy,inoursampletherewereseveral

discrepanciesinmedicationadherencerelatedcharacteristics.The sub-groupusedfortheMARS-5Ievaluationcomprisedmoremales, morepatientslivingwithoutapartner,withahighlevelof educa-tion,employed,onbiologicdrugs,thanthefullSOLEparticipants, althoughthestatisticalsigniﬁcance ofthesedifferences hasnot beenevaluated.Moreover,inthesubgroupanalysed,MARSscores didnotshowauniformdistribution,butweregenerallyabove20, indicatinggenerallyhighreportsofadherence.

Thestudydesign didnotafford a truetestof assessmentof test-retestreliabilityasthedurationbetweenassessmentswastoo long.Itisreasonabletoassumethat,forsomeparticipants,levels ofadherencemayhavechangedsignificantlyduringthisperiod.In thiscase,lowcorrelationbetweenMARSscoresat1vs3months couldbeareflectionofchangingadherenceratesratherthanlow test-retestreliability.Thefactthattest-reliabilityfigureswere sig-nificantlyhigherafterremovalofoutlierssupportsthisexplanation. BasedonthisdataweconsidertheMARS-5Itohaveadequate test-retestreliability.

IntheGermanandSwedishMARSlinguisticvalidation stud-ies,theintervalsbetweentestsforthetest-retestevaluationwere shorterthaninouranalysis,namely3-4weeksand≥7days respec-tively [38,39]. In the Portuguese study the interval was even shorter, consisting in only 2days [40]. Our interval was much longer,farfromtheidealtimespanof2–4weeks;thiscouldhave resultedinobjectivemajorchangesinpatientscharacteristics inﬂu-encingadherence,suchasgeneralhealthstatusandanxietylevel.

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Moreover, although the disease activity remained quite stable betweenthetwovisits(sincethiswasthemaincriteriaweused toselectthissubgroupofpatients),3monthsisalongenoughtime spanforthetypicalCDseasonalvariations[48]tobeobserved,with apossibleeffectonadherence.

The two validity analysis we conducted gave contradictory results.TheonebasedonMARS-5IcorrelationwithTSQMfailedto proveMARS-5Iconvergentvalidity.Onthecontrary,theonebased onMARS-5Icorrelationwiththephysicianevaluatedmedication adherencescoreshowedalowvalue,neverthelesswithstatistical significance.Theresultsofourfirstanalysiscouldbeduetothe factthatMARSandTSQMscalesassessverydifferentconstructs: thefirstoneassessesareportedbehaviour(reportedadherence), whilethesecondoneassessesaperception(perceptionof treat-mentsatisfaction).Thisdiscrepancyislikelytobethereasonof ourresults.Infact,usingtwoscalesmeasuringthesameconstruct (medicationadherence)suchasMARS-5Iandthephysician evalu-atedmedicationadherencescore,weobtainedafairbetterresult. OurSpearman’sRhovalue(0.15,p<0.014)wassimilartotheone obtainedintheGermanMARSevaluation[38](0.26,p<0.01),in whichaSatisfactionwithInformationaboutMedicineScale (SIMS-D)wasusedasacomparatorforMARS-5Iintheconvergentvalidity analysis.

Our exploratory data examining association between dichotomized MARS and other variables do not constitute a formal test of validity. Yet they are interesting, because they highlightindividual characteristicssigniﬁcantly associated with better reported adherence, allowing us to provide more tar-getedinterventionswiththeaimofsupportingadherenceinour patients.

In previously published studies parameters associated with greateradherencetomedical therapyinIBD patientswereage, follow-up bya gastroenterologist, and immunosuppressantuse [8,9].Lowerratesoftreatmentadherencewereassociatedwith employmentstatus, highscoresontheObstaclestoMedication UseScale,shortdiseaseduration, higheducationlevel, dissatis-factionwiththepatient–doctorrelationship,mooddisorders,and ageyoungerthan40[7–10,49].Moreover,patients’personalbeliefs abouttheIBDanditstreatmentareimportant,potentially modi-fiable,determinantsofbothadherenceandnonadherence[50,51]. AlargestudyofUKpatientswithIBDfoundthatnonadherence wasrelatedtoimplicitevaluationsofmaintenancetreatment,with nonadherencerelatedtodoubtsaboutpersonalneedfor mainte-nancetreatmentand concerns aboutpotential harmassociated withregularuseoverthelong-term[50].Thesefindingssuggest thatinterventionstoimproveadherenceshouldtakeaccountof theperceptions (e.g.medicationnecessitybeliefs andconcerns) aswellaspracticalities(e.g.capabilityandresources)influencing motivationsandabilitytoadheretotreatment[52].Interventions tosupportadherenceshouldthereforeensurethatdoubtsabout personalneedforthemedicationarenotbasedonmisconceptions aboutillnessandtreatment,andthatthepatientsconcernsabout treatmenthavebeenelicitedandaddressed[53].

Ouranalysissuggestsincreasingagemaybeassociatedwith improvedmedical adherence, and highlights for the first time thattreatmentwithbiologicdrugsissignificantlyassociatedwith higherreportedadherenceinCD.Thisisconsistentwithaprevious reportinpsoriasis,whereself-reportedadherencetobiologicswas foundtobesignificantlygreaterthanthatofotherdrugclasses[54]; thereasonsweresupposedtobeahighermotivationduetothe severityofthediseaseand/ortothetrainingpatientsaresupplied ontheuseofbiologics.Thisistruebothforthewholedrugclassand forthetwodifferentactiveingredientsconsideredinouranalysis (infliximabandadalimumab).InCD,adalimumabadherencehas beenreportedtobehigherthaninfliximabinasystematicreview [55].Theobserveddifferencesintheoddsofbeingfullyadherent

betweeninﬂiximabandadalimumabshowedinourstudycouldbe relatedmoretothetypeofadministrationthantothetypeofdrug itself.Infact,physiciansmightbemorepronetoadminister adali-mumabtoadherentpatientsandinﬂiximab,duetoitsintravenous administration,tolessadherentpatients[55].Adalimumab,onthe contrary,canbeadministeredsubcutaneouslybythepatient,after aninitialtraining.

Our analysisrepresentsthefirstattempt tovalidatean Ital-iantranslation ofMARSscaleusingdataofa wide,multicentre, observationalstudy.Wehaveconfirmedtheutilityofthistoolin medicationadherenceevaluationinpatientswithCD,andfor sim-plyfindingthoseathigherriskofreducedadherence,requiringan interventioninordertoimprovetheirtherapeuticoutcomes.

In ourstudy MARS-5I, theItalian translation of theoriginal EnglishMARSscale,showedasatisfactoryinternalconsistencyand alowbutstatisticallysigniﬁcantconvergentvaliditybasedonthe correlationwithaphysicianevaluatedmedicationadherencescore. ThelowlevelofMARS-5Itest-retestreliabilityemergedinthis analysisisprobablyduetothelongtimepassedbetweenthetwo questionnaireadministrations.Furtherstudies,withshorter inter-valsbetweentests,willbeneededtoclarifythispoint.

Acknowledgements

TheauthorswishtothankMartaMentarsiandGianniPaoletta (HavasLifeItaly)for helpin draftingthemanuscript and Laura Timelliforstatisticalanalysis.

Conﬂictofinterest

Nonedeclared.

Funding

AbbVieparticipatedinthedesign,studyconduct,andﬁnancial supportforthestudy,aswellasininterpretationofthedata,review, andapprovalofthemanuscript.

Ethicalapproval

TheSOLEstudyhasbeenapprovedbylocalEthicsCommittees accordingtoItalianregulations.

Informedconsent

Informedconsentwasobtainedfromallindividualparticipants includedinthestudy

Researchinvolvinghumanparticipants

All procedures performed in studies involving human par-ticipantswere in accordance withthe ethicalstandards of the institutionaland/ornationalresearchcommitteeandwiththe1964 Helsinkideclarationanditslateramendmentsorcomparable eth-icalstandards.”

Disclosureofpotentialconﬂictsofinterest

SaraDiFino,GiulianaGualberti,RoccoMerollaareemployees ofAbbVieandmayownAbbViestocks/options.MicheladiFonzo wasemployeesofAbbVie andmayown AbbViestocks/options. M.L.Scribanohasservedasaspeakerand/oradvisoryboard mem-berfor Abbvie, Biogen Idec,Janssen, Mundipharma, Pﬁzer,and Takeda.F.Caprioliservedasconsultantto:Mundipharma, Abb-vie,MSD,Takeda,Janssen,Roche,Celgene;hereceivedlecturefees fromAbbvie,Ferring,Takeda,AllergyTherapeutics,Janssen and

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unrestrictedresearchgrantsfromGiuliani,Sofar,MS&D,Takeda, Abbvie.A.Michielanundertookspeakerengagementswith hon-orariawithAstra Zenecaand ViforPharma. E.Calabrese reports oralpresentations(lectures)forAbbvieandJansen.F.Castiglione reportslectures/meetingboardswithTakeda,AbbVie,MSD,Chiesi, Sofar.G.BodinireceivedlecturefeesfromAbbvie,MSD,Otsuka andTakeda.G.CostantinoreportsattendancetoAdvisoryBoards forAbbvie.Prof.RobHornewassupportedbytheNational Insti-tutefor HealthResearch (NIHR)Collaboration forLeadership in AppliedHealthResearchandCare(CLAHRC)NorthThamesatBart’s HealthNHSTrust.Theviewsexpressedarethoseoftheauthor(s) andnotnecessarilythoseoftheNHS,theNIHRortheDepartment ofHealth.ProfessorHornehasundertakenspeakerengagements withhonorariawiththefollowingcompanies:Abbvie,Amgen, Bio-genIdec,GileadSciences,GlaxoSmithKline,Janssen,Pﬁzer,Roche, ShirePharmaceuticals,MSD,Astellas,Astrazeneca,DRSU,Erasmus andNovartis.ProfessorRobHorneisfounderandshareholderof aUCL-businessspinoutcompany(SpoonfulofSugar)providing consultancyonmedication-relatedbehaviourstohealthcare pol-icymakers,providersandindustry.A.Orlandoreports:servedasan advisoryboardmemberforAbbVie,Janssen,MSD,Takeda Pharma-ceutical;receivedlecturegrantsfromAbbVie,ChiesiFarmaceutici, MSD,Sofar,TakedaPharmaceutical.Thefollowingauthorsdeclare noconﬂictsof interests: A.Contaldo,AC Privitera,RM Bozzi,AF Ciccaglione,G.DelleFave,S.Saettone,P.Usai,P.Vernia.

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