Pruritus and pain constitute the main negative impact of atopic dermatitis from the patient's perspective: a systematic review

     Depósito de Investigación de la Universidad de Sevilla https://idus.us.es/ This is the original submission version (pre-peer review) of the following article: Pruritus and pain constitute the main negative impact of atopic dermatitis from the patient's perspective: a systematic review, Volume 35, Issue 3 Page 216- 234, (2024): May-Jun 2024, which has now been formally published in final form at Dermatitis at https://doi.org/10.1089/derm.2023.0163. This original submission version of the article may be used for non-commercial purposes in accordance with the Mary Ann Liebert, Inc., publishers’ self-archiving terms and conditions. Title:PruritusandPainConstitutetheMainNegativeImpactofAtopicDermatitis FromthePatient’sPerspective:ASystematicReview Authors: JoséCarlosArmario‐Hita,MD,PhD(1)JoseManuelCarrascosa,MD,PhD(2)ÁngelesFlórez,MD, PhD,(3)PedroHerranz,MD,PhD(4),JoséJuanPereyra‐Rodríguez,MD,PhD,(5)EstherSerra‐ Baldrich,MD,PhD,(6)JuanFranciscoSilvestre,MD,(7)MartaComellas,PharmD,PhD,(8)Olga Isidoro,MSc,PhD,(9)andFranciscoJavierOrtizdeFrutos,MD,PhD(10) (1)DermatologyDepartment,HospitalUniversitariodePuertoReal,UniversityofCádiz,Cádiz, Spain; (2)DermatologyDepartment,HospitalUniversitariGermansTriasiPujol,Badalona,Spain; (3)DermatologyDepartment,ComplejoHospitalarioUniversitariodePontevedra,Pontevedra, Spain; (4)DermatologyDepartment,HospitalUniversitarioLaPaz,Madrid,Spain; (5)DermatologyDepartment,HospitalUniversitarioVirgendelRocío,Sevilla,Spain;Schoolof Medicine.UniversidaddeSevilla,Sevilla,Spain; (6)DermatologyDepartment,HospitaldelaSantaCreuiSantPau,UniversitatAutónoma, Barcelona,Spain; (7)DermatologyDepartment,HospitalGeneralUniversitarioDrBalmis‐ISABIAL,Alicante,Spain; (8)OutcomesResearchDepartment,Outcomes’10,Castellón,Spain; (9)MedicalDepartment,Galderma,Madrid,Spain; (10)DermatologyDepartment,HospitalUniversitario12deOctubre,Madrid,Spain.  Correspondingautor: JoséJuanPereyra‐Rodríguez,MD,PhD DermatologyDepartment,HospitalUniversitarioVirgendelRocío Av.ManuelSiurot,S/n,Sevilla41013,Spain Email:[email protected]   Abstract Atopicdermatitis(AD)isaninflammatoryskindiseasecharacterizedbyintenseitchingand highlyvisiblesigns,representingagreatburdentothepatient.Despiteitsstraightforward diagnosis,ADseverityandburdencanbeunderestimatedinroutineclinicalpractice.Thisreview aimstodeterminetheimpactofADonpatients’lives,establishwhichdomainsoflifearemost affected,andidentifysymptomdriversofADburden.Asystematicliteraturereviewwas conductedinPubmed/Medline,WebofScienceandScopusfollowingCochraneandPRISMA recommendations.ObservationalstudiespublishedinEnglishorSpanishbetween January1st2018andAugust31st2022,evaluatingtheimpactofADanditssymptomsfromthe patient’sperspectivewereincluded.Reviewedstudieswereassessedforqualityfollowingthe STROBEChecklist.Atotalof28observationalstudiesevaluatingtheimpactofADandits symptomsfromthepatient’sperspectivewereincludedinthereview.AlldomainsoftheAD patient'slifewerefoundtobegreatlyaffected,includinghealth‐relatedqualityoflife(HRQoL), emotionalhealth,sleepdisorders,workimpairment,health‐careresourceutilization,cognitive function,anddevelopmentofcomorbidities.Themoreseverethedisease,thegreaterthe impact,worseninginpatientswithmoderateandsevereAD.Pruritusandpainarereportedto bethediseasesymptomswiththegreatestimpact.Inconclusion,ADimpactsseveraldomains ofpatients’lives,especiallyHRQoLandmentalhealth.Pruritusandpainareidentifiedasthe maindriversofADimpact,suggestingthatoptimalsymptomcontrolmayreducetheburden andimprovediseasemanagement.  Capsulesummary  Atopicdermatitis(AD)anditssymptomsaffectalldomainsofpatient’slife  PruritusandpainarethemaindriversofADburden  ControllingpruritusandpaininpatientswithADmayreducediseaseburdenposed onpatients’qualityoflife Introduction Atopicdermatitis(AD)isachronicrelapsing‐remittingdisease,typicallypresentingdryskin, eczema,andpruritus.IntheWesternpopulation,ADaffects10%to15%ofchildrenand2%to 10%ofadults1.Clinically,thereisanotablephenotypicvariabilitydrivenbyacomplexunderlying multifactorialpathogenesisinvolvingbothgeneticandenvironmentalfactors,whichinteract withtheskinandtheimmunesystem,leadingtoalossofskinbarrierintegrity,dysregulationof innateandadaptativeimmuneresponses,anddysbiosisoftheskinmicrobiome1‐3.ThemainAD symptoms(pruritus,pain,andsleeploss)andhighlyvisiblesigns(e.g.,redness,flaking,bleeding fromscratching)caninterferewithpatient'sdailylife,impairingtheirpsychosocialandwork capacities,andworseningtheirhealth‐relatedqualityoflife(HRQoL)4‐6.Inthisregard,several authorshaveshownthatmoresevereADsymptomsareassociatedwithahighernegative impactonpatients’lives4,5,7. SeverityofADcanbeassessedusingdifferentclinicalmeasurementscales8.TheInvestigator GlobalAssessment(IGA),SCORingAD(SCORAD)index9andEczemaAreaSeverityIndex (EASI)10havebeenvalidatedforthispurposebuttheiruseindailyclinicalpracticemaybelimited sincetheycanbetime‐consuming8. Alternatively,patient‐reportedoutcomemeasures(PROMs)enablediseaseimpactstobe evaluatedinmanydomainsfromthepatient’sperspective,providinganimportantcomplement toclinicaloutcomes11.Currently,severalvalidatedPROMsareavailable,butmostfocusonthe globalHRQoLimpairmentratherthancomprehensivelyevaluatingtheimpactofthedisease12. PROMswereoriginallydevelopedforclinicaltrials13;consequently,theburdenofADhas frequentlybeenunderestimatedinroutinepractice8,14.However,theuseofPROMsinroutine clinicalpracticehasbeenfoundvaluableinassessingdiseaseimpact11,15. Inviewofalltheabove,wedevisedthepresentsystematicreviewtogatherandsynthesize evidencefortheimpactofADfromthepatient’sperspectiveinclinicalpractice.Additionally,we aimedtodeterminewhichdomainsofthepatient’slifearemostgreatlyaffectedbythedisease andwhichdiseasesymptomshavethestrongestimpact.  Methods Searchstrategy AliteraturesearchwasconductedinSeptember2022intheinternational databasesPubmed/Medline,WebofScienceandScopusfollowingtheCochrane methodology16.StandardizedsearchfiltersandfreetextofMedicalSubjectHeadingtermswere usedwhenpossible.Thissearchwascomplementedbyamanualsearchingreyliteraturesearch engines(i.e.,GoogleScholar;https://scholar.google.es/)anddermatitis‐relatedwebsitessuch astheEuropeanAcademyofDermatologyandVenereology(https://www.eadv.org/)or theHarmonisingOutcomeMeasuresforEczema(http://www.homeforeczema.org/index.aspx). SearchtermsandstrategiesfollowedforeachdatabaseareshowninSupplementatyTable1.  Eligibilitycriteria ObservationalstudiespublishedbetweenJanuary1st2018andAugust31st2022,evaluatingthe impactofADanditssymptomsfromthepatient’sperspectivewereincluded.Onlystudies publishedinEnglishand/orSpanishwereselected. Clinicaltrials,economicevaluations,opinionarticles,letterstotheeditor,conferencepapers, narrativeorsystematicreviews,observationalstudiesfocusedonaspecificdrugandits characteristics,andobservationalstudiesaddressingtheimpactofADfromaperspectiveother thanthepatients’wereexcluded.  Studyselection TwoindependentresearchersselectedthestudiesfollowingthePreferredReportingItemsfor SystematicReviewsandMeta‐Analyses(PRISMA)recommendations17.Discrepancieswere solvedbyconsensusorthroughtheinvolvementofathirdteammember.  Dataextraction Datawereextractedbyoneresearcherandvalidatedbytheotherresearcher.Aspreviously stated,discrepanciesweresolvedbyconsensusorthroughtheinvolvementofathirdteam member. Thefollowingvariableswereextractedfromtheselectedstudies:studydesign(caseseries/case study,cross‐sectional,case‐control,retrospective,prospectivecohort),characteristicsofthe studypopulation(samplesize,typeofpopulation[adult,pediatric,and/oradolescent],mean age,gender,severityofthedisease[severe,moderate,mild;tooltoassessdiseaseseverity]), domainsofpatients’lifeaffectedbythedisease,symptomsthathavethegreatestimpact,study limitations,conclusions.  Qualityassessmentmethodology Thequalityoftheobservationalstudiesreviewedwasassessedaccordingto theSTrengtheningtheReportingofOBservationalstudiesinEpidemiology(STROBE)items18. Qualityassessmentdatawereextractedsimultaneouslywithdatarelatedtothestudy.  Results Articlesselection Theliteraturesearchyielded821citations.Ofthese,382wereeliminatedasduplicatesand399 werediscardedforfailingtomeeteligibilitycriteriaorfornotprovidingrelevantinformation. Afterreviewingthefulltextoftheremainingpublications,atotalof28publicationswere includedinthesystematicreview(Figure1).  Articlesdescription Allpublicationsincludedinthereviewwereobservationalstudies;22(78.6%)hadacrosssectionaldesign,three(10.7%)prospective,two(7.1%)retrospective,andone(3.6%) prospectiveandcross‐sectional(Table1). Qualityassessmentrevealedthat11publications(39.3%)metatleast80%ofSTROBE recommendations.Cross‐sectionalstudiesshowedavariablepercentageofwellreported STROBEitems,rangingfrom55%to91%.Theprospectivestudiespresentedahighpercentage (82‐86%)ofcompliancewiththerecommendations,whileoneoftheretrospectivestudiesonly reportedhalfoftheitemsappropriately.  ImpactofADonpatients’lives Themainfindingsofthereviewedstudiesweregroupedintoeightcategoriesaccordingtothe informationprovidedregardingtheimpactofADonpatients’lives(Table1):patients’HRQoL, emotionalhealth,sleepdisorders,workimpairment,lifestyleandsocialactivities,health‐care resourceutilization(HCRU),comorbidities,andcognitivefunction. Ineachcategory,informationwaspresentedaccordingtoADburden,burdenacrossdisease severityandimpactofdiseasesymptoms. Patients’health‐relatedqualityoflife TwentypublicationscontainingdataabouttheimpactofADonpatient’sHRQoLwereidentified. Tenstudies20,23,30‐32,34,36,40,45,46assessedADburdenintermsofpatients’HRQoL,showingthatAD impairedpatients’HRQoL20,23,30‐32,40,45,46,affectingboththeirphysicalandmentalhealth20,23,40,46. Tostudies34,36focusedonADimpactonHRQoLaccordingtoskinlesionlocation.Both establishedthatlesionsinvisibleareaswereassociatedwithalowerHRQoL.One36ofthese studiesalsoevaluatedtheimpactoflesionsinsensualareas,reportingthattheirpresence negativelyaffectedpatients’HRQoLandincreaseddiseaseburden. Sevenpublications20,22,26,35,39,40,45evaluatedtheburdenofADaccordingtodiseaseseveritywith resultsshowingdiscrepancies.Fourstudies22,26,39,40reportedasignificantlypoorerHRQoLin patientswithsevereAD.Ofthese,onestudy40foundacorrelationbetweenscoresobtained inHRQoLquestionnairesandPatientOrientedEczemaMeasure(POEM)andPatientOriented (PO)‐SCORADscores.Anotherpublication20associatedADseveritywithmentalandphysical impairment.Incontrast,threestudies20,35,45didnotfindastatisticallysignificantassociation betweenADseverityandpatients’HRQoL. Finally,ninestudies24,28‐30,35,37,41,44,45reporteddataontheburdenofADsymptoms affectingHRQoL.Thus,morefrequentandintensepruritusand/orpainwereassociatedwitha poorerHRQoL24,28,29,35,37,41,44.Inaddition,HRQoLimpairmentduetoADsymptomswas associatedwithdepression,sleepimpairment,andsuicidalideation30,35,45. EmotionalHealth TwelvepublicationsreportingdataabouttheimpactofADonemotionalhealthwereidentified. Ninestudies20,23,30‐32,38,42,45,46includeddataabouttheburdenofADonmentalhealth,reporting increaseddepressionandanxietyinpatientswithADcomparedwithcontrols.Oneof thesestudies31alsoshowedthatdiseaseseveritywasassociatedwithahigherprevalenceof suicidalideationinpatientswithADcomparedwithnon‐ADcontrols. Eightstudies20,22,25,27,30,38,42,45evaluatedtheemotionalimpactofADaccordingtodisease severity,reportingcontradictoryresults.Sixstudies22,25,27,30,38,42foundasignificantassociation betweenADseverityandahigherprevalenceofdepressionandanxiety.Incontrast,two studies20,45didnotfindsignificantdifferencesbetweenmildormild/moderateandsevereAD. Lastly,threestudies30,42,45assessedtheemotionalburdenofADsymptoms.Theyshowedthat pruritusandsleepdisturbancewerecorrelatedwithagreaterimpactonpatients’emotional healthdomains,suchasanxietyanddepression. Sleepdisorders Nineofthereviewedpublications20,22,23,29,31,33,35,44,45provideddataabouttheimpactofADon sleepimpairmentandsleepdisorders. Fourstudies20,23,29,31reporteddataaboutthediseaseburden.Threestudies20,23,29founda significantlyhigherpercentageofADpatientswithsleepdisorderscomparedwithcontrols, whilethefourth31didnotfindanyassociationbetweenADandsleepdisturbance. Fivestudies20,22,29,33,35evaluatedtheburdenofADacrossdiseaseseverity,withdiscrepanciesin theirresults.Twostudies22,35foundasignificantlypositivecorrelationbetweenADseverityand sleepimpairment;hence,patientswithmoderate/severeADreportedmoresleepimpairment thanthosewithmildAD.Incontrast,threestudiesdidnotobservethiscorrelation;oneofthe studies20didnotfindanysignificantdifferencesinsleepdisordersbetweenpatientswith moderate/severeandmildformsofAD;onestudy33onlyfoundasignificantassociationofsleep disturbanceandADinpatientswithsevereorverysevereAD;andfinally,onestudy29didnot findanycorrelationbetweenADseverityandsleepdisturbancesinpatientswithAD. Fivestudies29,33,35,44,45investigatedtheburdenofdiseasesymptoms.Threestudies29,33,45founda significantcorrelationbetweenpruritusand//orpainandsleepimpairment.Incontrast,one study35didnotfindthiscorrelation.Finally,onequalitativestudyusingfocusgroupsandpatient interviews44reportedthatpainwasnotalwayslimitedtoonetimeofthedayand,inparticular, itcouldaffectboththepatient’sandotherfamilymembers’sleep. Workimpairment Sevenpublications19‐24,37reportingdataontheimpactofADonworkproductivitywere identified. Twostudies20,23provideddataabouttheburdenofAD.Neitheronefoundsignificantdifferences betweenADpatientsandcontrolsregardingabsenteeism.Overall,bothstudiesfoundsignificant workimpairmentinADpatientscomparedwithcontrols. 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ThyssenJP,HallingAS,Schmid‐GrendelmeierP,Guttman‐YasskyE,SilverbergJI. Comorbiditiesofatopicdermatitis‐whatdoestheevidencesay?JAllergyClin Immunol.2023.  FigureLegends Figure1.PRISMAdiagramshowingthestudyselectionprocess  Figure 1.jpg (Imagen JPEG, 588 × 406 píxeles) https://buzonweb.us.es/correoweb/index.php/login/?_task=mail&_m.. . 1 de 1 12/07/2024, 10:1 4 Table1.Selectedstudiesandmainvariablesextracted Reference Study design STROBE (max.22) Populationsizeand subgroups Affecteddomains PROM Mainresults AndersenL,et al.202019 Crosssectional 16 Population size:1232 Subgroups: 134mild;825 moderate;141 severe1;87severe 2;49severe3 measuredwithPOSCORAD(<25mild; 25‐50moderate; >50severe) Workimpairment WPAI Mildvsmoderatevssevere# WPAIscores(mean±SD) Absenteeism Mild:2.1(10.1);moderate:4.2(14.0);severe:10.3(19.5) Presenteeism Mild:4.0(9.7);moderate:22.0(23.6);severe:43.4(28.5) Overallworkimpairment Mild:6.0(13.8);moderate:24.1(26.4);severe:47.5(29.7) Activityimpairment Mild:8.6(14.8);moderate:25.5(24.6);severe:52.4(27.0) ArimaK,etal. 201820 Retrospe ctive 11 Population size:1902 Subgroups: 1268non‐AD 634AD(290; 45.45%moderate/ severe,34854.54% mild)self‐ratedby thequestion:"How severeisyour dermatitis/eczema? " Workimpairment, comorbidities, emotional health,HRQoL,sleep disorders,HCRU SF‐36, WPAI,adhoc questions, selfreported ADvscontrol Comorbidities Arthritis:3.79vs0.87%,p<0.001;asthma:12.62vs2.44,p<0.001; nasalallergies/hayfever:36.91vs14.83%,p<0.001;high cholesterol:8.99vs4.26%.p<0.001;osteoporosis/osteopenia:1.42 vs0.47%,p<0.001 Moodandsleepdisorders Depression:10.25%vs4.25%,p<0.001;sleepdisorders:12.93%vs 4.57%,p<0.001;anxiety:3.31%vs1.03%,p<0.001 Health‐relatedqualityoflife SF‐36PCS:42.29vs46.05,p<0.001;SF‐36MCS:52.04vs54.12, p<0.001;SF‐6D:0.71vs0.76,p<0.001 Workproductivityandactivity Absenteeism:4.01vs3.54(WPAIscore);presenteeism:28.63%vs 22.37%;p<0.001;overallimpairment:30.61%vs24.62%,p<0.001; activityimpairment:32.18%vs24.72,p<0.001 Health‐careresourceutilization Mean(SD)numbersofvisitstohealth‐careproviders:8.06(16.90) vs3.05(6.27),p<0.001  Diseaseburdenaccordingtoseverity Comorbidities Nosignificantdifferencesintheself‐reportedprevalenceof comorbiditiesaccordingtoseverity Moodandsleepdisorders Nosignificantdifferencesaccordingtoseverity HRQoL MCS,PCSandSF‐36scoreswerenumericallylowerfor moderate/severeADpatientsvsmild;nostatisticalsignificance Workproductivityandactivity Presenteeism:Mild:26.10%vsModerate/severe:32.17%;p=0.018 OverallWorkImpairment:Mild:28.08%vsModerate/severe: 33.79%;p=0.040 Activityimpairment:Mild:30.06%Moderate/severe:35.14% p=0.023 HCRU Nosignificantdifferencesaccordingtoseverity ChanT,etal. 202121 Crosssectional 15 Populationsize:200 Subgroups: 70mild 72moderate 58severebasedon SCORADspecialist measure Workimpairment WPAI Mildvsmoderatevssevere WPAIscores(mean±SD) Absenteeism Mild:1.8(1.3);moderate:6.3(2.7);severe:5.6(3.3) Presenteeism Mild:23.7(13.6);moderate:42.1(10.3);severe:63.1(9.0) Workimpairment Mild:24.7(13.1);moderate:44.8(10.1);severe:65.0(7.8) Activityimpairment: Mild:29.9(10.1);moderate:44.7(9.6);severe:61.2(8.7) Allpvalues<0.001 deBruin‐ WellerM,et al.202022 Crosssectional 16 Population size:1467 Subgroups: Workimpairment, comorbidities, emotional health,HRQoL,sleep disorders DLQI,HADS, sleepVAS POSCORAD, PSQI,ad‐ Mildvsmoderatevssevere Atopiccomorbidities(%) Asthma:20.3mildvs31.7moderatevs43.5severe,p<0.001;food allergy:10.1mild,p<0.001vs18.8moderate,p<0.05vs25.3severe; 547mild 520moderate 400severe,based onIGA hoc question atopickeratoconjunctivitis:0.4mild,p<0.001vs1.0,p<0.05vs2.3 severe) Theproportionofparticipantswith≥1comorbidatopiccondition washigheramongpatientswithsevereAD(80.5%)comparedwith mild(58.9%,p<0.001)andmoderate(74.6%,p<0.05) Non‐atopiccomorbidities(%) Cardiovascular:8.4vs10.8vs15;musculoskeletal:6.2vs7.1vs8.8; endocrine:7.5vs10.0vs11.0;renalconditions:1.8vs2.7vs2.3; mentalconditions:41.7mild,p<0.001vs46.7moderate,p<0.05vs 54.3severe Theproportionofparticipantswith≥1comorbidnon‐atopic conditionwashigheramongpatientswithsevereAD(54.3%) comparedwithmild(41.7%,p<0.001)andmoderate(46.7%, p<0.05) HADSscalescore(mean±SD) Anxiety:5.5(4.0)mildvs7.3(4.2)moderatevs9.4(4.1)severe, p<0.001;depression:3.8(3.7)mildvs5.5(3.9)moderatevs8.2(4.4) severity,p<0.001 Productivitylast4weeks Atleastonedaymissed:33.3%mild,p<0.001vs52.4%moderate, p<0.05vs62.9%severe DLQIscalescore(mean±SD) HRQoL:5.5(4.9)mildvs10.5(6.3)moderatevs1.2(6.9)severe, p<0.001 PainNRSScale(meanscore;1‐10) Mild:1.7;moderate:3.0;severe:4.5;p<0.001 PruritusNRSScale(scoremean;1‐10) Mild:3.5;moderate:5.3;severe:4.1;p<0.001 PO‐SCORADItchVASScale(scoremean;1‐10) Mild:3.8;moderate:5.6;severe:7.3;p<0.001 Sleepdisturbances(scoremean;1‐10) Mild:2.0;moderate:3.6;severe:5.5;p<0.001 Verysevere:44.83%,17.24%,10.34%,27.59% SA‐EASI(none,mild,moderate,severe)# 1:64.06%,18.75%,15.63%,1.65% 2:50.79%,20.63%,20.63%,7.94% 3:41.27%,17.46%,25.4%,15.87%  Diseaseburdenaccordingtoseverity OnlyasubsetofsubjectswithsevereorveryseverePOEM, moderateandsevereself‐reportedglobalassessmentofAD,severe orverysevereVAS‐itch,andhighesttertileSA‐EASIscoreshad significantlyhigherORforallofaspectsofSDandSRI(p<0.05) LioPA,etal. 202034 Crosssectional 18 Populationsize:599 Subgroups: 254mild 309moderate 36severe HRQoL DLQI,EQ‐ 5D,ad‐hoc question CorrelationbetweenlocationandHRQoL(DLQI,EQ‐5D‐3L,EQ‐5D VAS,POEM) Mean:6.8(5.6),0.9(0.1),81.5(16.3),9.4(6.9) Headandneck:7.11(0.62),0.89*(‐0.02),78.6*(‐4.2),10.9*(2.3) Upperextremities:7.05(0.89),0.90*(‐0.02),80.8*(‐3.4),10.1* (2.55) Lowerextremities:7.21(1.16)*,0.89*(‐0.02),80.2*(‐2.8),10.0* (1.99) Front:7.85(1.29)*,0.90(0.0001),81.0(0.64),9.83(0.63) Back:7.13(0.45),0.89*(‐0.03),79.6(‐2.9),10.1(1.44) Face:7.79(1.47),0.88(‐0.02),75.9*(‐6.1),11.7*(2.91) Hands/fingers:7.74*(1.24),0.89*(‐0.02),80.4(‐1.9),11.6*(3.51) Pelvis/genital:9.43(1.21),0.73*(‐0.17),68.7*(‐12),11.9(1.06) Feet/toes:8.35(0.96),0.86*(‐0.05),78.8(‐1.0),11.5(1.20) *Significantdifferences(p<0.0334) MannC,etal. 202035 Crosssectional 18 Populationsize:61 Subgroups: 25AD 36urticaria HRQoL,sleep disorders DLQI,ISI Diseaseburden(mean±SD[range]) ISI‐noflare:8.7±5.6(0‐23) ISI‐flare:16.0±6.4(2‐27) ISIscoreshaveamaximumof28 DLQI:14.0±8.7(1‐28) PruritusVASscale:6.9±1.9(2‐9) NocorrelationfoundbetweenpruritusandISI  HRQoL CorrelationbetweenpruritusandDLQI:r=0.463,p=0.02  Diseaseburdenaccordingtoseverity Nostatisticallysignificantdifferencesbetweendiseaseseverity (EASI)andqualityoflife(DLQI).However,therewasasignificant correlationbetweendiseaseseverity(EASI)andsleep‐impairment globalscore(r=0.43,p=0.032)andwiththespecificitem“difficulty stayingasleep”(r=0.487,p=0.014) MiseryL,et al.201936 Prospect iveand crosssectional 19 Population size:1024 Subgroups: 283mild 414moderate 327severe (PO‐SCORAD) HRQoL,lifestyleand socialactivities ABS‐A, DLQI,EQ‐ 5D,SF‐12, ad‐hoc questions HRQoL(visibleareainvolvementvswithout)(mean±SD) ABS‐A:29.0±20.6vs14.9±18.8,p<0.0001;DLQI:10.4±7.5vs6.1 ±7.7,p<0.0001;EQ‐5D:0.68±0.28vs0.70±0.32,p<0.05;SF‐12 MCS:39.4±10.1vs43.8±9.3,p<0.0001  Involvementofsensualarea ABS‐A:38.2±19.5vs20.7±19.4,p<0.0001;DLQI:13.9±7.1vs7.6 ±7.2,p<0.0001;EQ‐5D:0.64±0.31vs0.71±0.28,p=0.0005;EQ5D‐ VAS:60.2±21.9vs64.9±22.1,p<0.0001;SF‐12MCS:37.0±9.3vs 41.8±10.1,p<0.0001  Genitalinvolvement ABS‐A:39.4±19.5vs23.7±19.4,p<0.001;DLQI:8.9±7.1vs4.5± 7.2,p<0.001;EQ5D‐VAS:58.5±21.2vs63.2±22.3,p<0.001;SF‐12 MCS:36.5±9.1vs40.9±10.2,p<0.001  Diseaseburdenaccordingtoseverity Mildvssevere(PO‐SCORAD) Impactonsexualdesire:1.8%vs9.5%,p<0.0001 Impactonpartner’ssexualdesire:0.7%vs4.3%,p<0.0001 MurotaH,et al.202137 Crosssectional 17 Populationsize:370 Subgroups: 141mildpruritus 117moderate pruritus 112severepruritus assessedwithWPNRSfrom0‐3(mild), 4‐6(moderate)and 7‐10(severe) Work impairment,HRQoL DLQI,WPAI Mildvsmoderatevssevere Workimpairment Mild:5.2%(12.4);moderate:21.7%(20.3);severe:38.1%(26.2) Qualityoflife(DLQIscores) Mild:1.8;moderate:4.2;severe:8.1 Impactonsleep(Aderm‐ISscores) Mild:1.6(3.6);moderate:6.6(6.1);severe:12.9(7.8) Impactondailyactivity(Aderm‐ISscores) Mild:1.6(3.5);moderate:6.4(6.4);severe:11.0(9.0) Impactonemotionalstate(Aderm‐ISscores) Mild:1.9(3.8);moderate:7.0(6.2);severe:13.5(9.3) Alldatasetap‐value<0,001,suggestingstaticalsignificance betweenpruritusseverityusing“mild”asareference. SchonmannY, etal.202038 Retrospe ctive 20 Population size:3,095,838 Subgroups: Depressioncohort: 1,588,277non‐AD 392,433AD Anxietycohort 1,827,908non‐AD 426,430AD Emotionalhealth Diagnoses reportedin primarycar eelectronic health records ADvscontrol Depression:HR1.14‐fold(99%CI,1.12‐1.16) Anxiety:HR1.17‐fold(99%CI,1.14‐1.19)  Diseaseburdenaccordingtoseverity Regardlessofatopiceczemaseverity,therewasanassociation betweenatopiceczemawithbothdepressionandanxiety: comparedtosubjectswithoutatopiceczema:themoreseverethe atopiceczema,thegreatertheriskofdepression(p<0.0001) Schwartzman G,etal.202239 Prospect ive 19 Populationsize:955 Subgroups:N/A HRQoL PHQ‐9, mEQ‐5D, PGH Burdenacrossseverity:Inamultivariatelinearregression modelPGH‐P4TandmEQ‐5Dscoreswereinverselyassociatedwith patient‐reportedglobalADseverity,POEM,EASI,objectiveSCORAD, IGA,NRSaverageandworstitch,andPROMISSRIandsleep disturbance,allwithstepwisedecreasesinphysicalhealthwith worseningseverity(allp<0.05insevere/verysevereAD).PGH‐M4T scoresweresimilarlyinverselyassociatedwithallseveritymeasures ofADanditch,PROMISSRIandPHQ‐9,withstepwisedecreasesof mentalhealthwithworseningseverity(allp<0.05insevere/very severeAD),butnotwithPROMISsleepdisturbance.ADseverityhad significantclinicalassociationswithmentaland physicalHRQoLimpairmentinadultswithAD.Moreseveredisease wasstronglyassociatedwithworseHRQoLscores SilverbergJ, etal.201840 Crosssectional 17 Population size:1787 Subgroups: 1185non‐AD 602AD(289mild, 175moderateand 34severe);selfreportedbythe patientsaskingthe question:Would youdescribeyour ADoreczemaas mild,moderate,or severe? HRQoL,lifestyleand socialactivities DLQI,SF‐12, ad‐hoc questions ADvscontrol HRQoL Fairorpooroverallhealth:25.8%vs15.8%,p<0,0001;being somewhatorverydissatisfiedwithlife:16.7%vs11.4%,p<0.05 SF‐12MCS:45.9vs50.9,p<0.0001;SF‐12PCS:53.0vs53.5, p<0.0001;DLQI:4.9vs1.1,p<0.0001 Burdenacrossdiseaseseverity:MoresevereADwasassociated withevenstrongereffectsonhealthratingandlifesatisfaction.In particular,35.0%and31.6%ofpatientswithself‐reportedsevere ADreportedonlyfairorpoorhealthandalsoreportedbeing somewhatorverydissatisfiedwithlife.POEM(p<0.0001)andPOSCORAD(p<0.0001)werealsosignificantlyassociatedwithpoor health.Diseaseseverityinallmeasureswasassociatedtobeing neithersatisfiedordissatisfied,somewhatorverydissatisfied. AdultswithmoderateandsevereADwerelesslikelytoreportitch orexcessivedrynessandscalingastheirmostburdensome symptoms.Ahigherproportionreportedblistersorbumps,redor inflamedskin,sleepdisturbance,pain,andopensoresoroozingas theirmostburdensomesymptoms Lifestyle AdultswithADreportedthatADlimitedtheirlifestyle(51.3%), causedthemtoavoidsocialinteractionbecauseoftheirappearance (39.1%),andimpactedtheiractivities(43.3%).Evenpatientswith mildADreportedthatADlimitedtheirlifestyle(34.5%),impacted activities(23.2%),orledtoavoidanceofsocialinteractions(17.7%) Burdenacrossseverity:TheseharmfuleffectsofADwereeven moreburdensomeinpersonswithself‐reportedglobalmoderate andsevereAD(p<0.0001forall).Inparticular,almostoneintwo adultswithsevereADreported‘quiteabit’or‘agreatdealof’ burdenintheseareas SilverbergJ, etal.2019A41 Crosssectional 17 Populationsize:596 Subgroups:N/A HRQoL DLQI Associationbetweenpainfrequencyand(adjustedOR[95%CI]): PO‐SCORAD:1.04(1.01‐1.07),p<0.0001 PO‐SCORADitch:1.15(1.02‐1.30),p<0.0001 PO‐SCORADsleep:1.02(0.92‐1.13),n.s. POEM:1.15(1.02‐1.30),p<0.0001 Associationbetweenpainintensityand(adjustedOR[95%CI]): PO‐SCORAD:0.06(0.03‐0.08),p<0.0001 PO‐SCORADitch:0.20(0.08‐0.32),p<0.0008 PO‐SCORADsleep:0.07(‐0.01‐0.14),n.s. POEM:0.12(0.07‐0.17),p<0.0001 Associationbetweenpainandqualityoflife(DLQI)(adjustedOR [95%CI]) PO‐SCORAD:0.21(0.17‐0.25),p<0.0001 PO‐SCORADitch:0.36(0.18‐0.54),p<0.0001 PO‐SCORADsleep:‐0.03(‐0.16‐0.10),n.s. POEM:0.11(0.03‐0.20),p<0.0001 Lesionsonhands:1.32(0.42‐2.22),p<0.004 SilverbergJ, etal.2019B42 Crosssectional 15 Population size:2893 Subgroups: 602AD 2291non‐AD Emotionalhealth HADS ADvscontrol HADS HigherproportionofabnormalHADSscore(>11)ofHADS‐A,HADS‐ Dorboth(48.4%vs35.4%vs26.6%,respectively) ADwasassociatedwithsignificantlyhighermeanHADS‐Aand HADS‐D,withsignificantlyincreasedHADS‐AandHADS‐Dscoresin patientswithmoderateandsevere/verysevereself‐reportedglobal ADseverity,POEM,PO‐SCORAD,PO‐SCORADitchandPO‐SCORAD sleep(p<0.0001forall) Higherself‐reportedprevalenceanddiagnosesofanxietyand depression(40.0%ADvs17.5%non‐AD) HigherprevalenceofanxietyanddepressionmeasuredbyHADSor reportedhealth‐carediagnosisofanxietyordepression(50.3%vs 27.3%) SilverbergJ, etal.202043 Prospect ive 18 Populationsize:386 Subgroups: 137mild 123moderate 116severe,selfreportedbythe patient(other classificationsif Cognitivefunction PROMIS cognitive function Mildvsmoderatevssevere Patient‐reportedADseverity(ref:clear)(T‐score[95%CI]) Mild:‐3.23(‐5.76,‐0.71),n.s.;moderate:‐5.49(‐8.06,‐2.91), p<0.0001;severe:‐5.95(‐8.58,‐3.32),p<0.0001 POEM(self‐reported)(ref:clear)(T‐score[95%CI]) Mild:‐1.77(‐2.78,‐0.76),n.s.;moderate:‐7.62(‐8.75,‐6.49), p<0.0001;severe:‐5.64(‐6.83,‐4.44),p<0.0001;verysevere:‐18.38 (‐20.25,‐16.51),p<0.0001 NRS‐WorstItch(ref:none)(T‐score[95%CI]) reportedbythe doctor) Mild:‐0.27(‐1.25,‐0.72),p<0.0001;moderate:‐3.74(‐4.82,‐2.67), p<0.0001;severe:‐6.72(‐7.99,‐5.45),p<0.0001;verysevere:‐12.40 (‐14.02,‐10.77),p<0.0001 SCORAD‐Sleep(ref:none)(T‐score[95%CI]) Mild:0.82(‐0.74,2.38),n.s.;moderate:‐4.00(‐5.77,‐2.23), p<0.0001;severe:‐6.87(‐8.90,‐4.85),p<0.0001 POEM‐Sleep(ref:none)(T‐score[95%CI]) 1‐2:‐0.57(‐1.87,0.73),n.s.;3‐4:‐6.10(‐7.90,‐4.31),p<0.0001;5‐6:‐ 3.87(‐5.88,‐1.86),p<0.0002;7:‐5.57(‐7.05,‐4.09),p<0.0001 NRSSkinPain(ref:none)(T‐score[95%CI]) Mild:‐5.58(‐7.58,‐3.58),p<0.0001;moderate:‐10.52(‐13.07,‐ 7.97),p<0.0001;severe:‐16.81(‐20.07,‐13.55),p<0.0001 SCORAD(Clinicallyreported)(ref:clear)(T‐score[95%CI]) Mild:reference;moderate:‐4.08(‐6.86,‐1.13),p<0.0001;severe:‐ 11.49(‐14.31,‐8.67),p<0.0001 Cognitiveimpairment Significantlyhigherimpairment(assessedwithPROMIS‐CFrelated toself‐reportedADseverity,POEM,EASI,SCORAD,Itch(Worstitch NRS),sleepdisturbances(SCORAD‐sleepandPOEM‐sleep)andpain (NRS‐Skinpain) SnyderA,et al.202144 Crosssectional 12 Populationsize:33 subgroups: 21patients 12familiars HRQoL,sleep disorders,lifestylean dsocialactivities Ad‐hoc questions, selfreported HRQoL IncreasedfrequencyandintensityofpainfromADleadsto poorerHRQoL Socialisolation Paincanaffectrelationshipsandnumerousdailyactivities. Sleepimpairment Painwasnotalwayslimitedtoonetimeofthedayandparticularly patientsandfamilymembersexperiencednegativeeffectsofpain onsleeping  TalamontiM, etal.202145 Crosssectional 14 Populationsize:352 Subgroups: 174AD 178non‐AD Emotional health,HRQoL,sleep disorders BDI,DLQI, TAS‐ 20,sleepVA S ADvscontrol Emotionalimpairment(mean±SD) TAS‐20:52.3(12.9)vs45.1(10.8),p<0.0001 BDI‐21:15.4(10.2)vs6.8(4.8),p<0.0001 HRQoL(mean±SD) DLQI**forpatientswithAD:13.8(7.0) **onlyADpatientscompletedDLQI Sleepdisorders NRS‐Pruritusisstronglycorrelatedwithsleepdisturbance (r=0.5621,p<0.00001) SleepdisturbanceiscorrelatedwithDLQIscore(r=0.2992,p<0.005) andBDIscore(r=0.307,p<0.005)  Diseaseburdenaccordingtoseverity Nostatisticallysignificantdifferencesbetweenmild‐to‐moderate andmoderate‐to‐severeADpatientsforemotionalhealth,sleep impairment,pruritusandqualityoflife TreudlerR,et al.202046 Crosssectional 18 Population size:9481 Subgroups: 372AD 9109non‐AD Emotional health,HRQoL, lifestyleandsocial activities CES‐D,GAD‐ 7,SF‐8, LSNS‐6 ADvscontrol Emotionalhealth(OR[95%CI] CES‐D:OR1.5(1.0,2.3),p=0.031 GAD‐7:OR1.5(1.0,2.2),p<0.049 Isolation LNSN‐6resultsdidnotshowanassociationbetweenADandsocial isolation HRQoL(mean) SF‐8PCS:46.9vs48.0,p<0.001 SF‐8MCS:50.6vs52.5,p<0.001 ABS‐A:AtopyBurdenScore–Adult;AD:atopicdermatitis;Aderm‐IS:AtopicDermatitisImpactScale;AIS:AthensInsomniaScore;BDI:BeckDepressionInventory;CES‐D:Centre forEpidemiologicStudiesDepressionScale;CI:confidenceinterval;DLQI:DermatologyLifeQualityIndex;EASI:EczemaAreaandSeverityIndex;EQ‐5D:EuroQoL–5 Dimensions;EQ‐5D‐3L(EuroQoL–5Dimensions3LevelVersion;GAD‐7:GeneralizedAnxietyDisorder–7;HADS:HospitalAnxietyandDepressionScale;HADS‐A:HADS anxiety;HADS‐D:HADS‐depression;HADS‐T:totalHADS;HCRU:health‐careresourceutilization;HR:hazardratio;HRQoL:Health‐RelatedQualityofLife;IC‐AD:inadequately controlledatopicdermatitis;IGA:InvestigatorGlobalAssessment;ISI:InsomniaSeverityIndex;LSNS‐6,LubbenSocialNetworkScale;MCS:mentalcomponentsummary; mEQ‐5D:mappedEQ‐5D;N/A:notavailable;NRS:NumericalRatingScale;n.s.:notsignificant;OR:oddsratio;PCS:physicalcomponentsummary;POEM:PatientOriented EczemaMeasure;PO‐SCORAD:PatientOrientedSCORingofAD;PGH:PROMISGlobalHealth;PGH‐M4T:PGHassociateditemswithmentalhealth;PGH‐P4T:PGHassociated itemswithphysicalhealth;PHQ‐9:PatientHealthQuestionnaire;PROMIS‐CF:PROMISCognitiveFunction;PROMIS‐SD:PROMISSleepDisorders;PROMIS‐SRI:PROMISSleep‐ RelatedImpairment;PSQI:PittsburghSleepQualityIndex;SA‐EASI:Self‐AdministeredEASI;SCORAD:SCORingAD;SD:standarddeviation;SF‐12:ShortForm12items;SF‐36: ShortForm36items;SF‐6D:ShortForm6‐Dimension;SF‐8:ShortForm8items;TAS‐20,TorontoAlexithymiaScale–20;T‐score:standardizedscore;VAS:VisualAnalogic Scale;WP:WorstPruritus;WPAI:WorkProductivityandActivityImpairment;#Statisticalsignificance(p‐value)notreported 