Pharmacol Res Perspect. 2020;e00679.
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The impact of vitamin D supplementation as an adjuvant
therapy on clinical outcomes in patients with severe atopic
dermatitis: A randomized controlled trial
Noha O. Mansour1 | Amal Ahmed Mohamed2 | Maha Hussein3 | Eman Eldemiry4 |
Aliaa Daifalla5 | Soha Hassanin6 | Nourelhuda Nassar7 | Doaa Ghaith8 |
Eman Mohamed Salah9
This is an op en access arti cle under the ter ms of the Creative C ommons Attribution L icense, which pe rmits use, dis tribu tion and reprod uction in any med ium,
provide d the original wor k is properly cited.
© 2020 The Authors. Pharm acolog y Research & Perspe ctivespublishe dbyBritishPharmacologicalSocietyandAme ricanSociet yforPharmacol ogyand
Exper iment alTher apeut icsandJohnWil ey&SonsLtd.
Abbreviations:AD,Atopicde rmati tis;EA SI,Ec zemaAre aandSev erit yIndex;N HTMRI ,Natio nalHep atolog yandTropi calMed icineRe searc hInsti tute;V itD,vita minD.
1Pharmacy Practice Department, Faculty of
Pharma cy,Mansou raUnive rsit y,Mansour a,
2Biochemistr yDepa rtme nt,National
Hepatol ogyandTropicalMe dicineResearc h
Instit ute, Cairo, Eg ypt
3Depar tment of Dermatology a nd
Androl ogy,NationalResearchCe ntre,C airo,
4Faculty of Pharma cy, Fellow of Clinica l
Pharma colog y,CairoUni versit yHospitals,
5Depar tmentofDermatology,Vener ology,
6Biochemistry Department, Faculty
ofPharma cy,Moder nUniver sityfor
Technology and Information, Cairo, Egypt
7Clinical Pathology Department, Elsahel
8Clinical and Chemical Pathology
Depar tment ,Facult yofMedicine,Cairo
9Depar tment of Dermatology, An drolog y,
SexualM edicin eandSTDs,Facultyof
Medicine,Helw anUniversity,Cairo,Eg ypt
Depar tment ,Facult yofPharmacy,Mansoura
Vitamin D supplementation withs tandardt reatment yielded positive clinicalout-
comes in mild and moderate atopic dermatitis; however, the potential benefit of vi-
tamin D in severe cases remains unclear. This study aimed to evaluate the impact
of vitamin D supplementation on response to standard treatment in pediatrics with
twice daily for 12 weeks.Theprimaryendpointswerethechange in mean Eczema
AreaandSeverity Index(EASI)scoreattheend ofthestudyandthemeanpercent
change in EASI score frombaselinetoweek 12. Eighty-six subjectscompleted the
study. The treated group achieved a significant higher level of 25 hydroxy vitamin
D(P < .001)comparedtocontrolgroupatweek12.ThemeanEASIscorewassig-
nificantlylowerinthetreatmentgroup comparedtoplacebo group (P = .035). The
percentchangeinEASI score from baselinedifferedsignificantlybetween the sup-
improves the clinical outcomes in severe atopic dermatitis.
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MANSOU R et Al.
1 | INTRODUCTION
disease with intermittent flares and debilitating effects on the
patient's qualit y of life. It is the most common skin disorder
inchildren,affecting approximately 15%to20% worldwide.1
atous plaques, and a defective epidermal barrier.2 The pathol-
ogy of AD is not entirely understood. It involves a complex
interplay of dysfunctions of immune response, genetic and
environmental factors.3 Currently, the conventional AD treat-
ments include immune modulatory agents, such as topical and/
or oral steroids and topical calcineurin inhibitors.4 The control
of patients with AD may be difficult to be achieved in some
patients; this suggests the presence of some other associated
factors. The findings obtained in both clinical and observa-
tional st udies reveal ed that the def iciency of vit amin D (Vi t
D) may be a fac tor to be conside red in the patho physiolog y
VitaminD3correlatewell withsynthesis of proteinsthat
are necessary for skin barrier function, these mechanisms
suggest a role of 1,25-dihydrox yvitamin D in modulating
AD severity.8M any researche s have investigate d differen ce
betwee n 25-dihydroxy vitamin D 25(O H) D levels in AD pe-
diatric patients and matched healthy control. A meta-analy-
sis of these s tudies found a m ean deference of −16 nmol/L
in pediatric AD patients compared to healthy control.6 There
is growing interest in the possible role of vit D deficiency in
the development of AD. The aggravation of AD in winter, es-
pecially in higher-latitude countries, where serum 25(OH)D
levels tend to be predominantly low in this season, has been
documented.7Inaddition ,ge neticpolym orphi smsoftheV itD
receptor have been identified as contributor to the develop-
ment of AD.8
A recent meta-analysis of interventional studies documented
that Vit Dsupplementation was linked to clinically relevant re-
duction in AD disease severit y both in adult and pediatric pa-
tients.6 The result s of this analysis must be interpreted with
caution particularly for children due to presence of multiple se-
rious limitations. First, the analysis included only one random-
izedcontrolled trial with very limitedsamplesize(n=20)inthe
age group from 1 to 18 years old.9 Another notable limitation is
that the AD patient population involved in this analysis consisted
mostly of mild and moderate AD with very few severe cases.9-
patients with severe AD who is limited yet important subset of
To the best of our knowledge, this is the first study to inves-
tigatepotential benefits of Vit D supplementationin children
and adolescents with severe AD. Therefore, the primary aim of
in conjunction with standard treatment in severe AD.
2 | METHODS
2.1 | Study design
This study was a double blind, randomized, parallel, placebo con-
trolled clinical trialperformedattheNational HepatologyandTropical
istered undertheidentifierNCT04468711.Thetrial was conducted in
accordance with Good Clinical Practice guidelines and the Declaration
ofH e ls ink i.Infor med co nse ntwasob t ai ned fr omt hepar ent sofa llc ase s.
2.2 | Subjects
Subjec ts enrolled in th e period from 6th Ju ne to 1th September,
2018. Inclusion criteria included: patients aged from 5 to 16 years
old, wit h a diagnosis of seve re AD accordi ng to Hanifin a nd Rajka
criteria, and the Eczema Area and Severity Index (EASI) score.12
Reasons for exclusion were serious skin disorder other than AD, tak-
ing systemic corticosteroids or anti-inflammatory medications, prior
vitamin D supplementation, receiving oral or topical antibiotics or
topical calcineurin inhibitors for at least 1 week prior to enrolment,
known gut absorption problem, presence of active skin infection at
baseline, and any known hepatic and/or renal disease.
Participants were allocated in 1:1 ratio to receive either vit amin
hydrocortisone cream twice daily for 3 months. We used a computer
random number generator to form the allocation list for the two com-
parison groups. Treatment allocation was concealed in sequentially
numbered, sealed, opaque envelopes from the patient s, and the out-
come assessors. The upper tolerable limit, defined as the highest level
of daily vitamin D3 intake that is safe in the general population, for
adolescents and adults.13 Data from clinical trials indicated that daily
supplem entation wi th this dose (1600/d) resul t in a clinicall y mean-
ingful AD severit y reduc tion.6 We assumed that this dose would be
safe and ef fective as well. Treatment assignment was masked from the
participants and the investigators. A diet ary history was obtained at
study entry with attention to potential sources of vitamin D, no signif-
icant group differences were prominent, and diets were stable during
the study. A single pediatric dermatologist performed all clinical eval-
uations at baseline and at the end of the study. At baseline patient
demographic data, laboratory analysis and clinical charac teristics were
2.3 | Serum 25(OH)D analysis
Two milliliters of blood were withdrawn from patients, allowed to
clot, and t hen centri fuged for 10 minute s and then kept f rozen at
−80°C at t he Centra l Labs of NHTM RI, Cairo , Egypt . Quantita tive
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MANSOU R et Al.
determination of serum 25(OH) D, using commercial automated
ELISA, DRG International Inc, USA, according to manufacture in-
structions, was per formed.14 For the primar y analysis in this study,
we categori zed the serum 2 5(OH)D levels in to three clini cally rel-
Guidelines15whicharedeficient(<20ng/m L),in su fficie nt(21-29ng/
2.4 | Clinical assessment
Dermatological examination was performed to all the patients to as-
sessthe dermatitisseverityusing EASI score.16 It is a tool used to
evaluate the severityofeczemainfourdefinedbody regions(head
andneck,torso, arms,and legs), evaluating severity of fourclinical
involveme nt) to 6 (90%-100% involvement), a nd severity is m eas-
ofEASIscores from0 toa maximumscore of72.Thepotential se-
verity stratafor EASIis0almostclear,0.1-1clear,1.1-7mild,7.1-21
moderate, 21.1-50 severe, 50-72 very severe.12 Patients were clini-
cally evaluated every 4 weeks.
2.5 | Outcomes
2.5.1 | Primary endpoints
2.5.2 | Secondary end points
Included propor tion of patients with a reduction from baseline to
week 12 of:
• ≥75%onEASIscore(E ASI75).
• <50%onEA SIscore(EASI<50).
2.6 | Statistical analysis
2.6.1 | Sample size
Consideringthe reduction in disease severity after VitD supple-
mentation reported by Sanchez-Armendariz et al,4 a sample size
of 84 patie nts was neede d to provide at leas t 80% power and a
two-sided type I errorless than 0.05. The sample size was calcu-
lated using the G*Power© software (Institutfür Experimentelle
Psychologie, Heinrich Heine Universität, Düsseldorf, Germany)
ve r sion 3 .1 .9.2.
as mean and standard deviation or median and range as appropri-
ate.Qualitativedata were expressed asfrequencyandpercentage.
Numeric data were tested for normalit y using Shapiro-Wilk test.
Data were found not normally distributed, so the nonparametric
tests were used. Comparison between two groups was done using
then post-Hoc test was used for pair-wise comparison based on
Kruskal-Wallisdistribution.Spearman-rho methodwasused totest
correlation between numerical variables. Wilcoxon-signed ranks
utive measures of numerical variables.
3 | RESULTS
3.1 | Participant characteristics
pleted the study and was included in the final analysis. At baseline,
both groups were comparable in demographic and clinical character-
istics. Patients’ demographics and clinical characteristics at baseline
3.2 | Serum 25 (OH) D concentrations
At base line , no statistic ally significan t difference was fo und between
both study arms regardingthe 25(OH)Dserum levels (P = .18). In
addition,distribution of 25(OH)Ddeficiency categories was similar
betwee n the two groups ( Table 1). Asso ciation betwee n baseline
25(OH) D levels andpotential deficiency risk factors wasexplored
in the whole study subjects. Inverse weak relationship was estab-
lishedbetweenbase line25(OH)Dserum levelsandthebodymass
index (BMI) (Spearman's rhor = −.4 4, P < .0 01). Weak association
was registered between baseline 25(OH)D serum levelsand initial
EASIscore(Spearman'srhor = .34, P =.001).
IntheV itDgroup,significant improvement in 25(OH) Dserum
levels was achieved postsupplementation compared to baseline
(P = <.001).Ninety-threepercent(n=4)oft hevit aminDg roupp op -
which toxicity has not been observed.17
Intheplaceb ogroup,levelof25(OH)Dwascomp arabletobase-
linelevel (P = .47) atthe end of the study.Atweek12,about 74%
of the placebo group subject s remained under levels of sufficiency
(<30ng/mL). Significantlyhigher levelwasrecordedbetweensup-
plementedgroup(36.11± 5.84) and placebo group (25.86±8.27)
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MANSOU R et Al.
Table 2 showed that children supplemented with vit D fared bet-
ter than those allocated to pla cebo. At the end of the study, the mean
percentage change from baseline in EASI score was significantly
greater with vitamin D group (56.44%) than with placebo group
(42.09%) (P =.0 39) .Figure2depic tsth ed if fe re ntresponsec at egor y
attained at the end of the study. Figure 3 showed that comparable
propor tion in the vitamin D group and placebo group (52.2% vs
59.5%)experiencedmodestresponse totreatment(E ASI <50).On
contrast, different patterns were notable between supplemented
patients and those allocated to placebo group regarding percentage
FIGURE 1 CONSORTflowdiagram
showing the flow of patients throughout
Assessed for eligibility (n=162)
Not meeting inclusion criteria (n=55)
Declined to participate (n= 15 )
Analysed (n= 44)
Drop out (n=3)
•Lost to follow-up (n=2)
Allocated to Vit. D (n= 47)
Drop out (n=3)
•Commencement of oral therapy
Allocated to placebo (n= 45)
Randomized (n= 92)
Treatment group Placebo group P value
Age(years)a 12(4.75) 11(5.5) .06
Male 26(59.1) 18(42.8)
Female 18(40.9) 24(57.1)
BMI(kg /m2) 27.1(5.3) 26. 6(4.7)
Normalweightn(%) 15(34.1) 12(28.6)
Overweightn(%) 13(29.5) 20(47.6)
Obesen(%) 16(36.4) 10(23.8)
Serum25(OH)Dlevels 22.8(6.2) 25.4(8.1) .18
<20ng/mL(deficient) 15(3 4.1) 11(26.1)
20-29ng/mL(insufficient) 22(50) 19(45.2)
≥30ng/mL(suf ficient) 7(15.9) 12(28.6)
EASIscore 44.4(6.28) 46.4(5.4) .10
Calcium(mg/mL) 8.81(0.87) 8.7(1.03) .49
Parathyroidhormone(pg/mL) 32.4(5.7) 32.1(6.7) .88
TABLE 1 Baseline demographics and
clinical characteristics for both groups
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MANSOU R et Al.
in the placebo group.
Potential predictors that might cause superior clinical outcomes
among pat ients who achi eved EASI 75 were fu rther invest igated.
nitude of change frombaselinein 25(OH)D (Spearman's rho r = .6,
P =.005). However,fair correlation was establishedbetween BMI
and % change i n EASI score (Sp earman's rho r = .54, P = .01) in
this subset of patients, which might indicate causality. To test the
hypothesis that different magnitude of change from baseline in
serum 25 (OH)D exist s among patie nts with bet ter respon se cate-
gory, the non-parametric Kruskal-Wallis test in combination with
pairwise post-hoc test was per formed to compare the respective
significant group; results presented in Figure 4. Pairwise compari-
sonsrevealedasignificantrelationshipbetweenbothEASI< 50 and
EASI 75(P < .001) and betweenEASI50 and E ASI 75 responders
significance when the different response categories were compared
regardingdistribution ofBMI among different respondents’ranks.
4 | DISCUSSION
centered around the use of topical steroid preparations and moistur-
with this initial conventional therapy might benefit from second-line
therapies, such as systemic and topical immunosuppressive medica-
tions.18Most ofthese therapieshavepotential adverseef fectsand
nearly all are off label for AD in children. The present study was de-
signed to test the hypothesis that vitamin D supplementation as an
adjuvant therapy might benefit the severe AD children, and since
recent evidence has demonstrated that it improved the clinical out-
come in mild and moderate AD pediatric patients.
According to our knowledge our study is the first to assess the
efficacy of vit D in conjunction with standard treatment in patients
of 25(OH)D deficiency was notable among all study population.
Similar finding has been previously reported in Egyptian children
with AD and in healthy control as well.3Tounde rstandthe25(OH) D
status associated with AD, the factorsthat might influence25(OH)
D deficiency were investigated. In the present study, lower base-
line 25(OH)D levels were observed inobese patients. Sometrials
reported similar inverse relationship,19 while others not.20 This neg-
ative influence of obesity has been suggested to be due to the lipo-
At the end of the study, a statistically significant difference was
themea n%chan gefromth ei rb as eline.Theimpa ctof VitDor alsup-
plementationasan adjuvanttherapyoneczemaseverity modifica-
tion has been previously investigated. In line with the results of the
present study,Oralvit Dsupplementreduced theskincolonization
TABLE 2 Changeinseverit yofADandserum25(OD)Dlevels
for both groups at the end of the study
MeanEASIscore 20.42(14.6) 27.47(10.11) .035
56.44(29.33) 42.09(19.22) .039
36.11(5.84) 25.86(8.27) <.0 01
FIGURE 2 SeverityofADattheendof
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MANSOU R et Al.
of S aureus and demonstrated clinical improvement in children with
moderateeczema.9 Similarly, oralVit D supplementation has been
shown to improve winter-related AD symptoms.21 The observed im-
provement in disease severity from vitamin D supplementation has
strong biologicalplausibility as1,25 (OH)Dcontributestohallmark
features of AD: altered barrier function, immune dysregulation, and
inadequate bacterial defense. This might explain the positive impact
of supplementation recorded in the present study. Opposing our
finding, Galli et al22reportedthatdailyoralVitD3 supplementation
children. Lack of correlation with our results might be attributed to
the difference inthe patient population asthe majority (53.9%)of
ina pilotstudy that VitD supplementation did not significantly in-
fluence t he severity of dis ease in children . The small sampl e size
(n=12)andshortdurationofvitDsupplementation1 might explain
this lack of connection with our result s.
The EA SI score was chose n by the internatio nal Harmonizing
OutcomesMeasures in Eczemagroup (HOME) tobe included asa
core clinical outcome measure in AD clinical trials.24Val idati ons tu d-
responsiveness which represent the key performance properties
ne ede df oranyou tcome in str u me nt. However, da t ar ega rd ing ho wa
formation are not available.25 It can be seen from checking the band-
ing of diff erent EAS I strata th at the distri bution of sever ity scale
across strata is not equal. This skewness makes changes in the lower
end of the score more clinically important than changes in the upper
end. There are no previous reports that clearly define a responder
thresholdfor%changefromb as el in einE ASIs co reforpatientswith
severeAD ;h ow ev er, str at ifyingpa ti ent sa ccord in gt o%re duc tionin
EA SIscore stoEAS I50an dE ASI75wa sco nsideredb ymanypivot al
trials to illustrate clinically important differences.26-2 8 At the end of
the study, significant difference between the two groups was ob-
tainedregarding proportionofpatientsachieving EASI<50,EASI
50 ,a n dE A S I75( P <.0 01) .I ntr eat men tgr oup ,3 8 .6%vs 7.1% in con -
trol group achieved EASI 75. However,the percentage of non-re-
sponders deemed comparable between the supplemented patients
andthoseallocatedtoplacebo (59.5%vs52.2% ,respectively).This
indicates that some supplemented patients might achieve excessive
benefit from treatment. Indeed, diverse factors could be linked to
FIGURE 3 Percentage of patients who
achieved <50%improvementinEA SI
FIGURE 4 Clusteredboxplotshowing(A)thedistribution
of change in vitamin D levels [P value <.001(treatmentgroup),
=.294(placebogroup)](B)thedistributionofBMI[P value = .057
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MANSOU R et Al.
this preferential response. On one hand, fair correlation between
dents. Moreover, 25(OH)D deficie ncy was high prevale nt among
response to supplementation in adults29 and adolescents.30So,it
is conceivable to suggest that the high %reduction in EASIscore
postsupplementation in some obese patients might be influenced
bythebaseline 25(OH)D concentration;however,thedistribution
egories. Further studies are needed to elucidate whether response
tosupplement ationwouldva ryaccord ingtotheBMIinpatientwith
On the other hand, statistically significant difference existed be-
tween the different response categories and magnitude of change
ways. Firstly, variation in the factors that negotiate absorption ef-
ficienc y of oral supp lementat ion in the gas trointest inal trac t (GIT)
might have existed among some supplemented patients. These fac-
tors include variations in the amount and type of fatty acids,31,32
dietar y fibers, and the interaction with other fat soluble micronutri-
ents.33Se cond,thehost-associatedfactorssu chasgeneticvariation
might provide another explanation.34 Thus, it is plausible to hypoth-
patients due to variation within these previously mentioned fac tors,
however, a clear cut is yet lacking.
One limitation of our study is that the study population was com-
prised of patients with limited ethnic diversit y, potentially restrict-
ingits generalizability.Futurestudieson more diverse populations
are needed. Another limitation, lack of data from other important
domains,such as patient reported outcomes. Moreover,given the
needed to determine if the benefits of supplementation would sus-
Inconclusion, our study sug geststhat oraldaily VitDsupple-
ment might provide clinical improvement in children with severe
AD. More inves tigations are ne eded to reveal fac tors associate d
with superior clinical outcomes in some supplemented patients. We
advocatefurthermulticenters tudieswithlar gersamplesizeofeth-
nic diverse population to validate the potential benefit of vit D on
clinica l outcomes of seve re pediatri c eczema. Fur ther stu dies are
also needed to examine whether the positive impact of supplemen-
tation would be maintained in pediatrics with winter-related severe
Parti cipated in resea rch design: Eman A ., Amal, Noha , and Maha.
Conduc ted the clinic al part: Ema n A, Aliaa, M aha, Eman E., So ha,
Nourelhuda, and Doaa.Performed data analysis: Noha, Eman, and
Soha, Ema n E. Drafted t he manuscript : Maha, Nourelh uda, Doaa,
DATA SHARING AND ACCESSIBILIT Y
The data that support the findings of this study are available from
the corresponding author upon reasonable request.
Noha O. Mansour https://orcid.org/0000-0002-4448-994X
Soha Hassanin https://orcid.org/0000-0001-8568-1033
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