Journal of Dermatological Science 102 (2021) 142–157

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Invited Review Article

Atopic dermatitis: Role of the skin barrier, environment, microbiome,

and therapeutic agents
Thomas Lugera,* , Masayuki Amagaib,c , Brigitte Drenod, Marie-Ange Dagnelied ,
Wilson Liaoe , Kenji Kabashimaf , Tamara Schikowskig , Ehrhardt Prokschh , Peter M. Eliasi,
Michel Simonj, Eric Simpsonk , Erin Grinichk , Matthias Schmuthl
a
Department of Dermatology, University of Münster, Münster, Germany
b
Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
c
Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
d
Dermatology Department, Nantes University, CHU Nantes, CIC 1413, CRCINA, Nantes, France
e
Department of Dermatology, University of California, San Francisco, CA, United States
f
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
g
IUF – Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
h
Department of Dermatology, University of Kiel, Kiel, Germany
i
San Francisco VA Medical Center, University of California, San Francisco, CA, United States
j
UDEAR, Inserm, University of Toulouse, U1056, Toulouse, France
k
Department of Dermatology, Oregon Health & Science University, Portland, OR, United States
l
Department of Dermatology, Medical University Innsbruck, Innsbruck, Austria

A R T I C L E I N F O A B S T R A C T

Article history: Atopic dermatitis (AD) is a chronic, inflammatory skin disorder characterized by eczematous and pruritic
Received 18 January 2021 skin lesions. In recent decades, the prevalence of AD has increased worldwide, most notably in
Received in revised form 28 April 2021 developing countries. The enormous progress in our understanding of the complex composition and
Accepted 29 April 2021
functions of the epidermal barrier allows for a deeper appreciation of the active role that the skin barrier
plays in the initiation and maintenance of skin inflammation. The epidermis forms a physical, chemical,
Keywords: immunological, neuro-sensory, and microbial barrier between the internal and external environment.
Skin barrier
Not only lesional, but also non-lesional areas of AD skin display many morphological, biochemical and
Atopic dermatitis
Filaggrin
functional differences compared with healthy skin. Supporting this notion, genetic defects affecting
Inflammation structural proteins of the skin barrier, including filaggrin, contribute to an increased risk of AD. There is
Microbiota evidence to suggest that natural environmental allergens and man-made pollutants are associated with
Treatment an increased likelihood of developing AD. A compromised epidermal barrier predisposes the skin to
increased permeability of these compounds. Numerous topical and systemic therapies for AD are
currently available or in development; while anti-inflammatory therapy is central to the treatment of AD,
some existing and novel therapies also appear to exert beneficial effects on skin barrier function. Further
research on the skin barrier, particularly addressing epidermal differentiation and inflammation, lipid
metabolism, and the role of bacterial communities for skin barrier function, will likely expand our
understanding of the complex etiology of AD and lead to identification of novel targets and the
development of new therapies.
© 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

1. Introduction prevalence of AD is estimated at 15–20 % in children and 1–3 %

in adults worldwide [3], with an increase observed in recent
Atopic dermatitis (AD) is a common, inflammatory, pruritic decades [3]. Both the prevalence of AD and recent trends in
skin disorder with a complex etiology, involving interactions prevalence vary between countries, most notably between high-
between the external environment and the skin [1,2]. The and low-income countries. This is particularly apparent for older

* Corresponding author at: Dermatology Clinic, University of Münster, Von-Esmarch-Straβe 58, 48149, Münster, Germany.
E-mail address: luger@uni-muenster.de (T. Luger).

https://doi.org/10.1016/j.jdermsci.2021.04.007
0923-1811/ © 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
T. Luger, M. Amagai, B. Dreno et al.
children (aged 13–14 years) for whom prevalence has increased
primarily in developing countries but has decreased mainly in
developed countries [4]. Early clinical signs of AD include skin
dryness, roughness and pruritus, particularly in sensitive skin
areas [1,5]. AD has a major impact on the quality of life of patients,
their parents and caregivers, influencing lifestyle (e.g., restricting
clothing, ability to participate in sports, sleep) as well as mental
health [6].
Profound alterations in skin barrier function, altered epidermal
morphology and stratum corneum (SC) lipid composition are well
characterized in AD along with T helper (Th)2-predominant
inflammation [7,8]. Notably, the identification of loss-of-function
mutations in the structural epidermal barrier filaggrin (FLG) gene
has shifted understanding of the pathophysiology of AD from a
purely immunological disorder towards a disorder substantially
driven by impaired skin barrier function [1,9]. The filaggrin
precursor, profilaggrin, is a complex, highly phosphorylated
polypeptide that is cleaved during cornification to release
functional filaggrin [10,11]. Filaggrin binds to the keratin cytoskel-
eton, facilitating the formation of corneocytes, which form the
outer surface of the epidermis [11]. In the upper SC, filaggrin is then
degraded to free amino acids and subsequent derivatives,
including urocanic acid and pyrrolidone-5-carboxylic acid, which
are part of the natural moisturizing factors [10–14].
Defects in skin barrier genes have been shown to play a key role
in development of allergic diseases [15,16]. For example, mutations
in FLG confer a significantly increased risk of developing AD
alongside asthma, allergic rhinitis, food allergy, and hay fever
[8,16]. In a study in Flg-null mice (Flg / ), newborn mice exhibited
dry, scaly skin, but had normal SC hydration and transepidermal
water loss (TEWL) [17]. Premature shedding of SC layers and
increased desquamation were observed under mechanical stress,
and antigens were able to penetrate the SC more efficiently [17].
These findings support the role of impaired barrier function as a
key component of AD development.
Defects in other skin barrier component genes, including serine
peptidase inhibitor Kazal type 5 (SPINK5) mutations [18] and
claudin-1 (CLDN1) impairment are associated with asthma, food
allergy, and allergic contact dermatitis [19–22]. Inflamed skin and
skin barrier dysfunction allow penetration of allergens and protein
antigens from the external environment, which can further trigger
the immune response and may lead to the development of
immunoglobulin (Ig)E-mediated allergies [23]. In this review, we
will explore the structure and function of the skin barrier,
including its dysfunction in AD, contributing factors and potential
approaches to treatment.
2. Epidermal changes in atopic dermatitis
The skin consists of many layers and forms a physical,
biochemical, immunological, microbial, and neuro-sensory barrier
between the internal and external environment (Fig. 1) [8,10,24].
Most of the protective function is provided by the epidermis, a
multi-layered epithelium comprising the SC, stratum granulosum
(SG), stratum spinosum (SS) and the stratum basale (SB) [25,26].
Keratinocytes are the predominant cell type in the epidermis,
and undergo differentiation in an oriented process from the SB, the
deepest epidermal layer, toward the external surface of the skin
[25]. The SB is mainly composed of proliferating keratinocytes that
are attached to the dermis via complex multi-protein structures
[27]. The SS overlies the SB, comprising a variety of cells that differ
in shape, structure and subcellular properties [28,29]. Within the
SS, keratinocytes start producing lamellar bodies - membrane-
bound organelles and tubuloreticular networks containing a
number of lipids, glycosidases and acid hydrolases that function
to deliver precursors of SC lipids into the intercellular space
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Journal of Dermatological Science 102 (2021) 142–157
[27,30,31]. The SG is the outermost layer of the epidermis that
contains living cells, abundant in cytoplasmic filaggrin-containing
keratohyalin granules [14,27,32]; formation of these liquid-like
keratohyalin condensates has recently been shown to be driven by
liquid-liquid phase separation of filaggrin proteins [32]. The cells in
the SG are responsible for the synthesis and modification of
proteins involved in cornification [14,27]. At the SG/SC transition,
keratinocytes undergo cell death to form corneocytes; large, flat
cells with a tetrakaidecahedron shape embedded in a lipid matrix,
devoid of nucleus and any cytoplasmic organelles, and tightly
linked by corneodesmosomes (cell-cell junctions) [14,33]. Recent
evidence suggests that as cells approach the skin surface, a pH shift
drives dissipation of the liquid-like keratohyalin granules leading
to corneocyte formation [32].
The SC comprises three layers with distinct barrier properties,
which likely correspond to the metabolic processing of filaggrin
[34]. The lower and middle layers function as outside-in barriers,
whilst the upper layer acts as a “sponge”, in which solutes (such as
ions) flow in, with some being retained [34]. In the SC, corneocytes
provide physical protection for the underlying epidermis [14,27].
Corneocytes are surrounded by a resistant structure called a
cornified cell envelope, a thick (10 nm) layer of crosslinked
proteins that are covalently bound to ceramide lipids that replace
the plasma membrane [14,35]. These envelopes are essential for
effective skin barrier function [35]. Together with extracellular
lipids derived from lamellar bodies and arranged in multiple
lamellar bilayers, corneocytes create a barrier to prevent water loss
and penetration of exogenous molecules from the external
environment [27,35].
A large proportion of SC lipids are synthesized in keratinocytes,
but some are also derived from extracutaneous sources [36]. The
composition and architecture of SC extracellular lipids are critical
for normal permeability and barrier function [37]. Several groups
have confirmed a particularly high percentage of ceramide species
(50 % dry weight of SC lipids) in the SC, including ultra-long acyl-
ceramide subclasses, together with free fatty acids and cholesterol,
whereas relatively few phospholipids are present [36,37]. An outer
coating of omega-hydroxy-ceramides is present on the protein-
enriched corneocytes in the SC, providing a link between these
cells and the lipid lamellae [38]. In addition to forming a
hydrophobic permeability barrier, some of the ceramides and free
fatty acids of the SC also exhibit antimicrobial properties which
contribute to the barrier to pathogens [36]. In AD, SC lipid
composition and architecture is disturbed [39].
In addition, in the living epidermal layers, tight junctions (cell-
to-cell junctions) form a barrier for body water and solutes at the
SG level, and have been shown to play an additional role in both
epidermal barrier function and cornification [40]. Organization of
epidermal tight junction barriers is a dynamic process that
involves intimate interactions between Langerhans cells and the
SG2 layer of keratinocytes [41]. When tight junction barriers are
intact, Langerhans cells can extend dendrites through them to
uptake external antigens that have infiltrated the SC barrier,
suggesting tight junctions in skin serve as a liquid-liquid interface
barrier [41].
The SC provides a physical barrier against harmful substances
from the environment [29]. If pathogens enter the body due to a
disrupted barrier, the immune response is important to protect the
living epidermal layers and the entire body [41]. In addition to
constituting an integral structural element of the epidermis,
keratinocytes are involved in both innate and adaptive immunity
[29]. Along with neutrophils, keratinocytes produce antimicrobial
peptides (AMPs) and act as a first line of defence against external
pathogens [29]. For example, keratinocytes have been shown to
produce pro-inflammatory cytokines such as interleukin (IL)-1β
and IL-18 via the inflammasome signaling pathway, and to interact
T. Luger, M. Amagai, B. Dreno et al. Journal of Dermatological Science 102 (2021) 142–157

Fig. 1. The components of the epidermal barrier form a microbial, physical, chemical, immunological and neuro-sensory barrier.
Microbial products contribute to a normal epidermal barrier in several ways. Microbes produce AMPs, as well as free fatty acids, and stimulate the innate immune system
[120,124]. The physical barrier consists of corneocytes, desmosomes, claudins and lipids [8,10,22]. The chemical barrier is composed of molecules that contribute to hydration
(e.g., NMFs) and the prevention of infections (e.g., AMPs) [10]. The immunological barrier involves components of the innate immune system (e.g., AMPs produced by
keratinocytes) and the adaptive immune system (e.g., LCs and lymphocytes) [8,10,254]. Components of the neuro-sensory system function as danger sensors and include
keratinocytes and ion channels expressed on cutaneous nerves [29,255]. Upon activation, sensory nerve endings release neuropeptides such as substance P, which mediates
itch, pain and inflammation [255–257].
AMP, antimicrobial peptide; DC, dendritic cell; ECM, extracellular matrix; Eo, eosinophil; IL, interleukin; ILC, innate lymphoid cell; LC, Langerhans cell; M, macrophage; N,
neutrophil; NMF, natural moisturizing factor; TLR, toll-like receptor.

with T cells, inducing T cell activation or antigen-specific tolerance
[29]. In addition to T cells and keratinocytes, Langerhans cells are
present in the epidermis, where they play an important role in
adaptive immunity [29].
Patients with AD exhibit injured skin that is inflamed, as
demonstrated by erythema and pruritus [42]. Acute skin lesions
are characterized by intensely pruritic papules over erythematous
skin; chronic skin lesions are distinguished by lichenification and
fibrotic papules [42,43]. Impairment of skin barrier function, as
assessed by increased TEWL values and increased percutaneous
penetration, is a characteristic of AD patients’ skin in both non-
lesional and lesional areas [22]. Non-lesional areas of skin may be
dry and scaling and display subclinical inflammation [13,44–48].
Lesional areas present marked intercellular edema (spongiosis),
prominent hyper- and sometimes parakeratosis and acanthosis
[42,49]. In terms of structural changes, abnormal keratohyalin
granules have been observed in the SG of AD skin, together with
thinning and sometimes, absence of this cell layer [50]. In addition,
atomic force microscopy studies have shown an increased number
of villus-like protrusions on the corneocyte surface in AD skin [51]
and corneocytes are reduced in size [52]. Furthermore, the
cornified envelope is defective with highly decreased compaction
of corneocytes and reduced intercellular lipids [53]. Abnormalities
are observed in lamellar body secretion in the epidermis of AD skin
[54], with lamellar bodies retained in the corneocyte matrix and
alterations observed in extracellular lamellae in the SC [54]. A
significant reduction in the proportion of very long chain
ceramides in the lipid composition as well as a lower amount of
total lipids have been observed in the SC of patients with AD, which
may explain the impaired water-barrier function of the skin [37].
Even more important is a reduction in the chain length of the fatty
acids in the ceramides, a reduction in the chain length of the free
fatty acids, as well as changes in the amounts of saturated and
unsaturated fatty acids, which correlate with SC lipid bilayer
structure [55]. Langerhans cells, mast cells and inflammatory
dendritic epidermal cells have also been observed in AD skin, with
the latter two cell types appearing to migrate from the dermis into
the epidermis [29,56–58]. The dendrites of Langerhans cells, but
not inflammatory dendritic epidermal cells, extend through the
tight junction barriers, probably to capture external antigens [58].
These differences in cell behavior may play a role in AD
pathophysiology [58].
An important aspect of the skin barrier is pH; the pH of normal
non-neonatal skin surface ranges from 4 to 6, but in AD it is often
increased towards neutral and basic levels [59,60]. Lesional skin
has the highest pH in patients with AD, and unaffected skin has a
higher pH than in control subjects [61]. Less acidic areas of skin
surface are more susceptible to AD expression; the higher pH of the
cheeks in infants, and of intertriginous and flexural skin in adults,
corresponds to the increased likelihood of AD lesions in these areas
[59]. The formation of the SC involves several pH-dependent
enzymes, particularly for the synthesis and arrangement of lipids
within the layer [60]. Increased pH disturbs barrier formation,
reduces the antimicrobial capability of the skin, and may cause
patients with AD to be more susceptible to infections by
Staphylococcus and other neutral-pH-favoring pathogenic bacteria

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on the skin [59]. Desquamation of the SC also occurs more rapidly
at neutral pH than at acidic pH, leading to decreased integrity of
the skin barrier [59].
Data indicate that multiple proteins involved in epidermal
development and barrier function are altered in AD skin (Fig. 2)
[62]. Gene and protein expression of cornified cell envelope
components including loricrin, involucrin, filaggrin, filaggrin-2,
hornerin and others are significantly reduced in AD, and this may
be correlated with the severity of disease [45,53,62–65]. On the
other hand, keratin K6/K16 are upregulated [45,53,66]. AD is also
associated with reduced expression of corneodesmosomal pro-
teins, most notably corneodesmosin [67–69].
3. Genetics of AD
As previously mentioned, defects in skin barrier genes can
contribute to the development of AD (Fig. 2). The heritability of AD
is approximately 75 % and the concordance rate is higher in
monozygotic twins compared with dizygotic twins (72 % vs 23 %),
indicating that genetic factors play a major role in the development
of AD [70]. Family genetic studies identified several possible AD
regions (e.g., ATOD1: 3q21); however, these studies were not
definitive in their results [71–73]. Subsequent genetic studies
recognized that AD is a disease likely involving common variants,
thus, several Genome Wide Association Studies (GWAS) were
pursued [74]. A study investigating over 360,000 cases of eczema,
asthma and hay fever versus healthy controls identified 99 AD risk
loci [75]. So far, the greatest genetic significance has been
demonstrated for mutations in the FLG gene, which lead to
defective skin barrier function [16]. The skin barrier may be most
important in AD initiation and is being targeted for AD primary
prevention with promising early results [76]. However, to date
these results have not been replicated in larger studies [77].
To date, defects have been noted in genes encoding four
important components of the epidermal barrier: corneocytes (FLG,
filaggrin-2 [FLG2], OVOL1, Small Proline Rich Protein 3 [SPRR3]),
lipid-rich matrix (Mattrin [TMEM79]), tight junctions (CLDN1), and
protease inhibitors (SPINK5) (Table 1 [12,16–18,22,78–88]) (Fig. 2).
Defects in FLG and FLG2 genes are associated with impairment of
the epidermal barrier and more persistent symptoms of AD
[16,89]. OVOL1 knockout reduces the production of filaggrin and
the integrity of the skin barrier, each of which is associated with a
greater risk of AD [8,15,16,82,85–87,90]. Further, a mutation in
SPRR3 has been associated with a 20 % increased risk of AD [80].
Presence of the missense mutation rs6684514 in the TMEM79 gene
impacts the lipid matrix of the skin barrier and is associated with
AD [83,84]. In addition, defects in genes involved in tight junctions
and epidermal remodeling, including CLDN1 and SPINK5, respec-
tively, have been associated with AD [18,22,78,88,91]. The
expression and activity of proteases, such as Kallikrein-related
peptidase 7 (KLK7) (formally known as stratum corneum
chymotryptic enzyme), are also important determinants of barrier
thickness and integrity [52]. A significant association between a
mutation in the gene encoding KLK7 and AD was found in a study

Fig. 2. Genetic and environmental factors lead to skin barrier breakdown in AD. [Reprinted and adapted from J Invest Dermatol, Vol 129(8), Cork MJ et al., Epidermal barrier
dysfunction in atopic dermatitis, pp. 1892-908, © 2009, with permission from Elsevier] [52].
AD is a heterogeneous condition in which a variety of genetic and environmental causes lead to skin barrier breakdown [1]. Filaggrin gene variants may lead to decreased
natural moisturizing factor, which reduces stratum corneum hydration and increases pH [16]. Increases in pH enhance protease (KLK5, KLK7 etc.) activity and inhibit lipid-
generating enzymes [52]. Together with defects in the genes encoding proteases and protease inhibitors (e.g., SPINK5), these changes increase the breakdown of
corneodesmosomes, deregulate desquamation and impair lipid lamellae formation [52,78]. Genetic changes in cornified envelope (e.g., FLG variants and SPRR3), lipid matrix
(e.g., TMEM79) and tight junction (CLDN1) components are thought to impair the structural integrity of the cornified envelope and lipid lamellae [16,22,80,83,84]. Tight
junction defects and increased pH impair antimicrobial activity, increasing the probability of S. aureus infections, which then worsen skin barrier breakdown [42,253].
Environmental factors such as soap, detergents and exogenous proteases further enhance protease activity, interacting with genetic defects to break down the skin barrier [1].
When the skin barrier is impaired, the penetration of irritants and allergens into the skin increases, triggering skin inflammation and raising protease activity [42,52].
*includes filaggrin.
AD, atopic dermatitis; CLDN1, Claudin 1; FLG, filaggrin; KLK5, Kallikrein-related peptidase 5; KLK7, Kallikrein-related peptidase 7; S. aureus, Staphylococcus aureus; SPINK5,
Serine Peptidase Inhibitor Kazal Type 5; SPRR3, Small Proline Rich Protein 3; TCS, topical corticosteroids; TMEM79, Transmembrane Protein 79.

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of 103 patients with AD and 261 matched controls [52]. In addition,
mice overexpressing human KLK7 develop skin changes similar to
those observed in chronic AD [52].
4. Influence of environment on AD
Natural allergens such as house dust mites, cockroaches, pet
dander and multiple pollens have all been reported to induce AD in
a subpopulation of patients, through cutaneous exposure [92].
Such airborne proteins penetrate the epidermis and worsen the
severity of AD [92]. The prevalence of AD due to airborne proteins
is hard to estimate as it is difficult to prove which airborne factors
are involved. Patients with AD relating to airborne proteins
typically have lesions on air-exposed skin areas, and a history of
exacerbation after exposure to airborne proteins [92]. In addition,
their disease is normally severe and resistant to conventional
therapies, and often co-occurs with asthma [92]. In a 5-year
retrospective study, patients who had a positive pin prick test for
inhalation allergens, including dust mites, grass pollen and weed
pollen, were more likely to have asthma and allergic rhinitis [93].
The authors concluded that the risk of developing asthma and
allergic rhinitis is very high in patients with AD [93]. The
mechanisms via which airborne proteins induce AD are only
partly understood [94]. One recent study used a mouse model of
AD to show that house dust mites directly activate clusters of
MRGPRB2+ mast cells and TRPV1+Tac1+ nociceptors (nociceptive
sensory neurons) to drive type 2 skin inflammation [94]. Therefore,
neuro-immune cross-talk may play a role in airborne protein-
mediated skin inflammation [94].
Other extrinsic environmental risk factors for AD development
include temperature, humidity, ultraviolet radiation, air pollutants,
tobacco smoke exposure, water hardness, rural versus urban living,
diet, breastfeeding, probiotics, and prebiotics [95]. These risk
factors are thought to contribute to AD by acting as pruritogens and
irritants, upregulating inflammatory processes and/or worsening
skin barrier function [95].
Several epidemiological studies have assessed the association
between air pollution particulates (nitric oxides [NOx], sulfur
dioxide [SO2], ozone [O3], general traffic exhaust emissions) and
the epidemiology of AD [96]. Unfortunately, available data cannot
support a meaningful meta-analysis to investigate this association
[96].
A recent systematic review of 57 environmental epidemiologic
studies was performed to determine if an association exists
between air pollution and AD [97]. In 31 studies, the association
between air pollution and the prevalence of AD was assessed. A
significant positive association between AD and traffic exhaust-
related emissions, especially from truck traffic, was found in 8 out
of 11 cross-sectional studies with small-scale measurement or
modeling of exposure [97]. Further, in 5 out of 5 studies, a
significant positive association was found between AD and air
pollution based on self-assessed traffic intensity, in particular that
of trucks [97]. An association between AD and measured
background pollution levels was detected in only 2 out of 15

Table 1
Genetic defects of the skin barrier associated with atopic dermatitis.

Skin barrier Mutations

component
Corneocyte  Filaggrin (FLG)
o Mutations strongly associated with AD in specific ethnicities [16,86]
o Deficiency leads to:
& Failure in skin barrier function [16]
& Decreased UCA and PCA (natural moisturizing factors) in the SC [12,79]
& Flg / mice have dry, scaly skin; premature shedding of SC layers and increased desquamation under mechanical stress; increased antigen
penetration of the SC [17]
 Filaggrin-2 (FLG2)
o S2377X (stop-gain mutation) and H1249R (missense mutation): >1.5 fold risk of AD persistence [81,89]
 Ovo Like Transcriptional Repressor 1 (OVOL1); transcription factor in suprabasal keratinocytes that promotes FLG expression [87]
o GWAS variant rs10791824 increases risk of developing AD by 12 % in Europeans [82]
 Small Proline Rich Protein 3 (SPRR3); cross-bridging protein in the cornified cell envelope [80]
o Variant rs28989168 with extra repeats of 8 amino acid sequence, increases the risk of developing AD by 20 % [80]

Lipid matrix  Mattrin (TMEM79); discovered through genetic analysis of Flaky Tail mouse [83]
o Missense mutation rs6684514 associated with human AD and defective skin barrier [84]
o Mouse models of TMEM79 negative mice displayed [83,84]:
& Increased IgE levels*
& Spontaneous dermatitis
& Atopy
& Increased cutaneous sensitization*
& Impaired lamellar body protein secretion
& Impaired SC formation

Tight junctions  Claudin-1 (CLDN1); suprabasal tight junction protein [22]

o Expression decreased in non-lesional AD skin [22]
o Genetically associated with AD in Europeans, African-Americans and Ethiopians [22,91]
o Deficiency associated with increased susceptibility to HSV-1 [253]
o Variant may potentiate effect of mold exposure on AD risk [88]

Epidermal  Serine Peptidase Inhibitor, Kazal Type 5 (SPINK5); epidermal protease activity inhibitor
remodeling o Autosomal recessive mutations in Netherton Syndrome and associated with AD and allergy [18,78]
o Genetically associated with AD in multiple studies in Japan, China and Taiwan [18,78]
o Mutations result in [78]:
& Decreased expression of filaggrin
& Increased expression of pro-Th2 cytokine TSLP

AD, atopic dermatitis; Flg / , Flg-null; GWAS, genome-wide association study; HSV-1, herpes simplex virus type 1; PCA, pyrrolidone-5-carboxylic acid; SC, stratum corneum;
t-UCA, trans-urocanic acid; TSLP, thymic stromal lymphopoietin.
*
when compared with wild-type mice.

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studies. Significant associations were found between maternal air
pollution exposure during pregnancy and AD in recent birth cohort
studies in South Korea, China, and Taiwan [98–102]; despite the
greater levels of fine particulate matter (PM10) in China, this
significant association with AD was found only for NO2, supporting
the relationship between traffic pollution and AD [97,99–101].
However, in corresponding studies in Europe and the USA, such
associations were unclear or not investigated [97]. In addition, in 7
out of 10 predominantly East Asian studies (in South Korea and
China), symptom intensity in individuals with existing AD was
observed to increase with greater concentrations of particulate
(PM10, PM 2.5) and gaseous (NO2, volatile organic compounds, O3,
SO2) air pollutants [97]; 4 of these studies indicated that
meteorological factors such as low relative humidity are also
associated with worsening AD [103–106].
While there is no evidence to indicate that AD is affected by
‘large scale’ varying exposure to air pollutants such as PM10 or SO2
[97], there are considerable data to suggest that ‘small scale’
varying exposure to traffic exhaust pollution (particularly truck
traffic) can influence the prevalence of AD [97]. In addition, traffic
exhaust emissions have been shown to increase the incidence (as
assessed through maternal exposure during pregnancy) and the
symptoms of AD [97]. Further research is required to identify
which particulates contribute to these observed effects, and the
potential mechanisms through which air pollution-induced health
effects are mediated. For this reason, there is virtually nothing
known about potential mechanisms that might mediate air
pollution-induced health effects relevant for AD. As air pollu-
tion-induced health effects require the penetration of pollutants
into viable skin, skin barrier integrity is most likely involved. In
support of this, a recent study found that topical exposure of
mouse skin to diesel exhaust particles increased the expression of
the neurotrophic factor artemin in keratinocytes, through a
mechanism involving the activation of the aryl hydrocarbon
receptor [107]. In addition, artemin was observed to induce the
growth of transient receptor potential cation channel subfamily V
member 1 (TRPV1)-positive nerve fibers in the skin and to cause
pruritus [107]. Furthermore, overexpression of the xenobiotic
receptor pregnane X receptor (PXR) impairs the epidermal barrier
and triggers a Th2 immune response [108,109].
5. Role of antimicrobial protein expression in AD
Patients with AD frequently suffer from skin infections caused
by bacteria and viruses [110,111]. Staphylococcus aureus (S. aureus)
is the most common bacterial infection afflicting patients with AD,
90 % of whom are colonized with S. aureus versus 5–30 % of healthy
individuals [111]. Impaired AMP expression in the skin of patients
with AD is suggested to contribute to the increased susceptibility
to bacterial infections [111].
Human beta-defensin (hBD)-2, hBD-3, and human cathelicidin
peptide (LL-37) are AMPs found in the epidermis; the target of LL-
37 is unknown, however hBD-2 is known to target Gram-negative
bacteria, and hBD-3 is known to target S. aureus [110–112]. In
comparisons between the epidermis of patients with AD and
patients with psoriasis, a markedly reduced expression of all three
AMPs was observed supporting the hypothesis of impaired AMP
expression in AD, probably as a consequence of the Th2 cytokine
effect [112,113].
Furthermore, an analysis of the skin of healthy individuals and
patients with psoriasis or AD found that hBD-2, hBD-3, RNase-7 (a
broad spectrum AMP), and psoriasin (a strong inhibitor of
Escherichia coli growth, also known as S100A7) showed increased
expression in the skin of patients with AD compared with the
epidermis of healthy individuals, but a weaker induction than that
seen in patients with psoriasis [114]. This upregulation of AMP
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Journal of Dermatological Science 102 (2021) 142–157
expression is thought to play a role in controlling bacterial
colonization and infections associated with skin barrier disruption
in AD [110,111]. However, the level of upregulation observed in the
skin of patients with AD was considerably lower than in patients
with psoriasis (in whom skin infections are less common),
indicating an inadequate increase in epidermal AMPs to prevent
bacterial colonization [110,112,114].
6. Role of the microbiome in AD
The skin microbiome represents the totality of microbes and
associated genes resident of the human skin. These communities
vary between each of the three layers of the skin (epidermis,
dermis, hypodermis) due to differences in physicochemical
environments, such as moisture, pH and oxygen concentration
[115,116]. The skin microbiome and its interaction with human
immunity is a vital consideration in understanding skin disease
pathophysiology [117–121]. Recent advances in genetic sequencing
technologies and computational tools have allowed sequencing of
a large proportion of the microbiome, which will further our
knowledge of interactions between host and bacterial communi-
ties [122].
Cutaneous microorganism communities closely interact with
host innate immune effectors including macrophages, natural
killer cells, and mast cells [123–125]. Of interest, commensal
microorganisms are also capable of modulating gene expression in
the skin and have been shown to be involved in the upregulation of
innate immune response genes and genes involved in cytokine
activity [124]. The skin's innate immune system consists of
resident or skin-recruiting effectors [126,127]. Crosstalk between
skin commensals and immune effectors is possible due to the
expression of PAMP (pathogen-associated molecular pattern)-
specific receptors (PRRs) [128]. PRRs are classified into four major
families [128,129]: Toll-like receptors (TLRs), C-type lectin
receptors (CLRs), nucleotide-binding oligomerization domain
(NOD)-like receptors (NLRs) and RIG-like receptors (RLRs). PRRs
allow cells involved in innate immunity to monitor and sense
commensal and pathogenic microorganisms and are generally
specific to certain classes of microbial pathogens [128,129]. With
these close interactions between skin microorganisms and
immune effectors, a balance is crucial to maintain skin homeosta-
sis and prevent unnecessary inflammatory responses. Imbalance
within the skin microbiome is a potent trigger for skin inflamma-
tion and is described in several inflammatory dermatoses, in
particular in AD [42,116,130–132].
Dermatological conditions such as psoriasis and AD have been
associated with loss of diversity in the skin microbiome
[42,116,130–134], with AD being characterized by the dispropor-
tionate colonization of S. aureus [42,130,131]. In addition,
Corynebacterium mastitidis, S. aureus and Corynebacteruim bovis
(C. bovis) have been found to emerge sequentially during AD onset
[135]. Antibiotics that specifically target these bacteria almost
completely reverse the associated dysbiosis and skin inflammation
[135]. S. aureus was found to drive AD formation, whilst C. bovis
induced Th2 cell responses [135]. The role of different dysbiotic
flora during AD onset suggests that the skin microbiome may be a
potential target for future therapeutic interventions [135].
Indeed, probiotics and prebiotics are being explored as
innovative treatments for dermatological diseases such as AD
[136–140]. Interestingly, nutritional supplementation with pre-
biotics and probiotics has been shown to improve symptoms,
quality of life and clinical severity of AD in some studies, although
this could not be verified in others [137,141].
The impact of topical treatment on the skin microbiome, and
consequent influence on AD, has also been explored in multiple
studies [142–149]. A study showed that long-term emollient use in
T. Luger, M. Amagai, B. Dreno et al. Journal of Dermatological Science 102 (2021) 142–157

infants at high-risk of developing AD reduced skin pH and
increased the proportion of Staphylococcus salivarius in the skin
[146]. Emollient-mediated microbiome changes may consequently
play a role in restoring skin dysbioses and preventing AD, although
additional studies are required to confirm this [146]. The topical
application of specific strains of bacteria has also been investigated
for the treatment of AD. One study highlighted the importance of
supplemented emollients in the management of AD; in this
randomized comparative trial, 60 patients with moderate AD were
treated with an emollient supplemented with a biomass of
Vitreoscilla filiformis, or a different emollient without biomass
supplementation, twice daily for 1 month [142]. Patients who
received the supplemented emollient experienced greater
improvements in AD scores than those treated with the
comparator emollient [142]. The authors concluded that the
supplemented emollient was able to normalize skin microbiota
and reduce the number and severity of AD flares compared with
emollient alone [142]. A recent open-label and real-world 7-day
study evaluated the use of an ‘emollient plus’ containing an
Aquaphilus dolomiae extract in 5,910 patients with a variety of skin
conditions (3,511 [65.2 %] patients had AD) [147]. Over the 7-day
study period, the emollient plus resulted in 56 % and 60 %
reductions in mean xerosis and pruritus severity, respectively
[147]. These improvements in xerosis and pruritus were significant
regardless of skin condition (P < 0.0001) [147]. In another recent
study, an ointment containing Lactobacillus reuteri DSM 17,938 was
safe and led to significant improvements in SCORing AD (SCORAD)
index and local SCORAD after 4 and 8 weeks of treatment in adults
with AD, compared with baseline values (P < 0.001) [148]. Finally, a
study conducted by the National Institutes of Health found that
specific strains of Roseomonas mucosa applied to lesional skin
provided clinical benefit to both children and adults with
established AD [149]. Additional studies of microbiome trans-
plants are currently underway in AD, including those that build on
previous research, demonstrating that reintroduction of coagu-
lase-negative Staphylococcus strains on the skin of patients with AD
(following isolation from healthy subjects and patients with AD)
reduced colonization by S. aureus [149,150].
Possible crosstalk between the skin microbiome and other
human body microbiomes is an emerging concept that suggests a
gut-skin axis [151–153]. The mechanisms by which the gut
microbiome influences skin homeostasis have not yet been fully

Fig. 3. The pathophysiology and treatment of AD. [Adapted from Kim J, et al. Allergy Asthma Proc. 2019] [258].
Inherited genetic defects and epigenetic changes in skin and immune components are thought to contribute to the immune dysregulation and skin barrier dysfunction that
underlies the symptoms observed in AD [18,72,158]. Immune abnormalities alter epidermal lipid composition and this together with tight junction defects allows microbes
and allergens to infiltrate the skin, leading to further skin inflammation and skin barrier impairment [42,253,258]. Gut microbial dysbiosis may also modulate systemic
immunity and promote pro-inflammatory responses [151–154]. Therapy for AD may be preventative or reactive [2]. Maintenance therapy with emollients is the main
underlying strategy in AD treatment, and is used to repair the skin barrier and prevent AD relapse [2,158]. Recent research has highlighted the possible utility of ceramide-
containing emollients and probiotics in the management of AD and the prevention of relapse [158,161,164,165]. Reactive treatment of AD typically involves the use of topical
anti-inflammatory agents (e.g., TCI and TCS) to correct immune dysregulation, emollients to hydrate and repair the skin and topical antibiotics in cases of bacterial
colonization [2,175–177,186,187]. In severe AD, systemic anti-inflammatory agents, biologics and light therapy may be used to target immune dysregulation [189,217–219].
Several new biologic agents and small molecule drugs are in development for the treatment of AD [249–252].
AD, atopic dermatitis; TCI, topical calcineurin inhibitor; TCS, topical corticosteroids.

148
T. Luger, M. Amagai, B. Dreno et al.
explored; however, according to recent studies, this could involve
the modulatory effect of gut bacteria commensals on systemic
immunity [154]. For example, specific gut microorganisms and
metabolites (retinoic acid, polysaccharide A) from Bacteroides
fragilis and Faecalibacterium prausnitzii are able to promote the
accumulation of regulatory T cells and Th cells, which facilitate
anti-inflammatory responses and pro-inflammatory responses,
respectively [155]. Further research is needed to investigate the
gut-skin axis and its impact on skin disease physiopathology.
Importantly, understanding these pathways will lead to novel
therapies based on targeting one organ (i.e., the gut) to improve the
health of another (i.e., the skin).
7. Prevention of AD
Treatment options for AD are illustrated in Fig. 3. The
management of AD focusses first on taking steps to prevent AD
and allow skin barrier recovery. Reducing contact with allergens
and irritants, with the use of specific barrier creams or ointments,
can give the skin barrier time to recover and prevent inflammation
[92,156]. Repair of the skin barrier can take longer than clinical
improvement, particularly when corticosteroids are used to reduce
the clinical signs of AD, such as reddening of the skin [157]. In these
instances, inflammatory cells may still be present and as such,
allergens must be avoided for a prolonged period to allow skin
barrier repair [157]. General skin care, generous use of emollients
containing lipid mixtures and water binding compounds [158], and
proactive treatment with topical corticosteroids (TCS) or topical
calcineurin inhibitors (TCIs) [159,160], can help to prevent AD
relapse.
There are several preventative measures under investigation
that specifically target the skin barrier. These include topical
formulations of cannabinoid receptor modulators, proteins,
adjusted pH, flavonoids, plasminogen activator type 2 receptor
(PAR2) inhibitors, and lipids [161–163]. Cer-dominant, triple-
physiologic lipid, barrier repair therapy for AD (Cer:cholesterol:
free fatty acids at a 3:1:1 M ratio), has been reported to target both
the reduction in lipids and the decline in Cer observed in AD,
therefore targeting two abnormalities central to skin barrier
dysfunction. This formulation, when provided at an acidic pH, has
shown efficacy in humans with AD [161,164]. A more recent study
investigated the use of a cream and lotion containing ceramides 1,
3 and 6-II, triglycerides and cholesterol [165]. Unlike earlier
studies, these agents were delivered via a multi-vesicular emulsion
(MVE) controlled-release system [165]. When compared with
three reference emollients in a double-blind, intra-subject,
vehicle-controlled, single open-application test, the test cream
and lotion were the only products to impart a clinically meaningful
improvement in skin hydration and dryness that was sustained for
24 h following a single application [165]. This may reduce the
burden of managing AD with typical emollients, which typically
require application 3–4 times per day [165].
Experimental barrier disruption and subsequent monitoring of
barrier recovery has been used to uncover disease mechanisms and
pathology that is not detected by the assessment of basal function
[166]. Using barrier recovery studies, signals and metabolic
responses to barrier abnormality have been identified, including
a delay in barrier recovery when cholesterol synthesis is inhibited
[167,168]. Barrier recovery studies have also been used to compare
the efficacy of putative preventive and therapeutic strategies. In
addition, the topical use of corticosteroids [169] and the systemic
use of cyclosporine (CsA) [170] and cytokine-receptor antibodies
(e.g., anti-IL-4 receptor antibody dupilumab) [171,172], have been
shown to indirectly enhance the skin barrier to a certain degree. In
contrast, allergic reaction, malnutrition and essential fatty acid
deficiency can delay skin barrier recovery [173,174].
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Journal of Dermatological Science 102 (2021) 142–157
8. Topical treatment for AD
Topical treatments are used in the management of AD to
suppress inflammation, relieve symptoms such as itching, restore
skin barrier function and to prevent relapse of AD. Due to the
reduced risk of adverse events when compared with systemic
treatments, topical treatments are well suited for patients with
mild-to-moderate AD [175]. Liberal use of emollients is an
important part of AD treatment, with long-term studies demon-
strating that use of emollients may be effective in reducing the risk
of AD development in infants, and in reducing the need for TCS in
established disease [76,146,158].
TCS have formed the cornerstone of AD treatment for more
than 50 years, and are recommended for the treatment of AD
globally [2,175–177]. There are many different compounds and
formulations of TCS, which can vary greatly in potency
[2,176,178]. TCS are recommended for the short-term treatment
of AD flares as, although highly effective at reducing inflammation
and pruritus, persistent use increases the risk of local side effects
on the skin [2,178]. More potent formulations are associated with
greater risk of adverse events [175,178], which can include skin
atrophy, skin barrier impairment, increased risk of skin infections
and tachyphylaxis [175,178–181]. The risk of systemic side effects
with the use of TCS is low and linked to the potency of the
formulation, extent of skin inflammation and the age of the
patient [175]. However, corticophobia (patient fear of TCS-related
side effects) is a substantial challenge that has arisen with the use
of TCS [175].
TCIs selectively inhibit nuclear factor of activated T cells (NFAT)
to decrease the activity of a range of transcription factors that
control cell division and reduce the expression of pro-inflamma-
tory cytokines, including cytokine Th1 and Th2 [182,183]. TCIs also
inhibit mast cell and neutrophil activation, release of inflammatory
mediators and directly influence nerve fiber function by binding to
the TRPV1 [2,175,176,182,184]. Binding to TRPV1 results in an initial
burning sensation with TCI use that typically improves with the
resolution of lesions [175,182,185].
AD management guidelines recommend the use of TCIs,
particularly pimecrolimus, for the treatment of mild-to-moderate
AD in sensitive skin areas [2,176,186–189]. Tacrolimus ointment is
approved for the treatment of moderate-to-severe AD: tacrolimus
ointment 0.03 % for the treatment of patients aged 2–15 years and
tacrolimus ointment 0.1 % for patients aged 16 years [176].
Pimecrolimus 1 % cream is approved for mild-to-moderate AD in
adults and children (aged 2 years), and is also approved in
several countries for use in children aged 3 months [190]. A
meta-analysis of the long-term treatment of children with AD
found both pimecrolimus and tacrolimus to have similar efficacy
in treating the clinical signs of AD [191]. Pimecrolimus and
tacrolimus have also demonstrated clinical benefits as mainte-
nance treatments for AD. When compared with vehicle treat-
ment, tacrolimus treatment significantly reduced the number of
disease exacerbations requiring substantial therapeutic interven-
tion (median difference, 2; P < 0.001) [159] and intermittent
treatment with pimecrolimus significantly reduced the median
time to first AD flare (P < 0.001) [192]. When compared with
conventional TCS, treatment of patients with AD with tacrolimus
0.1 % ointment for one year reduced the severity of skin atrophy,
which was associated with an improved skin barrier and increased
collagen synthesis [179,193]. In addition, in accordance with
European guidelines, pimecrolimus is recommended for the
treatment of facial lesions and children [2]. Contrary to historical
reports, there is no evidence for an association between the use of
TCIs and the occurrence of lymphomas or skin tumors [194]. While
transient application site burning is common following TCI
application, treatment with pimecrolimus has demonstrated less
T. Luger, M. Amagai, B. Dreno et al.
severe and shorter duration application site reactions, including
burning sensations, compared with tacrolimus in patients with AD
[195]. Importantly, pimecrolimus does not impair the skin barrier
and has been shown to restore the epidermal barrier in damaged
skin via the regulation of genes which are essential for normal skin
barrier function [157].
Novel topical treatments for AD have begun to emerge.
Phosphodiesterase 4 (PDE4) inhibitors, such as crisaborole and
difamilast, inhibit PDE4 to reduce the release of pro-inflammato-
ry cytokines [196,197]. Crisaborole is approved in the United
States (US) for the treatment of mild-to-moderate AD in patients
aged 2 years [198,199]. It has been reported to induce skin
barrier-related RNA transcripts and to decrease TEWL within 1–2
weeks of topical application [200]. Crisaborole 2 % ointment
significantly reduced the severity of pruritus compared with
vehicle treatment in a pooled analysis of clinical data [196], while
being well tolerated, with the most commonly reported
treatment-related adverse events being application site pain
and pruritus [196]. Similarly, difamilast 1 % cream has rapid and
sustained effects on pruritus and is currently being investigated
in the treatment of AD [197].
Janus kinase (JAK) has been implicated in AD, with inhibition of
JAK being associated with sustained anti-pruritic effects [201].
Tofacitinib is a potent pan-JAK antagonist developed in both
topical and oral formulations [202–204]. In a small clinical trial in
six patients with moderate-to-severe AD refractory to standard
treatment, a decrease in SCORAD with tofacitinib was observed
(36.5 % at week 8 to 12.2 % at week 29 [P < 0.05]) [205]. Ruxolitinib
is a potent JAK1/JAK2 inhibitor, which provides a high degree of
myelosuppression [206–208]. In a recent Phase 2 trial in patients
with AD, treatment with ruxolitinib cream significantly improved
the Eczema Area and Severity Index (EASI) score versus vehicle
cream at week 4 (71.6 % improvement vs 15.5 %, P < 0.001) [206].
Ruxolitinib cream also provided significant improvement in the
Investigators Global Assessment (IGA) score and pruritus com-
pared with vehicle at week 4, with only mild or moderate adverse
events reported [206]. A further pan-JAK inhibitor under
investigation for the treatment of AD is delgocitinib [209]. In a
Phase 2 randomized-controlled trial in adults with moderate-to-
severe AD, EASI scores were significantly improved at 4 weeks
following treatment with all doses of delgocitinib compared with
vehicle ointment (P < 0.001) [209]. All reported adverse events
were mild or moderate in severity, and included nasopharyngitis
and application-site skin infections [209]. There is preliminary
evidence from in vitro studies and from animal testing that JAK-
inhibition is beneficial for the skin barrier [210].
Tapinarof is a novel topical aryl hydrocarbon receptor (AhR)
agonist that has recently been investigated in patients with AD
[211,212]. In this study, the rate of treatment success (minimum 2-
grade IGA score improvement) with tapinarof cream at week 12
ranged from 34 to 53 % (dose dependent) and was significantly
higher than that with vehicle treatment (24–28 %). Further,
treatment success was maintained 4 weeks following tapinarof
therapy and treatment-emergent adverse events were mild-to-
moderate in intensity [211].
Liver X receptors (LXRs) are involved in the maintenance of the
epidermal skin barrier and inflammatory responses, forming a
promising target for the treatment of AD [213–215]. In a 3D-
cultured human skin model, the LXR antagonist GSK2033 reduced
the quantity and increased the mean chain length of monounsat-
urated ceramides and free fatty acids compared with control [214].
Conversely, when compared with control, the LXR agonist
T0901317 led to a lipid profile with increased quantities of
monounsaturated ceramides and free fatty acids followed by a
reduction in the mean chain length of these lipids more similar to
the lipid composition in diseased skin like Netherton syndrome or
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Journal of Dermatological Science 102 (2021) 142–157
AD in 3D in vitro skin models [214]. However, neither agonist nor
antagonist changed skin barrier function [214]. In human skin,
VTP-38543, a LXR agonist, has been shown to significantly increase
the expression of loricin and filaggrin within the epidermal skin
barrier compared with vehicle treatment in patients with mild-to-
moderate AD (P = 0.02) [216]. VTP-38543 also suppressed cellular
infiltrates and down-regulated expression of innate immunity
markers, including IL-6 [216]. Although the skin barrier was
restored, no improvement in clinical scores for AD were observed
[216].
9. Systemic treatment for AD
There are several available guidelines and reviews on the
efficacy, safety and clinical use of various systemic therapies for the
treatment of AD [189,217,218]. These guidelines provide recom-
mendations in terms of which treatments are best suited for the
severity of AD, but most do not provide guidance on when to
advance therapy from topical treatments. The International
Eczema Committee (IEC) Expert Panel provides an algorithm to
guide decision making on when to advance to systemic therapy
[219]. The algorithm considers factors such as the severity of AD,
level of patient education provided, any alternative diagnoses
(infections or allergic contact dermatitis), amount of time on TCS
treatment, quality of life of the patient and use of phototherapy
[219].
There are many systemic therapies that have demonstrated
clinical efficacy in the treatment of AD [189]; however, a limited
number of these therapies have been shown to improve barrier
integrity via the study of biomarkers [220]. Biomarkers provide an
objective measure of response to therapy and are particularly
important in diseases that have a complex etiology, such as AD
[220].
Narrow-band ultraviolet B (UVB) (311–312 nm) phototherapy
is utilized in the treatment of a wide range of conditions including
AD, vitiligo, generalized pruritus and psoriasis [221–224]. UVB
treatment has multiple modes of action including apoptosis of
infiltrating T cells [222], immunosuppression [221,225], inhibi-
tion of pro-inflammatory cytokines [226], antimicrobial proper-
ties against S. aureus [227], and upregulation of the cutaneous
vitamin D system [228]. Suberythemal doses of UVB radiation
have been shown to increase mRNA levels for key epidermal
enzymes for the synthesis of cholesterol, fatty acids, and
sphingolipids in mice [228]; increases in epidermal involucrin
and filaggrin expression were also observed, indicating suber-
ythemal doses of UVB may aid corneocyte formation and result in
overall enhancement of barrier function and homeostasis through
several mechanisms [228]. Treatment of AD with UVB photother-
apy has been shown to have many positive clinical effects;
however, due to the risk of possible adverse events, phototherapy
should be used only as a second-level treatment in adults and
children [2].
CsA is a strong immunosuppressant that has been used for the
treatment of many conditions, and is approved for the manage-
ment of AD in Europe [189]. CsA binds to cyclophilin, creating a
CsA-cyclophilin complex to reversibly suppress T cells [229,230].
The CsA-cyclophilin complex inhibits the activity of calcineurin
phosphatase, which is responsible for translocation and down-
stream activation of NFAT transcription factors (TFs) [229,230].
Consequently, the transcription of inflammatory cytokine genes,
IL-2 and IL-4, is blocked and the production of interferon gamma is
inhibited [229–231]. CsA can also bind to steroid-receptor-
associated-heat-shock protein 56, preventing the production of
pro-inflammatory cytokines IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, and
tumor necrosis factor-α [232]. Following administration, CsA
demonstrates rapid efficacy in patients with AD; however, disease
T. Luger, M. Amagai, B. Dreno et al.
reoccurrence may occur within 4 weeks of treatment discontinu-
ation [233]. In one study, treatment of AD with CsA has been shown
to reverse regenerative hyperplasia, indicated by reductions in
epidermal thickness and proliferation biomarkers K16 and Ki67
[234]. In patients with AD, serious adverse events are uncommon
as the doses used are generally lower than those in trials for organ
transplant [230,235–237]. CsA treatment is contraindicated in
patients with renal impairment and in patients with significant
uncontrolled hypertension, as well as in those who experience a
hypersensitivity reaction to CsA [238].
Vitamin D deficiency is common in patients with AD and in the
general population [239]. The majority of vitamin D is obtained
from UVB exposure to the skin, although some is ingested as part of
a healthy diet [240]. Vitamin D is involved in maintaining the
body’s calcium levels, but also in immune modulation [240]. For
example, vitamin D aids regulation of AMPs in keratinocytes
within the epidermis [241]. Reduced levels of AMPs are observed in
patients with AD, which could contribute to the greater number of
infections seen in these patients [241,242]. Vitamin D supplemen-
tation increases the level of AMPs, including cathelicidin and beta 2
defensin, in keratinocytes, neutrophils and monocytes [240,243].
Vitamin D supplementation in patients with AD has shown mixed
clinical efficacy in terms of clinical improvement and immune
response to treatment [189,242].
Dupilumab is a monoclonal antibody developed specifically for
the management of AD. Dupilumab is approved for the treatment
of adults with moderate-to-severe AD, and has recently been
approved by the US Food and Drug Administration for use in
adolescents (aged 12–17 years) with moderate-to-severe AD [244].
Dupilumab is a direct antagonist of the alpha subunit of both type 1
and type 2 IL-4 receptors [245]. By targeting the IL-4 receptor α
subunit, dupilumab blocks signaling of both IL-4 and IL-13 [246]
type 2 cytokines involved in pathogenesis of AD. Available data
demonstrate dupilumab to improve disease severity and reduce
epidermal hyperplasia and inflammation in AD [171,247,248].
Dupilumab has also demonstrated efficacy in improving skin
barrier integrity [171,172]. In a transcriptomic analysis of skin
biopsy specimens from patients with AD, dupilumab has been
shown to suppress levels of K16 (a marker for hyperplasia) and
increase expression of terminal differentiation proteins filaggrin
and loricrin [171]. In another study, treatment with dupilumab was
associated with significantly higher levels of filaggrin and loricrin
mRNA in lesional skin at 16 weeks versus baseline [172]. In the
same study, expression of lipid metabolism, tight junction and
membrane channel genes (ELOVL3, FAR2, CLDN8, CLDN23, and
AQP9) was significantly greater in dupilumab-treated patients
compared with a placebo group at 16 weeks; levels of epidermal
proliferation measures (MKi67, K16, IL24, and IL26) were also
significantly lower in patients treated with dupilumab compared
with placebo [172].
Clinical trials with biologics targeting IL-13 (tralokinumab and
lebrikizumab) and IL-31 (nemolizumab) are currently underway.
The data are promising, particularly concerning the improvement
of pruritus [249–251]. In addition, there are several small
molecules including JAK inhibitors, H4 antagonists, PDE4 inhib-
itors and AhR antagonists currently being investigated [252].
Biomarker studies to gauge treatment response, including with
phototherapy, CsA, dupilumab and vitamin D, are helping develop
understanding of the pathophysiology of AD. Research measuring
the effects of systemic treatment on other biophysical parameters
of barrier permeability such as pH, TEWL, hydration, and lipid
organization is needed to expand etiological understanding.
Further research is also needed regarding the true clinical benefit
of barrier restoration and whether systemic treatments that
improve the skin barrier translate into clinical advantages. Finally,
emerging data may allow targeting of specific molecular aspects of
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Journal of Dermatological Science 102 (2021) 142–157
the impaired skin barrier in AD, opening avenues for the
development of additional barrier-related therapies.
10. Conclusion
Advances in our understanding of the structural components of
the epidermal skin barrier, epidermal lipids and epidermal
differentiation, and in particular identification of FLG loss-of-
function mutations, has highlighted the importance of the skin
barrier in AD. Although skin barrier defects have been shown to
play a major role in the pathogenesis of AD, with genetic
alterations in epidermal barrier genes reported in AD and novel
treatment targets identified, further research is required to fully
understand the complex etiology of the disease. Together with a
genetic component, exposure to natural allergens, climate factors,
and possibly air pollutants have been shown to play a role in the
development of AD, although additional data are required to
determine the association between these particulates and AD, and
underlying mechanisms. In addition, identification of the gut-skin
axis and recent advances in genetic sequencing technologies will
likely lead to the improvement of treatment options for AD that
target the skin and gut microbiome. With the cornerstone of AD
treatment consisting of TCS, TCIs and emollients for many years,
novel topical and systemic treatments are emerging which target
the skin barrier. Future research exploring the association between
the skin barrier and AD is likely to increase our understanding of
the multifaceted etiology of the disorder, opening doors to new and
effective treatments.
Funding
The writing/editorial support was funded by Meda Pharma S.p.
A., a Viatris company.
Author’s declaration
The Authors made substantial contributions to conception and
design, acquisition of data, or analysis and interpretation of data.
The Authors drafted the article or reviewed it critically for
important intellectual content.
The Authors gave final approval of the version to be published.
Declaration of Competing Interest
T. Luger has participated as Principal Investigator in clinical
trials, advisory boards and has given lectures, sponsored by
Novartis, Lilly, La Roche Posay, Pfizer, Janssen, and Sanofi. He has
received consultancy/speaker honoraria from Novartis, Abbvie,
Galderma, La Roche Posay, Meda Pharma S.p.A. (a Viatris company),
Janssen, and Sanofi, and has acted as a scientific Advisory Board
member for Abbvie, Celgene, La Roche Posay, Janssen, Pfizer,
Menlo, Meda Pharma S.p.A. (a Viatris company), Galderma,
Symrise, and Lilly. He has received research grants from: Celgene,
Janssen-Cilag, Leo, Meda Pharma S.p.A. (a Viatris company), and
Pfizer.
M. Amagai has received research grants from Maruho, Kose, and
JSR.
B. Dreno has no relevant conflict of interest to declare.
M.A. Dagnelie has no relevant conflict of interest to declare.
W. Liao has received research grant funding from Abbvie,
Amgen, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, Sanofi,
and TRex Bio.
K. Kabashima has received consulting fees or advisory board
honoraria from Japan tobacco Inc., Chugai Pharmaceutical,
Maruho, and Pola Pharma, and has received research grants from
T. Luger, M. Amagai, B. Dreno et al.
LEO Pharma, Japan tobacco Inc., P&G Japan, Eli Lilly Japan, Tanabe
Mitsubishi, Ono Pharmaceutical, Kyowa Hakko Kirin, Pola Pharma,
AbbVie, Sanofi, and Kyorin Pharmaceutical.
T. Schikowski: No conflict of interest to declare.
E. Proksch has received funding from Bayer Consumer Care and
Dr. August Wolff, Arzneimittel.
P.M. Elias: No conflict of interest to declare.
M. Simon has received funding from Pierre Fabre Dermo-
Cosmétique, L’Oréal and BASF Beauty Care Solutions France. He is
co-author of patent #WO2012140095A1.
E. Simpson reports grants and personal fees from AbbVie, Eli
Lilly, Incyte, Leo Pharmaceutical, Pfizer and Regeneron. He reports
grants and fees from Novartis. He reports grants from Kyowa Hakko
Kirin and Merck and he reports personal fees from Dermira, Forte
Bio Rx, Menlo Therapeutics, Ortho Dermatologics and Sanofi-
Genzyme.
E.Grinich: No conflict of interest to declare.
M. Schmuth has received research grants from ExpanScience,
has participated as Principal Investigator in trials sponsored by
Roche, Amgen, MSD, GSK, Eli Lilly, Abbvie, Scenesse, Orfagen and
has received travel funds from Nogra Pharma. He has not accepted
any honoraria from industry for advisory boards or speakers’
bureau participation and does not own pharma stocks, equity or
patent licenses.
Acknowledgements
Medical writing support for the development of this review
article, under the direction of the authors, was provided by Jane
Murphy, Samuel McCracken and Jack Lassados of Ashfield
MedComms, an Ashfield Health company, and funded by Meda
Pharma S.p.A., a Viatris company.
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Thomas Luger, MD, is currently Senior Professor,
Department of Dermatology, University of Münster. He
obtained his MD from the University of Vienna. His
clinical interest is focused on inflammatory and autoim-
mune diseases of the skin, and his main areas of research
are the role of cytokines and neuropeptides in the
regulation of inflammation and immune tolerance. He is
Past-President of the German Society of Dermatology and
former Dean of the Medical Faculty of the University of
Münster. He is a member of the Austrian Academy of
Sciences and the German Academy of Sciences Leopol-
dina. He is currently Honorary Editor of the journal
Experimental Dermatology.