University of Dundee

Patients with atopic with loss-of-function mutations show good but lower responses to immunosuppressive treatment Roekevisch, E.; Leeflang, M. M. G.; Schram, M. E.; Campbell, L. E.; Irwin McLean, W. H.; Kezic, S. Published in: British Journal of

DOI: 10.1111/bjd.15191

Publication date: 2018

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Citation for published version (APA): Roekevisch, E., Leeflang, M. M. G., Schram, M. E., Campbell, L. E., Irwin McLean, W. H., Kezic, S., Bos, J. D., Spuls, P. I., & Middelkamp-Hup, M. A. (2018). Patients with with filaggrin loss-of-function mutations show good but lower responses to immunosuppressive treatment. British Journal of Dermatology, 177(6), 1745-1746. https://doi.org/10.1111/bjd.15191

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Download date: 25. Sep. 2021 with WileyTermsandConditionsforSelf-Archiving. form athttp://dx.doi.org/10.1111/bjd.15191.Thisarticlemaybeusedfornon-commercialpurposesinaccordance mutations showgoodbutlowerresponsestoimmunosuppressivetreatment',whichhasbeenpublishedinfinal his isthepeerreviewedversionoffollowingarticle:'Atopicdermatitispatientswithfilaggrinloss-of-function Accepted DateAccepted 26-Oct-2016 : This article isThis article by protected copyright. All rightsreserved. 10.1111/bjd.15191doi: thisarticle differences as to lead between the of thisversion cite and Version Record.Please copyediting, paginationbeen throughthe andproofreadingtypesetting, process,may which This article acceptedhas been for publication andundergone fullpeer review buthasnot Bos., P.I.Spuls.,M.A. Middelkamp Hup have declared that they have no conflict of interest. The rest ofthe authors, Roekevisch.,E. Mariska Leeflang., M.G. M.E. Schram.,L.E. Campbell., S. Kezic., J.D. W.H.I McLean hasfiled patents ongenetic testingtreatment and development related to the filaggrin gene. Disclosure of potential conflictinterest: of Funding: none [email protected] +31F 20 5669152 T +3120566 2488 1100 DD Amsterdam,The Netherlands P.O. Box 22700, University of Amsterdam Academic Medical Center, Department ofDermatology, A0-229 Roekevisch,E. MD Corresponding author 4 The Netherlands 3 Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands 2 Netherlands 1 type Article :Research Letter Revised Date:12-Oct-2016 DateReceived 01-Aug-2016 : Centre forDermatology and Genetic Medicine, University of Dundee, Dundee, UnitedKingdom Academic Medical Center, Coronel Institute of Occupational Health, Meibergdreef Amsterdam, 9,1105 AZ Academic Medical Center, Department ofClinical Epidemiology, Biostatistics andBioinformatics, AcademicMedical Center, Department ofDermatology, Meibergdreef 9, 1105 AZ Amsterdam, The Accepted ArticleRoekevisch E. Atopic dermatitis patientswith filaggrin loss- 1 , M. M. M.G. Leeflang :

2

, M. E. SchramM. P.I. Spuls immunosuppressive treatment. 1 , M.A. Middelkamp-Hup of 1 , L. , CampbellE. -function mutations show good but lower responses to 4 , W.H. Irwin McLean 1

4 , S. Kezic, S. 3 ,D. J. Bos 1 , This article isThis article by protected copyright. All rightsreserved. (lme4package in R(version 3.2.5) SCORAD divided significant difference betweentr I FLG randomization methotrexate (MTX) orazathioprine (AZA) mutations in whether between Filaggrin ( Research Letter VAS SD SCORAD50 SCORAD POEM PGA OSI NMF Non MTX LRM IGA FMG FLG EASI AZA AD Abbreviations used Immunosuppressive Atopicdermatitis, Atopiceczema, Filaggrin, Skinbarrier, Mutation, Azathioprine, Methotrexa Key words n then original RCT both MTX andAZA induced significant reduction

Accepted Article

-

genotype status (R501X, 2282del4, R2447X, S3247X and 3321delA mutations).

FMG

them

,

FLG FLG whi

FLG)

chwas obtainedat ba patients withsevere ADparticipat

mutations influence immunosuppressive treatment outcome inAD, westudied the effectof mutations and treatment intoa

mutations are a strong risk factor to developatopic dermatitis (AD).However, relationship the buccal mucosa swabswere collectedfrom ;

Visual Analogue Scale Standard Deviation I SCOring Atopic Dermatitis Patient Oriented Eczema Measurement Patient Global Assessment Online SupportingInformation Natural MoisturizingFactors (NMF) Non Filaggrin MutationGroup Methotrexate Linear Regressio Investigator Global Assessment Filaggrin Mutation Group Filaggrin gene Eczema Area and Severity Index Azathioprine AtopicDermatitis

mprovement of SCORAD withatleast 50%

FLG

treatment

mutation group (FMG) and non

, Treatment, outcome

eatments n Modeln . All SCORADvalues were obtainedfrom patients receivingsystemic

seline,

outcome in AD has notbeen thoroughlystudied. To week 2,4,8,12 and 24

.

(1 during a

)

We therefore pooled ing

in a single blinded randomized control 24weeks

- FMG.

36 of36

treatment regimen The primary outcome parameter wasthe

the and

all

s 42

analysed in SCORAD at 12 and 24 weeks patients together RCT patients

as repeated measure . (1 )

(86%) Two ye for thissub ledtrial (RCT) w to determine the ars after investigate te, ments - , study

without a

ith

and FLG

This article isThis article by protected copyright. All rightsreserved. improvement Acceptedexplain levels will stillpresent be in the end because oftheir genetically caused filagg of their AD duethe to immunosuppression,buttheir barrier functionimpairment and reduced filaggrinprotein of normal filaggrin proteinlevels inflammatoryinfiltrate will be abrogated, therefore allowingskin barrier restoration andlikely establishment decreasing comparable in the FMGand non study FLG barrier impairment inAD patients withsevere skininflamma AD patients witha It isinterestingspeculate to on comparable between groups inthe course of 24 weeks (Mann Whitney U te (FMG 83.8 gram, non immuno non from data analysis treatment ( non P <0 Article FMG decreasedwith showedimprovement of SCORADat week 24compared to baseline (OSI FLG status. For details The mainlimitation of this sub included variable. Astreatmentregimen (AZA orMTX)did not influence treatment success inFMG vs. non correctedfor age asa possible confounder and age was includedin the models asa potential confounder in the FMG vs. non the at week 24 were under topical immunosuppressive treatment alone. immuno FMG, week 4) in three patients. immunosuppressive treatment

- - mutations and correlated withthe SCORAD. mutation FMG FMG (P=0.02) andthe .01 (1 ) , the

). su suppressive treatment alone. One patient (FMG) stopped systemictreatment at week 12, we in the mixed models

Ho , ppressive treatment (FMG as a inflammation byimmunosuppressive treatment,downregulation of

Figure 1

expect lower therapeutic wever s

stagnates duringthe treatmentperiod and and their last scores, obtainedwithin weeks 2 ofstopping systemictherapy, were under topical

w significan ere

Two patients stoppedsystemic treatment because of adverse events see , the, FMG showed

, FLG thatinitiation at of the study ). in the course of 24 weeks,

found in 13

20.7 - When FMG 90gram, P=0.26) and AZA ( FMG 837.5 gram, non Methods se

- mutation. Th2 cytokines can down FMG (P<0.01,online supportin t difference was points

improvementin SCORADof patientsthe in FMG stagnated during the course ofthe the three SCORAD values as covariates visit, mutation, ageand interactionan term for visit *mutation.

- responses in theFMG

studywas the small sample size andthe inabilityto randomize on mechanisms underlying with or withouttopical -

patients ( (95%CI in the in the non FMG,which is supported similarby meanSCORAD in both groups ction atthe a trend towards 132 14.7 not reached (P=0.075) gram, non 36 - FMG. % - 26.6, P< 0.01) OSI

, the FMG

OSI

(4 level

) (

In contrast, FMG patients will also experience improvement As only patients withsevere were AD includedin our www.brjdermatol.org

Tabel - . FMG in the course over 24weeks

s less improvement inthe course of 24 weeks obtained under topical treatment alone were excluded In conclusion, g informationg (OSI)

of skin barrier impairmentandinflammation immunosuppressi

lower response to immunosuppressive showedless improvementin SCORAD

E2

- 120 regulate filaggrin protein expression

) and tion .

Every gram, . 31.3 pointsthe in non seems Median dosages

bothgroups showed a single patient, both inFMGand non

P=0.51) As themeanage was significantly higher

similar withand inpatients without ) Figure Figure ve treatment, except for three values , ,

Table E1 and our previous publication. st).

- and rin protein FMG 825 gram P=0.75) were

E1 FLG , and why median ) of topical . The ), all analyses were expression bythe

- (FMG,week 2; non FMG FMG (95%CI

mean deficiency.This may

dosages of MTX

significant the initial

co SCORADin the (3 treatment )

mpared tothe - and FLG FMG compared to and . W were 26.3

skin mutation he , values

we ( 1 n - - ) FMG,

36.2,

in -

This article isThis article by protected copyright. All rightsreserved. F 4 The Netherlands 3 Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands 2 Netherlands 1 Maritza A. Middelkamp Phyllis I.Spuls Jan D. Bos Sanja Kezic H. IrwinW. McLean Linda CampbellE. Mandy E. Schram Mariska M.G.Leeflang Evelien Roekevisch treatment success arenecessaryto confirm these findings. course of the treatmen immunosuppressive treatment success in se i mprovement in

igure1. AcademicMedical Center, Department ofDermatology, Meibergdreef 9, 1105 AZ Amsterdam, The AcceptedCentre forDermatology and Genetic Medicine, University of Dundee, Academic Medical Center, Coronel Institute of Occupational Health, Meibergdreef 9,1105 AZ Amsterdam, Academic Medical Center, Department ofClinical Epidemiology, Biostatistics and Article

Mean reduction (SD) inSCORAD from baseline till weeks,24 adjusted age for 1 , MD, 3 , PhD,

1 , MD,, PhD

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Dundee, UnitedKingdom may have anegative impact on n Bioinformatics, FLG

mutation status and

This article isThis article by protected copyright. All rightsreserved. 2013;168(2):326 BrJ Dermatol dermatitis. irritant contact occupational atopicder of 38(4):441 2006; Nat Genet dermatitis. atopic loss 162(3):472 2010; JDermatol genetics. Br population and mutations 2008; BrJ review. Dermatol asystematic dermatitis: atopic 170(3):617 2014; JBr Dermatol mutation andfilaggrin inflammation 2007;120(1):150 Clin Immunol JAllergy skinexpression. filaggrin dermatitis ofatopic modulation 9):1285 Sci2009;122(Pt Cell J disease. and skin barrierfunction 128(2):353 eczema. atopic forsevere azathioprine versus methotrexate of References weeks comparedto non SCORAD compared to baseline,however representsgray an overlap between groups. r Data includes all data points. combined Differences in outcomes between the filaggrin mutation group (FMG, n=13)and non Accepted Articleepresents - of - function variants of the epidermal barrier protein filaggrin are a major predisposing factor for for factor predisposing are amajor filaggrin barrierprotein epidermal ofthe variants function

systemic and topical immunosuppress

the (1) (1) -

(8 (7 (6) (5) (4) (3) (2) 9. matitis and loss matitis and

) )

Schram ME, Roekevisch E, Leeflang MM, Bos JD, Schmitt J, Spuls PI. J, Spuls JD,Schmitt MM, Bos Leeflang E, Roekevisch ME, Schram 95

% Visser MJ, Landeck MJ,Landeck L Visser AD,Terron Palmer CN, Irvine of spectrum atopic eczema: vulgarisand inichthyosis mutations M.FLG Akiyama Spuls PI. JD, MM,Bos ME,Leeflang EE,Schram Brenninkmeijer skin TSevere Biro et al. A, B,Kapitany K,NagyG, Irinyi G, Gaspar Mocsai Kim BE, MD,Howell in frontline: role inthe Filaggrin McLean WH. IrvineAD, C, Sutherland A, Sandilands

confidence interval for themean reduction in SCORADin the FMG andthe non - FMG

Ggplot package in wasR usedto drawthe Figures. (P=0.02), and - of - - function mutations in the filaggrin gene on the development of thedevelopment gene on thefilaggrin in mutations function 24.

, Campbell LE, McLean WH, Weidinger S, Calkoen F et al. Impact Impact et F al. S,Calkoen WH, Weidinger McLean LE, , Campbell Gao P, Grant Grant AV, Boguniew Gao P, similarly alter the skin barrier in patients with atopic dermatitis. dermatitis. with atopic in patients skinbarrier alterthe similarly FMG patients showed less improvement in SCORADin the course improvementstagnates during thecourse of thetreatment. These results show that ive treatment, or topical immunosuppressive treatment - - 6. Common et H,LeeSP al. Y,Liao A,Zhao Kwiatkowski

158(4):754

both groups showed improvement an in J Clin Immunol 2011; Immunol2011; J Clin Allergy - icz M, Debenedetto A et al. Cytokine Cytokine A et al. Debenedetto M, icz 94. -

7.

- 65. - 32. The

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FMG (n=23) grayareas Diagnostic criteria for criteria Diagnostic A randomized trial randomized A when on - FMG .

alone Dark of 24 - 5. .

This article isThis article by protected copyright. All rightsreserved. Accepted Article 131(2): 2013; Immunol Allergy Clin fo Foundation

(10) (9 ) r Statistical Computing, Vienna, Austria. URL https:// URL Austria. Vienna, Computing, r Statistical

McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J disease. skin inallergic filaggrin roleof Themultifunctional Irvine AD. McAleer MA, R computing. statistical for environment language and R: A Team(2016). Core 280 - 91.

www.R - project.org/ . 2016. 2016. .