Received: 25 April 2018 Revised: 17 June 2018 Accepted: 21 June 2018

DOI: 10.1111/dth.12659

REVIEW ARTICLE

Topical micronutrients in atopic dermatitis—An evidence-based

review
M. Maarouf1 | A. R. Vaughn2 | V. Y. Shi3

1
College of Medicine, University of Arizona,
Tucson, Arizona
2
College of Medicine, Drexel University,
Philadelphia, Pennsylvania
3
Department of Medicine, Division of
Dermatology, University of Arizona, Tucson,
Arizona
Correspondence
Vivian Y. Shi, MD, Department of
Dermatology, University of Arizona, 7165 N.
Pima Canyon Dr., Tucson, AZ 85718
Email: vshi@email.arizona.edu
Abstract
The role of dietary factors is an important and controversial topic in the pathogenesis of atopic
dermatitis (AD). Despite the preponderance of consumer products utilizing oral micronutrients
supplementation for relief AD symptoms, less attention has been paid on the utility of topical
micronutrients, specifically for individuals with AD. We review evidence on topical formulations
of vitamins (A, B, C, D, and E) and trace minerals (magnesium, manganese, zinc, and iodine) for
treatment of AD. While topical B, C, and E formulations appear to provide some benefit to AD
individuals, topical vitamin A has no utility, and topical vitamin D may exacerbate symptoms.
Magnesium, zinc, and iodine all appear to improve AD through anti-inflammatory and anti-
microbial effects, though future studies must evaluate their use as monotherapy. The exposition
of the effects that topical micronutrients have on AD offers an adjuvant treatment modality for
this common inflammatory dermatosis.

KEYWORDS

atopic dermatitis, micronutrients, minerals, topical therapy, vitamins

1 | I N T RO D UC T I O N
Atopic dermatitis (AD), the most common form of eczema, is a chronic
pruritic inflammatory skin condition with a multifactorial etiology
including immunologic, genetic, and environmental components. Its
incidence has steadily been increasing, and affects 20% of children
and 2–10% of adults from industrialized countries (Miller & Peden,
2014). In addition to inflammatory responses, epidermal barrier dys-
function is caused by microbial colonization and intrinsic barrier lipid
and protein deficiency (Howell et al., 2009; Kim, Leung, Bogunie-
wicz, & Howell, 2008). Oral intake of micronutrients such as vitamins
and minerals has been shown to play a modest role in AD (Amestejani
et al., 2012; Camargo et al., 2014; David, Wells, Sharpe, Gibbs, & Dev-
(Al-Niaimi & Chiang, 2017; Butt et al., 2017) that can be useful in AD
patients who have aberrant oxidative repair abilities. Minerals, such as
magnesium, zinc, and iodine, when used as bathing additives and anti-
septic solutions, have an added benefit of reducing inflammation and
bacterial colonization that notoriously afflicts AD lesions.
The goal of this review is to highlight current evidence on the
benefits of topical micronutrients in AD, and identify knowledge gaps
for future investigations.
2 | M A T E R I A L S A N D M ET H O D S
A review of the medical literature was completed in August 2017 by

lin, 1990; Jaffary, Faghihi, Mokhtarian, & Hosseini, 2015; Kim, Yoo, two research personnel. A search of PubMed, EMBASE, and Goo-

Jeong, Ko, & Ro, 2014; Leveque et al., 2003; Martindale et al., 2005;
Oh, Chung, Kim, Kwon, & Cho, 2010; Sidbury, Sullivan, Thadhani, &
Camargo, 2008; Sugiura et al., 2005; Toyran et al., 2012; Tsoureli-
Nikita, Hercogova, Lotti, & Menchini, 2002), while the role of topical
micronutrients is less well studied. Vitamins A and B induce cell prolif-
eration, which has the ability to strengthen epidermal barrier function
(EBF), while vitamins C and E exert potent anti-oxidative effects
gleScholar databases was conducted to identify all studies reporting
the use of topical micronutrients for atopic dermatitis. Search terms
included “atopic dermatitis” or “eczema” and “topical” and “micronutri-
ents” or “vitamin A” or “retinol” or “retinoic acid” or “retinaldehyde” or
“tretinoin” or “vitamin B,” or “thiamine,” or “riboflavin,” or “niacin,” or
“pantothenic acid,” or “pyridoxine,” or “biotin,” or “folic acid,” or
“cobalamin,” or “vitamin C,” or “ascorbic acid,” or “vitamin D,” or

Dermatologic Therapy. 2018;31:e12659. wileyonlinelibrary.com/journal/dth © 2018 Wiley Periodicals, Inc. 1 of 9

https://doi.org/10.1111/dth.12659
2 of 9
“vitamin E,” or “vitamin K,” or “trace minerals,” or “magnesium,” or
“manganese,” or “chlorine,” or “sodium,” or “potassium,” or “zinc,” or
“iodine,” or “copper,” or “iron,” or “selenium,” or “strontium.”
Literature used in this review was prospectively limited to case
reports, case–control studies, cross-sectional studies, and randomized
control trials (RCT) that were published in the English language.
Review articles were excluded. The authors conducted a manual
review of the titles and abstracts identified from the search. All stud-
ies were included, regardless if they led to clinical improvement. The
authors were not blinded to the names of authors, journals, or institu-
tions. The authors' conclusions are based on available evidence from
the 16 human and 4 murine studies that are reviewed herein.
3 | VITAMINS
3.1 | Vitamin A
Vitamin A is a fat-soluble vitamin and member of the retinoid family,
with topical derivatives including retinol, retinoic acid, retinaldehyde,
tretinoin, as well as synthetic derivatives. Vitamin A is an essential vita-
min that must be obtained through dietary sources such as leafy vege-
tables, papayas, carrots, tomatoes, eggs, and milk. Within the skin,
retinol and retinyl esters are essential for immune modulation, cellular
survival, differentiation, and proliferation (Ross & Harrison, 2007).
When used topically, vitamin A derivatives reduce signs of skin aging
through induction of epidermal thickening and glycosaminoglycan
deposition (Griffiths, Finkel, Tranfaglia, Hamilton, & Voorhees, 1993).
Additionally, topical vitamin A increases fibroblast growth and collagen
synthesis, while reducing the levels of collagen-degrading matrix
metalloproteinases (MMP) in both naturally aged, sun-protected skin,
and photoaged skin (Varani et al., 2000). Cutaneous manifestations of
vitamin A deficiency include xerosis, deep skin fissures, dry hair and
fingernails, and follicular hyperkeratosis (Ross & Harrison, 2007).
The skin of AD patients has significantly reduced retinoic acid and
retinol concentrations, suggesting AD skin may have perturbed reti-
noid signaling pathways (Mihaly, Gamlieli, Worm, & Ruhl, 2011).
Despite case series successfully using oral Alitretinoin (a synthetic ret-
inoid binding to all known retinoid receptors) to treat severe AD
(Grahovac, Molin, Prinz, Ruzicka, & Wollenberg, 2010; Son et al.,
2017), clinical trials evaluating the use of topical vitamin A derivatives
in AD are scarce. In a double blind, split-body study in 18 subjects
with eczema, researchers compared the clinical effects of triamcino-
lone acetonide 0.1% (TA) versus TA + retinoic acid 0.025% (TARA)
cream (Schmied, Piletta, & Saurat, 1993). No significant differences
were seen in response to the two treatments after 3 weeks, although
TARA-treated skin was associated with significantly more irritation.
The authors concluded that retinoic acid can be added to corticoste-
roid treatment to reduce the risk of dermo-epidermal atrophy induced
by topical steroids, without affecting anti-inflammatory responses
(Schmied et al., 1993). However, this balance may be difficult to
achieve, and careful lesion selection and dosing regimen must be con-
sidered, as retinoin is known to cause irritant contact dermatitis. This
is especially important among AD patients who already have sensitive
skin and defective barrier.
MAAROUF ET AL.
3.2 | Vitamin B
There are 8 B vitamins, which include vitamins B1 (thiamine), B2 (ribo-
flavin), B3 (niacin), B5 (pantothenic acid), B6 (pyridoxine), B7 (biotin),
B9 (folic acid), and B12 (cobalamin). B vitamins are important for main-
taining healthy mucous membranes and skin, nervous system func-
tion, normal cellular function, and energy production. With the
exception of small amounts of vitamin B3, humans are not able to syn-
thesize these water-soluble vitamins, and thus they must be obtained
through dietary intake (Said, 2011). In general, B vitamins are obtained
through animal products, such as poultry, fish, and eggs, but can also
be obtained through enriched cereals and supplementation. Clinical
manifestations of vitamin B deficiency are usually dependent on the
specific B vitamin. For instance, riboflavin deficiency is associated
with mucositis, cheilitis, and glossitis (Jen & Yan, 2012), while niacin
deficiency manifests as a photosensitivity dermatitis in a unique distri-
bution on the neck, hands, and feet (Isaac, 1998).
Inducible nitric oxide synthase is found in high levels within kera-
tinocytes in AD lesions. High levels of this enzyme are associated with
increased production of nitric oxide, and is often implicated in the
pathogenesis of AD (Ormerod et al., 1998). Vitamin B12 has potent
activity as an antioxidant nitric-oxide scavenger (Broderick et al.,
2005), and thus, may play an important role in AD lesions. Stucker
et al. compared topical vitamin B12 cream containing 0.07% cyanoco-
balamin to an identical placebo cream in a randomized, placebo-con-
trolled, split-body clinical trial in 49 adults with AD. After 8 weeks of
twice daily application, the modified Six Area Six Sign AD score
(SASSAD) decreased to a significantly greater extent on the vitamin
B12-treated body side than the placebo-treated side (55.34  5.74
and 28.87  4.86, respectively; p < .001). At the conclusion of the
treatment period, the investigators and the patients reported that the
overall efficacy of vitamin B12 cream was “good” (58%) or “very good”
(59%), while the placebo’s efficacy was rated as moderate (89%) and
poor (87%). Adverse events attributable to the intervention cream
included burning (n = 2), itching (n = 2), and redness (n = 1). Following
application of the placebo cream, 1 patient had itching and weeping
(Stucker et al., 2004). In a similar prospective, placebo-controlled
study using intra-individual split body comparison, Januchowski
et al. compared a cyanocobalamin 0.07% cream versus placebo in
26 AD children ages 6 months to 18 years old. After 4 weeks, both
the intervention and placebo-treated areas had a drop in total SCOR-
ing of AD (SCORAD) values, although the decrease in the vitamin
B12-treated group was significant compared with placebo at 2 and
4 weeks (p = .02 and 0.01, respectively) (Januchowski, 2009). In Nis-
tico et al.’s intra-individual split body RCT involving 22 mild AD
patients, the side of the body treated with MB12 (vitamin B12-barrier
cream) 2–3 times per day for 12 weeks had improvement in SCORAD
and decrease in pruritus from baseline compared to the side treated
with the control glycerol–petrolatum-based emollient cream
(p < .001) (Nistico et al., 2017).
B3 (niacin) deficiency can lead to pellagra, associated with derma-
titis, dementia, and diarrhea. Topical application of nicotinamide to
dry skin of healthy human volunteers results in increased epidermal
ceramide and free fatty acid production with concomitant decrease in
TEWL. These structural changes result in strengthened EBF that have
MAAROUF ET AL.
utility in AD skin. However, in a cohort analysis of female nurses,
increased supplementation (>18 mg/day niacin) resulted in a 16%
increased risk of developing AD (Drucker et al., 2017). Such effects on
the skin led Soma et al. to investigate the effect of a topical cream
containing nicotinamide 2% (a form of vitamin B3) versus white petro-
latum (WP) in 28 patients with AD for 8 weeks (Soma et al., 2005).
The nicotinamide-treated skin had a significant reduction in transepi-
dermal water loss (TEWL) after 8 weeks of twice daily treatment
(p < .05), whereas the WP-treated skin did not show a significant
decrease in TEWL. Based on skin capacitance measures, both nicotin-
amide and WP-treated areas showed a significant increase in stratum
corneum (SC) hydration after 4 weeks (p < .01) and 8 weeks (p < .01).
However, the nicotinamide-treated skin showed significantly higher
hydration than the WP-treated areas (p < .05). Although both groups
had a significant improvement in clinical appearance (dryness and scal-
ing), there was no significant difference between the two. Reported
adverse events included itching in two patients after nicotinamide
treatment. This study suggests nicotinamide cream may be superior to
WP in its ability to reduce TEWL and increase hydration in atopic skin,
possibility through its ability to stimulate keratinocyte production of
ceramides and other intercellular lipids (Tanno, Ota, Kitamura,
Katsube, & Inoue, 2000).
Vitamin B5 encourages wound healing by inducing keratinocyte
proliferation and increasing glutathione antioxidant in the skin
(Slyshenkov, Dymkowska, & Wojtczak, 2004). These promising func-
tions influenced researchers to investigate the effectiveness of an
ointment containing dexpanthenol 5% (vitamin B5) compared with
hydrocortisone 1% in 30 children with AD. In this intra-individual
split-body comparison study, there was no significant difference in
AD severity, as assessed by SCORAD, between the two treatments
after 4 weeks of twice daily application. No adverse events were
reported with either treatment, and the authors concluded that dex-
panthenol 5% ointment might be equally efficacious as hydrocortisone
1%, and may be used as an alternative therapy in children with mild to
moderate AD (Udompataikul & Limpa-o-vart, 2012).
3.3 | Vitamin C
Vitamin C, also known as ascorbic acid, is a water-soluble vitamin with
strong antioxidant properties. Vitamin C also plays an essential role in
collagen synthesis, wound healing, iron absorption, and many more
physiological processes throughout the body (Griffiths, Barker, Blei-
ker, Chalmers, & Creamer, 2016; Hallberg, Brune, & Rossander, 1989).
Vitamin C is an essential vitamin obtained from dietary fruits and veg-
etables. Although rare in developed countries, vitamin C deficiency
can lead to scurvy, characterized by easy bruising and bleeding gums,
follicular hyperkeratosis, poor wound healing, and “corkscrew” hairs
(Jen & Yan, 2012). Topical vitamin C is formulated into numerous skin
care products, aimed at reducing sings of skin aging by fighting free
radical damage, increasing collagen synthesis, and decreasing hyper-
pigmentation (Choi et al., 2010). The natural form of topical vitamin C
used in skin care products is l-asocorbic acid. Commonly used syn-
thetic forms of vitamin C are ascorbyl-6-palmitate, sodium ascorbyl
phosphate, ascorbyl glucoside, and tetrahexyldecyl ascorbate.
3 of 9
Sivaranjani et al. concluded that AD patients have a lower oxida-
tive repair ability associated with significantly lower serum level of
vitamin C than the healthy controls without AD (1.33 mg%
vs. 0.63 mg%, respectively, p = .001) (Sivaranjani, Rao, & Rajeev,
2013). Unfortunately, there are no published clinical trials looking at
the effects of topical natural vitamin C or synthetic vitamin C ana-
logues in AD patients.
Despite its positive antioxidant benefits, vitamin C is unstable,
easily oxidized, and does not easily penetrate into the dermis. To
overcome these limitations, zinc oxide (ZnO) has been compounded
with vitamin C. Its hydrophobic exterior allows the formulation to
penetrate target tissues and consistently release vitamin C for longer
than 12 hr (Lee, Jeon, Choi, Kim, & Kim, 2017). Using a mouse model
of house mite-induced AD, daily application of vitamin C-zinc oxide
complex cream (VitabridC12) for 6 days significantly decreased epider-
mal thickness (p < .05) and reduced mast cells (p < .05) compared with
the control group that were not treated with any cream. Because ZnO
has its own anti-inflammatory, antioxidant, and antimicrobial effects
that could influence the results (Jones, Ray, Ranjit, & Manna, 2008),
the group investigated the difference in inflammatory serum markers
between the ZnO vehicle (Vitabrid) compared with VitabridC12. Vitab-
ridC12 treated mice had significantly decreased expression of pro-
inflammatory IL-4 and chemokine ligand 4 (CCL4) and pro-allergic
cytokine thymic stromal lymphopoietin (TSLP) (p < .05), compared
with Vitabrid (Lee et al., 2017). These are promising results that
deserve further exploration in clinical trials.
3.4 | Vitamin D
Vitamin D is a fat-soluble hormone that plays an important role in cel-
lular proliferation and differentiation, calcium and phosphorus homeo-
stasis, and immunity (Strohle, 2011). The role of vitamin D deficiency
in the pathogenesis of AD has been widely studied, yet the value of
oral vitamin D supplementation in improving AD remains inconclusive.
Li et al. reported that the keratinocytes of mice treated for 4 days
with either 4 nm of 1α,25-(OH)2D3 or its low-calcemic analog MC903
(calcipotriol; Dovonex) exhibit dose-dependent elevations of TSLP RNA
and CYP24A1 [an 1α,25-(OH)2D3] inducible gene. To determine long-
term induction of AD, the mice were treated with MC903 (4 nmol) daily
or 1α,25-(OH)2D3 (0.25 nmol) every other day for 16 days. Application
sites of both interventions became erythematous, scaly, swollen,
crusted, and pruritic, identified by incessant scratching of the site. Biop-
sies of skin exposed to MC903 showed epidermal hyperplasia and a
heavy eosinophilic infiltrate. Additionally, serum IgE and IgG levels and
AD-associated cytokines (TSLP, IL-4, -5, -13, -31, -10, and -6) in the
MC903 group were markedly increased, suggesting that topical applica-
tion can induce systemic abnormalities (Li et al., 2006). Vitamin D ana-
logues used in this study upregulated the expression of TSLP, the
primary inflammatory molecule that provokes AD, demonstrating the
futility of vitamin D as a treatment for AD.
Turner et al. applied calcipotriene solution or isopropanol on a
Stat6VT transgenic AD-mouse model. After daily application for 7 days,
all mice from both interventions developed unresolving eczematous
dermatitis at the application sites lasting 10 weeks, at which time biop-
sies were taken. Histologic analysis of calcipotriene-treated sites
4 of 9
revealed parakeratosis, acanthosis, spongiosis, and perivascular and
interstitial lymphocyte-predominant infiltrate, consistent with AD-like
lesions, which was in contrast to the vehicle-treated skin and non-
lesional skin from Stat6VT mice. Analysis by qPCR demonstrated signif-
icant IL-4 expression in calcipotriene treated skin when compared with
isopropanol-treated skin (p < .01). Exact IgE values were not provided
(Turner et al., 2013). The results are consistent with the aforemen-
tioned study in that topical vitamin D analogue induces AD.
While the effects of topical vitamin D analogues on AD-animal
models are worrisome, there are no large studies that examine vitamin
D’s effect in humans. Turner et al. reported a severe flare of eczema-
tous dermatitis in a 2-year-old Indian boy 24 hr after receiving calci-
potriene 0.005% cream and solution to the face and scalp following a
misdiagnosis of psoriasis. The flare progressed over 5 days of calcipo-
triene use and regressed within 72 hr of calcipotriene discontinuation
and initiation of a low potency topical corticosteroid. Paradoxically,
the boy subsequently had a negative patch test to calcipotriene
cream, which proposes the possibility that the AD flare was caused by
an alternate cause. Alternatively, calcipotriene may not induce visible
dermatitis on non-lesional skin, but may exacerbate pre-existing active
AD lesions (Turner et al., 2013). Nevertheless, topical Vitamin D does
not appear to be beneficial in treating AD.
3.5 | Vitamin E
Vitamin E is an essential lipophilic antioxidant found in plasma,
membranes, and tissues, and can be obtained from dietary
vegetables, vegetable oils, cereals, and nuts (Thiele, Hsieh, &
Ekanayake-Mudiyanselage, 2005). In conquest of discovering nonste-
roidal compounds to treat delayed-type hypersensitivity reactions,
Tobe et al. synthesized a vitamin E analogue. Compound 28c
(CX-659S) was found to exert potent anti-inflammatory when admin-
istered topically (IC50 of 5.9 μM) on mice with picryl chloride-induced
contact hypersensitivity reaction (Tobe et al., 2000).
In a double-blind RCT, 44 patients with mild to moderate
(IGA2–3) AD and active facial and neck lesions were treated with
MD2011001 (a nonsteroidal topical cream containing vitamin E, epi-
gallocatechin gallate, and grape seed procyanidins) for 28 days. About
70% of the participants in the MD2011011 group and 89% of those
in the vehicle-only placebo group achieved an IGA of 0 or 1 (Patrizi
et al., 2016). Despite similarity in clinical response rate, approximately
90% of patients in the study group considered the tolerability of
MD2011001 to be “good” or “excellent,” with nearly 50% believing
that the formulation's tolerability was superior to other topical agents
they had used in the past. Significantly more participants in the vehicle
group reported skin irritation (49 vs. 24%, respectively, p = .034)
(Patrizi et al., 2016).
4 | TRACE MINERALS
4.1 | Magnesium
2+)
Magnesium (Mg has anti-inflammatory properties and plays a role
in cell proliferation and differentiation, exerts direct anti-inflammatory
MAAROUF ET AL.
effects by suppressing TNF-α and IL-12 production by epidermal cells,
and inhibits expression of B7-1 and B8-2 co-stimulatory molecules on
HLA-DR+ Langerhans cells (Schempp et al., 2000). Lipkin et al. reported
that whole skin and dermal magnesium levels were significantly higher
in patients with AD compared with healthy controls (1.5  0.4
vs. 0.9  0.4; p < .01), while epidermal magnesium content was not
significantly different between the two groups. This creates specula-
tion surrounding the presence of an inhibitor of magnesium utilization
in atopic skin (Lipkin, March, & Gowdey, 1964).
Ceramides are waxy lipid molecules that constitute the lamellar
sheets within the intercellular SC spaces, and function to strengthen
EBF. In a split-body double-blind RCT, 100 subjects with mild to mod-
erate AD were randomized to Group 1 [topical cream containing both
magnesium and ceramides (Cer-Mg) and hydrocortisone acetate 1%
(HC)] or Group II [Cer-Mg cream and emollient cream containing pea-
nut oil (EM)], and instructed to use their intervention twice daily for
6 weeks. Following the completion of the study, Group 1 showed sig-
nificant improvement in SCORAD (Cer-Mg: −9.0 and HC: −11.5) and
TEWL (no significant difference between interventions), while, in
Group II, Cer-Mg resulted in a significantly greater decrease in
SCORAD from baseline compared with the EM treatment (−6.7
vs. −3.5; p < .05) (Koppes et al., 2016). Cer-Mg cream appears to be
as effective as HC for alleviating symptoms associated with AD and
improving the skin barrier, while avoiding potential side effects of top-
ical corticosteroid therapy, such as skin atrophy and skin barrier
breakdown (Koppes et al., 2016). However, the cream utilized was a
compound of both ceramide and magnesium. Due to the known EBF-
repairing effects of ceramide, it is important to investigate the effects
of magnesium monotherapy alone.
Proksch et al. evaluated the efficacy of 5% magnesium-enriched
dead sea salt (DSS) solution soaks in 30 adults with AD (Proksch,
Nissen, Bremgartner, & Urquhart, 2005). In this split-body study, each
subject submerged one arm in tap water and the other arm in the 5%
magnesium-enriched DSS (Mavena® Dermaline Mg Dead Sea Salt) for
15 min daily for 6 weeks. The TEWL, SC hydration, skin roughness,
and skin redness were evaluated on the volar forearms at baseline,
and 4 hr after bathing at weeks 1, 3, 5, and 6. There was a statistically
significant decrease in TEWL in forearms treated with Mg-DSS com-
pared with placebo after 6 weeks (p < .05), suggesting that the
magnesium-enriched solution positively impacted EBF. After 6 weeks
of treatment, SC hydration in Mg-DSS arm increased by 14%, which
was significantly higher than the arms treated with tap water (p < .05).
The Mg-DSS group experienced decreased skin roughness after
3 weeks of treatment (p < .05) and decreased skin erythema after
6 weeks of treatment (p < .05), which were not observed in the tap
water-treated arms. The salt solution soaks were well tolerated, with-
out reports of irritation (Proksch et al., 2005).
4.2 | Manganese
Potassium permanganate (KMnO4) is a strong oxidizing agent and
microbicide that additionally promotes collagen synthesis. It has been
used for wound care, disinfection, and relieving symptoms of contact
dermatitis (Delgado-Enciso et al., 2018). In Stalder et al.’s week-long
RCT involving 20 children with AD treatment with topical desonide
MAAROUF ET AL. 5 of 9

TABLE 1 Summary of evidence for the role of topical micronutrients in atopic dermatitis

Reference Treatment Population (N) Study design Results

Mihaly et al. (2011) Vitamin A AD patients (n = 6) and healthy Ex vivo cross-sectional study - Compared with healthy subjects,
volunteers (n = 6) AD patients have significantly
lower gene expression of
retinoid-receptor pathways and
reduced concentrations of
retinoic acid and retinol.
Schmied et al. (1993) Vitamin A Eczema patients (n = 18) 3-week double-blind, split-body - No significant differences
study between TA cream 1% versus
TARA 0.025% after 3 weeks.
- TARA-treated skin was associated
with significantly more irritation
(p = .05).
Stucker et al. (2004) Vitamin B AD patients (n = 49) 8-week randomized - AD severity decreased to a
placebo-controlled split-body significantly greater extent on
study the vitamin B12-treated body
side than the placebo-treated
side (p < .001).
Januchowski (2009) Vitamin B AD pediatric patients (n = 26) 4-week prospective, - Significant decrease in SCORAD
placebo-controlled split-body among individuals in the vitamin
study B12-treated group.
Nistico et al. (2017) Vitamin B AD patients (n = 22) 12 week intra-individual split - Treatment with MB12 resulted in
body RCT a decline of SCORAD at
12 weeks.
- Treatment with MB12 reduced
mean pruritus.
Soma et al. (2005) Vitamin B AD patients (n = 28) 8-week RCT - Nicotinamide-treated skin had a
significant reduction in TEWL
(p < .05) and significant increase
in hydration (p < .01) compared
with white petrolatum placebo.
Udompataikul and Vitamin B AD pediatric patients (n = 30) Split body comparison study - No significant differences in AD
Limpa-o-vart severity after treatment with
(2012) either dexpanthenol 5% (vitamin
B5) or hydrocortisone 1%.
Sivaranjani Vitamin C AD patients (n = 25) and healthy Cross-sectional study - AD patients have a significantly
et al. (2013) controls (n = 25) lower serum level of vitamin C
than healthy controls without
AD.
Lee et al. (2017) Vitamin C Mice with Dermatophagoides Mouse study - Compared with placebo-treated
farina-induced AD mice, VitabridC12-treated mice
had significantly decreased
epidermal thickness (p < .05) and
significantly reduced mast cells
(p < .05).
Li et al. (2006) Vitamin D Mice Mouse study - increased expression of TSLP
cytokine and CYP24A1 in
keratinocytes with either
1α,25-(OH)2D3 or its
low-calcemic analog MC903.
- Long-term administration of
MC903 or 1α,25-(OH)2D3
resulted in AD-like lesions with
increased serum inflammatory
markers.
Turner et al. (2013) Vitamin D Stat6VT transgenic mice Mouse study - Calcipotriene solution resulted in
unresolving eczematous
dermatitis with significant IL-4
expression (p < .01).
Turner et al. (2013) Vitamin D Pediatric eczema patient (n = 1) Case report - Calcipotriene 0.005% cream and
solution resulted in a severe flare
of eczematous dermatitis, with
an elevated total serum IgE
(3,164 kU/L).
Tobe et al. (2000) Vitamin E Mice Mouse study - Potent anti-inflammatory and
anti-oxidative activity.
Patrizi et al. (2016) Vitamin E AD patients (n = 44) Double-blind RCT - Treatment with MD2011001
resulted in decline of IGA score.
6 of 9 MAAROUF ET AL.

TABLE 1 (Continued)

Reference Treatment Population (N) Study design Results

Lipkin et al. (1964) Magnesium AD patients (n = 10), healthy living Cross-sectional study - AD patients have increased whole
subjects (n = 16) and skin and dermal magnesium
normal-appearing cadavers - Significantly lower serum
(n = 5) magnesium in adults with AD
compared with healthy controls.
Proksch et al. (2005) Magnesium AD patients (n = 30) 6-week placebo-controlled - Daily soaks in
split-body RCT magnesium-enriched DSS
significantly decreased TEWL,
increased SC hydration,
decreased roughness, and
decreased redness.
Koppes et al. (2016) AD patients (n = 100) 6-week RCT - Cer-Mg cream significantly
decreased SCORAD and TEWL,
and increased SC hydration.
- No alterations of epidermal NMF
with Cer-mg treatment.
Stalder et al. (1992) Manganese Pediatric AD patients (n = 20) 1-week RCT - Less reduction of Staphylococcus
aureus colonization and less
improvement in clinical AD
scores compared with
chlorhexidine cohort.
Ilves et al. (2014) Zinc Mice Mouse study - Diminished local skin
inflammation (CD3+, CD4+, and
CD8+ T cells) by reducing
pro-inflammatory cytokines and
increasing anti-inflammatory
cytokines.
- Induced IgE antibody production.
Wiegand et al. (2013) Zinc AD patients (n = 12) 3-day pilot study - Decreased patient-reported
pruritus severity.
- Decreased erythema, edema and
papules, and excoriations.
Akiyama et al. (1997) Iodine AD patients (n = 150) 2-week case–control - Decreased erythema and
exudation (p < .05).

Abbreviations: AD, atopic dermatitis; RCT, randomized controlled trial; TA, triamcinolone acetonide; TARA, TA plus retinoic acid; DSS, Dead Sea Salt;
TEWL, transepidermal water loss; SC, stratum corneum; SCORAD, SCORing of Atopic Dermatitis; IGA, Investigator Global Assessment; NMF, natural mois-
turizing factors.

and once daily antiseptic with chlorhexidine (1:100) or KMnO4
(1:20,000) resulted in reduction of Staphylococcus aureus colonization
and improvement in clinical scores (intensity, extent, associated symp-
toms). Though there was no significant difference between the two
interventions, there was greater reduction of S. aureus and improve-
ment in AD symptoms in the chlorhexidine group compared with the
KmnO4 cohort. The tolerability of the antiseptic solutions were simi-
lar, so at this time, there is no heightened recommendation to use
manganese over chlorhexidine for the improvement of AD symptoms
(Stalder et al., 1992).
4.3 | Zinc
Zinc’s UV protective anti-inflammatory, antioxidative, and antibacter-
ial properties make it one of the most applied micronutrient in the
dermatologic world (Jones et al., 2008). Zinc is an integral component
of MMPs that control epidermal degradation and remodeling, suggest-
ing that the mineral plays an important role in cell growth, wound clo-
sure, and barrier formation (Hershfinkel, 2018). Furthermore, the zinc-
finger motifs in OVO-like proteins are involved in the expression of
filaggrin (FLG), a critical skin barrier protein. Mutations in FLG are
found in patients with AD (Tsuji et al., 2018). The recent identification
of the negative relationship between AD severity and erythrocyte zinc
levels suggests that zinc may be valuable in reducing the symptoms
associated with AD (Karabacak et al., 2016).
To identify which compound has greater effect based on pene-
trability, Ilves et al. investigated the effects of nano-sized zinc
oxide (nZnO) and bulk-sized (bZnO) on mechanically damaged
mouse skin with or without allergen/superantigen sensitization.
Epidermal and dermal thickness was reduced in ZnO-treated
groups, but was most significant in the nZnO group compared with
the bZnO group (p < .01). Both formulations diminished local skin
inflammation (CD3+, CD4+, and CD8+ T cells) by decreasing
pro-inflammatory cytokines (IL-1β, IL-6, TNF) and increasing anti-
inflammatory cytokines (IL-10 and IFN-γ) though greater in the
nZnO-exposed mice. While these formulations reduced local inflam-
matory response, the application of nZnO induced systemic produc-
tion of IgE antibodies. The authors theorize that high local
concentrations of Zn2+ in the skin can decrease inflammation.
However, high systemic concentrations reach the lymph nodes and
spleen, resulting in enhanced B-cell mediated IgE antibody produc-
tion (Ilves et al., 2014). Because of the opposing local versus sys-
temic inflammatory response observed, we remain elusive to the
actual benefits that ZnO can have on AD.
MAAROUF ET AL.
In a pilot trial involving 12 adult patients with AD, the use of ZnO
textile for three subsequent nights resulted in a decline in patient-
reported pruritus severity with a concomitant decline in patient-
reported all-cause impairment from pruritus (night sleep, professional
activities, leisure time, housework). Clinical improvement was
reported as decrease in erythema, edema, papules and excoriations
(Wiegand, Hipler, Boldt, Strehle, & Wollina, 2013). Despite these
encouraging results, the study is limited by the lack of a control group.
Functional fabrics are often expensive and may not be practical for
most AD patients and families.
4.4 | Iodine
Similar to KMNO4, iodine acts as an anti-microbial agent that can
reduce S. aureus colonization on AD lesions while upregulating anti-
microbial peptides. In a case–control study involving 150 AD patients,
once daily treatment with 10% povidone-iodine (PVP-I) solution for
14 days on eczematous lesions resulted in a decline in the degree of
erythema and exudation, which was significantly greater than the
reduction observed in the non-PVP-I group (both p < .05). Addition-
ally, there was a decline in the density of S. aureus on the active
eczematous lesions (Akiyama, Tada, Toi, Kanzaki, & Arata, 1997).
5 | DISCUSSION
Several topical vitamins hold promising in alleviating AD symptoms.
Topical vitamin C, B, and E appear to reduce SCORAD, improve bar-
rier function, and decrease serum and skin inflammatory mediators
(Table 1). While AD individuals have lower vitamin A-related receptors
expression compared with healthy controls, the use of vitamin A
derivatives does not seem to have increased efficacy over the steroid
alternatives; additionally, vitamin A may cause increased irritation in
patients who already have a degraded skin barrier. Current evidence
points toward detrimental effects of topical vitamin D on AD skin, and
its use in repairing AD skin is not recommended. There are currently
no studies evaluating the use of topical vitamin K in AD. Vitamin K is
a physiologically important molecule that assists the body in healing
wounds and bruising. Its’ aid in wound healing should encourage the
evaluation of its effect on the disrupted skin barrier in AD individuals.
Dermatologists should be aware of readily available topical vitamin
formulation that may exacerbate AD. For example, an ointment com-
bining vitamins A and D exists in the dermatologists’ armamentarium
for underprivileged atopic patients in some countries. Similar to the
use of its' individual components, this combination ointment aggra-
vates AD and should be avoided (Feily & Namazi, 2010).
Certain trace minerals such as magnesium, zinc, and iodine,
appear to improve AD through anti-inflammatory and anti-microbial
effects. The studies reviewed herein did not evaluate their use as
monotherapy. Thus, future studies should evaluate the singular use of
these ions in AD patients.
Anti-oxidative and anti-inflammatory effects of topical micronu-
trients may augment benefits from prescription topical medication
while limiting topical steroid use. While the current literature iden-
tifies the topical use of several micronutrients for repairing EBF and
7 of 9
reducing the symptoms of AD, larger scale adult and pediatric RCTs
that evaluate efficacy are needed. Identifying beneficial effects of
topical micronutrients can pave the way for development of
non-prescription formulations to reduce inflammation and symptom-
atology associated with AD.
6 | CONF LICT OF INT E RE ST
MM, ARV, and VYS have no relevant conflicts of interest to declare
for this manuscript.
ORCID
M. Maarouf http://orcid.org/0000-0003-2732-6492
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How to cite this article: Maarouf M, Vaughn AR, Shi VY. Topi-
cal micronutrients in atopic dermatitis—An evidence-based
review. Dermatologic Therapy. 2018;31:e12659. https://doi.
org/10.1111/dth.12659