PRIMER

Acne vulgaris
Sara Moradi Tuchayi1, Evgenia Makrantonaki24, Ruta Ganceviciene2,5, Clio Dessinioti2,6,
Steven R.Feldman1,7,8 and Christos C.Zouboulis2
Abstract | Acne vulgaris is a chronic inflammatory disease rather than a natural part of the life cycle as
colloquially viewed of the pilosebaceous unit (comprising the hair follicle, hair shaft and sebaceous
gland) and is among the most common dermatological conditions worldwide. Some of the key mechanisms
involved in the development of acne include disturbed sebaceous gland activity associated with
hyperseborrhoea (that is, increased sebum production) and alterations in sebum fatty acid composition,
dysregulation of the hormone microenvironment, interaction with neuropeptides, follicular hyperkeratin
ization, induction of inflammation and dysfunction of the innate and adaptive immunity. Grading of acne
involves lesion counting and photographic methods. However, there is a lack of consensus on the exact
grading criteria, which hampers the conduction and comparison of randomized controlled clinical trials
evaluating treatments. Prevention of acne relies on the successful management of modifiable risk factors,
such as underlying systemic diseases and lifestyle factors. Several treatments are available, but guidelines
suffer from a lack of data to make evidence-based recommendations. In addition, the complex combination
treatment regimens required to target different aspects of acne pathophysiology lead to poor adherence,
which undermines treatment success. Acne commonly causes scarring and reduces the quality of life of
patients. New treatment options with a shift towards targeting the early processes involved in acne
development instead of suppressing the effects of end products will enhance our ability to improve the
outcomes for patients with acne.

Acne vulgaris is a chronic inflammatory disease of the
pilosebaceous unit (comprising the hair follicle, hair shaft
and sebaceous gland; FIG.1) and is among the most com-
mon dermatological conditions worldwide, with an esti-
mated 650million people affected1,2. Acne is considered a
chronic disease owing to its prolonged course, pattern of
recurrence and relapse, and manifestations such as acute
outbreaks or slow onset. Moreover, acne causes profound
negative psychological and social effects on the quality
oflife of patients3.
Although progress has been made in understand-
ing the pathophysiology of acne and the mechanisms
of actions of available drugs to treat the disease, many
unanswered questions remain. The lack of a consensus
Correspondence to S.R.F. grading system also slows efforts to compare efficacies of
e-mail: sfeldman@
different medications in clinical studies, which is imped-
wakehealth.edu
Center for Dermatology
ing the formulation of a globally approved consensus
Research, Department of guideline. Given that abnormalities in several processes
Dermatology, Wake Forest (sebum production and sebocyte differentiation, prolif-
School of Medicine, eration and inflammation) can contribute to the devel-
4618Country Club Road,
Winston-Salem,
opment of acne, a multipronged treatment regimen is
NorthCarolina 27104, USA. needed in most patients. This complex regimen impairs
adherence, which is key for treatment success. Acne com-
Article number: 15029
doi:10.1038/nrdp.2015.29
monly results in scarring and post-inflammatory hyper-
Published online pigmentation, which has a subsequent impact on quality
17 September 2015 of life; hence, early and aggressive therapy is crucial.
Novel delivery strategies for and modifications of exist-
ing drugs are recent changes in acne treatment, in addi-
tion to the development of new medications that target
regulatory pathways involved in acne pathophysiology
instead of suppressing the effects of the end products of
these pathways. With myriad treatment options avail-
able, including oral isotretinoin (an agent that blocks all
the pathophysiological pathways of acne and has excel-
lent adherence but is associated with severe teratogeni
city), and several new therapies in development, better
treatment options may be available for patients soon. In
this Primer, we describe the following aspects of acne
vulgaris: epidemiology, pathophysiology, diagnostic
methods, available medications and new treatments, patient
quality of life and adherence to treatment.
Epidemiology
Most people experience acne during adolescence, with
>95% of teenage boys and 85% of teenage girls affected4,5.
Almost 20% of these young people have moderate-to-
severe acne6 (TABLE1), and as many as 50% continue to
suffer from acne in adulthood6,7. A systematic analysis
for the Global Burden of Disease study indicated that
acne was the eighth most prevalent disease globally in
2010, following only two other skin disease categories
on the list 2 (FIG.2).

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PRIMER
Author addresses
1
Center for Dermatology Research, Department of
Dermatology, Wake Forest School of Medicine,
4618Country Club Road, Winston-Salem,
North Carolina27104, USA.
2
Departments of Dermatology, Venereology, Allergology
and Immunology, Dessau Medical Center, Dessau, Germany.
3
Department of Dermatology and Allergology, Ulm
University, Ulm, Germany.
4
Research Group Geriatrics, Charit Universitaetsmedizin
Berlin, Berlin, Germany.
5
Clinic of Infectious, Chest Diseases, Dermatovenereology
and Allergology, Vilnius University, Lithuania.
6
Andreas Syngros Hospital, National and Capodistrian
University of Athens, Athens, Greece.
7
Department of Pathology, Wake Forest School of
Medicine, Winston-Salem, North Carolina, USA.
8
Department of Public Health Sciences, Wake Forest
School of Medicine, Winston-Salem, North Carolina, USA.
Acne is the most commonly diagnosed skin condition
in the United States according to the 2010 National
Ambulatory Medical Care Survey (NAMCS) factsheet
for dermatology8, and accounts for more than 5 million
visits to physicians each year 9. Acne was the most com-
mon condition seen by dermatologists in the United States
and the thirteenth most common condition by non-
dermatologists, resulting in the second most common
reason for referrals to dermatologists10; corresponding
data from other countries is lacking. Approximately two-
thirds of dermatology visits for acne are made by women11.
The mean age of patients with acne seeking treatment is
24years12, and one-third of total consultations for acne are
made by patients >25years of age13. When NAMCS data
were analysed according to specific age groups per diag-
nosis by dermatologists and by general practitioners dur-
ing skin disease-related appointments (19932010), acne
was the most frequent diagnosis for patients 544years of
age14. The mean age of children (age range: 618years)
seeking treatment for acne has decreased from 15.8years
in 1979 to 15.0years in 2007. This observation might be
indicative of an earlier onset of acne, which is in line with
the observation that puberty is also progressively starting
at an earlier age; however, the availability of better treat-
ment options may also have a role15. Currently, children as
young as 68years of age are seeking treatment15.
Not only is acne the most common dermatological
diagnosis in the overall population but it is also the most
common dermatological diagnosis in patients with skin
of colour. In the United States, acne is the most com-
monly diagnosed condition in African-American, Asian
and Hispanic patients presenting to the dermatolo-
gist, whereas the top dermatological diagnosis in white
patients is actinic keratosis16. Acne has been reported to be
more prevalent among black and Hispanic women than
in white, Asian and Continental Indian women17. Given
that acne is so prevalent, it has a high associated cost
estimated in 2004 in the United States at >US$3bil-
lion of total direct and indirect cost and approximately
US$12billion of intangible cost because of the quality of
life impact (estimated using willingness to pay)18.
2 | 2015 | VOLUME 1 www.nature.com/nrdp
2015 Macmillan Publishers Limited. All rights reserved
Mechanisms/pathophysiology
Acne develops in the pilosebaceous unit (FIG.1) and
involves many processes (FIG.3). Some of the key features
underlying acne development include disturbed seba-
ceous gland activity associated with hyperseborrhoea
(excessive sebum) and alterations in sebum fatty acid
composition, dysregulation of the hormone micro
environment, interaction with neuropeptides, follicu-
lar hyperkeratinization, induction of inflammation and
dysfunction of the innate and adaptive immunity. These
processes impair functioning of the pilos ebaceous
unit, which leads to the transition of a normal pore
to microcomedones, and further to comedones and
inflammatory lesions. Bacterial antigens can potenti-
ate the inflammatory process1921. Genetic studies of
heterozygous and homozygous twins and family stud-
ies have produced a growing body of evidence for the
role of hereditary factors in the risk of acne develop-
ment 2224. Acne can also be triggered or worsened by, for
example, ultraviolet radiation and other environmental
factors25,26, dietary factors27,28, smoking 29, stress and the
modern lifestyle30.
Sebum
Sebum is secreted by the sebaceous gland and comprises
an oily mixture of triglycerides, wax esters, squalene, free
fatty acids and small amounts of cholesterol, cholesterol
esters and diglycerides. Sebum production is regulated
by many factors that activate pathways involved in cell
proliferation and differentiation, lipogenesis, hormone
metabolism, and cytokine and chemokine release31
(FIG.4). Sebaceous lipogenesis is more complex than
previously thought, as ligand-independent, MYCN-
mediated hyperactivation of epidermal growth factor
receptor and induction of perilipins a major group
of proteins that coat lipid droplets may also regu-
late sebocyte differentiation and lipid production3234.
Excessive sebum is thought to be a key contributor to
acne development. However, not all patients with acne
experience hyperseborrhoea. In fact, the correlation
between sebum production and acne severity depends
on age and sex 3537; in men, acne is more dependent on
sebum production35.
Acne is also associated with alterations in the free fatty
acid composition of sebum. Sebum of patients with acne
contains less essential (that is, fatty acids that cannot be
synthesized by the body and can only be acquired from
the diet) free fatty acids (including linoleic acid) than
that of people without acne38,39. Pro-inflammatory sebum
lipid fractions (monounsaturated fatty acids (MUFAs)
and lipoperoxides; see below) have been associated with
the development of acne lesions, and the skin surface
lipid oxidant to antioxidant ratio is another acne stimu-
lus40. Specifically, sebum of patients with acne contains
lipoperoxides resulting from the peroxidation of the lipid
squalene41. Both lipoperoxides and MUFAs influence
keratinocyte proliferation and differentiation, contribut-
ing to follicular hyperkeratinization41,42. Different ethnic
groups have different lipid profiles; for example, specific
wax ester lipid fractions differ in quantity between white
and African Americans43.
 PRIMER

a Normal hair follicle b Whitehead comedone Figure 1 | Acne formation. Schematic representation of
the skin containing a sebaceous unit (parta) comprising
Hair
Follicular Whitehead the hair follicle and the sebaceous gland, which is
orice responsible for sebum production. Acne formation starts
Skin
surface when sebum and keratinous material shed from the skin
Enlargement
of follicle clog up a pore and trigger bacterial colonization, leading
Sebaceous opening to a closed or whitehead comedone (partb). As the
gland Bacteria whitehead comedone continues to expand, owing to more
Follicle
accumulation of sebum and keratinous material, the
follicular orifice opens and forms an open or blackhead
comedone (partc). The black colour is the result of oxidized
c Blackhead comedone d Papule lipids and the skin pigment melanin. More distension of the
comedone results in follicular rupture and inflammatory
Blackhead Inammation lesions such as papules (partd), pustules (parte) and
nodules or cysts (partf). Nodular acne is sometimes
inaccurately referred to as cystic or nodulocystic acne.
An acne cyst is not a true cyst as true cysts are linedby
White epithelium. Histological images of a pilosebaceous unit
blood cells (partg), a comedone (parth) and an inflammatory lesion
with rupture of the follicular walls (parti) are shown. Parts
gi reproduced with permission from REF.242, Wiley.

e Pustule f Nodule or cyst

g h i 5dihydrostestosterone (5DHT)), oestrogens (oestra-
Nature Reviews | Disease Primers
Systemic and local hormonal imbalance
Whether the primary abnormality causing acne is in the
level of circulating hormones or in the processing of hor-
mones in the peripheral tissue is debated. Typically, acne
starts during puberty when the hormone balance starts
to change dramatically.
In a cross-sectional, retrospective study, the andro-
genic hormone profile of 835 female patients with
acne >15years of age was analysed. In the 54.6% of
participants with signs of hyperandrogenism, the lev-
els of dehydroepiandrosterone (DHEA) were most
frequently elevated44. In a recent cross-sectional study,
androstenedione and testosterone levels were higher
(P<0.0001) in patients with acne than in healthy con-
trols. In addition, 17hydroxyprogesterone levels were
higher in male patients with acne than in healthy controls;
high levels of this androgen were associated with greater
acne severity. By contrast, 17hydroxyprogesterone
levels were not different in women with or without
acne, although studies are needed to investigate whether
17hydroxyprogesterone levels can be modulated with
adrenocorticotropin treatment. Furthermore, high
oestradiol levels in women had a protective effect45,46.
In addition to systemic changes in hormone levels,
local overproduction of steroids, in particular andro-
gens, is associated with acne. Sebocytes produce ster-
oid hormones including androgens (testosterone and
diol and oestrone) and glucocorticoids (corticosterone
and cortisol)47 (FIG.4). Cutaneous steroid production can
be regulated by locally produced corticotropin-releasing
hormone, adrenocorticotropic hormone or cytokines4749.
Patients with acne produce more testosterone and
5DHT in their skin than healthy controls50, which
enhances sebaceous gland activity 51,52 and stimulates
sebocyte function, respectively 40. However, testosterone
affects human sebocyte proliferation in a dose-dependent
manner invitro, but not lipid synthesis53,54. This finding
suggests that other factors might influence the seba-
ceous gland55, with peroxisome proliferator-activated
receptors (PPARs; see below) and their ligands being the
primary candidates53,54. In sebaceous glands, changes in
the expression of 17hydroxysteroid dehydrogenases,
the group of enzymes involved in the interconversion of
oestradiol, oestrone, testosterone and androstenedione,
can influence the expression of genes involved in lipo
genesis56. Moreover, the expression of 17hydroxysteroid
dehydrogenases is negatively correlated with the expres-
sion of PPAR one of the key induction factors of
adipocyte differentiation56.
Glucocorticoids also regulate the production of
sebum. Enzymes catalysing the conversion of cortisone
to active cortisol are highly expressed in keratinocytes,
fibroblasts and sebaceous glands, and are upregulated
in acne lesions47. In the SZ95 sebocyte cell line, dexa-
methasone treatment enhances lipid synthesis, partially
through the transcriptional induction of sterol regulatory
element-binding transcription factor1 (SREBF1; which

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PRIMER
encodes SREBP1) and by increasing Toll-like receptor2
(TLR2) mRNA levels57.
Adult women and men with acne have increased
serum levels of insulin-like growth factor 1 (IGF1). In
women, serum IGF1 levels are correlated with the num-
ber of acne lesions, facial sebum excretion rate in post-
adolescent patients and serum levels of 5DHT and
DHEA sulfate5860. IGF1 is detected in maturing sebocytes
and suprabasal sebaceous duct cells61. Animal studies
have shown that IGF1 stimulates sebocyte differentia-
tion62. By contrast, in humans, IGF1 stimulates keratino-
cyte proliferation63 and lipid synthesis46,64 by inducing
SREBF1 (REF.64) through the phosphoinositide3-kinase
(PI3K) and mitogen-activated protein kinase (MAPK)
signal transduction pathways65.
In addition to glucocorticoids and IGF1, other factors
regulate SREBF1 levels. A high glycaemic Western diet
and high dairy protein consumption are correlated with
activation of IGF1 signalling and the promotion of mam-
malian target of rapamycin (mTOR) signalling 66. mTOR
complex 1 has a crucial role in the PPAR-stimulated
lipid uptake and differentiation of sebocytes67 while at
the same time promoting lipid production by activating
SREBP1 (REF.68). Oestrogens might have an indirect IGF1
effect on the pathogenesis of acne46. Androgens rapidly
induce SREBP1 in animal models69. Testosterone only
induces the phosphorylation of mTOR in human sebo-
cytes in the presence of IGF1 (REF.56), suggesting that
local androgen production with circulating IGF1 has a
pivotal role in sebum synthesis andacne.
Neuropeptides
The sebaceous gland expresses functional receptors
for several neuropeptides, including the receptor for
corticotropin-releasing hormone70, melanocortins71,
endorphin, vasoactive intestinal polypeptide, neuro
peptide Y and calcitonin gene-related peptide 72.
Activation of these receptors in human sebocytes modu-
lates the production of cytokines, cell proliferation and
differentiation, lipogenesis and androgen metabolism.
SubstanceP, which can be elicited by stress, may stimu-
late the proliferation of sebaceous precursor cells and
increase sebaceous cell size. These observations suggest
that substanceP promotes the proliferation and differ-
entiation of sebaceous glands. The facial skin of patients
with acne is highly innervated, with a higher number
of substancePcontaining nerves and mast cells, and
strong expression of neutral endopeptidase involved
Table 1 | Classification of clinical forms of acne vulgaris
Acne Clinical type
severity
Mild Comedonal acne and
papulopustular acne
Moderate Papulopustular acne and nodular
acne
Severe Nodulocystic acne and conglobate
acne
*Number of lesions on the face.
4 | 2015 | VOLUME 1 www.nature.com/nrdp
2015 Macmillan Publishers Limited. All rights reserved
in the degradation of substanceP in sebaceous glands
compared with patients without acne73. Endopeptidase
inhibitors may have a therapeutic role inacne74.
Inflammation cascades
Whether hyperkeratinization of the follicular duct pre-
cedes the onset of inflammation or vice versa is debated75.
The finding that IL1 activity was found to be increased
around uninvolved follicles before the observation of
keratinocyte hyperproliferation and activation suggests
an inflammatory trigger 76,77. Indeed, once inflamma-
tion is established, inflammatory acne lesions upregulate
numerous genes, including those that encode matrix
metalloproteinases, defensin 4, IL8 and granulysin78.
Nuclear factor-B (NFB) is also activated in acne
lesions79, as are the NFBregulated cytokines such as
IL1, IL8, IL10 and tumour necrosis factor (TNF)80.
TNF induces lipogenesis through JNK, PI3K and AKT
pathways81. Increased levels of IL8 attract inflamma-
tory cells, including polymorphonuclear leukocytes and
lymphocytes79. IL17Apositive Tcells and Thelper17
(TH17)related cytokines are present in acne lesions and
might have a pivotal role in the disease82.
The levels and metabolic pathways of several inflam-
matory lipid mediators are also abnormal in acne lesions.
Prostaglandins are synthesized by the cyclooxygenase
(COX) enzymes. Sebocytes express both COX isozymes,
COX1 and COX2, and COX2 expression is selectively
upregulated in sebaceous glands of patients with acne83.
Activation of the platelet-activating factor signal-
ling pathway can regulate the levels of COX2, prosta
glandinE2 and IL8 in SZ95 sebocytes84. Transgenic
overexpression of Cox2 in the basal epidermis of mice
leads to increased prostaglandin E2 levels, which results
in sebaceous gland hyperplasia and excessive sebum pro-
duction. This observation suggests that COX2mediated
prostaglandin E2 synthesis could be involved in acne.
In addition, PPAR induces COX2, and increased
PPAR activity might further exacerbate this system85,86.
Leukotrienes are pro-inflammatory lipid mediators that
function as neutrophil attractants. Human sebocytes
express the enzymes needed for leukotriene production,
including lipooxygenases and leukotrieneA4 hydrolase.
Treatment of sebocytes with arachidonic acid stimulates
lipooxygenase expression and induces leukotrieneB4
synthesis83. Arachidonic acid also induces IL6 and
IL8. LeukotrieneA4 hydrolase and 5lipooxygenase are
expressed at a higher level in acne lesions than in normal
Comedones Papules and/ Nodules Nodules, cysts
or pustules and sinus
tracts
Comedones are the Small and few in None None
main lesions (<20*) number (<10*)
1040* 1040* 010* None
40100* and fused >40* >10* Many

Dental caries (baby teeth)
Low back pain
Dental caries
(permanent teeth)
Acne vulgaris
Mild hearing loss
Chronic
periodontitis Tension-type
headache
Other skin and
subcutaneous diseases
Migraine
Fungal skin diseases
Nature Reviews | Disease Primers
Figure 2 | The ten most prevalent diseases according to the Global Burden of
Disease study. Acne vulgaris was the eighth most prevalent disease globally in 2010,
whereas fungal skin diseases was fourth in global prevalence, and other skin and
subcutaneous diseases was in fifth place2. The category other skin and subcutaneous
diseases includes skin diseases (but excluding eczema, psoriasis, cellulitis, abscess,
impetigo and other bacterial diseases), scabies, fungal skin diseases, viral skin diseases,
acne vulgaris, alopecia areata, pruritus, urticaria and decubitus ulcer.
skin and in uninvolved skin of patients and may be
potential therapeutic targets83,87.
Propionibacterium acnes
The cutaneous microbiota might also be involved in
acne pathogenesis. A metagenomic analysis showed
that although the amount of Propionibacterium acnes on
the skin was similar between patients with acne (n=49)
and healthy controls (n=52), the strain populations
were different between the two groups. Certain P.acnes
strains were highly associated with acne, whereas other
strains were enriched on healthy skin88, which is impor-
tant given that different P.acnes strains have different
inflammatory potential. P.acnes typeIII is the most pro-
inflammatory strain and upregulates proteinase-
activated receptor2 (PAR2), TNF, matrix metalloprotein-
ase13 and tissue inhibitor of matrix metalloproteinase2
(REF.89). Certain P.acnes strains may be responsible for
infections that worsen acne lesions, an area that is being
further investigated9093.
P.acnes and associated antigens (namely, lipo
polys accharides) upregulate the expression of pro-
inflammatory cytokines in cultured sebocytes90. P.acnes
induces IL8 and TNF, whereas lipopolysaccharides
induce IL8, TNF and IL1. Viable P.acnes (but not heat-
killed organisms) stimulate the release of IL1, IL8 and
granulocytemacrophage colony-stimulating factor 94,95.
P.acnes also induces the expression of IL17 in peripheral
blood mononuclear cells, and IL17positive cells are pre-
sent in the infiltrate around comedones96. P.acnes can pro-
mote TH17 and TH1 response pathways, which are activated
in acne lesions, by inducing the secretion of IL17A and
IFN from CD4+ Tcells97. Furthermore, P.acnes triggers
NLRP3 (NOD-, LRR- and pyrin-containing 3; also
known as NALP3) inflammasome activation in mono-
cytes, macrophages and sebocytes; this activation
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 5
2015 Macmillan Publishers Limited. All rights reserved
PRIMER
depends on proteinases and reactive oxygen species
and results in IL1 secretion 80. Blocking NLRP3
expression blocks P.acnes-induced IL1 secretion in
sebocytes98. Interactions between P.acnes and macro
phages in the perifollicular dermis can induce IL1
and exacerbate inflammation80.
Keratinocytes and sebocytes can recognize and be
activated by P.acnes via CD1, CD14 and TLRs99101.
TLR2 activation in keratinocytes and sebaceous glands
triggers the release of IL1 invitro102. Bakry etal.103 have
documented differences in TLR2 expression between
acne-involved and normalskin.
Pilosebaceous glands express several antimicrobial
peptides (for example, psoriasin, defensins and catheli-
cidin), and the expression of these peptides is upregulated
in acne lesions104 and in the presence of P.acnes 90,91. In
addition, MUFAs, such as palmitoleic acid and oleic acid,
which have antimicrobial activity against Gram-positive
bacteria99, and enzymes involved in their synthesis (for
example, stearoyl coenzymeA desaturase1 (SCD1))
are present in the sebaceous gland105. The TLR2 ligand
macrophage-activating lipopeptide2 stimulates both
SCD1 and fatty acid desaturase2 (FADS2) mRNA expres-
sion in SZ95 sebocytes100. Lauric acid, a free fatty acid pre-
sent in sebum, has strong antimicrobial activity invitro
against skin bacteria, including P.acnes. Topical applica-
tion or intradermal injection of lauric acid invivo led
to remarkable therapeutic effectiveness against P.acnes-
induced inflammation and a profound reduction in the
number of bacteria106. Furthermore, lauric acid, palmitic
acid and oleic acid which are the typical free fatty acids
found in human sebum enhanced the defensin2
expression and antimicrobial activity of human sebo-
cytes against P.acnes107. This finding indicates that sebum
free fatty acids are involved in the disinfecting activity of
human skin through their direct antimicrobial charac-
teristics and by inducing the expression of antimicrobial
peptides in human sebocytes to enhance their innate
immune defence ability 106.
Modern lifestyle, diet and smoking
The modern lifestyle, which includes diet, stress, urban
noise, socioeconomic pressure, light stimuli and vari-
ations in sleep patterns, is a potential risk factor for
acne35,108. Diet might contribute substrates for synthe-
sis of sebaceous lipids109, such as the essential fatty acid
linoleic acid. Low-glycaemic-load diets may reduce
sebum production via endocrine effects, whereas
a typical Western diet exacerbates acne 42,110. Severe
caloric restriction curtails sebum excretion, which is
reversible by a normal diet 111,112. Changes in dietary
fat or carbohydrate intake can also alter sebum pro-
duction and composition113. The apparent absence of
acne in native non-Westernized people in Papua New
Guinea and Paraguay also supports this notion114. Total
cholesterol, low-density lipoprotein (LDL) choles-
terol, high-density lipoprotein (HDL) cholesterol and
apolipoprotein A1 were higher in patients with severe
acne than in healthy, age-matched controls (n=90);
however, the levels in patients were within the normal
range. Furthermore, lipid ratios for total cholesterol/
PRIMER

Hair
IGF1 Androgen excess Epithelial
hyperproliferation
PPAR ligands
Skin surface
Hyperseborrhoea
mTORC1 Regulatory with pro-
neuropeptides inammatory lipids

Sebaceous gland
SREBP1 Dietary lipids

Bacterial antigens Inammation

Follicle
Genetic factors
Propionibacterium
Environmental factors Smoking
acnes
Figure 3 | Tangled network of four core events in acne formation. Acne development depends on hyperseborrhoea,
Nature Reviews
epithelial hyperproliferation, Propionibacterium acnes activity within the follicle, and inflammation. | Disease
Androgens, Primers
ligands of
peroxisome proliferator-activated receptors (PPARs), regulatory neuropeptides with hormonal and non-hormonal activity,
and environmental factors lead to hyperseborrhoea, epithelial hyperproliferation in the ductus seboglandularis and
acro-infundibulum and the expression of pro-inflammatory chemokines and cytokines, which stimulate the development
of comedones and inflammatory lesions. IGF1, insulin-like growth factor 1; mTORC1, mammalian target of rapamycin
complex1; SREBP1, sterol regulatory element-binding protein 1. Adapted with permission from REF.243, Wiley.

HDL, LDL/HDL, triglycerides/HDL, apolipoproteinB/ 5q11.2 (rs38055; Pcombined=4.58109; OR:1.17) and

apolipoprotein A1, were all higher in patients with acne
than in controls, suggesting a possible dyslipidaemia in
patients with acne115. In addition, a lower body mass
index reduces the risk for acne lesions116,117.
The role of smoking in acne development is unclear.
Several studies have documented a positive correlation
between smoking, the number of cigarettes consumed
daily and acne development 118, whereas other studies
showed no correlation or even a protective role of smok-
ing 29,119. A potential mechanism by which smoking could
induce acne is by increasing oxidative stress that results
in a subsequent accumulation of lipid peroxide in come-
dones120 and an induction of phospholipaseA2dependent
inflammation signalling cascades.
Certain drugs such as anti-epileptic agents and anti-
cancer drugs (for example, tyrosine kinase inhibitors)
may also produce a monomorphic acne and acneiform
eruptions (dermatoses that resemble acne vulgaris)26.
The use of anabolic drugs induces severe forms of
acne121. Dioxin exposure can result in severe comedonal
acne (chloracne)25.
Genetics
Genetics have a role in the development of acne, as
evidenced by family and twin studies2224,122. Several
genetic polymorphisms affecting the expression and/or
function of genes have been investigated. Genes associ-
ated with acne included the IGF1 (CA)19 repeat poly
morphism123, the Pro12Ala polymorphism of PPARG124,
the IL6572G/C polymorphism and the IL1A889C/T
polymorphism125; however, further studies in this field
are needed. In addition, two genome-wide studies in
Han Chinese populations have found acne susceptibility
loci (1q24.2 and 11p11.2)126. A study conducted in the
United Kingdom comparing severe cases of acne with
controls found three significant associations 11q13.1
(rs478304; Pcombined=3.231011; odds ratio (OR):1.20),
1q41 (rs1159268; Pcombined=4.08108; OR:1.17)
linked to the transforming growth factor- cell signal-
ling pathway 127. In addition, a genome-wide association
study of 928 Americans of European descent with severe
acne revealed that the single-nucleotide polymor-
phism rs4133274 on 8q24 (72-kb upstream of MYCN)
was significantly associated with severe teenage acne
(P=1.7106)128. Proteomic analysis of sebaceous fol-
licular casts extracted from 18healthy individuals and
20individuals with acne has also provided an overview
of acne pathogenesis and identified proteins involved in
inflammation, wound healing and tissue remodelling,
such as myeloperoxidase, lactotransferrin, neutrophil
elastase inhibitor and, surprisingly, vimentin in acne-
affected skin129. These data represent early results and
more evidence is required to fully unravel the genetic
background ofacne.
Diagnosis, screening and prevention
Clinical presentation and grading
Acne affects body areas characterized by an increased
density of pilosebaceous glands, such as the face, chest
and back130. The initial acne lesion is the microcomedone,
which is an invisible (to the naked eye) microscopic
structure. During the course of acne, non-inflammatory
lesions form, including closed (whiteheads) and open
(blackheads) comedones, followed by inflammatory
lesions that include superficial lesions such as papules
and pustules (5mm in diameter) and deep pustules or
nodules130 (FIGS1,5).
Acne is diagnosed based on clinical examination
and can be classified according to severity, lesion type
and age of onset. Acne can be classified as mild, mod-
erate or severe and in accordance with the lesions that
predominate in a given patient: comedonal, papulo-
pustular, nodular, nodulocystic or conglobate acne
(acne conglobata)130 (TABLE1). Acne conglobata is a rare,

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 PRIMER

highly inflammatory, severe form of acne vulgaris, pre- the nose) is reliable137. Although stretching of the skin
senting with grouped comedones, nodules, abscesses facilitates the visualization of comedones, it is not per-
and interconnected draining sinus tracts. This subtype mitted for standard lesion counting because the degree
primarily affects adult males and manifests a chronic, of stretching might vary 135. The advantage of acne lesion
persistent course130. Furthermore, acne may be classified counting to grade acne is that individual lesions are pre-
on the basis of the age at presentation as neonatal acne cisely counted and classified as either non-inflammatory
(<4weeks of age), infantile acne (316months of age), or inflammatory lesions, which guarantees homogeneity
mid-childhood (17years of age), prepubertal (79years and facilitates comparison of different results of studies
of age), adolescent (1018years of age) or adult acne on acne treatments134,135. To locate deep lesions, palpa-
(>25years of age, either continuing from puberty or new tion is also necessary because they are not detected with
late-onset acne)131133. standard photographic methodology.
In clinical research studies, the assessment and grad- Acne grading systems have been proposed for use as
ing of acne includes lesion counting, as well as overall a complementary, easy to use and rapid mode of acne
grading systems supplemented with photographic meth- grade assessment and for the selection of eligible patients
ods134. Acne lesion counting includes the numbers of for therapeutic studies138,139. Overall scales might be less
open and closed comedones, papules, pustules and nod- quantitative but more relevant to clinicians and their
ules on the face or trunk135. For the photographic method, patients. Grading systems currently in use are listed
the photographs of the patients are compared with the in BOX1. Currently, no overall acne grading system is
appropriate standard136. In all cases, adequate lighting is considered to be a global standard, although efforts are
important to avoid omitting non-inflammatory lesions. underway to create a standard140,141.
Acne lesion counting should include the whole face (fore-
head, cheeks and chin) and not just a single facial area; Modern diagnostics through imaging
when appropriate, studies should include assessment of Various photographic methods have been proposed
acne lesions and progression in non-facial areas. Acne over the years to visualize acne and grade its severity,
lesion counting with recording of the lesions on a facial and to assess response to treatments134. Standard photo
template divided into five facial segments (including the graphs are a useful and reliable tool but need to use
chin and the right and left forehead and cheek, excluding the same lighting, distance from the patient, camera
and processing procedures. Furthermore, photographs
Sex steroids are limited by the difficulty in distinguish deep lesions
Sebocyte from active superficial lesions and are less accurate for
non-inflammatory lesions134,135.
Pregnenolone Cholesterol Modern imaging methods have provided new
opportunities for optimizing acne visualization and
Dierentiation Substance P improving the accuracy of the assessment of acne
Glucocorticoids DHEA Proliferation
severity and response to treatments142145. One study
CRH has shown that autoclassification of acne lesions with
Testosterone -MSH
Estradiol Lipoperoxides VIP a multispectral and multimodal facial imaging system
Progesterone IGF1 MUFAs Neuropeptide- have a strong correlation with results obtained by man-
-endorphin ual counting of lesions (both inflammatory and non-
inflammatory lesions) by expert physicians (correlation
Lipid Inammation Propionibacterium
production Chemoattractants acnes co-efficient of >0.9)144. Digital photography provides
LPS various advantages, such as supervised or automatic
image analysis and ease of storage of large numbers
EGFR NF-B TNF MMPs of photographs 145. Advanced imaging techniques
Perilipins Interleukins Granulysin
PPAR -defensin Bacteriosides include parallel polarization and orthogonal polari-
Prostglandins Leukotrienes zation imaging, stereoimage optical topometer imag-
ing to construct three-dimensional stereoimages, and
fluorescence photography. Parallel polarization imaging
Hormones Microbiota Pro-inammatory cytokines, lipid mediators, enhances the visualization of skin surface features, such
Neuropeptides Others antimicrobial peptides and MUFAs as papules, pore size, skin oiliness and acne scars145.
Orthogonal polarization (or cross-polarization) photo
Figure 4 | Pathophysiological processes involved in Natureacne vulgaris.
Reviews |The
Disease Primers graphy enhances the visualization of inflammatory
pathogenesis of acne involves several processes including sebum production, and acne lesions, erythema and skin brightness. Parallel-
sebocyte differentiation, proliferation and inflammation. These processes are regulated polarized and cross-polarized photography with video
by circulating sex hormone levels as well as locally synthesized hormones,
microscopy and sebum production measurement can
neuropeptides, the microbiota and pro-inflammatory cytokines, lipid mediators,
antimicrobial peptides and monounsaturated fatty acids (MUFAs). MSH,
be combined. Fluorescence photography using short
melanocyte-stimulating hormone; CRH, corticotropin-releasing hormone; DHEA, wavelengths (long ultraviolet A or blue-range light)
dehydroepiandrosterone; EGFR, epidermal growth factor receptor; IGF1, insulin-like can be used to visualize P.acnes density based on the
growth factor 1; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; NFB, nuclear porphyrin production and the corresponding orange
factor-B; PPAR, peroxisome proliferator-activated receptor-; TNF, tumour necrosis red fluorescence intensity. Multispectral images use
factor; VIP, vascular intestinal polypeptide. Fisher linear discriminant functions to classify acne

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 7

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PRIMER
Figure 5 | Clinical presentation of acne vulgaris.
Nature Reviews Acne
| Disease Primers
lesions, including comedones (white arrows), papule
(yellow arrow) and pustule (black arrow) on the facial skin.
and capture image data at specific wavelengths across
the electromagnetic spectrum136,145.
Differentiation from other dermatological conditions
Acne is clinically heterogeneous and differential diag-
nosis is based on the type of lesion, age at disease onset
and persistence of acne in adulthood. The differential
diagnosis is usually possible on clinical grounds and the
patients medical history; however, when in doubt, labo-
ratory tests, imaging or histopathological examination of
a skin biopsy may need to be performed to exclude other
conditions to establish a correct diagnosis146 (TABLE2). In
all cases, the presence of comedones is a prerequisite for
establishing diagnosis ofacne147.
On the basis of the age of presentation, neonatal acne
should be differentiated from skin infections (bacterial,
viral or fungal), transient benign pustular eruptions
(neonatal cephalic pustulosis, erythema toxicum neo-
natorum and transient neonatal pustular melanosis),
milia, sebaceous gland hyperplasia, miliaria, infantile
acne, acne induced by topical oils and ointments (acne
venenata infantum), drug-induced acneiform eruptions
and congenital adrenal hyperplasia19. The differential
diagnosis of childhood acne includes perioral dermati-
tis and childhood rosacea146. More complex conditions
that may need to be differentiated from acne vulgaris
include the synovitis acne pustulosis hyperostosis osteitis
(SAPHO) syndrome, and pyogenic arthritis, pyoderma
gangrenosum and acne (PAPA) syndrome19,148.
8 | 2015 | VOLUME 1 www.nature.com/nrdp
2015 Macmillan Publishers Limited. All rights reserved
Prevention
The prevention of acne relies on the successful manage-
ment of modifiable risk factors implicated in its devel-
opment, including underlying systemic diseases and
lifestyle factors. Acne may be the cutaneous manifesta-
tion of an underlying systemic disease such as congeni-
tal adrenal hyperplasia or polycystic ovary syndrome;
in these cases, the timely and successful management of
the underlying disease will prevent the presentation or
persistence of acne19,148.
Various lifestyle factors, such as dietary habits,
obesity and smoking, may influence the development
of acne149. However, the effect of lifestyle interventions
on acne remains a largely debated issue, as epidemio-
logical studies have produced contradictory results, and
well-designed trials that are able to produce evidence-
based results are largely lacking. A casecontrol study
that investigated the association of dietary habits in
people with acne (n=205) and without acne (n=358)
reported an increased risk of acne development only
with the increased consumption of milk (in particular,
skimmed milk) but not with the consumption of cheese
or chocolate117. Similarly, self-reported history of acne
was positively associated with intake of skimmed milk
in a prospective cohort study of 4,273 boys. Milk might
influence comedogenesis through hormonal pathways,
as milk contains androgens (precursors of dihydro
testosterone and other non-steroidal growth factors),
or through higher levels of IGF1, which might affect
the pilosebaceous unit 150. A community-based study
of high school pupils in Tehran, Iran (n=933) reported
that the regular consumption of sweets, nuts, chocolates
and oily foods was associated with increased acne sever-
ity 5. A cross-sectional study in 1,871 patients with acne
reported that frequent fat and sugar intake were associ-
ated with increased risk of acne151. However, other stud-
ies have failed to show an association between diet and
acne152. Considering these controversies, more studies
are warranted.
Very few randomized controlled studies have been
conducted to assess the role of dietary interventions
on acne. A low-glycaemic-load diet for 12weeks was
associated with a greater reduction in the total number
of acne lesions compared with the patients on a conven-
tional high-glycaemic-load diet (21.9 (95%CI: 26.8 to
19.0) versus 13.8 (95%CI: 19.1 to 8.5); P=0.01)
in one small trial (n=43; all participants had acne and
were male). The low-glycaemic-load diet was also asso-
ciated with weight reduction, decreased free androgen
index, increased IGF-binding protein 1 (IGFBP1) levels
(mean increase in log(IGFBP1): 0.14ng per ml) and
improved insulin sensitivity 153. Similar results were
obtained in a small number of patients (n=17) when
the low-glycaemic-load diet was given for 10weeks154.
Another randomized, blind, controlled study showed
that omega-3 fatty acids or linolenic acid (a omega-6
fatty acid) supplementation for 10weeks in 45 patients
with acne resulted in a significant improvement in the
acne severity grade and in inflammatory acne lesion
counts155. Omega-3 fatty acids may reduce inflamma-
tion by inhibiting pro-inflammatory cytokines, and
 PRIMER

linolenic acid can have anti-inflammatory actions Management

via inhibition of leukot rieneB4 (REF.155). Finally, a A large number of acne treatment products are available,
casecontrol study reported that individuals with and a wide range of combination products have been
a body mass index of >18.5 had an increased risk of introduced, which offer numerous treatment options
acne117. Obesity may be accompanied by peripheral to various patients with different preferences. However,
hyperandrogenism, which may be associated with large, well-designed, randomized controlled trials to
increased sebum production and the development assess and compare the effectiveness of acne treatment
of acne117. No association was found between smok- options are either lacking or have used different designs
ing and acne in this study, but another study has and methodologies, resulting in a scarcity of strong evi-
shown a correlation between smoking and comedonal dence to support many of the recommendations in acne
post-adolescentacne156. treatment guidelines. Hence, current guidelines rely on
the opinions of experts. Furthermore, for acne associated
with systemic diseases, therapeutic information is mostly
Box 1 | Commonly used acne grading scales at the level of case reports19,148.
Current guidelines for acne treatment include
Leeds grading technique* those from the Global Alliance to Improve Outcomes
0.251: physiological acne in Acne6,157, the American Academy of Dermatology/
1.510: clinical acne American Academy of Dermatology Association158, the
Revised Leeds grading technique European Dermatology Forum Evidence-based (S3)
13: non-inflamed acne on the face guidelines for the treatment of acne159, the European
112: acne on the face expert group on oral antibiotics in acne160, and the Forum
18: acne on the chest
for the Improvement of Clinical Trials in Acne position
on isotretinoin161. Some general principles that form
18: acne on the back
the foundation of these guidelines are as follows. Acne
Plewig and Kligman numerical grading of comedonal acne is no longer considered a natural part of the life cycle,
I: <10 comedones and to prevent its psychological and physical sequelae,
II: 1025 comedones early and aggressive treatment is necessary. Longitudinal
III: 2550 comedones studies of the natural history of acne focusing on the
IV: >50 comedones role of early treatment in preventing persistent disease
are yet to be conducted162. As a multifactorial disease,
Plewig and Kligman numerical grading of papulopustular acne
combination therapy seems to be the most reasonable
I: <10 inflammatory lesions
approach in most cases6. Guideline recommendations
II: 1020 inflammatory lesions
are categorized according to acne severity and the pres-
III: 2030 inflammatory lesions ence or absence of inflammation (TABLE3). Combination
IV: >30 inflammatory lesions of a topical retinoid plus an antimicrobial agent is rec-
Global Evaluation Acne scale|| ommended as first-line therapy for most patients with
0: no acne lesions; residual pigmentation and erythema may be seen acne, targeting multiple pathological factors in both
1: almost no lesions, with a few scattered open or closed comedones and very few inflammatory and non-inflammatory acne lesions. Two
papules key exceptions for this general rule are severe acne and
2: mild acne, in which <50% of the face is involved with a few comedones, papules mild comedogenic or non-inflammatory acne. For mild
and pustules comedogenic or non-inflammatory acne, treatment usu-
3: moderate acne, in which >50% of the face is involved with many papules, pustules, ally starts solely with a topical retinoid, whereas in the
comedones and a maximum of one nodule case of severe acne, oral isotretinoin therapy should be
4: severe acne, in which the entire face is involved, covered with many papules, considered early. To limit antibiotic resistance, antibiotic
pustules, comedones and rare nodules monotherapy should be avoided. In mild-to-moderate
5: Very severe acne with highly inflammatory lesions covering the whole face with the acne, topical antibiotics should be used with benzoyl
presence of nodules peroxide (BPO) and a topical retinoid, and oral anti-
biotics are better reserved for moderate-to-moderately
US FDAs Investigators Global Assessment for acne vulgaris
severe acne; the duration of antibiotic use should be lim-
0: no acne lesions
ited163. Isotretinoin remains the treatment of choice for
1: almost clear skin with rare non-inflammatory lesions and no more than one papule
severe acne, but several precautionary measures have to
2: mild acne with some non-inflammatory lesions and no more than a few papules or be taken during an isotretinoin course149,161.
pustules
3: moderate acne with many non-inflammatory lesions, some inflammatory lesions, Topical retinoids
and no more than one nodule
Topical retinoids are vitaminA derivatives. The bind-
4: severe acne with many non-inflammatory lesions and inflammatory lesions, but no ing of retinoids to their receptors the retinoic acid
more than a few nodular lesions receptors and the retinoid X receptors in keratino-
*Overall assessment of acne severity in different body areas (face, back and chest) based on cytes reduces follicular hyperkeratinization and decreases
reference greyscale facial photographs135. Revision of the Leeds grading to include reference adhesion164. This effect not only results in inhibition of
colour photographs and the introduction of grade 13 for non-inflammatory acne139. On one comedogenesis but also might enhance the penetra-
side of the face. ||In Europe240. In the United States241.
tion of other topical acne medications. Furthermore,

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PRIMER

Table 2 | Differential diagnosis of acne vulgaris

Condition Patient history Clinical presentation Diagnostic methods
Laboratory test Skin biopsy Imaging
Drug-induced History of drug intake, including Monomorphous papules N/A Degeneration of the N/A
acneiform halogenated compounds (iodides, or pustules; localization follicular epithelium, with a
eruptions radiopaque contrast materials and on the trunk and upper localized intrafollicular and
bromides), anti-epileptic drugs extremities perifollicular neutrophilic
(phenytoin and carbamazepine), inflammatory reaction
antidepressant drugs (lithium),
anti-tubercular drugs (isoniazid),
growth hormone, cyclosporine,
vitamins (B1, B6 and B12) and EGFR
inhibitors
Papulopustular More common in women No comedones; mild N/A Not diagnostic N/A
rosacea 3040years of age; chronic course flushing or erythema at the
convexities of the face
Gram-negative Long-term oral antibiotic treatment Papules and pustules Bacterial culture Infiltrate of inflammatory N/A
folliculitis for acne and Gram cells (mainly neutrophils,
staining later mixed with
lymphocytes) in the
follicular ostium and upper
regions of the follicle
Acne Affects adolescent boys; can be Sudden onset of Anaemia or Haemorrhagic epidermal Focal lytic
fulminans precipitated by oral isotretinoin haemorrhagic ulcerative leukocytosis necrosis and granulocytes bone lesions
intake acne mainly on the trunk; in the dermis or sacroiliitis
fever, myalgias and might be
arthralgias present
EGFR, epidermal growth factor receptor; N/A, not applicable.

retinoids have anti-inflammatory effects by inhibiting
the activation of the transcription factor AP1 (REF.165),
and by downregulating the expression of TLR2 (REF.166).
Owing to these comedolytic (that is, agents that break
up comedones and open up clogged pores) and anti-
inflammatory effects, topical retinoids are strongly
recommended in the treatment regimen of both com
edogenic and inflammatory acne as an initial and
maintenance treatment and to avoid relapses6. Topical
retinoids for the treatment of acne include tretinoin,
adapalene, tazarotene (which is not available in Europe),
retinaldehyde and topical isotretinoin (the latter two are
not available in the United States), which are all available
in various formulations and concentrations167. To pre-
vent acne development or maintain improvement and
avoid acne relapses, the application of appropriate topical
treatment is recommended159. The fact that the micro
comedone is the initial microscopic acne lesion high-
lights the need for applying topical acne therapies not
only on clinically apparent lesions but also on the whole
face to prevent the development of visible lesions159.
However, because they should be applied to the whole
affected area, topical treatments often cause irritation
and dryness. In addition, use of topical retinoids is not
recommended during pregnancy; tazarotene is classi-
fied as a pregnancy category X drug (that is, fetal risk
has been proven in investigational or marketing studies
in humans) and is contraindicated, whereas adapalene
and topical tretinoin are classified as pregnancy cat-
egory C drugs (that is, adverse effects have been shown
in animal studies, but controlled studies in humans are
still lacking). Several randomized trials have compared
different topical retinoids, but more studies are needed.
Adapalene products tend to be the most tolerable of treat-
ments. Topical retinoids are also reasonable choices for
maintenance therapy after initial successful treatment.
Topical antimicrobials
BPO. BPO, an organic peroxide derived from a by-
product of coal tar, has become the most widely used
topical acne medication in dermatology 168. BPO treat-
ment alone improves inflammatory acne157, and its
mechanisms of action include antimicrobial, anti-
inflammatory and keratolytic effects and wound-healing
activity 168. Although more potent than any prescription
antibiotic against P.acnes, BPO remains safe for human
use168. Low-strength (2.5% or 5%) BPO is recommended,
as it is less irritating than and as effective as higher
concentration preparations169.
For BPO, as with adapalene, the time to achieve a
25% reduction in the mean number of inflammatory
lesions does not change for different concentrations in
patients with mild-to-moderate papulopustular acne.
However, BPO seemed to act faster than topical ada-
palene, tretinoin and isotretinoin170. Some authors have
suggested starting treatment with BPO alone for mild
inflammatory acne, owing to the cost of retinoids, safety
and good results162. BPO is also available as a fixed-dose
combination product with adapalene that can help to
reduce the complexity of treatment.
Topical antibiotics. Erythromycin and clindamycin are
the most commonly used topical antibiotics in acne
treatment, both of which are available in different for-
mulations. Antibiotics (either topical or oral) are not
intended to be a monotherapy for acne. For example,

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topical antibiotics should only be used in combination
with BPO to help prevent the development of antibiotic-
resistant bacteria. Fixed-dose combination gels of topi-
cal antibiotics with BPO are also available171, as well as
a combined gel formulation of clindamycin with treti-
noin172,173. The clindamycin and BPO combination seems
to act more rapidly than adapalene; this combination
might be faster than BPO alone, but more studies are
needed to confirm this result 170. A combination of ada-
palene and BPO and that of clindamycin and BPO have
comparable times to achieve a 25% reduction in lesion
count 170,171. Dapsone gel is a newer topical antibiotic
choice. Although the mechanism of action of dapson is
not yet clear, it has shown good results in studies and
various new options are in development 174.
Other topical agents
Salicylic acid is a topical medication present in many
over-the-counter products, which has comedolytic
effects but may be less effective than retinoids. Another
topical agent, azelaic acid, has antibacterial, comedo-
lytic and anti-inflammatory properties and is consid-
ered as a potential first-line monotherapy for female
adult patients with acne, and a good choice for main-
tenance therapy owing to its good tolerability and
safety 175. Apotential adverse effect of azelaic acid is
hypopigmentation, which might be helpful in treat-
ing post-inflammatory hyperpigmentation. Although
most publications have investigated the 20% azelaic
acid cream formulation, the 15% gel was as efficient as
BPO and topical clindamycin for patients with mild-to-
moderate acne176. A novel study using the cyanoacrylate
technique a precise method for microcomedone
assessment in patients with mild-to-moderate acne
has shown an equivalent effect for azelaic acid 15% gel
compared with 0.1% adapalene177.
Oral antibiotics
Doxycycline and minocycline have replaced tetra
cycline and erythromycin in most cases of acne therapy.
Tetracycline, doxycycline and minocycline are contra
indicated in pregnancy and in children <9years of age;
erythromycin is only recommended in these cases.
Azithromycin is not commonly used owing to the risk of
increasing resistance, which is a crucial issue in other dis-
eases. As tetracyclines control acne through their direct
anti-inflammatory effects in addition to their antibiotic
property, using subantimicrobial doses of doxycycline is
promising, but more investigation is needed in this field.
Although minocycline is effective in acne treatment, its
superiority to other tetracyclines has not been proven178.
Extended-release minocycline has shown good results
in acne treatment 179, and cotrimoxazole is an alterna-
tive for severe acne. Several studies have compared the
efficacy of different antibiotics in acne therapy, but no
antibiotic demonstrated superior results.
To reduce the development of antibiotic resistance,
systemic antibiotic therapy should always be combined
with a topical retinoid or BPO and should be limited to a
period of 3months180; 46weeks after the start of treat-
ment is the appropriate time for response assessment160.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 11
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PRIMER
Concomitant treatment of oral and topical antibiotics, and
use of topical antibiotics without BPO should beavoided6.
However, an analysis of published data of 29,908 patients
from 2008 to 2010 demonstrated that the mean duration
of oral antibiotic therapy was 129days much longer
than indicated. Simultaneous topical retinoid therapy did
not occur in 57.8% of treatment courses181. There has been
a shift towards non-antibiotic treatment in acne manage-
ment182, but there is still the need to inform all physicians
about the importance of short (<3months) regimens in
different settings. A study of patients with preadolescent
acne found that dermatologists predominantly prescribe
topical retinoids for this age group, whereas primary care
physicians prescribe antibiotics, particularly oral anti
biotics183. That is, primary care doctors are not familiar
with using adapalene in teenagers.
Hormonal therapy
Hormonal agents that reduce androgen activity can be
given to reduce sebum production in women. Oral con-
traceptives and, in some countries, spironolactone are
commonly prescribed hormonal therapies. The use of
anti-androgen treatment is not limited to acne induced
by hyperandrogenism; this therapy also improves acne in
women with normal serum androgen levels157. Hormonal
therapy can be prescribed in combination with other
acne medications for postmenarcheal to premenopausal
women with moderate-to-severe acne who do not intend
to become pregnant. In addition, they will improve even
mild acne in patients who use this medication for con-
traception, menstrual cycle irregularities or patients who
experience cyclical acne flares184. Hormonal therapy may
be underused in women with acne185.
It takes 612months before one can evaluate hormo-
nal therapy results186. Meta-analyses of previous publi-
cations demonstrated that, although antibiotics might
be superior at 3months, oral hormonal anti-androgens
are equivalent to antibiotics at 6months in reducing
acne lesions and, therefore, could be a better first-line
alternative to systemic antibiotics for long-term acne
management in women186,187. There are multiple oral
hormonal anti-androgens on the market; patient pref-
erence, cost and adverse-effect profile should determine
the appropriate choice185.
Spironolactone, which has been long used in
treating women with acne and hirsutism, is not US
FDA approved for these disorders. Indeed, a study in
Cochrane Database of Systematic Reviews did not find
sufficient evidence to confirm spironolactone as effi-
cacious in acne or hirsutism187. Debate on the efficacy
of this medication, and the appropriate dosing, in the
medical literature still continues. Thus, spironolactone
therapy could be started for women with moderate-
to-severe acne who fail to respond to combinational
treatment regimens (TABLE3), before considering oral
isotretinoin therapy.
Although hormonal therapy for acne has long been
limited to systemic treatment in women, it seems that
topical anti-androgens are emerging; spironolactone
5% gel and cortexolone 17propionate 1% cream are
awaiting FDA approval for use in men and women188.
PRIMER

Table 3 | Summary of therapeutic recommendations*,

Recommendation Comedonal Mild-to-moderate papulopustular acne Severe papulopustular Severe nodular or
acne acne or moderate conglobate acne
nodular acne
High-strength None Adapalene plus BPO (f.c.) Isotretinoin* Isotretinoin*
recommendations BPO plus clindamycin (f.c.)

Medium-strength Topical Azelaic acid Systemic antibiotics# plus Systemic antibiotics# plus
recommendation retinoid|| BPO adapalene azelaic acid
Topical retinoid|| Systemic antibiotics# plus
Systemic antibiotic plus adapalene azelaic acid**
Systemic antibiotics plus
adapalene plus BPO (f.c.)
Low-strength Azelaic Blue light Systemic antibiotics# plus Systemic antibiotics#
recommendation acid Oral zinc BPO plus BPO
BPO Topical erythromycin plus isotretinoin (f.c.) Systemic antibiotics#
Topical erythromycin plus tretinoin (f.c.) plus adapalene,
Systemic antibiotic,# plus BPO Systemic antibiotics#
Systemic antibiotic,# plus azelaic acid plus adapalene plus BPO
Systemic antibiotic,# plus adapalene plus BPO (f.c.)
(f.c.)
Alternatives for None None Hormonal anti-androgens Hormonal anti-androgens
female patients plus topical treatment plus systemic antibiotics||||
Hormonal anti-androgens
plus systemic antibiotics||||
BPO, benzoyl peroxide; f.c., fixed-dose combination. *Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation
as a first-line therapy (for example, financial resources or reimbursement limitations, legal restrictions, availability and drug licensing). In case of more widespread
disease or moderate severity, initiation of a systemic treatment can be recommended. Systemic treatment with corticosteroids can be considered. ||Adapalene to
be preferred over tretinoin or isotretinoin. Only studies found on systemic antibiotics plus adapalene, isotretinoin and tretinoin can be considered for
combination treatment based on expert opinion. #Doxycycline and lymecycline. **Indirect evidence from nodular and conglobate acne and expert opinion.

Indirect evidence from a study also including chorhexidin, recommendation additionally based on expert opinion. Indirect evidence from severe
papularpustular acne. ||||Low strength of recommendation. Adapted with permission from REF.159, Wiley.

Oral isotretinoin
Oral isotretinoin has effects on all four pathophysiologi-
cal pathways of acne and can have a permanent effect
on the disease course. With a 90% reduction in sebum
production189 and almost 85% cure rate (that is, resolu-
tion without relapse)190, isotretinoin is a highly effective
drug to treat acne, but not a miracle for every patient191.
The effects of isotretinoin on sebum production might be
explained by cell cycle arrest or apoptosis188. Isotretinoin
influences the G1S phase of the cell cycle by decreasing
DNA synthesis, increasing p21 (encoded by CDKN1A)
protein expression and decreasing cyclin D1 protein
expression188 effects that are independent of retinoic
acid receptor activation. Isotretinoin also induces apop-
tosis in sebocytes. Reduced sebum production induced
by isotretinoin treatment may be the result of sebaceous
gland involution188. Oral isotretinoin is the treatment of
choice for severe, recalcitrant, nodular acne and may also
be started for patients with scarringacne.
Isotretinoin can cause numerous adverse effects, but
severe effects are rare161,186,192. Although uncommon,
depression is among one of the adverse effects and should
be monitored193. Owing to teratogenicity, physicians in
the United States should prescribe isotretinoin through
the iPLEDGE system, which is a risk evaluation mitiga-
tion strategy designed to prevent the use of isotretinoin
during pregnancy. Although isotretinoin may cause
severe birth defects, estimating the expected risk using
quality-adjusted life years (QALYs) shows that the QALY
benefit of treating patients with severe, moderate and
mild acne is 50-, 11- and 7-times greater, respectively,
than the risk of QALY loss from isotretinoin teratogeni
city 194. A micronized formulation of oral isotretinoin
(isotretinoin-lidose) with improved bioavailability and
better intestinal absorption helps to maintain stable lev-
els of isotretinoin in the plasma and carry a lower risk
of mucocutaneous events and hypertriglycaeridaemia195.
Oral isotretinoin treatment is a common reason for
patients with acne to visit dermatology departments
for support; it seems necessary to provide adequate
information when prescribing 196. In addition, there may
be racial and sex differences in the use of oral isotreti-
noin for acne management in the United States, with
black and female patients being less likely to receive oral
isotretinoin therapy 197.
Adjunctive therapies
Comedone extraction might help to relieve resist-
ant comedones but should be used in conjunc-
tion with conventional therapeutic medications 157.
Microdermabrasion, a technique that uses minute crys-
tals to exfoliate the skin, does not have sufficient medical
literature support to be considered effective in the man-
agement of acne, and future studies are needed6,158. The
same is true for chemical peeling with glycolic acid (an
hydroxy acid) or salicylic acid (a hydroxy acid)157,158.
Although clinical experience shows that intralesional
steroid injection is effective in treating nodular acne,
structured studies are needed to determine the appropri-
ate dosage158. Probable adverse effects of steroids should

12 | 2015 | VOLUME 1 www.nature.com/nrdp

2015 Macmillan Publishers Limited. All rights reserved


also be considered before starting therapy. Systemic ster-
oids can be administered as primary therapy together
with isotretinoin in severe acne cases with systemic signs
(acne fulminans)186.
Light therapy
Light therapy methods include broad-spectrum con-
tinuous-wave visible light sources (such as blue light
or red light), intense pulsed light, laser sources (such
as potassium titanyl phosphate lasers, pulsed dye lasers
and infrared lasers) and photodynamic therapy. These
modalities work through inhibition of P.acnes and/or
thermal damage to the sebaceous glands198.
Photodynamic therapy consists of application of a
photosensitizing agent, most commonly aminolevulinic
acid, or methyl aminolevulinic acid, followed by expo-
sure to blue or red light, lasers, pulsed light sources or
non-pulsed broad-spectrum light. Although photo-
dynamic therapy has been extensively studied in acne,
there is no consensus on a protocol. The use of low-dose
photodynamic therapy characterized by lower drug
concentrations, low-light doses and less-penetrating
blue light results in short-term effects probably through
antimicrobial or immunomodulatory effects. By contrast,
high-dose photodynamic therapy results in prolonged
effects owing to destruction of sebaceous glands198,199.
Aminolevulinic acid followed by red light which
penetrates more deeply into the skin and has effects on
non-inflammatory lesions in addition to inflammatory
lesions seems to be the optimal choice200. The common
adverse effects of photodynamic therapy are tolerable and
transient, but caution is warranted when treating patients
with dark skin owing to post-inflammatory pigmentary
changes201. Light therapies alone are not highly effective,
although redblue light was more effective than topical
5% BPO cream in the short term (4weeks to 1year)202.
Most photodynamic therapy trials have shown ben-
efit, especially with multiple treatment sessions202 and
for non-inflammatory acne lesions. However, even for
inflammatory acne lesions, photodynamic therapy was
less effective and less tolerable than topical 1% adapalene
gel202. Thus, although there has been progress in this field,
more evidence is needed to define the efficacy of light
therapies. Currently, they are considered as an adjunct
to medical therapies or for patients who do not desire
medicaltreatments6.
Adherence to treatment
Adherence to acne treatment is poor, as evidenced by
studies using indirect assessment tools as well as objective
electronic monitoring. For objective electronic monitor-
ing, adherence of typical patients (teenagers with acne
receiving topical BPO), who were not informed that they
were part of a clinical trial, decreased from 82% on day 1
to 45% at day43 (P<0.001)203.
Adherence to acne medications is important for treat-
ment efficacy, and seems to be an important component
of better health status, and pharmacological treatment of
acne does not add significantly to acne-related annual
health care costs (for the patient and the health care
system)204. Several predictors for adherence have been
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 13
2015 Macmillan Publishers Limited. All rights reserved
PRIMER
identified; with older age, married status, female sex,
out-of-pocket cost, oral isotretinoin, gel formulations,
once-daily formulations and convenient formulations
being positive predictors, whereas smoking, drinking
alcohol, unemployment and psychiatric morbidity are
negative predictors8. Good physicianpatient relation-
ships, education about the pathophysiology of acne and
considering the patients preference for the topical deliv-
ery vehicle can improve adherence. More frequent visits
to the physician increases adherence, and is superior to
a standard visiting schedule and daily reminder phone
calls to patients and parents205,206.
Evaluation of the psychiatric morbidity, especially
anxiety and depression, may be beneficial. Most topi-
cal acne treatment products cause irritation; informing
patients of possible adverse effects, providing written
instruction on how to manage irritation and dryness
and considering alternative treatments are helpful
strategies in this case207. A helpful factor in adherence
improvement is the use of fixed-dose combination prod-
ucts208,209. Several antibiotics and BPO combinations
are available, and an adapalene and BPO combination
adheres to both the BPO and the retinoid guidelines6.
Although fixed-dose combination topical formulations
might be part of a safer and more cost-effective alter-
native model to oral isotretinoin for treating severe
acne, the high adherence of isotretinoin treatment is
important to keep in mind. In a retrospective cohort
study of 24,438 patients from 2004 to 2007 using the
Marketscan Medicaid Database, a US national health
care claims database, adherence was measured among
different acne drug classes using the medication posses-
sion ratio (MPR). Patients were most adherent to oral
retinoids than any other acne drug classes (MPR: 0.78;
57% adherent) and the least adherent to oral antibiotics
(MPR: 0.21) and topical retinoids (MPR: 0.31)210.
Acne scars
Scars are important permanent sequelae of acne211,212.
Up to 95% of patients with acne have scars, with 30%
developing severe scars213. None of the currently avail-
able treatments achieve complete resolution of scars.
Prevention of scars by early and aggressive acne treat-
ment remains the best option. There are numerous
medical, surgical and procedural options that can help
to achieve profound cosmetic improvement in acne
scars. Using these methods in combination can even be
more successful6,214. There are two main types of acne
scars depending on the tissue response to inflammation:
scars caused by increased tissue formation (hypertrophic
and keloidal scars) and scars caused by loss of tissue
(atrophic scars). Atrophic acne scars are more com-
mon than keloids and hypertrophic scars, and can be
divided into three subtypes: icepick or Vshaped, rolling
or Mshaped and boxcar or Ushaped. Keloidal scars are
more common in darker-skinned individuals215.
Some scar treatments might be focused on a single
scar, such as surgical techniques including excision,
punch elevation, and subcision, debulking, skin graft or
dermal fillers. Other treatment options might be applied
to the entire affected area, including chemical peels,
PRIMER
Figure 6 | Acne conglobata. A male patient with acneNature Reviews
conglobata | Disease
on the face, Primers
presenting with grouped comedones, highly inflammatory nodules and
interconnectedsinus tracts.
laser therapy or dermabrasion. With the advent of laser
resurfacing, dermabrasion is now used less frequently.
Topical retinoids used with procedures improve results
and reduce the risk of changes in pigmentation6. Silicone
dressings focus on hypertrophic scars and are less effec-
tive in keloids216. Intralesional corticosteroids and cryo-
surgery are the most effective regimens in the treatment
of hypertrophic scars and keloids214,215.
Quality of life
The WHO defines quality of life as the individuals per-
ception of the position in life in the context of the culture
and value systems in which someone lives and in rela-
tion to his or her goals, expectations, standards and con-
cerns. Acne lesions modify the individuals perception
and affect every aspect of personal, social, vocational
and academic life 217. Patients with severe acne (FIG.6)
have higher unemployment rates than those without
acne218. Acne has a profound impact on a patients emo-
tions (self-embarrassment, self-esteem and feelings of
unworthiness), annoyance owing to physical symptoms
(pain and itch) and daily discomfort owing to treat-
ment 219,220. Patients with acne usually experience social
anxiety and shame; they avoid eye contact, grow their
hair long to cover the face, use makeup and choose a
specific clothing style to minimize the appearance of
acne lesions219,221,222. Patients with acne reported social,
psychological and emotional problems that were as great
as those reported by patients with asthma, epilepsy,
diabetes, back pain or arthritis223.
Acne is associated with an increased risk of depres-
sion, anxiety and body dissatisfaction211. Depression is
23times more prevalent in patients with acne than in
the general population, and the rate of depression was
twice as high in women with acne than in men224,225.
Patients with mild-to-moderate acne even exhibit
14 | 2015 | VOLUME 1 www.nature.com/nrdp
2015 Macmillan Publishers Limited. All rights reserved
higher depression scores than patients with alopecia
areata, atopic dermatitis or psoriasis. Although acne
might be more psychologically damaging to adolescents
than adults, a higher prevalence of depression in older
patients with acne has been observed226. Suicidal idea-
tion rates were higher among patients with acne than
patients with general medical conditions226. Acne is
frequently associated with scarring, which continues to
affect psychopathological well-being in later life227.
Acne alone may be a source of stress and anxiety, but
stress can also trigger or exacerbate acne even after con-
trolling for changes in diet and sleep habits; a vicious
cycle can occur. Neuroimmunological research may pro-
vide the first insight into the links between acne stress
and quality of life228,229.
The most frequent lesions associated with greater
impairment are cysts and nodules; even those who
have only comedones report symptoms (itch and pain)
and emotional effects (decreased self-esteem, diffi-
culties in building relationships and social activities).
However, the effect of acne on quality of life does not
always correlate with acne severity. For this reason, rec-
ognition of clinical and pertinent psychological signs
must be taken into account when individualizing treat-
ment. Importantly, effective acne therapy significantly
improves quality of life230,231.
Outlook
Although acne is a very common and costly disease,
it does not receive the attention it deserves. Acne was
among the under-represented diseases in Cochrane
Database of Systematic Reviews when matched with cor-
responding diseases with a similar burden defined by
disability-adjusted life years from the Global Burden of
Disease 2010 project 1,232234. Another study showed that
although acne caused the fourth greatest skin-related dis-
ability in the United States, it received less than half of the
funding that was given by National Institute of Arthritis
and Musculoskeletal and Skin Diseases to projectson
bacterial skin diseases, which only rank thirteenth
on the disability score235. To advance the understanding
and treatment of acne, one first needs to acknowledge
that it is an important problem.
Basic research is needed to define pathways and regu-
latory nodes that can potentially be targeted to prevent
and treat acne and requires a multidisciplinary approach,
including microbiology, endocrinology, immunology,
genetics and dermatology 31,87. On the basis of the results
obtained from these research projects, new therapeutic
agents have been developed or are under development75,236.
Formulation of consensus guidelines requires large, well-
designed, comparative, randomized controlled trials.
Development of a standardized, objective acne grading sys-
tem is a key factor needed for evaluating the results of clini-
cal studies, for facilitating comparison of results of different
studies and for developing clinical guidelines145. Basic sci-
ence can provide clues for the development of a reason-
able grading system. Large-scale longitudinal studies are
also necessary to observe the lifelong behavioural nature of
this disease in a population in depth. Current research pro-
vides a complex network of data, which is shallow in many
 PRIMER

areas and does not offer a strong foundation for further
advancement with an acceptablespeed.
Acne management requires a combination treat-
ment approach, and the resulting complexity reduces
adherence. A theoretically effective therapeutic regimen
will not achieve its full potential when adherence is low.
Isotretinoin is an example of a single drug with the ability
to permanently suppress all the pathophysiological routes
and is associated with good adherence, but teratogenic-
ity risk and adverse effects limit its use. P.acnes develops
resistance to antibiotics, therefore, new antibiotics may
not be helpful as monotherapy, at least not for long. By
contrast, non-antibiotic, anti-inflammatory systemic
treatments are required237,238. Topical medications alone
will not be sufficient to control severe acne. Systemic anti-
androgens cannot be prescribed in men, and they are not
always as effective in women and do not offer a perma-
nent cure. Phototherapy methods might be promising but
are costly because they require intensive involvement of a
medical expert during therapeutic sessions. The finding
that laser wavelengths of 1,720nm selectively target seba-
ceous glands239 has brought hope to establish a procedural
acne therapy with permanent effects that could replace the
need to rely on a teratogenic drug, such as isotretinoin.
Vaccines, treatments targeting different pathogenetic
factors, together with reformulations of available medi-
cations to improve absorption and reduce irritation are
different efforts in hope of better treatment options. Anti-
inflammatory agents may be good candidates for acne
therapy, and defining specific targets might limit adverse
effects. Future studies will continue to search for a safe
multipotential permanent cure for acne (TABLE4).

Table 4 | Novel agents for acne treatment

Category Drugs, comments Refs
Galenic formulations of Tretinoin in tocopheryl vesicles 244
existing retinoids
Gel containing adapalene-loaded solid lipid nanoparticles 245
New BPO formulation 5% BPO formulation in solubilized small-size particles 246
Retinoic acid metabolism- Topical rambazole 247
blocking agents
Oral talarozole 247
Agents controlling excess Cyproterone acetate in lipid nanoparticles (a topical anti-androgen for use 248
androgen in men and women)

1% cortexolone 17propionate cream (a topical anti-androgen 249

Antagonists of regulatory
neuropeptides
5Lipoxygenase inhibitors
Antimicrobial peptides
Neutralizing antibodies
targeting and inhibiting the
activation of cytokines
Vaccines targeting microbial Reduce P.acnes infection
products of P.acnes
PPAR modulator
Inhibitors of
pro-inflammatory skin lipids
BPO, benzoyl peroxide; IGF1, insulin-like growth factor 1; PPAR, peroxisome proliferator-activated receptor.
with anti-inflammatory properties that is better tolerated than tretinoin,
with rapid onset and without systemic action)
ASCJ9 (a curcumin analogue; reduces total inflammatory and 250
non-inflammatory lesions compared with placebo in moderate-to-severe
acne in men and women without adverse events)
SB204 (a nitric oxide-releasing donor gel, which has local antimicrobial 251
and anti-inflammatory actions and inhibits skin steroidogenesis resulting
in reduced androgen levels in the skin)
Hormone modulators such as epigallocatechin3gallate reduce sebum 252
production, inflammation and Propionibacteriumacnes viability by
suppressing IGF1 action
JNJ10229570 (a melanocortin 1 receptor and melanocortin 5 receptor 253
antagonist) modulates sebaceous differentiation resulting in decreased gland
size and a reduction in lipid production
Afamelanotide (Nle4D-Phe7--MSH; an melanocyte-stimulating hormone 254
analogue with anti-inflammatory actions)
Zileuton (oral formulation; improves inflammatory acne and directly inhibits 236238
sebum synthesis in a transient manner with a potency similar to that of low-dose
isotretinoin; the best alternative for oral antibiotics with minor liver toxicity)
Omiganan pentahydrochloride (reduces non-inflammatory and inflammatory 255
acne lesion counts)
Inhibitors of dipeptidyl peptidase IV and aminopeptidase N (stimulate 74
IL1 receptor antagonist and reduce sebaceous hyperplasia, follicular
hyperkeratosis and inflammation)
256
Metformin (decreases both fasting and stimulated plasma insulin levels 257
and reduces insulin resistance)
Free fatty acids (direct antibacterial activities against P.acnes and enhance 258261
the innate antibacterial defence of the skin, while reducing comedone size
and overall inflammation in acne)

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 15

2015 Macmillan Publishers Limited. All rights reserved

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PRIMER
Author contributions
Introduction (S.M.T., C.C.Z. and S.R.F.); Epidemiology (S.M.T.,
C.C.Z. and S.R.F.); Mechanisms/pathophysiology (S.M.T, E.M.,
R.G., C.D., C.C.Z. and S.R.F.); Diagnosis, screening and
prevention (S.M.T., E.M., R.G., C.D., C.C.Z. and S.R.F.);
Management (S.M.T., C.C.Z. and S.R.F.); Quality of life
(S.M.T., E.M., R.G., C.D., C.C.Z. and S.R.F.); Outlook (S.M.T.,
C.C.Z. and S.R.F.); overview of Primer (S.R.F.). S.M.T. and
E.M. contributed equally as first authors. S.R.F. and C.C.Z.
contributed equally as senior authors.
Competing interests
S.M.T. has no conflicts to disclose. E.M. has received an
honorarium and a grant from Immundiagnostik. R.G. is a
consultant for LOreal, and received honoraria as a speaker for
Bioderma, Stiefel/GlaxoSmithKline and LEO Pharma. C.D. has
received an honorarium as a speaker for Stiefel/
GlaxoSmithKline. S.R.F. is a speaker for Janssen and Taro; he is
also a consultant and speaker for Galderma, Stiefel/
GlaxoSmithKline, Abbott Laboratories and LEO Pharma. S.R.F.
has received grants from Galderma, Janssen, Abbott
Laboratories, Amgen, Stiefel/GlaxoSmithKline, Celgene and
20 | 2015 | VOLUME 1 www.nature.com/nrdp
Anacor. S.R.F. is also a consultant for Amgen, Baxter, Caremark,
Gerson Lehrman Group, Guidepoint Global, HanAll
Pharmaceutical, Kikaku, Eli Lilly, Merck, Merz, Mylan, Novartis,
Pfizer, Qurient, Suncare Research and Xenoport. S.R.F. is on an
advisory board for Pfizer. S.R.F. is also the founder of and holds
stock in Causa Research, and holds stock and is the majority
owner in Medical Quality Enhancement Corporation, and he
receives royalties from UpToDate and Xlibris. The Center for
Dermatology Research, Wake Forest School of Medicine, North
Carolina, USA, is supported by an unrestricted educational
grant from Galderma Laboratories. C.C.Z. has received
honoraria from AbbVie, Almirall, Basilea, Bayer Health Care,
Bioderma, Biogen-Idec, Dermira, Galderma, General Topics,
Glenmark, LEO Pharma, Philips Lifestyle, Pierre Fabre, Stiefel/
GlaxoSmithKline, Vichy and Xenon for participation on advisory
boards, or as a consultant, investigator or speaker. The
Departments of Dermatology, Venereology, Allergology and
Immunology, Dessau Medical Center, Dessau, Germany, have
received grants from AbbVie, AstraZeneca, Bioderma, Biogen-
Idec, Bristol-Meyers Squibb, Immundiagnostik, Intendis, LVMH,
Merz, Novartis, Pierre Fabre, and UCB for the participation of
C.C.Z. as an investigator, or on advisory boards.
2015 Macmillan Publishers Limited. All rights reserved