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
DOI 10.1007/s13555-017-0184-3
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
334 Dermatol Ther (Heidelb) (2017) 7:331–347
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
Dermatol Ther (Heidelb) (2017) 7:331–347 335
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
336 Dermatol Ther (Heidelb) (2017) 7:331–347
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
Dermatol Ther (Heidelb) (2017) 7:331–347 337
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
ngradedonelevelforseriousim
precision,
lowsamplesize
andconfi
denceintervalincludes
nodifference
(1),andappreciableharm
(1.25)
fDow
ngradedonelevelforseriousim
precision,
lowsamplesize,d
atahadto
beestimated
from
figure
338 Dermatol Ther (Heidelb) (2017) 7:331–347
Table3
Summaryof
findingstablestudyof
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
Participantsatisfaction
withthe
moisturiser—notmeasured
––
––
–The
studydidnotaddressthis
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
studydidnotaddressthis
outcom
e
Changein
useof
active
topical
treatm
ent—
notmeasured
––
––
–The
studydidnotaddressthis
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
Dermatol Ther (Heidelb) (2017) 7:331–347 339
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
studydidnotaddressthis
outcom
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,C
RM
Cetaphil�Restoraderm
�BodyMoisturizer
*The
risk
intheintervention
group(and
its95%
confi
denceinterval)isbasedon
theassumed
risk
inthecomparisongroupandtherelative
effect
oftheintervention
(and
its95%
CI)
aSimpson
[23]
bDow
ngradedonelevelforseriousdetectionbias,p
articipantswerenotblinded
cDow
ngradedtwolevelsforvery
seriousim
precision,
lowsamplesize
340 Dermatol Ther (Heidelb) (2017) 7:331–347
Table4
Summaryof
findingstablestudyof
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
Participantsatisfaction
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
Dermatol Ther (Heidelb) (2017) 7:331–347 341
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
studiesdidnotaddress
thisoutcom
e
Changein
useof
active
topical
treatm
ent—
notmeasured
––
––
–The
studiesdidnotaddress
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
342 Dermatol Ther (Heidelb) (2017) 7:331–347
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
studiesdidnotaddress
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,C
MCCetaphil�
Moisturisingcream,C
RM
Cetaphil�
RestoraDerm
�moisturiser
*The
risk
intheintervention
group(and
its95%
confi
denceinterval)isbasedon
theassumed
risk
inthecomparisongroupandtherelative
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
ngradedonelevelforseriousim
precision,
lowsamplesize
gSimpson
[22]
hDow
ngradedtwolevelsforvery
seriousim
precision,
lowsamplesize
andwedidnotdowngrade
foranything
else
Dermatol Ther (Heidelb) (2017) 7:331–347 343
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
344 Dermatol Ther (Heidelb) (2017) 7:331–347
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
Dermatol Ther (Heidelb) (2017) 7:331–347 345
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.
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