Frontiers in Dermatology and Venereology - a Series of Theme Issues in Relation to the 100-Year Anniversary of Actadv

ISSN 0001-5555 ActaDV Volume 100 2020 Theme issue

Advances in Dermatology and Venereology

A Non-profit International Journal for Interdisciplinary Skin Research, Clinical and Experimental Dermatology and Sexually Transmitted Diseases

Frontiers in Dermatology and Venereology - A series of theme issues in relation to the 100-year anniversary of ActaDV

Official Journal of - European Society for Dermatology and Psychiatry

Affiliated with - The International Forum for the Study of Itch

Immediate Open Access

Acta Dermato-Venereologica

www.medicaljournals.se/adv ACTA DERMATO-VENEREOLOGICA The journal was founded in 1920 by Professor Johan Almkvist. Since 1969 ownership has been vested in the Society for Publication of Acta Dermato-Venereologica, a non-profit organization. Since 2006 the journal is published online, independently without a commercial publisher. (For further information please see the journal’s website https://www. medicaljournals.se/acta)

ActaDV is a journal for clinical and experimental research in the field of dermatology and venereology and publishes high- quality papers in English dealing with new observations on basic dermatological and venereological research, as well as clinical investigations. Each volume also features a number of review articles in special areas, as well as Correspondence to the Editor to stimulate debate. New books are also reviewed. The journal has rapid publication times.

Editor-in-Chief: Olle Larkö, MD, PhD, Gothenburg Former Editors: Johan Almkvist 1920–1935 Deputy Editors: Sven Hellerström 1935–1969 Anette Bygum, MD, PhD, Odense Nils Thyresson 1969–1987 Magnus Lindberg, MD, PhD, Örebro Lennart Juhlin 1987–1999 Elisabet Nylander, MD, PhD, Umeå Anders Vahlquist 1999–2017 Kaisa Tasanen-Määttä, MD, PhD, Oulu Artur Schmidtchen 2018–2019

Section Editors: Tasuku Akiyama, Miami (Neurodermatology and Itch - Experimental) Annamari Ranki, Helsinki (Cutaneous lymphoma) Nicole Basset-Seguin, Paris (Skin cancer) Artur Schmidtchen, Lund (Wound healing and Innate immunity) Veronique Bataille, London (Melanoma, Naevi, Photobiology) Matthias Schmuth, Innsbruck (Genodermatoses and Keratinizing disorders, Josip Car, Singapore (Health Services Research and e-Health) Ichthyosis and Retinoids) Brigitte Dréno, Nantes (Acne and Rosacea) Lone Skov, Hellerup (Psoriasis) Regina Fölster-Holst, Kiel (Paediatric dermatology, Atopy and Parasitoses) Enikö Sonkoly, Stockholm (Psoriasis and related disorders) Jürg Hafner, Zürich (Skin cancer, Skin tumours, and Melanoma) Jacek Szepietowski, Wrocław (Psychodermatology) Jürgen Harder, Kiel (Cutaneous innate defense, Skin microbe interactions) Elke Weisshaar, Heidelberg (Itch and Neurodermatology) Roderick Hay, London (Cutaneous Infections) Margitta Worm, Berlin (Atopic dermatitis and Immunology) Kristian Kofoed, Copenhagen (STD and Microbiology) Claus Zachariae, Hellerup (Contact dermatitis, Acute dermatology) Veli-Matti Kähäri, Turku (Skin cancer) Magnus Ågren, Copenhagen (Wound healing & Extracellular matrix) Dennis Linder, Graz/Padua (Psychoderm., Dermato-epidemiology, e-Health)

Advisory Board: Masashi Akiyama, Nagoya Rudolf Happle, Freiburg Lisa Naysmith, Edinburgh Mona Ståhle, Stockholm Wilma Bergman, Leiden Lars Iversen, Aarhus Jonathan Rees, Edinburgh Sonja Ständer, Münster Tilo Biedermann, Munich Peter van de Kerkhof, Nijmegen Jean Revuz, Paris Jouni Uitto, Philadelphia Magnus Bruze, Malmö Irene Leigh, Dundee Johannes Ring, Munich Shyam Verma, Vadodara Earl Carstens, Davis John McGrath, London Matthias Ringkamp, Baltimore Gil Yosipovitch, Miami Charlotta Enerbäck, Linköping Maja Mockenhaupt, Freiburg Inger Rosdahl, Linköping Giovanna Zambruno, Rome Kilian Eyerich, Stockholm Dedee Murrell, Sydney Thomas Ruzicka, Munich Christos C. Zouboulis, Dessau

All correspondence concerning manuscripts, editorial matters and subscription should be addressed to: Acta Dermato-Venereologica S:t Johannesgatan 22, SE-753 12 Uppsala, Sweden Editorial Manager, Mrs Agneta Andersson Editorial Assistant: Ms Anna-Maria Andersson Please send an E-mail Please send an E-mail

Information to authors: Acta Dermato-Venereologica publishes papers/reports on scientific investigations in the field of dermatology and venereology, as well as reviews. Case reports and good preliminary clinical trials or experimental investigations are usually published as Short Communications. However, if such papers are of great news value they could still be published as full articles. Special contributions such as extensive feature articles and proceedings may be published as supplements to the journal. For detailed instructions to authors see https://www.medicaljournals.se/acta/instructions-to-author. Publication information: Everything is Open Access and no subscription fee. For publication fees: see https://www.medicaljournals.se/acta/ instructions-to-author.

Indexed in: See https://www.medicaljournals.se/acta/about/adv. Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Genodermatoses Blistering skindisorders Psoriasis Itch andpruriticdisorders Previous issues Atopic dermatitis Current issue • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Pustular Psoriasis:theDawnofaNewEra,H.Bachelez Psoriasis andCo-morbidity, M. Amin, E.B.Lee,T-F. Tsai, J.J.Wu Psoriasis and Treatment: Past,Presentand Future Aspects, C.Reid,C.E.M.Griffiths The Woronoff RinginPsoriasisandtheMechanismsofPostinflammatory Hypopigmentation,J.Prinz Psoriasis andGenetics,N.Dand,S.Mahil,F. Capon,C.H.Smith,M.A.SimpsonandJ.Barker Ichthyosis: A RoadModel forSkinResearch,A.Vahlquist, H.Törmä Genetics ofInheritedIchthyoses andRelatedDiseases,J.Fischer, E.Bourrat Molecular Genetics of Keratinization Disorders - What’s New About Ichthyosis, Diagnosis andManagementofInherited PalmoplantarKeratodermas,B.R.Thomas,E. A. O’Toole Legius SyndromeanditsRelationship withNeurofibromatosis Type 1,E.Denayer, E.Legius Dental Manifestations of Ehlers-Danlos Syndromes: A Systematic Review, I. Kapferer-Seebacher, D. Schnabl, J. Zschocke, F. M. Pope Kambe, G.Kokolakis,K.Krause Symptoms, Cutaneous with Presenting Diseases Genetic Autoinflammatory of Spectrum An EarlyDescriptionofa“HumanMosaic”InvolvingtheSkin: A Storyfrom1945,R.Happle Bullous DrugReactions,M.Mockenhaupt Current ConceptsofDermatitisHerpetiformis,T. Salmi,K.Hervonen Drug DevelopmentinPemphigoidDiseases,K.Bieber, R.J.Ludwig Collagen XVIIProcessingandBlisteringSkinDiseases,W. Nishie Skin Fragility:PerspectivesonEvidence-based Therapies, L.Bruckner-Tuderman A.G.S. Zink,S.Ständer Challenges inClinicalResearchandCarePruritus,M.P. Pereira, C.Zeidler, M.Storck, K. Agelopoulos, W.D. Philipp-Dormston, A NewGenerationof Treatments forItch,E.Fowler, G.Yosipovitch Itch andPsyche:Bilateral Associations, R.Reszke,J.C.Szepietowski Non-dermatological ChallengesofChronicItch,A.E.Kremer, T. Mettang,E.Weisshaar Mechanisms andManagementofItchinDrySkin,C.SagitaMoniaga,M.Tominaga, K.Takamori The ChallengeofBasicItchResearch,E.Carstens,T. Follansbee,M.I.Carstens Prevention of Atopic Dermatitis,H.C.Williams, J.Chalmers A Therapeutic Renaissance-Emerging Treatments for Atopic Dermatitis,C.H.Na,W. Baghoomian,E.L.Simpson Skin Microbiomein Atopic Dermatitis,S.M.Edslev, T. Agner, P. S. Andersen Genetics in Atopic Dermatitis:HistoricalPerspectiveandFutureProspects,S.J.Brown, M.S.Elias,Bradley Disease Mechanismsin Atopic Dermatitis: A Reviewof Aetiological Factors,J.P. Thyssen, M.R.Rinnov, C.Vestergaard Counting theBurden: Atopic DermatitisandHealth-relatedQualityofLife,F. Ali, J.Vyas, A.Y .Finlay Prevalence andIncidenceof Atopic Dermatitis: A SystematicReview, S.Bylund,L.B.vonKobyletzki,M.Svalstedt,Å.Svensson Theme editors: Anette BygumandMatthiasSchmuth Theme editor:KaisaTasanen Theme editors:LoneSkovandEniköSonkoly Theme editors:ElkeWeisshaar, Tasuku Akiyama andJacekSzepietowski Theme editors:MagnusLindberg andCarl-Fredrik Wahlgren Centenary theme issuesinVolume 100ofActaDermato-Venereologica Frontiers inDermatologyandVenereology An overview J. Uitto, L. Youssefian, A. H. Saeidian, H. Vahidnezhad H. Bonnekoh,M.Butze,T. Kallinich,N.

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis Skin malignancies Cutaneous andgenitalinfections • • • • • • • • • • • • • The ChangingSpectrumofSexually Transmitted InfectionsinEurope,A.Stary Skin Diseaseinthe Tropics andtheLessonsthatcanbeLearnedfromLeprosyOtherNeglectedDiseases,R.J.Hay Update oftheManagementCutaneousSquamous-cellCarcinoma,E.Maubec Biomarkers PredictingforResponseandRelapsewithMelanomaSystemic Therapy, S.J.Welsh, P. G.Corrie Cutaneous Melanoma– A ReviewofSystemic Therapies, K. A. Lee,P. Nathan Update ontheManagementofBasalCellCarcinoma,N.Basset-Seguin,F. Herms Melanoma RiskandMelanocyteBiology, J.U.Bertrand,E.Steingrimsson,F. Jouenne,B.Bressac-de Paillerets, L.Larue Melanoma Genomics,J. A. Newton-Bishop,D.T. Bishop,M.Harland It’s Not All Sunshine:Non-sun-relatedMelanomaRisk-factors,V. Bataille Melanoma EpidemiologyandSunExposure,S.Raimondi,M.Suppa,Gandini The ManagementofScabiesinthe21 We Like To Go? Y. Gräser, D.M.L.Saunte AHundred Years Infections: Do Fungal Where Superficial Diagnosing of From, Come WhereWe Are and Now WhereWe Would Skin InfectionsCausedbyStaphylococcusaureus, P. DelGiudice Theme editors:Veronique BatailleandNicoleBassetSeguin Theme editors:RoderickHayandKristianKofoed st Century: Past, Advances andPotentials,C.Bernigaud,K.Fischer, O.Chosidow Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Prevention of Atopic Dermatitis,H.C.Williams, J.Chalmers A Therapeutic Renaissance -Emerging Treatments for Atopic Dermatitis, C.H.Na,W. Baghoomian, Skin Microbiomein Atopic Dermatitis,S.M.Edslev, T. Agner, P. S. Andersen Genetics in Atopic Dermatitis:HistoricalPerspectiveandFutureProspects, S.J.Brown, M.S.Elias, Disease Mechanismsin Atopic Dermatitis: A Reviewof Aetiological Factors,J.P. Thyssen,M.R. Counting theBurden: Atopic Dermatitisand Health-relatedQualityofLife,F. Ali, J.Vyas, A.Y .Finlay Prevalence and Incidence of Atopic Dermatitis: A Systematic Review, S.Bylund, L. B. von Kobyletzki, TABLE OF CONTENTS E. L.Simpson M. Bradley Rinnov, C.Vestergaard M. Svalstedt,Å.Svensson Magnus Lindberg andCarl-Fredrik Wahlgren Atopic Dermatitis Theme Editors: 380–388 367–379 358–366 349–357 341–348 330–340 320–329 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Europe andtheUSA,recentdatasuggeststhatpre and hasasubstantialimpactonqualityoflife(1,2).In Scale). Cross-sectional and longitudinal epidemiolo and studyquality assessment (Newcastle–Ottawa performed inJune2019,followed bydata abstraction PubMed, EMBASEandGoogle (manualsearch)was and no studies on adults only; most studies were con doi: 10.2340/00015555-3510 to skindiseases(9). accounts forthe largest global burdenofdisability owing substantial variationbetween countries(1,3–8). and, among adults, it ranges between 7% and 14%, with valence of AD among children is approximately 20% A [email protected] versity Hospital, Lund University, SE-205 02 Malmö, Sweden. E-mail: Department of Dermatology, Kobyletzki, von B. Corr: Laura Skåne Uni- Acta DermVenereol 2020;100:adv00160. Accepted May 7,2020;Epubaheadofprint May 15,2020 incidence. Key words: systematic review; atopic dermatitis; prevalence; AD duringadulthood. tinents arestillneeded,especiallyon the incidenceof dies on childhood and adulthood AD in different con ducted in Europe and the USA. Epidemiological stu recent studieson incidenceof ADinthe 21 person-years inchildrenScotland. Therewerefew 1,000 per 93.4–97.9) CI (95% 95.6 to Italy in 10.6) ed from 10.2 (95% confidence interval (95% CI) 9.9– 26 on incidence of AD. In the 21 moderate/good-quality 378 studies were included: 352 on prevalence of AD and reviewed, references Of7,207 included. were definition) standardized or gical studiesof individualswith AD (doctor-diagnosed data from the21 (AD) duringchildhood andadulthood, focusing on of the prevalence and incidenceof atopic dermatitis tically reviewandanalyseepidemiological studies # 1 Simon BYLUND Review Prevalence andIncidenceofAtopicDermatitis:ASystematic Centenary theme section:ATOPICDERMATITIS The primary objective of this study was to systema Acta DermVenereol 2020;100: adv00160 n sa o 71 i Erp i aut, n 09% to22.6% in children in Asia. The 1-year incidence rang 0.96% and adults, in Europe in 17.1% to Asia in prevalence of doctor-diagnosed AD ranged from 1.2% Environmental Dermatology, Skåne University Hospital, Malmö, and Dermatology, Skåne Hospital, University Environmental Örebro University,Örebro, Department of These authorscontributed equally. AD leads to substantial social and financial costs and skin disease. AD causes anitchyrashanddryskin inflammatory common a is (AD) dermatitis topic Pediatrics, Örebro 1# , Laura B. VONKOBYLETZKI st century.Asystematic searchof 3 Department of Dermatology, Skåne UniversityHospital,LundUniversity,Malmö, University Hospital, Örebro, st century, the 1-year This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta SYSTEMATIC REVIEW 2–4# st , century Marika SVALSTEDT 2 University Healthcare Research Center, Faculty of Medicineand Health, ------

5 Hospital library, Central Hospital Karlstad, Region of Karlstad, Region Värmland, Sweden Hospital Central library, Hospital prevalence andincidenceof AD, whichmayunderesti and methods, result in heterogeneity in estimates of the factors suchasstudydesign,researchteams,location, and incidencedata(15).Differences acrossstudiesin contribute totheheterogeneityinreportedprevalence remains unclear(12–14). the incidenceacrossdifferent agegroupsandcountries Recent studies indicate evidence of adult-onset AD, but ximately 60%experienceremissioninadolescence(11). approximately 80%ofindividuals(10),andthatappro of theburden AD. and adulthood, withaparticularfocuson publications the prevalenceandincidence of AD duringchildhood tically reviewandanalyse epidemiologicalstudiesof from the21 of AD andarethususeful(16).Epidemiologicaldata criteria) are a validated measure for physician assessment United Kingdom Working Partydiagnostic criteria(UK physician diagnosis,isoftenthepreferredmethod. The nosis basedonvalidateddiagnosticcriteria,especially for healthcareplanningandpatientcounselling.Diag across different age groups and countries is essential can differ acrossagegroups andskintypes. features intermittent disease symptoms and signs, which of AD inchildrenandadults.Furthermore, AD often mate oroverestimate the “true” prevalence and incidence as new therapies are emerging. physicians, scientists and healthcare planning, especially century. The results will be useful for patient organizations, prisingly, in adults, studies on new cases were from the 20 with asmany as 9.6%newcasesof AD inchildren. Sur of adults and 22.6% of children were diagnosed with AD; continents, on children and adults. Each year, up to17.1% which includedmore than 7,000 articles withdata from all therefore necessary. A systematic review was performed, for the individual. An overview of how often AD occursis Atopic dermatitis iscommon, and isoften burdensome SIGNIFICANCE Differences in study design and definition of AD of definition and design study in Differences The onset of AD occurs during the first years of life in The primaryobjectiveofthis studywastosystema Knowledge of theprevalence andincidence of AD 5 and Åke SVENSSON Journal Compilation ©2020ActaDermato-Venereologica. st centurycouldincreaseourunderstanding 3 4 Department of Occupational and Department of Occupational and th -

- - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV on bothchildrenandadults. included, 337reportedonchildren and54onadultsor ted incidencefordoctor-diagnosed AD. Ofthepapers 1-year prevalencefordoctor-diagnosed AD, and6repor with datafrom,andincluding, 2000onwardsreported used data from 2000onwards. A total of20the studies inclusion criteria.Intotal,115 oftheincludedstudies the fulfilled 378 reviewed, articles the Of studies. 21 search and article reference list search identified another forfull-textreview. selected were articles A manual 966 these, Of abstracts. 7,207 identified search The Study selection RESULTS percentages, thenpercentageswerecalculated. (19). When numberswereprovidedintheoriginalarticlesbutnot Items forSystematicReviewsandMeta-Analyses(PRISMA) from 2000through2019. using theNOS. A particularfocuswasonpublicationsusingdata across age,sex,decade,andcountry/regionqualityassessment Secondary outcomes included the prevalenceand incidence of AD (y) prevalence,and/orlifetimeprevalence)andincidenceof AD. about prevalenceorincidencebysex. were contactedviae-mailwhenpossibletoobtaininformation resolved byauthorconsensus.Correspondingauthorsofstudies were performedbytwo authors (LvK,SB),anddiscrepancieswere nal studies (18). Screening, data extraction, and quality assessment cohort studies and a modified version of the NOS for cross-sectio were used,whichincluded theNewcastle–OttawaScale(NOS)for predefined eligibilitycriteriaweremet. ed independentlybytwoauthorsinordertoassesswhetherthe eczema only. Title, abstract,andfull-textscreeningwasperform populations (e.g.occupations),andstudiesofpatientswithhand vention studies,clinic-basedstudiesonspecificexposed 8 inFrench,andoneSpanish.Exclusioncriteriawere:inter Dutch, in article specifically, one included; also were languages amanualsearch,relevant articlesinother Following and German. (ISAAC) criteria(17). We primarilysearched forstudiesinEnglish or theInternationalStudyof Asthma and Allergies inChildren AD for criteria UK the as such definition, standardized a using logical studiesofindividualswith AD, diagnosedbyadoctoror The studyincludedcross-sectionalandlongitudinalepidemio Study selection,dataabstraction,andqualityassessment searched manuallyforpotentialadditionalstudies. screenedandGooglewas werealso and conferenceabstracts are describedinAppendix1.Referencelistsofincludedstudies developed incollaborationwithamedicallibrarian. The searches MeSH (MedicalSubjectHeading)headingsandkeywordswere search) was performed in June 2019. Pre-defined search terms and A systematicsearchofPubMed,EMBASE,andGoogle(manual MATERIALS ANDMETHODS country/region. prevalence and incidence across age, sex, decade, and from 2000through2019.Secondaryoutcomeswerethe This reviewisreportedaccordingtothePreferredReporting The primaryoutcomewasprevalence(pointprevalence,1-year Predefined data extraction sheets and quality assessment sheets Prevalence andincidenceofatopicdermatitis:asystematicreview - - - - The studies identified in the search in June 2019 inclu 2019 June in search the in identified studies The Study characteristics bers andreasonsforexclusion. or allergyandnotspecificallyonAD. *No assessment of atopic dermatitis (AD): data on asthma, allergic rhinitis diagram. Results of search strategy.flow (PRISMA) Meta-Analyses and Reporting ItemsforSystematicReviews 1. Preferred Fig. (21–25). The 1-yearprevalence of AD symptomsvaried AD symptomsinchildren ranged from1.7%to32.8% all data(1958–2018). The overallpointprevalenceof Studies onchildren andonboth children andadults: lu.se/record/e240247d-7664-4263-9918-3b38e704fd06). II andSupplements2–7(availablefromhttp://lup.lub. The resultsforprevalencearepresentedinTables I and Prevalence ofatopicdermatitis lu.se/record/e240247d-7664-4263-9918-3b38e704fd06). bed inSupplements1–7(availablefromhttp://lup.lub. and 11 used the Hanifin & Rajka criteria (20), as descri criteria wereused;only10studiesusedtheUK these startedin1958. tudinal studiesoftenusedbirthcohorts;theearliestof physical examinationandquestionnairedata.Thelongi and 2studiesreliedonadoctordiagnosisbasedboth diagnosis drawnfromstudyrecordsorpatient longitudinal studies. Twenty-eight studiesusedadoctor record/e240247d-7664-4263-9918-3b38e704fd06). characteristics, seeSupplement1(http://lup.lub.lu.se/ continents andonbothchildrenadults.Forstudy lion individuals.Somestudieswere conducted onseveral Study sampleswerebetween108tomorethan30mil several articlesreportedondatafromcountries. 20 inSouth America, 23in Africa, and14in Australia; conducted inEurope,122 Asia, 20inNorth America, ded datafrom1958to2017.Ofthesestudies,200were R The study flow diagram (Fig.1)reportsarticlenum diagram flow study The The definition of AD varied, and often the ISAAC the often and varied, AD of definition The studiesand36 342cross-sectional There were e co dat r d a s bas ( n i d

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- - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV SD: standard deviation. Theme issue:Atopic dermatitis Table II.Doctor-diagnosed1-yearprevalenceofatopicdermatitis(AD)inadultsassessedtheyear2000orlaterbycontinents doctor diagnosisrangedfrom1.2%to17.1%(1,32). Kuwait (28, 31), and the 1-year prevalence based on symptoms variedfrom1.3%inGermanyto22.7% 1.2% to9.7%(1,30). The 1-yearprevalenceof AD overall pointprevalenceof AD symptomsrangedfrom Studies onadults:alldata(1958–2018).Inadults,the Beijing (27,29). at age6–7yearswas1.4%inLithuaniaand36.2% Lifetime prevalenceofdoctor-diagnosed AD assessed age atassessmentoflifetimeprevalencewas6–7years. imately 22–23years,and36.2%inBeijing(27);the (26) in children and adults with a mean age of approx lifetime prevalence of1.2%was reported in Ethiopia Turkey in children aged 7–12 years (132), the same diagnosis of AD rangedfrom0.96%to22.6%(21–25). (28). The 1-yearprevalenceinchildrenbasedondoctor 2.0% in children in Urumqi (27), and 22.7% in Kuwait from 0.7%inchildrenandadultsEthiopia(26),to Table I.Doctor-diagnosed1-yearprevalenceofatopicdermatitis(AD)inchildrenassessedtheyear2000orlaterbycontinents 322 SD: standard deviation; GP:general practitioner. Horak etal.2014(252) Harangi et al.2007 (50) Dogruel, et al. 2016(79) Dell etal.2010(235) Civelek etal.2011(35) Abuabara et al. 2019 (34) Aberle et al. 2018 (193) Study Wijga etal.2011(156) Simpson etal. 2002(379) Shaw et al.2011(306) Oak et al. 2012 (36) Mohn etal. 2018(378) Lee etal.2016(274) Hwang et al. 2010 (255) Barbarot etal.2018(210) Abuabara et al. 2019 (34) Abuabara et al. 2018 (195) Study Hwang et al. 2010 (255) Zietze etal.2018(373) Werfel et al.2018(374) Latvala et al. 2005 (32) The lifetimeprevalenceof AD variedfrom 1.2% in S. Bylundetal. Study type survey study Multinational cross-sectional Health improvement network GP healthrecords register National health insurance Health insurance data Cross-sectional survey Military services assessment Study type Cross-sectional study Cross-sectional study Birth cohortstudy Cross-sectional study Cross-sectional study UK primary carecohortstudy Cross-sectional study surveys anda literature search practitioner records, population Survey basedongeneral GP healthrecords National health survey Cross-sectional study Cohort study Cross-sectional study Cohort study Japan (n UK (n Spain (n Italy (n Germany (n France (n Canada (n US (n 8,604,333 848,435 n 997,729 3.3 million 9,971 1.4 million n 8,604,333 37,570 373,954 277,934 79,272 252,538 102,353 16,019 1,454 (2005) 1,454 (2002) 1,377 5,493 6,755 1,687 8,947 = 19,986) = 10,001) = 9,897) = 9,924) = 10,911) = 9,964) = 10,004) = 9,971) - stated) (if nototherwise Age, years Mean 7–14 0–12 months 5–9 10–11 0–17 10–11 10–17 10–17 0–9 0–4 Children Middle-school students <6 1–18 <20 Age, years 18–64 75–99 18–74 33.8 mean All ages, 18+ 18–65 18–19 Studies of21 prevalence was18–26years(1,28,31,33). to 20.2%inKuwait;theageatassessmentoflifetime lifetime prevalenceofdoctor-diagnosed AD was14.6% Scandinavia betweenages0–29yearswas34.1%;the prevalence was18–26years. The prevalenceof AD in to 17.7%inKuwait;theageatassessmentoflifetime and for adults ranged from 3.0% to 17.7% (28, 31, 44). and foradultsrangedfrom3.0%to17.7%(28,31,44). ranged from4.4%to17.7%assessedatage7–15years, 32, 34–36).Forchildren,thelifetimesymptomprevalence adults, andfrom0.96%to22.6%inchildren Asia (1, AD rangedfrom1.2%in Asia to17.1%inEurope (28, 42, 43). The 1-year prevalence of doctor-diagnosed from 4.1%to22.7%andforadults7.3% 41). Forchildren,the1-yearsymptomprevalenceranged 0.64%–0.9% inIsraelto9.7%Denmark2010(1, to 18.2%in Turkey (39,40).Foradults,itvariedfrom children, thepointprevalencerangedfrom0%inNigeria ± The lifetimeprevalenceof AD rangedfrom1.7% SD age 8.4 ± ± 20.70 SD SD ± 1.2 st Italy to 8.1 for Germany 2.2 for Overall 4.9 8.7 5.1 (%) Europe One-year prevalence ofdoctor-diagnosed AD 1.6–1.9 2.23 1.2 1.2 centurydataforchildren andadults.For % Europe One-year prevalence ofdoctor-diagnosed AD 16.1 15.1 12.3 10.1 13.9 10.7 17.0 1.8 5.5 9.5 (%) Africa % Africa (%) America North Canada 4.4 US 3.5 % America North 21.4 % America South (%) America South Japan 2.1 (%) Asia 1.2 % Asia 22.6 14.3 4.3 0.94 2.0 (%) Australia % Australia Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV of AD inthe21 reporting repeatedmeasuresindicatedhigherproportions an increasefrom5.8%to7.7%,andinlife in 2002and2007 6–8-year-olds in Taiwan andreported assessed the prevalence ofparent-reported AD symptoms lence inthe21 23.9%. Inthe21 time prevalence of doctor-diagnosed AD from 18.0% to Trends bycontinent:21 and foradultsrangedfrom17.6%to20.2%(28,31,45). AD ranged from 4.7% to 20.2% assessed at age 7–15 years For children, the lifetime prevalence of doctor-diagnosed somewhat higherinthe21 such asEurope.IntheUSA,prevalencereportedwas of AD was generally lowercomparedwith other regions 58–60), butthe resultsaremixed (61–63)andprevalence Asia, some studies suggest an increasing prevalence (46, study fromNigeriareportedtheoppositetrend(57).In different years confirm this trend (54–56), although one studies thatreportedrepeatedmeasuresof AD across Africa, prevalenceof AD hasgenerallyincreased;some record/e240247d-7664-4263-9918-3b38e704fd06 in Supplements2–4(availablefromhttp://lup.lub.lu.se/ Trendsshown bycontinent:alldata(1958–2018).As studies thatreportedrepeatedmeasures(46–53). for stable seemed data and trend specific no was there higher prevalenceinrecentyearscomparedwiththe20 increase (53, 75).In Australia, moststudies suggested a increase in AD (67–74),althoughotherstudiesfoundno and studiesreportingrepeatedmeasuresalsosuggestan most studies reported an increasing incidence and preva measures suggestednocleartrend(64–66).InEurope, 20th century; however, the few studies reporting repeated [CI] 12.4–13.8)andinmales 10.8%(95%CI2.4–13.8). intervals confidence (95% 13.1% was adults female in and 5.8% in males (28). The 1-year symptom prevalence (80). Inadults,thepointprevalence was10.2% infemales prevalence forgirlsof9.64% andforboysof17.10% adolescents aged 12–14 years showed a 1-year symptom One good-qualitystudythatusedtheNOSassessmentin proportions were11.1% and8.1%,respectively (78,79). 35% inmalesatageupto1year;schoolchildrenthe quality studieswas24%infemalescomparedwith prevalence inmaleswasalsoreported(72). consistent acrossdifferent continents, althoughahigher e240247d-7664-4263-9918-3b38e704fd06 studies (Supplements5–7;http://lup.lub.lu.se/record/ (range 0.8–17.6%;1.4–37.3%,respectively)inmost 0.6–24.3%; 1.0–35.5%,respectively)thaninmales of doctor-diagnosed AD washigherinfemales(range The 1-yearprevalenceof AD andlifetimeprevalence 54 reported on the prevalence or incidence of AD bysex. Prevalence bysex:alldata(1958–2018).Ofstudies, measures studies(76,77). century, and this was confirmed in most of the repeated The point prevalence in children assessed ingood- The pointprevalenceinchildrenassessed st centurycomparedwiththe20 st st century. Forexample,Liao et al.(46) centuryinEuropeandNorth America st century data.In Asia, studies st centurycomparedwiththe ), and this was ), and this was th century ), in Prevalence andincidenceofatopicdermatitis:asystematicreview th - -

populations andthereforeameta-analysiswasnotper There washeterogeneityacrossstudydesigns and study Study designandassessmentmethods showed thehighestprevalence(22.6%)(28,36,81–84). reported 1-yearprevalenceinthe21 life, vonKobyletzkietal.(11) of months 18 first the during AD of incidence highest childhood. Forexample,Nissenetal.(83)reportedthe during infancyandtheincidencewasalsohighinearly all included studies, thehighest incidence of AD occurred Atopic dermatitisincidenceforalldata(1958–2018).In years in1968(85). of AD inadultswas7.41(6.27–8.74)per1,000person 1,000 person-yearsinchildrenScotland. The incidence interval (CI) 9.9–10.6) in Italy to 95.6(CI93.4–97.9) per The 1-year incidence ranged from 10.2 (95% confidence Atopic dermatitisincidencefor21 Incidence ofatopicdermatitis of AD. prevalence reported the affect significantly not did period study diagnosis. The numberoftimes AD wasmeasuredper a higherprevalenceof AD thanthoseusingphysician formed. Studiesusingsignsof AD (ISAAC)reported Strachan (84) by Williamsadults & for reported numbers similar and sen et al. (83), but higher prevalences were also reported prevalence lowerthan10%forchildren,similartoNis groups. Forexample,Burretal.(82)reporteda1-year eastern Europe. There wasnocleartrendregardingage prevalence was observedin China, central Asia, and was highinbothSwedenand Africa. However, lower lence acrosscontinents;forexample,prevalenceof AD e240247d-7664-4263-9918-3b38e704fd06). Onestudy shown inSupplement2( http://lup.lub.lu.se/record/ The study quality ranged from moderate to good, as Study quality (1, 52,86–90). adult-onset AD was 8.0% in Germany at age 28–30 years adolescence andadulthood. The reportedproportionof ever, a considerableincidencewasalsoreportedduring holm, Sweden,was53%ofallprevalentcases.How “new” incident cases in the last 12months in Stock found that,betweenage0–12years,theproportionof disease onsetbytheageof7years.Ballardinietal.(81) infancy, and Williams et al. (84) tely 80%ofchildrenwith AD haddiseaseonsetduring studies were conducted in the 21 incidence of AD wasreportedin17 studies; ofthese,6 across populations. There werenodifferences inpreva The prevalenceof AD wasstableacrossagegroupsand Prevalence byageandcontinent:alldata(1958–2018). . However, whenconsideringtherangeof Theme issue:Atopic dermatitis reported thatapproxima reported that 66% had st century (Table III ). st centurydata.The st century, children 323 - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis 324 Table III. Summary of study results regarding incidence of atopic dermatitis in children and adults from the year 2000 and onwards

Age, One-year Year of Study size Age, years years at incidence One-year S. Bylundetal. Author, year Study enrollment/ (participants, Females (range) at study Definition of Incidence baseline (if incidence Female and reference type study start n) (%) Country enrollment end Follow-up eczema definition applicable) (95% CI) Male incidence incidence

Anandan C et al., Cohort 1995 unclear nr Scotland All ages All ages 8 Doctor diagnose Incidence rate nr 10.2 (9.9–10.6) 8.8 (8.4–9.2) 11.6 2009 (87) and symptoms of eczema per (11.1–12.1) 1,000 patients per year Cantarutti et al., Cohort 2006–12 145,233 47.9 Italy 0–13 0–13 6 Doctor diagnose Incidence per 14.1 16.5 (15.6–17.5) nr nr 2015 (37) 1,000 person- (13.4–14.7) years Halkjaer LB et al., Birth 2001 411 50.6 Denmark At age 1 1–2 Scheduled Doctor diagnose Incidence At 1 year 31% 10% from age 1 to nr nr 2006 (344) cohort month visits every 6 and symptoms of atopic age 2 years months. Age dermatitis per at last follow- year up 3 years Mebrahtu et al. Cohort 2012–14 13,734 nr UK 0 3–7 Median 5.55; Doctor diagnose Incidence rate nr 95.6 96.5 (93.4–99.7) 94.8 2016 (38) range, 0–7.6 or treatment- per 1,000 (93.4–97.9) (91.7–98) based algorithm person-years Mebrahtu et al., Cohort 2012–14 13,734 nr UK 0 3–7 Median 5.55; Doctor diagnose One year 52.4 (51.5–53.2) nr nr 2016 (38) range, 0–7.6 or treatment- incidence, % based algorithm Mohn et al., 2018 Cohort 2009–15 357,451 (2009) nr Norway < 6 6–12 6 Doctor diagnose Incidence rate 2009: 0.028 2014: 0.034 nr nr (378) 373,954 (2014) or treatment- per patient- (0.028–0.029) (0.033–0.035) based algorithm years. 2014: 0.073 (0.071–0.075) Simpson et al. Cohort 2001–05 >30 million nr UK All ages nr 4 Doctor diagnose Age and sex 9.6 (9.5–9.7) 13.6 (13.5–13.7) nr nr 2008 (52) standardized one-year incidence per 1,000 patient- years

nr: not reported; SD: standard deviation. Australia. This may be partlyexplained bydif seldom assessedin Africa, South America, and doctor-diagnosed 1-yearprevalence of AD was estimates acrossdifferent agegroups. results suggestthattherearesteadyprevalence considerably. However, with this in mind, the time periods difficult. The study size also varied comparisons betweengeographicalregionsand nents, cultures,andtimeperiods. This makes conti across differ may AD of definition and Furthermore, theappearance,knowledgeof, criteria wereusedandthestudy designsdiffered. in different settings.Severaldifferent diagnostic of AD epidemiology the compare to difficult it dicate ahighprevalenceof AD acrosscontinents. individuals from all continents. The findings in tional andbirthcohortstudiesofseveralmillion This wasasystematicreviewof378cross-sec DISCUSSION mating theprevalenceandincidenceof (91). AD “general population”,thuspotentiallyoveresti included high-riskinfantsinadditiontothe childhood oradulthood. excluded prevalent AD diagnosedduringlater reported oninfant-onset AD andthismayhave dies. However, itispossiblethatsome relevant strategy wasdesignedtodetect allrelevantstu andthesearch oflanguagerestrictions, cause No articleswereexcluded from thereviewbe Strengths andlimitations of adultincident AD. factors associated and definition the on needed was highinallagegroups,andmorestudiesare some settings(72).Interestingly, theincidence males maybearesultofsurveillancebiasin sex differences. A higherprevalenceof AD in however, there were conflicting results regarding of AD for females than for males across all ages; AD. Somestudiessuggestedahigherprevalence be explainedbyhighpersistenceoradultonset of adults. The high prevalence of AD in adults could ahighprevalenceof was inchildren and AD data for Asia weremoreheterogeneous. There tury, especially in Africa and even in Europe. The higher duringthe21 rance data. often usedgeneralpractitionerdatasetsorinsu ferences inhealthcare,astheEuropeanstudies There weremorestudiesonchildren,and The studies were heterogeneous,whichmade Some studies,suchastheCOPSACstudy, The reportedprevalenceof AD wasusually st centurythanthe20 th cen ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV at age13–14years. The presentdataarealsoinaccord 12-month prevalenceof7.9% atage6–7yearsand7.3% a systematicreviewusing ISAACdatawithamean The resultsofthisstudycompare wellwithresultsfrom Comparison withotherstudies variations. may be useful, as prevalence of AD can show seasonal and lifetimeprevalence. This comprehensivereporting This reviewreportspointprevalence,1-year rent methodsof AD assessmentshouldbekeptinmind. of risk factors; however, the factthat studies used diffe prevalence and patterns disease in changes reflect may until 2017. The changesinprevalenceandincidence her socioeconomicstatusweremorelikelytoparticipate. tion. Itispossiblethatindividualswith AD whohadhig only a few studies reported data on socioeconomic posi and reportedprevalenceof AD symptoms. atment, which might have influenced disease symptoms Most epidemiological studies had noinformation ontre is possiblethatotherformsofdermatitiswereincluded. AD isimportant,asitaffects thereportedproportions;it reported on AD as a secondary outcome. The definition of sess theprevalenceandincidenceof AD, whereasothers findings inhighlydiversesettingsandpopulations. and datafromallcontinents. The studythusreportson large representativecohorts,datafromseveraldecades, based epidemiological studies, including those with The findings report data from representative population- search andacriticalassessmentofthereviewedstudies. similar studydesignandmethod(93). the prevalenceof AD symptomsin56countriesusinga data. Incontrast,thestudyby Williams etal.compared the summarize to difficult it made used questionnaires ferences instudydesign and slight differences in the studies, liketheISAACoradaptedcriteria,dif self-report measurestodiagnose AD areneeded. similar diagnosticcriteriaisveryuseful,andvalidated AD insomegroups.However, comparisonofdatausing groups ofpatientsmayoverestimateorunderestimate types, usingthesamediagnosticcriteriafordifferent and signs of AD may vary across age groups and skin infancy mighthavebeenmissed(92). As thesymptoms sease and thus some cases of AD with onset later than stable. ISAAC criteria,andotherwise-reported AD werequite using doctor-diagnosed AD, self-reported AD using changed overthedecades;however, thetrendsindata have may AD of definitions The missed. were studies The studies in this reviewincluded data from 1958 Many studieslackeddataonparticipationrate,and However, someincludedstudiesweredesignedtoas This systematicreviewincludedacomprehensive Although similar diagnostic criteria wereused in some Some diagnosticcriteriaincludedinfantonsetofdi Prevalence andincidenceofatopicdermatitis:asystematicreview ------this papersarenumberedinaccordancewiththecom counselling. study haverelevance forhealthcare planning and patient assessment of AD maybeuseful. The resultsofthis Further standardizationandvalidationforself-reported and usedworldwide,whichpermitsdatacomparisons. The ISAAC criteria andthe UK criteria are validated of AD, andvalidateddiagnosticcriteriaareimportant. studies usequestionnairedatatoassesstheprevalence even suggestriskfactorsthatneedtargeting. Most of diseasemechanisms(97).Changesinincidencecan standing ofincidenceisimportantfortheunderstanding comprehensive worldwideassessmentisneeded. on theepidemiologyof AD inEuropeandtheUSA;a tools andasimilarstudydesign. There aremorestudies studies areneededusingthesamevalidateddiagnostic AD mayvaryaccordingtodiagnosticmethods.More Pols etal.(95)reportedthattheassessedprevalenceof by review findings. A our to similar was children and (96), aprevalenceof AD foradolescents/youngadults tury (94, 95). In a systematic review by Abuabara et al. 3b38e704fd06.) shown at:http://lup.lub.lu.se/record/e240247d-7664-4263-9918- (complete list of references also appearing in the supplements REFERENCES edanzediting.com/ac) foreditingadraftofthismanuscript. The authors thank Diane Williams, PhD, from Edanz Group(www. ACKNOWLEDGEMENTS tures inordertoimprovefutureepidemiologicalstudies. assessment of AD mustbemorestandardizedacrosscul ally on the incidence of AD during adulthood. However, of AD inthe21 rica. There are only a few recent studies on the incidence and reachedastableplateauinEuropeNorth Ame common disorderthathasincreasedinmostcontinents As assessed by both patients and physicians, AD is a Conclusion 4263-9918-3b38e704fd06. shown at:http://lup.lub.lu.se/record/e240247d-7664- ofreferencesalsoappearinginthesupplements plete list lower prevalenceinthe20 (17). The results are in line with studies suggesting a no clearpatternofprevalence AD acrosscontinents with datafromISAACstudiessuggestingthatthereis adulthood AD in different continents are needed, especi USA. Moreepidemiologicalstudiesonchildhoodand most studies have been conducted in Europe and the Below, the14referencesappearingin Tables I–IIIof There isalsoalackofincidencestudies. An under 1. Jensen C. AtopicJensen C. toadulthood fromadolescence dermatitis Mortz CG,AndersenKE,Dellgren C,Barington T, Bindslev- st centuryandnostudiesonadultsonly; th centurythaninthe21 Theme issue:Atopic dermatitis st cen 325 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis 326 11. 10. 21. 20. 19. 18. 17. 16. 15. 14. 13. 12. 9. 8. 7. 6. 5. 4. 3. 2.

Lindstrom CB, Svensson A. Factors associated with remis von Kobyletzki LB, Breeze BornehagCG, E,LarssonM, Atopic dermatitis.Nature Rev Dis Primers 2018; 4: 1. Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. conditions. JInvest Dermatol 2014; 134: 1527–1534. 2010: an analysis of the prevalence and impact of skin Margolis DJ, etal.Theglobal burdenofskindiseasein Hay RJ, Johns NE, Williams HC, Bolliger IW, Dellavalle RP, Venereol 2019;99: 964–970. in Swedish adults:apopulation-basedstudy. ActaDerm Svensson Å, Kobyletzki LB. dermatitisBurden of atopic Theodosiou G, Montgomery S, Metsini A, Dalgard FJ, hood acne, ephelides, warts, atopicdermatitis, psoriasis, Yang YC,ChengYW, LaiCS, ChenW. Prevalence ofchild titis. ActaDerm Venereol Suppl1980;92: 44–47. Hanifin JM, Rajka G. Diagnostic features of atopic derma 2009; 339:b2700. healthcare interventions: explanation and elaboration. BMJ tematic reviews and meta-analyses of studies that evaluate Ioannidis JP, etal.ThePRISMAstatement forreportingsys Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, demiology/oxford.asp. Available from:http://www.ohri.ca/programs/clinical_epi the quality of nonrandomised studies in meta-analyses. M, et al. The Newcastle–Ottawa Scale (NOS) for assessing Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos J 1995; 8: 483–491. in Childhood (ISAAC): rationale and methods. Eur Respir tinez F, et al. International Study of Asthma and Allergies Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Mar 131: 383–396. discriminators for atopic dermatitis. Br J Dermatol 1994; for Atopic Dermatitis. I.Derivation of a minimumsetof Hunter JJ, et al. The U.K. Working Party’s Criteria Diagnostic Williams HC, BurneyPG,Hay RJ, ArcherCB, ShipleyMJ, Res Policy 2002; 7: 51–61. critical appraisal of guidelines and practice. J Health Serv heterogeneity in systematic reviews of clinical trials: a Higgins J, Thompson S, Deeks J, Altman D. Statistical J Korean Med Sci 2017; 32:1360–1366. Atopic Dermatitis in Adults Are Different according to Onset. Son JH, Chung BY, Kim HO, Park CW. Clinical Features of Dermatol Res 2017; 309: 443–452. persistent versusdermatitis: adult-onset disease. Arch atopic studyonadult multicentre AnItalian N,etal. Balato Megna M, Patruno C, Balato A, Rongioletti F, Stingeni L, 2013; 68: 498–506. atopic dermatitisinadolescentandadultpatients. Allergy R, Diepgen T, et al. Characterization of different courses of Garmhausen D, Hagemann T, Bieber T, Dimitriou I,Fimmers study. ActaDerm Venereol 2014;94: 179–184. sion of eczema in children: a population-based follow-up Venereol 2015;29: 1180–1187. sociations with environmental factors. J Eur Acad Dermatol Ferrari M,etal.Adulteczema inItaly:prevalence andas Pesce G, Marcon A, Carosso A, Antonicelli L, Cazzoletti L, Childhood (ISAAC Phase Two). Allergo J 2008; 17: 79–81. two of the International Study of Asthma and Allergies in flexural eczema and atopic sensitization. Results from phase Rzehak P, et al. International variation in prevalence of Kleiner A,FlohrC,Weiland S, Weinmayr G,Büchele 526–535. study.a population-based 2007; 37: ExpAllergy Clin M, etal.Eczema, atopy andallergenexposureinadults: Harrop J, ChinnS, Verlato G,OlivieriM,NorbackD, Wjst childhood atopic dermatitis. Allergy 2014; 69: 3–16. Flohr C, Mann J. New insights into the epidemiology of Allergy Asthma Proc2012;33: 227–234. DaVeiga SP. Epidemiology of atopic dermatitis: a review. 2017; 38: 3–8. of life, and associated complications. Allergy Asthma Proc Drucker AM. Atopic dermatitis: Burden of illness, quality bidities. Allergy2015;70:836–845. in theTOACS cohort:prevalence, persistenceandcomor S. Bylundetal. ------29. 28. 27. 26. 25. 24. 23. 39. 38. 37. 36. 35. 34. 33. 32. 31. 30. 22.

Kudzyte J, GriskaE,Bojarskas J. Timetrendsinthepreva 2017: 2184193. in Kuwait: across-sectionalstudy. Biomed Res Int2017; and eczema andtheirmultimorbidity amongyoung adults Ziyab AH. Prevalence and risk factors of asthma, rhinitis, 128–133. in Urumqi and Beijing. J Paediatr Child Health 2000; 36: valence of childhood asthma, allergic rhinitis and eczema Zhao T, Wang HJ, Chen Y, Xiao M, Duo L,Liu G, etal. Pre Clin Exp Allergy 2004; 34:779–785. atopic dermatitis symptoms in rural and urban Ethiopia. Williams HC,etal.Prevalence andassociatedfactors of Yemaneberhan H, Flohr C, Lewis SA, Bekele Z, Parry E, children. P R Health Sci J 2007;26: 127–133. prevalence school PuertoRican in dermatitis ofatopic Maymi MA,SomolinosAL,Nazario CM,SanchezJL.The community. BMC Dermatol 2018;18: 11. and associatedhealth-relatedquality oflifeinarural Lao vong M,KidoikhammouanS, etal.Assessingskindisease Wootton CI, Bell S, Philavanh A, Phommachack K, Souka 112: 434–438. children in Diyarbakir, Turkey. Arch Argent Pediatr 2014; et al.Prevalence of skindisordersamongprimaryschool Sula B, Ucmak D, Saka G, Akdeniz S, Yavuz E, Yakut Y, 52–53. examined 20years ago. ActaDerm Venereol 1997;77: panese population: comparison with the disease frequency factors ofatopiceczema inTurkish adolescents.Pediatr Akcay A,Tamay Z,ErginA, GulerN.Prevalence and risk Epidemiol 2016; 30: 594–602. findings from the Born in Bradford Cohort. Paediatr Perinat eczema, disorders, children: den ofwheezing in andrhinitis Mebrahtu TF, Feltbower Parslow RG, andbur RC.Incidence 2015; 32: 668–678. retrospective, population-based study. Pediatr Dermatol from2006to2012:a children Italian in diseases skin Cantarutti L,etal.Epidemiologyoffrequentlyoccurring Cantarutti A, Dona D, Visentin F, Borgia E, Scamarcia A, Korean Acad2012;42: 992–1000. atopic dermatitisamongKorean middleschoolstudents.J Oak JW, LeeHS. Prevalence rate with andfactorsassociated study. J Investig Allergol Clin Immunol 2011; 21: 270–277. in schoolchildren aged 10–11 years: a national multicenter et al. Prevalence, burden, and risk factors of atopic eczema Civelek E, Sahiner UM, Yuksel H, Boz AB, Orhan F, Uner A, network. AnnInternMed 2019; 170:354–356. seen in primary care: data from the health improvement Langan SM. Prevalence of atopic eczema among patients Abuabara K, Magyari Linos DJ,CE, E, A, Margolis McCulloch 2003; 3:4. symptoms assessed in a questionnaire study. BMC Dermatol living environment, socio-economic status and respiratory son A. Prevalence of self-reported eczema inrelationto Montnemery P, U, Nihlen Goran C,NybergP, Lofdahl Svens nationwide study, 1966–2003.BMJ2005;330:1186–1187. in prevalence of asthma and allergy in Finnish young men: Latvala J, von Hertzen L,LindholmH,Haahtela T. Trends Cancer 2006;119:695–701. cancer of the prostate, breast, lung and colorectum. Int J Diepgen TL. Atopic diseases, immunoglobulin E and risk of Wang H, Rothenbacher D, Low M, Stegmaier C, Brenner H, 30: 20–28. 19-year-old Korean malesubjects.Ann Dermatol 2018; and clinicalcharacteristics accordingtodiseaseonsetin al. The prevalence and risk factors of atopic dermatitis Kwon IH, Won CH, Lee DH, Kim SW, Park GH, Seo SJ, et Lithuania. Medicina(Kaunas) 2008; 44:944–952. Results from ISAAC phase I and III studies in Kaunas, lence of asthma and allergy among 6-7-year-old children. Prevalence of infantile and early childhood eczema in a Ja Sugiura H,Uchiyama M,OmotoSasaki K,Uehara M. Venereol 2007;21: 643–649. a community-based clinicalsurvey. JEurAcadDermatol alopecia areata and keloid in Kaohsiung County, Taiwan: ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 57. 56. 55. 54. 53. 52. 51. 50. 49. 48. 47. 46. 45. 44. 43. 42. 41. 40.

junctivitis, and atopic eczema in 6- to 7-year-old Nigerian and severity of symptoms ofasthma,allergicrhinocon Falade AG, Olawuyi JF, Osinusi K, Onadeko BO. Prevalence Immunol 2007; 18: 560–565. in African adolescents from 1995 to 2002. Pediatr Allergy prevalence ofasthma,allergic rhinitisand atopiceczema Zar HJ, Ehrlich RI, Workman L, Weinberg EG. The changing 514–518. in Uasin Gishu district, Kenya. East Afr Med J 2002; 79: allergic rhinitisanddermatitis inprimaryschoolchildren Esamai F, Ayaya S, Nyandiko W. Prevalence ofasthma, 371–377. ISAAC phase I and III. Int J Tuberc Lung Dis 2006; 10: asthma and other allergic disease symptoms in Morocco: Chan-Yeung M, et al. Prevalence and trend of self-reported N, Benouhoud Trombati A, Afif A, Aichane Z, Bouayad Int J Hyg Environ Health 2016; 219:343–348. chool children: Results from three cross-sectional studies. parent reportedprevalence ofallergies inBavarian pres Ratzel U, von Mutius E, et al. No further increase in the Weber A, Herr C, Hendrowarsito L, Meyer N, Nennstiel- 558–563. national primary care database. J R Soc Med 2008; 101: and prevalence of multiple allergic disorders recorded in a Simpson CR, Newton J, Hippisley-Cox J, Sheikh A. Incidence BMC Public Health2013; 13: 585. munities in Cyprus: a bi-communal cross-sectional study. children from the Greek-Cypriot and Turkish-Cypriot com M, Arifoglu K, et al. Prevalence of asthma and allergies in Lamnisos D, MoustakiM,Kolokotroni O, Koksoy H,Faiz 964–968. County, Hungary. JEurAcadDermatolVenereol 2007;21: lence of atopic dermatitis among schoolchildren in Baranya preva the in interval 3-year a within increase significant Harangi F, Fogarasy A,MullerSchneider I,Sebok B. No Immunol 2012; 23: 464–471. rhinitis and eczema in Irish schoolchildren. Pediatr Allergy JO. The 2002–2007 trends of prevalence of asthma, allergic Duggan EM, SturleyJ, Fitzgerald AP, Perry IJ, Hourihane Polska 2004; 79:385–392(inPolish). allergic diseases in children – Fact or artefact?]. Pediatria Brozek G,Zejda J. [Increaseinthefrequencyof diagnosed Mex 2018; 65: 331–340(inSpanish). Mexican late adolescents over a 7-year period]. Rev Alerg et al. [Trends in asthma prevalence and its symptoms in TR, Navarro-Lozano TI, Bedolla-Pulido Bedolla-Pulido E, Morales-Romero J, Bedolla-Barajas M, López-Cota GA, Pediatr Neonatol 2009; 50:18–25. allergic diseases in central Taiwan over the past 15 years. Liao PF, SunHL,LuKH,LueKH.Prevalence ofchildhood Allergol ClinImmunol 2008; 18:31–35. rhinitis, andasthma inacity inwesternTurkey. JInvestig P, etal.Prevalence andcomorbidity ofallergiceczema, Yuksel H,Dinc G,SakarA,YilmazO, Yorgancioglu A,Celik in Turkey. Pediatr Dermatol 2008; 25:399–401. demiology of atopic dermatitis in primary schoolchildren Ergin S, Ozsahin A,ErdoganBS, AktanS, Zencir M.Epi Asthma Immunol2005; 95: 579–585. 13- to14-year-old childreninTaipei, Taiwan. AnnAllergy severity of symptoms of asthma, rhinitis, and eczema in Yan DC, OuLS, Tsai TL,Wu WF, Huang JL.Prevalence and population. J Invest Dermatol 2019;139:583–590. and disease burden of atopic dermatitis in the US adult study: a cross-sectional study examining the prevalence Fonacier L,GelfandJM,etal. Atopic dermatitisinAmerica FuxenchChiesa ZC, M,Boyle JK,Boguniewicz Block J, tion withmigraine. Pediatr Dermatol 2017; 34: 247–252. adolescents from 1998 to 2013: trends in time and associa Molho-Pessach V, Zlotogorski A. Atopic dermatitis in Israeli Shreberk-Hassidim R, Hassidim A, Gronovich Y, Dalal A, 2005; 22: 6–10. ders in school children in Ibadan, Nigeria. Pediatr Dermatol Ogunbiyi AO, OwoajeE, Ndahi A. Prevalence of skindisor Dermatol 2014;31: 319–325. Prevalence andincidenceofatopicdermatitis:asystematicreview ------75. 74. 73. 72. 71. 70. 69. 68. 67. 66. 65. 64. 63. 62. 61. 60. 59. 58.

eczema in5-to8-yr-old Maltesechildren(ISAAC). Pediatr H. Increasing prevalence of asthma, allergic rhinitis but not Montefort S, EllulP, MontefortM,Caruana S, AgiusMuscat 315–320. Estonian schoolchildren.Pediatr AllergyImmunol2005; 16: in seasonal allergic rhinitis and eczema over 8 years among Annus T, Riikjarv MA, Rahu K,Bjorksten B. Modestincrease Allergy Immunol 2007;18: 149–153. 14-yr-old childrenfrom thenorth-eastof England.Pediatr asthma, rhinitisandatopiceczema in6-to7-and13- M.TrendsShamssain theprevalence in andseverity of 572–579. phase IIIsurveys inMunster, Germany. Allergy2003;58: adolescents increasing? Results from ISAAC phase I and Weiland SK,etal.Areasthma andallergiesinchildren W,Maziak BehrensT, Brasky Rzehak DuhmeH, TM, P, 2009; 64: 798–800. asthma and allergies from 1995 to 2002 in France. Allergy dard P. prevalence trends in Time andseverity ofchildhood Annesi-Maesano I, Mourad C, Daures JP, Kalaboka S, Go 556–562. old Swiss children from 1992 to 2001. Allergy 2006; 61: asthma, allergicrhinitisandatopicdermatitisin5-7-year Trends etal. K,SennhauserFH, Sahli prevalence in of Grize L, Gassner M, Wuthrich B, Bringolf-Isler B, Takken- in England. J RSocMed2009; 102: 108–117. and of the for prescribing medication epidemiology eczema Newton J,Simpson CR, Hippisley-Cox J, Sheikh A. Trends in to theintrinsictype. Br J Dermatol 2000;143:992–998. J. The excess of atopic eczema in East Germany is related Schafer T, Kramer U, Vieluf D, AbeckD, BehrendtH,Ring during the 1990s. Acta Derm Venereol 2005; 85: 244–247. incidence of atopic dermatitis among children in Denmark Olesen AB, Bang K, Juul S, Thestrup-Pedersen K. Stable Three. J Trop Pediatr 2007; 53: 13–21. years old):comparisonbetween ISAAC Phases One and allergic diseases among Brazilian schoolchildren (13–14 Rosario theprevalence Changesin NA,etal. ofasthma and Sole D, MeloKC,Camelo-NunesIC,Freitas LS, Britto M, 2008; 31: 146–150 (in Portuguese). III by socioeconomic status]. Rev Bras Alergia Imunopatol Federal District. ComparisonbetweenISAAC phasesIand Borges VM. [Atopic dermatitis among adolescents from Borges WG,Burns DAR, Guimaraes FATM, Felizola MLBM, 368–374. from Cuernavaca, Mexico. AllergyAsthmaProc2007;28: of asthma and other allergic diseases in schoolchildren H, Ramirez-Aguilar M, Romieu I. Trends in the prevalence Barraza-Villarreal A,Hernandez-Cadena L,Moreno-Macias 284–289. An ISAAC Study (Phase III). Med Princ Pract 2008; 17: of asthmaandallergicdiseasesamongKuwaiti children. Owayed A, Behbehani N, Al-Momen J. prevalenceChanging 609–611. Allergies inChildhood)PhaseThree.JAsthma2007;44: Thai children-ISAAC (International Study of Asthma and trends of the prevalence of asthma, rhinitis and eczema in Trakultivakorn M,Sangsupawanich P, Vichyanond P. Time ISAAC surveys 5years apart.JAsthma2009;46:541–545. allergic diseasesofschoolchildrenincentral taiwan. From Liao MF, LiaoMN,LinSN,ChenJY, HuangJL.Prevalence of 145: 966–973. Prefecture, Japan, from 1985 to 1997. Br J Dermatol 2001; dermatitis inschoolchildren:longitudinalstudyOsaka Yura A, Shimizu T. Trends in the prevalence of atopic 2000. J Korean MedSci2004; 19: 716–723. allergy in school-aged children in Korea between 1995 and al. Epidemiological change of atopic dermatitis and food Oh JW, Pyun BY, Choung JT, Ahn KM, Kim CH, Song SW, et 2001. Clin ExpAllergy 2007; 37: 543–551. of atopic eczema in Taiwanese adolescents from 1995 to Lee YL, Li CW, Sung FC, Guo YL. Increasing prevalence and allergies in childhood. Med Princ Pract 2004; 13: 20–25. primary school children: the international study of asthma Theme issue:Atopic dermatitis 327 - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis 328 94. 93. 92. 91. 90. 89. 88. 87. 86. 85. 84. 83. 82. 81. 80. 79. 78. 77. 76.

matitis in adults: systematic review on population studies. Mathiesen SM,ThomsenSF. Theprevalence ofatopicder 1999; 103:125–138. Asthma andAllergiesinChildhood.JAllergyClinImmunol of symptoms of atopic eczema in the International Study of Worldwide AndersonR,etal. G, variations theprevalence in Williams H, Robertson C, Stewart A, Ait-Khaled N, Anabwani matitis Working Party. Br J Dermatol 1996; 135:12–17. population setting. UK Diagnostic Criteria for Atopic Der of theU.K. diagnostic criteriaforatopicdermatitis ina Williams HC,Burney PG,Pembroke AC,Hay RJ. Validation Immunol 2004; 93: 381–389. from a longitudinal birth cohort study. Ann Allergy Asthma (COPSAC): Childhood in rationale, design, data andbaseline Bisgaard H. The Copenhagen Prospective Study on Asthma e6317. tertiary hospitals of China. Medicine (Baltimore) 2017; 96: valence and clinical features of adult atopic dermatitis in Wang X,ShiXD, LiLF, ZhouP, ShenYW, SongQK. Pre S179. childhood atopic dermatitis. J Invest Dermatol 2013; 133: rities in the prevalence, severity and health outcomes of Silverberg JI, Hanifin JM, Simpson EL. Racial/ethnic dispa (atopic dermatitis). Acta Derm Venereol 1956; 36: 11–22. Hellerstrom S, Lidman H. Studies of Besnier’s prurigo 2009; 102:431–442. in Scotland: analyses of national databases. J R Soc Med A. Epidemiology and disease burden from allergic disease Anandan C,Gupta R, Simpson CR,FischbacherC,Sheikh spective study. Exogenous Dermatology 2003; 2: 60–63. M, et al. Atopic dermatitis in Tunisia: a multicentre retro Amri M, Youssef M, Kharfi M, Cherif F, Masmoudi A, Kourda Immunol 2008;122:280–285. Clin age. JAllergy to middle incidence and persistence: a cohort study from childhood rin LC, WhartonCL,etal.Childhoodeczema andasthma Burgess JA, Dharmage SC, Byrnes GB, Matheson MC, Gur study. Br J Dermatol 1998;139:834–839. eczema: observations from theBritish 1958 birth cohort Williams HC, Strachan DP. Thenatural historyofchildhood to adulthood. Pediatr Allergy Immunol 2013; 24: 549–555. course of sensitization and allergic diseases from childhood Nissen SP, Kjaer HF, HostA, NielsenJ, Halken S. Thenatural study. Br J Dermatol 2013;168:1339–1342. natural history of eczema from birth to adult life: a cohort Burr ML, Dunstan FD, Hand S, Ingram JR, Jones KP. The Allergy 2012; 67:537–544. and rhinitis to age 12: data from the BAMSE birth cohort. E, et al. Development and comorbidity of eczema, asthma Ballardini N,Kull I,LindT, HallnerE,AlmqvistC,Ostblom Province, Iran. Macedonian J MedSci2016;4:619–623. asthma in students of guidance schools in Mazandaran Tavakoli S. Theprevalence ofallergicrhinitis,eczema and Zamanfar D, J, Gaffari S, Behzadnia Yazdani-Charati J, munopathol (Madr) 2016; 44:214–220. cohort studyof infantsinsoutheastTurkey. AllergolIm Prevalence of andriskfactors foratopic dermatitis:abirth Dogruel D, Bingol G, Altintas DU, Yilmaz M, Kendirli SG. 2000; 80: 353–356. valence of atopic dermatitis in Korea. Acta Derm Venereol Kim CW, Park CJ, Kim JW, Koo DW, Kim KW, Kim TY. Pre Med JAust 2004;180:273–276. in Melbourne schoolchildren: have we reached the peak? Robertson CF, Roberts MF, Kappers JH. Asthma prevalence of birth.Int J Epidemiol2008;37:559–569. lian Capital Territory with further consideration of country prevalence from 2000 to 2005 at school entry in theAustra Kljakovic M.Atemporal declineinasthmabutnoteczema Ponsonby N,Pezic AL,Glasgow A,Dwyer T, Ciszek K, Allergy Immunol 2009;20: 67–71. S. Bylundetal. ------374. 252. 235. 210. 195. 193. 132. 379. 378. 373. 306. 274. 255. 156. 97. 96. 95.

Werfel T, Girolomoni G, Gadkari A, Auziere S, Puig L, Bar 2018; 21: S431. the german statutory health insurance system. Value Health with atopicdermatitis:analysisof longitudinaldatafrom C. Epidemiologyandtreatmentpatternsinadultpatients Zietze HA, Augustin M, Kienitz C, Theobald K, Ihle P, Cabral diseases inAustrian schoolchildreninconjunctionwithur C, von MutiusE,etal. Prevalence ofwheezingandatopic Horak E,Morass B, UlmerH,GenuneitJ, Braun-Fahrlander Respir J2010; 17: e1–6. Child Health Evaluation Questionnaire (T-CHEQ) Study. Can ofTorontosample fromtheToronto results children: school et al. Asthma and allergic disease prevalence in a diverse Dell SD, Foty RG, Gilbert NL, Jerret M, To T, Walter SD, 73: 1284–1293. adults: resultsfromaninternationalsurvey. Allergy2018; Simpson EL, et al. Epidemiology of atopic dermatitis in Barbarot S, Auziere S, Gadkari A, Girolomoni G,Puig L, based cohort study. Br J Dermatol 2018;179:e58. eczema ofatopic lence AUKpopulation- acrossthelifespan: Abuabara K, Magyari A, Margolis DJ, Langan M. The preva children inEasternCroatia. Acta Clin 2018;57: 82–90. Gudelj A,etal.Allergicdiseasesandatopy amongschool Aberle N,KljaicBukvicB, Blekic M,Vuckovic M,Bardak D, A3464–A3464. ren in the Netherlands. Ned Tijdschr Geneeskd 2011; 155: ignorance. Vet Dermatol 2013; 24: 3-9.e1-2. seven progressandseven areasofnotable areasofnotable Williams HC. Epidemiology of human atopic dermatitis – Allergy 2018; 73:696–704. tematic review and meta-analysis of longitudinal studies. general practice data. Clin Exp Allergy2002;32: 37–42. aetiology. Apopulation-basedstudyusingcomputerized seases driven by Th1 and Th2subsets suggests a common L, Prescott GJ, et al. Coincidence of immune-mediated di Simpson CR, Anderson WJ, Helms PJ, Taylor MW, Watson study inNorway. JAMA Netw2018; 1: e184145. and earlychildhoodinanationwide prescriptionregistry Lagerlov P. Incidence trends of atopic dermatitis in infancy Mohn CH,BlixHS, Halvorsen JA, NafstadP, Valberg M, German SocDermatol 2018;16: 6. Germany’s results from aninternational survey. JDDG: J barot S, etal.Epidemiologyofatopicdermatitisinadults: 131: 67–73. tional Survey ofChildren’s Health.JInvest Dermatol2011; prevalence intheUnitedStates:datafrom2003Na Shaw TE, Currie GP, Koudelka CW, Simpson EL. Eczema 8: 79–83. Examination Survey. Allergy Asthma Immunol Res 2016; From the2008–2011Korean NationalHealthandNutrition lence of Atopic Dermatitis in Korean Children Based on Data Lee JH,Han KD, KimKM,Park YG,LeeJY, Park YM.Preva Derm Venereol 2010;90: 589–594. asthma inTaiwan: anational study2000to2007.Acta et al. Prevalence of atopic dermatitis, allergic rhinitis and Hwang CY, Chen YJ, Lin MW, Chen TJ, Chu SY, Chen CC, 126: 532–536. ban, rural orfarmresidence.WienKlinWochenschr 2014; prevalence of atopic dermatitis beyond childhood: a sys Abuabara K,Yu AM,Okhovat JP, AllenIE,Langan SM.The review. Scand J PrimHealthCare2016;34:143–150. in general practice and the open population: a systematic Bindels PJ. Atopic dermatitis, asthma andallergicrhinitis Pols DH, Wartna JB, Moed H, van Alphen EI, Bohnen AM, Dermatol OnlineJ 2019; 25. pii: 13030/qt6nj0x5k0. Wijga AH, Beckers MCB. Complaints and illnesses in child incidence data. J Asthma2010; 47: 1128–1135. allergic diseasesinschoolchildrenfrom 1992to2007with Demir AU, Celikel S, Karakaya G,Kalyoncu AF. Asthma and ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Appendix 1 #2. #3. #4. #6. #7. #9. #10. #11. N ...... S Em 12 r 11 10 8no 9 8 4or7(5321) 7 1 6 2or3(7138602) 5 4 1 i 3 R 2 1 ------S S #1. #5. #8. D ncide earc e earc o. ataba ssi

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Theme issue:Atopic dermatitis 329 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV doi: 10.2340/00015555-3511 methods makingtruedatacomparison difficult. diverse andbasedondifferent diagnosticandsampling to atopy. Furthermore cannot be assumed this presentation is always attributable between flexural eczema and atopy (7, 8) and therefore it AD sampleintheworlddemonstratedaweakassociation largest the of study two phase IgE. A allergen-specific phenotypic eczemathatisassociatedwithcirculating of caseslabelledas AD arenotinfacttruly‘atopic’ i.e. extensive epidemiologicaldata. Worldwide, upto50% globally (6),buttherearechallengesincollatingthe the most prevalent chronic inflammatory skin condition from malignanciestocardiovasculareffects (5).Itis systemic disorder given its wide-ranging associations anatomical region(4). AD hasalsobeendescribedasa with varyingclinicalpresentationsaccordingtoageor mation (3). The characteristicsof AD areheterogenous T cine, CardiffUniversity, Cardiff, UK.E-mail:[email protected] Corr: Acta DermVenereol 2020;100;adv00161. Accepted May 7,2020;EpubaheadofprintMay 15,2020 titis. derma life; of quality dermatitis; atopic Key words: eczema; mily Reported FROM-16. OutcomeMeasure, questionnaires ortheFamily DLQIor thegenericFa specific dermatitis atopic several using measured be Quality Theimpacton of partnersandfamily Life. can Dermatology Quality of LifeandInfantsDermatology are the Dermatology Quality of Life(DLQI),Children’s lity of lifequestionnaires: themost frequently used qua adults usingseveraldifferent canbemeasured impactofatopic dermatitiscurrent and on children and to planappropriate The patient andcarersupport. thisimpacttoable to informclinicaldecisions measure caregivers andfamily members.Itisimportant to be patient of lives the on impact significant also is there andadultsdermatitis isextensive onchildren and matory skincondition globally. Theburdenof atopic 1 Faraz ALI of Life Counting the Burden: Atopic Dermatitis and Health-related Quality Centenary theme section:ATOPICDERMATITIS Acta DermVenereol 2020;100: adv00161 Atopic dermatitis is the most prevalent chronic inflam system dysfunction (2) and psycho-neurogenic inflam psycho-neurogenic and (2) dysfunction system a combination of epithelial barrier defects, (1) immune (QoL). The pathophysiologyof AD ispostulatedtobe Institute of InfectionandImmunity, and tis (AD)hasaprofoundimpactonqualityoflife he dry, itchy, eczematous skinofatopicdermati Dr Faraz Ali, Institute of Infection and Immunity, School of Medi- of Immunity,School and Infection of Institute Ali, Faraz Dr 1 , Jui VYAS 2 andAndrew Y. FINLAY prevalence studies are often ad hoc prevalence studies are often 2 Centre for Medical Education, School of Medicine,Cardiff University, Cardiff, UK 1 This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta REVIEW ARTICLE ------particular ontheQoL measures recommended by Har focusses onthemeasurementofQoL in AD patients,in mental health,workproductivityandQoL. This review this effect ismulti-dimensional withimplicationsfor caregivers andfamilymembers(9).Inaffected adults, and there is also significant impact on the lives of patient has providedastandardised platformtoidentifyovera Study of Asthma and Allergies inChildren (ISAAC) paediatric population (9). The advent ofthe International be generalisedtootherpopulations. described inthecorrespondingreferenceandmaynot population the to relate review this in quoted figures from apopulationcross-section. The variousprevalence for example if data from a clinic is measured rather than the methodology ofmany surveysleads toselection bias, surveys of AD prevalence, contributing to confusion, and several differing diagnostic criteria that may be used in represent thegeneralpopulation.However, thereare criteria andtheabilitytogatherdatafromsubjectsthat disease depends on there being clear agreed diagnostic The determinationofaccurateprevalencedataforany OFATOPICDERMATITIS EPIDEMIOLOGY hout thismanuscript“qualityoflife”referstoHRQoL. aspect ofthewiderconcept“qualitylife”. Throug different ages,socialgroupsandcountries. the implicationsofwiderimpactthat AD hasacross monising Outcome Measures for Eczema (HOME), and n QL a re dsrpin f h ms rlvn instru ments isalso presentedinthisarticle. relevant most the of description brief a QoL; ing availablemeasur are for tools of myriad A relatives. close and patients of QoL the on dermatitis atopic of impact the of atopic dermatitis sufferers. This review aims to evaluate members family close and partners caregivers, to extend also may impairment QoL This (QoL). life of quality tient on pa impact significant a to contribute often treatment of demands the as well as dermatitis atopic of symptoms condition globally that affects both children and adults. The skin inflammatory common most the is dermatitis Atopic SIGNIFICANCE The burden of disease of AD on children is extensive Most AD epidemiologicaldatahavefocussed onthe specific a is (HRQoL) life of quality Health-related Journal Compilation ©2020ActaDermato-Venereologica. - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV maceutical industry. In the US during the late 1980s there else (16). The initialdriveforPROs wasledbythephar treatment, withoutinterpretation byaclinicianoranyone mes directlyfromapatientabout ahealthconditionorits A PatientReported Outcome (PRO)isanyreport thatco PATIENT REPORTED OUTCOMEMEASURES monitoring responsetotherapy. also usefulintheassessmentofnoveltherapies,and the clinicianconcerningchoiceoftherapy. This datais by it,becausethisinformationisessentialtoinform the impactofthisconditioninthosewhoareaffected burden ofdiseasefrom AD. Itisimperativetomeasure were allassociatedwithpersistentdisease. Disease severity, duration,lateronsetandfemalesex experiencing persistentdiseaseat20yearsfollow-up. mean ageof AD diagnosiswas 1.6years,with<5%cases et al.(15)analysed110,000 casesandreportedthatthe practitioners, or self-reporting may over-diagnose. Kim may bebecausemildercasesdonotpresenttogeneral (11.4–24.2%)This (14). self-reported when than lower of AD assessed by general practitioners (1.8–9.5%) was Netherlands and the UK demonstrated that the prevalence in northerncountriessuchastheUK(12). than higher was disease mild of prevalence the Europe reported having the most severe AD, whereas in southern subjects USA used, was measure which of Regardless criteria, withunder10%havingaphysiciandiagnosis. UK modified Party using Working self-diagnosed jects age (p<0.05).However, astudylimitationwasthatsub with AD thenbecominglessprevalentwithincreasing and males. Peak prevalence was from age 25 to 45 years, no significant difference in prevalence between females valence in females, but in the UK and the USA there was countries and regions. Generally, there was a higher pre to 8.1% (Italy), and there were further variations within criteria. Prevalencevaluesrangedfrom2.1%(Japan) worldwide usingstandardisedmethodsanddiagnostic survey on representative samples of adults (ages 18–64) Recently, Barbarot et al. (12) conducted an international ranging from 0.3% (Switzerland) to 6.2% (Estonia) (13). rates prevalence identified and subjects European and US from data collated study (ECRHS) Survey Health Respiratory Community European The population. point prevalenceis4.4%(12). in Latin America and Africa. In the European Union the to 24.6%(Columbia)withgenerallyhighervaluesseen subjects) theprevalence values range from0.2%(China) 660,000 13–14, (ages teenagers For (11). countries 60 from years 6–7 aged children 380,000 of sample a in prevalence ranged from 0.9% (India) to 22.5% (Ecuador) million childrensuffering with AD worldwide(10). The As the above studies demonstrate, there is a large A systematic review of 13 studies conducted in the There havebeenseveralstudiesexaminingtheadult - - - - childhood chronic diseases such as cerebral palsy, epi sufferers. of AD the variousaspectsofQoL impairmentacrosstherange and health-economicdecisions.Itisvitaltounderstand treatment influence also should family for implications assessment, butthelong-termeffects aswellwider term’ and‘family’ (22). The ‘now’ isimportantforcurrent proposed thatarekeytoQoL evaluation:‘now’,‘long- dermatology. Three dimensionsinparticularhavebeen across efficacy intervention and disease monitoring QoL measurement has become an integral aspect of QUALITY OFLIFE THE IMPACTOFATOPICDERMATITIS ON status, orgeneralHRQoL. development ofaPROharmonisationgroup(21). of outcomemeasuressubsequentlydevelopedledtothe outcome” wascoinedintheyear2000andplethora health relatedoutcome(20). The term“patientreported tical companyroseresultinginaneconomicimpactofa pharmaceu the of value market efficacy, stock than the press, although the endpoint measured tolerability rather anti-hypertensives: when the results were publishedbythe measure usedasanendpointinaclinicaltrialinvolved in oncologytrials(19).However, areportofPRO (FDA) initiated the requirement for QoL assessments clinical research.” The FoodandDrug Administration and practice office in wellbeing patient the “monitoring mes Studyconcludedthattoolsshouldbedevelopedfor having to explain several misconceptions (27), eventually sense ofbeingdifferent due toalienatingcommentsand friends whenolder(26).Growing up,theydevelopa Parents fearthattheirchildren maybeunabletomake the latterarelikelytoincludemoreseverecases. differ betweenprimaryand secondarycaresettingsas of AD isoftennotafocusinstudies:QoL scoresmay ving themofa‘normalchildhood’(25). The chronicity when feeding,changingclothesandplaying,thusdepri AD areoftenaffected onadailybasisincludingproblems a widerangeofreportedimpacts AD. Childrenwith on health-relatedQoL.Howeverineachstudytherewas AD andfoundthat AD had,onaverage, amoderate effect (24) identified data from 37 studies on 4082 children with al. et Olsen by (23). review fibrosis A cystic and lepsy of the health care system. This landmark Medical Outco components specific by affected were care of outcomes al. (18) conducted an observational study to ascertain how plans on health outcomes (17). Following this, Tarlov et health status to understand the impact of health insurance Insurance experimentcollectedpatients’ self-reportof input in assessing treatment. The seminal Rand Health was anincreasedawarenessoftheimportancepatient The impactof AD onchildreniscomparabletoother PROs may include evaluation ofsymptoms, functional There aresimilarconcerns for teensandadolescents. Quality oflifeinatopicdermatitis Theme issue:Atopic dermatitis 331 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis identify trendsinoutcomeinstruments usedin AD trials. review byRehal& Armstrong (40)in2011 attemptedto dermatology, especiallyinpsoriasisand AD. A systematic A plethoraofQoL measureshavebeendevelopedwithin DERMATITIS A BRIEF HISTORY OFQOLINATOPIC of thediseaseechoingthroughdecades. alter thelifecourseofpeopleaffected, withtheimpact impact ofthediseaseonsuchdecisionscantherefore by havingachronicskindiseasesuchas AD (39). The sions about whether to have children may be influenced of education,choicecareer, choiceofpartnerordeci from anearlystage(38). of research given the ‘web of relationships’ involved mon childhood condition, is a particularly relevant field questionnaires toascertainthisimpact. AD, beingacom dimension ofhealthcare,withtheadventseveralnew of diseaseisincreasinglybeingrecognisedasanother impact broader This (37). patient the with relationship This effect maybeexperiencedbyanyonewithaclose vers, aconceptdescribedas‘TheGreaterPatient’ (36). impacts ontheextendedfamilyaswellcaregi at leastpartlycompromised(35). from severe AD, 88% felt their ability to tackle life was depressive symptoms(35).Ofthosesubjectssuffering severe to 1189moderate demonstrated with AD people intimacy and feelings of guilt due to AD. Over 10% of work intheprecedingyearanddescribeproblemswith of day one least at miss adults of 57% (35): disease of clothing. The burdenincreaseswith increasingseverity embarrassment fromtheir AD impactingtheirchoiceof effect ontheirQoL.Manydescribepain,stinging and patients reportthat AD hasamoderatetoextremelylarge had symptomonsetinchildhood.(34).Overhalfofadult (33). In a review of two cohorts, 38% of adults with AD blem, but the prevalence in adults ranges between 3–5% vement inQoL withhighsatisfactionrates. impro significant demonstrated support psychological ‘young adult’ clinicsfor AD patientswithopenaccess (32). area this of in trial need A specialised a identified has England in Health of Department the and period from paediatrictoadultclinicsisoftenachallenging help them decide appropriate careers (31). The transition work wherehaving AD mayinvolveriskisimportantto influence career pathways. Advice to adolescents about study tobeashigh96%(30).Nevertheless, AD may with topicaltreatmentinthisgroupwasreportedone demic performanceinadolescents(29)andcompliance wider effect onschool-work, AD does not impact aca ferent’ (28). Despite the debilitating nature of AD and the leading toafeelingofisolationandtheneedbe‘dif 332 Several major life changing decisions, such as choice Whether thepatientisachild,teenageroradult, AD AD has long been considered mainly a childhood pro F. Alietal. ------(42). The studiesassessingthevalidityofdifferent instru OMERACT filter of truth, discrimination and feasibility (COS) to be developed for AD. All scales had to pass the 2010 (41)andadecisionwasmadeforcoreoutcomeset in held was HOME on Conference International first Noting themyriadofoutcomeassessmentsfor AD, the ATOPIC DERMATITIS HARMONISING OUTCOMEMEASURES FOR patient evaluationandmanagement. indicated theemerging importanceofQoL measuresfor 2010 to 1985 from instruments QoL of use in increase matitis (PQol-AD). The authorssurmisedthatanoverall (PIQol-AD) andParentsofChildrenwith Atopic Der Parents IndexofQualityLifein Atopic Dermatitis the QoL offamilymemberspatientswith AD: DFI, (IDQoL). lity ofLifequestionnaire measured Three tools and PIQoL-AD)measuredimpact ofQoL on caregivers. on QoL peakedin2012. Three instruments(DFI,FDLQI reporting articles of number the that found also (48) al. possibly duetothedifferent databasessearched.Hillet contrast to the 22 reported by Heinl and colleagues (47), in QoLmeasures 28 found al. et Hill instruments. used DLQI, CDLQI, IDQoL and DFIwere the most commonly the Again, QoL. measured studies identified 135 the and QoL instruments for patients with AD. Only 45 of systematic reviewlookingattrendsindiseaseseverity (DFI, PIQoL-AD). of AD oncarersofpatientswhichtwowerenamed theimpact measured used instruments.Fourinstruments DLQI, CDLQI,IDQolandDFIwerethemostfrequently measures, however confirming Rehal et al’s finding, the QOL of use increasing of evidence find not did (47) al. the studybyRehaletal.mentionedabove,(40),Heinl Unlike found. were instruments QOL unnamed 4 and named Eighteen measures. QoL used 63 only however 2002–2014, approximately 90% of studies used a PRO, from included studies 303 the In database. (GREAT) eczema trials using the Global Resource of Eczema Trials in 2016conductedastudyonQoL instrumentsusedin the PRO for measuring symptoms (46). Heinl et al. (47) as (POEM) Measure Eczema Oriented Patient mended recom IV HOME (45), severity disease outcome the for instrument the as recommended was ) (EASI Index Severity and Area Eczema meeting III HOME the At clinical signs, long-term control of flares and QoL (44). In 2011, 4outcomedomainswereagreedon:symptoms, ments were required to pass the COSMINchecklist (43). Life QualityIndex(DLQI)andInfantDermatologyQua followed byDermatitisFamilyIndex(DFI),Dermatology Quality ofLife(CDLQI)wasthemostfrequentlyused for measuring QoL, ofwhich the Children’s Dermatology identified were instruments Eleven QoLmeasurements. Of the 382 studies included, only 67 studies incorporated Around the same time Hill et al. (48) conducted a conducted (48) al. et Hill time same the Around - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV QoL of infants. Two newinstrumentswhichhadbeende children andtheproxymeasureIDQoL tomeasurethe DLQI andCDLQItomeasuretheQoL ofadultsand recommend to agreed was it (50) meeting VII HOME various interventionmeasures. Therefore, atthe2019 methods for measuring QoL in AD in order to compare single studies,highlightedtheimportanceofstandardised the abovestudies,withsomeinstrumentsusedonlyin in timeduetoconcernswithvalidationcertainareas. the QoL instrumentscouldberecommendedatthatpoint intensity wasnecessary. Itwasalsodecidedthatnoneof for long-termcontrolandthatfurtherresearchonitch It wasagreedthatanewinstrumentshouldbedeveloped areas ofresearchforatooltomeasurechildren’s QoL (49). for long-term controlanditsmeasurement as wellasfuture ture hasbeenexaminedwith respectstodimensionality (54–56). research struc clinical DLQI in The use its as studies with regards to its psychometric properties as well to givetheDLQIscore(maximum 30). treatment. The ten question scores (each 0–3) are added and school,personalrelationshipstheimpactof on symptomsandfeelings,dailyactivities,leisure,work minutes. The DLQI assesses the impact of skin disease week recallperiod.Itiscompleted,onaverage,intwo The questionnairewasdevelopedfromtheanswers. question “listallthewaysyourskindiseaseaffects you”. initial development, 120patients answered the open-ended perform andscoreinroutineclinicalpractice.Duringthe in over 80 countries (53). The DLQI is quick and easy to loped in1994(52). There areover110 translations,used The DLQI is a dermatology-specific questionnaire deve Dermatology LifeQualityIndex rison andcombinationofdata. provides thepotentialforimprovedassessment,compa measures core of set a identifying by initiative, HOME individual studies, making comparison impossible. The reduced bydifferent outcomemeasuresbeingused in Historically, thevalueof clinicalresearchhasbeen INITIATIVE HOME BYTHE CHOSEN DERMATITIS QUALITY OFLIFEINSTRUMENTS FOR ATOPIC primary endpoint toensure comparability intrial results. for AD shouldbemeasuredatbaselineandendofthe to measuresymptoms.ItwasalsoagreedthattheCOS itch was recommended in addition to POEM as the PRO Rating Scale(NRS-11) (51)tomeasuretheintensity of measuring long-termcontrol.Inaddition,theNumerical for recommended were (RECAP) Eczema Atopic of V, Recap TestControl and Dermatitis (ADAPT) Atopic veloped in response to the recommendations from HOME However, thesheernumberofQoL instrumentsin HOME V concentrated on the definition core outcome The DLQI has been extensively validated in numerous The DLQI is a 10-item questionnaire with a one - - - - described includingconcernsregardingunder-representa across dermatology(55,64),severallimitationshavebeen paper formatdemonstratingequivalence(63). nic formathasbeendevelopedandvalidatedagainstthe further testingatanindividualsubjectlevel. An electro model isvalidatedforlarge groupsofdata,itrequires utilising multiplequestionnaires.However, thoughthe more precise health economic data without the need for measures areoftenunabletocapture,therebygenerating generic that data disease-specific of capture the lows al model The (62). scores EQ-5D generic from values utility dermatology-specific of prediction the allowing regression logistic ordinal using EQ-5D the to mapped of manynovelQoL questionnaires. The DLQIhasbeen and usedasthestandardcomparatorinvalidation other measureshighlightingitsconstructvalidity(54), numerous with correlated significantly been has DLQI fect. This bandingcanhelpinformclinicaldecisions. The indicates no effect on a patient’s life and 11–20 a large ef ningful score interpretation. For example, score band 0–1 their clinicaldecisions. this intoaccountaspartof theinformationinforming “Not relevant”answers,to enquirefurtherandtotake QoL questionnaire,to note whetheror not there wereany clinician reviewingacompleted DLQI,orindeedany clinical judgement. A simpleapproachwouldbeforany decision forindividualpatients,andnotusedtorestrict be usedtohelpthecliniciantakemostappropriate method isusedtocalculatethem,DLQIscoresshould Whatever (68). scores DLQI of interpretation the into lidation studies to be performed and introduce confusion impractical inbusyclinics,requireawiderangeofreva scoring system may not be appropriate (67) and would be answers given(66). be adjusteddependingonthenumberof“Notrelevant” It has therefore been suggested that the final score should has severelyimpactedthataspectoftherespondent’s life. question may be “not relevant” may be that the skin disease ning the use of some therapy, even though the reason that a critical levelthatisusedtohelpinformaclinicianconcer possible score. Some subjects might therefore not reach a “not relevant”thegreaterimpactonmaximum score isreduced. The morequestionsthatareanswered respondent’s usual life pattern, then the overall maximum because thelifeaspectenquiredaboutisnotpartof “Not relevant”.Ifthesubjectdoesthisforonequestion, 8 of the 10 items it is possible for the respondent to choose when “not relevant” optionsarechosen.IntheDLQI,for Furthermore, thereareconcernsoverscoreinterpretation tion ofemotionalaspectsanditsuni-dimensionality(65). reliability (59,60). test–retest high with 58) (57, change to responsive is It indicating oneto4factorsacrossvariousstudies(54). Although the DLQI is the most commonly used measure Although the DLQI is the most commonly used measure However, introducing anadditional more complicated The DLQIvalidatedscorebanding(61)allowsmea Quality oflifeinatopicdermatitis Theme issue:Atopic dermatitis 333 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis (82). Itisa10-itemquestionnaire withaoneweekrecall measure oftheQoL of childrenundertheageof4years The IDQoL is a dermatitis specific parent/caregiver proxy Infants’ Dermatitis QualityofLifeindex the QoL ofchildren(50). core QoL instrumentformeasuringtheimpactof AD on between 6–8points(81). it hasbeensuggestedthattheMCIDforCDLQIis all skindiseases.However, foruseinchildrenwith AD difference (MCID)forCDLQI describedforuseacross (80). There is no published minimal clinically important 2 min and has score bands to give meaning to the scores validated extensively (77–79). It is completed in mean in (76). children younger to appeals been has CDLQI The Each question has 4 possible answers. A cartoon version within thelastweekchildwasinschooloronholiday. has achoiceoftwooptionsdependentonwhetherornot personal relationships,sleepandtreatment.Onequestion on symptoms and feelings, leisure, school or holidays, life. The CDLQImeasuresimpactoverthelastweek children, askinghowtheirskinconditionaffected their questionnaire wasdeveloped,basedon169repliesfrom 10-item A (75). years 4–16 aged children of QoL the The CDLQImeasurestheimpactofskinconditionson Children’s DermatologyLifeQualityIndex extensive furthervalidation. analysis ofinterventionalstudies.However, thisrequires MCID’ concept has (74) to allow a more distinguishing ‘multiple- a proposed have We(73). points 4 is value ditional meaningtoQoL scorechanges. The DLQIMCID ad (72). provides patients This and clinicians by ficant the minimalchangeinscoreconsideredclinicallysigni The minimalclinicallyimportantdifference (MCID) is Minimal ClinicallyImportantDifference of AD ontheQoL ofadultpatientswith AD (50). tiative asthecoreinstrumentformeasuringimpact guidelines orregistriesinatleast40countries. clinical care,andtheDLQIisincorporatedinnational because oftheirexperienceitsusefulnessinroutine embedded theuseofDLQIintheirroutinepractice towards patient-centredmedicine.Manyclinicianshave have become familiar (71), contributing to a cultural shift first QoL measure with which dermatologists worldwide terpretability ofitsscoreshaveledtotheDLQIbeing of the questions, the simplicity of its use and the easy in to afundamentalmeasure.However, thehighfacevalidity for the refinement of items and to convert the ordinal scale having been subject to Rasch analysis (69, 70), a method tensively validated,theDLQIhasbeencriticisedfornot 334 Although many properties oftheDLQIhavebeenex The CDLQI has been recommended by HOME as the The DLQI has been recommended by the HOME ini F. Alietal. - - - - - global prevalenceestimatedat229millionpeopleaf one oftop50mostcommoncausesdisease,witha is Eczema (85). worldwide diseases skin all of burden disease surveyrevealedthateczemacausesthehighest skin of burden global DALYs,the Using (84). disease state andisaddedtothenumberofyearslostduethat multiplied bythenumberofyearslivedinthathealth burden ofacertaindisease,thedisabilityweightingis (DALYs) areyearsofhealthylifelost. To calculatethe of healthylifelived,Disability Adjusted Life Years Whereas Quality Adjusted Life Years (QALYs) areyears Disability adjustedlifeyears meaning bandshavenotbeendescribedfortheIDQoL. nimal clinicallyimportantdifference anddescriptivescore strength tobegainedbyalwaysusingthesameset. The mi huge aredeveloped,butthereis more appropriatemeasures measuring theimpactof AD ontheQoL ofinfants(50). recommended by HOME as the core QoL instrument for been has IDQoL The (83). described been have aspects ages andisfrequentlyusedin AD trialsand validation giver. The IDQoL hadbeentranslatedintoseverallangu the severity of dermatitis as perceived by the parent/care undressing, andbathtime. An additionalquestionrecords ming, familyactivities,mealtimes,treatment,dressingand logical strain and embarrassment may all be experienced logical strainandembarrassment mayallbeexperienced by children e.g.sleep disturbance, restlessness,psycho experienced symptoms The (90). implications financial ly impactsparentalworkresponsibilities andthereforehas for treatment application and extra housework also direct of thecurrentburdenonwiderfamily. Dedicatingtime Parents may choose not to have further children because (89). exhaustion and frustration in resulting parents, for andhyperactivitymaybedemanding restlessness as such (88). Furthermore, the associated behavioural difficulties affected asskinirritationmaylimitphysicalinteractions of AD. Itispostulatedthatparentandchildbonding experiences childhood/adolescent and parental collated affectedare parents too. A (87) study meta-ethnography especially whenyoungchildrenareaffected. Inevitably the QoL of the patient (86) and also the main caregivers, The treatmentprocesscanhaveanadverseimpacton lients alongwithvarioustopicalandsystemicmeasures. attention. Treatment for AD includesregularuseofemol AD isachronicdiseasesothesymptomsrequireconstant Impact onparents IMPACTOFATOPICDERMATITISFAMILY close familymembers. the QoL ofnotonlythosedirectlyaffected butalsotheir fected. However, itmustberememberedthat AD affects of itchandscratch,mood,timetosleep,playingorswim period. The itemsmeasuretheperceivedimpactonQoL The core measures chosen may change in the future if The core measures chosen may change in the future if ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV a major effect on the QoL of parents. The most frequently mean FDLQI score (range 0–30) was 13.6 (mean age32years)ofchildren with AD inCroatia. The may havebeencontributory. anxiety and stressrelatedtocaringforchildren with AD not changetheconclusions,andotherfactorssuchas severe AD. Adjusting forchildsleepdisturbancesdid reported larger effects inmothersofchildrenwith more mothers ofchildrenwithactive AD. The authorsalso day-time exhaustionweremorefrequentlyreportedin and sleep insufficient subjectively asleep, falling in children never having reported AD. However, difficulty mothers ofchildrenwithactive AD andmotherswith duration andearlymorningawakeningweresimilarin on two occasions. After adjusting forconfounders, sleep dermatitis flexural of presence the of basis the on AD from birth to 10 years. Children were classified as having pairs in the UK were followed up by Ramirez et al. (96) nal, population-based cohort study 11,649 mother–child a directeffect oftheeczema. asthma. This wasrelatedmoretothesleeplossthan her scoresofdepressionthanmotherschildrenwith increased anxiety scores, the mothers had two-fold hig no sleep. While bothparentsofchildrenwith AD had sleep. In contrast, parents of children with asthma lost a medianof39minandfathers45 with eczemasuffered sleeploss,withthemotherslosing had changed,leadingtofeelingsofguiltandsadness. felt thatdynamicsbetweenparentsandothersiblings ignored byhealthprofessionals. The participantsalso sleep losswasnormalisedbyotherfamilymembersand effect onthewholefamily. The participantsfeltthatthe to fatiguewithparentsperceivingthishadanegative a desireforlongeruninterruptedsleep.Sleeplossled sleep. Mostparentsacceptedthesleeplossbutexpressed interviewed. All but one parent experienced fragmented SCORing Atopic Dermatitis(SCORADs)of> mothers and one Eleven father, parents. with children such aged 0–2 in years with sleep of perceptions the into children with AD. Angelhoff etal.(94)conductedastudy explained byhealthprofessionals(93). sequelae oftopicalcorticosteroidsbeinginadequately flicting advice on management, including the long-term child with AD (91). maybeexacerbatedbycon Anxiety neglecting otherchildrenbecauseoftheirfocusonthe wrong duringpregnancy, ordevelopasenseofguiltfor their affected child.Mothersmayfeeltheydidsomething issues mayplayanimportantroleinparentalattitudesto like, oftenresulting intheneedforcoercion(92).Cultural determinant ofthechild’s well-being(26,91). second handbyparentsandthereforetheirQoL isakey Pustisek et al. (97) studied the QoL of 171 parents parents 171 of QoL the studied (97) al. et Pustisek In contrast,inanongoinglarge prospective,longitudi Moore etal.(95)reportedthat parentsofchildren Loss ofsleepisanotherfamiliarthemeinparents Parents report having to apply creams that children dis ± 6.0. indicating indicating 6.0. 15 were - - - -

and theircarers,feelingexhausted, stressedanddepres 99) coupledwithsleepdeprivation canleavepatients, in thefamilyhasachroniccondition(108). and thesiblingbondmayalsobeaffected whenachild levels ofdistress(102). The parentchildrelationship also beensuggestedthatsiblingsmayhaveincreased has it but (107), peers their QoLas same the have may been used.Siblingsofchildrenwithchronicconditions diseases, due to the wide variety of instruments that have the QoL ofsiblingsskindiseasecomparedto other It is difficult to compare from the literature the effect on of childrenaffected withskin conditions,including AD. a lackofinformationontheimpactQoL onsiblings medical conditions, notably cancers (101–106), there is on theQoL ofsiblingschildrenaffected withother beaffected.may also therearemanystudiesWhilst childhood siblings usually live together and their lives parents, whoaregenerallythecaregivers,however, in close relations(36).Inchildhood AD thisincludesthe encompass theinterdependenceofpatientswiththeir Basra &Finlayproposedtheterm“GreaterPatient’ to Impact onsiblings about thisdebilitatingcondition(87). empowered bylearningabout AD andeducatingothers a deeper emotional closeness (26). Parents also feel discomfort ofphysicalsymptoms,thisoverallcreates time holdingchildren closer, andbalanced with the To stop children from scratching, parents spend more the extratimespenttreatingandsupervisingthem(100). develop astrengthenedbondwiththeirchildrenthrough resulting fromachildsuffering with AD. Parentsmay female with over half onmaternity leave orunemployed. be becausemostparticipantsinPustisek’s studywere were thelowestscoringitemsonFDLQI:thiscould the study by Pustisek et al. (97) where work or education was ontheirworkoreducation. This wasincontrastto hips withothers,howeverthegreatestimpactonfathers other peopleweremoreaffected thanfathers’ relations expenditure wassimilar, mothers’ relationshipswith Whilst theimpactonsociallife,sparetimeanddaily a greaterimpactontheQoL ofmothersthanfathers. rents QoL withtheFDLQI,foundthatchildren’s AD had and fathersmayvary. Marciniaketal.(99)assessingpa parents ofchildrenwith AD andacorrelationwithQoL. in levels stress higher indicating years, 30–40 aged son further investigation. siblings ofpatientsaffected with AD: thisareaneeds on repercussions be therefore may There 97). (96, sed score was 20.0 in a Ukraine study (98). The mean Perceived Stress Scale child, householdexpenditureandemotionaldistress,as recorded problems were time spent looking after the These negative interactions with family members (94, These negativeinteractions withfamilymembers(94, Counter-intuitively, theremaybepositiveoutcomes The impact of a child’s eczema on the QoL of mothers ±

5.8, 7 points higher than the average per Quality oflifeinatopicdermatitis Theme issue:Atopic dermatitis 335 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis PIQoL-AD pointsovertime isconsideredmeaningful. The lower the score, the better the QoL, a change of 2–3 AD, this is a 28-item unidimensional questionnaire (123). interviews with parents of children up to age 8 years with ofmultinationalqualitative onthebasis (122). Developed sess theimpactofchild’s AD ontheQoL ofparents as to measure specific AD another is PIQoL-AD The Parents IndexofQoL in Atopic Dermatitis eczema studies(40,47,121). most frequently used instruments for measuring QoL in DFI, alongwithDLQI,CDLQIandIDQoL isone ofthe measurement propertieshavebeenreviewed(120). The its and specific eczema being of advantage the has DFI 119).(118,The descriptors scoring non-validated used banding descriptorsfortheDFI,butsomestudieshave validated no are There points. 0–3 from scored is tion relationships and impact of child’s treatment. Each ques on shopping,expenditure,tiredness,emotionaldistress, others inthefamily, familyleisureactivities,time spent of housework,foodpreparationandfeeding,sleep the impactoverlastweekonQoL inthedomains 10-item dermatitisspecificquestionnairemeasures This (117). members family adult their on QoL the on tology measurestheimpactofhavingachildwith AD derma in questionnaire QoL family first the DFI, The Dermatitis FamilyIndex conditions (97,99,112–116). in various studies involving AD and other dermatological translated into several languages (111) andhas been used been has FDLQI The (0–3). scale 4-point a on scored job/study, housework and expenditure. Each question is leisure activities,sociallife,burdenofcare,impacton mains ofemotionalandphysical wellbeing, relationships, skin condition (110). The questionnaire includes the do of adultfamilymemberspeopleanyagewith period ofonemonth,assessingtheimpactonQoL The FDLQIisa10-itemquestionnaire,withrecall Family DermatologyLifeQualityIndex MEMBERS QUALITY OFLIFEINSTRUMENTS FOR FAMILY logy LifeQualityIndex(FDLQI)shouldbeused(109). AD, iffamilyimpactismeasured,theFamilyDermato research registriesforpaediatricandadultpatientswith (TREAT) Registry Taskforce has recommended that for ressed this. However, the TREatment of ATopic eczema patients with AD. The HOME initiative has not yet add measuring the impact ofQoL onfamily members of specific and AD specific validated instruments exist for sing theQoL offamilymembers.Severaldermatology 336 The above findings illustrate the importance of asses F. Alietal. ------fields has allowed diagnosis of ophthalmic and neurolo visual measuring hypertension, of control and fication measure: measuringblood pressure hasenabledidenti exists as an ‘art’. Advances have followed the ability to The same applies in medicine, a field of science that co- something, itdoesn’t really exist,atleasttoascientist. change. Itcouldalmostbesaidthatifyoucan’t measure impossible tomakemeaningfulcomparisonsordetect Without measurement,itmay bepossibletodescribe,but measure somecharacteristicofwhatisbeingstudied. to able be to essential is it endeavour, scientific any In DISCUSSION fected children the IOFshouldonlybeusedforfamilymembersofaf be used in the family members of patients of any age, or disability. However, unliketheFROM-16,whichcan mily membersofchildrensuffering withchronicillness validated tomeasuretheimpactofQoL ontheadultfa medical conditions. meaningful comparisonsinQoL trialsinvolvingdifferent disciplines inmedicine,thusmakingiteasiertomake to comparetheQoL offamilymembersacrossdifferent characteristics arebeingstudied.FROM-16canbeused pleted inGermanyand Thailand andfurthervalidation com been respectively.have Validation2, studies and answers: ‘Notatall’,‘A little’ and‘A lot’ scoring0,1 main with 10 questions. Each question has three possible with 6questionsandthePersonalSocialLifedo domain Emotional the of consists FROM-16 min. 2 is any agewithdisease. The averagecompletiontime the QoL of any adult member of the family of a patient of on relativesofpatientsfrom26medicalspecialties. Family Reported Outcome Measure (FROM-16), based the developed (127) al. et Golics specialities. different compare theimpactonQoL offamilymembersbetween cannot questionnaires specific condition and Speciality Family ReportedOutcomeMeasure from anyoftheindividualdomains(126). to bea12%changefromthetotalscoreor not havescorebanddescriptors,theMCIDisconsidered completed inapproximately6min(125). Whilst itdoes period isthelast4weeksandquestionnairecanbe Likert Scales giving a maximum score of 180. The recall parent emotion. This 45-itemquestionnaireuses5-point behaviour, familyandsocialfunction,parentsleep of the domains ofsymptoms, activity limitations and the ageof6years(124).ItmeasuresimpactonQoL AD combinedwithaproxymeasureforchildrenunder CADIS isaQoL measure forparentsofchildrenwith Childhood Atopic DermatitisImpactScale(CADIS) The Impact on Family Scale (IOF) (128, 129) has been FROM-16 has16questionsandcanbeusedtoassess ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV longer ignorethemandwe are obligedtocreativelyde disease. Having identified the QoL problems we can no the over-riding aim must be to effectively suppress the des starkchallengestothe health careteam.Ofcourse, crucial contributiontothesuccessoftherapy. family members,andidentifyingtheirneedsmaymake a restimated. Therefore, understanding theexperiencesof adherence toagreedtreatmentplansshouldnotbeunde withtherapy.to persist The roleofthefamilyinpromoting of topicalemollientsanddrugs,givingencouragement patient with practical therapeutic help, such as application the “Greater Therapist”, asfamilymemberssupportthe member with AD. Butthe“GreaterPatient”alsoactsas experience impactontheirQoL throughhavinga family many novelpowerfulsystemictherapiesfor AD. especially over the coming decade with the advent of more appropriatetherapeuticdecisionsmaybemade, having insightintotheindividualpatient’s experience, it islikelythatthesameappliesatleasttoadult AD. By dermatologists werenotaggressiveenoughwiththerapy: USA determined that patients with psoriasis felt that their the and Europe in studies multicentre Large condition. which thelivesofpeoplewith AD areaffected bytheir conditions mustalsobeconsidered. used toinformresourceallocation,wideraspectsofthe extremely serious. Therefore, whenQoL measuresare QoL, butifuntreatedthelong-termconsequencescanbe that istreatedappropriatelymayhavealowimpacton melanoma, mayhave. And havinga basal cellcarcinoma understanding theriskofmortality, sayofamalignant of skindiseases,suchasthepsychologicalimpactthat overlook criticalaspectsoftherealityimpacts allocation. However, useofQoL datainthiswaymay lation agenciestoinformdecisionsconcerningresource sometimes usedbynationalorinternationaldrugregu is this and data, EQ-5D from calculated typically is (EQ-5D). Utility information giving QALY information include the Short-Form 36, the WHOQOL and EuroQoL be used across all diseases. Examples of such measures also awiderangeofquestionnairesthataredesignedto in generalorof AD inparticular. However, thereare designed to measure the impact on QoL of skin diseases insight intotherealburdenofdiseasessuchas AD. in combinationwithquantitativestudiestogainmore addition, qualitativestudiesshouldbeusedmoreoften understand whatourpatientsareexperiencing(130).In of delivering the highest quality of care, we need to better delayed focushascoincidedwitharealisationthat,aspart focus onmeasurementcamelatetooursubject.Butthis Perhaps becauseofthevisualnaturedermatology, a is usedasanalerttodiabetesandprostatichypertrophy. gical conditionsandmeasuringfrequencyofmicturition Being abletomeasurethe QoL impactof AD provi The GreaterPatient,theclosefamilymembers,mayall This reviewhasdescribedsomeofthemanywaysin This review has focussed on questionnaires specifically - - - - REFERENCES these royaltiesaccordingtoCardiff Universitypolicy. quality of life questionnaires are used. AYF receives a share of these when royalties companies with-profit charges University DLQI, CDLQI,IDQoL,DFI,FDLQIandFROM-16.Cardiff advisory panelfor Amgen. AYF isjointcopyrightownerofthe Lilly, Janssen, Novartis, LEO, and Abbvie. JV has been on a paid interest: FA of Conflict has receivedhonorariaandgrantsfrom ACKNOWLEDGEMENT tools toassessprospectivelytheimpactof AD onQoL. velop methodstoaddresstheseissues. We nowhavethe 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. analysis of systematic reviews published in 2016. Part 2: Part 2016. in published reviews An systematic of analysis eczema? atopic in new What’s KE. Harman KS, mas Lloyd-LaveryRogersGrindlayDJC, L, Solman A, Tho NK, pulation-based study. Clin Exp Allergy 2007; 37: 526–535. et al. Eczema, atopy and allergen exposure in adults: a po Harrop J, Chinn S, Verlato G, Olivieri M, Norbäck D, Wjst M, 73: 1284–1293. in adults: dermatitisResults from atopic an international of survey. Epidemiology Allergy 2018; al. et E, Simpson L, Puig G, Girolomoni A, Gadkari S, Auziere S, Barbarot Clin Immunol2009; 124: 1251–1258. e1223. Allergy J Three. Phase ISAAC from children in symptoms MI, Group IPTS. Global variations in prevalence of eczema Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher 1999; 103:125–138. Asthma and Allergies in Childhood. J Allergy Clin Immunol of symptoms of atopic eczema in the International Study of G, Anderson R, et al. Worldwide variations in the prevalence Williams H, Robertson C, Stewart A, Aït-Khaled N, Anabwani III. J Investig Allergol Clin Immunol 2010; 20: 469–475. ma in 6 to 7-year-old schoolchildren in Spain: ISAAC phase AG, Aguinaga IO, et al. Diet and prevalence of atopic ecze Suárez-Varela MM, Alvarez L, Kogan M, Ferreira JC, Martínez ignorance. Vet Dermatol 2013; 24: 3–e2. ven areas of notable progress and seven areas of notable Williams HC. Epidemiology of human atopic dermatitis–se Immunol 2008; 121: 141–147. Asthma and Allergies in Childhood Phase Two. J Allergy Clin of Study International the from findings eczema: flexural in sensitization atopic of role The al. et B, Brunekreef L, Bråbäck B, Björkstén G, Weinmayr SK, Weiland C, Flohr 2010. Lancet 2012;380:2197–2223. a systematic 1990–2010: analysis for regions, the Global 21 Burden of in Disease Study injuries and diseases 291 (DALYs)for years life Disability-adjusted al. et C, chaud Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Mi AD, Flaxman VosT,M, CJ,Murray Naghavi R, Lozano Invest Dermatol 2017;137:18–25. J disorder. systemic a is dermatitis atopic that suggest comorbidities Increasing al. et M, Amagai K, Kabashima AS, Paller Guttman-YasskyE, JI, Silverberg PM, Brunner Dermatol 2019; 80: 390-401. characteristics. clinical dermatitis atopic of differencesage-related and regional the meta-analysisof Yew YW, Thyssen JP, Silverberg JI. A systematic review and in 823children.ActaDerm Venereol 2008; 88: 234–239. with quality of life, coping behaviour and SCORAD severity Atopic Dermatitis Intervention Study (GADIS): correlations Lobcorzilius T, et al. Itch intensity evaluated in the German Weisshaar E, Diepgen TL, Bruckner T, Fartasch M, Kupfer J, 4: 1. 2018; Primers ReviewsDisease Nature dermatitis. Atopic AD.T, Irvine Bieber K, LA, Kabashima Beck WeidingerS, factor for atopic dermatitis. Nat Genet 2006; 38: 441. epidermal barrier protein filaggrin are a major predisposing SP,the Lee of variantsloss-of-functionH, Common al. et Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao Quality oflifeinatopicdermatitis Theme issue:Atopic dermatitis J Am Acad 337 - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis 338 33. 32. 31. 30. 29. 28. 27. 26. 25. 24. 23. 22. 21. 20. 19. 18. 17. 16. 15. matol Venereol 2018; 32:850–878. dermatitis) in adults and children: part II. J Eur Acad Der (atopic eczema atopic of treatment for guidelines ropean Eu Consensus-based al. et A, Fink-Wagner M, Deleuran S, Christen-Zaech T, Bieber S, Barbarot A, Wollenberg logical support. Clin Exp Dermatol 2019; 44:893–896. Adult dermatology clinic with embedded specialist psycho RN, et al. Establishing and developing a Teenage and Young De Vere Hunt I, Chapman K, Wali G, Bullus S, Fisher R, Matin 519–524. 113: 2016; Int Arztebl Dtsch patients. allergy young for advice F. Career Rueff C, Vogelberg D, Nowak K, Radon 2018; 179:709–716. Dermatol J Br BAMSE. cohort birth population-based the from data eczema: with adolescents among cocorticoids glu topical and emollients of Use al. et N, Andersson E, Lundin S, Wahlgren CF, Bergstrom A, Johansson EK, Dahlen asthma or atopic disease. Clin Exp Allergy 2019: 892–899. K, AlmqvistC.Academicachievement ofadolescentswith Holmberg S, Afshar C, Lundholm J, Söderberg BK, Brew sis. Dev Neurorehabil2007; 10: 133–141. theappearance-related concerns of young exploring people with it!”:psoria change cant that you thing and the sees is everyone skin “Ur M. Morris N, Rumsey FE, Fox tured interviews. Acta Derm Venereol 2008; 88: 143–150. epidermolysis bullosa: a qualitative study with semi-struc MF.Jonkman with children by experienced problems Main van Scheppingen C, Lettinga AT, Duipmans JC, Maathuis CG, families. Pediatrics 2004;114:607–611. of atopic dermatitis on young American children and their Effects MM. Chren ML, Williams IJ, Frieden SL, Chamlin Pract 2006; 60:984–992. titis: the misery of living with childhood eczema. Int J Clin Lewis-Jones S. Quality of life and childhood atopic derma meta-analysis. Br JDermatol 2016; 174: 853–861. a (CDLQI): Index Quality Life Children’sDermatology the of life impact of childhood skin conditions measured using Olsen JR, Gallacher J, Finlay AY, Piguet V, Francis NA. Quality matol 2006; 155:145–151. Der J Br diseases. childhood chronic and other with disease children skin with children in life of quality of ment impair of study comparative P,A Beattie M. Lewis-Jones 169: 963–964. burden:‘now’,‘long‘family’.term’and 2013; Dermatol J Br disease skin of dimensions three AY. The Finlay tion, February 16, 2001.Value Health2003;6: 522–531. monization Group Meeting at the Food and Drug Administra Force Report of the Patient-Reported Outcomes Task(PRO) Hoc Har Ad An Communication: and Development Drug intoPatient’s Perspective the Incorporating al. et D, vicki Acquadro C, Berzon R, Dubois D, Leidy NK, Marquis P, Re New York, 1986:p. 1. ed. Eastern Journal. WallStreet stock. of price in jump a pressure: findings of medical journal are leaked, prompting Bishop J. Squibb drug called superior in easing high blood Treat Rep 1985; 69: 1155–1159. Cancer drugs. anticancer new of approval for quirements re Administration Drug and Food TempleR. JR, Johnson 1989; 262:925–930. JAMAResultsCare. the Medical Monitoring of for Methods Zubkoff M. The Medical Outcomes Study: An Application of E, Perrin EC, Jr, Nelson Tarlov JE, WareS, Greenfield AR, Care 1979; 17: 1–131. Med Study. Insurance Health Rand’s status in fielded health measures adult of Overview al. et WH, Rogers CA, Donald AL, Stewart A, Davies-Avery JE, Ware RH, Brook Pharmacol Ther 2008; 84:281–283. evaluation of medical products for regulatory approval. the Clin in measures outcome patient-reported of use The A. Burke L, Kennedy D, Miskala P, Papadopoulos E, Trentacosti analysis. JAm AcadDermatol 2016; 75: 681–687. meta- and review systematic a (AD): dermatitis atopic of Persistence JI. Silverberg EL, Simpson LX, JP,Chao Kim 2019; 44: 370–375. Epidemiology, aetiology and risk factors. Clin Exp Dermatol F. Alietal. ------41. 40. 39. 38. 37. 36. 35. 51. 50. 49. 48. 47. 46. 45. 44. 43. 42. 34. Eczema (HOME).Report from the First International Con International First the from (HOME).Report Eczema Schmitt J, Williams H. Harmonising Outcome Measures for pone.0017520. [e17520]. Available from https://doi.org/10.1371/journal. One [serial online] 2011 [cited 2019 September PLoS 26]; 6(4): 1985–2010. Instruments Quality-of-Life and verity SystematicA Dermatitis: Review Trendsof Se Disease in Rehal B, Armstrong A. Health Outcome Measures in Atopic 1344–1355. general medicine. J Eur Acad Dermatol Venereol 2014; 28: decisions (MLCD s): a qualitative study in dermatology and et al. Chronic disease influences over 40 major life-changing Bhatti ZU, Finlay AY, Bolton C, George L, Halcox J, Jones S, Venereol 2017;31: 1429–1439. Dermatol Acad JEur instruments. of dermatology-specific review a caregivers: and family on conditions logical dermato of impact the Measuring al. et AWM, Evers FJ, P,ChernyshovDalgardF, AY, SS, Finlay Sampogna Salek care. JRSocMed2013; 106: 399–407. medical of aspect critical a members: family on disease of impact The S. AY,Salek Finlay MKA, Basra CJ, Golics 156: 929–937. 2007; Dermatol J Br concept. Patient diseases: Greater skin the of impact family The A. Finlay M, Basra Dermatol Venereol 2019;33: 1331–1340. fering – results from a large EU-Study in adults. J Eur Acad et al. Atopic eczema: burden of disease and individual suf M, Schielein U, Mensing I, Seitz B, Arents A, Zink J, Ring wed through midlife. J Allergy Clin Immunol 2019: 710–719. tric validation and responder definition for assessing itch assessing for definition responder and validation tric L, et al. Peak Pruritus Numerical Rating Scale: psychome Yosipovitch G, Reaney M, Mastey V, Eckert L, Abbé A, Nelson and-events/home-vii-meeting-2019.aspx. Available from http://www.homeforeczema.org/meetings- Eczema (HOME). online] [cited 2019 September 26]; 2019. ForMeasures Outcome Harmonising Homeforeczema.org. Br JDermatol 2018;178: e332–e341. initiative). (HOME trials clinical eczema/dermatitis atopic for measures outcome core harmonize to meeting sensus con international fifth the from Report al. P,et Spuls C, Chalmers J, Thomas K, Apfelbacher C, Williams H, Prinsen systematic review. a J Am dermatitis: Acad atopic Dermatol 2016; with 75: patients 906–917. for instruments life of Dunnick CA. Recent trends in disease severity and quality AW, Armstrong TL, Braunberger AK, Pishkenari MK, Hill Venereol 2016;96: 596–604. patient-reported outcomes. A systematic review. Acta Derm trials: quality of life instruments used and their relation to Heinl D, Chalmers J, Nankervis H, Apfelbacher CJ. Eczema initiative). Br J Dermatol 2016;175:69–79. measures for atopic eczema/dermatitis clinical trials (HOME ternational consensus meeting to harmonize core outcomein fourth the from Report al. et J, Schmitt VonL, Kobyletzki K, Thomas C, Apfelbacher E, Simpson J, Chalmers Dermatol 2014; 171:1318–1325. J Br (HOME). trials clinical eczema/dermatitis atopic for measures outcome core harmonise to meeting consensus international third the from Report al. LF,et EL, Simpson Chalmers JR, Schmitt J, Apfelbacher C, Dohil M, Eichenfield II meeting. Allergy 2012; 67: 1111–1117. measures for atopic eczema research: results of the outcome HOME on consensus Towardsglobal al. et E, ekevisch Ro J, Chalmers K, Thomas M, P,Boers Spuls J, Schmitt J Clin Epidemiol 2007;60: 34–42. questionnaires. status health for of properties proposed measurement were criteria Quality al. et J, Dekker DL, Knol DA, Windt der van MR, Boer de SD, TerweeBot CB, 1998; 25: 198–199. filter for Outcome Measures in Rheumatology. OMERACT J The P. Rheumatol Tugwell CV, Strand P, Brooks M, Boers Br JDermatol 2010;163: 1166–1168. sensus Meeting (HOME 1), 24 July 2010, Munich, Germany. from 2 nationally representative British birth cohorts follo Strachan DP, et al. Clinical onset of atopic eczema: Results DJ, Margolis A, Sullivan CE, YeMcCulloch K, M, Abuabara ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 70. 69. 68. 67. 66. 65. 64. 63. 62. 61. 60. 59. 58. 57. 56. 55. 54. 53. 52. forward. JInvest Dermatol 2012; 132: 11–13. move to time index: quality life Dermatology T. Nijsten Derm Venereol 2006;86: 289–290. dermatology life quality index (DLQI): a commentary. Acta the of SP.Dimensionality McKenna DM, T,Meads Nijsten Dermatol 2018;179:1021–1022. J Br needed. are judgement clinical and interpretation Informed mean? scores do AY,F.What Finlay Sampogna 939–940. 180: 2019; Dermatol J Br populations. independent two in score, DLQI-R the modification, scoring Index Quality Life Dermatology the of Evaluation J. Gelfand J, Barbieri 1102–1108. 179: 2018; Dermatol J Br psoriasis. in Index Quality Life al. Proposal of a new scoring formula for the Dermatology Rencz F, Gulacsi L, Pentek M, Poor AK, Sardy M, Hollo P, et 2726–2739. 127: 2007; Dermatol Invest J instruments. life of quality review of generic and dermatology-specific health-related Critical T. Nijsten J, Busschbach ML, Essink-Bot H, Both Acad Dermatol Venereol 2014;28: 333–337. Eur J therapies. biological with treated patients in burden the correlation between disease severity and psychological dex (PASI) and the Dermatology Life Quality Index (DLQI): Mattei PL, Corey KC, Kimball AB. Psoriasis Area Severity In 2017; 177:1306–1315. Life Quality Index: evidence of equivalence. Br J Dermatol the paper-based and electronic versions of the Dermatology Ali FM, Johns N, Finlay AY, Salek MS, Piguet V. Comparison 3025–3034. of 26: 2017; Res valuesLife Qual regression. utility logistic ordinal using EQ-5D to scores DLQI the of Mapping al. AY,FinlayF, V,R, Dalgard KayPiguet J,et FM, Kupfer Ali Dermatol 2005; 125:659–664. Invest J mean? scores index quality life dermatology do Translating the science of quality of life into practice: what AY.Finlay MS, Salek MA, Harrison Y,CL, Hongbo Thomas https://doi.org/10.1186/1477-7525-4-46. from Available [46]. 4(1): 26]; September 2019 [cited 2006 online] [serial Outcomes Life of Quality and Health Quality Index: validity and reliability in patients with acne. J, Ohya Y, et al. Japanese version of the Dermatology Life TakahashiY,Suzukamo N, Y,Miyachi M, Nakamura Green 39: 826–831. 2000; Dermatol J Int Town,Africa. Cape South in groups ethnic and social different from patients in life of quality Jobanputra R, Bachmann M. The effect of skin diseases on 2003; 149:318–322. to clinical change in patients with psoriasis. Br J Dermatol IndexQuality Life Dermatology the D,of Sensitivity al. et Mazzotti E, Picardi A, Sampogna F, Sera F, Pasquini P,575–578. 133: Abeni 1995; Dermatol J Br quality. life improves greatly Kurwa HA, Finlay AY. Dermatology in-patient management J Dermatol 2020;182:104–111. Br adults. in severity dermatitis atopic for outcomes patient-reported five of ValidationPY, al. Ong et MH, son Silverberg JI, Margolis DJ, Boguniewicz M, Fonacier L, Gray J Dermatol 2017; 176: 577–593. randomizedBrin psoriasis. forstruments trials controlled in quality-of-life of use the of review systematic A al. et AY,Finlay MS, Salek VyasAA, AtwanAC, J, Cueva FM, Ali 2008; 159:997–1035. review of validation data and clinical results. Br J Dermatol matology Life Quality Index 1994–2007: a comprehensive Basra MK, Fenech R, Gatt RM, Salek MS, Finlay AY. The Der lity-of-life-questionnaires/dermatology-life-quality-index. https://www.cardiff.ac.uk/medicine/resources/qua from Available January). 2020(30 26]; September 2019 [cited cardiff.ac.uk. Dermatology Life Quality Index. online] 2019 Dermatol 1994;19: 210–216. Exp Clin use. clinical routine for measure practical simple Finlay AY, Khan G. Dermatology Life Quality Index (DLQI)—a 2019; 181:761–769. Dermatol J Br dermatitis. atopic moderate-to-severe in - - - - - 80. 92. 91. 90. 89. 88. 87. 86. 85. 84. 83. 82. 81. 79. 78. 77. 76. 75. 74. 73. 72. 71. Severity stratification of Children’s Dermatology Life Qua Waters A,SandhuD, BeattieP, EzughahF, Lewis-Jones S. (CDLQI), 1995–2012. Br J Dermatol 2013; 169: 734–759. properties of the Children’s Dermatology Life Quality Index nes M, Basra M, et al. Clinical experience and psychometric dy exploring carers’ experiences of barriers and facilitators Muller I, et al. Managing childhood eczema: qualitative stu YardleyH, Burgess M, Santer SJ,Ersser L, Lewis-Jones S, with Chinesemothers.J Adv Nurs2012; 68: 2247–2255. study phenomenological interpretive An eczema: atopic with living adolescents and Children RL. Lee WK, Cheung 241–247. 6: 1997; Nurs Clin J eczema. atopic severe with child a for caring mothers of experiences The K. Luker BE, Elliott habil 2007; 10: 113–123. Neurore Dev interventions. and issues adolescents: and Rumsey N, Harcourt D. Visible difference amongst children dermatitis. Dermatol Ther 2006; 19:104–107. atopic childhood of burden psychosocial The SL. Chamlin 19: 175–185. and review of the qualitative literature. Body image 2016; experience of adolescent chronic skin and conditions: A child, meta-ethnography Parental, AR. Thompson K, Ablett Venereol 2018;98: 563–569. dermatological patients: A multinational study. Acta Derm in life of quality impairing in therapy of role The al. et U, Balieva FN, Finlay AY, Kupfer J, Aragones LT, Lien L, Gieler J Invest Dermatol 2014; 134: 1527–1534. an analysis of the prevalence and impact of skin conditions. Margolis DJ, et al. The global burden of skin disease in 2010: IW,Bolliger HC, Williams NE, Johns RJ,Hay Dellavalle RP, BMJ 1999; 319:1423–1425. years. life adjusted disability of validity and ethics with problems DALYlife: of value The T,E. Arnesen Nord 169: 760–768. 2013; Dermatol J Br application. clinical and validation of experience of decade a ndex: I ife L of uality Q ermatitis D Infants’ S. Salek A, Finlay V,S, Gada Ungaro M, Basra Quality of LifeIndex.BrJ Dermatol 2001; 144: 104–110. Lewis-Jones MS, Finlay AY, Dykes PJ. The Infants’ Dermatitis Dermatitis. Dermatology and therapy 2019; 9: 799–805. logy Life Quality Index (CDLQI) in Adolescents with Atopic Oriented Eczema Measure (POEM) and Children’s Dermato lemin I, Reaney M, et al. Responder Threshold for Patient- Simpson EL, de Bruin-Weller M, Eckert L, Whalley D, Guil lity Index (CDLQI) scores. Br J Dermatol 2010; 163: 121. Salek M, Jung S, Brincat-Ruffini L, MacFarlane L, Lewis-Jo Invest Dermatol 2012;132:2534–2543. J application. clinical its to contribution a Scale: Impact AtopicDermatitisChildhood validation the Italian of al. et Neri E, Agostini F, Gremigni P, Gobbi F, Casu G, 2015; 98: 968–973. Chamlin SL, Thai Assoc Med J (CDLQI). index quality children’slife dermatology of version Thai the of reliability and validity W,P.NgamcherdtrakulWisuthsarewong R, NitiyaromThe of the cartoon version. Br J Dermatol 2003; 148: 285–290. A. The Children’s Dermatology Life Quality Index: validation J,DykesSharpe P, I, S, Man Holme Lewis-Jones FinlayM, Br J Dermatol 1995;132: 942–949. Quality Index (CDLQI): initial validation and practical use. Lewis-Jones MS, Finlay AY. The Children’s Dermatology Life Derm Venereol 2018;98: 715–717. Difference (2MCID): A New Twist on an Old Concept. Acta Ali FM, Salek MS, Finlay AY. Two Minimal Clinically Important (DLQI): further data. Dermatology 2015; 230: 27–33. and responsiveness of the Dermatology Life Quality Index difference important clinically minimal AY. the Finlay Determining R, Sturkey L, Camilleri MS, Salek MK, Basra 41: 582–592. 2003; Care Med deviation. standard a half of universality remarkable the life: of quality health-related in changes of Interpretation KW. Wyrwich JA, Sloan GR, Norman outcomes. J Invest Dermatol 2012; 132:2464–2465. quality index (DLQI): a paradigm shift to patient-centered AY,Finlay V,Piguet BasraMK, life Dermatology MS. Salek Quality oflifeinatopicdermatitis Theme issue:Atopic dermatitis 339 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis 340 112. 111. 110. 109. 108. 107. 106. 105. 104. 103. 102. 101. 100. 99. 98. 97. 96. 95. 94. 93. Hadžavdić S, Vurnek M, Niseteo T. The significance of significance The T. Niseteo M, Vurnek S, Hadžavdić Ljubojević M, Živković Vurnek M, Šitum N, Pustišek life-questionnaires/family-dermatology-life-quality-index. https://www.cardiff.ac.uk/medicine/resources/quality-of- from Available 26]. September 2019 [cited 2019 online] Index. Quality Life Dermatology Family cardiff.ac.uk. disease. BrJDermatol 2007; 156: 528–538. skin of impact secondary the measuring Index: Quality Basra M, Sue-Ho R, Finlay A. The Family Dermatology Life research registries. Br J Dermatol 2019;181:492–504. treatment eczema atopic for dataset core the measure to when and (TREAT)Taskforce:Registryhow on consensus Irvine AD, Arents BWM, et al. TREatment of ATopicCJ, Apfelbacher eczema AL, Bosma LAA, Gerbens FM, Vermeulen Nurs 2015;30: 102–116. of children with chronic illness: a literature review. J Pediatr Knecht C, Hellmers C, Metzing S. The perspective of siblings 2015; 19: 154–166. quality of life different from their peers? J Child Health Care their Is illness: chronic a with children of siblings Belgian Havermans T, Croock ID, Vercruysse T, Goethals E, Diest IV.2015; 82: 545–548. children with chronic neurological disorders. Indian J Pediatr of siblings unaffected of life of Quality D.P, RanaMishra Psychiatry 2016;21:618–633. CFS/ME patients: a mixed-methods study. Clin Child Psychol paediatric of siblings among quality-of-life and wellbeing Velleman S, Collin SM, Beasant L, Crawley E. Psychological adjustment. Melbourne: The University of Melbourne, 2017. on parental differential treatment, sibling relationships and Glazner JA. “What about me?”: The impact of cystic fibrosis 2019; 210:112–117. e119. brosis on unaffected siblings: a systematic review. J Pediatr fi cystic of Impact C. Radbourne R, Browne J, Chudleigh 37: 166–184. health conditions: A meta-analysis. J Pediatr Psychol 2012; chronic with children of families in siblings of functioning VermaesIP, PsychologicalHJ. Bakelvan AM, Susante van tematic review. Psychooncology 2018;27:1467–1479. sys updated An cancer: with children of siblings among factors risk and functioning Psychosocial MA. Alderfer AL, Long KA, Lehmann V, Gerhardt CA, Carpenter AL, Marsland infants with allergy. J Clin Nurs2012;21: 170–179. for care to abilities their affecting factors of perceptions Alanne S, Laitinen K, Soderlund R, Paavilainen E. Mothers’ 2017; 97: 711–714. rents of children with atopic dermatitis. Acta Derm Venereol Marciniak J, Reich A, Szepietowski JC. Quality of life of pa Dermatol Venereol 2015;29: 1221–1224. Acad Eur J dermatitis. atopic with children in instruments dermatology-specific and disease-specific by life assessed of quality family of impairment the of Comparison MKA. Basra AA, ReznikovaPV,LD, ChernyshovKaliuzhna Dermatol 2016;33: 28–32. Pediatr Dermatitis. Atopic with Children with Families Lifein of Quality M. Šitum M, Živković Vurnek N, Pustišek JAMA dermatology2019;155:556–563. AtopicDermatitis.With Children of Mothers in Exhaustion CE, Kidd SA, et al. Assessment of Sleep Disturbances and McCulloch AA, Prather SM, Langan S, Chen FD, Ramirez 2006; 154:514–518. and well-being: a sleep prospective comparative parental study. on Br asthma J Dermatol and eczema childhood of Moore K, David TJ, Murray CS, Child F, Arkwright PD. Effect with Atopic Dermatitis. J Pediatr Nurs 2018; 43: e59–e65. Children Parentsof in Loss Sleep Exploring Study graphic Cope withEveryday Life, INeedtoSleep”–A Phenomeno Angelhoff C, Askenteg H, Wikner U, Edéll-Gustafsson U. “To focus groups.Australas JDermatol 2010; 51: 168–174. ment of childhood atopic dermatitis explored using parent treat the in confounders other and phobia Corticosteroid G. Fischer A, Blaszczynski S, Fearns E, Hong SD, Smith to treatment adherence. J Adv Nurs 2013; 69: 2493–2501. F. Alietal. - - - - - 124. 123. 122. 121. 120. 119. 118. 130. 129. 128. 127. 126. 125. 117. 116. 115. 114. 113. Chamlin SL, Lai J-S, Cella D, Frieden IJ, Williams ML, Man AD scores. Qual Life Res 2005; 14:2235. of children with atopic dermatitis: interpretation of PIQoL- Meads D, McKenna S, Kahler K. The quality of life of parents Life Res 2005;14: 231–241. index of quality of life in atopic dermatitis (PIQoL-AD). Qual T, Niero M, et al. International development of the parents’ McKenna SP, Whalley D, Dewar AL, Erdman RA, Kohlmann of life. J Eur Acad Dermatol Venereol 2017; 31: 576–593. Dermatology ofand Venereology Academy (EADV) Task European the Force on of quality paper Position dermatitis. Salek M, Poot F, et al. Quality of life measurement in atopic Chernyshov P, Tomas-Aragones L, Manolache L, Marron S, 169: 31–46. 2013; Dermatol J Br application. clinical and properties Family Impact questionnaire: a review of its measurement Dodington SR, Basra M, Finlay AY, Salek M. The Dermatitis 2012; 87: 717–723. ren and teenagers with atopic dermatitis. An Bras Dermatol Amaral CS, March MP, Sant’Anna CC. Quality of life in child the patients’ family. Pediatr Dermatol 2010; 27: 618–623. Al Shobaili HA. The impact of childhood atopic dermatitis on 138: 107–113. matitis Family Impact Questionnaire. Br J Dermatol 1998; Life. J Eur Acad Dermatol Venereol 2017; 31:424–431. of Quality on TaskForce EADV the by statement opinion important in dermatology clinical practice: An expert-based burgh O, Evers AW, et al. Why quality of life measurement is Finlay AY, Salek M, Abeni D, Tomás-Aragonés L, van Cranen scale. J Pediatr 2006;149:257–261. Cabanela RL. Validity of the revised Impact on Family (IOF) Williams AR, Piamjariyakul U, Williams PD, Bruggeman SK, 465–472. on-family scale: preliminary findings. Med Care 1980; impact- 18: an of development The CK. Riessman RE, Stein ner or family member. Qual LifeRes 2014; 23:317–326. part the on disease of impact the assess to (FROM-16)© Measure Outcome Reported Family the of validation and Golics CJ, Basra MKA, Finlay AY, Salek S. The development Br JDermatol 2020;182: 348–354. Scale. Impact Dermatitis Atopic Childhood the for scores smallest detectablechangeandminimalimportant bacher CJ. Evaluation of responsiveness and estimation of Apfel AJ, Mancini D, Cella JS, Lai SL, Chamlin M, Gabes J Invest Dermatol 2005; 125: 1106–1111. for young children with atopic dermatitis and their families. Impact Scale: initial validation of a quality-of-life measure J-S, et al. Development of the Childhood Atopic Dermatitis Chamlin SL, Cella D, Frieden IJ, Williams ML, Mancini AJ, Lai sponsiveness. Arch Dermatol 2007; 143: 768–772. re validity,and concurrent and discriminativereliability, Scale: Impact Dermatitis Atopic Childhood al. et AJ, cini The family impact of childhood atopic dermatitis: the Der RG. AY,P,Owens FinlayReid V,MS, Lewis-JonesLawson Dermatol 2019;80: 1389–1394. and universalis: totalis, A prospective, areata, cross-sectional study. alopecia J with Am Acad children of parents in life of quality and disease of Severity al. et CE, Cheng M, Putterman E, Patel DP, Andrade G, Harfmann KL, Hogeling 2015; 23: 778–780. members living with leg ulcer patients. Wound Repair Regen Zakopoulou N, Zouridaki E. Quality of life in G reek family I, Chatzimichail V, Efstathiou C, Christodoulou A, Kouris J AmAcadDermatol 2014;71: 302–307. patients. psoriasis with living persons in life of Quality A. V,Buendía-Eisman García-Mellado C, Garrido-Colmenero I, Valenzuela-Salas S, Arias-Santiago E, Martínez-García Allergy 2015; 45: 779–787. clinical improvement after Lactobacillus show exposure. Clin dermatitis Exp atopic with Children JY. Wang IJ, Wang Dermatol Venereol 2016;30: 806–812. atopic dermatitis: a randomized controlled trial. J Eur Acad childhood on intervention educational parental structured ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV or remitting,asshownbyepidemiologicalstudies(1). In large proportionsofaffected patients AD ischronic which affects 15–20% of childrenand 3–5% of adults. This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta have shownthatpatientswho presentwith AD in adult onset AD” isimportant in absolutenumbers,asstudies 7 years(2).Itiscurrentlyunclear towhatdegree“late- nearly allcasesof AD arediagnosed beforetheageof by arecentprospectiveDanish study, whichshowedthat AD predominatelybeginsinearly childhood, as indicated EARLY CHILDHOOD INCIDENCE OFATOPICDERMATITIS PEAKS IN important diseasemechanismsin AD. nistic therapyagainstinterleukins(IL)4,13,22and31. AD, as well as the significant clinical effects of antago filaggrin gene (FLG)mutationsasastrongriskfactorfor chanism of AD, e.g.throughthediscoveryofcommon advancements inourunderstandingofthediseaseme stood. However, inrecentyears,therehasbeenmajor A mail: [email protected] and Gentofte HospitalsvejHospital, 15, DK-2900 Hellerup, Denmark. E- Corr: Jacob Acta DermVenereol 2020;100;adv00162. Accepted May 7,2020;EpubaheadofprintMay 15,2020 homechanism; risk. Key words: atopic dermatitis; aetiology; pathophysiology; pat ly understandthis complexskindisease. still not understood. isneededto Further ful research dramatically in years, many recent basic aspectsare our understandingof atopic dermatitis hasimproved and altered Whilstges, skinmicrobiota arediscussed. andskinbarrierchan complex hostimmuneresponse disposition, environmental insults, atopic triggers, inatopic dermatitis.sease mechanisms Geneticpre data to provide anoverview of themost important di reviews epidemiological, clinical and experimental and3–5%ofadults.15–20% of Thisarticle children dition which affects characterized anddryskin, byitch 1 Jacob P. THYSSEN Factors Disease MechanismsinAtopicDermatitis: AReview ofAetiological Atopic dermatitis is a prevalent inflammatory skin con Hospital, Aarhus, Denmark Journal Compilation ©2020ActaDermato-Venereologica. Department of Dermatology and Allergy, Herlev and Gentofte Hospital, Hellerup, and The pathogenesisof AD iscomplexandpoorlyunder This reviewprovidesaholisticoverviewofthemost skin conditioncharacterizedbyitchanddryskin, inflammatory prevalent a is (AD) dermatitis topic P. Thyssen, Department of Dermatology and Allergy, Herlev 1 , Maria Rasmussen RINNOV 1 andChristianVESTERGAARD REVIEW ARTICLE Centenary theme section:ATOPICDERMATITIS ------to adecreaseinthethresholdlevelagainstcommontrig skin barrierisvulnerabletostress(5–7). This willlead normally beginsinearlychildhood;atimewherethe or recurrenceofpreviousdisease(4).Nonetheless, AD adolescence hasbeenassociatedwithnewonsetof AD exposures. As an example,useofcosmeticproductsin may changeovertime,inconcertwithnewcausative be thecasefor AD. Moreover, theepidemiologyof AD disease mechanisms,anditispossiblethatthismayalso asthma, patientswithadultonsetseemtohavedifferent childhood didnotrecallthiswhenaskedasadults(3).In aged 31–42yearswithaschoolhealthrecordof AD in adults Swedish of 29% approximately that finding the previous disease. This notionisstronglyemphasizedby that thediseasemaythereforerepresentre-activationof hood mayhaveforgotten abouttheirchildhood AD, and other ethnicgroupsareunder-represented, andthatthe it isclearthatthephenotypic characteristicsobservedin in patientswithpredominately Europeanancestry, and & Rajka criteria were unintentionally developed for use of heritability the that (9). high Hanifin The very is AD shown have studies twin and criteria, Rajka & Hanifin predisposition toatopicdiseaseisamajorcriterionofthe darkening, aswellfacialpallor. Importantly, family associated withFLGmutations),infra-orbitalfoldsor as xerosis,palmarhyperlinearity, keratosispilaris(all a listofphenotypicandheritablecharacteristics,such including of AD, diagnosis a make to order in fulfilled a certainnumberofmajorandminorcriterianeedtobe that dictate criteria These (8). AD for criteria Rajka & Hanifin the by indicated as syndrome, clinical a is AD GENETIC PREDISPOSITION is centraltotheriskofdeveloping AD. gers. As discussedinthisreview, theskinbarrierdefect dermatitis. view of the pathogenesis and pathomechanism of atopic matitis and itsprophylaxis. This review provides an over which may improve thepredictionof onset of atopic der studies have provided insight into the pathomechanism, The aetiology of atopic dermatitis is poorly understood, but SIGNIFICANCE 2 2 Department of Dermatology, Aarhus University Acta DermVenereol 2020;100: adv00162 doi: 10.2340/00015555-3512 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis level islargely unknown. changes have influenced the risk of AD at a mechanistic sociated with AD (19).However, howtheenvironmental as factors genetic of proportion small a only identified this theory, large genome-wideassociation studieshave part oftheendemicproportions AD. Insupportof environmental changesorinsultscouldexplainalarge and lesstimespentoutside.Epigeneticchangesdueto fewer people living together in the same household, and solar irradiation, as a result of increased hygiene, at thesametimereducedexposuretomicroorganisms cosmetics, tobacco,processedfood,andairpollution,but increased useof,orexposureto,householdproducts, resulted indramaticchangeshumanexposure,with the aetiologyof AD epidemic.Modernsocietyhas stressors cannotbeoveremphasizedwhenexplaining The crucial role ofenvironmental exposure and skin ENVIRONMENTAL EXPOSURE in carriersofFLGmutationswhohave AD (18). increased risk of allergic asthma, rhinitis and food allergy and riskofsensitization,which,inturn,mayexplainthe or secondary, results in increased penetration of allergens primary whether filaggrin, of deficiency Importantly,a lowing facilitatedpenetrationofultraviolet(UV)(17). fol D vitamin of synthesis increased to due benefits from the Equator, is probably explained by evolutionary of exposed skinareas,aswelltheincreasedprevalence on filaggrin of down-regulation The (6). age of years pronounced, reductioninNMF, whichmaylastuntil3 to beginonthecheeksisalsoexplainedbyalocal,very for tendency AD The (16). reduced much are filaggrin, moisturizing factors(NMF),adegradationproductof from thatofadultskin;forexample,thelevelsnatural skin barrier in the 2 first years of infancy is very different may reduce the risk of AD (15). Importantly, the normal that dailyapplicationofemollientsinhigh-riskinfants FLG mutations, can predict AD at 12 months of age, and dry skinatbirthand2monthsofage,independent development of AD. Sincethen,ithasbeenshownthat mary skinbarrierimpairmentasacrucialfactorforthe paediatric AD, and led to a strong re-emphasis on pri provided anew, andmuchneeded,basisforthestudyof these mutations(14). The discoveryofFLGmutations life (13), whereas children with later onset do not have AD develop their skin disease within their first 2 years of risk of AD (12).NearlyallcarriersofFLGmutationswith lergens, andtherefore,expectedly, astronglyincreased enhanced penetrationand reactivity tochemicals andal elevated pH,increasedcolonizationwithstaphylococci, on thelipsisassociatedwith AD in Asian subjects(11). An exampleistherecentobservationthatpigmentation criteria mayfailwhenusedinthesepopulations(10). 342 FLG mutationsleadtodryskin,characterizedby FLG mutationsinpopulationsthathavemigratedfar J. P.Thyssenetal. - - - - pollutant, can directly down-regulate synthesis of filag (25) in patients with AD, and toluene, a common air results inincreasedwaterlossfromtheskinsurface example, short-termexposuretoairborneformaldehyde chemicals negativelyaffect theepidermalbarrier. For also beenassociatedwith AD (23,24),perhapsbecause pollution andbeingborninanewlybuilthomehave cleavage ofcornedesmosomes(20).Exposuretoair pH, which,amongotheraspects,resultsinpremature may increasetheriskof AD, possiblyduetoincreased dermatitis (22). Similarly, bathing infants in hard water which cannegativelyaffect theskinbarrierandresultin as welllowambienthumidityduetoindoorheating, probably explained byskin exposure to low temperatures, has beenstronglyassociatedwith AD (20,21). This is hemisphere, orbeingexposedtoadryandcoldclimate, barrier, which,amongotheraspects,reducesStaphyloc sub-erythemogenic doses of UVB irradiation on the skin 28). This couldbeexplainedbythepositiveeffects of of skinmalignancy, seemstoprotectagainst AD (27, which isnormallyavoidedininfancy, toreducetherisk grin (26). Interestingly, exposure to solar irradiation, excessive Th2 skewinchildhood)(Fig.1). against thecrucialmicroorganisms thatcouldprevent are exposedto AD triggers(orwhoareoverlyprotected who and impairment barrier skin significant have who AD occursmainlyingenetically predisposedindividuals area iscomplex,andlittleevidenceexists.Collectively, trients mayaffect thechild’s immuneresponse,butthis higher prevalenceof AD ininfants(34).Similarly, nu the Th2 skew induced by alcohol intake may lead to a can affect theriskof AD, butishasbeensuggestedthat It isunclearhownutrientsandalcoholuseinmothers biome canaffect thetolerance-reactivitybalance(33). but itisalsopossiblethatchangesinthehostgutmicro reduce theriskof can strongly couldbeconfounded, AD for AD per se. The finding that neonate exposure to dogs it isprobablymoreimportantforallergic diseasesthan mediated by T-helper (Th)cell2,including AD (32),but that microbialexposuremayreducetheriskofdiseases cells inpatientswith AD (31). The farmtheorysuggests may also be aconsequenceof the increased demand for T children with AD comparedwithcontrols,althoughthis in sizes thymus larger significantly found study a tion, to develop AD (30). Inindirectsupportofthisassump decreases the numberof circulating T cells that canact of AD by20%,suggestingthatremovalofthethymus (29). Moreover, thymectomy in infancyreduces the risk infants premature in AD of risk reduced significantly tivity onthedevelopmentof AD isemphasizedbythe The crucialroleofearly-agealterationsinimmuneac EARLY ALTERATIONS INTHE IMMUNE SYSTEM cocus aureus colonization,itch,and T-cell invasion. Being bornintheautumnorwinterNorthern ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV whereas factorsthatdecreasetherisk arerepresentedby (AD). may impacttheriskofatopic dermatitis interact and environmental riskexposures and 1. Theoretical outlineofhowgeneticriskgenes Fig. AD isunclear, colonizationwithS.aureus isverycom While the exactroleofbacteriainpathogenesis AUREUS PATHOGENIC ROLE OFSTAPHYLOCOCCUS of newflares(38). with applicationtwiceweekly, workstoreduce therisk Prophylactic use of topical anti-inflammatory agents, e.g. tion seemstobeinadequateinthetreatmentof AD (37). inflamma of control simultaneous without restoration need fortopicalcorticosteroids(36).However, barrier to subsequent flares in emollient users, and the reduced of emollientusetotreat AD isthestronglyincreasedtime fectants and antibiotics. Evidence supporting the benefits finally, decreasing the burden of or immunemodulatingdrugs,aswelllighttherapy, and, and itchwithuseoftopical/oralimmunesuppressants the skin barrier with emollients, reducing inflammation cycle. Cliniciansattempttostopthiscyclebyrestoring and additionalbarrierimpairment,thuscreatingavicious relentless sensationofitch(35). This leadstoscratching and in turn may drive both eczema severity andthe tion, andinwhichS.aureus colonizationmayincrease, skin barrier impairment leads to (further) skin inflamma AD isaskinconditioninwhichprimary(orsecondary) VICIOUS CYCLEINATOPICDERMATITIS If a child reaches the threshold bar for AD, the disease manifest. will Factors that increase the risk of AD are represented by S. aureus byuseofdisin green verticallines - - - - . OnceADhasmanifested,thelines areshownin While theskinhostsmostdiversecommensalcom SKIN ANDDISEASE MICROBIOME CONTROL the firststepinskincolonization(47). to regulatethestrengthofS.aureus corneocyteadhesion, levels of filaggrin degradation products, i.e. NMF, seem growth inhibition of the filaggrin proteins (45, 46). The due toincreasedpH,butalsothelackofdirect 7-fold higherriskofS.aureus skininfections,inpart (44). Individualswith AD andFLGmutationshavea keratinocyte membranesleadingtocellulardamage in pores forms which α-toxins, release also S. aureus of T cellsviaasuperantigen-mediatedmechanism(43). by activating mast cells (42), and induces up-regulation (41), andS.aureus toxinincreasestheallergic response cytokines isactivatedbyproteasesreleasedS.aureus and allowinvasion(40).Moreover, theexpressionof Th2 protease activity, corneodesmosomes, destroy whichwill to colonizetheskin(39).S.aureus caninduceserine ced inpatientswith AD, which,inturn,allowsbacteria kill Gram-negative and Gram-positive bacteria, are redu peptides, whichworkasbroad-spectrumantibioticsto mon in lesional and non-lesional AD skin. Antimicrobial understood (48,49). An animalstudyshowedthat species, theroleofskinmicrobiomein AD ispoorly munity ofhumans,withover1,000different bacterial Disease mechanismsinatopicdermatitis Theme issue:Atopic dermatitis red . yellow vertical lines, 343 - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis attempt torestoretheskinbarrierand prevent excessive water loss,acanthosisoccurs,ofteninconjunctionwith mildspongiosis. synthesis is compromised at several levels, which acts in concert with protein dysfunction to allow increased loss of water from the skin surface. In an irritants and microorganisms to invade. Tight junction reduction further allows antigen presenting cells to move upwards and meet the antigens. Lipid elevated barrierwith adryandleakyskin to turnleading proteins, in junction andtight of filaggrin colonize bacteriato allows which pH, andallergens, Fig. 2.Important skin in barrier atopic changes dermatitis (AD). generalized skindisease. (53), probablyreinforcingtheimpressionof AD asa are largely extentandseverity determinedbydisease populations (61–63). The changes innon-lesionalskin S. aureus, inpartduetothecreationofresident T-cell exogenous stressors,suchasskinirritants,allergens and reover, AD skin displays areduced reactivity threshold to surface, andincreasedpenetrationofchemicals(60).Mo show elevatedpH,increasedwaterlossfromtheskin (59). Thus, skinmeasurementsinnon-lesional AD skin changes intheepidermallamellarbilayerarchitecture acid sphingosinearereduced,andthereimportant without food allergy. Thus, filaggrin and ω-hydroxy fatty skin thatarenotfoundinchildrenwith AD andcontrols lergy havestratumcorneumabnormalities innon-lesional cells and their cytokines. Children with AD and food al on dendriticCD1a,alongwithincreasednumbersof T well as increased expression of high-affinity IgE receptor synthesis ofantimicrobialpeptidesandlipids,(52–58)as loricrin, hornerin,andtightjunctions,butalsodecreased epidermal proteins, e.g. filaggrin, filaggrin 2, involucrin, 2). It shows decreased or altered synthesis of important is alsodifferent fromtheskinofnormalcontrols(Fig. It isimportanttounderstandthatnon-lesional AD skin LESIONAL SKIN DYSFUNCTIONAL LESIONAL ANDNON- diversity (51). rium speciesincreaseinnumbersalongwithmicrobial Streptococcus, (50). Moreover, followingsuccessfultreatmentof AD, mation, henceindicatinganimportantpathogenicrole inflam chronic drove and secretion IL-1α intracellular triggered dysbiosis microbial and deficiency filaggrin 344 J. P.Thyssenetal. Propionibacterium, andCorynebacte Innate and acquired inflammation in AD leads to downregulation and degradation - - - - that sweatingfromexercisewasacommonexacerbator various stressors. A surveyinchildrenwith AD showed To date,therehasbeenlittleresearchintothereactivityto ATOPIC TRIGGERS climatic factors(66). area whichisexposedtoenvironmentalpollutantsand to beslightlylesseffective infacialskin;ananatomical antibodies againsttheIL-4andIL-13receptorsseems and typeofelicitor. Interestingly, ofmonoclonal use skin exposure, possible co-infection, climatic effects, would beexpectedtodependongenetics,age,sitesof addition tothe Th2 axis. The exactimmuneresponse as discussedbelow, activatethe Th1 and Th17 axisin in AD couldleadtosecretionofvariouscytokines,and into theprimaryandsustainedskinbarrierimpairment of microorganisms, chemicals, irritants and allergens skin. Thus, thecontinuousbombardmentandpenetration skin barrier impairment in lesional and non-lesional AD explained bythecrucialpathogenicroleofsustained heterogeneous cytokine landscape could also, in part, be While certain endotypes of AD are suspected to exist, the degree this should affect treatment strategy (64,65). as wellbetweendifferent ethnicgroups,andtowhat ferences existbetween AD skinofchildrenandadults, in AD. It is presently unclear whether significant dif significant whether unclear presently is It AD. in stromal lymphopoietin(TSLP)haveimportantroles limited to,IL-1,IL-17,IL-22,IL-31IL-33,andthymic and IL-13,aswellothercytokines,including,butnot Type 2immunity-associated cytokines, such as IL-4 STRESSORS DEFICIENT SKIN BARRIER AND EXOGENOUS HETEROGENEOUS INFLAMMATORY RESPONSE, - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV cells alsorelease Th2 cytokines,nowincreasinglyre skin barrier proteins, such as filaggrin. Innate lymphoid which, inturn,down-regulate expressionofimportant deviation isobservedinacute andchronic AD lesions, nately Th2 (IL-4,IL-5,IL-13,IL-31)and Th22 (IL-22) munopathophysiology of AD in detail. Briefly, predomi It isbeyondthescopeofthisreviewtodescribeim RESPONSECOMPLEX IMMUNE and cytokineswillbetargeted inthefuture. of theabove-mentionedcytokines,butotherchemokines published dataclearlyindicatetherelativeimportance against TSLP, IL-33and IL-17C areongoing. These (81). Clinical studies into the developmentof antibodies the effects on AD havenotbeenappropriatelyexamined inhibition significantly reduced itch in patients with AD, worked inpatientswithsevere AD (80). While IL-31 the severityof AD, whereasIL-22inhibitionmostly IL-4, but alsoIL-13,antagonismshave proven toreduce mainly date, cytokines. To specific against antagonists sponse in AD has been derived fromclinicaltrials using The mostimportantknowledgeabouttheimmunere RESPONSE CYTOKINE ANTAGONISM ANDTHEIMMUNE IL-4 secretionintheepidermis(79). and found that exposure to hard wateris associated with various atopictriggersinindividualswithnormalskin A recentstudyexaminedtheskinimmuneresponseto this translates into clinical relevance is currently unclear. but Th1 immuneresponseinnon-atopicskin(78).How patients with AD causes Th2 immuneresponseactivity, to experimentalandenvironmentalcontactallergens in Th1 immuneresponse(76,77).Furthermore,exposure reactions, asopposedtomanyotherallergens thatelicit been showntoelicit Th2 immuneactivityinpatchtest gens, e.g.fragrancesandcertainrubberchemicals,have AD individualsthroughIL-4release(75).Contactaller lergens maycauseworseningof AD ingrass-allergic the riskofskininfections(74).Exposuretograssal stratum corneum,decreaseslipidsynthesis,andincreases psychological stressreducestherecoverytimeof axis in AD skincouldalsobeimportant(73).Moreover, unresponsive peripheral hypothalamic-pituitary-adrenal but notincontrols(72). The dysfunctionalandpartly stress leadstoscratchingbehaviourinpatientswith AD, psychological stressandsleepdeprivation.Inductionof triggers for AD includeexposuretowool,hot weather, well-established Other (71). deficiency filaggrin to due be relevant(70),aswellobstructionofsweatducts mis duetodysfunctionaltightjunctionfunctioncould effects ofheating(69),leakingsweatintotheepider (68) and,atleastinpart,couldbeexplainedbythedirect of AD (67). While theexactmechanismsisunknown ------the balancebetweenthese2celltypesiscentraltodeve an importantroleinimpairmentoftheskinbarrier(84). to 25% of patients with AD, indicating that IgE may play etc. (82).Interestingly, IgEmaytarget keratinocytesinup exogenous factors,e.g.S.aureus, detergents, allergens, response intermsof AD andextrinsicfactorstodescribe which affect theskinbarrierfunctionorimmune inborn factorse.g.FLGmutations, Th2 skewing,etc., suggested to use the terms intrinsic factors to describe may alsobesensitizedandviceversa.Ithasevenbeen levels ofIgE.However, patients withnormalIgElevels place, andintrinsic AD, inwhichpatientshavenormal into extrinsic AD, whereallergic sensitizationhastaken lergies (83). Previously, this has been used to subtype AD and atopicco-morbidities,includingasthmafoodal dendritic cells.ElevatedlevelsofIgEcorrelatewith AD to IgEandrecruitmastcells,eosinophils,basophils may, in many patients, lead to antibody isotype switching sis andincreasesS.aureuscells colonization. TheTh2 Th2 inflammation inhibits antimicrobial peptide synthe the skinandriskofacuteinflammation(53). controls, suggestingincreasedimmuno-surveillancein healthy comparedwith numberoflymphocytes increased and chemokines,aswelloftheirreceptors,an there is increased expression of inflammatory cytokines (82). Yet, eveninhealthyskinfrompatientswith AD, both acuteandchronic IL-17activationcanbefound AD, parallel activationofthe Th1 axisisobserved,andin ferred toastype2immunity. Inchronic AD lesions,a such asthecentralnervous system andvascularsystem, in AD cannegativelyaffect thefunctionofotherorgans, is intriguing to consider that the systemic inflammation of circulatingcytokinesand chemokines(87). While it Adult patients with AD have significantly elevated levels ROLE INFLAMMATION OFSYSTEMIC medicine forpatientswith AD (87). result ofthismaybethedevelopmentpersonalized differs slightlyandgivesrise todifferent subtypes. The and that,evenwithinthegroupofpatientswith AD, this have different propensitytoreactexogenousstimuli disease (86).Rather, itindicatesthatpatientswith AD show thattheimmuneresponseisprimecauseof 147 different soluble factors, yet this does not, in itself, at least3different subtypesof AD, basedonanalysisof undertaken (85). A recentworkwasabletodistinguish subtypes basedonserumlevelsofcytokineshasbeen AD, and a huge work in developing a taxonomy for AD IL-13, IL-12,havebeenreportedtobeassociatedwith example, ST2 (a member of the interleukin 1 family), of AD. Singlenucleotidepolymorphisms(SNPs)in,for immune-deficiency/imbalance might be the prime cause lopment oftolerance.Itisnotknownwhetheraprimary Regulatory T cellscansuppressthe Th2 response, and Apart from the negative influence on the skin barrier, Disease mechanismsinatopicdermatitis Theme issue:Atopic dermatitis 345 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis REFERENCES interest todeclare. of conflicts no has MRR Co. & Lilly Eli and LeoPharma Sanofi, has beeninvestigator, speaker, or consultant forNovartis, Abbvie, from LEO Pharma, Abbvie, Regeneron, and Sanofi-Genzyme. CV Genzyme, andLEOPharma,receivedspeakerhonorarium Sanofi- Regeneron, Pfizer, Abbvie, for investigator an been me, Eli Lilly & Co., Pfizer, Abbvie, LEO Pharma, and Sanofi-Genzy Conflicts of interest: unrestricted grantfromtheLundbeckFoundation. an by supported financially are Funding sources:MRR and JPT ACKNOWLEDGEMENTS this complexskindisease. questions. Inconclusion,moreresearchisneededinto than controls? These arejustsomeofmanyunanswered triggers for AD? Why do AD childrenhavefewernaevi in the majority of children? What is the role of foods as AD of resolution the explains What flare? AD an gers trig What disease? flexural a AD is Why controlled? is eczema flexural once clear to tend areas flexural the understood. Forexample,whydo AD lesionsoutside proved inrecentyears,manybasicaspectsarestillnot chanisms of AD. While understandingof AD hasim This reviewhighlightssomeimportantdiseaseme CONCLUSION reaching theskin. is explained bypsychological stress orbycytokines during orafterasthmaattacks,itisunclearwhetherthis patients with AD experienceworsening oftheir AD inflammation could play an important role. While some severity ofboth AD andasthma supportthatsystemic the sharedtype2immunityandeffect ofdupilumabon link betweenasthmaand AD isnotfullyunderstood, but major riskfactor for ADD and depressive symptoms. The Decreased sleepqualityduetoitchis,however, alsoa lopment, byaffecting thegliacellsandneurogenesis. compartments and negatively affect cognitive deve barrier andbecomeabsorbedintothecerebrospinal is possiblethatcytokinesmaycausealeakyblood–brain depression, autism and attention deficit disorders, and it this. Nonetheless, AD hasbeenassociatedwithanxiety, there is currently noconvincing evidence to support 346 2. 4. 3. 1. Thorsteinsdottir S, J,Stokholm Thyssen JP, Norgaard S, Puangpet P, Lai-Cheong J, McFadden JP. Chemical atopy. Moberg C,MedingB, Stenberg B, Svensson A,LindbergM. Margolis JS, Abuabara K,Bilker W, HoffstadO, MargolisDJ. Thorsen J, Chawes BL,etal.Genetic,clinical,andenviron Remembering childhoodatopicdermatitis asanadult:fac Dermatol 2014;150:593–600. Persistence of mild to moderate atopic dermatitis. JAMA 557–560. 155: 2006; Dermatol J Br recollection. influence that tors in childhood.JAMA Dermatol 2019; 155: 50–57. mental factors associated with persistent atopic dermatitis J. P.Thyssenetal. JPT hasattendedadvisoryboardsforRoche, ------10. 15. 23. 14. 22. 19. 13. 12. 11. 24. 21. 20. 18. 17. 16. 9. 6. 8. 5. 7. Cheng R, Guo Y, Huang L, Hao F, Gao X, Bieber T, et al. Cur Kelleher M, Dunn-Galvin A, Hourihane JO, Murray D, Campbell Schultz Larsen F. Atopic dermatitis: a genetic-epidemiologic Wen HJ, ChenPC,ChiangTL,LinSJ, ChuangYL,GuoYL. McAleer MA, Jakasa I, Raj N, O’Donnell CPF, Lane ME, Raw Rupnik H,Rijavec M,Korosec P. Filaggrinloss-of-function Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. McNally NJ, Williams HC, Phillips DR. Atopic eczema and the Kezic S, Novak N, Jakasa I, Jungersted JM, Simon M, Brand Fluhr JW, Darlenski R, Taieb A, Hachem JP, Baudouin C, Bisgaard H, Simpson A, Palmer CN, Bonnelykke K, McLean Thyssen JP, Kezic S. Causes of epidermal filaggrin reduction Kang MK.Atopic Shin LeeMH, JeongKH, IH, pigmenta labial Wester RC,NoonanPK,ColeMP, MaibachHI.Percutaneous Hidaka T, Ogawa E,Kobayashi EH,SuzukiT, Funayama R, are factors Climatic EL. Simpson J, Hanifin JI, Silverberg Engebretsen KA, Bager P, Wohlfahrt J, Skov L, Zachariae C, Rodriguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown epider of benefits evolutionary JP.trade-off: Thyssen The Nikolovski J, StamatasGN,Kollias N,WiegandBC.Barrier and predictsatopicdermatitisat1year. JAllergyClinIm transepidermal water loss at 2 days and 2 months predates LE, McLean WH, et al. Skin barrier dysfunction measured by 1993; 28: 719–723. study inapopulation-based twinsample. J AmAcadDermatol Predicting risk for early infantile atopic dermatitis by here 172: 455–461. develops in late childhood or adulthood. Br J Dermatol 2015; mutations are not associated with atopic dermatitis that Acta Derm Venereol 1980; Suppl92:44–47. home environment. Br J Dermatol 2001; 145:730–736. 483–492. complete butnotfullycompetent.ExpDermatol 2010;19: Msika P, etal. Functionalskinadaptationininfancy–almost 2008; 5:e131. mutations enhancedby neonatalcatexposure.PLoSMed loss-of-function filaggrin infancy: in eczema of onset the I, Mukhopadhyay S, et al. Gene-environment interaction in and their role in the pathogenesis of atopic dermatitis. J Al comparison tothe adult. Pediat Res 1977;11: 737–739. absorption of testosterone in the newborn rhesus monkey: atopic dermatitis and air pollution via induction of the neu Nagashima T, et al. The aryl hydrocarbon receptor AhR links States. J Invest Dermatol 2013;133:1752–1759. associated withchildhoodeczema prevalence intheUnited infants by domestic water hardness and season of birth: Co Nybo AndersenAM,etal.Prevalence ofatopicdermatitis in J AllergyClinImmunol2009;123: 1361–1370.e7. in eczema and asthma: robust risk factors in atopic disease. SJ, Cordell HJ, et al. Meta-analysis of filaggrin polymorphisms function andwater-holding andtransport propertiesof in Contact Dermatitis 2013;68:208–213. lergy Clin Immunol 2014; 134: 792–799. dermatitis. IntJDermatol 2018; 57: 817–821. tion: a newdiagnosticfeatureinAsianpatientswithatopic 2017; 72: 1277–1278. rent Allergystatus in of China. in diagnosis atopic dermatitis 2018; 179:431–441. activity: implicationsfor atopicdermatitis.Br JDermatol sing enzyme activity, corneocytephenotypes and plasmin filaggrin-derived natural moisturizing factor, filaggrin-proces lings AV, etal. Early-life regionaland temporal variation in rotrophic factor artemin.NatureImmunol2017; 18:64–73. 1166–1172. ditary and environmental factors. Br J Dermatol 2009; 161: hort study. Immunol 2017; J Clin 139: Allergy 1568–1574.e1. (Landmark Ed)2014;19:542–556. ner JM, et al. Skin barrier in atopic dermatitis. Front Biosci 235–236. the atopic dermatitis epidemic. Br J Dermatol 2018; 179: of price the at came skin cheek on deficiency filaggrin mal 2008; 128:1728–1736. Dermatol Invest J life. of year first the through develop to fant stratum corneum are different from adult and continue munol 2015; 135:930–935.e1. ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 43. 42. 41. 33. 40. 36. 32. 39. 35. 31. 29. 38. 37. 34. 30. 28. 27. 26. 25. Skov L,OlsenJV, Giorno R,Schlievert PM,BaadsgaardO, Nakamura Y, Oscherwitz J, Cease KB, Chan SM, Munoz- Nakatsuji T, Chen TH, Two AM, Chun KA, Narala S, Geha S,Thorsteinsdottir Thyssen JP, Stokholm J, NH, WaaVissing Williams MR,NakatsujiT, SanfordJA, VrbanacAF, Gallo RL. Wiren K, Nohlgard C, Nyberg F, Holm L, Svensson M, Jo Flohr C, Yeo L. Atopic dermatitis and the hygiene hypothesis Schauber J, GalloRL.Antimicrobial peptidesandtheskin Elias PM, Steinhoff M. “Outside-to-inside” (and now back to Olesen AB, Andersen G, Jeppesen DL, Benn CS, Juul S, Barbarot S, Gras-Leguen Darmaun E, Garrot H, C,Colas aii J Gpa K Rjgpln . nemtet dosing R.Intermittent Rajagopalan AK, Gupta J, Hanifin Czarnowicki T, Dohlman AB, Malik K, Antonini D, Bisson Halling-Overgaard AS, HamannCR,Holm RP, LinnebergA, Thyssen JP, Andersen YMF, Zhang H, Gislason G, Skov L, Rueter K, Jones AP, Siafarikas A, Lim EM, Bear N, Noakes Thyssen JP, Zirwas MJ, Elias PM. Potential role of reduced Lee H,ShinJJ, Bae HC,Ryu WI,SonSW. Toluene down Kim J, Han Y, Ahn JH, Kim SW, Lee SI, Lee KH, et al. Airborne 2000; 105:820–826. superantigen-mediated mechanism. J Allergy Clin Immunol normal and atopic skin induces up-regulation of T cells by a Leung DY. Applicationof Staphylococcal enterotoxin Bon 2013; 503:397–401. by disease skin activating allergic induces Nature mastcells. Planillo R, Hasegawa M, et al. Staphylococcus delta-toxin J Invest Dermatol 2016; 136: 2192–2200. defects in atopic dermatitis to trigger cytokine expression. RS, etal. Staphylococcus aureus exploits epidermal barrier 377–384. activity in keratinocytes. J Invest Dermatol 2017; 137: Staphylococcus aureusinduces increased serineprotease revisited. Curr Probl Dermatol 2011; 41: 1–34. 124: R13–18. immune defense system. J Allergy Clin Immunol 2009; Invest Dermatol 2008;128:1067–1070. “outside”) pathogenicmechanisms inatopic dermatitis.J Venereol 2005;85: 240–243. current A atopic study.dermatitis. cross-sectional Acta Derm Thestrup-Pedersen K.Thymus is enlargedinchildrenwith infants born extremely preterm compared with higher gesta D, Larroque B, et al. Lower risk of atopic dermatitis among 147: 528–537. risk of relapse in atopic dermatitis patients. Br J Dermatol 2002; the for reducing cream propionate fluticasone of Dermatol Venereol 2018;32: 1238–1245. use –ameta-analysis andsystematicreview. J EurAcad Silverberg JI, Egeberg A, et al. Atopic dermatitis and alcohol 1741–1743. thymectomy: a Danish register study. Allergy 2018; 73: Egeberg A. Incidence of pediatric atopic dermatitis following 2019; 143:1012–1020.e2. eczema and immune development. J Allergy Clin Immunol PS, et al. Direct infant UV light exposure is associated with environmental UVexposureas adriver of thecurrentepi formaldehyde causesskinbarrierdysfunctioninatopicder Asthma Immunol2018; 120: 631–640.e11. atopic dermatitis:arandomized controlledtrial.AnnAllergy activation onepidermalbarrierfeaturesinmildtomoderate nette R,ChanTC, etal. Effect ofshort-term liver Xreceptor Acad Dermatol Venereol 2009;23: 1267–1272. prospective andrandomized controlledclinical trial.JEur moisturizing cream delays relapse of atopic dermatitis: a hannesson A,etal.Treatment withabarrier-strengthening 2016;71:1736–1744. Allergy dermatitis. ofatopic incidence ge J, Bisgaard H. Domestic dog exposure at birth reduces the tional age.BrJ Dermatol 2013; 169: 1257–1264. 136: 1163–1169. demic of atopicdermatitis. J AllergyClinImmunol2015; 2017; 139:355–358.5. transcription-dependent pathways. JAllergy ClinImmunol regulated kinase and signal transducer and activator of signal- the extracellular via expression filaggrin regulates matitis. Br JDermatol 2016; 175: 357–363. ------63. 62. 61. 44. 60. 59. 58. 54. 50. 47. 57. 53. 49. 46. 56. 52. 51. 48. 45. 55. Nassif A, Chan SC, Storrs FJ, Hanifin JM. Abnormal skin ir skin Abnormal JM. Hanifin FJ, Storrs SC, Chan A, Nassif Strange P, Skov L, Lisby S, Nielsen PL, Baadsgaard O. Brunner PM, Emerson RO, Tipton C, Garcet S, Khattri S, Coats Song L, Hobaugh MR, Shustak C, Cheley S, Bayley H, Gouaux Halling-Overgaard AS, Kezic S, Jakasa I,EngebretsenKA, Leung DYM, Calatroni A, Zaramela LS, LeBeau PK, Dyjack Hamid Q, Boguniewicz M, Leung DY. Differential in situ Jensen JM,Folster-Holst R,Baranowsky A,SchunckM,Wino Archer NK, Jo JH, Lee SK, Kim D, Smith B, Ortines RV, et al. Feuillie C,Vitry P, McAleerMA, Kezic S, IrvineAD, Geoghegan Wollenberg A, Wen S, Bieber T. Phenotyping of epidermal Suarez-Farinas M,TintleSJ, Shemer A,ChiricozziNograles Polkowska-Pruszynska B, Gerkowicz A, Krasowska D. The Cai SC, Chen H, Koh WP, Common JE, van Bever HP, McLean Semper AE, Heron K, Woollard AC, Kochan JP, Friedmann Pellerin L, Henry J, Hsu CY, Balica S, Jean-Decoster C, Mechin Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Bjerre RD, Bandier J, Skov L, Engstrand L, Johansen JD. The Miajlovic H, Fallon PG, Irvine AD, Foster TJ. Effect of filaggrin Di Nardo A, Wertz P, Giannetti A, Seidenari S. Ceramide and 132: 27–33. intact atopicskininducesdermatitis. Arch Dermatol 1996; Staphylococcal enterotoxin Bappliedonintactnormaland clones withlesionaltissues.Allergy2017;72:2017–2025. I, et al. Nonlesional atopic dermatitis skin shares similar T-cell JE. StructureofstaphylococcalJE. aheptame alpha-hemolysin, 177: 84–106. dermatitis skin: a systematic review. Br J Dermatol 2017; Maibach H, Thyssen JP. Skin absorption through atopic Transl Med 2019;11. pii: eaav2685. atopic dermatitis with food allergy as a unique endotype. Sci N, Brar K, et al. The nonlesional skin surface distinguishes dermatitis. J ClinInvest 1994; 94: 870–876. acuteversus in geneexpression cytokine atopic chronic Injury, drive deficiency filaggrin and dysbiosis, inflam skin JA, et al. Adhesion of staphylococcus aureus to corneocy micromethod. Cytometry 1999; 37:147–155. cytometric flow a of applications clinical cells: dendritic 127: 954–964.e1–4. variable immune abnormalities. J Allergy Clin Immunol 2011; characterized by broad terminal differentiation defects and K, Cardinale I, et al. Nonlesional atopic dermatitis skin is 34: 455–464. diseases –anupdate.JEurAcadDermatol Venereol 2020; gut microbiome alterations in allergic and inflammatory skin dermatitis. Br J Dermatol 2012;166:200–203. skin infection in Singaporean Chinese patients with atopic WH, etal.Filaggrinmutationsareassociated withrecurrent and rhinitis. J Allergy Clin Immunol 2003; 112:411–419. with diseaseactivity inatopic dermatitis, allergicasthma, Langerhans’ cells of clinically uninvolved skin is associated PS, Church MK, et al. Surface expression of Fc epsilon RI on 131: 1094–1102. and nonlesionalatopicskin.JAllergyClinImmunol2013; lesional both in proteins filaggrin-like of Defects al. et MC, disease flares and treatment in children with atopic derma et al.Temporal shifts intheskinmicrobiomeassociated with review. Br JDermatol 2017; 177: 1272–1278. role of the skin microbiome in atopic dermatitis: a systematic 1184–1190.e3. Staphylococcus aureus. J Allergy Clin Immunol 2010; 126: breakdown productsongrowthof and proteinexpressionby dermatitis. Acta Derm Venereol 1998; 78: 27–30. cholesterol composition of the skin of patients with atopic titis. GenomeRes 2012;22:850–859. Immunol 2019; 143: 1426–1443.e6. throughkeratinocytemation IL-1alpha Clin JAllergy release. moisturizing factorlevels. mBio 2018; 9.pii:e01184–18. tes fromatopicdermatitispatientsiscontrolledby natural ric transmembrane pore. Science 1996; 274: 1859–1866. ritancy in atopic dermatitis and in atopy without dermatitis. Invest Dermatol 2004;122:1423–1431. activity and epidermaldifferentiation inatopicdermatitis.J to-Morbach S, Neumann C, et al. Impaired sphingomyelinase Disease mechanismsinatopicdermatitis Theme issue:Atopic dermatitis 347 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 74. 73. 67. 72. 66. 76. 71. 69. 65. 75. 70. 68. 64. Theme issue:Atopic dermatitis 348 Hall JM, Cruser D, Podawiltz A, Mummert DI, Jones H, Mum Slominski AT,Slominski JP,Szaflarski PM, Plonka MA, Zmijewski Paus Williams JR, Burr ML, Williams HC. Factors influencing atopic Mochizuki H,Lavery MJ, Nattkemper LA,AlbornozC,Valdes Silverberg JI, Simpson EL, Ardeleanu M, Thaci D, Barbarot S, Newell L,Polak ME,Perera J, OwenC,Boyd P, PickardC,et Rerknimitr P, Tanizaki H,Yamamoto Y, AmanoW, Nakajima Murota H, Yamaga K, Ono E, Katayama I. Sweat in the patho Chan TC, Sanyal RD, Pavel AB, Glickman J, Zheng X, Xu H, Werfel T, Heratizadeh A, Niebuhr M, Kapp A, Roesner LM, Yamaga K,MurotaH,Tamura A, Miyata H,OhmiM,Kikuta J, Hendricks AJ, Vaughn AR, Clark AK, Yosipovitch G, Shi VY. Zhou L,LeonardA,Pavel AB, MalikK,Raja A,GlickmanJ, through skin, and why. Endocrinol 2018; 159: 1992–2007. R. How UV light touches the brain and endocrine system dermatitis – a questionnaire survey of schoolchildren’s per 821–827. dermatitis and healthy controls. Br J Dermatol 2019; 180: sensation andscratching behaviour inpatientswithatopic Rodriguez R, Stull C,etal.Impactofacutestressonitch trials. Br J Dermatol 2019; 181:80–87. Assessment: a pooled analysis of data from two phase III or almost clear skin according to the Investigator’s Global to patients with atopic dermatitis who do not achieve clear Bagel J, et al. Dupilumab provides important clinical benefits al. Sensitization via healthy skin programs Th2 responses in Dermatol 2017; 137:248–251. to sweat duct obstruction in filaggrin mutant mice. J Invest lead may level filaggrin Decreased al. et C, Nakashima S, 2018; 142:1013–1017. skewing with psoriasiform features. J Allergy Clin Immunol et al.Atopic dermatitisinChinesepatientsshowsTH2/TH17 Allergy Clin Immunol2015; 136: 96–103.e9. pollen exposure in an environmental challenge chamber. J Karch A,etal.Exacerbation of atopicdermatitisongrass J Invest Dermatol 2018; 138: 1279–1287. gland to contribute to the pathogenesis of atopic dermatitis. et al. Claudin-3 loss causes leakage of sweat from the sweat Dermatol Sci2018; 89: 105–111. Sweat mechanismsanddysfunctions inatopicdermatitis.J Clin Immunol2019; 144: 144–156. moderate-to-severepatients with J atopic dermatitis. Allergy of phenotype molecular the in changes Age-specific al. et Pract 2012; 2012:403908. system inatopicdermatitisand psoriasis.Dermatology Res response: roles of the HPA axis and the sympathetic nervous mert ME.Psychological stressandthecutaneousimmune Int2018;67:455–459. Allergol dermatitis. ofatopic genesis ceptions. Br JDermatol 2004; 150: 1154–1161. Arch Dermatol 1994;130: 1402–1407. J. P.Thyssenetal. - - - 80. 79. 78. 87. 77. 84. 82. 86. 83. 81. 85. Guttman-Yassky E, Brunner PM, Neumann AU, S,Khattri Engebretsen KA,Kezic S, Jakasa I,Hedengran A,Linneberg Correa daRosa J, MalajianD, ShemerA,Rozenblit M,Dhingra Thijs JL, Strickland I, Bruijnzeel-Koomen C, Nierkens S, Gio Dhingra N,ShemerA,CorreadaRosa J, Rozenblit M,Fuentes- Altrichter S, Kriehuber E, Moser J, Valenta R, Kopp T, Stingl Eyerich K,Novak N.Immunologyof atopic eczema: over Thijs JL, Strickland I, Bruijnzeel-Koomen C, Nierkens S, Nygaard U, HvidM, Johansen C,Buchner M, Folster-Holst A, G, Wollenberg Pulka JM, Hanifin M, Furue K, Kabashima Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed to-severe atopic dermatitis inadequately controlled by con (an IL-22 monoclonalantibody)inadultswithmoderate- Pavel AB, Malik K, et al. Efficacy and safety of fezakinumab Br J Dermatol 2018;179: 679–688. moisturizing factors and cytokines in healthy adult epidermis. A, Skov L, et al. Effect of atopic skin stressors on natural 135: 712–720. to commonallergensinskin.JAllergyClinImmunol2015; attenuated and distinct contact hypersensitivity responses N, Czarnowicki T, et al. Patients with atopic dermatitis have 362–372. in immune response. J Allergy Clin Immunol 2014; 134: differences allergen-dependent identifies skin contactdermatitis of profiling Molecular al. et JK, Gittler J, Duculan G. Serum IgE autoantibodies target keratinocytes in pa 140: 730–737. on serum biomarker analysis. J Allergy Clin Immunol 2017; in atopic dermatitis: identification of patient clusters based Giovannone B, Csomor E, et al. Moving toward endotypes 133: 2372–2380. individuals with atopic dermatitis. J Invest Dermatol 2013; 1930–1938. atopic dermatitis. J Eur Acad Dermatol Venereol 2016; 30: biomarkers in endophenotypic profiling of adult and childhood R, Deleuran M, et al. TSLP, IL-31, IL-33 and sST2 are new 1121–1130.e7. term extensionstudy. JAllergyClinImmunol2018;142: to-severe atopic dermatitis: randomized, phase II, long- Galus R, et al. Nemolizumab in patients with moderate- Health Sci2016;10: 96–120. Z. Molecular genetic of atopic dermatitis: an update. Int J coming the Th1/Th2 paradigm. Allergy 2013; 68: 974–982. trial. JAm AcadDermatol 2018;78: 872–881.e6. ventional treatments:Arandomized, phase2a double-blind, Immunol 2018; 141: 1523–1526. that atopicdermatitisisa systemicdisease.J AllergyClin vannone B, Knol EF, et al. Serum biomarker profiles suggest 2232–2239. tients withatopicdermatitis.JInvest Dermatol 2008;128: - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV disorder withalifetimeprevalenceof10–20%indeve This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta “seasonal disorders,”noticing thatheexperiencedinthe ringworm, causedbyanitching ofhisskin”aswell ”…noting anumberofhard, drypatchessuggesting suffered from symptoms and signs of atopic diseases the RomanbiographerSuetonius, theEmperor Augustus and sleep;italsoimpliesasocioeconomicburden(3). self-confidence including life, of quality health-related response. Having AD hasaseverelynegativeimpacton to skinbarrierdysfunctionandalteredimmunological genetic, biologicalandenvironmentalfactorsleading cally “complexdisease”,withinteractionsofmultiple loped countries(1,2). AD isconsidered tobeageneti A dundee.ac.uk University of Dundee, Dundee DD1 9SY, Scotland, s.j.brown@ UK. E-mail: Group, Divisionof Medicine, Molecular School of and Medicine, Clinical Wellcome Trust Senior Research Fellow in Clinical Science, Skin Research Corr: Acta DermVenereol 2020;100:adv00163. Accepted May 7,2020;EpubaheadofprintMay 15,2020 me-wide; risk;phenotype; transcriptome. Key words: atopic dermatitis; eczema; filaggrin; genetic; geno plex disease,tooptimise patient benefit. opportunities of personalised medicine for this com tion, but further is needed research to fully realise the this Together interven therapeutic for avenues inflammation. identified has work skin atopic to leading mechanisms has considerablyimproved of knowledge understanding ofanalyses. An geneticrisk factors tion studies to refront of popula from genetic large-scale research, arealsoimportant.immune function is at thefo AD systemic and skin influencing variants but AD, for fied aggrin, remain the strongest genetic riskfactor identi mutations inFLG, encoding the skin barrier protein fil association andanimalmodelling.Loss-of-function linkage,candidate genestudies,genome-wideinclude high heritability; strategiesto investigategeneticrisk shows AD genetics. AD of field the in developments of ronmental factors. This review provides an overview sing fromtheinterplayofmultiple geneticandenvi 2 1 Sara Prospects Genetics inAtopicDermatitis: Historical Perspective andFuture Atopic isacommon, dermatitis complextrait, (AD) ari Journal Compilation ©2020ActaDermato-Venereologica. Dermatology andVenereology Unit, Departmentof Medicine Solna, Karolinska Institute, Stockholm, Sweden Skin Research Group, Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland, and AD hasbeenknownfromancient times. According to J. BROWN Sara J Brown, Professor of Molecular and Genetic Dermatology & eczema, is a common chronic inflammatory skin inflammatory chronic common a is eczema, topic dermatitis(AD),synonymouswithatopic 1 , in vitro Martina S. ELIAS models and detailed molecular 1 andMaria BRADLEY REVIEW ARTICLE 2 Centenary theme section:ATOPICDERMATITIS ------to thedevelopmentof AD issubstantialand thisheri 9). These datademonstratethatthe genetic contribution monozygotic twinsand21–23% indizygotictwins(8, studies haveshownaconcordance rateof72–86%in address the genetic component is to study twins. These shared environment and/or shared genes and awayto have AD (6,7).Familialaggregationcanbedueto ~3-fold and~5-fold,respectively, ifoneorbothparents developing AD 1.5-fold, whereas theriskisincreased in oneparentisestimatedtoincreaseachild’s risk of of allriskfactors. The presenceofanyatopicdisease of atopic diseases, inparticular AD, is the strongest is attributabletogenetic factors(5). A familyhistory the proportionofvariationwithinaclinicalfeaturethat of geneticheritability. The term ‘heritability’ refersto viduals withinfamilies,demonstratingtheimportance familial aggregation, with clustering ofaffected indi It canclearlybeobservedthatatopicdiseasesshowa Heritability of AD: familyandtwinstudies YEARS? DERMATITIS GENETICS OVER THEPAST 100 WHAT HAVEWELEARNEDABOUTATOPIC techniques and a view to future opportunities in the field. over recentdecades,therapidescalationofmolecular perspective ontheprogressionofgeneticstudiesin AD sirocco blew, catarrh”(4). early spring“atightnessofthediaphragm;andwhen atopic dermatitis. a patient’s genetic make-up and their individual type of personalised medicine, in which treatment is tailored to and eventually it is hoped that these insights will lead to tion. Already thisknowledge has been appliedtotreatment inflamma and barrier leaky a to lead can that skin the in dermatitis has improved our understanding of mechanisms variation thatcontributestoan individual’s riskof atopic herited genetic risk. Research to understand the genetic lies, showing that this disease occurs partly because of in Atopic dermatitis (alsocalledeczema) often runsinfami SIGNIFICANCE This reviewaimstoprovidereaderswithahistorical Acta DermVenereol 2020;100: adv00163 doi: 10.2340/00015555-3513 - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis AD were performed and several more loci were identified the followingyears,additionalgenome-widestudiesin susceptibility locus on chromosome 3q21 (16). During a major identified AD in study genome-wide first The distributed atknownlocationsthroughoutthegenome. viduals. Informativemarkershavemanyallelesandare tetra-nucleotide repeats)showvariationbetweenindi such asrepeatedDNA sequences,mostlydi-,tri-,and marker thefactthatamarker(oftenmicrosatellite ploits Genetic linkageisamethod for mapping genes. Itex Linkage studies has beenusedtoprovideinsightinto AD. ‘hypothesis-driven’ approach.Eachofthesestrategies a is this loci; or genes identified previously of function ofthepathogenesisand “educated guesses”orknowledge for study. The selectioncanbebasedonearlierstudies, considered tobeofinterestforthephenotypeareselected gene approach is a strategy inwhich certain loci orgenes In contrast,directedgeneticanalysissuchasacandidate the trait in question; it is a ‘hypothesis-free’ approach. the functionofgenesisnotrequired,norbiology wide associationstudies)apre-existingknowledgeof broad genomicanalyses(genome-widelinkage,genome- genetic componentsincomplexdiseasessuchas AD. In Various different tostudy havebeenused strategies Strategies fortheinvestigationofgeneticrisk ulcerative colitis(15). 7–38% forperiodontitis(14)andapproximately67%in other inflammatory barrier diseases show heritability of psoriasis heritability is approximately 68% (13) whilst heritability foracomplextrait(12).Forcomparison, tability hasbeenestimatedat70–80%(10,11) –ahigh 350 S. J.Brownetal. - - risk ofgetting AD inamutationcarrierisincreased3-fold patients carryaFLGnullmutation.Inmeta-analysisthe patients withmoderatetosevere AD upto40%ofthe null mutationsinthepopulation(21). Among European Together these4nullmutationsaccountfor> in EuropeareR501X,2282del4,R2447XandS3247X. vulgaris. The mostcommonloss-of-functionmutations the commonmonogeneticdryskindisorderichthyosis to 10%intheNorthernEuropeanpopulation. They cause function ofthestratumcorneum(Fig.1). skin hydration,alowpHandotheraspectofthebarrier contribute to the natural moisturising factors, maintaining filaggrin monomers are degraded into amino acids, which an intensive protein-lipid matrix. Consequently, these which condense in the cytoskeleton of keratin to form aggrin is dephosphorylatedanddegradedinto monomers, ferentiation. During keratinocyte differentiation, profil integrity and it is an important marker of keratinocyte dif the developmentofkeratinocytestomaintainepidermal role in the development of AD. Filaggrin is involved in blished theimpairedskinbarrierfunctionashavingakey 2006 (18). This wasamajorbreakthroughandalsoesta in AD for gene susceptibility a as identified was gene the linkbetweenichthyosisvulgarisand AD, theFLG Filaggrin (FLG).Usingacandidategeneapproach,and Candidate genes below. The techniqueofGWAS inmoredetail described is have subsequentlyreplacedgenome-widelinkage(17). fine-mapping. Genome-wide association studies (GWAS) were oftentoowideandtheyrequiredlabourintensive including 1q21,3p,17q,18q,11.13q. However, theseloci Loss-of-function mutationsinFLGarepresentup SB: stratum basale. stratum granulosum; SS: stratum spinosum; differentiation. SC: stratum corneum; SG: is an important marker of keratinocyte in the stratum corneum (19, 20). Filaggrin contributing to ‘natural moisturising factors’ then degraded torelease amino acids, process into filaggrin monomers which are protein profilaggrin is cleaved in a stepwise in theepidermis. processing Fig. 1. Filaggrin expression and 90% of The pro- - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV resemble AD. Nethertonsyndrome(OMIM#256500)is the studyofmonogenicdiseases thathavefeatures p11.2 andIL-13onchromosome 5q31.1(24,41). 5q31.1, the IL-4 receptor located on chromosome 16p12.1- mune response,forinstanceIL-4locatedonchromosome replicated by GWAS are genes involved in the Th2 im approach, supportedbyknowledgeof AD biology, and genes thathasbeendetectedthroughacandidategene Some othercandidategenesinatopicdermatitis.Other found. of geneinvolvedin AD developmentthatstillaretobe be yetunknown,additionalfactors/genesorfunctions are extremelyimportantin AD pathogenesis,theremust skin, resulting in additional barrier impairment (39, 40). the in expression filaggrin suppress to shown been also have TNF-α and IL-31, IL-25, 22, IL- IL-17A, IL-13, gene sequence. The effects ofcytokines,suchasIL-4, effect(38) byadose-dependent repetitive withinthis on eachallele)isassociatedwithreducedriskof AD in theskin.Havingmorerepeats(12comparedto10 expressed monomer filaggrin of amount the determine sequences or‘copynumbervariations’ inFLGthat filter intheskin(37). to a reduction in filaggrin’s role as an endogenous UVB individuals withFLGnullmutations,whichmaybedue Vitamin D3levels are 10%higher in German and Danish through itsroleinincreasingvitaminDbiosynthesis. nary advantageinhigher latitudes (i.e.Northern Europe) Additionally, filaggrin deficiency may confer an evolutio with fections, conferring‘naturalvaccination’ toindividuals in to immunity enhance may skin filaggrin-deficient advantage. The increased skin barrier permeability in duetoanevolutionarybeen hypothesizedthatthisis so prevalentinthewhiteEuropeanpopulation,ithas possible susceptibilitygene(34,35). a as identified been also has FLG mutationsandFLG2 Americans haveshownaslightlyhigherfrequencyof pears tobelessthan1%(31–33).Studieson African to date and the prevalence of people of African ancestryhasbeenrelativelylimited in Research 27–30). (25, family-specific are mutations of mutationvariesfrom3%toover50%,andmany worldwide (25,26).In Asian countries,theprevalence different populationsand> nor sufficienttocause AD(24). this indicatesthatFLGmutationsareneithernecessary FLG mutationsdonotdevelopanyatopicdiseaseand FLG nullmutationsand>50%ofindividualscarrying only ~20%ofpatientswithmild-to-moderate AD carry (odds ratio3.12)(22,23).However, amongEuropeans More candidate genes have been detected through Even thoughFLG mutations and the filaggrin protein Besides mutationsthereareintragenicrepetitivegene To addressthequestionofwhyFLGmutationsare The frequencyofFLGnullmutationsdiverges in FLG mutationsduringEuropeanpandemics(36). 50 havebeencharacterized FLG null mutations ap - - - - models, in which genes can be silenced orbeoverexpres canbesilenced models, inwhichgenes in skin barrier biology (51). (ii) Genetically engineered protein mattrin which is also postulated to have a role nonsense mutationinthenovelgeneMattencoding a as identified and mouse tail flaky the from separated FLG mutations. More recently the in aprematurestopcodon(50),analogoustothehuman been identified as a 1-bp deletion in the of arecessivematted(ma)trait(49). The ftmutationhas mouse mutationarosespontaneouslyonthebackground the NC/Ngamouse(47,48). The Flakytail(ft)recessive and mouse tail flaky the are these of well-known most strains ofmicethatdevelop AD-like phenotypes. The models canbedividedinto3maincategories:(i)Inbred sing ononeormoreaspectsofhuman AD. The mouse been described and generated overthe years, each focu that hasbeenstudiedanddocumented(46). geneity. Apart fromhumans,dogshavespontaneous AD easily control the environment and create genetic homo Animal modelshavetheadvantagesthatonecanmore Animal models disorders andextremephenotypes,asdiscussedbelow. as aresultofnewapproachestoassessingmonogenic pulations (42–45).Othercandidategeneswillbestudied between thymus. In several studies, there has been an association expressed inepithelialandmucosalsurfacesthe helial Kazal-Type-Related Inhibitor(LEKTI)whichis in Fig.2andeachisdescribedbelow. information; anoverviewof theseapproachesisgiven molecular analysistechniques providecomplimentary pace overrecentdecades.Large-scale andmorefocused genomic analysistechniques hasoccurredatarapid and throughout the world. The advance of genetic and the activecollaborationoflarge consortiaacrossEurope technologies. This hasbeenpowerfullyfacilitated by AD researchtobeattheforefrontofapplyingnew relevant tissues –both skin and blood –has allowed The prevalenceof AD andtheaccessibilityofdisease- ITS APPLICATION OF CURRENT GENETICTECHNOLOGYAND ATOPIC DERMATITIS IS ATTHEFOREFRONT house dustmite(asrecentlyreviewed(54)). withforexampletheallergensagents ovalbuminand thatcanbeinducedbyexogenous mice (53).(iii)Models sed, forexampletheclaudin-1(52)andFlgknockout encodes a15-domainproteaseinhibitorLymphoepit 5 gene(SPINK5)locatedonchromosome5q32. Netherton isintheSerineProteaseInhibitorKazal-Type and increasedIgElevels. The genemutationunderlying a rare monogenic disease with AD-like lesions in the skin There arealsoseveral AD mousemodelsthathave SPINK5 variantsand AD, alsoindifferent po Genetics inatopicdermatitis Theme issue:Atopic dermatitis ma trait has been gene resulting Flg gene resulting 351 - - - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis from thesamelocusonchromosome 11q13.5, mayalso gene, (56). Another to AD effect onskinbarrierformation andfunctionofrelevance bases away;EMSYhasrecentlybeenshownto havean 11q13.5 whichinteractswith agene,EMSY,> mechanism. One example is the region on chromosome require detailed follow-up worktoascertain afunctional regions arebetweengenes,meaningthattheirfunctions cytokine clusteronchromosome5.Manyoftheother on chromosome 1q21.3 (whichincludesFLG)andthe effects, suchastheepidermaldifferentiation complex AD risk. Some loci include well established genetic DNA) have been identified as showing association with synthesized thesestudies(55).Over30loci(regionsof populations worldwide,andarecentmeta-analysishas status. GWAS havebeenconductedinseveraldifferent to identifydifferences thatareassociatedwithdisease compared between large numbers of cases and controls, single nucleotidepolymorphismsacrossthegenomeare GWAS isatechniqueinwhichverylarge numbersof Genome-wide associationstudies whole exome sequencing;AD:atopicdermatitis. phenome-wide association study; WGS, whole genome sequencing; WES, therapy development. GWAS, genome-wide association study; PheWAS, Fig. 2.Complimentary strategies forgeneticanalysisleadingto 352 S. J.Brownetal. LRRC32, >60kilobasesaway 30 kilo - as wellnonsenseandmissense mutationsinpre other genes within the epidermal differentiation complex, vulgaris hasrevealedrarevariantsinFLGandseveral lead toloss-of-functionorotherfunctionaleffect. variant requires careful assessment to define which may likely tohaveadirectfunctionaleffect; however, each RNAs. WES focusesonexonsbecausetheyaremost code forproteins,andalsoexonicregionsinnon-coding studies thegeneticsequenceofDNA inexonsthat Whole exomesequencing(WES)isatechniquethat sequencing Whole exomesequencingandwholegenome technique mayalsobeappliedtodrugrepositioning(59). with genotypesmayberevealedusingPheWAS andthe (58). Unexpectedorpreviouslyunknownassociations rhinitis andfoodallergy inaPheWAS study, asexpected with atopicphenotypesincluding AD, asthma, allergic loss offunctionvariantinFLGshowsstrongassociation association withsinglegeneticvariants.Forexample,a which large numbersofphenotypictraitsaretestedfor Phenome-wide association(PheWAS) isatechniquein Phenome-wide associationstudies to besmaller. ditional riskloci,althoughtheireffect sizesarelikely skin cellsviaepigeneticmechanisms, rangingfromma and pathophysiologicaleffects whichcouldimpacton In thecontextof AD, therearemultipleenvironmental sion thatoccurwithoutalteration totheDNA sequence. ‘Epigenetic’ referstoheritable changesingeneexpres Epigenetic studies no large WGS havebeenreportedin AD. WGS isalsoalimitingfactortosamplesizeanddate their functional effects are not well defined. The cost of variants ona large scale remains verychallenging as werful than WES, but the interpretation of non-coding WGS generates more data and is potentially more po regulatory mechanismsaresituatedinintergenic DNA. becausemany ofthe exons, as wellas genic regions netic susceptibility(60). AD appearstoshowconsiderableheterogeneityinge recurrently-mutated causalgenesinthispopulationand disease-associated variants. There wasnoevidenceof than rather variation population-specific indicate dings fin these of Some (60). ADAM33, EVPLandNLRP1 viously unreported candidate genes including because larger samplesizesallowthedetectionofad pleiotropic effects thatarisefromgeneticvariation. play arolein AD pathogenesis(57),demonstratingthe WES in22Ethiopianpeoplewith AD andichthyosis Whole genomesequencing(WGS)sequencesinter Further, larger, meta-GWAS studiesareon-going, GTF2H5, ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV protein-coding messenger RNA (mRNA), ribosomal been transcribedfromDNA. These molecules include lecules thatarepresentinacell ortissue,havingrecently Transcriptomic analysisdescribesthestudyofRNA mo Transcriptome analysis of relevanceto AD (56,67). control ofpromotor-enhancer interactionslikelytobe to differentiating keratinocytes, tocharacterisespacial well as cell-state-specific,Hi-C analysis has been applied Importantly, sincethe3Dinteractionsarecell-typeas the dynamic process and identify candidate genes (68). different celllinesandatdifferent timepointstoreveal ractions canbesequenced. This analysisisperformedin as enhancers. Then, selectedpromoter–enhancerinte genome andregionsimportantingeneregulationsuch 67). HiCap uses probes to capture promoters across the so thatinteractingregionsaresequencedtogether(65, with formaldehydepriortodigestionandsequencing regions tobedelineated. The techniquescrosslinkDNA (5C) andHi-CorHi-Cap,have allowed theseinteracting advances includingchromosomalconformationcapture enhancer elements together (66). Recent technological promotorand bybringing distant of geneexpression plex and dynamic process facilitateslong range control in closeproximitythe3Dgenome(65). This com that arefarfromeachotherinthelinearDNA arebrought dimensional space. Due to this folding, genomic regions folded andwrappedaroundproteinstructuresinthree- a straightlinearmolecule,butinvivoitisextensively DNA mayberepresenteddiagrammaticallyasifitwere Three-dimensional DNA analyses understand epigeneticcontrolin AD. skin (63).Considerablefurtherworkisneededtofully of numbermiRNAshasbeenreportedinlesional AD mRNA translationordegradation.Differential expression an additionallevelofepigeneticcontrolbyregulating coding RNA includingmicroRNAs(miRNAs)confer sion ofskinbarrierandinnateimmunegenes(64).Non- andthesecorrelatewithchangesintheexpres epidermis ation are observed between lesional and non-lesional AD to AD pathogenesis (63).Keydifferences in DNA methyl epigenetic controloftheimmunesystemandskinbarrier viewed (62)). A numberofstudieshavelinkedabnormal precise control ofskin development and homeostasis (re the genome.Epigeneticmechanismsarecentralto regulatory featuressuchaspromotorsandenhancersin histone modifications can be used to predict and delineate Specific (61). polymerases and factors transcription regulate chromatinstructureandDNA accessibilityto DNA These and methylation. modifications histone are allergic effects. Two important epigenetic mechanisms ternal factors in utero , to early life exposures, irritant and - - - - - (72). These techniquesoffer theprospecttostudyindi DNA andRNA sequencing,aswellproteinanalysis samples. However single cell analysis is now feasible, for been carriedoutusingwholeskinbiopsies,orepidermal Most ofthemolecularanalysesonskintodatehave Single cellanalysis signature (70)thatimprovesaftertreatment(71). (69). The AD lesional skin transcriptome shows a disease tion oflipidmetabolismandanactivatedstressresponse transcriptome, includingbarrierimpairment,dysregula from an AD patientshowprofoundabnormalitiesinthe skin uninflamed) (clinically ‘non-lesional’ so-called analyses areverysensitive;skinbiopsysamplesfrom inflammatory conditions, including AD. Transcriptomic blood may also provide valuable insight into skin-related matological conditions,buttranscriptomicsofserumor lysis performed on skin itself is most relevant for der compared toundifferentiated cells. Transcriptome ana dent; differentiated cellsshowdifferent geneexpression candidate genesinvitro (seebelow). vance to AD, thetechnique canbeusedtoinvestigate in severalformsofepidermolysis bullosaandofrele cas9 editinghasbeenusedto correctthegeneticdefects andorganismscells (75). Within dermatology, CRISPR- edit, modifyandmarkgenomiclociinawiderangeof target, efficiently and precisely to researchers allowed cost-effective and relatively easy-to-use technology has technique hasrevolutionisedmolecularbiology. This effects ofgeneticvariationtobetesteddirectlyandthe targeted editing. Application ofCRISPR-cas9allows the to directthecas9enzyme to cleave DNA in precisely- exploited forgeneticengineering;guide-RNAsareused motif. In 2012 it was reported that this mechanism canbe DNA selectivelyatsequencescontainingtheCRISPR (CRISPR-associated protein 9) is an enzyme that cleaves part oftheirimmuneresponsetophageinfection.Cas9 repeat) sequences are found in bacterial DNA and form CRISPR (clustered regularly interspaced palindromic CRISPR-cas9 geneediting murine datafromtheKasperlab(74). interrogation ofskin transcriptome analysis, forexample already releasedpublisheddataandtoolstoallowthe is eagerlyawaited.Severalresearchlaboratorieshave to researchers(73)andtheskincomponentofthisatlas collaboration tomake single cell analyticaldataavailable complex organ. The HumanCell Atlas isaninternational the functionalandstructuralheterogeneityofskinasa into insight gain and types cell new define cells, vidual dynamic systemanditiscell-typecellstate-depen from seconds to minutes. The transcriptome is a highly micro RNA (miRNA)and others; theirhalf-livesrange RNA, transferlongnon-codingRNA (lncRNA), Genetics inatopicdermatitis Theme issue:Atopic dermatitis 353 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV and (77) measuresthe‘inside-to-outside’ barrierfunction pathophysiology. Transepidermal water loss (TEWL) also offers opportunities togainunderstandingofthe Theme issue:Atopic dermatitis ce developacompetentbidirectional epidermalbarrier Organotypic skin models grownat the air liquid interfa Functional analysesinvitro sion, orCRISPR-cas9editing ofgenesinterest. other AD candidategenes,byknockdown,over-expres testing for opportunity the and effects genetic specific mechanisms andtherapeuticoptions. represents ausefulmodelforthestudyof AD disease mirrors manychangesobservedinthe AD skinandthus (85, 86). Filaggrin deficient organotypic skin, therefore, protein expressionsignaturesconsistentwith AD skin granules, increasedparacellularpermeability(83,84)and observed in AD skin. These includealackofkeratohyalin many ofthestructural,molecularandfunctionaldefects recapitulate broadly expression filaggrin in deficient similar to thatobservedin AD (82). Organotypic models IL-13) stimulate a spongiotic epidermal morphology, FLG-mutant keratinocytes (81). Th2 cytokines (IL-4 and FLG cells with AD-relevant cytokinesandthesecondmodels ment oforganotypic models derived from normal healthy one of two basic approaches: the first involves the treat models of AD havebeendescribedwhichgenerallyuse plement of epidermal lipids (79, 80). Several organotypic andanappropriatecom rentiation/proliferative markers morphology, spatiotemporalexpressionofterminaldiffe pitulate many features ofhuman epidermis including: animal models.Multi-layeredorganotypic modelsreca bridge thegapbetweenculturedcellsinmonolayerand Three-dimensional organotypic modelsofhumanskin Organotypic modelsofatopicdermatitis relevance to AD (78). sampling theskintranscriptome,proteomeandlipidsof can be used as a relatively non-invasive methods for quantitative measureofwatercontent;andtape-stripping pacitance orconductanceofthestratumcorneumgivea mutations inWAS as by (such caused inflammation Wiskott-Aldrich, skin and various immunodeficiency syndromes with AD-like dermatitis, multipleallergies andmetabolicwasting) inflammation), include Netherton syndrome,these‘humanknock-out’ models pes whichincludefeaturesof AD. Followingonfrom has increased ourunderstanding ofsevere phenoty Clinical observationfollowed-upwithgeneticanalysis Functional analysesinvivo 354 Functional analysisoftheskin AD patientsinvivo Organotypic modelsallowtheinvestigationoftissue- it is proportional to skin inflammation; ca inflammation; skin to proportional is it in vivo deficient AD through gene silencing or the use of use the or silencing gene through deficient AD S. J.Brownetal. CARD11 mutations(causingsystemicatopic DSG1 and DSP ) (76). mutations (causing severe mutations (causing severe ------this tissueallowsdermatologicalstudiestotakeadvan tissue-specific effects in skin; the relative accessibility of mechanistic information.Outstandingquestionsinvolve regions ofthegenomewhicharelikelytoholdimportant more detailed interrogation ofthe coding and non-coding Improvements in technology have allowed more and The majorityofheritabilityin AD remainsunexplained. More detailedgeneticstudies standing forthebenefitofpatients. Symposium on Atopic Dermatitis(ISAD)has recently information forclinical care (90). The International the accuracy, utilityandacceptabilityofusing genomic in humangenomicsresearch becausethiswillincrease diversity prioritise to field the in call a been has There have provided valuable complimentary insight (89). genetic riskin African (35)and Asian (88)populations AD isdifferent indifferent ethnicitiesandstudiesof European ancestry. However, theclinicalphenotype of to datein AD hasbeenconductedinpeopleofwhite As describedabove,themajorityofgeneticresearch More inclusivegeneticresearch and computationalrequirements. cost financial their in challenging remain studies These and gene-environmentinteractionsofrelevanceto AD. the statisticalpowertodetectgene-geneinteractions numbers of cases and controls will be required to achieve in otherriskloci.Onagenome-widelevel,evenlarger and moredetailedanalysesarerequiredtoassessCNV within detailed transcriptomeanalyses.Copynumbervariation tage ofdirectsamplingforepigeneticstudiesandmore large amountofworktofullycapitalizeonnovelunder The rapidprogressmadeinrecentyearsstillleavesa WORK OUTSTANDING QUESTIONS ANDFUTURE (56, 83,85). genes andtheFLG deficiency on skin barrier function boththeeffectinvestigate uncharacterized ofpreviously (56). These techniqueshavebeenusedsuccessfullyto also bedeterminedbymeasuringtherateof TEWL the inside-outsidebarrieroforganotypic culturescan Analogous totheinvivosituationdescribedabove, layers iftheskinbarrierisimmatureorimpaired(83). but can permeate into the deeper epidermal and dermal from the epidermis by the lipid-rich stratum corneum dye suchasLuciferyellow. This isnaturallyexcluded organotypic modelsusingtopicallyappliedhydrophilic analysis (87). The outside-in barrier can be quantified in they aretractableforphysiologicallyrelevantfunctional offer theadvantageovermonolayercellcultures,that with similar biophysical properties to human skin. They FLG hasadose-dependenteffect on AD (38) - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV genetic risk,withamulti-ethnic perspective,providing of understanding refine will techniques New patients: of unlikely thatanothersingle geneexistswiththeimpact capacity forsequencingDNA andRNA. Whilst itis the last20years,broughtaboutbyincreasedtechnical has beenaparticularlyrapidexplosionofknowledgein variation contributes to human health and disease. There understanding moreofthedetailhowDNA sequence pairs inlength. entire humangenome–approximately3billionbase Project wascompleted,providingasequenceofthe Genome Projectbeganandin2003theHuman the doublehelixstructureofDNA;in1990Human tion; in1953James Watson andFrancisCrickreported DNA fibres to study their structure using X-ray diffrac crystallise to first the was Franklin Rosalind 1952, In CONCLUSION: THEFUTURELOOKS BRIGHT drug developmentandclinicaluse(93). but success in this endeavour would ultimately transform andmolecularbasesfordisease, testing thephysiological relationship betweengenomicsanddrugdevelopment, era of‘personalisedmedicine’ isexpectedtobringanew AD inincreasinglypreciseandpersonaliseddetail. The genetic studies continue to identify causal pathways for mademorethanadecadeago,but was genetic discovery remains a challenging therapeutic target, even though the deficiency Filaggrin (92). success clinical of chances informed byhumangeneticstudieshaveabove-average a phenotypeanddrugsdevelopedtotarget apathway provide acausativelinkbetweensequencevariantand is notmerelyanacademicexercise.Geneticstudiescan The questforunderstandinggeneticmechanismsin AD Application ofgeneticdiscoveriestodrugdevelopment of moleculardata. likely to be required to gain full benefit from the wealth learning andmorepowerfulinsilicoanalyses(76)are diversity ofthistrait,furtherdevelopmentsinmachine clinical impact.Furthermore,giventhecomplexityand for translation allow to sufficiently pathophysiology will berequiredtoincreaseourunderstandingof AD by thefullcomplementoftechniquesdescribedabove the combinationandintegrationofinformationprovided However, inflammation. skin atopic of cause’ ‘root or understanding AD mechanisms,particularlythe initial Genetic studieshavegivenimportantinformationfor Integration of-omicsforpersonalisedmedicine (91). in Africa on AD published apositionstatementcallingformoreresearch Since this time, we have progressed a long way in alongway haveprogressed time,we this Since FLG upon AD risk,thefutureappearsbrightfor AD - 12. 11. 10. 17. 16. 14. 15. 13. REFERENCES The authorshavenoconflictsofinterest todeclare. by theSwedishSkinFoundation(Hudfonden). Fellowship (ref106865/Z/15/Z)awardedtoSJB.MBisfunded MSE and SJBare funded by a Wellcome Trust Senior Research ACKNOWLEDGEMENT disease. see astep-changeinthemanagementofthischallenging vidual patientwith AD. The next100yearsislikelyto indi each for mechanisms disease specific to targeted macological interventions. These will increasingly be powerful insighttodrivethedevelopmentofnewphar 6. 5. 4. 9. 3. 8. 2. 7. 1. Timpson NJ, Greenwood CMT, Soranzo N,Lawson DJ, Ric Thomsen SF, Kyvik KO, Backer V. Etiologicalrelationshipsin Apfelbacher CJ, Diepgen TL,SchmittJ. Determinants of ec NIH. Genetics Home Reference: What is heritability? 2019. Thomsen SF, Ulrik CS, Kyvik KO, Hjelmborg JB, Skadhauge Mier P.Mier BrJ syndrome? oftheatopic description Earliest Stemmler S, Hoffjan S. Trying to understand the genetics Larsen FS, NV, Holm K. Atopic Henningsen A dermatitis. Drucker AM, Wang AR, Li WQ, Sevetson E, Block JK, Qureshi Lee YA, Wahn U, Kehrt R, Tarani L,Businco L,Gustafsson Nibali L, Bayliss-Chapman J, Almofareh SA, Zhou Y, Divaris Schultz Larsen F. Atopic dermatitis: a genetic-epidemiologic Deckers IA,McLeanS, LinssenS, MommersM,van Schayck Gordon H, Trier Moller F, Andersen V, Harbord M. Heritability Lonnberg AS, Skov L,SkyttheA,Kyvik KO, Pedersen OB, Wadonda-Kabondo N, Sterne JA, Golding J, Kennedy CT, Weidinger S, Novak N.Atopic dermatitis.Lancet2016;387: 11: 112–120. atopy: areview of twinstudies. Twin Res HumGenet 2008; Proc 2007;28: 535–539. etiology ofatopicdermatitis:atwinstudy. AllergyAsthma LR, SteffensenI,etal.Importanceof geneticfactorsinthe Dermatol 1975; 92: 359–359. of atopicdermatitis. Mol Cell Probes2016; 30: 374–385. sample. J Am AcadDermatol 1986; 15: 487–494. genetic-epidemiologic study in a population-based twin 2017; 137:26–30. for the EczemaNational Association. J Invest Dermatol AA. The Burden of Atopic Dermatitis: Summary of a Report maps tochromosome3q21.NatGenet2000; 26:470–473. D, et al. A major susceptibility locus for atopic dermatitis K, Vieira AR.WhatIstheHeritability of Periodontitis? ASys 1993; 28: 719–723. study inapopulation-based twinsample. J AmAcadDermatol 2012; 7:e39803. a systematic review of epidemiological studies. PLoS One incidence and prevalence of atopic eczema 1990–2010: CP, SheikhA.Investigating internationaltimetrendsinthe 21: 1428–1434. genome-wide association studies. Inflamm Bowel Dis 2015; study twin first the to from disease: bowel inflammatory in Br JDermatol 2013;169: 412–416. Thomsen SF. Heritability of psoriasis in a large twin sample. birth cohort study. Arch Dis Childhood 2004; 89:917–921. hayfever, and asthma with dermatitis atopic in infancy: Archer CB, eczema, ofparental Association MG. Dunnill 1109–1122. tematic Review. JDent Res 2019;98: 632–641. 2018; 19: 110–124. contribution tohumantraits anddisease.NatRev Genet hards JB. Genetic architecture: the shape of the genetic Allergy 2011; 66:206–213. zema: population-basedcross-sectionalstudyinGermany. Genetics inatopicdermatitis Theme issue:Atopic dermatitis 355 - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 26. 25. 34. 31. 24. 36. 33. 30. 23. 21. 19. 37. 35. 32. 29. 28. 27. 22. 20. Theme issue:Atopic dermatitis 18. 356 O’Regan GM, Irvine AD. The role of filaggrin loss-of-function Chen H,CommonJE,Haines RL,Balakrishnan A,Brown SJ, Margolis DJ, GuptaJ, ApterAJ, Ganguly T, Hoffstad O, Pa Thawer-Esmail F, Jakasa I, Todd G, Wen Y, Brown SJ, Kroboth Weidinger S, Beck LA,BieberT, Kabashima K,IrvineAD. Irvine AD, McLean WH. Breaking the (un)sound barrier: filag Winge MC,BilchaKD, LiedenA, ShibeshiD, SandilandsA, Nomura T, Sandilands A, Akiyama M, Liao H, Evans AT, Sakai Rodriguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown A, Terron-KwiatkowskiSandilands P, A, Hull O’Regan G, Irvine AD, McLean WH, Leung DY. Filaggrin mutations as Thyssen JP, Thuesen B, Huth C, Standl M, Carson CG, Heinrich Almoguera B, Vazquez L, Mentch F, March ME, Connolly JJ, Thyssen JP, Godoy-Gijon E, Elias PM. Ichthyosis vulgaris: Hamada T, Sandilands A, Fukuda S, Sakaguchi S, Ohyama Enomoto H,Hirata K,OtsukaKawai T, Takahashi T, Hirota Pigors M, Common JEA, Wong X, Malik S, Scott CA, Tabarra Brown SJ. Molecularmechanismsinatopiceczema: insights Kabashima K. New concept of the pathogenesis of atopic Palmer CN,IrvineAD, Terron-Kwiatkowski A,Zhao Y, Liao mutations in atopic dermatitis. Curr Opin Allergy Clin Im 165: 106–114. Chinese and Br European J populations. Dermatol 2011; betweenSingaporean differences highlights dermatitis atopic in mutations filaggrin-null of spectrum Wide al. et CS, Goh K, etal.SouthAfricanamaXhosapatientswithatopicderma Atopic dermatitis.NatRev Dis Primers2018;4: 1. atopic dermatitis. Br J Dermatol 2011; 165:1074–1080. loss-of-function variants found in Ethiopian patients with noother but mutation filaggrin Novel al. CF, et Wahlgren Allergy Clin Immunol2007; 119: 434–440. patients with ichthyosis vulgaris and atopic dermatitis. J K, et al. Unique mutations in the filaggrin gene in Japanese J AllergyClinImmunol2009;123: 1361–1370 e1367. in eczema and asthma: robust risk factors in atopic disease. SJ, Cordell HJ, et al. Meta-analysis of filaggrin polymorphisms uncovers prevalentfilaggrin muta and encoding rare gene Clayton T, Watson R,etal.Comprehensive analysis of the Clin Immunol2019; 143: 1229–1231. Americans and replicationin European Americans.JAllergy Peissig PL, et al. Novel locus for atopic dermatitis in African 1155–1166. 168: 2013; JDermatol Br disease. mutation filaggrin the J atopic dermatitis. Invest Dermatol 2008; 128: 1323–1325. a Japanesefamilywithichthyosis vulgaris complicatedby mutation p.R501X with prevalent mutation c.3321delA in filaggrin the of occurrence novo De al. et S, Yasumoto B, dermatitis and elevated levels of IgE in the Japanese popu T, etal.Filaggrinnullmutationsareassociatedwithatopic N, et al. Exome sequencing and rare variant analysis reve gained from genetic studies. J Pathol 2017; 241: 140–145. as a trinity. J Dermatol Sci2013; 70: 3–11. dermatitis: interplay among the barrier, allergy, and pruritus factor foratopicdermatitis. NatGenet2006;38:441–446. epidermal barrier protein filaggrin are a major predisposing H, LeeSP, etal.Commonloss-of-function variants ofthe 2006; 126:1200–1202. grin isamajorgenefor atopicdermatitis.J Invest Dermatol jects. J Allergy Clin Immunol2014; 133: 784–789. more persistentatopicdermatitisinAfrican Americansub padopoulos M, et al. Filaggrin-2 variation is associated with Immunol 2014; 133: 280–282e281–282. but no loss-of-function mutations in filaggrin. J Allergy Clin products breakdown filaggrin of levels decreased have titis 53: 615–621. lation: afamilyandcase-controlstudy. JHumGenet2008; 2018; 138:2674–2677. atopic eczema and additional risk genes. J Invest Dermatol als multiple filaggrin mutations in Bangladeshi families with munol 2008; 8:406–410. 2007; 39: 650–654. tions in ichthyosis vulgaris and atopic eczema. Nat Genet 365: 1315–1327. sociated withskinandallergicdiseases.NEnglJMed2011; S. J.Brownetal. ------49. 53. 48. 42. 52. 47. 44. 41. 55. 51. 46. 43. 40. 39. 38. 54. 50. 45. Presland RB,Presland BoggessD, SP, Lewis P, C,Fleckman Hull Sund Kawasaki H,NagaoK,Kubo A,HataT, ShimizuA,MizunoH, Vestergaard C, Yoneyama H, Matsushima K. The NC/Nga Walley AJ, Chavanas S, Moffatt MF, Esnouf RM, Ubhi B, Law Atsugi T, Yokouchi M, Hirano T, Hirabayashi A, Nagai T, Matsuda H, Watanabe N, Geba GP, Sperl J, Tsudzuki M, Hiroi Weidinger S, BaurechtH,Wagenpfeil S, HendersonJ, Novak Al-Shobaili HA, Ahmed AA, Alnomair N, Alobead ZA, Rasheed Paternoster L, M, WaageStandl J, Baurecht HotzeH, M, Saunders SP, GohCS, BrownSJ, Palmer CN,Porter RM,Cole Nuttall TJ, MarsellaR,Rosenbaum MR,GonzalesAJ, Fadok Hubiche T, Ged C,BenardA,Leaute-Labreze C,McElreavey Kim BE, Howell MD, Guttman-Yassky E, Gilleaudeau PM, Howell MD, KimBE, GaoP, Grant AV, BoguniewiczM,Debe Brown SJ, Kroboth K, Sandilands A, Campbell LE, Pohler E, Kim D, Kobayashi T, NagaoK.Research Techniques Made Fallon T, Sasaki PG, SaundersSP, LE, A,Campbell Sandilands Asad S, Tapia-Paez I, Montano Montes A, Wahlgren CF, Bilcha et al. Altered stratum corneum barrier and enhanced percu 6: 209–210. mouse: a model for atopic dermatitis. Mol Med Today 2000; 1-deficient mice. J Invest Dermatol 2020; 140: 298–308.e5. fromclaudin- lessons glands: multicellular in barrier junction Ohyama occursoutsidethetight secretion M,etal.Holocrine 1997; 9:461–466. IgEhyperproductionwith IntImmunol NC/Nga mice. in J, et al. Development of atopic dermatitis-like skin lesion N, Sandilands A, et al. Analysis of the individual and ag Health Sci(Qassim)2016; 10: 96–120. Z. MolecularGeneticofAtopic dermatitis:AnUpdate. IntJ Strachan DP, etal.Multi-ancestry genome-wide association J AllergyClinImmunol2013;132: 1121–1129. predisposing gene for atopic dermatitis in human subjects. C, etal.Tmem79/Mattisthemattedmousegeneanda 1291–1300. atopic dermatitis in dogs. J Am Vet Med Assoc 2019; 254: VA. Updateonpathogenesis,diagnosis, andtreatmentof Venereol 2007;87: 499–505. genotypes ina Frenchatopicdermatitis cohort.Acta Derm K, de Verneuil H, et al. Analysis of SPINK 5, KLK 7 and FLG Dermatol 2011;131:1272–1279. for TNF-alpha antagoniststoimprove skinbarrier. JInvest role kinase: c-Jun N-terminal through loricrin and filaggrin Cardinale IR, Boguniewicz M, et al. TNF-alpha downregulates Kezic S, et al. Intragenic copy number variation within filag 2019; 139:984–990e981. Simple: MouseModelsofAtopic Dermatitis. JInvest Dermatol priming. NatGenet 2009; 41:602–608. mouse Flggenefacilitatesenhancedpercutaneousallergen Mangan NE, et al. A homozygous frameshift mutation in the Derm Venereol 2019;99: 101–102. Variants inEthiopianPatients with Atopic Dermatitis. Acta KD, NordenskjoldM,etal.Evaluation ofSingleNucleotide mutations is associated with increased serum mutations is associated with 25-hydroxyvi (FLG) filaggrin by caused abnormality barrier Skin al. et J, peptidase peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to ec peptidase inhibitorKazal type 5(SPINK5),kallikrein-related gregate genetic contributions of previously identified serine atopic disease. Nat Genet 2001; 29:175–178. rence R, et al. Gene polymorphism in Netherton and common 150–155. filaggrin skin expression. J Allergy Clin Immunol 2007; 120: nedetto A,etal.Cytokinemodulationofatopicdermatitis dependent effect. J Invest Dermatol 2012; 132: 98–104. grin contributestotheriskofatopicdermatitiswithadose- 1204–1207 e1202. tamin Dconcentrations. JAllergyClinImmunol2012;130: Clin Immunol2012; 129: 1538–1546 e1536. Allergy J mice. filaggrin-null in responses immune taneous 1072–1081. disease ichthyosis vulgaris.JInvest Dermatol 2000; 115: (ft/ft) mice: an animal model for the filaggrin-deficient skin berg JP. Loss of normal profilaggrin and filaggrin in flaky tail zema 2008;122:560–568.e564. Immunol Clin JAllergy risk. ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 70. 64. 76. 69. 63. 75. 68. 62. 74. 73. 67. 61. 58. 72. 66. 60. 57. 71. 65. 59. 56. Suarez-Farinas M, Ungar B, Correa da Rosa J, Ewald DA, Rodriguez E,Baurecht H,Wahn AF, KretschmerA,Hotze M, Eyerich K,BrownSJ, Perez WhiteBE,Tanaka RJ, Bissonette C,KrobothK,SchurchNJ,Cole A,Sherstnev Sandilands Liang Y, ChangC,LuQ. Thegeneticsandepigeneticsof Doudna JA, frontier Thenew editing. Genome E. Charpentier Anil A, Spalinskas R, Akerborg O, Sahlen P. HiCapTools: a Kang S, Chovatiya G,Tumbar T. Epigeneticcontrolinskin Joost S. The molecularanatomy ofmouseskinduringhair https://www.humancellatlas.org/. Human SkinAtlas 2019. Rubin AJ, Barajas BC,Furlan-Magaril M,Lopez-Pajares V, A.PerceptionsBird Nature2007;447: ofepigenetics. Loset M, Brown SJ, Saunes M, Hveem K. Genetics of atopic Heath JR, Ribas A, Mischel PS. Single-cell analysis tools S,Schoenfelder Fraser P. Long-range enhancer-promoter Taylan F, Nilsson D, Asad S, Lieden A, Wahlgren CF, Winge Manz J, Rodriguez E,ElSharawy A,OesauEM,Petersen BS, Beck LA, Thaci D, Hamilton JD, Graham NM, Bieber T, Rocklin W. Xie Zheng H, in of 3Dgenomeorganization Therole Rastegar-Mojarad M, Ye Z, Kolesar JM, Hebbring SJ, Lin SM. Elias MS, Wright SC, Remenyi J, Abbott JC, Bray SE, Cole C, Rozenblit M, Gonzalez J, et al. RNA sequencing atopic der Zeilinger S, etal.Anintegrated epigeneticandtranscrip 2014; 134:82–91. in patients with atopic dermatitis. J Allergy Clin Immunol pathways mechanistic identifies skin pediatric of analysis transcriptomic Filaggrin-stratified al. et GM, O’Regan A, Rev AllergyImmunol2016;51: 315–328. Clin polymorphisms. other and dermatitis-filaggrin atopic 346: 1258096. of genome engineering with CRISPR-Cas9. Science 2014; Bioinformatics 2018;34: 675–677. targeted chromosome conformation capture applications. software suitefor probe design andproximity detectionfor 2019; 28: 453–463. development, homeostasis and injury repair. Exp Dermatol growth and rest. bioRxiv 2019. terminal differentiation. NatGenet2017;49:1522–1528. pre-established enhancer-promoter contacts cooperate in Mumbach MR, Howard I, et al. Lineage-specific dynamic and 396–398. dermatitis: from DNA sequence to clinical relevance. Der 2016; 15: 204–216. for drug discovery and development. Nat Rev Drug Discov 20: 437–455. contacts in gene expression control. Nat Rev Genet 2019; Immunol 2015; 136: 507–509e519. with ichthyosis vulgarisandatopicdermatitis.JAllergyClin MC, et al. Whole-exome sequencing of Ethiopian patients dermatitis risk.JInvest Dermatol 2016; 136: 2380–2386. to atopic contributors significant as GARP encoding gene in the variants missense low-frequency identifies testing Baurecht H, et al. Targeted resequencing and functional severe atopic dermatitis. N Engl J Med 2014; 371: 130–139. R, etal.Dupilumab treatmentinadultswithmoderate-to- 2019; 20: 535–550. development andcelldifferentiation. Nat Rev MolCellBio association studies. Nat Biotechnol 2015;33: 342–345. fromphenome-wide fordrugrepositioning Opportunities Immunol 2019; 144: 470–481. withrelevance barrier skin Clin JAllergy dermatitis. toatopic et al. EMSY expression affects multiple components of the J AllergyClinImmunol2015;135: 1218–1227. therapeutic potential mechanismswith disease implications. novel into insights provides profiling transcriptome matitis Dermatol 2014; 134:1873–1883. DNA methylation associated with atopic dermatitis. J Invest of patterns tissue-specific distinct reveals analysis tomic matology 2019;235:355–364. loci foratopicdermatitis.NatGenet2015;47:1449–1456. study of 21,000 cases and 95,000 controls identifies new risk - - - 79. 78. 77. 89. 84. 93. 91. 88. 83. 82. 81. 80. 92. 90. 87. 86. 85. Mertsching H,Weimer M,Kersen S, Brunner H.Humanskin Eui Kim B, Kim Eui Goleva PS, Kim E, C,Taylor NorquestK,Bronchick Alexander H, Brown S, Danby S, Flohr C. Research Techniques Kaufman BP, Guttman-Yassky E,AlexisAF. Atopic dermatitis Pendaries V, Malaisse J, Pellerin L, Le Lamer M, Nachat R, Dugger SA, Platt A, Goldstein DB. Drug development in the Schmid-Grendelmeier P, Takaoka R, Ahogo KC, Belachew WA, Noda S, Suarez-Farinas M, UngarB, Kim SJ, de Guzman Mildner M,JinJ, Eckhart L,Kezic S, GruberF, Barresi C,et Danso MO, van DrongelenV, MulderA,van EschJ, ScottH, Niehues H, Schalkwijk J, van Vlijmen-Willems I, Rodijk- Thakoersing VS, van Smeden J, Mulder AA,Vreeken RJ, El Kamb S, A,Harper asa genetics StefanssonK.Human Hindorff LA,BonhamVL,BrodyLC, GinozaMEC,HutterCM, Zhang Z,Michniak-Kohn BB. Tissueengineeredhumanskin Elias MS, Long HA, Newman CF, Wilson PA, West A, McGill MS,Elias Wright SC,NicholsonWV, Morrison KD, PrescottAR, equivalent as an alternative to animal testing. GMS Kran dermatitis. J Invest Dermatol 2019;139:2387–2389.e1. tape stripping highlights abnormal stratum corneum in atopic P, etal.Side-by-side comparisonofskin biopsiesand skin e2291. a Research Tool. JInvest Dermatol 2018;138:2295–2300 Made Simple: Transepidermal Water Loss Measurement as 2019; 143:36–45. of theInternationalEczema Council.JAllergyClinImmunol dermatitis: Areviewandperspectives by anexpertpanel R, Dhar S, et al. Human and computational models of atopic in diverse racial and ethnic groups-Variations in epide reconstructed humanepidermisimpairskeratinocyte diffe Kezic S, et al. Knockdown of filaggrin in a three-dimensional 183–196. era of precision medicine. Nat Rev Drug Discov 2018; 17: Dermatitis in Sub-Saharan Africa: current status and road Brown SJ, CorreiaJC,etal.Position StatementonAtopic 136: 1254–1264. increased TH17 polarization. J Allergy Clin Immunol 2015; combines features of atopicdermatitisandpsoriasiswith Strong C,Xu H,etal.TheAsianatopicdermatitis phenotype Dermatol 2010; 130:2286–2294. and increases UV sensitivity in a human skin model. J Invest al. Knockdown of filaggrin impairs diffusion barrier function proteins and stratum corneum lipids in human skin equiva atopic dermatitis-like features on epidermal differentiation van SmedenJ, etal.TNF-alpha andTh2cytokinesinduce im show not do keratinocytes null filaggrin of equivalents Olthuis D, van Rossum MM, Wladykowski E, et al. Epidermal Ghalbzouri A, Bouwstra JA. Increased presence of monoun 2013; 31: 975–978. foundation for innovative drug development. Nat Biotechnol research. NatRev Genet 2018; 19: 175–185. Manolio TA, et al. Prioritizing diversity in human genomics equivalents. Pharmaceutics2012;4:26–41. molecular signaturescharacteristic of atopiceczema. JAl PJ, et al. Proteomic analysis of filaggrin deficiency identifies skin organoid model shows evidence of increased transcriptio filaggrin-deficient a of analysis TenProteomic al. et S,Have lents. J Invest Dermatol 2014;134:1941–1950. 139: 1979–1981 e1913. paired skin barrier function. J Allergy Clin Immunol 2017; equivalents. JInvest Dermatol 2013; 133: 59–67. saturated fatty acidsinthestratum corneumof humanskin kenhhyg Interdiszip2008;3:Doc11. map. JEur Acad Dermatol Venereol 2019; 33:2019–2028. Dermatol 2018;27: 340–357. miology, genetics,clinicalpresentation andtreatment. Exp lergy Clin Immunol 2017; 140: 1299–1309. peer review]. Wellcome Open Research 2019; 4: 134. disordered axon guidance. [version 1;peer review: awaiting nal-translational activity, keratinocyte-immune crosstalk and rentiation. J Invest Dermatol 2014; 134: 2938–2946. Genetics inatopicdermatitis Theme issue:Atopic dermatitis 357 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV pathogenesis ofthediseaseiscomplexandincludesim (1,2). 2–10% ofadultsindevelopedcountries The Copenhagen, and doi: 10.2340/00015555-3514 microbial all of composition the as defined is term this community.scientific Often, the in “microbiome” term microbiome as well as microbe-host interactions in AD. provide anoverviewofthe recentliteratureontheskin diversity on AD skin(8–13). The aimofthisreviewisto cutaneous advanced DNA sequencing technologies, it is evident that sible toexaminecompletemicrobialcommunitiesusing tion (4–8). Within recent years, where it has become pos which isassociatedwithdiseaseseverityandexacerba burden ofStaphylococcus aureus skin colonization, (3). Furthermore, patients with AD have an increased system withenhanced Th2, Th17, and Th22 signalling paired skinbarrierfunctionandanimbalancedimmune A E-mail: [email protected] Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark. Corr: Paal S. Andersen, Department of Bacteria, Parasites, and Fungi, Acta DermVenereol 2020;100:adv00164. Accepted May 7,2020;EpubaheadofprintMay 15,2020 aureus Key words: atopicdermatitis;skinmicrobiome; Staphylococcus atopic dermatitis. literatureview of therecent on the skinmicrobiome in anover to provide aims review This flare-ups. duce specific S. aureus strains can in that indicating mice, toshown elicitatopic dermatitis-like phenotypes in aureus skincolonizationhanced aureus. Inaddition, byS. S. deficiency in atopic dermatitis skin might be related to the en Filaggrin controls. and patients in similar although distribution ofthe mostis common species diverse on theskinof patients with atopic dermatitis, communities andmoreIn contrast,fungal arericher nities on healthy skin,andincreasingdiseaseseverity. diversitycomparedwithreduced the bacterialcommu rized byincreasingabundanceof S.aureus,leadingto nization. The skin bacterial communities are characte aureusskincolo Staphylococcus barrier andenhanced immunesystemsignalling,impairedskin balanced sease with acomplexpathogenesis im that includes 1 Sofie M.EDSLEV Skin MicrobiomeinAtopicDermatitis Centenary theme section:ATOPICDERMATITIS Acta DermVenereol 2020;100: adv00164 Atopic dermatitis is a common inflammatory skin di skin inflammatory common a is dermatitis Atopic Department of Bacteria, Parasites, and Fungi, Statens Serum Institut, There is no single established accepted definition of the skin disease thataffects 10–20%of children and inflammatory common a is (AD) dermatitis topic ; filaggrin. expressing variant virulence factors have been variantvirulencefactors havebeen expressing S. aureus isassociatedwithdecreasedbacterial 3 Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg,Denmark 1 , Tove AGNER 2 andPaal S. ANDERSEN This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta REVIEW ARTICLE 1,3 ------diverse microbiotacompared withadults (21–23). changes duringpuberty, withchildrenhaving amore ment (20).How nisms fromotherhumansand thesurroundingenviron spite of the constant exposure to external microorga community compositionisratherstableovertime,de including bacteriaandfungi.Inadults,themicrobial space andcompetingfornutritionalresources(18,19). antimicrobial molecules, or indirectly by occupying impede growthofpathogens,eitherdirectlybysecreting (17). In addition, commensal skin microorganisms can from keratinocytes and glands provide a chemical barrier barrier, andantimicrobialpeptideslipidssecreted corneocytes inthestratumcorneumformaphysical genic microbial invasion. Tight connections between The skin is an important first-line defence against patho HEALTHY SKIN MICROBIOME therefore notdescribedindetailthisreview. for studyingtheskinmicrobiome,andmethodsare Grogan etal.(16)havesummarizedthetechniquesused by diversityandtaxonomyanalysis(Box2).Recently, be examined byDNA sequencing (Box 1 ) followed based assays,andcompletemicrobialcommunitiescan (15). Inthisreview, thelatterdefinitionisused. genomes, andthesurroundingenvironmental conditions microorganisms inahabitat(the“microbiota”),their all as defined be should “microbiome” word the that and “metagenome” the describes rather definition this genes inacommunity(14),butithasbeenargued that sease severity and exacerbation. di with association its and dermatitis atopic in microflora cently publishedliterature regarding changes inthe skin disease. This review aimstoprovide an overview of re infections and probably contributes to aggravation of the Staphylococcus aureus, a bacterium thatcan cause skin The greatest difference is due to increased abundance of stitutes all microorganisms present on the skin surface. is associated with changes in the skin microbiota, which con disease The flares. eczema with skin itchy and dry by Atopic dermatitis isa common skindisease characterized SIGNIFICANCE The skinmicrobiotaconsistsofdiverseorganisms, Skin microorganisms can be identified using culture- 2 Department of Dermatology, Bispebjerg University Hospital, Journal Compilation ©2020ActaDermato-Venereologica. ever, thecompositionofmicrobiota ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV and richcomparedwithmoistskin(e.g.nares,axillary dominated byCutibacteriumacnesandarelessdiverse facial areasandtheupperpartofchestback)are and topography(24,26,27).Sebaceousskinsites(e.g. on theskin,includingpH,moisture,sebumcontent, conditions microenvironmental the by influenced are 23, 24,26).MicrobialrichnessandShannon-diversity bacteria arecommonskin-colonizing(9,21, Streptococcus, Betaproteobacteria,andGammaproteo Propionibacterium (25)),Micrococcus, Staphylococcus, shown thatCorynebacterium,Cutibacterium(formerly skin areas(24).16SrRNA genesequenceanalysishas biota, representingmorethan70%ofspeciesinmost Bacteria constitutethegreatestproportionofmicro • • • • communities and organisms microbial of examination for Assays Box 1. • • • Box 2.Diversityandtaxonomyanalysis discrimination betweenlive and dead organisms. which also applies to the amplicon DNA sequencing method, is the lack of metagenomic studies are basedon minor sample sets. Another disadvantage, a high resolution making the method very expensive. As a consequence, most of shot-gun sequencingis that deep-sequencing is required in ordertoobtain properties ofthecommunity, specific e.g.metabolicpathway genes.Adisadvantage examining as well as level strain the at microbiota the constituting the complete genomes of the microbiota. Thisallows to detect all species Metagenomic shot-gun sequencing:Shot-gun sequencingisusedtoexamine problem for low biomass samples, such as skin samples. microbial contaminants and human skin cells, which especially constitutes a this method is that all available target DNA is sequenced, including DNA from impossible todifferentiate betweenrelatedspecies.Anotherdisadvantage of microbial communities, though this method has its limitations as it often is advantage of targeted amplicon sequencing is thus the ability to examine whole to study eukaryotic microbial communities, such as fungal communities. An spacer regionsITS1/2 and variable regionsof the18SrRNAgenecanbeused to examine the composition of the bacterial community. The transcriptional rRNA genecanbeusedtoidentify mostbacteriainasample,makingitpossible Targeted sequencing: Sequencing of amplicon selected variable regions of the 16S strains are examined. sites withinindividuals.A disadvantage ofthismethodisthat onlyselected relatedness, e.g.toexaminethesimilarity ofstrains isolated from distinctskin single strain. Thismethodisespecially usefulfor comparing strains andtheir of interest allows to examine the genetic content and thus properties of the microorganism specific of genomes Sequencing sequencing: genome Whole examine themicrobial community as a whole. do not that grow easilyunderstandardlaboratory microorganisms conditionsandthat itisnotpossibleto detect to difficult is it that are Disadvantages methods. Also, it is known that the detected microbes are alive and viable. for antimicrobial resistance and examine the gene content using molecular are method this of the possibility touseisolatedstrains for additionalanalysis,e.g.testing Advantages ofinterest. microorganisms viable specific Culture assays: Plating and culturing of samples in order to detect and isolate Taxonomy analysis: Analysisofspeciesdistributionsin a community/sample. Beta-diversity: Diversity between samples. Alpha-diversity: Diversity withinsamples. • • • • • the pairwisedistance measures. Hierarchical clustering:Samples areclusteredinadendrogram based on together. The axes determine the degree of variance betweensamples. measures.Sampleswithsimilarcommunitydistance structuresareclustered Ordination plots:Visualization of beta-diversity based onthepairwise • • • • distance-based methods, e.g.: Pairwise comparison of community structures can be measured using richness and evenness. Shannon Index: a diversity measure that takes into account both species Richness: thetotal number of species or uniquesequencesin a sample. of species. of species. Does not take into account the phylogenetic relatedness Bray-Curtis: Dissimilarity measure based on the relative abundances Does nottake into account the phylogenetic relatednessof species. Jaccard: Dissimilarity measurebased onspeciespresence/absence data. of species. abundances of species. Takes into account the phylogenetic relatedness Unweighted UniFrac: Dissimilarity measure based ontherelative absence data. Takes into account the phylogenetic relatedness of species. Weighted UniFrac: Dissimilarity measure based on species presence/ - - and filaggrin breakdown products act as natural moisturi essential forthealignmentofkeratinincorneocytes, gene encoding the skin protein filaggrin (30). Filaggrin is populations isloss-of-functionmutationsintheFLG major geneticriskfactorof AD in Asian andCaucasian skin areasdependingontheagegroupinvestigated. A on theskinmicrobiomein AD havefocussedondistinct widespread disease). Consequently, published studies the head, neck, hands, and flexural areas (and sometimes and adolescents and adults bychronic lesions comprising affected byeczemaattheantecubitalandpoplitealfossa, the extremities.Children(2–12yearsofage)aremostly of thecheeks,scalp,neck,trunk,andextensorparts Infants (< the clinicalpresentationof AD changeswithage(29). with eczema flares and disease exacerbation. Interestingly, AD isclinicallycharacterizedbyred,dry, anditchyskin, SKIN INATOPICDERMATITIS MICROBIOME common andabundanthabitant(27,28). the skinmicrobiota (24),with Malassezia being the most abundances aregreatest(24).Fungiconstitute1–5%of Corynebacterium spp.andStaphylococcusrelative rial speciesisover-represented inmoistskin,although relative abundancesexceeding 40%inbothhealthy common bacterialgenusat the perioralskin,withmean AD andhealthycontrols.Streptococcus wasthemost largest difference observedbetweenpatients with severe AD skincomparedwithhealthy controlskin,withthe healthy controls. The microbialdiversitywas lower on clinical signsof AD atthesamplesiteandinage-matched community compositioninperioralskininfantswith AD (35,36).Zhengetal.(35)examinedthebacterial nity composition on skin from infants with and without case-control studieshavecomparedthebacterialcommu being over-represented atdifferent ages(10,21). Two in AD differs betweenagegroups,withdistinctbacteria As in healthy control skin, the skin microbial composition infancy Bacterial communityonatopicdermatitisskinduring normal healthyskin,asdescribedbelow. bial communitiesarealteredon AD skincomparedwith to analteredskinecologyin AD (31–34). Also, micro free fattyacids,followedbyanincreaseinskinpH,lead (3). Filaggrin deficiency and reduced levels of NMFs and AD independentlyofloss-of-functionmutationsinFLG in deficiency filaggrin to lead thus and expression, FLG skin-barrier. Th2 and Th22 cytokinescandown-regulate Thus, filaggrin is important for maintaining a functional zing factors(NMFs) important forproperskin hydration. abundant speciesindryskin,whereasnosinglebacte (e.g. volarforearm)(24,26).C.acnesisalsothemost anddryskin andpoplitealfossa) vault, antecubitalfossa, 1 year)areprimarilyaffected byacutelesions Skin microbiomeinatopicdermatitis Theme issue:Atopic dermatitis 359 - - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis (Fig. 1)(40,43). greater on AD skincomparedwithhealthycontrol skin significantly is load bacterial total the that explain also an enhancedburdenofS.aureus ontheskin. This could colonization withthesebacteria, butmainlyaresultof S. aureus on AD skinisprobablynotduetodecreased children (40). Thus, theincreasedrelativeabundanceof were observedbetween AD andhealthycontrolskin in Corynebacterium, in absoluteabundancesofthe3commonskinbacteria pared withhealthycontrolskin(40–42).Nodifference cutaneous of Quantification 35). 21, (8–13, of less diverse,andaredominatedbyincreasedproportions on skinofchildrenandadultswithestablished AD are Several studieshaveshownthatbacterialcommunities childhood andadulthood Bacterial communityonatopicdermatitisskinduring development of AD stillneedsfurtherinvestigation. possible roleofcutaneousS.aureus colonizationduring among infantswithfamilialpredisposition(39). Thus, a not consideredtobeariskfactorfor AD development aureus inbothhealthyand AD individuals(6,38),was tion oftheanteriornares,whichisamajorhabitatforS. and adultswith AD (6).Inaddition,S.aureus coloniza lower comparedwiththeprevalenceinolderchildren colonization were lessthan15% and thus remarkably age-matched controls.However, frequenciesofS.aureus years ofage)developing AD comparedwithnon-AD the timeofdiagnosisamonginfantsandtoddlers(0–2 at higher significantly were skin fossa antecubital and that frequencies of cated theopposite(37). Thus, Meylanetal.(37)found indi has analysis culture-based life, of year first the in an essential marker for AD during diseasedevelopment colonization attheantecubitalandpoplitealfossaisnot AD (8,10). Although thiscould indicatethatS.aureus teal fossa skin regions in older childrenandadultswith aureus isfrequentlydetectedonantecubitalandpopli in anyoftheskinsamples(36),despitefactthatS. well can influence the results.S.aureus was not identified active diseaseatthesamplingtime-points,whichvery of infants who not necessarily had developed AD or had without AD (36).Importantly, the AD groupconsisted popliteal fossaweregenerallysimilarininfantswithor on skinfromthecheeks,nosetip,antecubitalfossa,and primarily cantly reducedandreplacedwithStaphylococcusspp, signifi relative abundancesofStreptococcuswere spp. moderate AD. However, inthesevere AD patientgroup, control skinandlesionalfrompatientswithmild/ 360 of aureus is due to a significant greater absolute abundance abundances hasshownthattheproportionalincreaseofS. S. aureus comparedwithcommunitiesonhealthyskin S. aureus on AD lesionalandnon-lesional skincom S. M.Edslevetal. S. aureus. In contrast, bacterial communities Cutibacterium, and S. aureus colonization at axillary Streptococcus S. aureus - - - - -

but notasmuchinlesionalskin. aureus of abundances increased significantly to AD lesional skin compared with healthy control skin, which mainly is due healthy skin. skin and of bacteriainatopic dermatitis (AD) abundances 1. Absolute Fig. temporal bacterialvariationonantecubitalandpopli conclusions. Three studiesfoundthatthebacterialdi lesional andnon-lesional AD skin,butwithdifferent ups. Severalstudieshavecomparedalpha-diversityon that skin bacterial diversity is only reduced during flare- post-flare, and healthy control skin, which could indicate rence in alpha-diversity was observed between baseline, healthy control samples (8, 12). Yet, no significant diffe compared withS.aureus proportionalabundancesinthe post-flare sample time-point, but were still slightly higher the at significantly decreased abundances ofS.aureus at higher risk of developing AD (44). The proportional infants withafamilyhistoryofatopicdiseasesandthus skin ofthecheek,volar- anddorsalforearminhealthy varius contributedtogreaterbacterialdiversityonthe in vitro (45).Inaddition,higherproportionsofS.sali has been shown to possess anti-inflammatory potentials mensal bacteriaoftheoralcavity, intestinesandskinthat abundance ofStreptococcus salivarius(8,44),acom S. aureus wasaccompaniedbyadecreaseintherelative of thesamples. The increaseinrelativeabundancesof abundances ofS.aureus, whichexceeded40%inmany during AD flares was associated with increased relative baseline and post-flare samples. The decreased diversity with compared sites, skin both at flares during reduced significantly was diversity Bacterial 12). (8, episode flare an AD after and during children in skin fossa teal (9, 10).Neitheragenorsamplingsitescanexplainthe un-affected AD skin compared with healthy control skin that thediversitywasequallyreducedonaffected and lesional skin (13, 21, 46), whereas 2 other studies found versity wasloweronlesionalskincomparedwithnon- Kong and colleagues (8) were the first to examine the absoluteabundances are also increased in AD non-lesional skin, Bacterial densities are significantly greater on greater significantly are densities Bacterial S. aureus in AD lesional skin. S. - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV community on AD skin,andonlyinadults Asian haveexaminedtheeukaryotic microbial studies Few skin Eukaryotic microbial communityonatopicdermatitis resistance (48,49). as treatmentpracticeleadingtoselectionofantibiotic mutations inFLG(7),orduetoextrinsicfactors,such have beenassociatedwithcarriageofloss-of-function intrinsic factorsin AD, e.g.CC1S.aureus colonization prevalence of CC1 tients compared with healthy controls (47). The increased more oftendetectedonskinandinnaresfrom AD pa as in AD, of specific subspecies of strains isolatedfrom AD skin(42). Also, colonization are capableofkillingS.aureus comparedwithCoNS isolated fromtheskinofhealthyindividualsmoreoften example, Nakatsujietal.haveshownthatCoNSstrains strains withinaspeciescanhavedistinctphenotypes.For species level analysis might not be sufficient, as distinct CoNS spp. in AD still needs to be clarified. Furthermore, AD patients(12),suggestingthatapotentialroleforthe after a flare-up episode was identified among paediatric capitis attheantecubital-andpoplitealfossaduringor the proportion of either S. epidermidis , S. hominis or S. of eczemalocallyontheskin.However, nochangesin dances ofS.aureus cancontributetothedevelopment of the lesional skin samples were dominated by ferent distributionofStaphylococcalspecies.One-third patients, withthegreatestvariancebeingduetoadif between lesionalandnon-lesionalskinareasinadult AD munity composition (beta-diversity) varied significantly colonization, lipidcompositionorpH). only are associated with lesional skin areas (e.g. S.aureus but other AD-related factorsinorontheskinthatnot not theeczemaitselfthatdriveschangesindiversity, conflicting results. These studies might indicate that it is among the staphylococcal species towards greater abun greater towards staphylococcal species the among non-lesional skin,andthatchangesinthedistribution enhanced staphylococcalgrowthonbothlesionaland be hypothesizedthattheskinecologyin AD supports AD skinattheantecubitalfossa(9,46).Itcouldthus lower on healthy control skin compared with non-lesional common colonizersofmoistskin,theirabundanceswere are CoNS identified the Though (46). skin lesional AD in acuteandchroniclesionalskincomparedwithnon- CoNS arereducedandS.aureus abundancesincreased Baurecht et al.have shown that relative abundances of non-lesional skin in a majority ofpatients. Inaccordance, and staphylococcal species (CoNS), such as proportions ofS.aureus. Instead,coagulase-negative few non-lesional skin samples were characterized by high (relative abundancesgreaterthan50%),whereasonlya Clausen etal.(9)discoveredthatthebacterialcom S. hominis,dominatedthebacterialcommunityon S. aureus clonalcomplex1(CC1)strainsare S. aureus colonization might be due to S. aureus seemstobefavoured S. epidermidis S. aureus - - - -

impaired skin barrier and skin inflammation, has a wi a has inflammation, skin and barrier skin impaired hypothesis thatthe AD phenotype, such asanoverall the supports finding This skin. non-lesional or lesional AD, regardlessofwhethersampleswerecollectedfrom control skinthantoareasinpatientswithsevere more similartothecommunitycompositionofhealthy popliteal fossainpatientswithmild/moderate AD was the bacterial community composition in antecubital- and the skin(9,10,13,54).Brandweinetal.(10)foundthat severe diseasehavingthelowestbacterialdiversityon and non-lesional skin sites, with patients with more AD severity scores have been identified in both lesional Significant differences in alpha- and beta-diversity across changes inskinmicrobial communities Atopic dermatitisdiseaseseverityisassociatedwith in ordertovalidatethepresentedresults. thus, additionalstudieswithmoreattendeesareneeded eukaryotic microbialcommunitiesin AD islimited,and in 10%ofsamples)(51). The literatureregardingskin with healthycontrolskinfromthesamearea(presence on thecheeks(presencein100%ofsamples),compared was foundtobeover-represented on AD lesionalskin skin (51,53). Another fungal species, Candida albicans, of AD patientswithactivedisease and healthy control tions of these 2 species were found between lesional skin tional abundance of from thosewithmild/moderate AD (51). from patients with severe AD compared with samples showed distinctcommunity compositionsinsamples the fungalcommunityonskin, asbeta-diversityanalysis there isanassociationbetween AD severityscoresand nities on AD skinaresparse,butonestudyimplies that population (54). whereas noassociationwasdetectedinapaediatric AD increasing severity scores among adult patients (13,57), S. aureus absolute abundances have been associated with skin in relation to AD severity have been published. Thus, conflicting results regarding total with increasing AD severity scores (10–13). However, reus, at least at the antecubital fossa, have been associated (6, 7,55,56),andincreasedrelativeabundancesofS.au more prevalent among patients with more severe disease only onlesionalskinareas. despread effect on the skin microbial community and not without AD (52).However, nodifferences in the propor of AD (noactivedisease)comparedwithindividuals history a with individuals of skin the on identified was healthy controlskin(50,51). An increaseinthepropor was thedominantfungusinboth AD lesionalskinand 51). AD lesional skin compared with healthy controlskin (50, nities, whichwasfoundtobericherandmorediverseon populations (50–52).Focushasbeenonfungalcommu Studies investigatingeukaryoticmicrobialcommu significantly is colonization nasal and S. aureusskin Malassezia, especiallyM.globosaandrestricta, Skin microbiomeinatopicdermatitis M. dermatitis and Theme issue:Atopic dermatitis S. aureus densitieson M. sympodialis 361 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis S. aureus intothedermisskinlayer. Nakatsujietal.(43) deficiency is also associated with enhanced migration of to increasedS.aureus adherence in epidermis, filaggrin skin pH caused by UCA and PCA deficiency. In addition of-function mutations(7)mightbeduetochangesin aureus colonizationamong AD patientswithFLGloss- adherence tokeratinocytes(58,59). Thus, increased S. the geneencodingclumpingfactorB,whichmediates of pH in AD, has been associated with increased expression growth skin acidification, have been shown to reduce pyrrolidone carboxylic acid (PCA), which contribute to filaggrin breakdown products urocanic acid (UCA) and colonization on theskin.In accordance, presenceofthe indicate that filaggrin can influence bacterial growth and on lesionalskinandinanteriornares(7). These studies as well as with an increased risk of S. aureus colonization community compositiononnon-lesional AD skin(9,46), been associatedwithchangesintheoverallbacterial In AD, loss-of-function mutationsintheFLGgenehave microbial communities Atopic dermatitispathogenesisfacilitateschangesinskin nections iselaboratedbelow. community (Fig.2). The mechanismbehindthesecon litate the maintenance of an imbalanced skin microbial to furtherskinbarrierimpairment,and,inturn,canfaci factors then can induce skin inflammation and contribute of grin deficiency in skin leading to enhanced colonization (12, 60–62). Thus, a vicious circle might exist, with filag aureus can induce skin inflammation and aggravate AD skin microbialcommunities(43,58,59).Moreover, S. pH, and skin inflammation, can promote changes in the type, including impairedskin barrier function, increased Functional analysisstudiessuggestthatthe AD pheno skin. What are themechanisms behind these differences? on AD andgreaterabundanceofS.aureusrepresentation skin, andthatthegreatestdifference isduetoanover- communities on AD skindiffer fromthoseofhealthy Microbiome studieshavemadeitevidentthatmicrobial DERMATITIS MICROBE-HOST INTERACTIONS INATOPIC 362 S. aureus, whichthroughtheexpressionofvirulence S. aureus genesinvolvedincolonization,including S. M.Edslevetal. in vitro (58). More neutral pH, reflecting the skin S. aureus - - - -

and contribution to skin barrier disruptions (68). The den in the membranes of keratinocytes, leading to cell lysis 67). Alpha-haemolysin adherestosphingomyelinlipids skin comparedwithkeratinocytesinhealthy(66, been showntoadheremoreeasilykeratinocytesin AD toxin), avirulencefactorsecretedbyS.aureus, hasthus virulence. Alpha-haemolysin (also known as alpha- reus colonization,butalsomorevulnerabletoS.aureus tients withmoresevere AD. This study highlysuggests pronounced inmiceinoculatedwithS.aureus frompa immune cells,including Th2 and Th17 cells, wasmore of infiltration cutaneous and thickening epidermal by assessed inflammation, Skin predisposition. genetic no able to induce skin inflammation in wild-type mice with AD skin, but not S. aureus from normal healthy skin, was Byrd etal.(12)haveshownthatS.aureus isolatedfrom S. aureusasaninducerofclinicalatopicdermatitis activation (Table I). enhanced in AD probablybothfavoursS.aureus colonizationand deficiency filaggrin Thus, 67). (66, efficiency binding sphingomyelinase, thusenhancingalpha-haemolysin well as Th2 cytokinespromotedown-regulationof acid enzyme acid sphingomyelinase. Filaggrin deficiency as adherence sitesforalpha-haemolysin,isregulatedbythe sity ofsphingomyelinlipids,andthustheamountfree compared withthegeneralpopulation(63–65). fungal speciesMalasseziafurfurandCandidaalbicans, cluding allergens fromS.aureus andtheskincolonizing hypersensitive toawiderangeofmicrobialallergens, in corroborate this,patientswith AD arealsomoreoften type I allergic responses in sensitized individuals. To is alsomorepermeabletoallergens, whichcantrigger with adisruptedskinbarrier(43).Disrupted AD skin easily intothedeeperskinlayersofpatientswith AD control skin,indicatingthatS.aureus canmigratemore in dermisof AD lesionalskincomparedwithhealthy absolute abundanceofS.aureus was significantly greater could activatethehostimmunesystem.Inhumans, hanced penetrationofS.aureus intothedermiswhereit and physical skin disruptions (tape stripping), led to en genetic predisposition (FLG loss-of-function mutations) showed thatskinbarrierimpairmentin mice, inducedby AD skinmightnotonlybemoresusceptibletoS.au S. aureus mediatedcytotoxicityandimmune virulence. and genesis human factorsinvolvedinAD patho between 2. Proposedconnections Fig. S. aureus S. colonization and - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 77) andathirdstudyreported analpha-haemolysingene alpha-haemolysin on AD skin(30–63%ofisolates)(76, studies foundlowerproportions ofS.aureus producing barrier disruptions in AD (61).However, two other could makealpha-haemolysin apotentinducerofskin 67) (66, toxin the of efficiency binding enhanced for which incombinationwith AD geneticpredisposition aureus fromhealthyvolunteers(33%ofisolates)(61), of isolates)comparedwithproductionratesamongS. be producedmorefrequentlyby AD S.aureus (91% (assessed bySCORAD)(73,75). aureus has been associated with increased AD severity 74). Furthermore,carriageofenterotoxinproducingS. with and often carrygenesencodingenterotoxins(sea, 73). Studiesindicatesthat likely ismediatedbyenhanced T-cell signalling(72, lunteers andpatientswith (72),aneffectAD which erythema andepidermalthickeninginbothhealthyvo enterotoxin B(SEB)toskinhavebeenshowncause mation. Thus, topicalapplicationofstaphylococcal inflam skin induced important mediatorsofS.aureus compared withS.aureus fromhealthyskin(12). inflammation skin eliciting at better were skin lesional might explainwhyS.aureus strainsisolatedfrom AD findings These (62). AD with patients on skin lesional among production hasbeenfoundtobeconsiderablyhigher isolated fromhealthycontrolskin(60),anddelta-toxin lated from AD skin compared with those from in abundant more significantly are cripts IL-4 expression(62,71).Interestingly, PSM-alphatrans mast celldegranulation,IgEproductionandenhanced effect thatprobablyismediatedbydelta-toxininduced mediate Another PSM,knownasdelta-toxin,wasalsoableto (human keratinocytes)andinvivo(mice)(60,69,70). (IL)-17A mediated pro-inflammatory responses on secretionofPSM-alpha,whichpromotesinterleukin flammation and barrier disruption in mice are dependent and enterotoxins. rulence factors,suchasphenol-solublemodulins(PSM) S. aureus is probably mediated by theproduction of vi similar tothoseobservedin AD. The detectedeffect of that certainstrainsofS.aureus areable to elicitlesions Table I.TheeffectoffilaggrindeficiencyonS.aureus Increased density of sphingomyelin lipids in keratinocyte membranes Impaired skin barrier Increased skinpH Primary outcomes Effect offilaggrindeficiency In one study, alpha-haemolysin was also foundto S. aureus enterotoxinshavealsobeen proposed tobe Several studies indicate thatS.aureus inducedskinin sed) and more often produce these toxins compared S. aureus isolatedfromnon-ADindividuals(73, S. aureus fromlesionalskincomparedwithnon- S. aureus induced skin inflammation in mice, an S. aureus from AD skin more S. aureus iso skincolonizationandvirulence S. aureus seb, in vitro sec, Secondary outcomes Enhanced binding of alpha-haemolysin (cytotoxic S. aureus virulence factor) Enhanced Enhanced ------control skin atopic dermatitisaureus skincomparedwithS. aureus in S. factors upregulated Table II.Virulence PSM: phenol-soluble modulin;IL: interleukin. (hla) expressionfrequencyof59%amongS.aureus na Comparative studies also imply that topical corticosteroid Comparative studiesalsoimplythattopicalcorticosteroid is dependentofseveralweekscontinuoustreatment. of topicalcorticosteroidonskinmicrobialcommunities improvement wasobserved(35). Thus, apossibleeffect clinical an alpha-diversity, though on influence no had and richness(40,81),whereas7–10daysoftreatment Shannon-diversity bacterial in increases significant to in AD, haveshownthat4–6weeksoftreatmentled corticosteroid treatmentonskinmicrobialcommunities examiningtheeffectProspective studies oftopical based creams isa common treatment of AD lesions. Topical applicationofcorticosteroid(glucocorticoids) ON SKIN COMMUNITIES MICROBIAL TREATMENTS DERMATITIS OFATOPIC EFFECT involved in AD isgiveninTable II. of thedescribedS.aureus virulencefactorsshowntobe andS.aureus factors host (58,59,79). factors A summary S. aureus skincolonizationin AD mightbothbedueto aureus lineages (79). Thus, the increased prevalence of other with compared affinity binding higher slightly reus, whichisadominantclonein AD (7,79,80),hada aureus from healthyskin (79). In addition, CC1 to increasedadheringcorneocytes,comparedwithS. enhanced bindingactivityofclumpingfactorB,leading lonize theskin.S.aureus isolatedfrom AD skinhasan co first must ups. Inordertocausedisease,S.aureus flare- of cause direct a be even might and exacerbation that toxins, isupregulatedinS.aureus colonizing AD skin. elucidate whether alpha-haemolysin, and other S.aureus to need studies future Thus, results. the influence can population-based differences anduseofdistinctassays sal isolatesfromhealthycarriers(78),highlightingthat S. aureus migration through the epidermal barrier and into dermis S. aureus growth andcolonization PSM-alpha Virulence factors Delta-toxin Alpha-haemolysin Enterotoxin B Clumping factor B The above-mentionedstudiessupportthehypothesis S. aureus virulenceisamajordriverof AD disease Skin barrier disruptions Skin inflammation Clinical outcomes Skin inflammation Skin barrier disruptions Skin inflammation S. aureus colonization Skin microbiomeinatopicdermatitis Theme issue:Atopic dermatitis Mediators Protease activity Protease activity IL-17A signalling IgE release Mast cell degranulation IL-4 signalling Keratinocyte lysis T-cell signalling Cell adherence fromhealthy isolated from (67) (43) (58, 59) Refs Refs (60, 70) (62, 71) (61) (72) (79) S. au 363 S. - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis skin colonizationisprobably facilitatedby AD-related and adultswith AD. The enhancedburden ofS.aureus children in flares and severity disease with associated of Multiple studieshaveshown thatincreasedabundance CONCLUSION for antibioticresistanceamongskinbacteria(85–87). cutaneous bacterialcommunitycompositionandselect (42). Oraladministeredantibioticsmightalsoimpactthe commensal skinbacteriawithanti-S.aureus properties S. aureus anti-virulencetherapy(71)orapplicationof colonization. Futuretreatmentapproachescouldinclude areneededforthecontrolofS.aureustreatment regimens AD skinandnares(48,49),signifyingthatalternative high prevalenceoffusidicacidresistantS.aureus on by fusidicacid(84),andrecentstudieshaveshowna rial speciesonskin,includingCoNS,arealsoinhibited Unfortunately, bacterialgrowthofothercommonbacte is anarrow-spectrumantibioticusedagainstS.aureus. countries, is topical applicationof fusidic acid, which aureus skincolonization. influence may signalling Th2-mediated of reduction IL-4/IL-13 signalling,andthestudythusshowsthat weeks aftertreatmenttermination.Dupilumabinhibits non-lesional AD skin.However, thiseffect waslost18 absolute creased alpha-diversityandadecreaseinrelative community (13).Sixteenweeksoftreatmentledtoin adults withsevereandchronic AD, ontheskinbacterial offered therapy systemic anti-inflammatory an ment, to moisturizers foralongerperiod. group thatwillbedeniedtreatmentwithemollientsand to setupsuchstudy, asitwouldincludean AD patient biome, it might be challenging and ethically unjustifiable the long-term effect of emollient usage on the skin micro (83). Although it indeedwouldbeinteresting to examine proportions ofStaphylococcusspp.on AD lesionalskin dicates that emollient application leads to decreased has onskinmicrobialcommunities,butonestudyin little isknownaboutwhateffect thistreatmentapproach use, extensive Despite flare-ups. prevents and integrity emollients andmoisturizers,whichrestoreskinbarrier corticosteroids (82). of properties anti-inflammatory the to due conditions S. aureus aswelltoageneralimprovementonskin 9, 81). This effect mightbeduetodirectinhibitionof ces ofS.aureus comparedwithnon-treatedpatients(8, diverse bacterialpopulationwithlowerrelativeabundan treatments priortosamplecollectionsoftenhaveamore nity, as AD patientsundergoing topicalcorticosteroid treatments haveaneffect ontheskinmicrobialcommu 364 Another commontreatmentpractice,atleastinsome One studyhasexaminedtheeffect ofdupilumabtreat A keystonetreatmentpracticein AD isapplicationof S. aureus and loss of bacterial diversity on skin are S. M.Edslevetal. S. aureus abundances onlesional as well as S. ------

12. 11. 10. The authorshavenoconflictsofinterest todeclare. novel anti-bacterialtreatmentapproaches. these of safety and efficiency potentials, the explore to research field of great interest. Future studies are needed potential target forfuturetreatmentstrategies,andisa tion, hashighlightedtheskinmicrobialcommunityasa regarding and needsfurtherinvestigation.Increasingknowledge red to be present prior to AD development is still unclear, REFERENCES Whether bacterialcommunitydysbiosisisalsoconside manifestations in AD patientswithestablisheddisease. community maybeanimportantinduceroftheclinical Thus, changesinthecompositionofskinbacterial can induce skin inflammation and skin barrier disruption. can exacerbate AD byexpressingvirulencefactors that skin. FunctionalassaysindicatethatcutaneousS.aureus on AD contribute totheincreaseddensityofS.aureus bacterial strainswithS.aureus inhibitorypropertiesmay commensal of deficiency addition, In impairment. rier and NMFsleadingtoincreasedskinpHbar changes in the skin, including reduced levels of filaggrin 5. 9. 8. 7. 6. 4. 3. 2. 1. Byrd AL,DemingC,CassidySKB, Harrison OJ, NgWI, Conlan Li W, Xu X, Wen H, Wang Z, Ding C, Liu X, et al. Inverse Williams JV, Vowels BR, Honig PJ, Leyden JJ. Brandwein M, Fuks G, Israel A, Sabbah F, Hodak E, Szitenberg Clausen ML, Agner T, Lilje B, Edslev SM, Johannesen TB, Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Clausen ML,EdslevSM,AndersenPS, ClemmensenK,Krog Totte JE, van der Feltz WT, Hennekam M, van Belkum A, van Leyden JJ, MarplesRR,KligmanAM.Staphylococcus aureus Leung DY, Guttman-Yassky E. Deciphering the complexities Carroll CL, Balkrishnan R, Feldman SR, Fleischer AB, Jr., Manu Henriksen L, Simonsen J, Haerskjold A, Linder M, Kieler H, S, et al. Staphylococcus aureus and Staphylococcus epider dermatitis. J Invest Dermatol 2019; 139:1779–1787.e12. association betweentheskinand oral microbiotainatopic Photochem Photobiol 2019;95: 1446–1453. patients dermatitis accompany dead sea climatotherapy. A, et al. Skin microbiome compositional changes in atopic Andersen PS. severity ofdisease Association micro skin with disease flares and treatment in children with atopic derma et al.Temporal shifts intheskinmicrobiomeassociated with Zuuren EJ, Pasmans Prevalence SG. andoddsofStaphylococ 525–530. in the lesions of atopic dermatitis. Br J Dermatol 1974; 90: of atopic dermatitis: shifting paradigms in treatment ap Thomsen SF, et al. Incidence rates of atopic dermatitis, asth JAMA Dermatol 2018; 154: 293–300. biome and filaggrin gene mutations in adult atopic dermatitis. titis. GenomeRes 2012;22:850–859. J Dermatol 2017; 177: 1394–1400. eczema and its association with filaggrin gene mutations. Br KA,AgnerT.felt Staphylococcus atopic in aureuscolonization and meta-analysis. Br J Dermatol 2016; 175:687–695. cus aureus carriage in atopic dermatitis: a systematic review 15: 194–198. of patientswithatopicdermatitis.Pediatr Dermatol 1998; lation from thelesions,hands,andanteriornares proaches. J AllergyClinImmunol2014; 134: 769–779. family, and society. Pediatr Dermatol 2005; 22: 192–199. el JC.Theburden of atopic dermatitis: impactonthepatient, children. JAllergyClinImmunol2015;136:360–366.e362. ma, andallergic rhinoconjunctivitisinDanish andSwedish S. aureus as a potent promoter of AD exacerba S. aureus iso ------

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 25. 24. 23. 22. 21. 20. 32. 19. 31. 18. 30. 17. 29. 16. 28. 15. 34. 27. 14. 33. 26. 13. Scholz CF, KilianM.Thenatural historyofcutaneous pro Oh J, ByrdAL,Deming C,Conlan S, Kong HH,Segre JA. Oh J, Conlan S, Polley EC, Segre JA, Kong HH. Shifts in Jo JH,Deming C,Kennedy EA,ConlanS, Polley EC, Ng WI, Shi B, Bangayan NJ, Curd E, Taylor PA, Gallo RL, Leung DYM, Oh J, ByrdAL,Park M,Kong SegreJA. HH, Temporal stability Seidenari S, Giusti G. Objective assessment of theskinof S,Naik Bouladoux C, N, MolloyWilhelm MJ, R,Salcedo Jakasa I, Koster ES, Calkoen F, McLean WH, Campbell LE, Sanford JA, GalloRL.Functionsoftheskinmicrobiotain Cabanillas B, Novak N. Atopic dermatitis and filaggrin. Curr Brandner JM.Importance of tightjunctions in relation to Bieber T, D’Erme AM,AkdisCA,Traidl-Hoffmann C,Lauener Grogan MD, Bartow-McKenney C, Flowers L, Knight SAB, Gao Z, Perez-Perez GI, Chen Y, Blaser MJ. Quantitation of Marchesi JR, Ravel J. The vocabulary of microbiome research: van Smeden J, Bouwstra JA. Stratum corneum lipids: their Findley K,OhJ, Yang J, ConlanS, Deming C,Meyer JA, et Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Kezic S, Kemperman PM, Koster ES, deJonghCM,ThioHB, Grice EA,Kong HH,ConlanS, DemingCB, Davis J, Young Callewaert C, Nakatsuji T, Knight R, Kosciolek T, Vrbanac A, skin metagenome. Nature 2014; 514: 59–64. Biogeography andindividuality shapefunctioninthehuman adults. GenomeMed2012; 4: 77. human skin and nares microbiota of healthy children and 2356–2363. converge JInvest adulthood. in 2016;136: Dermatol et al. Diverse human skin fungal communities in children 1233–1236. adult atopic dermatitis. J Allergy Clin Immunol 2016; 138: et al.Theskinmicrobiomeisdifferent inpediatricversus of thehumanskinmicrobiome.Cell2016;165: 854–866. children affected by atopic dermatitis: a study of pH, capa 1115–1119. immunity by resident commensals. Science 2012; 337: Kastenmuller W, etal.Compartmentalized controlofskin function mutations. J Invest Dermatol 2011; 131: 540–542. patients with atopic dermatitis in relation to filaggrin loss-of- Bos JD, et al. Skin barrier function in healthy subjects and health anddisease.SeminImmunol2013; 25: 370–377. Ppin Immunol2016; 42: 1–8. skin barrier function. Curr Probl Dermatol 2016; 49: 27–37. J AllergyClinImmunol2017;139: S58–s64. of atopic dermatitis: where are we, and where should we go? phenotypes Clinical etal. andendophenotypes G, Schappi R, 747–752.e741. profiling the skin microbiota. J Invest Dermatol 2019; 139: Uberoi A, Grice EA. Research techniques made simple: Clin Microbiol2010; 48: 3575–3581. major human cutaneousbacterialand fungalpopulations.J a proposal.Microbiome2015;3:31. atopic dermatitis patients. Curr Probl Dermatol 2016; 49: role fortheskinbarrierfunction inhealthy subjectsand in humanskin.Nature2013;498:367–370. Topographical. diversity communities andbacterial offungal Nat Rev Microbiol 2018; 16:143–155. stratum corneum. J Invest Dermatol 2008; 128: 2117–2119. gene lead to reduced level of natural moisturizing factor inthe Campbell LE, et al. Loss-of-function mutations in the filaggrin skin microbiome.Science 2009; 324:1190–1192. AC, et al. Topographical and temporal diversity of the human 191–202.e7. diversity inatopicdermatitis.JInvest Dermatol 2020;140: staphylococcus aureus colonization and increases microbial Kotol P, et al. IL-4Ralpha blockadeby dupilumab decreases skin. ActaDerm Venereol 1995;75: 429–433. citance and TEWL in eczematous and clinically uninvolved crobiol 2016;66: 4422–4432. and Pseudopropionibacterium gen. nov. Int J Syst Evol Mi Acidipropionibacterium gen.nov., Cutibacteriumgen.nov. the genusPropionibacteriumtoproposednovel genera pionibacteria, and reclassification of selected species within Sci Transl Med 2017; 9.pii:eaal4651. midis strain diversity underlying pediatric atopic dermatitis. - - - 46. 45. 44. 38. 35. 43. 37. 51. 48. 42. 41. 40. 39. 36. 52. 50. 49. 47. Baurecht H, Ruhlemann MC,Rodriguez E,ThielkingF, Har Kaci G,GoudercourtD, Dennin V, Pot B, Dore J, EhrlichSD, et Glatz M, Jo JH, Kennedy EA, Polley EC, Segre JA, Simpson Kluytmans J, van Belkum A, Verbrugh H. Nasal carriage of Zheng Y, Wang Q, Ma L, Chen Y, Gao Y, Zhang G, et al. Alte Nakatsuji T, Chen TH, Two AM, Chun KA, Narala S, Geha Meylan P, Lang C, Mermoud S, Johannsen A, Norrenberg S, Zhang E, Tanaka T, Tajima M, Tsuboi R, Nishikawa A, Sugita Edslev SM, Clausen ML, Agner T, Stegger M, Andersen PS. Nakatsuji T, ChenTH,Narala S, ChunKA,Two AM,Yun T, Tauber M,Balica S, HsuCY, Jean-Decoster C,Lauze C,Re Gonzalez ME, Schaffer JV, Orlow SJ, Gao Z, Li H, Alekseyenko Skov L, Halkjaer LB, Agner T, Frimodt-Moller N, Jarlov JO, Kennedy EA, Connolly J, Hourihane JO, Fallon PG, McLean Chng KR, Tay AS, Li C, Ng AH, Wang J, Suri BK, et al. Whole Han SH,CheonHI,HurMS, KimMJ, Jung WH,LeeYW, etal. Harkins CP, McAleerMA, Bennett D, McHugh M, Fleury OM, Iwamoto K,Moriwaki M,Miyake R,HideM.Staphylococcus Appl Environ Microbiol2014; 80: 928–934. a commensalbacteriumof theoral cavity anddigestive tract. al. Anti-inflammatory properties of Streptococcus salivarius, 2018; 13: e0192443. infants at risk for developing atopic dermatitis. PloS One EL, et al. Emollient use alters skin barrier and microbes in Staphylococcus aureus: epidemiology, underlying mecha J Invest Dermatol 2016; 136: 2192–2200. defects in atopic dermatitis to trigger cytokine expression. RS, etal. Staphylococcus aureus exploits epidermal barrier J Invest Dermatol 2017; 137: 2497–2504. precedes the clinical diagnosis of atopic dermatitis in infancy. Hohl D, etal.Skincolonizationby staphylococcus aureus with atopicdermatitisandinhealthy subjects.MicrobiolIm T. Characterization of the skin fungal microbiota in patients Staphylococcus in resistance der atopic aureusfromDanish revealsanalysis Genomic different mechanisms of acid fusidic 8–26. atopic dermatitis. SciTransl Med2017;9. in deficient are and aureus Staphylococcus against protect et al.Antimicrobialsfromhumanskincommensalbacteria AV, et al. Cutaneous microbiome effects of fluticasone propio Bisgaard H. Neonatal colonization with Staphylococcus au 139: 166–172. of atopic dermatitis at 1 year. J Allergy Clin Immunol 2017; staphylococci at 2 months is associated with a lower risk commensal with colonization early dermatitis: of atopic WHI, Murray D, et al. Skin microbiome before development metagenome profiling reveals skin microbiome-dependent skin reveals profiling metagenome dermatitis. ExpDermatol 2018;27: 366–373. Analysis of the skin mycobiome in adult patients with atopic Pettigrew KA, et al. The widespread use of topical antimi and skin immunity. AllergolInt2019; 68: 309–315. aureus in atopic dermatitis: Strain-specific cell wall proteins 137: 1272–1274.e1273. severity in atopic dermatitis. J Allergy Clin Immunol 2016; and nonlesional skin is strongly associated with disease doules D, etal.Staphylococcus aureus density onlesional dermatitis. J Am Acad Dermatol 2016; 75: 481–493.e488. nate creamandadjunctive bleachbathsinchildhoodatopic Br JDermatol 2009;160: 1286–1291. reus is not associated with development of atopic dermatitis. 505–520. nisms, and associated risks. Clin Microbiol Rev 1997; 10: 2019; 38: 1677–1685. infants withatopicdermatitis. EurJClinMicrobiolInfect Dis severity and treatment in the perioral zone of theskin of rations intheskinmicrobiomeareassociatedwithdisease munol 2011; 55:625–632. 2018; 179:951–958. isolated from patientswith atopic dermatitis. Br J Dermatol Staphylococcus in for resistance enriches crobials aureus patients.JAntimicrobChemother2018;73:856–861. matitis 141: 1668–1676.e1616. skin microbiome configuration. J Allergy Clin Immunol 2018; integrity, and eczematous inflammation are associated with der I, Erkens AS, et al. Epidermal lipid composition, barrier Skin microbiomeinatopicdermatitis Theme issue:Atopic dermatitis 365 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 60. 59. 58. 69. 65. 63. 57. 68. 67. 66. 64. 62. 61. 56. 55. 54. 53. Theme issue:Atopic dermatitis 366 Williams MR, Costa SK, Zaramela LS, Khalil S, Todd DA, Mempel M, Schmidt T, Weidinger S, Schnopp C, Foster T, Ring Miajlovic H, Fallon PG, Irvine AD, Foster TJ. Effect of filaggrin Liu H,ArcherNK,Dillen CA,Wang Y, AshbaughAG,Ortines Jinnestal CL, Belfrage E, Back O, Schmidtchen A, Sonesson Prohic A, Jovovic Sadikovic T, Krupalija-Fazlic M, Kuskunovic- Guzik TJ, Bzowska M, Kasprowicz A, Czerniawska-Mysik G, Seiti Yamada Yoshikawa F, Feitosa de Lima J, Notomi Sato Brauweiler AM,Bin L,KimBE, Oyoshi MK,GehaRS, Goleva Brauweiler AM, Goleva E, Leung DYM. Th2 cytokines increase Faergemann J. Atopic dermatitisandfungi.ClinMicrob Rev Nakamura Y, Oscherwitz J, Cease KB, Chan SM, Munoz- Hong SW, ChoiEB, MinTK,KimJH,MH,JeonSG,etal. Simpson EL, Villarreal M, Jepson B, Rafaels N, David G, Hill SE, Yung A, Rademaker M. Prevalence of Staphylococ Totte JEE, Pardo LM, Fieten KB, Vos MC, van den Broek TJ, Amoako DG,BesterLA,SomboroAM,Baijnath S, Govind on theskinprotectsagainst epidermalinjuryinatopicder Winter HL,etal.Quorumsensingbetweenbacterialspecies 452–456. in a new adhesion assay. J Invest Dermatol 1998; 111: proteins in the attachment to cultured HaCaT keratinocytes J, et al. Role of Staphylococcus aureus surface-associated 1184–1190.e1183. Staphylococcus aureus. J Allergy Clin Immunol 2010; 126: breakdown productsongrowthof and proteinexpressionby drives skin inflammation via IL-36-mediated T cell responses. RV, et al. Staphylococcus aureus epicutaneous exposure A. Skin barrier impairment correlates with cutaneous Stap Vlahovljak S. Malasseziaspeciesinhealthy skinandinder 2005; 35: 448–455. to clinicalandimmunologicalparameters. ClinExpAllergy Staphylococcus aureus in atopic dermatitis: relationship Wojcik K, Szmyd D, et al. Persistent skin colonization with Toxins 2019; 11. pii: E321. role ofstaphylococcus aureustoxins inatopicdermatitis. M, AlefeLeuzziRamos Y, AokiV, LeaoOrfali R.Exploringthe protects againststaphylococcal alpha-toxin-induced kerati E, etal.Filaggrin-dependentsecretionof sphingomyelinase death through the signal transducer and activator of trans Staphylococcus aureus alpha toxin-induced keratinocyte 2002; 15: 545–563. 2013; 503:397–401. by disease skin activating allergic induces Nature mastcells. Planillo R, Hasegawa M, et al. Staphylococcus delta-toxin on the development of atopic dermatitis induced by Staphy extracellularAn importantroleofalpha-hemolysinin vesicles endotype. JInvest Dermatol 2018; 138: 2224–2233. colonized with staphylococcus aureus have a distinct phenotype and dermatitis atopic with Patients al. et J, Hanifin Schuren FHJ, etal.Thenasalandskinmicrobiomeareas South Africa:aninvestigation ofmethicillinresistantStap mechanisms intheprivate healthsectorinKwaZulu-Natal, CN, Essack SY. Plasmid-mediated resistance and virulence e421–422. nocyte death. J Allergy Clin Immunol 2013; 131: 421–427. 6(STAT6).cription JInvest 2014;134:2114–2121. Dermatol dermatitis. IntJDermatol 2014; 53: 27–33. associated microbial antigens in adult patients with atopic hylococcus aureus colonization and sensitization to skin- matological conditions. Int J Dermatol 2016; 55: 494–504. lococcus aureus. PloS One2014;9:e100499. matitis. Sci Transl Med 2019; 11; eaat8329. 2011; 52: 27–31. dermatitis: a New Zealand experience. Australas J Dermatol cus aureusandantibioticresistanceinchildrenwithatopic Br JDermatol 2019;181: 796–804. sociated withdiseaseseverity inpediatricatopicdermatitis. a threemonth period. Int J InfectDis 2016;46: 38–41. hylococcus aureus(MRSA) clinicalisolatescollectedduring 1: 16106. susceptibility to atopic dermatitis flare. Nat Microbiol 2016; S. M.Edslevetal. ------86. 79. 85. 82. 70. 78. 75. 73. 84. 81. 77. 76. 74. 72. 71. 87. 83. 80. Kelhala HL, Aho VTE, Fyhrquist N, Pereira PAB, Kubin ME, Pau Fleury OM, McAleer MA, Feuillie C, Formosa-Dague C, San Flores GE, Caporaso JG, Henley JB, Rideout JR, Domogala D, Goggin R, Jardeleza C, Wormald PJ, Vreugde S. Corticoste Nakagawa S, Matsumoto M, Katayama Y, Oguma R, Waka Aarestrup FM,LarsenHD, EriksenNH,ElsbergCS, JensenNE. Tomi NS, Kranke B, AbererE.Staphylococcal toxins inpa Bunikowski R, Mielke ME, Skarabis H, Worm M, Anagnosto Castanheira M, Watters AA, Mendes RE, Farrell DJ, Jones RN. Kwon S, ChoiJY, ShinJW, HuhCH,Park KC,Du MH,etal. Wichmann K, Uter W, Weiss J, Breuer K, Heratizadeh A, Mai Breuer K, Wittmann M, Kempe K, Kapp A, Mai U, Dittrich- Schlievert PM, Case LC, Strandberg KL,Abrams BB, Leung Skov L,OlsenJV, GiornoR,Schlievert PM,Baadsgaard O, Baldry M, Nakamura Y, Nakagawa S, Frees D, Matsue H, Xu H, Li H. Acne, the Skin Microbiome, and Antibiotic Treat Seite S, Bieber T. Barrierfunction andmicrobioticdysbiosis Harkins CP, Pettigrew KA, Oravcova K, Gardner J, Hearn of the human microbiome.GenomeBiol 2014; 15: 531. Chase J, etal.Temporal variability isapersonalized feature APMIS 1999;107:425–430. pheno- and genotype and variation in phenotypic expression. aureus of bovine and human origin. A comparison between Staphylococcus in andbeta-haemolysin Frequency ofalpha- 65: 1353–1358. European countries (2008). J Antimicrob Chemother 2010; resistance mechanisms among Staphylococcus spp. from Occurrence and molecular characterization of fusidic acid 99: 284–290. treatment of atopic dermatitis. Acta Derm Venereol 2019; Changes in lesional and non-lesional skin microbiome during Cell HostMicrobe2017;22: 653–666.e655. severe Br atopic dermatitis. J Dermatol 2009; 161: 300–305. aureus from theskinofhighlysensitized adult patientswith U, etal.Isolationofalpha-toxin-producing Staphylococcus Breiholz O, etal.Alpha-toxin isproducedby skincoloni Infect Dis 2008;46:1562–1567. from patientswithsteroid-resistant atopic dermatitis.Clin isolates aureus Staphylococcus DY. of profile Superantigen 2000; 105:820–826. superantigen-mediated mechanism. J Allergy Clin Immunol normal and atopic skin induces up-regulation of T cells by a Leung DY. Applicationof Staphylococcal enterotoxin Bon compound astherapy forstaphylococcus aureus-inducedin Nunez G,etal.ApplicationofanAGR-specific antivirulence 8: 479–483. in atopicdermatitis.Clin Cosmet Investig Dermatol 2015; disease flare. JInvest Dermatol 2018;138:336–343. staphylococcus aureus colonization during atopic eczema RMR, Rice D, et al. The microevolution and epidemiology of ment. AmJClin Dermatol 2019; 20:335–344. 1088–1095. response inatopicdermatitis.ClinExtAllergy2005;35: zing Staphylococcus aureusandinducesaThelpertype 1 53: 67–72. and in healthy control subjects. J Am Acad Dermatol 2005; tients with psoriasis, atopic dermatitis, and erythroderma, dermatitis. J Allergy Clin Immunol2000;105:814–819. effect of Staphylococcus aureus-derived exotoxins in atopic poulos I, Kolde G, et al. Evidence for a disease-promoting flammatory skin disease. J Infect Dis 2018; 218: 1009–1013. Microbe 2017; 22:667–677.e665. Host Cell inflammation. skin IL-17-dependent orchestrate PSMalpha peptidesinducekeratinocyte alarmin releaseto bayashi S, Nygaard T, et al. Staphylococcus aureus virulent the skinmicrobiotainacne.Exp Dermatol 2018; 27:30–36. lin L, et al. Isotretinoin and lymecycline treatments modify an invitro study. Laryngoscope2014; 124: 602–607. roids directly reduce Staphylococcus aureus biofilm growth: dermatitis. Infect Immun2017;85.pii:e00994–16. adherence ofstaphylococcus aureustocorneocytesinatopic severe E, Bennett DE, et al. Clumping factor B promotes ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV skin diseasethatoftenpresentsininfancyandmayper This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta University, Portland, OR, USA be due to the various cytokine profiles of AD (6). Con (6). AD of profiles cytokine various the to due be lenging duetoavarietyof AD phenotypes,which may treatments for AD in the clinical setting is often chal contribute toapoorqualityof life(QoL)(4,5).Selecting health comorbidities, and suicidal ideation, all of which pruritus, increasedriskofsleepdisturbances,mental moderate-to-severe diseasewithsymptomsincluding (2, 3). Approximately onethirdofall AD patientshave dysregulation, and disruptions in the skin microbiota environmental factors,skinbarrierdysfunction,immune of AD iscomplexandinvolvesgeneticpredispositions, sist orre-emerge inadulthood(1). The patho W SW BondAve, Portland, OR97225,USA. E-mail:[email protected] Corr: EricL. Simpson, MD, Oregon Health and Science University, 3303 Acta DermVenereol 2020;100;adv00165. Accepted May 7,2020;EpubaheadofprintMay 15,2020 logics; smallmoleculeinhibitors. Key words: atopicdermatitis;targeted therapeutic agents; bio- date conferenceabstractsandpresentations. tis utilizing andup-to- recently publishedmanuscripts dermati atopic of field the in therapies emerging sing Thisreviewaimsto coverthemostthe future. promi AD patientswill allow foramore tailored in approach better understanding of individual amongst differences A andsafertherapeutic forAD. approaches effective inhibitorscule indevelopment hold promises formore biologicstherapeutic agentsincluding andsmallmole Targeted overexpression. Th1/Th17 of degree varying a with response 2/Th22 (Th) cell T helper dominant understanding of the a ADpathogenesis, suggesting progress medicineprovidesusabetter inmolecular in themidstof atherapeutic renaissanceinAD.Recent or long-termunacceptable toxicities. We are currently efficacy inadequate with treatments to led pathways inflammatory underlying the account into take to ling rather non-specific despite AD’s complex etiology. Fai conventional therapeutic modalities forADremained a wide variety of clinical phenotypes. Until recently, mune dysregulation with andskinbarrierdysfunction that bycomplexim ischaracterized taneous disease 1 Chan HoNA Dermatitis A TherapeuticRenaissance –EmergingTreatments forAtopic Atopic dermatitis (AD) is a chronic, inflammatory cu inflammatory chronic, a is (AD) dermatitis Atopic Journal Compilation ©2020ActaDermato-Venereologica. Department of Dermatology, College of Medicine, Chosun University, Gwangju, South Korea, dermatitis (AD) is a chronic, pruritic inflammatory ith anincreasingprevalenceworldwide,atopic 1 , Wenelia BAGHOOMIAN , 3 Department of Dermatology, Oregon Health and Science University, Portland,OR,USA 2 andEricL.SIMPSON physiology physiology REVIEW ARTICLE Centenary theme section:ATOPICDERMATITIS ------3 and recombinant interferon (IFN)-γ mRNA were prima while inacutelesions, predominantly observed Th1 cells and interleukin(IL)-4messenger RNA (mRNA)were questionable relevanceto AD. Inthismodel, Th2 cells with system model artificial an – tests patch allergen (Th1) paradigm emerged fromstudiesinvolvinginhalant in thechronicphase(7). This acute(Th2)and chronic acute phaseofthedisease,andaskewed Th1 response driven byapredominanthelper T (Th)2responseinthe For manyyears, AD pathophysiologywasthoughttobe an array ofadaptive and innate immune derangements. Analysis of the skin and blood of patients with AD reveal PATHOPHYSIOLOGY OFATOPICDERMATITIS lized therapeutictreatmentapproachfor AD inthefuture. molecule inhibitors. We canexpect to seeamorepersona an era oftargeted therapeutics, such as biologics and small munopathogenesis andheterogeneityof AD hasinitiated the pastfewyears,ourincreasingknowledgeofim defects underlyingtheparticularpatient’s disease.Over or defect molecular specific the target should treatment the multifactorialetiologyof AD, theidealtherapeutic safe long-termsystemictreatmentfor AD. Considering there remainsalarge unmetneedforaneffective and Thus, reactions. drug adverse or efficacy inadequate to therapydue require systemic who control inmanypatients and mycophenolatemofetilprovideinadequatelong-term corticosteroids, cyclosporine, methotrexate, azathioprine, ventional systemicimmunosuppressiveagentsincluding dermatitis. to create tailoredand personalized treatments for atopic large-scale and long-term clinical trials are needed in order 2 axis have been largely unsuccessful. Further datausing the type of outside cytokines specific target to tempting additional cytokinepathways. However, data to dateat certain phenotypes of atopic dermatitis may be driven by physiology of atopic dermatitis. Besides type 2 cytokines, patho the in cytokines 2 type of importance the confirms variable clinical manifestations. The success of dupilumab to its chronic nature, multifaceted pathophysiology, and Effective treatment of atopic dermatitis iscomplicateddue SIGNIFICANCE 2 School of Medicine, Oregon Health and Science Acta DermVenereol 2020;100: adv00165 doi: 10.2340/00015555-3515 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis tion (20).Group2innatelymphoidcells(ILC2s),which scratch sensory nerves,isupregulatedin AD lesionsandtriggers loop (19).IL-31,aninterleukinthatinducesitchingvia which results in Th2 polarization anda positive feedback IL-13 induce keratinocytes to secrete additional TSLP, rier lipidssuchasceramides(17,18).Notably, IL-4and expression of barrier proteins such as filaggrin, and bar like mastcellsandeosinophils. They alsoinhibitthe cells inflammatory additional of activation the mediate 16). Th2 cells release IL-4, IL-5, IL-13, and IL-31, which of IL-5dependenteosinophilsintotheskin(Fig.1)(15, immunoglobulin (Ig)Eclassswitchingandrecruitment and activateaseriesof Th2-mediated eventssuchas inflammation tissue local drive cytokines These 33. thymic stromallymphopoietin(TSLP),IL-25,andIL- thymus- andactivation-regulatedchemokine(TARC), via thereleaseofcytokinesandchemokines,including inflammation potentiate or initiate keratinocytes rupted Dis (14). filaggrin protein barrier skin the for encodes such asloss-of-functionmutationsintheFLGgenethat via genetically driven alterations inskin barrier function and keratinocytes.Epidermaldisruptionmayalsooccur vation ofnonlymphoidcellslikeLangerhans(LC) irritants, allergens, andpathogensgiverisetotheacti chronic phaseofthedisease(9). an upregulationof Th1 cells,recruitandcoordinatethe signals (12, 13). Intensification of these axes, along with Th22 relatedsignalsandtoalesserdegree Th17 related In theacutephase,lesionsdisplayoveractivationof Th2/ both theacuteandchronicstagesofdisease(9–11). and amuchmorevariable Th1/Th17 responsethroughout AD has a stronger association with a Th2/Th22 response patients with AD, notpatchtests,havesuggestedthat using findings Recent (8). lesions chronic in seen rily 368 In AD skin, disruption ofthe epidermal barrier by C. H.Naetal. ing behavior, which may further drive inflamma - - - - predominance and lack any other atopic diathesis (25). predominance andlackanyotheratopicdiathesis(25). sic phenotypehavingnormalIgElevelsshowsfemale personal andfamilyatopicbackground,whiletheintrin historically defined as patientswith high serum IgE levels, presentation andresponsetotherapy, extrinsic AD was versus extrinsictype.Inspiteofasimilarityinclinical versus chronicdisease,andpatientsexhibitingintrinsic withacute pediatric patientsversusadultpatients,subjects include classifications AD Other identified. been also decent, African American decent,and Asian originhave various ethnicbackgroundssuchasEuropean American molecular signalingabnormalities(25–28).Subtypesof IgE status,S.aureus colonizationstatus,andunderlying status, mutational gene filaggrin ethnicity,chronicity, by different endotypes and phenotypes including age, classified subtypes AD several reveals research Recent OF ATOPICDERMATITIS CLINICAL ANDMOLECULAR HETEROGENEITY era ofinnovationandnoveltherapeuticdevelopment. date informationregarding this unique and promising investigation. The aimofthisreviewistoprovideup well asbroader T cellinhibitors,arealsocurrentlyunder targeted drugs involving the Th22 and Th17 pathways, as approved for AD, have been developed (23, 24). Multiple like dupilumab, which represents the first biologic drug the criticalroleof Th2 axisin AD, anti-Th2 agents drugs are currently in the therapeutic pipeline. Given underlying AD, numeroustargeted andbroad-acting and aberrantepidermaldifferentiation (9). released by Th22 cellspromotesepidermalhyperplasia In conjunctionwithIL-17releasedby Th17 cells,IL-22 IL-5 andIL-13thatperpetuates Th2 immunity(21,22). are activated bykeratinocyte mediators, release both By identifying a growing number of immune pathways By identifyingagrowingnumberofimmunepathways monophosphate; IFN-γ:interferon-γ. PDE4: phosphodiesterase4; cAMP: cyclic adenosine homologous molecules expressed on Th2 lymphocytes; 4; DC: dendritic cell;CRTH2: chemoattractant receptor- subfamily V memberhistamine 1;H4R: receptor type cells; TRPV1: transient receptor potential cation channel hydrocarbon receptor; ILC2: group 2 innate lymphoid Th: helper T; AMPs: antimicrobialpeptides;AhR: aryl acute and chronic stages of AD. AD: atopic dermatitis; the throughout intensified are disruption barrier and and IL-22 released by Th22 cells, epidermal hyperplasia into the skin. Together with IL-17 released by Th17 cells class switching and accumulation of inflammatory cells 13, and IL-31, thereby leading to immunoglobulin (Ig) E and activate a series of Th2 cytokines such as IL-4, IL-5, IL- inflammation tissue local drive cytokines These lymphopoietin (TSLP), interleukin (IL) -25, and IL-33. activation-regulated chemokine (TARC), thymic stromal of cytokines and chemokines, thymus-including and initiates or potentiates inflammation through the release dermatitis (AD). Fig. 1. Immune pathophysiology of atopic In AD skin, epidermal disruption - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Table I.NoveltopicaltargetedtherapiesofAD(inorbeyondphaseIItrial) AD include the useoftopical corticosteroids (TCS)as for of Topical therapies AD. gement anti-inflammatory therapies arestillanessentialcomponentinthemana Despite theadventofnewsystemicagents,topical TOPICAL THERAPIES or helppredictthenaturalcourse. better toaparticulartherapeutic(i.e.,precisionmedicine) clinically relevantiftheyidentifypatientsthatrespond clinical relevanceofemerging endotypeswillbedeemed useful toolsindevelopingtargeted treatmentsfor AD. The of these subtypes, these findings and others can serve as though further studies are needed to confirm the reliability Th2 cytokine expression in “lichenified” phenotypes. Al phenotypes, whileclusters2and3showlowerlevelsof er levelsof Th2 cytokineexpressionin“erythematous” endotype clustersof AD (29).Clusters1 and 4 show high 4 identified AD moderate-to-severe with patients adult study basedontheanalysisofserumbiomarkers193 AD alsoappeartolackany Th1 activation(25). A Dutch American patientswith AD andpediatricpatientswith Asian descent, and patients withintrinsic AD. African- dominant Th17 subtypeinpediatricpatients,patientsof the general AD population, there appears to be a relatively in identified Th2/Th22 of polarization strong a Despite S. aureus Aryl hydrocarbon receptor (AhR) Janus kinase (JAK) Phosphodiesterase 4(PDE4) Target Coagulase-negative Staphylococcus Ruxolitinib/INCB18424 Delgocitinib/JTE-052/LEO124249 LEO29102 DRM02 Lotamilast/RVT-501/E6005 AN2898 Roflumilast MM36/OPA-15406 Roseomonas mucosa bacteria GSK2894512 Tapinarof/ WBI-1001/benvitimod/ Tofacitinib Crisaborole/AN2728 Agent - first approved in 2016 by the US Food and Drug Ad Drug and Food US the by 2016 in approved first and AD (32).Crisaborole,atopicalPDE4inhibitorwas psoriasis as such diseases skin inflammatory chronic in cytokines inflammatory of down-regulation the in in cyclic adenosine monophosphate (cAMP), resulting enzyme activity. InhibitionofPDE4leadstoan increase that AD monocytes display overactive phosphodiesterase observation the made first (31) colleagues and Hanifin PDE4 inhibitors (AhR), andtheskinmicrobiome(Table I). (STAT) signalingpathway, arylhydrocarbonreceptor (JAK)-signal transducerandactivatoroftranscription to modulatephosphodiesterase(PDE)4,Januskinase for patients.Newtopicalagentsarenowbeingstudied topical therapies, there remains a significant unmet need and stinging(30).Giventheselimitationsintraditional verse events. The useof TCI isoftenlimitedbyburning AD overtheageof2years. Two phaseIIItrialsshowed ministration (FDA)forpatientswithmild-to-moderate cause telangiectasia,skinatrophy, dyschromia,andad agents. Additionally, the prolonged use of TCS may however, areofteninadequatelycontrolledwiththese recommended. Moderate-to-severepatientswith AD, as analternativeto TCS inareaswhere TCS useisnot first-line therapywith topical calcineurin inhibitors (TCI) Commensal interaction JAK 1/2 inhibitor JAK 1/3 inhibitor PDE4 inhibitor PDE4 inhibitor PDE4 inhibitor PDE4 inhibitor PDE4 inhibitor PDE4 inhibitor Commensal interaction AhR agonist JAK 1/3 inhibitor PDE4 inhibitor Mechanism II ongoing I/II completed III ongoing II completed IIa completed II completed II completed II completed I/II completed II completed II completed III completed III ongoing II completed I/II completed II completed I/II completed II completed IV ongoing III ongoing III completed II completed II completed I/II completed Phase status Emerging treatmentsforAD Theme issue:Atopic dermatitis Clinical trials NCT02144142 NCT03151148 NCT03745638 NCT03745651 NCT03011892 NCT01037881 NCT01037881 NCT01993420 NCT03394677 NCT02950922 NCT01461941 NCT02094235 NCT01179880 NCT01301508 NCT03916081 NCT01856764 NCT03908970 NCT03911401 NCT03961529 NCT03018691 NCT02914548 NCT02068352 NCT02945657 NCT03018275 NCT01098734 NCT02564055 NCT00837551 NCT02001181 NCT03539601 NCT03868098 NCT04040192 NCT02118792 NCT02118766 NCT03954158 NCT01602341 NCT03233529 NCT01652885 369 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis of JAKinhibitionholdsthe potentialtobringgreateref Th2, Th17, and Th22). The broader immune modulation immune axesinvolvedinthe pathogenesisof AD (Th1, JAK-STAT and SYK pathwaysdownregulatesmultiple chemokine ligand)20(41). Consequently, targeting the along withinducingtheproductionofCCL (C-C motif role in byrecruiting Th17 signaling totheskin Th17 cells ferentiation (40). The SYKpathwayplaysanimportant including IL-17,Bcellactivation,andkeratinocytedif cytokines pro-inflammatory of release the in involved tyrosine kinase(SYK)isanon-receptor inhibitory effects onvarious cytokinepathways.Spleen variable selectivity, resultinginoverlappingbutdistinct inhibitors target different combinationsofkinaseswith the activationoftargeted geneexpression(Fig.2).JAK increase theproductionofagroupSTATs, leadingto nase (TYK)2)phosphorylateintracellularreceptorsand associated kinases (JAK1, JAK2, JAK3, and tyrosine ki receptor 4 of family (38–40). AJAK IFN-γ and IL-33, as IL-4,IL-5,IL-6,IL-12,IL-13,IL-22,IL-23,IL-31, the signalingofmultiple AD-related cytokinessuch trials. The JAK-STAT pathwayhasbeenimplicatedin topical applicationshave also shown promise inclinical been mostlystudiedassystemictherapeuticsfor AD, JAK-STAT signalingpathway. Although theyhave JAK inhibitorsaresmallmoleculesthatinhibitthe JAK andotherkinaseinhibitors systemic absorptionorcutaneousatrophy. mild-to-moderate AD without the potential for significant a safeapproachtolong-termmanagementofselected III trials.Overall,topicalPDE4inhibitorsappeartobe LEO29102 arecurrentlyundergoing phaseIIand including roflumilast, AN2898, lotamilast, DRM02, and persisted for8weeks(37). Various PDE4inhibitors Index (EASI)scoreatweek1comparedtoplaceboand Severity and Area Eczema in improvement significant selectivity forPDE4B,athigherconcentrationshowed MM36 (OPA-15406), anotherPDE4inhibitorwithhigh other topical agentslike TCS and TCI (NCT03539601). to compared crisaborole of efficacy the evaluate to ted agents iscurrentlylacking. A newstudyhasbeeninitia topical other with data efficacy comparative but (36) use longer-term for safety its confirmed weeks 48 over practice than that reported in trials. A study of crisaborole of theseeventsareseeminglymorecommoninclinical burning, andstinging.However, theclinicalprevalence amongst patients.Limitedadverseeventsincludedpain, reported andgooddrugtolerabilitywere ofpruritus signs achieves successovervehicletreatment(35).Improved 14 patientsareneededtobetreatedbeforeoneperson between 8 and 14. (34). This translates to between 8 and relatively large numberneededtotreat(NNT),ranging score (33). A large vehicleeffect, however, leadstoa in theInvestigator’s StaticGlobal Assessment (ISGA) significant efficacy with 51% clear and 48% almost clear 370 C. H.Naetal. - - - - the nucleus,leadingtoactivation oftargetedgeneexpression. of transcription (STAT). Phosphorylated STATs dimerize and translocate to and increase the production of a group of signal transducer and activator JAK3, and tyrosine kinase (TYK) 2)phosphorylate intracellular receptors Janus kinase (JAK) family of four receptor associated kinases (JAK1, JAK2, Fig. 2.JAK-STATpathway.A cytokine binds toitscellsurface receptor. A Other JAKinhibitorssuch as cerdulatinib(RVT-502), a in EASIscoreatweek4than triamcinolonecream0.1%. nib athigherdoses(1.5%)showed greaterimprovements 0.5% and 1.5% arms versus vehicle (46). Topical ruxoliti significant efficacy in EASI score at week 4 in the cream (INCB018424), apotent JAK1/JAK2 inhibitor, showed son (44).InanongoingphaseIItrial,topicalruxolitinib control arm,althoughtherewasnostatisticalcompari were similar to the tacrolimus 0.1% ointment active in mEASIscorewiththehigherdosesofdelgocitinib tion onitchtransmissionbyneurons(45).Improvements (81% vs.29%(placebo),p by day2andalarge reductioninEASIscorebyweek4 pruritus of reduction significant showed AD moderate a potent JAK1/JAK3 inhibitor, for patients with mild-to- AD models(42). A phaseIIatrialinvestigatingtofacitinib, inmouse andenhanceskin barrier functions ling pathways in potentialadverseeventsaswell. ficacy. However, this theoretically results in an increase pathway (20)orpossiblyviadirecteffect ofJAKinhibi inhibition ofIL-31signalingmediatedbytheJAK-STAT were alsoobservedbyday1,whichwaslikelyduetothe pruritus in Improvements (44). profile safety favorable Investigator’s Global Assessment (IGA)scoreswith a of AD by week 4, and low modified EASI (mEASI) and showed significant improvement in the overall symptoms inhibitor, (JAK1-3,TYK2) 124249),apanJAK 052/LEO mild pruritus. A controlledstudyofdelgocitinib(JTE- site reactionsreportedintwosubjectsweremildpainor Topical JAKinhibitorsdecreaseIL-4andIL-13signa < 0.001) (43). The application - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV could theoretically yield a remittive effect on the disease. commensals live beneficial transplanting that speculate Should this approach provide efficacy, it is intriguing to sequence of barrier dysfunction or type 2 inflammation. in AD isaprimarydriverofthe diseaseormerelyacon These studieswillhelpelucidatewhetherthedysbiosis testing coagulase-negativeStaphylococcusareunderway. I/II trialusingRoseomonasmucosaandaphaseII clinical improvements in AD (57).Currently, aphase S. aureus colonizationand tides leadstoadecreasein Staphylococci enrichedwithnovelanti-S. aureus pep that autologous transplantation of coagulase-negative and areductionof TCS use(56). Another studyreported with clinicalimprovementin AD severityandpruritus, found thatthecommensalbacteriumprovidedpatients application of Roseomonas mucosa topical with trial open-label recent A AD. of flare-up as apotentialmechanismfordiseaseprogressionand Increased biomarkers suchas TARC, periostin,andCCL26(55). eosinophil counts,andincreasedlevelsofvarious Th2 allergen sensitization,elevatedIgElevels, serum lactatedehydrogenase(LDH)levels,increased severe skindisease,reducedbarrierfunction,increased racteristics ofS.aureus-colonized patientsincludemore and endotypeforpatientscolonizedwithS.aureus. Cha of AD (54).Recent research suggests a unique phenotype flare the worsen and initiate to shown aureus,been has microbial diversityandanincreaseincolonizationofS. Cutaneous dysbiosis,characterizedbyareductionin Commensal organisms (53). Phase3studiesareanticipated. potential forsystemicabsorptionathigherconcentrations nausea and/orvomitingwereobserved. This suggeststhe dies ofhigherdosetapinarofat2%,headache,diarrhea, patients withmild-to-severe AD (51,52).Inearlierstu scores ofboth0.5%and1%dosinggroupsatweek6in IGA in efficacy significant and AD mild-to-moderate EASI andIGA scores wereseen at week4 in patients with (50). In two phase II trials, significant improvements in the bacterialsymbiontsofentomopathogenicnematodes AhR agonist, isanaturally derived molecule produced by Tapinarof an (benvitimod/GSK2894512/WBI-1001), tion and can restore epidermalbarrierfunction (48, 49). the balance of Th17 and regulatory T (Treg) cell produc signaling pathways(47).Ithasthepotentialtoimpact factor that is involved in both pro- and anti-inflammatory The AhR isacytosolicligand-activated transcription AhR agonist no dataareavailableforreviewatthistime. rently beingevaluatedinphaseI/IItrialsof AD, however tropomyosin receptorkinase A (TrkA) inhibitor, arecur dual JAKandSYKinhibitor, andSNA-125,aJAK3 S. aureus colonization hasbeen proposed for patients with AD ------antimicrobial peptides,andencourageS.aureus coloni and lipids filaggrin, like proteins structural barrier of disturb skinbarrierfunctionbyinhibitingtheproduction the recruitment of additional inflammatory cells, but also reveal increased IL-4/IL-13 levels that not only lead to responsible fortheproductionofIgE.Cellculturestudies are and responses inflammatory Th2 of mediators key IL-4 and/orIL-13antagonists.andarethe Targeting Th2pathway provide alternativestodupilumab(Table II). inhibitors arenowbeingdevelopedandinvestigatedto of dupilumab,anumberbiologicsandsmallmolecule and effective therapyforlong-termuse.Sincetheadvent drug approved for AD, has filled this large void for a safe fective long-term therapies. Dupilumab, the first biologic treatments, thereisstillanunmetneedforsafeandef toxicities withtraditionalimmunosuppressantlong-term and mycophenolatemofetil.Giventheriskofpotential corticosteroids, cyclosporine, methotrexate, azathioprine, phototherapy orsystemic immunomodulators such as morbidities (58). Traditionally, systemictherapiesinclude events (63). A LIBERTY AD CAFÉ study with concomi local injectionreactionsand conjunctivitisasadverse with only combined exhibiting when TCS profile safety lumab showedanimproved diseaseactivitywithagood (LIBERTY AD overall improvementinQoL.InanotherphaseIIIstudy pruritus, anxiety, anddepression. They alsoreportedan also reported impro vements intheirsymptomsincluding between 44–51% versus placebo (12–15%) (24). Patients ving a75%reductioninEASIscore(EASI-75)ranging disease atweek16,withtheproportionofpatientsachie dupilumab everyotherweekshowedimprovement in adult patientswithmoderate-to-severe AD who received phase IIItrialofidenticaldesign(SOLO1andSOLO2), over theageof12yearsinUS2019(62).In a was extended to patients with moderate-to-severe AD in adultstheUSandEurope2017,itsapproval Dupilumab was approved to treat moderate-to-severe AD (61). subunit receptor IL-4Rα shared their blocking by (mAb), inhibitsboththeIL-4andIL-13signalingpathway (10, 60).Dupilumab,afullyhumanmonoclonal antibody and non-lesional AD, andcorrelateswithdiseaseseverity zation (57,59).IL-13isoverexpressedinbothlesional prior treatment history, financial considerations, and co and considerations, history,financial treatment prior and include individual factors such as patient preferences, of disease severity, an understanding of the impact on QoL, or offer systemic treatments should involveanassessment Council (IEC) consensus paper, the decision to commence topical therapies. According toanInternationalEczema is inadequatelycontrolledwithappropriateamountsof adult patientswithmoderate-to-severe AD whosedisease Systemic treatmentsmaybeappropriateforpediatricand SYSTEMIC THERAPIES CHRONOS), ayear-long trialofdupi Emerging treatmentsforAD Theme issue:Atopic dermatitis 371 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis Table II.Novelsystemictargetedtherapiesofatopicdermatitis(AD)(inorbeyondphaseIItrial) 372 Neuropeptide substance P and neurokinin 1receptor (NK1R) Histamine receptor lymphocytes (CRTH2) Chemoattractant receptor-homologous molecules expressed on Th2 Phosphodiesterase (PDE) 4 Janus kinase (JAK) Janus kinase (JAK) Small molecules Interleukin (IL)-1α IgE T-helper 1/ T-helper 17 T-helper22 T-helper 2 Biologics Target C. H.Naetal. Serlopitant/VPD-737 Tradipitant/VLY-686 ZPL-389 Fevipiprant/QAW039 OC000459/ODC-9101 Apremilast ASN002/Gusacitinib Abrocitinib/PF-04965842 Upadacitinib/ABT494 Barcitinib Bermekimab/MABp1 Ligelizumab/QGE031 Omalizumab MOR106 Secukinumab Ustekinumab Ustekinumab Fezakinumab/ILV-094 Mepolizumab Nemolizumab/CIM331 Nemolizumab/CIM331 KHK4083 GBR830 MEDI9929 Tezepelumab/AMG157/ Tralokinumab Lebrikizumab Pitrakinra/Aeroderm Dupilumab Agent NK1R inhibitor NK1R inhibitor H4R inhibitor CRTH2 mAb CRTH2 mAb PDE4 inhibitor inhibitor JAK/spleen tyrosine kinase JAK1 inhibitor JAK1 inhibitor JAK1/2 inhibitor Anti-IL-1α mAb Anti-IgE mAb Anti-IgE mAb Anti-IL-17C mAb Anti-IL-17A mAb Anti-IL-12/23p40 mAb Anti-IL-22 mAb Anti-IL-5 mAb Anti-IL-31RA mAb Anti-OX40 mAb Anti-TSLP mAb Anti-TSLP mAb Anti-IL-13 mAb Anti-IL-13 mAb Anti-IL-4 mAb Anti-IL-4Rα mAb Mechanism Oral Oral Oral Oral Oral Oral Oral Oral Oral Oral Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Intravenous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Route III ongoing II completed III ongoing III completed II completed II ongoing II completed IIb completed IIa completed II completed II terminated II completed III ongoing III completed II ongoing II completed III ongoing II completed III ongoing III completed II completed II ongoing II completed II completed IV completed II completed II terminated II completed II completed II completed II terminated III ongoing II ongoing II completed II ongoing IIb ongoing II completed II ongoing IIa completed III ongoing III completed II completed III ongoing II completed IIa completed IV ongoing Phase status NCT03540160 NCT02975206 NCT04140695 NCT03568331 NCT02651714 NCT03517566 NCT03948334 NCT02424253 NCT01785602 NCT02002208 NCT00931242 NCT02087943 NCT03654755 NCT03531957 NCT03796676 NCT03720470 NCT03422822 NCT03627767 NCT03575871 NCT03349060 NCT03915496 NCT02780167 NCT03661138 NCT03738397 NCT03568318 NCT03569293 NCT03607422 NCT02925117 NCT03952559 NCT03428100 NCT03334435 NCT03435081 NCT03559270 NCT03334396 NCT03733301 NCT03334422 NCT02576938 NCT04021862 NCT03496974 NCT01552629 NCT00822783 NCT02300701 NCT01179529 NCT03864627 NCT03568071 NCT03568136 NCT02594098 NCT01945086 NCT01806662 NCT01941537 NCT03055195 NCT03989349 NCT03985943 NCT03989206 NCT03921411 NCT03100344 NCT01986933 NCT03703102 NCT03568162 NCT02683928 NCT03809663 NCT02525094 NCT03526861 NCT03761537 NCT03587805 NCT03131648 NCT03160885 NCT03363854 NCT03562377 NCT02347176 NCT04146363 NCT04178967 NCT02465606 NCT03443024 NCT02340234 NCT00676884 NCT00676884 NCT03667014 NCT03389893 NCT03293030 NCT03411837 Clinical trials Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV lebrikizumab atthe125mg doseevery4weeksandat press releasefromaphaseIIb trial,patientstreatedwith placebo-controlled phaseII trial(TREBLE).Inarecent mandatory TCS usetwicedaily (p tients with moderate-to-severe AD with concomitant group response of EASI-50 of 62% at week 12 for pa (EASI-50) of82%atweek12ascomparedtoaplacebo every 4weeksachievedan50%reductioninEASIscore (73). Lebrikizumab,ananti-IL-13mAb,at125mgdose lesion inflammatory the at eosinophil of accumulation keratinocyte toproduceCCL26,therebycausingan chronic lesionsof AD (72).LikeIL-4,IL-13induces and acute both in expressed is and inflammation lergic IL-13 antagonists.playsanimportantroleinal further developmentisunknown. However, no results have been reported and the status of that targets onlyIL-4,hasbeentestedinaphaseIIatrial. type 2cytokines(62).Pitrakinra(Aeroderm),abiologic nosinusitis withnasalpolyposisthatarealsodrivenby or oralcorticosteroid-dependent asthma andchronic rhi moderate-to-severe asthmawith eosinophilic phenotype Dupilumab wasalsorecentlyapprovedbytheFDA for as noend-organ damagehasbeenobserved(70,71). therapy (70).Nolaboratorymonitoringisrequired cination responsesarealsonotaffected bydupilumab observed protectionagainstskininfections(65). Vac dysbiosis – perhaps the mechanism that explains the placebo (69).Dupilumabappearstocorrect AD skin and bacterialnon-herpeticskininfectionscomparedto significantly reduced risk of serious or severe infections with increased overall infection rates. Studies reveal to be immunosuppressive and has not been associated suitable forlong-termuse.Dupilumabdoesnotappear light ontotheetiologyofthisadverseeffect. (24). Ongoingmechanisticstudieswillhopefullyshed was notobservedinstudiesof asthma or chronic sinusitis therapy onlyoccursinpatientswith AD. This side effect reasons, theconjunctivitisassociatedwithdupilumab ous topical anti-inflammatory approaches. For unknown mild tomoderate in severity and can be treated with vari understood sideeffect (68). The conjunctivitisisusually disease, isacommon(5–28%ofpatients)butpoorly compared toplacebo(66,67). for patientswithmoderate-to-severe AD ondupilumab ficant increased efficacy and a well-tolerated safety profile (65). Two meta-analyses demonstrated statistically signi barrier function, including genes for loricrin and filaggrin sion ofgenesthatcontrolepidermaldifferentiation and inflammatory cell infiltrates. It also enhances the expres markers, Th17/Th22-related epidermalhyperplasia,and veal that dupilumab reduces expression of Th2 immunity intolerant to cyclosporine (64). Translational studies re in moderate-to-severeadult AD whowererefractoryor tant useof TCS exhibitedanEASI-75of63%atweek16 Overall, dupilumabappearstobeasafetherapy Dupilumab-induced conjunctivitis,orocularsurface = 0.026) (74)ina ------scores comparedtoplaceboat16weeks(75). Tralo dose- andfrequency-dependentimprovementsinEASI the 250 mg dose every 2 or 4 weeks showed significantly derived TSLP activates dendritic cells to induce thepro Th2 allergic inflammatory response (77). Keratinocyte- is alsoknowntoplayanimportantroleininitiatingthe axis Inhibitors ofthe TSLP-OX40 axis.The TSLP-OX40 targeting limitedtoonlycertainbiologics is thepathway. to revealwhetherconjunctivitis isanIL-13class effect or and self-limited(74, 76). PhaseIIIdatawill be important sopharyngitis, and headaches that are common but mild events, includingupperrespiratoryinfections(URIs),na adverse limited with profile safety acceptable an show Overall, IL-13inhibitorsappeartobewelltoleratedand without TCS is underway to better evaluate its efficacy. trial (NCT03131648)usingtralokinumabmonotherapy and there were no significant adverse effects. A phase III cebo. PatientsreportedimprovementinQoL andpruritus, likely diminishedtheeffect sizewhencomparedtopla of IL-13activity(76).Heavyuseconcomitant TCS particularly in patients with high serum biomarker levels improvement in EASI and IGA scores in a phase II study, significant showed mAb, anti-IL-13 another kinumab, disease activity (84).Nemolizumab, an anti-IL-31RA and chronic AD andplaysacriticalroleinpruritus acute in increased significantly is IL-31 (83). neurons receptor (IL-31R) is expressed on C-fibers of peripheral duced byactivated Th2 cellsandmastcells. The IL-31 IL-31, dubbedthe“itchcytokine”ispredominantlypro scratch cycleisoneofthemaingoalsinmanaging AD. IL-31 receptor antagonists.Interruptionoftheitch- (NCT03533751). (NCT01732510), an anti-IL33 mAb Etokimab (ANB020) hibitors includinga TSLP receptorantagonistMK-8226 (PoC) trialstestingvarious TSLP-OX40 axis-relatedin Currently, therehavebeenseveralproof-of-concept An additionalphase II trial (NCT03703102)isunderway. even atweek22suggestingalong-lastingresponse(82). 6 weeks showed acontinuous reduction in EASI score with KHK4083,ananti-OX40mAb,every2weeksfor (81). InaphaseItrial(NCT03096223),patientstreated and significant improvement in EASI-50 versus placebo fety profile, decreased inflammatory serum biomarkers, mAb, waswelltoleratedandshowedanacceptablesa group (80). In aphase IIa trial, GBR830, an anti-OX40 mably duetoheavyconcomitant TCS useintheplacebo week 12inpatientswithmoderate-to-severe AD, presu at placebo to compared response EASI-50 significant a phase IIatrial(NCT02525094),however, itdidnotshow to beapotentialsuppressorofthe Th2 pathway. Ina (AMG157/MEDI9929), ananti-TSLP mAb,isregarded of OX40ligandondendriticcells(78,79). Tezepelumab appears toamplify TSLP’s effect ofinducingexpression IL-33 (19). (TNF)-α factor necrosis tumor and IL-13, duction of Th2 immunitycytokinessuchasIL-4,IL-5, Emerging treatmentsforAD Theme issue:Atopic dermatitis 373 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis a higherIL-22baseline,suggesting aneffect ofIL-22 with patients in efficacy better a had fezakinumab led including URIsasadverseevents. A recentstudyrevea profile, safety limited a with well-tolerated overall was improvement withfezakinumab versusplacebo(92).It of severe AD (SCORAD score >50) showed significant SCORAD scorecomparedtoplacebo,butasub-analysis the reducing in significance reach not did mAb, IL-22 the NationalInstitutesofHealth,fezakinumab,ananti- with diseaseseverity(60).InaphaseIItrialfundedby increased in AD lesionsandexpressionlevelscorrelate and tight junction production (91). IL-22 is significantly rier function by inhibiting keratinocyte differentiation IL-22 promotesepidermalhyperplasiaanddisruptsbar Targeting Th22pathway futility criteriafollowinginterimanalysis. terminated early, asthisstudyreachedpre-determined effectiveness in the AD subtype with eosinophilia but was moderate-to-severe the hadbeenimplementedtotest AD ficacy in treating eosinophilic asthma, a phase II trial for peripheral bloodeosinophiliccount(90).Givenitsef pruritus scoring,and TARC levelsdespitedecreasingthe cance inSCORing Atopic Dermatitis(SCORAD)score, a pilot study for AD but did not reach statistical signifi approved forsevereeosinophilicasthma,wastestedin hagitis (89). Mepolizumab, ananti-IL-5 mAb recently flammatory diseases like asthma and eosinophilic esop in allergic Th2 with patients of tissue inflamed within of thedisease.IL-5inducesmigrationeosinophils valence intissueandbloodfoundthroughoutthecourse large roleinthepathogenesisof AD duetotheirhighpre IL-5 antagonist. Eosinophils are speculated to play a nodularis arecurrentlyunderway. NCT03816891) forchronicpruriticdiseasesandprurigo study (88). Additional phaseIIstudies(NCT03858634, patients withmoderate-to-severe AD inaphaseIa/Ib fety andtolerabilityaswellananti-pruriticeffect in sa good showed KPL-716 fibrosis. and inflammation, Th2 pruritus, in implicated signal inflammatory an M, oncostatin and IL-31 both inhibiting (anti-OSMRβ) KPL-716 isananti-oncostatinMreceptorbetamAb butresultshavenotyetbeenpublished. (NCT01614756), an anti-IL-31mAb,wascompletedasaphaseIbtrial the 30mgdosebeingmosteffective (87).BMS-981164, week 24versusplaceboandwaswelltolerated,with at scores itch and IGA EASI, improved significantly (86). A recentphaseIIbtrialrevealedthatnemolizumab including nasopharyngitis, AD exacerbations, andURIs over the 64 weeks trial with limited adverse events, and continued itch suppression and was well-tolerated In another long-term phase II trial, it showed significant moderate-to-severe AD in a 12-weekphaseIItrial(85). gue scale (VAS) scores forpruritus in patients with analo visual in reduction significant a showed mAb, 374 C. H.Naetal. ------surface of inflammatory dendritic cells (IDECs) characte cell the on present also is IgE cascades. inflammatory activation andtheinitiationofsensitizationinallergic product ofthe Th2 axis.Itisimplicatedinbasophilic IgE is a hallmark for atopic diseases and is a downstream IgE antagonists AD inphaseIItrials. secukinumab, an anti-IL-17A mAb, are being tested for a phaseItrial(NCT02739009)(101).MOR106and maintained over2monthsafterstoppingtreatmentin week 4atthehigherdoseandtreatmentresponse an anti-IL-17CmAb,exhibitedEASI-50of83%at although itwasgenerallywell-tolerated(100).MOR106, placebo, versus efficacy meaningful show not did mg with severe AD treatedwithustekinumab45mgand90 for AD (99). In another phase II trial in Japan, patients over placebowithconcomitant TCS useinaphaseIItrial psoriasis, did not demonstrate significant improvements in efficacy with IL-12/IL-23p40 antagonizing mAb a promise inseveralreportsof AD (97,98),ustekinumab, be a keratinocyte-derived cytokine (96). Despite showing Th17 cells and innate immune cells, IL-17C appears to responses (95).UnlikeIL-17A whichisproducedby and T cells, leading to the amplification of cell immune show complementarycooperationbetweenkeratinocytes interleukins, IL-17A-F. Among them,IL-17A andIL-17C ments (94). The IL-17familyconsistsof6members treat after AD decreased significantly is and pathways targeting therapies.IL-23initiatesboth Th17 and Th22 patients maybepotentialcandidatesforIL-17/IL-23 markers likethosefoundinpsoriasis(25). Thus, these and elderly AD showhigherexpressionof Th17-related Some phenotypessuchas Asian, intrinsic,pediatric, Targeting Th17pathway and/or psoriasiform Th17/Th22 endotypes(25). subtype patientsshowingdominant Th22 polarization pediatric AD and intrinsic, African American, Asian, antagonizing IL-22couldbeapromisingoptionamongst (93). Treatmentaxis and Th22 passing Th1,Th2,Th17, with ligelizumab (QGE031), a high affinity anti-IgE Ab, not yetbeenposted.Inaphase IItrial,patientstreated for severepediatric AD wascompleted,butresultshave efficacy over placebo in an RCT (103). A phase IV trial ble efficacy for AD, omalizumab did not show improved asthma. Despitesomecaseseriesdemonstratingfavora IgG1κ antibody used in chronic spontaneous urticaria and Omalizumab isarecombinanthumanizedmonoclonal treatments in AD haveshownlargely negativeresults. anti-IgE (25).However for anti-IgE drugs candidates for atopicmarchearlyoninlifemaybegoodtargeted levels ofIgEandpediatric AD subtypewith atendency ristic of AD (102). Extrinsic AD subtypes defined by high blockade on multiple inflammatory pathways encom pathways inflammatory multiple on blockade - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV reduction in pruritus as early as week 1 and a significant riatic arthritis.InaphaseIIb trial,upadacitinibshowed arthritis, Crohn’s disease, ankylosing spondylitis and pso is currentlyunderwayinclinical trialsforrheumatoid Upadacitinib (ABT-494), aselectiveoralJAK1inhibitor, TCS and longer-term endpoints are stillbeingrecruited. als forbaricitinibthatincludecombinationtherapywith moderate-to-severe AD (112). A number ofphaseIIItri mg and 4 mg with a good safety profile for patients with significant clinical efficacy in both baricitinib doses of 2 confirmed BREEZE-AD2 and BREEZE-AD1 trials III kinase, andnasopharyngitiswerereported. Two phase events including headache, increased creatine phospho ments inpruritusandsleep.Dose-dependentadverse reported toleratingthemedicationwellwithimprove baricitinib incombinationwith TCS (111). Patientsalso 16, 61%(4mg)versus37%(placebo)whentreatedwith week at EASI-50 in improvements significant showed a phaseIItrial,patientswithmoderate-to-severe AD and theUSfortreatmentofrheumatoidarthritis.In potent oralJAK1/JAK2inhibitorapprovedintheEU a is Baricitinib (40). AD in pruritus and inflammation pathway mayplayanimportantroleinmediatingboth signals throughJAK1/TYK2(110). The JAK-STAT IL-4 requiressignalingthroughJAK1/3whileIL-13 pathogenesis of AD, includingIL-4andIL-13.Notably, mediator in signaling numerous cytokines involved in the inflammatory skin diseases including AD. JAK is a key JAK inhibitorspotentiallyhaveawideapplicationin JAK inhibitors tial ofthisnoveltherapyin AD. Controlled studiesareneededtobetterassessthepoten significant improvements at all clinical endpoints (109). trial of38patients with moderate-to-severe AD revealed diseases likehidradenitissuppurativaand AD. A phaseII cancer, but is now being evaluated for inflammatory skin activity. The drugfailed in a phase IIIforcolorectal IL-1α blocking by activity immunomodulating shows mab (MABp1)isanaturallyderivedhumanmAbthat leading toepithelialbarrierbreakdown(108).Bermeki also enhancesmatrixmetalloproteinasesactivity, thereby IL-1α (107). in AD found cascade inflammatory the of ratinocytes, which may play a key role in the initiation attractive target as its major reservoir appears to be ke an is cytokine, pro-inflammatory prototypical a IL-1α, IL-1α antagonist appear tohavesignificantclinicalactivityin AD. potential (105,106). To donot date,anti-IgEapproaches (NCT02148744) havebeencompleted,butshowlimited such asMEDI4212(NCT01544348)andXmAb7195 (104). The phaseItrialsusingotheranti-IgEagents, reduction intheseverityfor AD comparedtoplacebo significant a show not did weeks 12 for weeks 2 every ------Chemoattractant receptor-homologous moleculesexpres expressed onTh2lymphocytesantagonists Chemoattractant receptor-homologous molecules to seriousadverseeventlikecellulitis(119). Th17/Th22 relatedbiomarkers,itwasdiscontinueddue a dose of 40 mg showed clinical efficacy and decreased of 30mgcomparedtoplacebo. Although apremilastat no significant change in EASI score at week 12 at a dose (118). However, inaphaseIItrial,apremilastshowed arthritis, showedpromisingresultsinan AD pilotstudy oral PDE4 inhibitor approved for psoriasis and psoriatic an Apremilast, IL-10. cytokine anti-inflammatory the IL-31, andIL-33(117). PDEinhibitoralsoupregulates involved in AD including IL-2,IL-5,IL-13IL-17,IL-22, leading toadownregulationofnumbercytokines PDE4 inhibitorincreasesintracellularcAMP levels, PDE4 inhibitor in SCORADwithnoadverseevents(116). a smallopen-labelstudyshowedimpressivereductions with longerdurationisstillongoing.Oraltofacitinibin in Th2/Th22 biomarkers (115). Another phase II trial vement inclinicalseverityatweek4withareduction mulation alsostimulatesIL-31 production(124).JNJ- cells, keratinocytes, and sensory neural cells. H4sti receptor type4(H4R)isexpressed on Th2 cells, Th17 itching hasbeenratherdisappointing (123).Histamine roles ofH1andH2blockade in AD and AD-associated Histamine (H)isaknownitch-inducingmediator. Yet, the Histamine receptor type4antagonists did notdemonstrateefficacy(121,122). fevipiprant (QAW039) had been completed, but results two CRTH2 antagonists,OC000459 (ODC-9101)and migration intheskin(120). Two PoCphaseIItrialsfor and basophils.Itstimulatestheinitiationof Th2 cell D2 receptorthatisexpressedon Th2 cells,eosinophils, sed on Th2 lymphocytes (CRTH2) is a prostaglandin of pan-JAK(JAK1-3, TYK2) andSYK,showedimpro (NCT03139981), ASN002 (Gusacitinib),adualinhibitor are nowbeing investigated. Ina short-term clinical Itrial Other phaseIIItrialswithlong-termtreatmentperiods good tolerabilityandnounexpectedsafetyevents(114). of abrocitinib showed statistically significant results with line resultsdetailedinapressreleaseofphaseIIItrial and IGA 12versus placebo(40). atweek scores The top- inhibitor, showeddose-dependentimprovementinEASI trial, abrocitinib(PF-04965842),aselectiveoralJAK1 to-severe AD are also currently underway. In a phase IIb phase IIItrialsincludingyoungerpatientswithmoderate- events included URIsand AD exacerbations. Further in patientswithmoderate-to-severe AD (113). Adverse dose-dependent improvementinEASIscoreatweek2 Emerging treatmentsforAD Theme issue:Atopic dermatitis 375 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis REFERENCES and PDE4areeagerlyawaited. approaches targeting inflammation, the microbiome, itch, AD. The resultsofstudiesforseveralotherpromising in order to create tailored and personalized treatments for HOME initiative(www.homeforeczema.org) areneeded of lifeandlong-termcontrolasrecommendedbythe outcome measures that assess signs, symptoms, quality- large-scale and longer-termclinical trials withproper by morecomplexcytokineendotypes.Furtherdatausing JAK inhibitionmayhelppatientswith AD thataredriven type 2axishavelargely beenunsuccessful.Broadacting attempting to specifically target cytokines outside of the by additionalcytokinepathways.However, datatodate 2 cytokines,certainphenotypesof AD maybedriven kines inthepathophysiologyof AD. Inadditiontotype cyto 2 type of importance central the confirms AD in chronic courseofthedisease. The successofdupilumab pathophysiology, variable clinical manifestations, and nagement of AD iscomplicatedduetoitsmultifaceted Despite itshighprevalenceworldwide,effective ma CONCLUSION significant (130). to placebo.However, thedifferences werenotstatistically revealed numericdifferences compared inpruritusscores subjects takingoralserlopitant(VPD-737)for6weeks phase IItrialinvolving AD patientswithseverepruritus, phase IIItrialfortradipitantiscurrentlyunderway. Ina tion inpruritus VAS frombaseline(p (VLY-686) for 4 weeks experienced a significant reduc chronic pruritus,patientstreatedwithoraltradipitant (128). InaPoCphaseIItrialforpatientswith AD and decreased scratchingbehavior in AD mousemodels AD disease activity (127). The NK1R antagonist prompts (NK1R), thereceptorforsubstanceP, isassociatedwith Neuropeptide substance P and neurokinin 1 receptor antagonists Neuropeptide substanceP andneurokinin 1receptor are stillongoing. in pruritus(126). Additional phaseIItrialsofZPL-389 use of TCS. However, there was no significant reduction patients withmoderate-to-severe AD withconcomitant scores werefoundatweek8comparedtoplacebofor antagonist, significant reductions in EASI and SCORAD (125). InaphaseIItrialtestingZPL-389,anotherH4R placebo to compared pruritus in reduction significant agranulocytosis (NCT01497119) althoughitdidshow a phaseIIatrialduetoseriousadverseeventsincluding 39758979, anH4Rantagonist,wasterminatedearlyin 376 1. Simpson E, et al. Epidemiology of atopic dermatitis in Barbarot S, Auziere S, Gadkari A, Girolomoni G,Puig L, C. H.Naetal. 0.0001) (129). A(129). < 0.0001) - - - 20. 19. 18. 17. 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 117: 411–417. 2006; Immunol Clin Allergy J inflammation. skin atopic L, etal.IL-31: anewlinkbetweenTcellsandpruritusin Sonkoly E,MullerA, LauermaAI,Pivarcsi A,Soto H,Kemeny munol 2002; 3:673. TSLP. producing by inflammation allergic ated Im Nature B, et al. Human epithelial cells triggerdendritic cell–medi V,Soumelis Reche PA, Kanzler H, Yuan W, Edward G, Homey lents. J Invest Dermatol 2014; 134:1941–1950. proteins andstratum equiva humanskin in corneumlipids atopic dermatitis–like features on epidermal differentiation induce cytokines Th2 and TNF-α al. et J, Smeden Van H, Danso MO, Van Drongelen V, Mulder A, Van Esch J, Scott inflammationin disease. Nat Rev Drug Discov 2016; 15: 35. Yancopoulos GD. Targeting key proximal drivers oftype 2 Gandhi NA,Bennett BL,Graham NM,PirozziG,Stahl N, munol 2017; 140:633–643. atopic dermatitis:endofthedrought?JAllergyClinIm Paller AS, Kabashima K, BieberT. Therapeutic pipelinefor titis. J Clin CellImmunol2011; 2. pii:110. Brandt EB, Sivaprasad U. Th2cytokinesandatopicderma factor for atopic dermatitis. Nature Genet 2006; 38: 441. epidermal barrier protein filaggrin are a major predisposing H, Lee SP, et al. Common loss-of-function variants of the Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao munol Pract 2014;2: 371–379. Im Clin JAllergy implications. important clinical story with and immune dysregulation in atopic dermatitis: an evolving Czarnowicki T, Krueger JG, Guttman-Yassky E. Skin barrier J Invest Dermatol 2008; 128: 2625–2630. Possible pathogenic role of Th17 cells for atopic dermatitis. Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y. 73: 311–318. erapeutic paradigms inatopicdermatitis. Cytokine2015; Malajian D, Guttman-Yassky E.Newpathogenicand th Clin Immunol2016; 138: 336–349. gic mechanisms in patients with atopic dermatitis. J Allergy Guttman-Yassky and immunolo E, et molecular al. Cellular Werfel T, Allam J-P, Biedermann T, Eyerich K, Gilles S, Clin Immunol2012; 130: 1344–1354. characterizes acuteandchronicatopicdermatitis.JAllergy of TH2/TH22 cytokines and selective epidermal proteins J, KJ, Gulewicz Wang CQ, Progressive etal. activation Gittler JK,ShemerA,Suárez-Fariñas M,Fuentes-Duculan patients. J Invest Dermatol 1995; 105: 407–410. patch allergen test in inhalant reactions of atopic dermatitis mann J. Analysisofthecytokinepatternexpressedinsitu Grewe M, Walther S, Gyufko K, Czech W, Schöpf E, Krut Immunol Today 1998;19: 359–361. Th2 cellsin the immunopathogenesisofatopicdermatitis. Langeveld-Wildschut AG, Ruzicka T, et al. A role for Th1 and Grewe M, Bruijnzeel-Koomen CA, Schöpf E, Thepen T, subsets. JAllergyClinImmunol2015;136:941–951.e943. imbalance, whereas adults acquire CLA+ TH22/TC22 cell cellonly acutaneouslymphocyteantigen(CLA)+TH2/TH1 A, NodaS, etal.Earlypediatricatopicdermatitisshows Czarnowicki T, Esaki H, Gonzalez J, Malajian D, Shemer J AmAcadDermatol 2019; 80: 402–410. suicidal ideation: A systematic review and meta-analysis. Association between atopic dermatitis, depression, and Patel KR,ImmaneniS, SingamV, Rastogi S, Silverberg JI. 74: 491–498. trial ofdupilumabinadults.JAmAcadDermatol 2016; atopic dermatitis (AD): insights from a phase 2b clinical Graham NM, et al. Patient burden of moderate to severe T, Bieber EL, Simpson Eckert L,Wu M, Ardeleanu R, 122: 263–269. 2019; AsthmaImmunol AnnAllergy dermatitis. atopic Nakatsuji T, GalloRL.Theroleof theskinmicrobiomein Immunol Rev 2017; 278: 246–262. mental factorsinthepathogenesisof atopicdermatitis. Kabashima K. The interplay between genetic and environ Otsuka A, Nomura T, Rerknimitr P, Seidel JA, Honda T, 73: 1284–1293. adults: Results from an international survey. Allergy 2018; ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 39. 38. 37. 36. 35. 34. 33. 32. 31. 30. 29. 28. 27. 26. 25. 24. 23. 22. 21. 2018; 78: S53–S62. for atopic dermatitis: JAK inhibitors. J Am Acad Dermatol therapies Emerging L. Eichenfield D, Schairer DG, Cotter Clin Invest 2002; 109: 1279–1283. Pernis AB, Rothman PB. JAK-STAT signaling in asthma. J 2016; 75: 297–305. study. placebo-controlled double-blind, JAmAcadDermatol moderate atopic dermatitis (AD): a phase-II randomized, treatment of adult and adolescent patients with mild to selective phosphodiesterase-4 inhibitor, (PDE4) the in Secci A,etal.OPA-15406, anovel, topical,nonsteroidal, LFS, IJ, Gold Fölster-Holst Frieden R, CN, Ellis JM, Hanifin dermatitis. J Am Acad Dermatol 2017; 77: 641–649. e645. 2% in children and adults with mild to moderate atopic Spellman M, et al. Long-term safety of crisaborole ointment Eichenfield LF, Call RS, Forsha DW, Fowler Jr J, Hebert AA, risk measures. J Am Acad Dermatol 2007; 56:664–671. matology: numberneededtotreatand itsrelationtoother Manriquez JJ, VilloutaMF, Evidence-based der WilliamsHC. appraisal. Br J Dermatol 2018;178:659–662. in childrenand adults does not lookpromising:acritical topical crisaboroleinthetreatmentofatopicdermatitis for benefit of Magnitude H. Williams L, Solman A, Ahmed and adults. J Am AcadDermatol 2016;75:494–503. e496. for thetopical treatment of atopic dermatitis (AD) inchildren a novel, nonsteroidal phosphodiesterase 4(PDE4)inhibitor M, Call RS, et al. Efficacy and safety of crisaborole ointment, Paller AS, Tom MG,BlumenthalRL,Boguniewicz WL,Lebwohl Targets 2007;6: 17–26. of allergic skin diseases and psoriasis. Inflamm Allergy Drug selective phosphodiesterase 4 inhibitors for the treatment Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly atopic dermatitis. J Dermatol Sci 1990; 1:1–6. Hanifin JM. Phosphodiesterase and immune dysfunction in tients with atopic dermatitis. BMC Pediatrics 2016;16: 75. pa pediatric in inhibitors calcineurin costeroids andtopical review of published trials: long-term safety of topical corti JaworskiEC, Siegfried JC, Kaiser JD, Hebert AA. Systematic 140: 730–737. on serum biomarker analysis. J Allergy Clin Immunol 2017; in atopic dermatitis: identification of patient clusters based Giovannone B, Csomor E, et al. Moving toward endotypes Thijs JL, Strickland I, Bruijnzeel-Koomen CA, Nierkens S, 136: 1254–1264. increased TH17 polarization. J Allergy Clin Immunol 2015; combines features ofatopicdermatitisandpsoriasiswith Strong C,Xu phenotype dermatitis atopic TheAsian etal. H, Noda S, Suárez-Fariñas M,UngarB, KimSJ, deGuzman 2016; 138:1639–1651. TH2 butalsoTH17polarized inskin.JAllergyClinImmunol T, Tran G, et al. Early-onset pediatric atopic dermatitis is Esaki H, Brunner PM,Renert-Yuval Y, CzarnowickiT, Huynh 2012; 129:1031–1039. e1031. murine model of filaggrin deficiency. J Allergy Clin Immunol stratum corneumofpatientswithatopicdermatitisandina sociated with enhanced expression of IL-1 cytokines in the ders S, etal.Filaggrin loss-of-function mutationsareas Kezic S, O’Regan GM,LutterR,JakasaI,Koster ES, Saun peutics. JAllergyClin Immunol 2019; 143: 1–11. dermatitis endotypes and implicationsfortargetedthera Czarnowicki T, HeH,KruegerJG,Guttman-Yassky E.Atopic in atopic dermatitis. N EnglJ Med 2016; 375: 2335–2348. Cork MJ, et al. Two phase 3 trials of dupilumab versus placebo Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, dose-ranging phase 2b trial.Lancet2016; 387: 40–52. by topicaltreatments:arandomised, placebo-controlled, derate-to-severe atopicdermatitisinadequatelycontrolled mo with adults in dupilumab of safety and Efficacy al. et D,Thaçi T, BeckLA,Bieber EL, Simpson Blauvelt A,Papp K, 210: 2939–2950. innate lymphoid cells in atopic dermatitis. J Exp Med 2013; D, Wang X,etal.Arolefor IL-25 andIL-33–driven type-2 JL,SaundersSP, M,Barlow Salimi Xue L,Gutowska-Owsiak gic inflammation. Curr Opin Immunol 2013; 25: 738–744. Kim BS,Kim Wojno EDT, D. Artis andaller cells Innatelymphoid ------50. 49. 48. 47. 46. 45. 44. 43. 42. 41. 58. 57. 56. 55. 54. 53. 52. 51. 40. Li J,Li WuG, Chen WebsterH, pig two of Identification JM. Acad SciUSA 2008; 105:9721–9726. participates inthedevelopment ofTh17cells.ProcNatl Aryl hydrocarbon receptor regulates Stat1 activation and Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T. dermatitis. J ClinInvest 2013; 123: 917–927. tar induces AHR-dependent skin barrier repair in atopic Vlijmen-Willems IM,Hato SV, van derValk PG,etal.Coal van den Bogaard EH, Bergboer JG, Vonk-Bergers M, van disorders. J Invest Dermatol 2015;135:2572–2576. skin: consequences for prevention and treatment of skin faced roleofarylhydrocarbon receptorsignalinginthe Haarmann-Stemmann T, EsserC,KrutmannJ. TheJanus- September 12–16, 2018. Dermatitis (Abstract). 27th EADV congress, Paris, France, Efficacy of Topical Ruxolitinib in Adult Patients With Atopic and Active-Controlled Study to Evaluate the Safety and Kim B. APhase2,Randomized, Dose-Ranging, Vehicle- to mediate chronic itch.Cell2017; 171: 217–228. e213. Sensory neurons co-opt classical immune signaling pathways FengOetjen LK,MackMR, J, CJ, Guo H, TM,Niu Whelan etal. controlled clinical study. Br J Dermatol 2018; 178:424–432. dermatitis: a phase II, multicentre, randomized, vehicle- Japanese adult patients with moderate-to-severe atopic and safety of topicalJTE-052,aJanuskinaseinhibitor, Efficacy T. in Nagata A, Igarashi O, Nemoto H, Nakagawa 902–911. a phaseIIrandomized trial.Br J Dermatol 2016; 175: Mallbris L, et al. Topical tofacitinib for atopic dermatitis: Bissonnette R,Papp K,Poulin Y, Gooderham M,Raman M, 2015; 136:667–677. e667. activator oftranscription Immunol 3signaling.JAllergyClin transducer signal throughsuppressing function barrier and G, etal.TheJanuskinaseinhibitorJTE-052improves skin Amano W, S, Nakajima Kunugi NumataY, H, KitohA,Egawa Dermatol 2015;135:490–498. Dependent K63-Linked Ubiquitination of TRAF6. J Invest ates IL− 17-Induced CCL20 Expression by Targeting Act1- Wu N-L,HuangD-Y, Tsou H-N,LinY-C, LinW-W. Syk Medi titis: anupdate.Am J ClinDermatol 2019; 20: 181–192. Barbarot S, Deleuran M, et al. When does atopic dermatitis Simpson EL, Bruin-Weller M, Flohr C, Ardern-Jones MR, in atopic dermatitis. SciTransl Med2017;9:eaah4680. deficient are and aureus Staphylococcus against protect et al.Antimicrobialsfromhuman skincommensalbacteria Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, Yun T, JCI Insight 2018; 3.pii:120608. plantation withRoseomonas mucosaforatopicdermatitis. Williams KW, et al. First-in-human topical microbiome trans Myles IA, Earland NJ, Anderson ED, Moore IN, Kieh MD, endotype. JInvest Dermatol 2018; 138: 2224–2233. with Staphylococcus aureushave adistinctphenotype and colonized dermatitis atopic with Patients al. et J, Hanifin Simpson EL, Villarreal M, Jepson B, Rafaels N, David G, dermatitis. Genome Res 2012; 22:850–859. atopic with children in treatment and flares disease with et al.Temporal shiftsintheskinmicrobiome associated Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, safety results: 5243. J Am Acad Dermatol 2017; 76; AB247. macokinetics, systemic exposure, and preliminary efficacy/ R.TapinarofBissonnette Phar dermatitis: creamforatopic Maeda-Chubachi T, JohnsonL,Bullman J, CollingwoodT, trial. Br J Dermatol 2012; 166:853–860. multicentre, randomized, placebo-controlleddouble-blind mild tosevere atopicdermatitis: resultsfroma12-week, al. Efficacy and safety of topical WBI-1001 in patients with Poulin R, Bissonnette Y, ZhouY, Tan J, Webster H, Hong J, et 2010; 146:446–449. randomized, Arch trial. Dermatol clinical placebo-controlled in the WBI-1001 treatment ofatopic dermatitis:resultsfromaphase 2A, topical of safety and Efficacy al. et L, Bissonnette R,ChenG,BolducC,MaariLyle M,Tang Appl Environluminescens. 1995; 61: Microbiol 4329–4333. ments anda hydroxystilbene antibioticfromPhotorhabdus He H, Guttman-Yassky E. JAK inhibitors for atopic derma Emerging treatmentsforAD Theme issue:Atopic dermatitis 377 - - - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis 378 75. 74. 73. 72. 71. 70. 69. 68. 67. 66. 65. 64. 63. 62. 61. 60. 59. Press release [Internet]. California: Dermira Inc. 2019 (TREBLE). J Am Acad Dermatol 2018; 78: 863–871. e811. costeroids: a randomized, placebo-controlled phase II trial atopic dermatitis inadequately controlled by topical corti monoclonal antibody) in adults withmoderate-to-severe A, et al. Efficacy and safety of lebrikizumab (an anti-IL-13 Simpson EL, Flohr C, Eichenfield LF, Bieber T, Sofen H, 2004; 4:276–284. Taïeb dermatitis: inflammatory signals. Curr Allergy Asthma Rep Esche C, deBenedetto A, Beck LA. Keratinocytes in atopic dermatitis. J Allergy Clin Immunol1996;98: 225–231. Leung DY. In vivo expression of IL-12 and IL-13 in atopic Hamid Q, NaseerT, MinshallEM,SongYL, BoguniewiczM, CHRONOS). Br J Dermatol 2020;182:1120–1135. (LIBERTY AD SOLO 1,LIBERTY AD SOLO 2,LIBERTY AD severe atopic dermatitis: resultsfrom threephase IIItrials Q, etal. Laboratory safety ofdupilumabinmoderate-to- Wollenberg A,Beck L,Blauvelt A,SimpsonE,ChenZ, dermatitis. J Am Acad Dermatol 2019; 80: 158–167. e151. controlled trial in adults with moderate-to-severe atopic of vaccine-induced immunity: a randomized, placebo- B, Petro CD, etal.Dupilumab doesnotaffect correlates Blauvelt Tyring EL, A,Simpson LA,Shumel SK,Purcell J Clin Immunol 2019;20:443–456. Atopicin AComprehensive Dermatitis: Pooled Am Analysis. Bruin-Weller TrialsM, et al. Infections Clinical in Dupilumab Eichenfield LF, Bieber T, Beck LA, Simpson EL, Thaçi D, de 6: 1778–1780.e1771. teristics and treatment. J Allergy Clin Immunol Pract 2018; dermatitis patients treated with dupilumab–clinical charac M, de Bruin-Weller M. Conjunctivitis occurring in atopic Wollenberg A, AriensL,Thurau S, van LuijkC,Seegräber 2018; 90: 190–198. a systematic review and meta-analysis. J Dermatol Sci pilumab treatment in moderate-to-severe atopic dermatitis: Wang F-P, Tang X-J, Wei C-Q, Xu L-R, Mao H,LuoF-M.Du Allergy Clin Immunol2017; 140: 888–891. e886. dermatitis: a meta-analysis of randomized clinical trials. J and safety of dupilumab for the treatment of adult atopic Han Y, Chen Y, Liu X, Zhang J, Su H, Wen H, et al. Efficacy 155–172. with atopic dermatitis. J Allergy Clin Immunol 2019; 143: improves systemic and cutaneous abnormalities in patients M, Ardeleanu M, Esaki H, et al. Dupilumab progressively Guttman-Yassky E, Bissonnette R, Ungar B, Suárez-Fariñas J Dermatol 2018; 178: 1083–1101. randomized phase III clinical trial (LIBERTY AD CAFÉ). Br treatment is medically inadvisable: a placebo-controlled, quate response or intolerance to ciclosporin A or when this treatment inadultswithatopicdermatitisaninade A, etal.Dupilumab withconcomitanttopicalcorticosteroid de Bruin-Weller M,ThaçiD, SmithC,Reich K,CorkM,Radin controlled, phase3trial.Lancet2017;389: 2287–2303. RONOS): a1-year, randomised, double-blinded,placebo- and concomitant topical corticosteroids (LIBERTY AD CH moderate-to-severe atopic dermatitis with dupilumab Weisman J, Pariser D, etal.Long-termmanagement of Blauvelt A, de Bruin-Weller M, Gooderham M, Cather JC, U.S., Bridgewater, NJ; 2019. neron Pharmaceuticals, Inc., Tarrytown, NY; Sanofi-Aventis DUPIXENT® (dupilumab) Injection. Package insert. Rege eosinophil levels. N Engl JMed2013; 368: 2455–2466. da F, et al. Dupilumab in persistent asthma with elevated Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieran J Invest Dermatol 2017; 137: 603–613. biomarkers highlights the systemic nature of the disease. Shemer A, et al. An integrated model of atopic dermatitis Ungar B, Garcet S, Gonzalez J, Dhingra N, da Rosa JC, cells. ClinExpImmunol2005; 141: 459–466. CCL26 production in a human keratinocyte cell line, HaCaT kamura K, et al. Interleukin-4 and interleukin-13 enhance Kagami S, Saeki H, Komine M, Kakinuma T, Tsunemi Y, Na Dermatol 2017;77: 623–633. pert paneloftheInternationalEczema Council.JAmAcad warrant systemic therapy? Recommendations from an ex C. H.Naetal. ------85. 84. 83. 82. 81. 93. 92. 91. 90. 89. 88. 87. 86. 80. 79. 78. 77. 76. Ruzicka T, Hanifin JM, Furue M, Pulka G, Mlynarczyk I, Wol 2018;78:S37–S42. JAmAcadDermatol dermatitis. atopic 31RA developmentin 13andinterleukin interleukin for Thyssen CR, Hamann JP. against antibodies Monoclonal Immunol 2004; 5: 752. by activated T cells, induces dermatitis in mice. Nature SR, HaugenHS, etal. Interleukin 31, acytokineproduced A,BilsboroughJ, SR,Sprecher C,Hammond Dillon Presnell link/181203_02_KHK4083_en.pdf. library/events/main/02/teaserItems1/0/linkList/00/ [Dec 8]. Available from: https://ir.kyowakirin.com/en/ of KHK4083 in subjects with atopic dermatitis. 2018 Kyowa Kirin Inc. Product monograph. A phase I study 2019;144:482–493.e7. Immunol Clin JAllergy dermatitis. gene signatures and clinical scores in patients with atopic N, Xu H, et al. GBR 830, an anti-OX40, improves skin Guttman-Yassky E, Pavel AB, Zhou L, Estrada YD, Zhang J AmAcadDermatol 2019;80: 1013–1021. vere atopic dermatitis: A randomized phase 2a clinical trial. dermatitis stratifies tissue responses to fezakinumab. J fezakinumab. to responses tissue stratifies dermatitis S, et al. Baseline IL-22 expression in patients with atopic Brunner PM, Pavel AB, Khattri S, Leonard A, Malik K, Rose 2a trial.JAmAcadDermatol 2018; 78: 872–881. e876. ventional treatments: a randomized, double-blind, phase to-severe atopic dermatitis inadequately controlled by con (an IL-22 monoclonalantibody) inadultswithmoderate- Pavel AB, Malik K, et al. Efficacy and safety of fezakinumab Guttman-Yassky E, Brunner PM, Neumann AU, Khattri S, titis. Curr Opin Allergy Clin Immunol2014; 14: 417–422. Peng W, Novak N.Recent developments inatopic derma Allergy 2005; 60:693–696. body (mepolizumab) for the treatment of atopic dermatitis. et al.Anti-IL-5 recombinanthumanized monoclonalanti Oldhoff J, Darsow U, Werfel T, Katzer K, Wulf A, Laifaoui J, in severe eosinophilic asthma. Biologics 2017; 11:81. Haldar P. Patient profiles and clinical utility of mepolizumab congress, Paris, France, September12–16,2018. and subjects with atopic dermatitis (Abstract). 27th EADV M receptorbetamonoclonalantibody, inhealthy volunteers Mikhak Z.First-in-human studyof KPL-716, anti-oncostatin vere 2020;145:173–182. Immunol Clin JAllergy pruritus. in adults with moderate-to-severe atopic dermatitis and se Phase2Brandomizedenberg A,etal. studyofnemolizumab Silverberg JI,PinterA,PulkaG,Poulin Y, BouazizJ-D, Woll 1121–1130. e1127. term extensionstudy. JAllergyClinImmunol2018;142: to-severe atopic dermatitis: Randomized, phase II, long- Galus R,etal.Nemolizumabinpatientswithmoderate- Kabashima K, Furue M, Hanifin JM, Pulka G, Wollenberg A, for atopic dermatitis. NEnglJMed2017; 376: 826–835. lenberg A, et al. Anti–interleukin-31 receptor A antibody monoclonal antibody, in the treatment of moderate to se et al. Tezepelumab, an anti–thymic stromal lymphopoietin Simpson EL, Parnes JR, She D, Crouch S, Rees W, Mo M, dendritic cells. Immunity 2006; 24:827–838. memory Tcellsby thymic stromallymphopoietin-activated central ofhumanTH2 and polarization Maintenance R, etal. Wang Y-H, ItoT, Wang Y-H, HomeyB, Watanabe N,Martin function ofOX40 ligand.AllergolInt 2014; 63:443–455. maintenance of Th2 immune responses by enhancing the Tanaka A, Vien PTX, et al. IL-33 promotes the induction and Murakami-Satsutani N, Ito T, Nakanishi T, Inagaki N, Immunol 2012; 129: 1048–1055. e1046. Clin JAllergy receptorsignaling. lymphopoietin stromal epicutaneous sensitization with protein antigen via thymic Hara-Chikuma M, et al. Langerhans cells are critical in S,Nakajima T, IgyártóBZ,Honda Egawa OtsukaA, G, 2019; 143:135–141. tralokinumab, an anti–IL-13 mAb. JAllergyClinImmunol Kell C,Ranade K,etal.Treatment of atopicdermatitiswith Wollenberg MD, A,Howell Guttman-Yassky E,Silverberg JI, news-releases/default.aspx. Dermatitis. Available from:https://investor.dermira.com/ Phase 2b Study of Lebrikizumab in patients with Atopic [Mar 18]. Dermira Announces Positive Topline Results from ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 112. 111. 110. 109. 108. 107. 106. 105. 104. 103. 102. 101. 100. 99. 98. 97. 96. 95. 94. Simpson E. Efficacy and safety of baricitinib in moderate- in baricitinib of safety and Efficacy E. Simpson dose study. JAmAcadDermatol 2019;80:913–921. e919. double-blinded, randomized placebo-controlled multiple- moderate-to-severe atopic dermatitis:a phase2parallel, Wilke A, Prescilla R, et al. Baricitinib in adult patients with Guttman-Yassky E,Silverberg JI,NemotoO, Forman SB, evolving web. JAllergyClinImmunol2003;111:677–690. Hershey GKK. IL-13 receptors and signaling pathways: an Washington, DC, USA, March 1–5 2019. for Atopic (Abstract). Dermatitis AAD meeting,annual Simpson E. Bermekimab is a Rapid and Effective Treatment skin. Surgery2005;138: 932–939. activationproteolytic by ofmetalloproteinase-9 human Interleukin-1α–induced WL. Garner S, Y-P, Downey Han alpha. MedRes Rev 2017;37:180–216. skin diseasesandtherationale fortargetinginterleukin-1 role of interleukin-1 in inflammatory and malignant human Bou-Dargham MJ, Khamis ZI, Cognetta AB, Sang QXA. The 2018; 8:27. antibodies to eliminating IgE+ B cells. Clin Transl Allergy for IgE-mediated allergic diseases: from neutralizing IgE Hu J, Chen J, Ye L, Cai Z, Sun J, Ji K. Anti-IgE therapy 33: 225–251. subjects with atopy: a phase I study. Adv Therapy 2016; fety ananti-IgE ofMEDI4212, antibody, monoclonal in S, and sa pharmacodynamics, Pharmacokinetics, et al. Sheldon E, Schwickart M, Li J, Kim K, Crouch S, Parveen displaypdf.nov?trialresultid=12404. 15]. Available from: https://www.novctrd.com/CtrdWeb/ Novartis Clinical Trial No. CQGE031X2201. 2016 [Mar Blackwell, Hoboken, USA, 2016: p. 37–37. proof-of-concept study. Wiley Dermatology: Experimental dermatitis: a randomized, double-blind, placebo-controlled, anti-IgE antibody inpatients withmoderate tosevere atopic high-affinity a of pharmacodynamics and safety Efficacy, Bangert C, Loesche C,JonesJ, Weiss D, BieberT, StinglG. 113: 949–957. T-cell phenotypes invitro. J Allergy Clin Immunol 2004; dendritic cells induces chemotactic signals and different cell–like epidermal dendritic inflammatory and cells ritic dend cell–like langerhans of engagement FcεRI al. et S, Novak N, Valenta R, Bohle B, Laffer S, Haberstok J, Kraft Diego, CA, USA. of Dermatology Annual Meeting; Feb 16-20, 2018; San dermatitis: phase 1 study. Presented at: American Academy new approach for treatment of moderate-to-severe atopic Härtle S, etal.MOR106,ananti-IL-17C mAb, apotential Thaçi D, Constantin MM, Rojkovich B, Timmis H, Klöpfer P, Dermatol 2017; 177:419–427. zed, double-blind, placebo-controlled, phase II study. Br J Japanese patientswithsevere atopicdermatitis:arandomi in ustekinumab of safety Tamamura and Efficacy al. et R, Kabashima H, Saeki K,Tokura Y, Murata Y, Shiraishi A, Dermatol 2017;26: 28–35. moderate-to-severe with adults Exp dermatitis. atopic in treatment ustekinumab of safety and Efficacy al. et M, Khattri S, Brunner PM, Garcet S, Finney R, Cohen SR, Oliva ustekinumab. Int J Dermatol 2012; 51: 115–116. Treatment of severe refractory adultatopicdermatitiswith Puya R, Alvarez-López M, Velez A, Asuncion EC, Moreno JC. reports 2015; 1: 25. therapy inrefractory severe atopicdermatitis.JAAD case Shroff A,Guttman-Yassky useofustekinumab Successful E. 2011; 12: 1159. of epithelialcellsinanautocrinemanner. NatureImmunol Lesch J, et al. IL-17C regulates the innate immune function Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, J AllergyClinImmunol2017;140: 645–653. and thedevelopment ofnovel targeted immunetherapies. Hawkes JE, Chan TC, Krueger JG. Psoriasis pathogenesis dermatitis. J Allergy Clin Immunol 2014;134:1293–1300. nature in skin of patients with moderate-to-severe atopic X, Kostic A, et al. Dupilumab improves the molecular sig Hamilton JD, Suárez-Fariñas M, Dhingra N, Cardinale I, Li Allergy Clin Immunol2019; 143: 142–154. - - - - - 119. 118. 117. 116. 115. 114. 113. 130. 129. 128. 127. 126. 125. 124. 123. 122. 121. 120. Simpson EL, Imafuku S, Poulin Y, Ungar B, Zhou L, Ma dermatitis inadults. Arch Dermatol 2012;148:890–897. an oral phosphodiesterase inhibitor(apremilast)for atopic Samrao studyof Apilot EL. Simpson R, A,BerryTM,Goreshi open-label study. J Drugs Dermatol 2013; 12:888–897. of apremilast in recalcitrant plaque psoriasis: a phase II pharmacodynamics Efficacy, tolerability, and al. et C, Hu Gottlieb AB, Matheson RT, Menter A, Leonardi CL,Day RM, citrate. J Am Acad Dermatol 2015;73:395–399. dermatitis withtheoral Januskinaseinhibitortofacitinib Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis patients.JInvest Dermatol 2018; 138: S95. atopic moderate-to-severe in inflammation cutaneous SYK signalingimproves clinicaloutcomesandassociated Toker S, etal.559ASN002 adualoral inhibitorofJAK/ Guttman-Yassky E,Pavel A, Song T, Zammit H, Kim D, press-release. Dermatitis. Available from: https://www.pfizer.com/news/ Venereology for Abrocitinib in Moderate to Severe Atopic 28th at the Congress oftheEuropeanAcademy ofDermatology and 3 Data Phase Positive Presents Pfizer 12]. [Oct 2019 Inc. York:Pfizer New [Internet]. release Press meeting, San Diego, USA, February 16–20, 2018. Patients with Atopic Dermatitis (Abstract). AAD annual Randomized, Placebo-ControlledTrial of Upadacitinibfor Guttman-Yassky Results Primary E. fromaPhase2b, June 10–15,2019. 24th World Congress of Dermatology meeting, Milan, Italy, 16-week trials(BREEZE-AD1 andBREEZE-AD2) (Abstract) notherapy randomized, placebo-controlled double-blind, pruritus. ExpertOpinInvestig Drugs 2019; 28:659–666. receptor for antagonist treatment serlopitant of chronic Ständer S, SpellmanMC,Kwon P, Yosipovitch G.TheNK1 pruritus-in-atopic-dermatitis-300045700.html. itant-phase-ii-proof-of-concept-study-results-for-chronic- news-releases/vanda-pharmaceuticals-announces-tradip Sep 30]. Available from: https://www.prnewswire.com/ Chronic PruritusinAtopic Dermatitis. [lastaccessed2019 Tradipitant Phase II Proof of Concept Study Results for ticals 2015 [Mar 4]. Vanda Pharmaceuticals Announces PR Newswire[Internet].Washington: Vanda Pharmaceu dermatitis model. Eur J Pharmacol 2004; 491: 191–194. volvement of substancePinscratching behaviour inanatopic Ohmura T, Hayashi T, SatohY, Konomi A,JungB, In SatohH. J Dermatol 2002; 147: 71–79. plasma markers of disease activity in atopic dermatitis. Br hashi M. Nerve growth factor and substance P are useful Toyoda M,Nakamura M,MakinoT, HinoT, Kagoura M,Moro J AllergyClinImmunol2019;143: 1830–1837. e1834. antagonist ZPL-3893787 in patients with atopic dermatitis. nez P, et al. Efficacy and safety of the histamine H4 receptor Werfel T, Layton G,Yeadon M,WhitlockL,OsterlohI,Jime atopic dermatitis. J Dermatol 2015; 42:129–139. Japaneseadultswithmoderatetagonist (JNJ-39758979)in controlled, multicenter, parallel-group studyof aH4R-an Phase2a,randomized,A, etal. placebo- double-blind, Murata Y, Song M, Kikuchi H, Hisamichi K, Xu XL, Greenspan 619–625. expressed on TH2 cells. J Allergy Clin Immunol 2009; 123: Stark H, Werfel T. The histamine H4 receptor is functionally Gutzmer R, Mommert S, Gschwandtner M, Zwingmann K, eczema. Cochrane Database Syst Rev 2013;(2):CD007770. Weisshaar E.Oral H1antihistaminesasmonotherapy for Apfelbacher CJ vZE, Fedorowicz Z, Jupiter A, Matterne U, https://www.clinicaltrials.gov/ct2/show/NCT01785602. https://www.clinicaltrials.gov/ct2/show/NCT02002208. Immunol 2016; 137: 907–918. e909. cell subpopulationwithenhancedfunction.JAllergyClin TH2 human effector pathogenic proeosinophilic a defines Arceo S, et al. Hematopoietic prostaglandin D synthase Mitson-Salazar A,YinY, Wansley DL, Young M,BolanH, 139: 1063–1072. patients with atopic dermatitis. J Invest Dermatol 2019; lik K,etal.Aphase2randomized trialofapremilastin to-severe atopic dermatitis: results of two phase 3 mo Emerging treatmentsforAD Theme issue:Atopic dermatitis 379 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV doi: 10.2340/00015555-3516 discoveries intothehuman microbiomeand to enhancetheskinbarrier. Basicscience interventions and probiotics of field the in increased overthelast10 years, especially the numberof AD preventionstudieshas to publichealthmanipulation. However, amenable are that factors risk identifiable of research, lackoffundingandalimitedchoice lack ofresearchskillcapacityinprevention research infavourofbasicscience(Fig.1), include alackofinterestinpopulation-based vention”. Reasonsforlackofresearchcould eczema] AND treatment (August14 search (usingtheterms[atopicdermatitisOR ted topicofresearchuntilrecently. A PubMed D [email protected] Queen’s Medical Centre Campus, Nottingham, NG7 2UK, UK. E-mail: Hy Corr: Prof. Hywel C. Williams, Nottingham University Hopsitals NHS Trust Acta DermVenereol 2020;100:adv00166. Accepted May 7,2020;EpubaheadofprintMay 15,2020 tion. Key words: atopic dermatitis; atopic eczema; eczema; preven tion mightbedirectedat fetalprogramming inutero directed interventions maybetooand more atten late, immunological major influence ADatbirth through thatcharacterise infant- changes to trying that sible and results from national trials areawaited. Itispos vent interest, ADandfood allergyhasreceivedrecent analysis. Skin barrier enhancement from birth to pre data meta- patient individual from benefit might and around 20%,although the studiesare quite variable that suggest probiotics could reduce ADincidenceby exception of omega-3 fatty acids. Systematic reviews possible the with benefit any shown not also have D Vitamin as such supplements Maternal/infant benefit. and afterbirthhavegenerallynot convincing shown duce ingestedorairborneallergensduringpregnancy Centre of Evidence-Based Dermatology, University of Nottingham, Nottingham, UK Hywel C.WILLIAMS Prevention ofAtopicDermatitis Centenary theme section:ATOPICDERMATITIS dermatitis (AD)hasbeenarelativelyneglec and prolonged orbreastfeeding, interventions that re reviews of prevention strategiespromoting exclusive intoresearch AD prevention has been slow. Systematic Despite advances in atopic dermatitis treatments, (AD) Acta DermVenereol 2020;100: adv00166 when diseasetermswerecombinedwith“pre revealed 19,755 hits, compared with just 3,150 is betterthancure”,preventionofatopic espite the familiar adagethat“prevention and JoanneC.CHALMERS th 2019) This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta - - REVIEW ARTICLE as whetherdiseaseprevention ispossible. last 50 years has been dominated by interest in cellsrather than broader questions such populations. Researchinto AD relative to research mechanisms into AD over the Fig. 1.Askewedinterest toward cellular and molecular atopic dermatitis (AD) . ------pathological events(Fig.2). Whilst somedrugssuchas who seek medical help after a long chain ofirreversible focussing solelyondrugtreatmentofsickindividuals way tomanagetheburdenofadiseasesuchas AD than disease isarguably amuchmorelogicalandcost-effective precise carcinogenswerediscovered(3).Preventionof demiological researchlongbeforethemechanismsand to preventlungcancerbecameapparentfromsimpleepi essential. For example, the benefits of stopping smoking effects ofpreventionaremediatedisinterestingbutnot research, understandingthemechanismsbywhich that canbemanipulatedisanessentialpartofprevention to thisrecenttrend(1,2). Whilst identifyingriskfactors genetics of AD mayhaveplayedapartincontributing barrier stronger can prevent eczema. trying to find out if special creams that make a baby’s skin are still not sure what combination is best. New research is reduces the risk of eczema by around 20%, although we biotics (friendly gut bacteria) during pregnancy probably reducing house dust mite do not seem to work. Taking pro timing of starting solids,supplements like Vitamin D and so far to prevent eczema including exclusive breastfeeding, food allergy and asthma. Most things that have been tried should be possible to prevent eczema (atopic dermatitis), Just like wecan prevent infectious diseases like polio, it SIGNIFICANCE Journal Compilation ©2020ActaDermato-Venereologica. - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV smallpox, polioandmeasles aretestamenttothepower conquest ofmanyinfectious diseasessuchasdiphtheria, diabetes by 50%, rarely achieves such publicity (9). The the headlines,exercise,that canlowertheincidenceof that reduceglycohemoglobin levelsby0.5%oftenmake our attentiontothefactthat whereasnewdiabetesdrugs power ofpreventionandwhatitrequires” Woolf draws prevention ispotentiallyhuge.Inhisarticleentitled“The pared with treatments fora disease. Yet the power of their powerisoftennotappreciatedbyindividualscom Because preventionstrategiesactatapopulationlevel, The powerofprevention SOME KEYBASIC CONSIDERATIONS reviews (8). for RCTs that mightnotyetbeincludedinsystematic Global ResourceforEczema Trials (GREAT) database systematic reviews where possible (6,7). We usedthe systematic reviewsorthemostrecentandcomprehensive tion inthiscollection,weinsteadrefertooverviewsof than summariseall102systematicreviewson AD preven information scientist(Dr. DouglasGrindlay)(5).Rather systematic reviewswhichisupdatedmonthlybyasenior Evidence-Based Dermatologyinternationalcollectionof Systematic reviews were harvested from the Centre of evidence andRCTs asthe evidence sourcewherepossible. The authorshavechosentousesystematicreviewsof approaches designedtoenhancetheexternalskinbarrier. restrictions orsupplements,aeroallergen avoidanceand to tryandprevent AD suchasmaternalandinfantdietary then explorethemaininterventionsthathavebeenused controlled trial(RCT)ofemollientstoprevent AD. We direct experienceindesigningandrunningarandomised critically appraisingstudiesof AD prevention,usingour considerations whendesigningor by introducingthereadertokey environmental allergens. We start evidence ofIgEsensitisationto tion ofclinicalphenotypeplus rather than the scientific defini to describetheclinicalphenotype, We usethetermatopicdermatitis atopic eczemaorjust“eczema”(4). as AD, whichissynonymouswith will refertothediseaseofinterest titis. Throughout thisarticle,we on thepreventionofatopicderma review thecurrentstateofscience with potentialadverseeffects. expensive, andallareassociated like diseases theyareoftenAD, modify ratherthancurechronic tion can be curative, most only penicillin forstreptococcalinfec This article attempts to critically This articleattemptstocritically - - - with expensive drugswhopresenttosecondarycareafteralongchainofpathologicalevents. reduce the burden of disease at a population level than the current approach of treating sick individuals is rarely discussed at international meetings, an upstream approach is a far more logical approach to is Fig. 2.Where intervention most effective? Although the concept of prevention of atopic dermatitis - - dertake interventionsthatcould prevent AD in theirnew highly motivated(duringpregnancy orsoonafter)toun themselves orwitnessedit in familymembersareoften of this approach is that parents whohave experienced AD such as asthma, hay-fever or food allergy. The advantage degree relativewith AD orassociatedallergic diseases first- a with families to born babies e.g. population risk Participants. Most AD preventionstudiestarget ahigh- vention trials(12). considering thedesignandcriticalappraisalof AD pre to understandthestructureofRCTs andisusefulwhen (PICO) isaframeworkusedinevidence-basedmedicine Intervention,ComparatorandOutcomesParticipant, studies and Outcomesframeworktoatopicdermatitisprevention Application oftheParticipant,Intervention,Comparator operate (11). disease – i.e. where health care professionals normally or improvementinqualityoflifethosewithestablished whereas tertiarypreventionisthereductionofsymptoms tecting adiseaseatanearlystagetopreventworsening, health effects occur. Secondarypreventionimpliesde Primary prevention typically refersto intervening before Primary, secondaryandtertiaryprevention of population-basedinterventions(10). timely remindersofthe“invisible”andpowerfuleffects about vaccinesafety, termed“vaccinehesitancy”,are cent re-emergence ofmeaslesduetomisguidedbeliefs have contracted the disease in the first place. The re The place. first the in disease the contracted have and implementingvaccinesasitisunclearwhowould these diseasesareseldom“grateful”tothosedeveloping of prevention,yetindividualswhowouldhavecontracted Prevention ofatopicdermatitis Theme issue:Atopic dermatitis 381 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis Boca Raton, CRCPress Inc., 1997. Williams HC, Strachan DP (eds). The Challenge of Dermato-Epidemiology. at a population level. Adapted from HC. AtopicWilliams Dermatitis. In: high risk approach would only prevent 57% (120/120+90) of AD cases babies develop AD compared with 15% without such a family history, a a strong family history of atopy and 60% do not. If 30% of the high risk an average Western population where 40% of 1,000 adult coupleshave risk vslow risk prevention approach for atopic dermatitis. Fig. 3.Hypothetical example of the prevention yield from a high reduce adherencetoanintervention. such astransientstingingafteremollientapplicationcan floor.bathroom a on effects adverse minor Furthermore, even smallrisks,suchastheslippingonemollientsspilt will havealowthresholdforrejectinginterventionswith disease frommethotrexatetherapy, healthyindividuals with severe AD might accept the risk of nausea and liver is paramountinpreventionstudies. Whilst individuals proceeding tofullscaleevaluation(16). Assessing safety Testing acceptabilityofinterventionsisessentialbefore (15). trial) BEEP the in as life of year first the for daily population reach(suchasadvicetouseemollientsonce and use no soap) versus those that are likely to have wider a daytotheirchildfor2years,washonlyinsoftwater achieve alarger effect (suchasapplyingemollienttwice a trade-off betweenintensityofinterventionwhichmight whom willremainunknowntothem.Here,thereisoften prevent diseaseinaproportionofpeople–theidentity to undergo elaborate changes to their lives in order to terventions giventhathealthypeoplearebeingasked Another keyconsiderationistheacceptabilityofin house dustmiteinthehomeenvironmentisachievable. hough itmaybepossibleintime)whilstareduction cannot bedirectlymanipulatedinutero atpresent(alt mutations gene filaggrin example, For manipulated. be disease isathoroughknowledgeofriskfactorsthatcan Intervention. An essentialstepin thepreventionofany previously (14). and lowriskapproachesto AD preventionsuggested (13). community offers littletoeachparticipatingindividual” Rose to denote “a measure that brings large benefits to the is knownasthepreventionparadox–atermcoinedby phenomenon This child. their to benefit perceived little will belessmotivatedtoactonsomethingthatof parents as substantial, is modification change behaviour tion suchasallnewbornsischallenging,especiallyifthe population impact.However, tacklinganentirepopula is toonarrow, theinterventionmayhavealimitedoverall baby. The disadvantageisthatiftheselectedpopulation 382 illustrates thepossibletrade-offFig. 3illustrates betweenhigh H. C.WilliamsandJ.Chalmers Depicts - - - number switching from severe to moderate or mild to very severity canresultinlarge gainsin absolutetermsforthe (Fig. 4),evensmallshiftsinthereduction ofpopulation of AD prevalence in any population is skewed to the left important goal in AD prevention trials. Because the shape morbidity andresultinmosthealthcareusage)isalsoan more severeformsofthedisease(whichcausemost prevention ofdiseaseistheultimategoal, in the last year) at the age of2years (15). Whilst complete fulfilling the UK refinement of the Hanifin & Rajka criteria of outcome primary the assessing (those is AD year first is whythemainBEEP trialofemollientsusedduringthe ting AD oractively treatingnewmild AD (16,21). This whether the apparent benefit was assess due to to emollients preven difficult it making period, intervention the of might prevent AD, outcomes were assessed at the end two smallpreliminarystudiesthatsuggestedemollients ment effects frompreventioneffects. Forexample,inthe the interventionperiodbyaclearmargin toseparatetreat intermittent itchyskinconditionlastingatleast4weeks. Hanifin & Rajka criteria are used to denote a continuous or suggested a compromise whereby the UK refinement of the bly nottrue AD) arecommon ininfancy. Simpsonet al.(20) transient irritanteczematousdermatoses(whichareproba develop an eczematous rash is also fraught with problems as they day first the on baby a diagnosing in confidently AD case which, by definition, has not yet become chronic. Yet cumulative incidence, is problematic when defining a new Hanifin & Rajka criteria), whilst acceptable for measuring that “chronicrelapsingcourse”(amajorcriterionforthe study withoutreferencing the source.It is importanttonote that to unique definitions used 21 and (19), criteria Rajka & Hanifin the used 28 case, incident an define not did 27 AD usedinpreventionstudies.Of102includedstudies, of case incident an of definitions of review systematic an incidentcaseof AD. Simpsonetal.(18)undertooka a prevention study. There is a lack of research on defining trying topreventnew(incident)casesfromdevelopingin (prevalent cases)seektoreducediseaseseverity, one is Outcomes. Whereas clinical trials ofpeople with AD neglect” thatcanresultinresentfuldemoralisation(17). altruistic rewards to overcome the notion of “control materials withpatientsthatimplyactivemonitoringand and offer the opportunity to develop patient information studies thattestrandomisationandretentionareessential they don’t getthe“newactive”intervention.Feasibility equipoise iscarefullyexplained,parentsmaydropoutif the “notreatment”groupcanbechallenging,andunless a 50:50chancethattheirnewbabywillbeallocatedto with afamilyhistoryof AD totakepartinastudywith of placebo (e.g. inactive probiotics). Convincing parents form some or control, attention an defined), not often is AD preventiontrialsaretypically“standardcare”(which of aneffective activetreatment,controlinterventionsfor Comparator. Intheabsenceofaclearreferencestandard Ideally outcomeassessmentshouldbeseparatedfrom - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV and whoconsumemosthealthresources. reducing the absolute proportion with severe disease who suffer the most could have a huge impact on pushing more into subclinical disease and shifting thepopulationseverity of disease distribution to the left (red curve) populations. Even if atopicdermatitiscannot be prevented completely, withatopic number dermatitis (x-axis) versus in two hypothesized representation Fig. 4.Schematic of atopic dermatitis severity blinded, itisessentialtoincludesomeformofobjective lient applicationorinstallingawatersoftenercannotbe the fact that because many interventions such as emol and exploredintheanalysis. A secondchallengeliesin the home.Contaminationshouldthereforebemeasured professionals, suchasreductionofhousedustmitesin accessed byparticipantswithouttheneedforhealthcare problem iftheinterventionissomethingthatcanbeeasily particular a be can which beneficial), something on out in thecontrolgroup(becausetheythinkaremissing behaviours canincludecontaminationoftheintervention confound thestudyresultarerecorded.Sometimessuch team, andanypost-randomisationbehavioursthatcould regularity ofcontactandincentivesfromtheresearch that bothgroupsaretreatedinthesamewaytermsof thatcanaffectbehaviours important itis so risk, AD the interventiongroupcanresultindifferent ancillary and controlgroupsdifferently. Moreattentiongivento formance bias which results from treating intervention per is first The trials. prevention AD in consideration truly randomandconcealed,twobiasesrequirespecial before recruitmentstartsandensuringrandomisationis duce RCT biasessuchasregistrationofstudyprotocols Reducing bias.Inadditiontostandardapproachesre up individualsfromRCTs thatstartatbirthtoolderages. have alaterageofonsetaddingtothecostfollowing measured even in large studies, and conditions like asthma making it unlikely that beneficial effects will be precisely challenges, e.g.truefoodallergy hasalowincidence too. Measuringotheratopicdiseasespresenttheirown diseases these in seen are benefits whether evaluate to asthma andhayfever, AD preventionstudiesalsoneed related toother“atopic”diseasessuchasfoodallergy, an olderageisreallyabonus.Giventhat AD isclosely whether simplydelayingonsetofamiserablediseaseto outcome thatcanbeconsideredalthoughitisdebatable mild/subclinical disease. Time toonsetof AD isanother - - - duration ofexclusivebreastfeeding,dietarysupplemen hydrolysed formulamilk(extensiveandpartial),extended in thesamemeta-analysis.Interventionsincludeduseof data fromonetrialhadbeenincludedmorethanonce from the review on probiotics had to be re-analysed as considered methodologicallysound,althoughthedata participants mettheinclusioncriteria. All 7reviewswere Seven systematic reviews containing 39 RCTs and 11,897 cluded participantsbetweentheagesofzeroand18years. be combined,searchdatewithinthelast5years,andin reviews hadtoincludesomequantitativedatathatcould data wherepossibleusingCochranemethods.Included qualitative methodswereusedtocollateandcombine 2011 (searchdateupto August 2010). Quantitativeand undertook anoverviewofallsuchsystematicreviewsin AD prevention, a group(including the two authors) of Cochraneandnon-Cochranesystematicreviewson vention. The 2011 overviewofsystematicreviews ofprimarypre Primary prevention THE EVIDENCE more realisticindicatorofpopulationbenefit. sounding relativeriskreductionsinordertoprovidea as absolute risk reductions as well as the more impressive findings present should Studies bias. information of risk vestigators blindedtointerventionstatus)mitigatethe nal/infant interventions include exclusive breastfeeding, nal/infant interventionsinclude exclusivebreastfeeding, Also knownasthe“insideout” approach,ingestedmater Interventions thatare ingestedbymothers and/orinfants. The post2011 overviewera ventions with no evidence of benefit could still be useful. interventions hadlowprecision,indicatingthatsomeinter of the interventions tested, the risk estimates for most 0.78). Despite the lackof any convincingsignalsfor any reduced AD incidence by60%(RR0.40,95%CI0.21to that prolonged exclusive breastfeeding (at least 6 months) decreased atopy. Onenon-randomisedstudysuggested those that did, there was no evidence that the interventions truly atopicwasmissingfrommostofthestudies,andin developing those onwhether Data no prebiotics. were AD by 58%(RR:0.42;95%CI:0.21,0.84)comparedwith of beneficial bacteria in the gut) decreased AD incidence that prebiotics (ingested substances that favour the growth high riskof developing AD based on just one RCT found benefit for AD prevention. A subgroup analysis of those at None ofthepooledinterventionsshowedclearevidence defined. adequately rarely was risk although families, Participants werefromamixtureofhighandlowerrisk soy formula milks, along with prebiotics and probiotics. antigen avoidanceduringpregnancy, lactationorboth, tation withomega-3andomega-6oils,maternaldietary outcome assessment (e.g. visible eczema recordedby in In anattempttoreconciletheincreasingnumber Prevention ofatopicdermatitis Theme issue:Atopic dermatitis 383 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV certainty ofevidence (29). A more recentandwellcon low with but benefit of evidence clear no found diseases in womenandchildrenasameansofpreventingallergic 3 non-RCTs that addressed vitamin D supplementation review (searchdateJanuary2016)foundoneRCT and are involvedin AD development(28). A 2017systematic immune systemandskinbarrierfunction,bothofwhich the and function barrier skin on influence regulatory a Theme issue:Atopic dermatitis ploring the possible health benefits of yoghurt consumption the abilitytocombinestudies. Onesystematicreviewex leading toconsiderableheterogeneity whichimpactson various combinationsofthese andfordifferent periods, pregnancy, duringlactation, totheinfantafterbirthand ingredients, andtheycanbegiventothemotherduring as probioticsandprebioticsrefertoaverywiderangeof complicated is field The (32). momentum gathering is bacteria tothrive)orboth(synbiotics)canprevent AD thatencouragebeneficialdigestible foodingredients (non- prebiotics or microbiome) gut pro-inflammatory live bacteriaoryeaststhatcanrestoreadysfunctional RCTs forearlyonset AD (31). studies, butapossibleprotectiveeffect inthe3included found mixedresultsfor AD preventionfromobservational pregnancy during intake fish) from as (such acids fatty systematic review of omega-3 long-chain polyunsaturated supplementation in the primaryprevention of AD (30). A D vitamin infant of benefit clear no found RCT ducted and severity of between low vitamin D preventative interventionstemsfromtheassociation vention fromearlyintroductionofallergenic foods(27). RCT included in the review found no benefit for AD pre prevent eggandpeanutallergy. rance does not increase AD or food allergy risk, but may allergenic foodsinyearoneoflifetotryandinducetole review foundlimitedtostrongevidencethatintroducing allergy orasthma(moderateevidence)(26). The same of andtherisk complementary feedingsisstarted food AD, milk) foundnoclearevidencebetweentheageatwhich other foodsanddrinkscomplement human orformula observational studiesofcomplementaryfeeding(whereby AD prevention(25). A 2019systematicreviewofmainly for allergenic foods of avoidance maternal of benefit any of bias(24). A Cochranereviewof5trialsfailedtoshow milk feedingstudieshavebeenjudgedtobeathighrisk of half (23). a replicated Around be to needs that finding a function, lung not but eczema flexural self-reported in Belarus) thatpromotedbreastfeedingfoundareduction of AD (22).Onelarge clusterRCT (thePROBIT trialin studies suggeststhatitdoesnotappeartobeprotective a systematicreviewof16moderatequalityobservational ding (exclusive or prolonged) has clear benefits for infants, restrictions, anddietarysupplements. Although breastfee delay orearlyintroductionoffoodsotherthanmilk,dietary 384 The evidence that ingested probiotics (non-pathogenic The evidencethatingestedprobiotics(non-pathogenic Interest invitaminDsupplementationasapossible H. C.WilliamsandJ.Chalmers AD. Vitamin D is also known to have levels and increased incidence The one well-conducted The onewell-conducted - - - - - of probioticsupplementation(I (risk ratio0.78;95%CI0.68–0.90;I (risk of probioticson AD developmentfrom19probiotictrials arrived atsimilarconclusionsregardingaprotectiveeffect systematic reviewofdietduringpregnancyandinfancy high-quality and life. broader of A months 6 first the for are started during pregnancy and continued in the infant to conclude that benefits are only realised when probiotics authors the prompting benefit, such show not did natally mainly accountedbyfollow-uptime(I of studyheterogeneitywasalsoassessedandfoundtobe in the first two years of life rather than later (34). Sources pregnancy and infancy and in preventing AD developing those in whom probiotic supplementation occurred during those receivingLactobacillusandBifidobacterium, for for strongest were benefits that suggested analysis group review of house dust mite avoidance strategies (alone or review ofhousedustmiteavoidance strategies(aloneor and measurestoenhancethe skinbarrier. A systematic increasing exposuretoananthroposophic environment borne allergens such as house dust mite at the time of birth, tion and foodallergy have included attempts to reduce air main “outsidein”approachesforpreventing AD, sensitisa Interventions directed attheexternalskinsurface.The probiotics, whenandwhy(38). gate data – would better identify who benefits most from patient whotakepartinclinicaltrialsratherthanaggre that gathersandcombinesdatabelongingtoindividual data (IPD)meta-analysis – a type ofsystematic review recommendations (37). A high-quality individual patient and a stimulus for further studies rather than firm clinical evidence for benefit in allergic diseases was still uncertain probiotics across all humandiseasesconcludedthat the eity ofstudiesremains(36). A comprehensivereviewof for AD prevention, concerns regarding the heterogen nel has determined that there is a net benefit of probiotics whereby probiotics whereby 0.69; 95%CI0.58–0.82,Fig.5)(35). Analysis ofstudies AD preventionforprobioticscomparedwithcontrols(OR on effect beneficial a showed 2018) March to inception RCTs andonehighqualitycohortstudy, searchdatefrom systematic reviewthatpooled28studies(27goodquality imprecision, andindirectnessofstudyresults. alone wasweakduetohighriskofbias,inconsistency, for realising a protective benefit. The evidence of prebiotics than infantprobioticsupplementationthatwasimportant Subgroup analysissuggestedthatitwasmaternalrather risk reductionof44casesper1,000;95%CI20–64)(24). supplementation duringpregnancyand/orinfancy. Sub 0.81, 95% CI: 0.70–0.93) for those receiving probiotic and May2018showedareductionin AD incidence(RR 2019 of22pooledtrialspublishedbetweenJanuary2008 more contemporarysetting(33). A systematicreviewin and called for new studies thatevaluatedsuchfoodsina prevention, AD for benefit possible a suggested studies among infantsandtoddlers thatincludedtwooldercohort Although the World Allergy Organisation guideline pa were providedonlyprenatallyorpost were 2 53.5%). A moreextensive 2 61% and an absolute 61%andanabsolute 2 62.7%) and length 62.7%)andlength ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Journal ofClinicalDermatology. allergenic foods(peanut,milk,wheat, andegg)between3 week toage9months)and(iii ) consecutiveintroductionof no interventionwith(ii)skincare(oil-bathatleast5 days/ simultaneously. The PreventADALL trialcompares (i two ormoreinterventions are carriedoutandassessed study (PreventADALL), the Preventing Atopic Dermatitisand Allergies inchildren year oflifeinbabiesborntoatopicfamilies. The second, first the for emollient daily investigating is trial) (BEEP) studies (Barrier Enhancement forEczema Prevention these of first The 43). 21, 16, (15, AD prevent can birth been setuptotestthehypothesisthatemollientsfrom to familieswithatopy, twolarge preventionRCTs have born infants of skin the on emollients using from benefit the resultsoftwosmallpilotRCTs thatsuggestedalarge sitisation tofoodallergens occurs(41,42).Stimulatedby eczema developmentandmaybetheroutebywhichsen and foodallergy (40).Impairedskinbarriermayprecede of skinbarrierenhancementasameanspreventing AD benefits potential the on increased has interest function, barrier skin healthy for protein essential an – filaggrin loss-of-function mutationsinFLG,thegeneencoding the discoveryofastrongassociationbetween AD and ideas fornewpossibleprimaryinterventions(39).Since observational studiessofar, butareafruitfulsourceof environments suchasfarmanimalshavebeenlimitedto associations betweenearlyexposurestoanthroposophic the riskofdeveloping AD. Studiesthathavefoundstrong October 2014) concluded such modalitiesdo not decrease with allergen avoidance)thatincluded7RCTs (searchdate (I p suggests clear benefit (OR 0.69; 95% confidence interval (CI) 0.58–0.82; combining 28 evaluated studies. Although the summary odds ratio (OR) Forest a plot depicting meta-analysis that used a random effects model Fig. 5.Thepreventive effect of probiotics in atopic dermatitis. < 2

= 0.0001), there was considerable heterogeneity between the studies 53.6%) (33). Reproduced with kind permission from the American is a factorial trial – a trial whereby is a factorial trial – a trial whereby - ) the PreventADALL study(50). designs suchasfactorialtrialscurrentlybeingdonein replication, unlessthecomponentsareseparatedusing they canbecomeblackboxesthatarenotamenableto a “throwineverythingthatmightwork”strategyis produce more thanthe sum of the whole. The hazardof has a small beneficial effect, especially if they interact to possible tocombinemultipleinterventionseachofwhich ment onesimpleinterventiontoprevent AD, itmightbe approachesCombined . toimple itmightbeeasier Whilst also worthyoffurtherresearch(49). one thatislessfavourableforthedevelopmentof AD are that serve to influence the early skin microbiome towards Other directtoskinapproachessuchas“probioticcreams” care interventionforpreventionofatopicdisease)(47,48). planned meta-analysisconsortiumcalledSCiPAD (Skin most ofthesestudiesnowformpartaprospectively- prevent AD in high and low risk populations (46). Together, explore thepotentialofdifferent skinbarrierproductsto tion (44). At least10othersimilarpreventiontrialsthat found noevidenceofaprotectiveeffect ofeitherinterven study wasafactorialtrialofemollientandsynbiotics emollient onbarrier measurements (46). The second larger was not statistically significant, and there was no effect of that emollienttherapymayreduce AD incidence,butthis suggested study first The 45). (44, barrier skin the hance side effects inordertobenefitthe few. then 90%arguably undergo “overtreatment” andincur longed topical corticosteroids benefit from such therapy, 10% ofthosegivenearlyaggressive treatmentwithpro especially withregardsto safety. Ifforexample,only vention, secondary prevention should not be taken lightly, worth consideringinthiscontext(53).Likeprimarypre also are appears first when AD scratching from damage approaches suchasbehaviouralmethodstolimitskin disease chronicity(52).Othernon-pharmacological components, aphenomenonthatmightbekeytodriving duals developingautoimmunity towards their own skin treatment anti-inflammatory topical enhanced to assigned domly AD betweentheagesof7–13 weeksoldwillberan underway inJapan,which650infantswhodevelop notion. Onesuchstudyofaggressiveearlytreatmentis terms ofremissionordecreasingseverityisanattractive an attempttoalterthesubsequentcourseofdiseasein in appears first it when aggressively more TreatingAD Secondary prevention containing ingredientssuch as ceramide designedtoen published in2019,bothofwhichusedcomplexemollients are notavailableatthetimeofwriting. Two trialswere feeding strategies. Results of BEEP and PreventADALL and 4 monthsofage(iv)bothskincomplementary scratching canleadtoacascadethatresultsinindivi Poorly controlleddiseaseresultinginskindamagefrom preventing foodallergy andreducing AD severity(51). or conventional Prevention ofatopicdermatitis treatment with theaim of Theme issue:Atopic dermatitis 385 ------

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Atopic dermatitis importance of AD inadults,pointingoutthataround one years oflife.Recentstudies havedrawnattentiontothe is with good reason as AD typically starts in the first few Most oftheevidencediscussed relatestoearlylife. This What aboutadult-onsetatopic dermatitis? for personalisedmedicine. often appearsarandomprocessoffers excitingprospects what in flares of prediction Better (62). sufferers of AD become keyconsiderationsinimprovingqualityoflife embracing theconceptofoveralldiseasecontrolhave and flares of prevention condition, relapsing chronic a in reducinglaterdiseaseseverity(61).Giventhat AD is effect beneficial small a have may disease early for tion Another reviewsuggestedthat Vitamin Dsupplementa keep control”asillustratedschematicallyinFig.6(60). tive therapyisinitiated–theconceptof“getcontrolthen important to consider induction ofremission before proac (59). When considering prevention of flares, it is equally weekly topical tacrolimus (RR 0.78, 95% CI0.60–1.00) CI 0.38–0.55) with more modest reductions in flares with risk of further flares by around half (relative risk 0.46, 95% Schmitt et al. showed that topical fluticasone reduced the the number of subsequent flares (58). A meta-analysis by stabilised. This hasbeenshowntodramaticallyreduce consecutive daysperweek)forthosewhohavebeen years hasbeentheconceptofproactivetreatment(two important advancesindiseasetreatmentoverthelast30 cations andsequelae.Inrelationto AD, oneofthemost treatment, preventionofdeterioration,diseasecompli In itsbroadestsensetertiarypreventionreferstodisease Tertiary prevention mite wasstoppedduetolackofbenefit(57). with AD who were sensitised to grass and/or house dust of levocetirizineforthepreventionasthmainchildren RCT fromETAC calledtheEPAAC studyexploredtheuse in asubsequentCochranereview(55,56). A follow-up treatment of AD – an observation that has been confirmed either, throwingdoubtonthe value of anti-histamines in the severity of AD wasnotreducedinthecetirizinegroup Although urticaria rates were less in the intervention group, that asthmacouldbepreventedbysuchanapproach(54). its anti-histamineeffect. The ETAC studydidnotshow it mightinhibiteosinophiltrackingtothelungsaswell or placebofor18months.Cetirizinewaschosenbecause between 1and 2years ofage were randomised to cetirizine study (ETAC) whereby795childrenwithnewonset AD was thebasisofEarly Treatment ofthe Atopic Child aconcept asthma.Such as such development ofconditions the prevent can identified first is AD when initiated are secondary preventionof AD iswhetherinterventionsthat but anotherimportantquestiontoconsiderinrelation of earlyinterventionsthatprimarilyaimtoprevent AD, lergy and asthmahave only been considered inthe context 386 So far, prevention of related diseases such as food al H. C.WilliamsandJ.Chalmers - - - - the JournalofAllergyandClinicalImmunology. hence better overall disease control. Reproduced with kindpermission from approach results inmore disease state being pushed and into asubclinical When contrasted against moretraditional reactive approaches,theproactive Evidence-Based Dermatology “get control and keep control” approach). of two consecutive days of topical treatment (also known as the Centre of topical treatment followed by prevention of disease flaresprinciple of inducing remission of blast of atopic dermatitiswithan initial with weekly pulses dermatitis. A more subtleinterpretation of tertiary prevention isthe Fig. 6.The concept of getting control then keepingcontrol in atopic to emerge onbarrierenhancement asastrategyfor AD at high risk of developing allergy. New evidence is likely infants athighriskofdeveloping allergy; and(iii)infants having an allergic child; (ii gests usingprobioticsin:(i from preventionofeczema. The WAO guidelinepanelsug likely net benefit from using probiotics resulting primarily Organisation guidelinepaneltodeterminethatthereisa populations aroundtheworld, prompting the World Allergy different in tested when safety good and benefit modest the useofprobiotics. Probiotic usehasconsistently shown to the lack of positive findings forAD prevention has been not atopic in the scientific sense (66). The main exception fact that around halfofpeoplewith“atopic”dermatitis are rather fruitlessobsessionwithallergic factorsdespitethe new insight.Past research hasalsobeenconcernedwitha interventions are often tested again and again with little tend toberepeatedratherthanlearned,andthesameold tion level.Errorsinthedesignandreportingofstudies interventions thatarelikelytobeeffective atapopula AD havethrownupveryfewsignalsofsimple,safe The lastfewdecadesofresearchintotheprevention CONCLUSIONS needs tobereplicated(65). paradoxically increased with niacin intake, a finding that epidermal waterloss.Instead,itfoundthatadult AD was adult AD sinceniacinhasbeenfoundtodecreasetrans men postulatedthatniacinintakemightprotectagainst for preventionstudies(64).Onestudyof67,643USwo factors foradult-onset AD inordertoidentifycandidates first time in adulthood (63). Less is known about the risk in 4ofthosewithadult AD appeartodevelopitforthe ) pregnant women at high risk of ) pregnantwomenathighrisk of ) women who are breastfeeding ) women who are breastfeeding - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 10. REFERENCES Assessment Programme. the UKNationalInstituteforHealthResearch Technology Enhancement forEczemaPrevention(BEEP)studyfundedby interest: BothauthorsareinvolvedintheBarrier of Conflicts ACKNOWLEDGEMENT otherwise bedestinedtoalifewith AD. order tobenefitfuturegenerationsofchildrenwhomight between cautious recommendation andimplementation in patient datameta-analysismayhelptobridgethegap analysis ofthe28orsoexistingstudiesusingindividual refined more a conducting and stopping trials, probiotic than theinfantenvironment.Ratherconductingmore (69). The foetal environment may be a better place to focus dysfunctional immuneresponsecouldbeexploredfurther lergic sensitisation,derivativeproductsthatswitchoff the inverse relationshipbetweenhelminthexposureandal the Given considered. be might substances beneficial harmful exposures,explorationofincreasingpotentially for AD (67,68).Ratherthanconsideringreductionof specific and internal factors that make up the “exposome” place to start and by reconsidering the host of non-specific, allergic diseasesconductedbyGenunietetal.(67)isagood sive overviewofsystematicreviewsepidemiology interventions thatdonotlookpromising. The comprehen risk factorsratherthandoingmorestudiesonthesame SCiPAD prospectivelyplannedmeta-analysis. prevention overthenext5years,especiallythrough 9. 8. 7. 6. 5. 4. 3. 2. 1. In terms of future research, it is worth exploring new In termsoffutureresearch,itisworthexploringnew Woolf SH.Thepowerof prevention andwhatitrequires.JAMA Global Resource for Eczema Trials (GREAT Database), Centre Nankervis H,ThomasKS, Delamere FM,Barbarot S, Rogers Foisy M,Boyle RJ, ChalmersJR,SimpsonEL,Williams HC. reviews systematic Based Centre Dermatology of Evidence Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, AB. R, Hill Doll and Smoking of carcinoma the preliminary lung; Brown SJ. Molecular mechanisms in atopic eczema: insights Quinn SC, Jamison AM, Freimuth VS. Measles outbreaks and Kim JE, Kim HS. microbiome of the skin and gut in atopic der 2008; 299:2437–2439. GD4/Home/Index.php –accessed 14th August 2019. of EvidenceBased Dermatology, www.greatdatabase.org.uk/ for eczema. Programme Grants for Applied Research 2016. NK, Williams HC. Scoping systematic review of treatments Evid Based Child Health 2011; 6: 1322–1339. children: an overview of Cochrane and non-Cochrane reviews. Overview of Reviews The prevention of eczema in infants and 14th August 2019. cebd/resources/eczema-systematic-reviews.aspx, accessed on eczema https://www.nottingham.ac.uk/research/groups/ munol 2004; 113:832–836. World Allergy Organization, October 2003. J Allergy Clin Im use: Report of the Nomenclature Review Committee of the Lockey RF,, etal.Revised nomenclaturefor allergyfor global report. gained fromgenetic studies. JPathol 2017; 241: 140–145. novel management strategies. J Clin Med2019;8:pii: E444. finding and pathophysiology the understanding (AD): matitis Immunother 2019;22:1–5. and strategies for addressing vaccine hesitancy. Hum Vaccin public attitudestowards vaccine exemptions: somecautions BMJ 1950; 2:739–748. - - - - 20. 19. 18. 17. 16. 15. 14. 13. 12. 31. 30. 29. 28. 27. 26. 25. 24. 23. 22. 21. 11. Williams HC, BurneyPG,Pembroke HC, Williams AC,Hay RJ. TheU.K. Working Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Simpson EL,Keck LE,Chalmers JR,Williams HC.Howshould Torgerson DJ, B. Sibbald What trials. controlled Understanding MJ Cork KS, Thomas JM, Hanifin JR, Chalmers EL, Simpson EJ, Mitchell RH, JR, Haines Chalmers Thomas KS, Brown SJ Ridd Williams HC. Atopic dermatitis. In: Williams HC, Strachan DP Rose G. Strategy of prevention: lessons from cardiovascular Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The Best KP, Gold M, Kennedy D, Martin J, Makrides M. Omega-3 Rueter K, Jones AP, Siafarikas A, Lim E-M, Bear N, Noakes PS, Yepes-Nunez JJ, Brozek JL, Fiocchi A, Pawankar R, Cuello- Palmer DJ. VitaminD andthedevelopment of atopiceczema. Perkin MR, Logan K, Tseng A, Raji B, Ayis S, Peacock J, et al. Obbagy JE, EnglishLK,Wong YP, Butte NF, Dewey KG,Fleischer Kramer MS, Kakuma R. Maternal dietary antigen avoidance V,Garcia-Larsen Ierodiakonou D, K,CunhaS, Jarrold Chivinge Flohr C, Henderson AJ, Kramer MS, Patel R, Thompson J, Gungor D, Nadaud P, LaPergola CC, Dreibelbis C, Ping Wong YP, Horimukai K,MoritaNaritaM,Kondo M,Kitazawa H,Nozaki Gordon RS, Jr. An operational classification of disease preven Party’s Diagnostic Criteriafor Atopic Dermatitis. III.Indepen Acta Derm Venereol 1980;Suppl92: 44–47. 2012; 130:137–144. review ofprimaryprevention studies.JAllergyClinImmunol an incident case of atopic dermatitis be defined? A systematic is a patient preferencetrial?BMJ 1998;316:360. Allergy ClinImmunol2014; 134: 818–823. rier from birth offers effective atopic dermatitis prevention. J McLean WHI,etal.Emollientenhancementoftheskinbar protocol for a randomised controlled trial. Trials 2017; 18: 343. for preventing atopiceczema inhigh-riskchildren(TheBEEPtrial): life of year first the during emollient of application body M, etal.Effectiveness andcost-effectiveness of dailyall-over- CRC Press Inc., 1997, p. 125-144. (editors). The Challenge of Dermato-Epidemiology. Boca Raton, disease. BrMedJ1981; 282: 1847–1851. ACP journal club1995;123:A12–13. akey question: clinical well-built decisions. toevidence-based 107–109. tion. Public health reports (Washington, DC: 1974) 1983; 98: trials. AmJClin Nutr 2016; 103: 128–143. analysis of observational studies and randomized controlled outcomes in the offspring: a systematic review and meta- long-chain PUFA intake during pregnancy andallergic disease 1012–1020.e1012. and immune development. J Allergy Clin Immunol 2019; 143: eczema with associated exposureis DirectinfantUVlight et al. randomized studies. Allergy 2018; 73: 37–49. allergy prevention: Systematic review ofrandomized and non- ZhangeY, C, Garcia primary in Dsupplementation Vitamin etal. J Clin Med 2015; 4:1036–1050. fed infants.N Engl J Med 2016; 374: 1733–1743. Randomized trial of introduction of allergenic foods in breast- review. Am J ClinNutr2019;109:890s–934s. dermatitis/eczema, asystematic rhinitis: asthma,andallergic DM, et al. Complementary feeding and food allergy, atopic Rev 2012: Cd000133. treating atopicdiseasein the child.Cochrane Database Syst pregnancy during or lactation, or both, for preventing or and meta-analysis. PLoS medicine 2018; 15: e1002507. risk of allergic or autoimmune disease: A systematic review J, Robinson Z, et al. Diet during pregnancy and infancy and Pediatr 2017:172; e174064. age 16years: follow-up ofthePROBITrandomized trial.JAMA breastfeeding onasthma,lungfunction, andatopiceczema at Rifas-Shiman SL, et al. Effect of an intervention to promote 772s–799s. the lifespan: asystematicreview. AmJClinNutr2019;109: andasthmathroughout dermatitis, atopic rhinitis, allergic Terry N, et al. Infant milk-feeding practices and food allergies, 134: 824–830e826. velopment of atopic dermatitis. J Allergy Clin Immunol 2014; M, etal.Applicationofmoisturizer toneonatesprevents de dent hospitalvalidation. Br J Dermatol 1994;131:406–416. Prevention ofatopicdermatitis Theme issue:Atopic dermatitis 387 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 51. 49. 48. 46. 41. 38. 37. 34. 50. 47. 42. 39. 35. 43. 40. 36. 44. 45. Theme issue:Atopic dermatitis 32. 388 33. Yamamoto-Hanada K,Kobayashi T, Williams HC, Mikami, M, Totte J, deWitJ, Pardo L,SchurenF, van Doorn M,Pasmans S. Kelleher MM, Cro S, Cornelius V, Axon E, Lodrup Carlsen KC, Lowe A,SuJ, Tang M,LodgeCJ, MathesonM,AllenKJ, et Kelleher JO, A,Hourihane M,Dunn-Galvin Murray D, Campbell Riley RD, LambertPC,Abo-Zaid G.Meta-analysis of individual Rondanelli M, Faliva MA, Perna S, Giacosa A,Peroni G, Castel Yin DG, He Z, Duan XY, Fan FX, Liao XB, Wang QC. Zhongguo Lodrup Carlsen KC, Rehbinder EM, Skjerven HO, Hauger Carl Kelleher M,CroS. SCiPAD (Skincareintervention forpreven Broeks SA, Brand PL. Atopic dermatitis is associated with a Campbell BE,LodgeCJ, LoweAJ, Burgess JA, Matheson MC, Li L, Han Z, Niu X, Zhang G, Jia Y, Zhang S, et al. Probiotic Rehbinder EM,WingerAJ, LandroL,AsarnojA,Berents TL, Loset M,BrownSJ, Saunes M,Hveem K.Geneticsof atopic Fiocchi A,Pawankar R,Cuello-GarciaC,AhnK,Al-Hammadi McClanahan D, Wong A, Kezic S, Samrao A,Hajar T, HillE,et Dissanayake E, Tani Y, Nagai K, Sahara M, Mitsuishi C, Togawa Szari S, Quinn JA. Supporting a healthy microbiome for the Donovan SM, Rao G. Health benefits of yogurt among infants 2018; 73: 2063–2070. and ALLergies in Children – the PreventADALL study. Allergy sen M, Fatnes TA, Fugelli P, et al. Preventing Atopic Dermatitis 2020; 2:CD013534. venting eczema and food allergy. Cochrane Database Syst Rev ipd_meta-analysis.pdf 2019. cochrane.org/files/public/uploads/cs_cochrane_jan_2019_ tion ofatopicdisease)https://skin.cochrane.org/sites/skin. and Immunol 2019;180:202–211. randomized, non-treatment controlled trial. Int Arch Allergy matitis orfood allergy innewborninfants:A2xfactorial, tology 2019; 235: 355–364. 8: 521–543. now? A review of existing meta-analyses. Gut Microbes 2017; lazzi AM.Usingprobioticsinclinicalpractice: Wherearewe Probiotics. The World Allergy Organization Journal 2015; 8: 4. versity Guidelines for Allergic Disease Prevention (GLAD-P): tion reviews 2019; 77: 478–486. Saito-Abe M,Morita K,etal. Earlyaggressive intervention for trial (MAAS trial).Trials 2017; 18: 404. the microbiome:studyprotocolforarandomized controlled dermatitis and the effect on steroid use, disease severity and Targeted anti-staphylococcal therapy atopic in endolysins with Skjerven HO, etal. Skincareinterventions ininfantsforpre barrier improvement strategy. BMJ Open 2019;9:e024594. infants withafamilyhistoryof allergic diseaseusinga skin prevent atopic dermatitis, food allergy and sensitisation in al. PEBBLES study protocol: a randomised controlled trial to 2015; 135:930–935.e931. and predicts atopic dermatitis at 1 year. J Allergy Clin Immunol transepidermal water loss at 2 days and 2 months predates le, McClean WHI, et al. Skin barrier dysfunction measured by 340: c221. data: participant rationale, conduct, and reporting. BMJ 2010; Dang Dai Er Ke Za Zhi 2019; 21: 82–88. Paediatrica 2017;106: 485–488. Acta inchildren. ofpolysensitisation risk increased fivefold Allergy 2015; 45: 744–757. of atopy: asystematicreviewandmeta-analysis. ClinExp Dharmage SC.Exposureto‘farming’ andobjective markers Clin Dermatol 2019; 20: 367–377. and children:asystematicreview meta-analysis. Am J supplementation forprevention ofatopicdermatitisininfants Br J Dermatol 2019;181:218–219. Carlsen KH,etal.Dry skinand skinbarrierinearlyinfancy. dermatitis: FromDNA sequencetoclinicalrelevance. Derma S, Agarwal A,etal.World AllergyOrganization-McMasterUni Venereol 2019;33:2087–2094. of atopic dermatitis in high-risk infants. J Eur Acad Dermatol and filaggrin-associated amino acids for the primary prevention Arandomizedal. ceramide with ofanemollient trial controlled Y, et al. Skin care and synbiotics for prevention of atopic der 2019; 57: 286–293. primary prevention of eczema. Clin Rev Allergy Immunol and toddlers aged 4 to 24 months: a systematic review. Nutri H. C.WilliamsandJ.Chalmers ------59. 58. 57. 56. 55. 54. 53. 52. 69. 68. 67. 66. 65. 64. 63. 62. 61. 60. Schmitt J, von Kobyletzki L, Svensson A, Apfelbacher C. Efficacy Wollenberg A, Ehmann LM. Long term treatment concepts and https://clinicaltrials.gov NCT00152464 – Prolongation of the of Diepgen TL. infants with Long-term treatment cetirizine with Matterne U, Bohmer MM, Weisshaar E, Jupiter A, Carter B, Warner JO. Adouble-blinded,randomized, placebo-controlled Bewley A. Habit reversal therapy quickly and significantly con Tang TS, Bieber T, Williams HC. Does “autoreactivity” play a Flohr C, Quinnell RJ, Britton J. Do helminth parasites protect Stefanovic N, Flohr C, Irvine AD. The exposome in atopic Genuneit J, AM, Apfelbacher Seibold CJ, Konstantinou GN, Flohr C,Weiland SK,Weinmayr G,Björkstén B, Bråbäck L, Drucker AM, Li WQ, Park MK, Li T, Qureshi AA, Cho E. Niacin Abuabara K, Ye M, McCulloch CE, Sullivan A, Margolis DJ, Lee HH, Patel KR, Singam V, Rastogi S, Silverberg JI. A sys Chalmers JR, Thomas KS, ApfelbacherC, Williams, HC, Prin Hattangdi-Haridas SR, Lanham-New SA, Wong WHS, Ho Tang TS, BieberT, Williams HC. Aretheconceptsofinduction and tolerability of proactive treatment with topical corticoste 253–260. proactive therapy for atopic eczema. Ann Dermatol 2012; 24: NCT00160563. Published2005.Accessed16thAugust, 2019. in young atopicchildren.https://clinicaltrials.gov/ct2/show/ of levocetirizine (LCTZ) in preventing the onset of asthma safety and efficacy the evaluate to study months 36 – ren) EPAAC™ trial (The Early Prevention of Asthma in Atopic Child Allergy Immunol2002;13: 278–286. placebo-controlled trial(theETAC trial)over 18months.Pediatr atopic dermatitis: a multi-country, double-blind, randomized, 2019; 1:Cd012167. to topical treatmentfor eczema. Cochrane Database Syst Rev Apfelbacher CJ. Oral H1antihistaminesas‘add-on’ therapy 929–937. posttreatment follow-up. JAllergyClinImmunol2001;108: with atopic dermatitis: 18 months’ treatment and 18 months’ trial ofcetirizineinpreventing theonsetof asthmainchildren Br J Dermatol 2018;178:584–585. tributes to the management of children with atopic eczema. 1209–1215.e1202. role inatopicdermatitis?JAllergyClinImmunol2012;129: controlled trial. Clin transl allergy 2018; 8: 47. group controlled trial (PACI Study)-protocol for a randomized lergy: a multicenter, investigator-blinded, randomized, parallel 39: 20–32. 2009; Allergy Exp Clin atopy disease? against andallergic dermatitis. Allergy 2020; 75: 63–74. in AllergyEpidemiology. Allergy2017; 72: 849–856. Koplin JJ, Grutta SLa, et al. Overview of Systematic Reviews 121: 141–147.e144. Allergies in Childhood Phase Two. J Allergy Clin Immunol 2008; eczema: findings from the International Study of Asthma and Brunekreef B, et al. The role of atopic sensitization in flexural Allergy ClinImmunol2017; 139: 2020–2022.e2022. intake and incident adult-onset atopic dermatitis in women. J through midlife. J Allergy Clin Immunol 2019; 144: 710–719. from 2 nationally representative British birth cohorts followed Strachan DP, et al. Clinical onset of atopic eczema: Results 2019; 80: 1526–1532.e1527. notype ofadult-onset atopicdermatitis.JAmAcadDermatol tematic reviewandmeta-analysis oftheprevalence andphe Dermatol 2018;178:e332–e341. atopic eczema/dermatitis clinicaltrials(HOMEinitiative). Br J international fifth consensus meetingtoharmonize coreoutcomemeasuresfor the from Report al. et PI, Spuls CA, sen and children. Nutrients2019; 11: E1854. dermatitis: a systematic review and meta-analysis in adults d supplementation on disease severity in patients with atopic vitamin of effects and deficiency D Vitamin AL. Darling MHK, 1615–1625.e1611. dermatitis clinically useful? J Allergy Clin Immunol 2014; 133: of remission and treatment of subclinical inflammation in atopic J Dermatol 2011; 164: 415–428. review and meta-analysis of randomized controlled trials. Br roids and calcineurin inhibitors for atopic eczema: systematic infantile atopic dermatitis to prevent development of food al ------