performance and tolerability of the moisturizers cetaphil ... · review performance and...

REVIEW

Performance and Tolerability of the MoisturizersCetaphil� and Excipial� in Atopic Dermatitis: Whatis the Evidence Based on Randomized Trials?

Esther J. van Zuuren . Zbys Fedorowicz . Bernd W. M. Arents

Received: April 6, 2017 / Published online: June 9, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Introduction: Moisturizers play a prominentrole in the management of atopic dermatitis byimproving the impaired skin barrier functionand enhancing skin hydration. Their efficacywas evaluated in a recently published CochraneReview ‘Emollients and moisturizers foreczema’.Objective: In the present review, we summarizethe performance and safety of Cetaphil� andExcipial� moisturizing products.Methods: This review was carried out in com-pliance with standard Cochrane methodologi-cal procedures, which means independent

study selection, data extraction, assessment ofrisk of bias, and analyses by two reviewauthors. The quality of evidence for the pre-defined outcomes was rated with the GRADEapproach. The prespecified outcomes of thereview included participant assessments, satis-faction, adverse events, investigator assess-ments, prevention of flares, change in use oftopical active treatment, skin barrier functionand quality of life.Results: Four randomized controlled studiesexamining these moisturizers were included inthe previously published Cochrane Review. Forthe performance and tolerability of thesemoisturizers, there was very low to moderatequality evidence for the prespecified outcomes.Conclusion: The results from these four studiesare in line with those of the Cochrane Reviewthat moisturizers themselves have beneficialeffects, and that combining moisturizers withactive topical treatment produced better resultswhen compared to active topical treatmentalone.

Keywords: Atopic dermatitis; Evidence-baseddermatology; GRADE approach; Moisturizers

INTRODUCTION

Atopic dermatitis, also known as atopic eczemaor just eczema, is a chronic inflammatory skindisease that is characterized by decreased skin

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E. J. van Zuuren (&)Dermatology Department, Leiden UniversityMedical Center, Leiden, The Netherlandse-mail: [email protected]

Z. FedorowiczBahrain Branch, Cochrane, Awali, Bahrain

B. W. M. ArentsDutch Association for People with Atopic Dermatitis(VMCE: Vereniging voor Mensen metConstitutioneel Eczeem), Nijkerk, The Netherlands

Dermatol Ther (Heidelb) (2017) 7:331–347

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barrier function, (very) dry skin and inflamma-tory lesions which cause intense itch leading toscratching [1]. The etiology of atopic dermatitiscontinues to attract research interest, and,although it is not yet fully understood, mostprobably it has a multifactorial origin (e.g.,genetic, environmental and immunological)[2]. In the absence of specific laboratory or his-tological findings [3], the diagnosis of atopicdermatitis is based on clinical signs and symp-toms, by using, e.g., the criteria of Hanifin andRajka or the UK Working Party’s diagnosticcriteria for atopic dermatitis [4, 5]. Atopic der-matitis has a lifetime prevalence of 10–20% indeveloped countries [3]. The prevalence rates indeveloping countries are more difficult to esti-mate due to the use of different outcome mea-sures and diagnostic criteria but seem toincrease in certain parts of Africa and easternAsia [6]. Since 60% of the diagnoses are made inthe 1st year of life and 85% before age 5,prevalence is highest in children [3, 7]. A recentmeta-analysis showed that 80% of children withthe disease have outgrown it within 8 years ofonset and this percentage reaches 95% at20 years after onset [8]. This meta-analysis alsoreported that the risk factors for persistence ofthe disease are twofold: late-onset and greaterdisease severity. The severity of the disease canvary quite markedly, with data indicating that80% of affected children have a mild form, and20% a moderate to severe form [8]. Atopic der-matitis is further characterized by intermittentperiods of milder symptoms, which are inter-spersed with sudden relapses or flare-ups (exac-erbations) [3].

Treatment of atopic dermatitis consists ofthe avoidance of triggers that may exacerbatethe disease (e.g., allergens, irritants), of restor-ing skin barrier function with moisturizers andby decreasing inflammation through the use oftopical corticosteroids or topical immunomod-ulators [9]. In more severe cases, systemictreatment with immunomodulators or pho-totherapy might have to be considered [9]. Thecharacteristic flare-ups which can occur in ato-pic dermatitis make the prevention of flares andexacerbations one of the key aims of long-termcontrol [1].

Impaired Skin Barrier

The impairment of the skin barrier in atopicskin, both lesional and non-lesional, continuesto be a topic of interest [10–17]. The twomechanisms for this impairment are discussedfurther here. Dysfunction of the corneocytes inthe stratum corneum results in a decrease inproduction of the protein filaggrin. Filaggrinitself is broken down into amino acids (e.g.,arginine) and smaller molecules such as urea,organic acids (e.g., lactic acid), sugars and elec-trolytes, which together form the naturalmoisturizing factor (NMF) [10, 12, 13]. NMF isthe skin’s natural humectant and is essential forkeeping the stratum corneum properly hydra-ted, which is necessary for all the biochemicalprocesses that take place in the skin [10]. Thelamellar bodies within the epithelial cells of theskin deliver other ingredients for the intercel-lular membrane of the stratum corneum, suchas free fatty acids, cholesterol and ceramides(50% of the total lipid weight concerns cer-amides) [10, 13, 14]. In people with atopic der-matitis, this production is dysregulated, causinga different composition of the various cer-amides and a lack of, e.g., ceramide-1 and cer-amide-3, which in turn leads to an increase intransepidermal water loss (TEWL) [10, 11]. Inview of this impairment of skin barrier function,moisturizing of the skin is considered anessential part of the treatment regimen forpeople with atopic dermatitis [1]. There is thus arationality to use moisturizers with ingredientsthat mimic the composition of the intercellularmembrane by using, for instance, humectants,emollients and lipids, or other lacking sub-stances, and to use occlusives to reduce or fur-ther prevent TEWL.

Efficacy of Moisturizers

Most studies evaluating the efficacy of mois-turizers on dry skin or the improvement of skindisorders have an open label design and oftendon’t include a control group. Studies assessingmoisturizers cannot be fairly compared withstudies conducted to demonstrate the efficacyand safety of drugs, for which methodologically

332 Dermatol Ther (Heidelb) (2017) 7:331–347

robust and randomized controlled trials arerequired to obtain approval by the drug regis-tration authorities (e.g., Food and DrugAdministration or European MedicinesAgency). Moisturizers are most often sold overthe counter without prescription, and thereforethe development of these moisturizers tends tofocus more on tolerance and status of skincondition (young or old skin, dry skin, sensitiveskin or inflamed skin), rather than onimprovement of atopic dermatitis per se as astand-alone treatment. The consequences are,as has been reported in a meta-analysis onmoisturizers in atopic dermatitis and relatedskin disorders, that studies evaluating the effi-cacy of moisturizers often do not meet the highstandards with regards to methodology, e.g., ofappropriate study size, adequately randomizedand blinded, and using standardized outcomemeasures [18]. The efficacy and safety of emol-lients and moisturizers in atopic dermatitis hasrecently been evaluated in a Cochrane Reviewtitled ‘Emollients and moisturizers for eczema’[19]. This review reported that ample use ofmoisturizers reduces the rate of flares, prolongsthe time to flare and enhances the efficacy oftopical active treatment. This current reviewfocuses on three of the moisturizers evaluated:Cetaphil� Moisturizing Cream (CMC), Ceta-phil� RestoraDerm�Moisturizer (CRM) andExcipial� U lipo lotion (EUL). These products,contain certain ingredients that may restorebarrier function albeit each in a different way,such as humectants, lipids and/or ceramides (ortheir precursors). Four randomized controlledstudies which evaluated these products wereincluded in the Cochrane Review [20–23].

METHODS

The protocol and subsequent review on whichthis sub-analysis is based, were previously pub-lished in the Cochrane Library [19, 24]. Thisarticle is based on previously conducted studiesand does not involve any new studies of humanor animal subjects performed by any of theauthors. The following databases were searchedup to December 2015: the Cochrane Skin GroupSpecialized Register, CENTRAL (2015, Issue 11),

MEDLINE (from 1946), EMBASE (from 1974),LILACS (from 1982), GREAT database, fiveongoing trials registers (ISRCTN, ClinicalTri-als.gov, the Australian New Zealand ClinicalTrial Registry, WHO International Clinical Tri-als Registry and the EU Clinical Trials Register)and references of the included studies (see, forsearch strategy of MEDLINE Appendix 1, Elec-tronic Supplemental material). Only random-ized controlled trials (RCT) evaluating theefficacy and safety of moisturizers in peoplewith atopic dermatitis, eczema, or atopiceczema were eligible for inclusion. Tworeviewers (E.J.v.Z. and Z.F.) independentlyreviewed all studies from the searches. Thismanuscript provides a more in-depth evalua-tion of the specific RCTs which addressed CMC,CRM and EUL moisturizers.

Outcome Measures

Our primary outcome measures were (1) par-ticipant-assessed change in disease severity, (2)participant’s satisfaction with the moisturizerand (3) the proportion of participants with anadverse event. Secondary outcome measureswere investigator-assessed change in diseaseseverity, prevention of flares, change in use ofactive topical treatment, changes in epidermalbarrier function and change in quality of life.

Data Extraction and Synthesis

Trial details of eligible studies were extractedindependently by two review authors usingpre-piloted data extraction forms (E.J.v.Z. andZ.F.). The risk of bias assessments were madeusing the Cochrane domain-based evaluationtool as described in Chapter 8, Sect. 8.5, in theCochrane Handbook for Systematic Reviews ofInterventions [25]. Mean differences (MD) werecalculated for continuous outcomes and fordichotomous data we calculated risk ratios (RR).All outcomes were reported with their associ-ated 95% confidence intervals (CI). We used theI2 statistic in meta-analyses to assess hetero-geneity [25]. The quality (or certainty) of theevidence for the prespecified outcomes wasrated using the GRADE approach [26]. Further

Dermatol Ther (Heidelb) (2017) 7:331–347 333

details on the data analysis are reported in thefull Cochrane Systematic Review [19].

RESULTS

Full details of the process of study selection areprovided in Fig. 1. Four studies which examineda total of 296 adult patients were included(Table 1). Two studies [20, 23] were assessed asat unclear risk of bias, and two studies [21, 22]as at high risk of bias. Lack of blinding of thepatients was the principal reason that thestudies were judged as high risk of bias (Fig. 2).

In the study of Gehring and Gloor, EULcontaining 4% urea twice daily was compared

to hydrocortisone acetate 1% in EUL in 69participants over a period of 1 week [20]. Dis-ease severity was assessed by the participants asroughness of the skin on a visual analogue scale(VAS) from 1 to 10, with higher being better.VAS scores increased from baseline after 1 weekby 2.19 [1.31 standard deviation (SD)] in the 31patients treated with EUL and 2.60 (0.98 SD) inthe 32 patients that applied hydrocortisoneacetate 1% in EUL with a MD of -0.41 (95% CI-0.98 to 0.16; P = 0.16). Our primary outcomesparticipant satisfaction and adverse events werenot evaluated. Investigators assessed redness ona 1–4 scale (lower score being less red). Thechanges in redness after 1 week were -0.84(0.66 SD) in the EUL group and -1.00 (0.52 SD)

through other sources

31 ongoing trials

database searching

removed

5631 records screened

eligibility

criteria in Cochrane review

5471 excluded based on

47 studies appeared to be

same study

with reasons: -Controlled clinical trial (2)

(3)

31 ongoing studies (including NCT02589392 with Cetaphil® Restoraderm® moisturizer)

and/or Excipial®

Fig. 1 Flow diagram


Table1

Characteristics

oftheincluded

studiesandresults

Stud

yID

design

andlocation

Participants:

gend

er/age/eczem

astatus

Intervention

andcomparator

Outcomes

asrepo

rted

Con

clusions

Gehring

[20]

Double-blind

Single-center

Germany

69(39female/24

male/6gend

erun

reported)

Eczem

a

Meanage27

years

1week

A:EULb.i.d.(31)

B:Hydrocortison

eacetate1%

inEULb.i.d.(32)

EULcontains

4%urea

Participant-assessed

change

inroughn

ess(1–1

0,higher

better):groupA

2.19

(1.31)

vsgroupB

2.60

(0.98)

Investigator-assessedredn

ess(1–4

,low

erbetter):

groupA

-0.84

(0.66)

vsgroupB-1.00

(0.52)

Investigator-assessedroughn

ess(1–4

,low

erbetter):

groupA

-0.97

(0.59)

vsgroupB-1.06

(0.46)

Changein

TEWL:group

A-8.2g/m

2 /hvsgroupB

-8g/m

2 /h

Sixlosses

tofollow-up

(8.7%),un

clearfrom

which

group

Hanifin[21]

Investigator-blin

d

Multicenter

US

Within-participant

80(51female/29

male)

Mild

tomoderate

eczema

Meanage24.4years

3weeks

A:d

esonide0.05%

lotion

b.i.d.

plus

CMC

ononeside

B:desonide

0.05%

lotion

b.i.d.

oncontralateralside

Treatmentpreference:side

A96%

vsside

B4%

Adverse

events:side

A10

vs.sideB11

after1week

and0vs

2after3weeks

Markedto

excellent

improvem

ent:side

A70%

vs.

side

B55%

Com

bination

oftopical

active

treatm

entwitha

moisturiser

ismore

effectivethan

topical

active

treatm

entalone

Simpson

[22]

Investigator-blin

d

Multicenter

US

Within-participant

127(gender

unreported)

Mild

tomoderate

eczema

Meanagenot

reported

4weeks

A:routineuseof

topical

corticosteroidsplus

CRM

ononeside

B:routineuseof

topical

corticosteroidson

contralateralside

Treatmentsatisfaction:84%–9

6.7%

feltthat

addition

ofmoisturiser

resultedin

better

effect

Changein

EASI:side

A-1.28

(1.94)

vs.group

B-1.01

(1.50)

Changein

skin

capacitance:side

A5.4vs.sideB3

Com

bination

oftopical

active

treatm

entwitha

moisturiser

ismore

effectivethan

topical

active

treatm

entalone

Simpson

[23]

Investigator-blin

ded

Single-center

Germany

Within-participant

20(16female/4male)

Controlledatopic

derm

atitisanddry

skin

Meanage40.9years

27days

A:CRM

b.i.d.o

noneleg

B:no

moisturiser

oncontralateralleg

Adverse

events:none

oneither

leg

Changeon

drynessscale(0–4

):side

A-1.15

(0.41)

vs.sideB-0.91

(0.58)

Changein

TEWL:side

A-1.59

g/m

2 /hvs.sideB

-0.42

g/m

2 /h(1.13)

Changein

skin

capacitance:side

A16.91(6.3)vs.

side

B3.3(3.86)

There

was

astatistically

significant

difference

infavorof

CRM

forall

theseoutcom

es

b.i.d.twicedaily,C

MCCetaphil�

moisturisingcream,C

RM

CetaphilR

estoraderm

�moisturizer,E

ASI

Eczem

aAreaSeverity

Index,EULExcipial�

Ulipolotion,

HRhazard

ratio,

TEWLtransepiderm

alwater

loss


in the hydrocortisone acetate 1% in EUL group(MD 0.16, 95% CI -0.13 to 0.45; P = 0.29).Roughness was also assessed on a scale from 1 to4 and showed changes of -0.97 (0.59 SD) and-1.06 (0.45 SD), respectively, with a MD of 0.09(95% CI -0.18 to 0.36; P = 0.52). The othersecondary outcomes were not assessed. Thequality of the evidence was low to moderate forthe addressed outcomes (see Table 2).

A study by Simpson et al. had a within par-ticipant design in which CRM twice daily wascompared to ‘no moisturizer’ on the contralat-eral leg of 20 patients over a period of 27 days[23]. Two of our primary outcomes, diseaseseverity as assessed by the participants and theirsatisfaction with the moisturizer, were notevaluated. Adverse events were evaluated andthere were none reported to the treatment. Inthis study, the investigators used a dryness scale

(0–4, higher score being worse) to assess diseaseseverity. The reductions reported at the end of27 days were 1.15 (0.41 SD) on the legs of the 20patients treated with CRM and 0.91 (0.58 SD)on the non-treated contralateral legs with amean of the paired differences of -0.24 (95% CI-0.42 to -0.06). In addition, both TEWL(measured with an evaporimeter) and skinhydration (measured with a corneometer) wereused to investigate changes in skin barrierfunction. The reduction in TEWL was 1.59 g/m2/h (0.97 SD) on the CRM treated legs and0.42 g/m2/h (1.13 SD) on the contralateral legswith a mean of the paired differences of-1.17 g/m2/h (95% CI -1.52 to -0.82). How-ever, both of these reductions can be regardedas relatively minimal. Skin hydration improvedby 16.91 units (6.31 SD) on the CRM treatedlegs and by 3.3 (3.86 SD) on the non-treated

Fig. 2 Risk of bias summary


Table2

Summaryof

findingstablestudyof

Gehring

andGloor

[20]

EULtwicedaily

comparedto

hydrocortisone

acetate1%

inEULtwicedaily

foratop

icderm

atitis

Patientor

population:atopicderm

atitis

Intervention:EULtwicedaily

Com

parison:

hydrocortisone

acetate1%

inEULtwicedaily

Outcomes

Anticipated

absolute

effects*

(95%

CI)

Relative

effect

(95%

CI)

No.

ofparticipants

(studies)

Qualityof

theevidence

(GRADE)

Com

ments

Riskwithhydrocortisone

acetate1%

inEUL

twicedaily

RiskwithEULtwicedaily

Changefrom

baselin

ein

disease

severity

asassessed

bythe

participants(roughnessof

theskin)

Assessedwith:

VisualAnalogue

Scale(VAS)

Scalefrom

:1to

10(higher

better)

Follow-up:

mean1week

The

meanchange

from

baselin

ein

disease

severity

asassessed

bythepatientswas

2.60

(0.98)

The

meanchange

from

baselin

ein

disease

severity

asassessed

bythepatientsin

theintervention

group

was

0.41

lower

(0.98

lower

to0.16

higher)

–63

(1RCT)a

LOW

b,c

P=

0.16

Nodifference

betweenthetwo

treatm

entgroups

after

1week

Participantsatisfaction

with

themoisturiser—not

measured

––

––

–The

studydidnotaddress

thisoutcom

e

Num

berof

participants

reportingan

adverseevent—

notmeasured

––

––

–The

studydidnotaddress

thisoutcom

e

Changefrom

baselin

ein

disease

severity

asassessed

bythe

investigators

Assessedwith:

Likertscale

Scalefrom

:1to

4(low

erbetter)

Follow-up:

mean1week

The

meanchange

from

baselin

ein

diseaseseverity

asassessed

bytheinvestigatorswas

-1(0.52)

The

meanchange

from

baselin

ein

diseaseseverity

asassessed

bytheinvestigatorsin

the

intervention

groupwas

0.16

higher

(0.13lower

to0.45

higher)

–63

(1RCT)a

LOW

c,d

P=

0.29.T

here

was

nodifference

accordingto

the

investigatorsbetweenthe

twotreatm

entarms

Num

berof

participants

experiencing

aflare—not

measured

––

––

–The

studydidnotaddress

thisoutcom

e

Changein

useof

active

topical

treatm

ent—

notmeasured

––

––

–The

studydidnotaddress

thisoutcom

e


Table2

continued

Outcomes

Anticipated

absolute

effects*

(95%

CI)

Relative

effect

(95%

CI)

No.

ofparticipants

(studies)

Qualityof

theevidence

(GRADE)

Com

ments

Riskwithhydrocortisone

acetate1%

inEUL

twicedaily

RiskwithEULtwicedaily

Changein

skin

barrierfunction

Assessedwith:

transepiderm

alwater

loss

Follow-up:

mean1week

The

meanchange

inskin

barrierfunction

was

8g/m

2 /h

The

meanchange

inskin

barrier

function

intheintervention

groupwas

0.2g/m

2 /hlower

–63

(1RCT)a

MODERATEf

Datahadto

beestimated

from

figure

Changein

health-related

qualityof

life—

not

measured

––

––

–The

studydidnotaddress

thisoutcom

e

GRADEWorking

Group

grades

ofevidence

Highquality:Wearevery

confi

dent

that

thetrue

effect

liescloseto

that

oftheestimateof

theeffect

Moderatequality:Wearemoderatelyconfi

dent

intheeffect

estimate:The

true

effect

islikelyto

becloseto

theestimateof

theeffect,b

utthereisapossibility

that

itissubstantially

different

Low

quality:Our

confi

dencein

theeffect

estimateislim

ited:The

true

effect

may

besubstantially

differentfrom

theestimateof

theeffect

Verylowquality:Wehave

very

little

confi

dencein

theeffect

estimate:The

true

effect

islikelyto

besubstantially

differentfrom

theestimateof

effect

CIconfi

denceinterval,E

ULExcipial�

Ulipolotion,M

Dmeandifference

*The

risk

intheintervention

group(and

its95%

confi

denceinterval)isbasedon

theassumed

risk

inthecomparisongroupandtherelative

effect

oftheintervention

(and

its95%

CI)

aGehring

[20]

bDow

ngradedonelevelforseriousindirectness,‘roughn

ess’of

theskin

isnotthesameas

‘disease

severity’

cDow

ngradedonelevelforseriousim

precision,

lowsamplesize

andconfi

denceintervalincludes

appreciableharm

(0.75)

andno

difference

(1)

dDow

ngradedonelevelforseriousindirectness,‘redn

ess’of

theskin

isnotthesameas

diseaseseverity

eDow


precision,

lowsamplesize

andconfi

denceintervalincludes

nodifference

(1),andappreciableharm

(1.25)

fDow


precision,

lowsamplesize,d

atahadto

beestimated

from

figure


Table3

Summaryof


Simpson

[23]

CRM

comparedto

nomoisturizer

foreczema

Patientor

population:eczema

Intervention:CRM

Com

parison:

nomoisturizer

Outcomes

Anticipated

absolute

effects*

(95%

CI)

Relativeeffect

(95%

CI)

No.

ofparticipants

(studies)

Qualityof

the

evidence

(GRADE)

Com

ments

Riskwithno

moisturizer

RiskwithCRM

Changefrom

baselin

ein

disease

severity

asassessed

bythe

participants—notmeasured

––

––

–The

studydidnotaddressthis

outcom

e


withthe

moisturiser—notmeasured

––

––

–The


outcom

e

Num

berof

participantsreportingan

adverseevent

Follow-up:

mean27

days

20(1

RCT)a

VERYLOW

b,c

There

wereno

adverseevents

reported

oneither

leg

(within-participantdesign)

Changefrom

baselin

ein

disease

severity

asassessed

bythe

investigators

Assessedwith:

drynessscale

Scalefrom

0to

4(higherworse)

Follow-up:

mean27

days

The

reductions

were1.15

(0.41SD

)on

thelegs

ofthe20

patientstreated

withCRM

and0.91

(0.58)

onthecontralaterallegs

(nomoisturizer)witha

meanof

thepaired

differencesof

-0.24

(95%

CI-0.42

to-0.06)

20(1

RCT)a

LOW

cStudywithawithin-participant

design

Num

berof

participantsexperiencing

aflare—notmeasured

––

––

–The


outcom

e

Changein

useof

active

topical

treatm

ent—

notmeasured

––

––

–The


outcom

e

Changein

skin

barrierfunction

Assessedwith:

transepiderm

alwater

lossandcorneometry

Follow-up:

mean27

days

The

reductionin

TEWLwas

1.59

g/m

2 /h(0.97SD

)on

theCRM

treatedlegs

and

0.42

g/m

2 /h(1.13SD

)on

thecontralaterallegs

witha

meanof

thepaired

differences

of-1.17

g/m

2 /h(95%

CI

-1.52

to-0.82).Both

reductions

canbe

regarded

assm

all.Skin

hydration

improved

by16.91un

its

(6.31SD

)on

theCRM

treatedlegs

andby

3.3

(3.86SD

)on

thenon-treated

contralaterallegs

(mean

ofthepaired

differences

13.61,

95%

CI11.60–

15.60)

20(1

RCT)a

LOW

cStudywithawithin-participant

design


contralateral legs (mean of the paired differ-ences 13.61, 95% CI 11.60–15.60). There was astatistically significant difference in favor ofCRM for all of these specific investiga-tor-assessed outcomes. None of the other sec-ondary outcomes (prevention of flares, changein active topical treatment and quality of life)were assessed in this study. The quality of theevidence was rated low to very low for the pre-specified outcomes that were addressed (seeTable 3).

The two studies at high risk of bias (due tolack of blinding of the participants) evaluatedtopical corticosteroids plus moisturizer versustopical corticosteroid alone [21, 22].

In Hanifin et al. desonide 0.05% lotion twicedaily in combination with the use of moistur-izing cream three times daily (CMC) was com-pared over a period of 3 weeks to desonide0.05% lotion twice daily, in 80 participants in awithin-participant study design [21]. In thewithin-participant design study of Simpsonet al., routine use of topical corticosteroidscombined with twice daily CRM was comparedto routine use of topical corticosteroids alonewithout the use of any moisturizer [22]. Thisstudy examined these comparisons in 123patients over a 4-week period [22]. Partici-pant-assessed disease severity was not assessedin either of the two studies. However, althoughparticipant satisfaction was measured in both, itdid not involve the more direct measurement ofour outcome of ‘satisfaction’. Thus, in Hanifinet al. [21], it was measured as ‘preference’, andin Simpson et al. [22] as ‘perception of theproduct’. In Hanifin et al. [21], the combinedtherapy of desonide 0.05% lotion plus mois-turizing cream was preferred by 96% of the 78participants and the remaining 4% preferred thedesonide 0.05% lotion without the use of anymoisturizer. In the other study [22], between84.3% and 96.7% of the 123 participantsreported that adding CRM to topical corticos-teroids ‘‘reduces inflammation, relieves dry anditchy skin, provides long-lasting hydration,leaves skin protected and maintains healthyskin’’ [22]. Adverse events were only reported inone of the two studies [21]. After the 1st week ofthe study, 10 of the 80 participants reportedburning and stinging on the side treated withT

able3

contiuned

Outcomes

Anticipated

absolute

effects*

(95%

CI)

Relativeeffect

(95%

CI)

No.

ofparticipants

(studies)

Qualityof

the

evidence

(GRADE)

Com

ments

Riskwithno

moisturizer

RiskwithCRM

Changein

health-related

qualityof

life—

notmeasured

––

––

–The


outcom

e

GRADEWorking

Group

grades

ofevidence


confi

dent

that

thetrue

effect

liescloseto

that

oftheestimateof

theeffect


dent

intheeffect

estimate:The

true

effect

islikelyto

becloseto

theestimateof

theeffect,b


that

itissubstantially

different

Low

quality:Our

confi

dencein

theeffect

estimateislim

ited:The

true

effect

may

besubstantially

differentfrom

theestimateof

theeffect


very

little

confi

dencein

theeffect

estimate:The

true

effect

islikelyto

besubstantially

differentfrom

theestimateof

effect

CIconfi

denceinterval,C

RM

Cetaphil�Restoraderm

�BodyMoisturizer

*The

risk

intheintervention

group(and

its95%

confi


theassumed

risk


effect

oftheintervention

(and

its95%

CI)

aSimpson

[23]

bDow

ngradedonelevelforseriousdetectionbias,p

articipantswerenotblinded

cDow

ngradedtwolevelsforvery

seriousim

precision,

lowsamplesize


Table4

Summaryof


Hanifin[21]

andstudyof

Simpson

[22]

Top

ical

corticosteroids1

CMC

orCRM

comparedto

topicalcorticosteroidsalon

eforeczema

Patientor

population:eczema

Intervention:topicalcorticosteroids?

CMC

orCRM

Com

parison:

topicalcorticosteroidsalone

Outcomes

Anticipated

absolute

effects*(95%

CI)

Relativeeffect

(95%

CI)

No.

ofparticipants

(studies)

Qualityof

the

evidence

(GRADE)

Com

ments

Riskwithtopical

corticosteroidsalon

eRiskwithtopical

corticosteroids1

CMC

orCRM

Changefrom

baselin

ein

disease

severity

asassessed

bythe

participants—notmeasured

––

––

–The

studiesdidnotaddress

thisoutcom

e


with

themoisturiser

Follow-up:

range3–

4weeks

InHanifinet

al.[21],thecombined

therapyof

desonide

0.05%

lotion

plus

moisturizingcream

was

preferredin

96%

ofthe78

participantsandonly4%

preferredthedesonide

0.05%

lotion

without

theuseof

any

moisturizer.Intheotherstudy

[22],b

etween84.3%

and96.7%

ofthe123participantsreported

that

adding

CRM

totopical

corticosteroids‘‘reduces

inflammation,

relievesdryanditchyskin,p

rovides

long

lastinghydration,

leaves

skin

protectedandmaintains

healthyskin’’

201(2

RCTs)a

LOW

b,c,d

Bothstudieshada

within-participantdesign.

Inboth

studiestheaddition

ofthemoisturizer

increased

theeffect

oftopicalcorticosteroids

Num

berof

participants

reportingan

adverseevent

Follow-up:

mean3weeks

After

1weekstudyduration,1

0of

the

80participantsreported

burning

andstinging

ontheside

wereboth

desonide

0.05%

aswellas

moisturizer

was

appliedcomparedto

11reports

ontheside

onlytreatedwithdesonide

0.05%

lotion.H

owever,after

3weeks

noadverseeventswerementioned

forthecombinedtreatm

ent,but

twoparticipantsstill

reported

burningandstinging

ontheside

treatedwithonlydesonide

0.05%

lotion

80(1

RCT)e

LOW

b,f


Table4

continued

Outcomes

Anticipated

absolute

effects*

(95%

CI)

Relativeeffect

(95%

CI)

No.

ofparticipants

(studies)

Qualityof

the

evidence

(GRADE)

Com

ments

Riskwithtopical

corticosteroidsalon

eRiskwithtopical

corticosteroids1

CMC

orCRM

Changefrom

baselin

ein

disease

severity

asassessed

bythe

investigators

Follow-up:

range3–

4weeks

Hanifinet

al.[21]assessed

as‘global

assessmentof

improvem

ent’.

Of

the78

participants70%

were

markedlyim

proved

toclearon

thebody

side

treatedwith

desonide

0.05%

lotion

with

moisturizer

used

threetimes

adayversus

55%

ontheside

that

was

treatedwithonly

desonide

0.05%

lotion

(investigatorsreported

aPvalue

of\0.01).In

Simpson

etal.[22],

EASI

was

used

(score

0–72,h

igher

isworse).Ontheside

treatedwith

both

desonide

0.05%

lotion

and

moisturiser

thereductionwas

1.28

(1.94SD

)andon

thedesonide

0.05%

lotion

‘only’treatedside

1.0

(1.50SD

)withameanof

thepaired

differencesof

-0.27

(95%

CI

-0.52

to-0.02)

201(2

RCTs)a

MODERATEf

Bothstudieshave

awithin-participantdesign

InSimpson

2011;the

reductions

inEASI

were

smallon

both

sidesand

notmeeting

theminim

alim

portantdifference

of6.6[27]

Num

berof

participants

experiencing

aflare—not

measured

––

––

–The


thisoutcom

e

Changein

useof

active

topical

treatm

ent—

notmeasured

––

––

–The


thisoutcom

e

Changein

skin

barrierfunction

Assessedwith:

corneometry

Follow-up:

mean4weeks

Ontheside

treatedwithtopical

corticosteroidsin

combination

withmoisturizer

skin

hydration

increasedby

5.4arbitraryun

its

andon

theside

treatedwithonly

topicalcorticosteroidsby

3arbitrary

units

123(1

RCT)g

LOW

hThe

studyhasa

within-participantdesign.

Bothim

provem

entsare

small,no

SDswereprovided


Table4

continued

Outcomes

Anticipated

absolute

effects*(95%

CI)

Relativeeffect

(95%

CI)

No.

ofparticipants

(studies)

Qualityof

the

evidence

(GRADE)

Com

ments

Riskwithtopical

corticosteroidsalon

eRiskwithtopical

corticosteroids1

CMC

orCRM

Changein

health-related

qualityof

life—

not

measured

––

––

–The


thisoutcom

e

GRADEWorking

Group

grades

ofevidence


confi

dent

that

thetrue

effect

liescloseto

that

oftheestimateof

theeffect


dent

intheeffect

estimate:The

true

effect

islikelyto

becloseto

theestimateof

theeffect,b


that

itissubstantially

different

Low

quality:Our

confi

dencein

theeffect

estimateislim

ited:The

true

effect

may

besubstantially

differentfrom

theestimateof

theeffect


very

little

confi

dencein

theeffect

estimate:The

true

effect

islikelyto

besubstantially

differentfrom

theestimateof

effect

CIconfi

denceinterval,C

MCCetaphil�

Moisturisingcream,C

RM

Cetaphil�

RestoraDerm

�moisturiser

*The

risk

intheintervention

group(and

its95%

confi


theassumed

risk


effect

oftheintervention

(and

its95%

CI)

aHanifin[21],Sim

pson

[22]

bDow

ngradedonelevelforseriousrisk

ofdetectionbias,p

articipantswerenotblinded

cDow

ngradedonelevelforseriousindirectness,inboth

studiesasurrogateoutcom

ewas

measured

dWedidnotdowngrade

forim

precision,

aswellalreadydowngradedforrisk

ofbias

andindirectness,and

furtherdowngrading

was

notfeltappropriate

eHanifin[21]

fDow


precision,

lowsamplesize

gSimpson

[22]

hDow

ngradedtwolevelsforvery

seriousim

precision,

lowsamplesize

andwedidnotdowngrade

foranything

else


desonide 0.05% and moisturizer, compared to11 reports on the side treated with desonide0.05% lotion alone. However, after 3 weeks, noadverse events were reported for the combinedtreatment, but two participants still reportedburning and stinging on the side treated withdesonide 0.05% lotion alone [21].

The investigators in Hanifin et al. assesseddisease severity as ‘global assessment ofimprovement’ [21]. Based on a per-protocolanalysis of 78 participants and their assessments,70% of the participants were markedly improvedto ‘clear’ on the body side treated with desonide0.05% lotion with moisturizer used three times aday, versus 55% on the side that was treated withonly desonide 0.05% lotion (investigatorsreported a P value of\0.01).

The investigators in Simpson et al. used theEczema Area and Severity Index (EASI; score0–72, higher is worse) [22]. The reductions inEASI were small on both sides and did not meetthe minimal important difference (MID) of 6.6[27]. On the side treated with desonide 0.05%lotion and moisturizer the reduction was 1.28(1.94 SD) and on the desonide 0.05% lotion‘only’ treated side 1.0 (1.50 SD), with a mean ofthe paired differences of -0.27 (95% CI -0.52to -0.02), which although statistically signifi-cant is not clinically important.

Only Simpson et al. investigated skin barrierfunction using corneometry [22]. On the sidetreated with topical corticosteroids combinedwith moisturizer, skin hydration increased by5.4 arbitrary units compared to 3 arbitrary unitson the side treated with topical corticosteroidsalone, both of which were considered smallimprovements. The other secondary outcomes(prevention of flares, change in topical activetreatments and quality of life) were not assessedin these two studies. The quality of evidencewas rated low to moderate for the addressedoutcomes (see Table 4).

DISCUSSION

The duration of the studies did not last beyond4 weeks, and three of the four studies addressedthe efficacy of moisturizers combined withtopical corticosteroids in atopic dermatitis

[20–22]. One study was conducted in peoplewith controlled atopic dermatitis [23]. However,none of the studies were designed as mainte-nance studies to evaluate the efficacy of mois-turizers in preventing flares.

One randomized controlled trial, which wasconducted 20 years ago, evaluated EUL, amoisturizer containing 4% urea and 36% lipids[20]. As only the 1st week of this 2-week studywas randomized, we could only include the 1stweek’s data. Based on these data, we can con-clude that adding hydrocortisone acetate 1% tothe EUL did not make a difference in terms ofefficacy compared to EUL used alone.

Urea is normally present in healthy skin aspart of the natural moisturizing factor (NMF) inthe stratum corneum [14]. Urea is a humectantwith water attracting properties from dermisinto epidermis and aids in holding water in thestratum corneum [14, 28, 29]. In atopic skinepidermal barrier function is impaired, TEWL isincreased and the ability to retain water in theskin is decreased [14, 29]. Urea-containingmoisturizers enhance hydration, but also appearto improve skin barrier function and antimi-crobial defense [30]. In concentrations of 10%and higher, urea works as a keratolytic agentand therefore urea-containing moisturizerswork well on both dry and scaly skin.

Based on the published Cochrane Review,there was low to moderate quality evidence forthe effect of urea-containing moisturizers, andthese could reduce the risk of flare by one-thirdwhen compared to the use of no moisturizer orcompared to its vehicle. A long-term studyconducted over a period of 180 days alsodemonstrated that urea 5%-containing creamcould, after the atopic dermatitis had been (al-most) cleared with topical corticosteroids,reduce the number of patients having a flareduring the 6-months follow-up, as well asincrease the time to flare when compared to amoisturizer without urea [31]. Over the last20 years, the urea-containing product line(which includes EUL) has expanded its devel-opment to ‘‘hydrate to relieve, protect, andrepair the most dry and frustrating skin’’ [32].

Whereas it is unlikely that many more ran-domized controlled trials with urea-containingmoisturizers will be conducted, the benefits of


urea appear to be already well acknowledged bymost physicians as well as patients, even in theabsence of robustly designed and conductedstudies. The most important reasons for down-grading the quality of the evidence for urea-con-tainingmoisturizers in theCochrane Reviewwerelow sample sizes, making the effect estimate lessprecise (due to wide confidence interval) and riskof bias (e.g., lack of blinding) [19]. The absence ofhigh-quality evidence is more directly related tothe poormethodological quality and lownumberof existing studies than to the efficacy of theurea-containing moisturizers.

The other three included studies evaluatedCRM and CMC [21–23]. The study of Simpsonet al. demonstrated that CRM performed betteron all assessed outcomes than no moisturizer,albeit based on very low- to low-quality evi-dence [23]. This product has been especiallydeveloped for atopic skin, and contains occlu-sives, emollients and humectants to restore andmaintain barrier function and preventtransepidermal water loss [10]. Additionalinclusion of NMFs and pseudoceramides amongothers within this product have been shown tobe capable of augmenting the water-bindingand -holding properties of the stratum corneum[10, 13]. The recently published CochraneReview emphasized that most moisturizersshowed some beneficial effects; however, theextent of the benefits varied among the inclu-ded studies [19]. Nonetheless, it was clear thatthe use of moisturizers prolonged time to flare,reduced the number of flares, and, when mois-turizers were abundantly and frequentlyapplied, also reduced the need for topical activetreatment. Another important conclusion of theCochrane Review was that there was moder-ate-quality evidence that adding a moisturizerto topical active treatment was more effectivethan topical active treatment alone [19]. Thiswas confirmed by two of the studies in thisreport which evaluated CRM in combinationwith active treatment and CMC [21, 22].

CONCLUSIONS

The four randomized controlled studies includedin this review on EUL, CMC and CRM show that

they have to a certain extent beneficial effects fortheir use in atopic dermatitis, including as anadd-on to augment topical active treatment,although the quality of the evidence was verylow to moderate for the prespecified outcomes.

The conclusions reached in these studies arein concordance with those drawn in theCochrane Review, and essentially reinforce therationality and benefits of moisturizer therapy.Gaps in the evidence included a lack of clarity asto which moisturizers are preferred for the dif-ferent parts of the body and any indication ofhow personal preferences and external factors(e.g., weather, seasons) influenced the choice ofmoisturizer. Most importantly, there was anoticeable lack of assessment of the compara-tive effectiveness of the moisturizers, e.g., as towhich are most appropriate for the actual dis-ease status (acute or chronic) and severity (mild,moderate or severe). Therefore, clinical deci-sion-making on the choice of moisturizershould be based not only on the available evi-dence but should also take into account theexperiences and preferences of the individualsuffering from atopic dermatitis, as well as thedirect costs for the patients.

ACKNOWLEDGEMENTS

Prof Zbys Fedorowicz had contract support fromGalderma for participating in the developmentof this manuscript to include article processingcharges. All authors had full access to all of thedata in this study and take complete responsi-bility for the integrity of the data and accuracyof the data analysis. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thismanuscript, take responsibility for the integrityof the work as a whole, and have given finalapproval for the version to be published.

Disclosures. Esther J van Zuuren, ZbysFedorowicz and Bernd WM Arents have nothingto disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studies


and does not involve any new studies of humanor animal subjects performed by any of theauthors.

Data Availability. All data generated oranalyzed during this study are included in thispublished article.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any non-commercial use, distribution, and reproductionin any medium, provided you give appropriatecredit to the original author(s) and the source,provide a link to the Creative Commons license,and indicate if changes were made.

REFERENCES

1. Wollenberg A, Oranje A, Deleuran M, Simon D,Szalai Z, Kunz B, et al. ETFAD/EADV Eczema taskforce 2015 position paper on diagnosis and treat-ment of atopic dermatitis in adult and paediatricpatients. J Eur Acad Dermatol Venereol.2016;30:729–47.

2. Peng W, Novak N. Pathogenesis of atopic dermati-tis. Clin Exp Allergy. 2015;45:566–74.

3. Weidinger S, Novak N. Atopic dermatitis. Lancet.2016;387:1109–22.

4. Hanifin JM, Rajka G. Diagnostic features of atopicdermatitis. Acta Dermatol Venereol.1980;92(Suppl.):44–7.

5. Williams HC, Burney PG, Hay RJ, Archer CB, Ship-ley MJ, Hunter JJ, et al. The UK working party’sdiagnostic criteria for atopic dermatitis. I. Deriva-tion of a minimum set of discriminators for atopicdermatitis. Br J Dermatol. 1994;131:383–96.

6. Deckers IA, McLean S, Linssen S, Mommers M, vanSchayk CP, Sheikh A. Investigating internationaltime trends in the incidence and prevalence ofatopic eczema 1990–2010: a systematic review ofepidemiological studies. PLoS ONE. 2012;7:e39803.

7. Bieber T. Atopic dermatitis. N Engl J Med.2008;358:1483–94.

8. Kim JP, Chao LX, Simpson EL, Silverberg JI. Persis-tence of atopic dermatitis (AD): a systematic review

and meta-analysis. J Am Acad Dermatol.2016;75:681–7.

9. Nankervis H, Thomas KS, Delamere FM, Barbarot S,Rogers NK, Williams HC. Scoping systematic reviewof treatments for eczema. Southampt (UK) NIHR JLibr. 2016;4:1–480.

10. Del Rosso JQ. Repair and maintenance of the epi-dermal barrier in patients diagnosed with atopicdermatitis: an evaluation of the components of abody wash-moisturizer skin care regimen directedat management of atopic skin. J Clin Aesthet Der-matol. 2011;4:45–55.

11. Janssens M, van Smeden J, Gooris GS, Bras W,Portale G, Caspers PJ, et al. Increase in short-chainceramides correlates with an altered lipid organi-zation and decreased barrier function in atopiceczema patients. J Lipid Res. 2012;53:2755–66.

12. Fowler J. Understanding the role of natural mois-turizing factor in skin hydration. Pract Dermatol.2012;9:36–40.

13. Del Rosso JQ, Kircik KH. The integration of physi-ologically-targeted skin care in the management ofatopic dermatitis: focus on the use of a cleanser andmoisturizer system incorporating a ceramide pre-cursor, filaggrin degradation products, and specific‘‘skin-barrier-friendly’’ excipients. J Drugs Dermatol.2013;12:s85–91.

14. Moncrief G, Cork M, Lawton S, Kokiet S, Daly C,Clark C. Use of emollients in dry-skin conditions:consensus statement. Clin Exp Dermatol.2013;38:231–8.

15. Angelova-Fisher I, Dapic I, Hoek AK, Jakasa I, Fis-cher TW, Zillikens D, et al. Skin barrier integrity andnatural moisturising factor levels after cumulativedermal exposure to alkaline agents in atopic der-matitis. Acta Derm Venereol. 2014;94:640–4.

16. Riethmuller C, McAleer MA, Koppes SA, AbdayemR, Franz J, Haftek M, et al. Filaggrin breakdownproducts determine corneocyte conformation inpatient with atopic dermatitis. J Allergy ClinImmunol. 2015;136:1573–80.

17. Halling-Overgaard AS, Kezic S, Jakasa, EngebretsenKA, Maibach H, Thyssen JP. Skin absorptionthrough atopic dermatitis skin: a systematic review.Br J Dermatol. 2016. (epub ahead of print).

18. Lindh JD, Bradley M. Clinical effectiveness ofmoisturizers in atopic dermatitis and related disor-ders: a systematic review. Am J Clin Dermatol.2015;16:341–59.

19. van Zuuren EJ, Fedorowicz Z, Christensen R, Lavri-jsen A, Arents BWM. Emollients and moisturisers


http://creativecommons.org/licenses/by-nc/4.0/

http://creativecommons.org/licenses/by-nc/4.0/

for eczema. Cochrane Database Syst Rev.2017;2:CD02119.

20. Gehring W, Gloor M. Treatment of the atopic der-matitis with a water-in-oil emulsion with or with-out the addition of hydrocortisone-results of acontrolled double-blind randomized study usingclinical evaluation and bioengineering methods.Z Hautkr. 1996;71:554–60.

21. Hanifin JM, Hebert AA, Mays SR, Paller AS, SherertzEF, Wagner AM, et al. Effects of a low-potencycorticosteroid lotion plus a moisturizing regimen inthe treatment of atopic dermatitis. Curr Ther ResClin Exp. 1998;59:227–33.

22. Simpson E, Dutronc Y. A new body moisturiserincreases skin hydration and improves atopic der-matitis symptoms among children and adults.J Drugs Dermatol. 2011;10:744–9.

23. Simpson E, Bohling A, Bielfeldt S, Bosc C, Ker-rouche N. Improvement of skin barrier function inatopic dermatitis patients with a new moisturizercontaining a ceramide precursor. J Dermatol Treat.2013;24:122–5.

24. van Zuuren EJ, Fedorowicz Z, Lavrijsen A, Chris-tensen R, Arents B. Emollients and moisturisers foreczema. Cochrane Database Syst Rev.2016;3:CD012119.

25. Higgins JPT, Green S. Cochrane handbook for sys-tematic reviews of interventions. Version 5.1.0(updated March 2011). http://www.cochrane-handbook.org. Accessed 19 March 2017.

26. Schunemann H, Bro _zek J, Guyatt G, Oxman A.GRADE handbook for grading quality of evidenceand strength of recommendations. Updated Octo-ber 2013. http://www.guidelinedevelopment.org/handbook. Accessed 19 March 2017.

27. Schram ME, Spuls PI, Leeflang MM, Lindeboom R,Bos JD, Schmitt J. EASI, (objective) SCORAD andPOEM for atopic eczema: responsiveness and min-imal clinically important difference. Allergy.2012;67:99–106.

28. Sirikudta W, Kulthanan K, Varothai S, Nuchkull P.Moisturizers for patients with atopic dermatitis: anoverview. J Allergy Ther. 2013;4:1–7.

29. Mack Correa MC, Nebus J. Management of patientswith atopic dermatitis: the role of emollient ther-apy. Dermatol Res Pract. 2012;2012:836931.

30. Grether-Beck S, Felsner I, Brenden H, Krutmann J.Urea uptake enhances barrier function andantimicrobial defense in humans by regulatingepidermal gene expression. J Invest Dermatol.2012;132:1561–72.

31. Akerstrom U, Reitamo S, Langeland T, Berg M,Rustad L, Korhonen L. Comparison of moisturizingcreams for the prevention of atopic dermatitisrelapse: a randomized double-blind controlledmulticentre clinical trial. Acta Derm Venereol.2015;95:587–92.

32. Excipial�. http://www.excipial.ca/en. Accessed 19March 2017.


http://www.cochrane-handbook.org

http://www.cochrane-handbook.org

http://www.guidelinedevelopment.org/handbook

http://www.guidelinedevelopment.org/handbook

http://www.excipial.ca/en

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