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Tr a n s l a t i o n o f R e s e a r c h t o P a t i e n t C a r e
Section Editors: Whitney High, MD; James Q. Del Rosso, DO; Jacquelyn Levin, DO

therapies used to treat AV can induce

alterations within the epidermis that

Acne Vulgaris and the can lead to changes that disrupt

some of the normal physiological
functions of the epidermis, including

Epidermal Barrier the stratum corneum (SC). In the

case of AV, one needs to also
consider the follicular epithelial
Is Acne Vulgaris Associated with Inherent barrier, which is directly involved
with changes that occur during both
Epidermal Abnormalities that Cause comedogenesis, and in stages of
inflammation, especially with
Impairment of Barrier Functions? follicular rupture.

Do Any Topical Acne Therapies Alter the Is There a Connection Between

Specific Alterations in the Follicular
Structural and/or Functional Integrity Epidermis and the Development of
Acne Lesions?
of the Epidermal Barrier? Alterations in follicular
keratinization are integral
components of the pathogenesis of
AV and occur in the subclinical
a stages of acne lesion formation
Diane Thiboutot, MD; bJames Q. Del Rosso, DO (microcomedo formation).1 Filaggrin
Professor of Dermatology, The Pennsylvania State is a key protein in epidermal
University College of Medicine, Hershey Pennsylvania; differentiation and contributes to the
Dermatology Residency Program, Director, structural and functional integrity of
the SC. Within acne lesions, there is
Valley Hospital Medical Center, Las Vegas, Nevada an increase in filaggrin expression in
keratinocytes lining the follicle wall.2
In addition, Propionibacterium
acnes has been shown to increase
filaggrin expression in cultured
Abstract of proper skin care as a component keratinocytes and also in explants of
Acne vulgaris is a common of the management of acne vulgaris is human skin.3 Importantly, it is not
dermatological disorder that supported by the information that is known if the changes in filaggrin
predominantly affects teenagers, but currently available. expression noted in AV are primary
can also affect preadolescents and or secondary events.4 An interesting
post-teen individuals. Despite the Background hypothesis was raised by the results
fact that acne vulgaris is the most Unlike in atopic dermatitis, of a study examining filaggrin
common skin disorder encountered epidermal barrier dysfunction is not mutations in patients with xerosis.5
in ambulatory dermatology practice what usually comes to mind when Study subjects were queried for a
in the United States, there has been one is asked to describe or list history of skin disorders and signs
limited research on the epidermal cutaneous abnormalities associated and symptoms of dry skin. Whole
permeability barrier in untreated skin with acne vulgaris (AV). Although blood samples were obtained with
of people with acne vulgaris and also more studies are needed, there is a DNA extracted and analyzed for null
after use of acne therapies. This body of literature that supports the mutations in filaggrin. The odds ratio
article reviews the research results concept that AV is associated with of having AV was 0.3 in the subjects
and discusses the available literature inherent abnormalities in epidermal carrying one copy of the null
on this subject area. The importance barrier functions. In addition, some mutation. Although this was not


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statistically significant, and a history

of AV was self-reported, the authors
hypothesized that a null mutation in
the filaggrin gene could be protective
against AV.4 An additional study
tested this hypothesis in a cohort of
Singaporean Chinese patients
presenting with AV where they
evaluated and performed screening
for 22 types of filaggrin null
mutations in 287 patients with AV
and in more than 400 control
subjects. A comparative analysis
failed to identify a statistically
significant negative association
between AV and filaggrin mutations
in this population. The suggested
concept that a reduced ability to Figure 1. Observations in facial skin in acne vulgaris. Focus on findings that may
express filaggrin due to genetic impact epidermal barrier functions*
mutation correlates directly with a
lesser ability to form acne lesions is
interesting; however, studies to date
do not provide cogent evidence to the facial skin of people without AV.6 water loss (TEWL), and conductance
clearly support this hypothesis. In addition, the normal-appearing within the SC of male patients with
facial skin of patients with AV can mild-to-moderate AV (n=36), age
Epidermal Permeability Barrier exhibit specific perifollicular and range 14 to 26 years, and age-
Characteristics and Acne Vulgaris follicular patterns of inflammatory matched male control subjects
In AV, the barrier functions of both cellular infiltration and inflammatory (n=29).13 They found that the
the epidermis of the exposed skin marker expression that are very patients with AV exhibited markedly
surface and that which comprises the similar to the patterns observed in higher sebum secretion and greater
follicular epithelial lining are early acne papules present for 6 TEWL and markedly decreased SC
significant to consider. Both may be hours.7 These findings and the conductance (corneometry testing).
involved in pathophysiological observations of others suggest that The combined findings of higher
mechanisms associated with AV or subclinical inflammation is present TEWL and lower SC hydration
with impaired physiological properties early in the emergence of acne lesion (decreased conductance) noted in
of the SC, such as regulation of water development even in the absence of the patients with AV compared to
flux and/or epidermal hydration. follicular hyperkeratinization.711 As controls supports SC permeability
Figure 1 depicts findings that may more attention is now being given to barrier impairment associated with
correlate with epidermal barrier the role of various barrier functions AV. In addition, acne patients had
functions in acne-prone facial skin of of the epidermis (especially the SC) significantly reduced free
individuals with AV. in different disease states, it is sphingosine and total ceramides in
Surface epidermis. The facial important to know if there are any their SC, which is indicative of a
skin of patients with AV differs from inherent structural or functional deficient intercellular lipid membrane
normal skin of people without AV in epidermal barrier aberrations in AV and correlates with impairment of
several ways. Although exceptions that may be important to address the SC permeability barrier. The
may exist, sebum production is therapeutically, especially as certain increase in TEWL and decrease in SC
higher and the size of sebaceous medications used to treat AV can hydration (conductance) were of
glands are larger in people with acne- alter some epidermal properties.12 greater magnitude in patients with
prone facial skin who are already Yamamato et al13 examined sebum AV of moderate severity as compared
known to have AV as compared with secretion, SC lipids, transepidermal to those with mild acne severity and


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quantity was 59-percent higher,

squalene was increased
approximately two-fold, and free
fatty acids were decreased. A relative
essential fatty acid deficiency has
also been discussed related to
pilosebaceous unit contents.19,20 In AV,
increased sebum flow dilutes linoleic
acid resulting in a relative deficiency
which may play a role in

How Do Some Topical Acne

Therapies Alter Epidermal
Barrier Functions?
Some topical medications,
systemic medications, and physical
procedures used to treat AV and/or
Figure 2. Observations in facial skin in acne vulgaris. Focus on findings that may
acne scarring can lead to alterations
impact epidermal barrier functions*
in SC permeability barrier function
based on documentation of increased
TEWL and in some cases visible signs
of xerosis. Increases in TEWL have
as compared to normal control follicular wall can lead to various been reported with benzoyl peroxide,
subjects.13 These latter findings degrees of rupture with subsequent tretinoin, tazarotene, and
suggest that the degree of SC leakage of sebum, keratin, bacteria, isotretinoin.2125 See Figure 2, which
permeability barrier impairment and cellular debris into the dermis. depicts findings in acne-treated skin
correlates directly with the severity The presence of these substances, that can be related to epidermal
of AV.13 which are foreign to the dermis, barrier functions. Various efforts
Follicular epidermis provokes further inflammation that is have been made to minimize
(epithelium). In addition to the deeper, eventuating in the emergence impairments of the SC permeability
exposed epidermis of the of a nodular or nodulocystic acne barrier induced by acne therapies.
integumentary surface, the follicular lesion. Benzoyl peroxide. Benzoyl
epithelium also contributes to It is important to differentiate the peroxide (BP) has been used
cutaneous barrier functions. Loss of lipids and other components of the extensively for the treatment of AV
physical barrier integrity sometimes intercellular lipid membrane of the for more than six decades, offering
occurs when the intensity of SC, the core structural component of the ability to markedly reduce counts
inflammation reduces the strength of the epidermal permeability barrier, and suppress the proliferation of P.
the follicular wall. In AV, the from the lipids and other acnes, including inhibition of the
proliferation of P. acnes within the components of sebum that reside in emergence of antibiotic-resistant
follicle initiates several inflammatory the pilosebaceous follicle. Lipids in strains of the organism.2628
cascades related to innate, acquired, sebum are distinct from the SC It is well known that BP can cause
and humoral immunological lipids.12,1618 Also, the content of cutaneous irritation in some patients,
responses; direct inflammatory effects sebum in patients with AV may be which appears to be dependent on
of enzymes (i.e., lipases, matrix different from individuals without AV. concentration, vehicle formulation,
metalloproteases); and inflammation In a small study of males, age range type of adjunctive skin care, other
triggered by catalytic breakdown 15 to 25 years, with AV (n=9) and concomitant acne medications, and
products.14,15 When intrafollicular and without AV (n=9), the sebum content the inherent skin sensitivity of the
perifollicular inflammatory processes differed between the two groups.18 In individual. Allergic contact dermatitis
markedly intensify, attenuation of the the males with AV, the sebum from BP is much less common than


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irritant dermatitis. Despite the to a few weeks. As more effects in skin, it has been stated that
widespread use of BP over many inflammatory lesions emerge over the separation of therapeutic from
years for AV in both prescription and time, use of a topical retinoid is still toxic effects of topical and systemic
over-the-counter formulations, there suggested as these agents reduce retinoids may be difficult, because
is a paucity of data on what both comedonal and inflammatory the same cellular mechanisms are
epidermal effects BP may induce, acne lesions related to multiple operative.31 In both animals and
although it has been shown to exhibit modes of action.2629 Depending on humans, topical retinoids induce
some keratolytic activity.28 the severity of AV, use of a topical acanthosis, hypergranulosis, and a
In one study, investigators retinoid in combination with other relative decrease in SC thickness,
attempted to offset the 1.8-fold topical agents, and also in likely related to augmented cell
increase in TEWL from application of combination with oral therapy for AV, turnover.31 In mouse skin, topical
BP 10% by topical administration of supports the foundation of the global retinoid application increased
alpha-tocotrienol, an isomer of guidelines that have been published epidermal labeling index, with a
vitamin E.22 The changes induced by on acne management.26,29 plateau effect noted after
BP suggest that this agent induces The ability of a topical retinoid to approximately one week as
damage to the SC lipid bilayer, which inhibit microcomedo formation, acanthosis peaks. After
results in an increase in TEWL and decrease both comedones and approximately two weeks, acanthosis
also creates some impairment of the inflammatory lesions of AV, interfere reverts partially toward baseline
epidermal antioxidant barrier by with dermal matrix dedradation, and followed by the reaching of a steady-
reducing levels of vitamin E. promote remodeling of upper dermal state equilibrium, which persists
Application of alpha-tocotrienol did collagen and elastic tissue reflect a thereafter.31 Interestingly, this 2- to 3-
mitigate BP-induced peroxidation of variety of modulating effects on week time course of epidermal
SC lipids, but did not offset the different cellular mechanisms in alteration prior to stabilization
increase in TEWL.22 skin.2931 These include alterations in correlates with the time course of
Topical retinoids. Since the epidermal keratinization and retinoid dermatitis. This observation
availability of topical tretinoin in the differentiation, downregulation of suggests that the visible changes of
United States in 1971, topical toll-like receptor-2 (TLR2) retinoid dermatitis that occur early
retinoid therapy has been a major expression, decrease in dermal after starting topical retinoid therapy
part of the foundation of therapy for matrix degradation that is promoted at least partially reflect the
AV.26,29 The subsequent availability of by chronic photodamage, and therapeutic mechanisms of action
adapalene in 1996 and tazarotene in alteration of various transcription that the topical retinoid initiates
1997, both in cream and gel factors involved in patterns of within the epidermis.
formulations and in two different cutaneous inflammation.2931 After As topical retinoids enhance
concentrations, expanded the choices initiation of treatment with a topical desquamation with a reduction in SC
available to clinicians when selecting retinoid, many patients develop thickness and function, alteration in
a topical retinoid for treatment of AV. visible dermatitis changes (erythema, permeability barrier function is a
The efficacy and overall favorable fine scaling, desquamation) usually likely sequelae.32 Concurrent
safety of the available topical within the first two weeks, referred moisturizer use to pre-emptively
retinoids used to treat AV is well to as retinoid dermatitis. These skin reduce the SC permeability barrier
established, with use of a topical changes are almost always transient impairment induced by topical
retinoid suggested from the outset and diminish with continued retinoid application has been
when AV develops in the preteen or application over the first 2 to 4 weeks evaluated with a reduction in signs
early teenage years, especially as of use. and symptoms associated with
many cases exhibit multiple Topical retinoids have been shown retinoid dermatitis without an
comedonal lesions at this point in to exhibit effects on various targets, apparent loss of efficacy.33 Moisturizer
time. Application of a topical retinoid cells, and pathways involved in the application to reduce the signs and
each day reduces microcomedo normal physiology of the epidermis symptoms of retinoid dermatitis after
formation and stopping the topical and dermis and on mechanisms they develop has also been reported
retinoid leads to an increase in involved in the pathogenesis of AV. and is often self-initiated by
microcomedo formation within days As a result of this broad range of patients.34 In a study of tretinoin


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cream 0.025% in women with is an office-based procedure that is Summary

photoaging (n=50) between the ages commonly used in some clinical Although data are somewhat
of 35 and 55 years, application of a practices and also at spas and limited, AV does appear to be
moisturizer for two weeks before and salons. Therefore, many patients associated with some inherent
during tretinoin treatment prevented who are using current treatment for epidermal barrier impairments, with
an increase in TEWL.21 AV may undergo the procedure and consideration given to characteristics
Topical retinoid application also not be aware that it could of both the follicular SC and the
induces desmosomal shedding within potentially predispose the patient to surface SC. Although follicular
the stratum spinosum, a decrease in cutaneous irritation associated with keratinocytes in acne lesions exhibit
tonofilaments, and some deposition topical agents used for AV. Two increased filaggrin expression, the
of nonmucin glycoconjugates, studies have documented a transient relevance of this in acne
leading to SC loosening and upper increase in TEWL and increased SC pathogenesis is not entirely clear.
epidermal dyshesion.31 The hydration following Acne-prone facial skin in individuals
magnitude of these effects are less microdermabrasion. TEWL with AV is associated overall with
than with oral retinoids, which are evaluations were completed higher magnitudes of sebum
associated with a greater magnitude following microdermabrasion with production and larger sebaceous
of skin fragility.31 Nevertheless, the either sodium chloride or aluminum glands as compared to facial skin of
changes induced by topical retinoid oxide crystals.35 Both TEWL and SC individuals without AV.
use, which promote epidermal hydration were significantly In addition, there are some data
dyshesion, explain the superficial increased 24 hours following suggesting that SC permeability
denudation of skin reported by microdermabrasion with both types barrier impairment occurs inherently
patients who undergo tape striping- of crystals. TEWL returned to in facial skin of patients with AV, the
type techniques to remove unwanted baseline at seven days in both magnitude of impairment correlates
hair usually on the upper lip or groups, with SC hydration with severity of AV, and decreased
eyebrow region. maintained in the sodium chloride levels of free sphingosine and total
Changes in the SC permeability group. A second study demonstrated ceramides suggest some deficiency of
barrier associated with both topical and that TEWL increased immediately the intercellular lipid membrane.
oral retinoid therapy do not appear to after diamond microdermabrasion, In addition, certain medications
be related to any reduction in SC lipids which remained significantly used to treat AV can cause
comprising the intercellular lipid increased at 24 hours and returned alterations in SC integrity and
membrane of the SC.31 to baseline by Day 2.36 function, either via the active
Topical and oral antibiotics. TEWL was assessed in patients ingredient, the vehicle, or both,
Alteration of the cutaneous flora by with AV (n=8) treated on two which can result in signs and
antibiotics, either topical or oral, occasions, two weeks apart, with symptoms of cutaneous irritation. .
changes the microbiome.27 This can photodynamic therapy using Providing specific skin care
result in physiological changes within methylaminolevulinic acid and red recommendations, including product
the epidermis as the spectrum of light (MAL-PDT) at baseline, 4, 8, selection and proper use, is an
organisms comprising the skin flora is and 12 weeks following the second important part of the management of
altered. The prevalence of resistant treatment.37 These outcomes were AV and may adjunctively augment
organisms, such as P. acnes and compared to TEWL measurements the efficacy of topical medications in
Staphylococcus epidermidis also obtained from untreated acne reducing acne lesions. More research
increases, as does colonization of the subjects (n=8). No significant is needed in this very important and
nasopharyngeal region with bacteria differences in TEWL were noted clinically relevant area related to AV
that may potentially be pathogenic to between the treated and untreated and its management.
the patient or others (i.e., groups or at any time point compared
Streptococcus pyogenes).27 to baseline. These investigators References
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Dr. Thiboutot has been a consultant or investigator for Allergan, Galderma, Photocure, Stiefel, and Valeant. Dr. Del Rosso has
served as a consultant, speaker, and/or researcher for Allergan; Bayer Healthcare Pharmaceuticals; Dermira; Eisai; Galderma;
LeoPharma; Onset Dermatologics; Obagi Medical Products (OMP); PharmaDerm; Primus; Promius; Ranbaxy; Taro
Pharmaceuticals; TriaBeauty; Unilever; Medicis, a Division of Valeant Pharmaceuticals; and Warner-Chilcott. Address
correspondence to: James Q. Del Rosso, DO; E-mail: jqdelrosso@yahoo.com.


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