14

Acneiform Disorders PART

Chapter 78 :: Acne Vulgaris

:: Carolyn Goh, Carol Cheng, George Agak,
Andrea L. Zaenglein, Emmy M. Graber,
Diane M. Thiboutot, & Jenny Kim

Acne has no predilection for ethnicity; thus, it is an

AT-A-GLANCE important disease worldwide and is considered one of
the top 10 most prevalent global diseases.3-5 It is also
■ Acne vulgaris is a common disorder of the considered the third most important disease defined
pilosebaceous unit. by the global burden of disease.6 Acne patients report
■ There are four key elements of pathogenesis: a Dermatology Life Quality Index (DLQI) score of 11.9,
(1) follicular epidermal hyperproliferation, (2) considered more detrimental to quality of life than
sebum production, (3) the presence and activity of psoriasis (DLQI = 8.8). Thus, acne is not only impor-
Propionibacterium acnes, and (4) inflammation and tant for health of a significant number of people in the
immune response. United States but has an impact globally.
■ Clinical features include comedones, papules, Acne can occur at any age, starting at birth with neo-
pustules, and nodules on the face, chest, and back. natal acne (presents in the first few weeks of life) and
infantile acne (presents between 1 and 12 months) and
■ Treatment often includes combinations of oral and
extending into adulthood. Acne may persist from ado-
topical agents such as antimicrobials, retinoids,
lescence into adulthood, or it can have its onset after the
and hormonal agents. Laser and light sources are
adolescent period. The prevalence of acne in adolescents
additional treatment options.
is higher in males, but in adults is higher in females. The
prevalence rates in adults have been reported to be as
high as 64% in the 20s and 43% in the 30s.7 After the age
INTRODUCTION of 50 years, 15% of women and 7% of men have been
reported to have acne.8 Because the age of adrenarche
Acne vulgaris is a common disorder of the pilose-
appears to be dropping over the years, patients may
baceous unit that is seen primarily in adolescents.
be presenting with acne at an earlier age.9 Globally, the
Most cases of acne present with a pleomorphic array
incidence of acne vulgaris appears to be rising. The
of lesions, consisting of comedones, papules, pus-
reasons are unclear, although increased exposure to a
tules, and nodules with varying extent and severity.
westernized diet is postulated.2
Although the course of acne may be limited in the
Family history of acne has been reported in 62.9%
majority of patients, the sequelae can be lifelong, with
scar formation and psychological impairment, espe- to 78% of patients.10,11 Those with family history tend
cially in young people. to be male and have an earlier onset of acne, trun-
cal involvement, and scarring.11 Several twin studies
have been done, finding that 81% of acne variation is
EPIDEMIOLOGY caused by genetic factors as opposed to 19% environ-
mental factors and that as many as 98% of monozy-
Acne is one of the top three most common skin diseases, gotic twins both have acne versus 55% of dizygotic
particularly in adolescents and young adults, in whom twins.9 The severity of acne may also be genetically
the prevalence is estimated at 85% (ages 12–25 years).1,2 determined.9

Kang_CH078_p1391-1418.indd 1391 07/12/18 4:23 pm

14 Males tend to have more severe acne, and nodulo-
cystic acne has been reported to be more common in
on testosterone replacement therapy. Finally, inquir-
ing about supplements is important. In particular,
white males than in black males.6,12 Acne also appears those containing whey protein have been associated
to be more severe in patients with the XYY genotype.13 with onset or worsening of acne vulgaris.23
Individual genes responsible for this high herita-
bility remain unclear. Several candidate gene-based
studies have identified a few genetic variants asso-
ciated with acne in tumor necrosis factor-a (TNF-a), CUTANEOUS FINDINGS
tumor necrosis factor receptor 2(TNFR2),14 interleukin-1A
(IL1A),15,16 cytochrome P450, family 17 (CYP17),17 Toll- The primary site of acne is the face and to a lesser
like receptor 2(TLR2),14 and Toll-like receptor 4 (TLR4).18 degree the back, chest, and shoulders. On the trunk,
Genome-wide association studies (GWASs)19 have also lesions tend to be concentrated near the midline. Acne
been reported on this common skin condition. vulgaris is characterized by several lesion types: non-
Interestingly, there are two indigenous populations inflammatory comedones (open or closed) and inflam-
Part 14

that have been described—one in Papua New Guinea matory lesions (red papules, pustules, or nodules)
and the other in Paraguay—that do not develop acne.6 (Fig. 78-1). Although one type of lesion may predomi-
Although this may be genetically determined, envi- nate, close inspection usually reveals the presence of
ronmental factors may also be at play because these several types of lesions. Closed comedones are known
::

groups have not been exposed to a westernized diet. as “whiteheads” (Fig. 78-1A), and open comedones are
Acneiform Disorders

known as “blackheads” (Fig. 78-1B). The open comedo

CLINICAL FEATURES appears as a flat or slightly raised lesion with a central

dark-colored follicular impaction of keratin and lipid.
It is dark because of oxidation (Fig. 78-2). Closed com-
HISTORY edones appear as cream to white, slightly elevated,
small papules and do not have a clinically visible ori-
Most patients with acne vulgaris report a gradual onset fice (Fig. 78-1A). Stretching, side lighting, or palpation
of lesions around puberty. Some may develop acne of the skin can be helpful in detecting the lesions.
in the years preceding puberty, but others may not The inflammatory lesions vary from small erythem-
develop acne until after puberty. Because of the typical atous papules to pustules and large, tender, fluctuant
gradual onset, careful history should be obtained from nodules (see Figs. 78-1C and 78-1D and Figs. 78-2–78-4).
patients describing an abrupt onset of acne to poten- Some of the large nodules were previously called
tially reveal an underlying etiology, such as a medica- “cysts,” and the term nodulocystic has been used to
tion or an androgen-secreting tumor. describe severe cases of inflammatory acne. True cysts
Hyperandrogenism should be considered in a female are rarely found in acne; this term should be aban-
patient whose acne is severe, in the jawline or lower doned and substituted with severe nodular acne (see
face distribution, sudden in onset, or associated with Figs. 78-1D and 78-4). The evolution of an acne lesion
hirsutism or irregular menstrual periods. The patient is unclear. Although the majority of inflammatory
should be asked about the frequency and character lesions appear to originate from comedones (54%),
of her menstrual periods and whether her acne flares a significant number of inflammatory (26%) lesions
with changes in her menstrual cycle. Flares of acne per- arise from normal uninvolved skin.24 The mechanisms
imenstrually, however, are common in acne vulgaris, involved in the evolution of an inflammatory lesion are
with 56% of adult women reporting worsening of acne still unclear, but an inflammatory process is thought to
before menses.20 Other signs that may suggest a diag- play a role. Whether the lesion appears as a papule,
nosis of hyperandrogenism include deepening of the pustule, or nodule depends on the extent and location
voice, an increase in libido, hirsutism, and acanthosis of the inflammatory infiltrate in the dermis.
nigricans.
A complete medication history is also important
because some medications can cause an abrupt onset of
a monomorphous acneiform eruption. Drug-induced NONCUTANEOUS FINDINGS
acne may be caused by anabolic steroids, corticoste-
roids, corticotropin, phenytoin, lithium, isoniazid, Acne vulgaris is usually an isolated cutaneous finding.
vitamin B complexes, halogenated compounds, and However, it can be part of several syndromes, includ-
certain chemotherapy medications, particularly with ing those that are associated with hyperandrogenism
epidermal growth factor receptor (EGFR) inhibi- and inflammatory states (see Chap. 80).
tors. Furthermore, many patients may be on hor-
monal therapy, which can exacerbate or induce acne
vulgaris. Progestin-only contraceptives, including
injectables and intrauterine devices, can exacerbate COMPLICATIONS
or induce acne vulgaris.21 Women approaching or in
menopause may be on hormone therapy, including All types of acne lesions have the potential to resolve
1392 progesterone, and some are treated with dehydroepi- with sequelae. Almost all acne lesions leave a tran-
androsterone (DHEA) or testosterone.22 Men may be sient macular erythema after resolution. In darker skin

Kang_CH078_p1391-1418.indd 1392 07/12/18 4:23 pm

 14

Chapter 78 :: Acne Vulgaris

A B

C D

Figure 78-1 Clinicopathologic correlation of acne lesions. A, Closed comedone. The follicular infundibulum is distended,
filled with keratin and sebum, and the follicular epithelium is attenuated. The follicular ostium is narrow. B, Open com-
edone. Resembles the closed comedone with the exception of a patulous follicular ostium. C, Inflammatory papule. Acute
and chronic inflammatory cells surround and infiltrate the follicle, which shows infundibular hyperkeratosis. D, Nodule.
The follicle is filled with acute inflammatory cells. With the rupture of the distended follicle, there is a foreign body granu-
lomatous response.

A B

Figure 78-2 Mild acne vulgaris. A, A 13-year-old girl with mild acne vulgaris. Scattered comedones or inflammatory lesions
(or both) are seen, usually limited to less than half of the face. The T-zone of the face is commonly involved. No nodules are 1393
present. B, An adult female with primarily inflammatory acne. Note the typical involvement of the jawline.

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14 Part 14
::
Acneiform Disorders

A B

Figure 78-3 Moderate acne vulgaris. A, A 15-year-old male patient with moderate acne. Typically, more than half of the
face is involved with increasing numbers of lesions, usually a mix of lesions is seen: papules, pustules, and comedones.
Infrequent and limited nodules may be present. Chest and back involvement may also be moderately affected. B, A
16-year-old female patient with open and deep closed comedones. Scarring and postinflammatory changes are possible
sequelae.

types, postinflammatory hyperpigmentation may per- acne are more likely to be passed over by prospective
sist for months after resolution of acne lesions. In some employers.29 A cross-sectional study found that 14% of
individuals, acne lesions may result in permanent students reported “problem acne,” which was associ-
scarring. Acne scars can be atrophic or hypertrophic.25 ated with an increased risk of depressive symptoms as
Atrophic scars can be further categorized based on size well as suicidal thoughts and attempts.32,33 One study
and shape: ice pick, boxcar, or rolling26 (Fig. 78-5). Ice has estimated the prevalence of suicidal ideation in
pick scars are narrow, deep scars that are widest at the patients with acne as 7%.34 In adolescents, two large
surface of the skin and taper to a point in the dermis, studies have shown that anxiety, depression, and sui-
typically less than 2 mm in diameter. Boxcar scars are cidal ideation are higher in those with self-described
wide sharply demarcated scars that do not taper to a “problem acne” or “substantial acne.” These findings
point at the base and range in size from 1.5 to 4 mm. highlight the importance of appropriate psychiatric
Rolling scars are shallow, wide scars (often >4–5 mm) screening and referral. Importantly, the impact of acne
that have an undulating appearance. Perifollicular on patients’ lives was often independent of severity,
elastolysis is another type of scar, which typically pres- such that some patients with only minimal acne expe-
ents as atrophic soft papules on the upper part of the rience psychological and psychosocial distress.35 Thus,
trunk.27 Hypertrophic and keloidal scars, in addition to although some consider acne “cosmetic,” its impact on
sinus tracts, can also form. one’s well-being can be significant.
Although not life threatening, acne leads to signifi-
cant morbidity, including depression, anxiety, and psy-
chosocial stress, and is a major cause of psychosocial
ETIOLOGY AND
and psychological impairment for young people,28,29
triggering anxiety and mood disorders and affecting
PATHOGENESIS
self-esteem.30,31 It is ranked third among chronic skin Current understanding of acne is that it is a com-
diseases for causing disability, as measured by equiva- plex and multifactorial inflammatory disease. Recent
lent years of “healthy” life lost by virtue of being in studies are better defining the cellular and molecular
states of poor health or disability.3 Patients experience mechanisms involved in acne and the importance of
social isolation and are reluctant to participate in group inflammation and the immune response. The patho-
activities. Unemployment rates are higher among genesis of acne is multifaceted, and at least four factors
adults with acne than those without. Self-esteem issues have been identified. These key elements (Fig. 78-6) are
are also likely to be the driving force behind higher (1) follicular epidermal hyperproliferation, (2) sebum
1394 rates of unemployment in people with acne; however, production, (3) Propionibacterium acnes, and (4) inflam-
there is also an existing bias whereby patients with mation and immune response. Each of these processes

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 14

Chapter 78 :: Acne Vulgaris

A B

Figure 78-4 Severe acne vulgaris. A, A 17-year-old female patient with extensive acne. Numerous pustules and nodular
lesions admixed with comedones and smaller papules cover the entire face. B, Deep, friable nodules that coalesce into
pseudocysts in acne conglobata. C, Chest and back involvement can be extensive and severe. Scarring is a common com-
plication in severe acne.

are interrelated and under hormonal and immune sulfate (DHEA-S) by 17-β hydroxysteroid dehydro-
influence. genase (HSD) and 5-α reductase enzymes (Fig. 78-7).
It is thought that all clinical lesions begin with the Compared with epidermal keratinocytes, follicular
microcomedo and develop into clinical lesions— keratinocytes have increased 17-β HSD and 5-α reduc-
comedones, inflammatory lesions, and scarring. Fol- tase, thus enhancing DHT production.36,37 DHT may
licular epidermal hyperproliferation results in the stimulate follicular keratinocyte proliferation. Also sup-
formation of a microcomedo. The epithelium of the porting the role of androgens in acne pathogenesis is
upper hair follicle, the infundibulum, becomes hyper- the evidence that individuals with complete androgen
keratotic with increased cohesion of the keratinocytes, insensitivity do not develop acne.38
resulting in the obstruction of the follicular ostium, Follicular keratinocyte proliferation is also regu-
where keratin, sebum, and bacteria begin to accumulate lated by linoleic acid, an essential fatty acid in the skin.
in the follicle and cause dilation of the upper hair fol- Low levels of linoleic acid induce follicular keratino-
licle, producing a microcomedo. Exactly what initiates cyte hyperproliferation and the production of proin-
and stimulates the hyperproliferation and increased flammatory cytokines. The levels of linoleic acid are
adhesion of keratinocytes is unknown. Several pro- decreased in individuals with acne and normalize after
posed factors in keratinocyte hyperproliferation include successful treatment with isotretinoin.39
androgen stimulation, decreased linoleic acid, increased In addition to androgens and linoleic acid, IL-1 α
IL-1-α activity, and effects of P. acnes. Dihydrotestoster- has been shown to contribute to keratinocyte hyper-
one (DHT) is a potent androgen that may play a role in proliferation. IL-1α induces follicular keratinocyte 1395
acne. DHT is converted from dehydroepiandrosterone hyperproliferation and microcomedone formation,

Kang_CH078_p1391-1418.indd 1395 07/12/18 4:23 pm

14

A
Part 14
::
Acneiform Disorders

B C

Figure 78-5 Acne vulgaris, scarring. A, Honeycomb scarring in a young girl with mild to moderate inflammatory acne.
B, Extensive keloidal scarring occurring as sequelae of acne fulminans. C. Rolling scars.

Acne pathogenesis

Inflammatory Nodule
Microcomedone Comedone papule or pustule
Hyperkeratotic Accumulation of Further expansion Rupture of follicular
infundibulum shed corneocytes of follicular unit wall
Cohesive and sebum Proliferation of Marked perifollicular
corneocytes Dilation of follicular Proprionibacterium inflammation
Sebum secretion ostium acnes Scarring
Perifollicular
inflammation
A B C D
1396
Figure 78-6 A–D Acne pathogenesis.

Kang_CH078_p1391-1418.indd 1396 07/12/18 4:23 pm

 Pathways of steroid metabolism
14
Pituitary

DHEAS
FSH LH ACTH 3β-HSD

Androstenedione
17β-HSD

Testosterone

Chapter 78 :: Acne Vulgaris

Ovary Adrenal
5α-Reductase

17 Preg DHT
A A E
17 Prog DHEA
T T

A DOC

T Cortisol
Skin

Figure 78-7 Pathways of steroid metabolism. Dehydroepiandrosterone (DHEA) is a weak androgen that is converted to
the more potent testosterone by 3β-hydroxysteroid dehydrogenase (HSD) and 17β-HSD. 5-α Reductase then converts
testosterone to dihydrotestosterone (DHT), the predominant hormonal effector on the sebaceous gland. The sebaceous
gland expresses each of these enzymes. A, androstenedione; ACTH, adrenocorticotropin-stimulating hormone; DHEAS,
dehydroepiandrosterone sulfate; DOC, deoxycortisol E, estrogen; FSH, follicle-stimulating hormone; LH, luteinizing
hormone; T, testosterone.

and IL-1 receptor antagonists inhibit microcomedone fatty acids promote P. acnes colonization and induction
formation.40,41 The initial event that upregulates the of inflammation.47 Lipoperoxides also found in sebum
production of IL-1α has not been determined. Fibro- induce proinflammatory cytokines and activate the
blast growth factor receptor (FGFR)-2 signaling is peroxisome proliferator-activated receptors (PPAR)
also involved in follicular hyperkeratinization. There pathway, resulting in increased sebum.48,49
is a long-established relationship between acne and Androgenic hormones activate sebocyte prolifera-
Apert syndrome, a complex bony malformation syn- tion and differentiation and the induction of sebum
drome, caused by a gain-of-function mutation in the production. Similar to their action on the follicular
gene encoding FGFR-2. Mutations in FGFR-2 in a infundibular keratinocytes, androgen hormones bind
mosaic distribution underlie a nevus comedonicus- to and influence sebocyte activity.50 Those with acne
like lesion.42 The FGFR-2 pathway is androgen depen- have higher average serum androgen levels (although
dent, and proposed mechanisms in acne include an still within normal range) than unaffected control par-
increased production of IL-1α and 5-α reductase.43,44 ticipants.51,52 5-α Reductase, the enzyme responsible
The second and key feature in the pathogenesis of for converting testosterone to the potent DHT, has
acne is the production of sebum from the sebaceous greatest activity in areas of skin prone to acne, face,
gland. Human sebum are composed mainly of triglyc- chest, and back.44
erides found ubiquitously and of unique lipids, such The role of estrogen on sebum production is not well
as squalene and wax esters not found anywhere else in defined. The dose of estrogen required to decrease
the body, including the surface of the skin.45 Increased sebum production is greater than the dose required
sebum secretion has been associated with acne. On aver- to inhibit ovulation.53 The mechanisms by which
age, people with acne excrete more sebum than those estrogens may work include (1) directly opposing the
without acne, and secretion rates have been shown to effects of androgens within the sebaceous gland, (2)
correlate with the severity of clinical manifestations, inhibiting the production of androgens by gonadal tis-
although the quality of sebum is the same between the sue via a negative feedback loop on pituitary gonado-
two groups.46 The main component of sebum, triglyc- tropin release, and (3) regulating genes that suppress
erides, is important in acne pathogenesis. Triglycerides sebaceous gland growth or lipid production.54
are broken down into free fatty acids by P. acnes, nor- Corticotropin-releasing hormone may also play a 1397
mal flora of the pilosebaceous unit. In return, these free role. It is released by the hypothalamus and increased

Kang_CH078_p1391-1418.indd 1397 07/12/18 4:23 pm

14 in response to stress. Corticotropin-releasing hormone
receptors are present on a vast number of cells, includ-
individuals with healthy skin. These acne-associated
types were present in significant quantity in approxi-
ing keratinocytes and sebocytes, and are upregulated mately 30% to 40% of patients but with acne rarely in
in the sebocytes of patients with acne.55 individuals with healthy skin. Conversely, the phy-
The microcomedo continue to expand with densely lotype II, ribotype 6 subgroup was found to be 99%
packed keratin, sebum, and bacteria. Eventually, this associated with healthy skin. Additionally, P. acnes iso-
distension causes follicular wall rupture. The extru- lates belonging to phylotype III were not found in acne
sion of the keratin, sebum, and bacteria into the dermis lesions but composed approximately 20% of isolates
results in a brisk inflammatory response. The predom- from healthy skin.64 The genomes of acne-enriched and
inant cell type within 24 hours of comedo rupture is healthy skin–associated strains were sequenced,59,68
the lymphocyte. CD4+ lymphocytes are found around revealing that the phylotypes associated with acne
the pilosebaceous unit, and CD8+ cells are found peri- selectively harbor a plasmid and two chromosomal
vascularly. One to two days after comedo rupture, the regions that contain genes possibly involved in patho-
neutrophil becomes the predominant cell type sur- genesis, adhesion to epithelial tissues, or induction
Part 14

rounding the burst microcomedo.56 of human immune response.59,68 Moreover, the levels
It was originally thought that inflammation follows of porphyrin production and vitamin B12 regulation
comedo formation, but there is evidence that dermal were recently shown to be different between acne- and
inflammation may actually precede comedo forma- health-associated strains, suggesting a potential molec-
::

tion. Biopsies taken from comedo-free acne-prone skin ular mechanism for disease-associated strains in acne
Acneiform Disorders

demonstrate increased dermal inflammation com- pathogenesis and for health-associated strains in skin
pared with normal skin. Biopsies of newly formed health.69 Metabolite-mediated interactions between the
comedos demonstrate even greater inflammation.57 host and the skin microbiota may also play an essential
This may suggest that inflammation actually precedes role in acne development.70
comedo formation, again emphasizing the interplay Sebocyte differentiation and proinflammatory cyto-
between all of the pathogenic factors. kine and chemokine responses are varied depending
P. acnes is one of the key factors involved in acne on the strain of P. acnes predominating within the fol-
pathogenesis. P. acnes is a gram-positive, anaerobic, licle.35 Certain strains of P. acnes induce a differential
microaerophilic bacterium found in the sebaceous fol- host immune response. P. acnes ribotypes associated
licle and is the dominant bacterial inhabitant of the with acne induced distinct T helper 1 (Th1) and Th17
human sebaceous gland,58 accounting for almost 90% responses, which potentially contribute to inflamma-
of the bacterial 16S transcripts.59 P. acnes is generally tion in acne, but P. acnes ribotypes associated with
believed to play a major role in the pathogenesis of health-induced high levels of IL-10, which presumably
acne vulgaris, in part by eliciting a host inflamma- regulate and inhibit inflammatory responses.71
tory response.60 S. epidermidis is also present in follicles P. acnes directly induces inflammation through vari-
but is located near the surface, suggesting that it does ous mechanisms. The cell wall of P.  acnes contains a
not contribute to the deeper inflammatory process.58 carbohydrate antigen that stimulates antibody devel-
There is a significant increase in P. acnes colonization opment. Patients with the most severe acne have been
at puberty, the time when acne commonly develops, shown to have the highest titers of antibodies.72 The
and teenagers with acne can have as many as 100- antipropionobacterium antibody enhances the inflam-
fold more P. acnes bacteria present on their skin than matory response by activating complement initiating a
healthy age-matched counterparts.61 However, there cascade of proinflammatory events.73 P. acnes also facili-
are no consistent data correlating the raw number of tates inflammation by eliciting a delayed-type hypersen-
P. acnes organisms present in a sebaceous follicle and sitivity response and by producing lipases, proteases,
the severity of the acne.61 hyaluronidases, and chemotactic factors.72,74 Reactive
Previously, a shotgun approach to target all P. acnes oxygen species (ROS) and lysosomal enzymes are
with antibiotics has been used, which has led to sig- released by neutrophils and levels may correlate with
nificant bacterial resistance in up to 60% clinical iso- severity.75 Additionally, P.  acnes stimulates host innate
lates, directly correlating with antibiotic treatment responses via secretion of proinflammatory cytokines
failure.61-63 and chemokines from peripheral blood mononuclear
The recent association of specific P. acnes strains with cells (PBMCs) and monocytes60,76 and inflammatory
acne versus healthy skin supports the concept that P. cytokines and antimicrobial peptides such as human
acnes is an etiologic agent in the pathogenesis of acne. β-defensin-2 (hBD2) from KC77,78 and sebocytes.35
Certain P. acnes strains, as identified by multilocus The mechanisms by which P. acnes triggers the innate
sequence typing, were found to be associated with immune response has been studied and includes the
acne, designated as type IA1 or IC strains.64-67 Acne- activation of pattern recognition receptors (PRRs),
associated types were further investigated using full which recognize conserved pathogen-associated
genome sequencing in conjunction with ribotyping.59,68 molecular patterns (PAMPs) and activate specific sig-
Specifically, phylotype IB-1 was associated with acne, naling cascades, resulting in the induction of immune
as were the ribotype 4 and 5 subgroups of phylo- response genes. P. acnes-induced secretion of proinflam-
type IA-2. The ribotype 1 subgroup of phylotype matory cytokines IL-8, IL-12, and TNF-α in monocytes
1398 IA-2, together with phylotypes IA-1, IB-2, and IB-3, has been shown to involve TLR2,60 which is expressed
was found evenly distributed in acne patients and on macrophages surrounding the sebaceous follicles of

Kang_CH078_p1391-1418.indd 1398 07/12/18 4:23 pm

 acne lesions,60 as well as in the epidermis of inflam-
matory acne lesions.79 More recently, P. acnes has been
although a high proportion were skin-homing mem-
ory and effector cells, and inflammation was increased
14
shown to induce IL-1β secretion and inflammasome and activated in resolving lesions.96
activation via NLRP3 and caspase-1 in monocytes and Finally, the impact of diet on acne is an emerg-
macrophages,80,81 as well as sebocytes.82 Both NLRP3 ing area of interest in the pathogenesis of acne.
and caspase-1 colocalize with macrophages in acne Recent studies provide evidence that high glycemic
lesions,80 keratinocytes,77,78 and sebocytes.35 Although load diets may exacerbate acne and dairy ingestion
many of the P. acnes ligands that trigger these PRRs appears to be weakly associated with acne,97-99 but
and pathways are not known, experimental evidence some studies do not support the role of diet.100,101
points to a possible role for P. acnes peptidoglycan in Both are thought to increase insulin-like growth
TLR2 activation60,76 and a component of peptidoglycan factor (IGF)-1 with possible increase in androgen
muramyl dipeptide (MDP), which in P. acnes is com- activity and sebocyte modulation, therefore pro-
posed of the canonical N-acetylmuramic acid residue moting acne.97,102 Several studies have reported that
linked to the L-alanine D-isoglutamine dipeptide.83 molecular interplay of forkhead box transcription

Chapter 78 :: Acne Vulgaris

MDP is a ligand for NOD2,84,85 a cytoplasmic PRR, and factor (Fox)O1 and mammalian target of rapamycin
can also activate the inflammasome via NLRP3,86 hint- (mTOR)–mediated nutrient signaling are important
ing at a possible role for NOD2 in P. acnes–induced in acne.103,104 The roles of omega-3 fatty acids, anti-
immune activation. oxidants, zinc, vitamin A, and dietary fiber in acne
The antimicrobial peptides histone H4 and catheli- remain to be elucidated. Thus, further randomized
cidin are also secreted locally in response to P.  acnes. controlled studies are needed to have a clear under-
Histone H4 exerts direct microbial killing, and catheli- standing of how diet influences acne.
cidin interacts with components of the innate immune
system, such as β defensins and psoriasin, in response
to P. acnes,87,88 Another indicator of the role of innate
immunity in the pathogenesis of acne is the differ-
DIAGNOSIS
entiation of peripheral blood monocytes to CD209+ The diagnosis of acne vulgaris is typically made by
macrophages and CD1b+ dendritic cells in response to clinical history and physical examination, but in some
P. acnes.89 instances, further workup may be indicated.
A role for the adaptive immune response has also
been suggested based on the detection of CD4+ T cells
in the inflammatory infiltrate from early acne lesions,56
and both Th1 and Th17 responses are prominent in LABORATORY TESTING
vitro and in vivo at the site of disease.90-92 Both Th1 and
Th17 cells can trigger antimicrobial activity against Laboratory workup may be indicated in patients with
bacteria, but the lysis of these bacteria can release acne if hyperandrogenism is suspected, particularly
components that directly activate the innate immune in children ages 1 to 7 years who may have midchild-
response, resulting in inflammation. Moreover, Th17 hood acne (see Chap. 80). There are numerous clini-
characteristically induce the recruitment of neutro- cal studies relating acne to elevated serum levels of
phils, which contribute to antibacterial activity but androgens in both adolescents and adults. Among
also cause tissue injury. ROS and lysosomal enzymes 623 prepubertal girls, girls with acne had increased
are also released by neutrophils and levels may cor- levels of DHEAS as compared with age-matched con-
relate with severity.75,93,94 trol participants without acne.105 DHEAS can serve
The mechanism of acne scarring is not clear, and as a precursor for testosterone and DHT. Elevated
although scar formation correlates with inflammatory serum levels of androgens have been found in cases
response, there is no direct correlation of severity of of severe nodular acne and in acne associated with a
disease and development of scar formation can occur variety of endocrine conditions, including congenital
in mild to moderate acne.95 adrenal hyperplasia (11β- and 21β-hydroxylase defi-
It has been shown that P. acnes induces metallopro- ciencies), ovarian or adrenal tumors, and polycystic
teinase (MMP) 1 and 9 and the expression of tissue ovarian syndrome (PCOS). However, in the majority
inhibitors of metalloproteinase (TIMP)-1, the main of patients with acne, serum androgens are within the
regulator of MMP-9 and MMP-1. Furthermore, ATRA normal range.93,106
downregulates MMP and augments TIMP-1, suggest- Excess androgens may be produced by either the
ing that one way that ATRA may improve acne scar- adrenal gland or ovary. The laboratory workup should
ring is through the modulation of MMP and TIMP include measurement of serum DHEAS, total testoster-
expression, shifting from a matrix-degradative pheno- one, and free testosterone, with free testosterone con-
type to a matrix-preserving phenotype. sidered the most sensitive test for PCOS.107 Additional
T-cell responses also appear to determine the out- tests to consider include the luteinizing hormone (LH)
come of scar formation. In nonscarring lesions, initial to follicle-stimulating hormone (FSH) ratio or serum
robust inflammatory response with influx of CD4+ 17-hydroxyprogesterone to identify an adrenal source
nonspecific response with few memory T cells were of androgens in cases in which testing does not clearly
shown, which subsided in resolution. In contrast, in indicate an adrenal or ovarian source of androgens. 1399
scarring lesions, CD4+ T-cell numbers were smaller, Testing should be obtained just before or during the

Kang_CH078_p1391-1418.indd 1399 07/12/18 4:23 pm

14 menstrual period, not midcycle at the time of ovula-
tion. Patients taking contraceptives that prevent ovu- TABLE 78-1
lation will need to discontinue their medication for at Differential Diagnosis of Acne
least 1 month before testing. Values of DHEAS in the
range of 4000 to 8000 ng/mL (units may vary at dif- Most Likely
■ Closed comedonal acne
ferent laboratories) may be associated with congenital
■ Milia
adrenal hyperplasia. Patients with a serum level of
■ Sebaceous hyperplasia
DHEAS greater than 8000 ng/mL could have an adre-
■ Open comedonal acne
nal tumor and should be referred to an endocrinolo- ■ Dilated pore of Winer
gist for further evaluation. An ovarian source of excess ■ Favre–Racouchot syndrome
androgens can be suspected in cases when the serum ■ Inflammatory acne
total testosterone is greater than 150 ng/dL. Serum ■ Rosacea
total testosterone in the range of 150 to 200 ng/dL or ■ Perioral dermatitis
an increased LH-to-FSH ratio (>2.0) can be found in ■ Neonatal acne
■ Miliaria rubra
Part 14

cases of PCOS. Greater elevations in serum testoster-

■ Neonatal cephalic pustulosis
one may indicate an ovarian tumor, and appropriate
referral should be made. It is important to emphasize Consider
that there is a significant amount of variability in indi- ■ Closed comedonal acne
■ Osteoma cutis
::

vidual serum androgen levels. Therefore, in cases in

■ Trichoepitheliomas
Acneiform Disorders

which abnormal results are obtained, repeat testing

■ Trichodiscomas
should be considered before proceeding with addi-
■ Fibrofolliculomas
tional workup or therapy. ■ Eruptive vellus hair cysts, steatocystoma multiplex
■ Colloid milia
■ Flat warts
■ Open comedonal acne
PATHOLOGY ■ Trichostasis spinulosa
■ Nevus comedonicus
The histopathology of acne vulgaris varies with the ■ Inflammatory acne
■ Pseudofolliculitis barbae, acne keloidalis nuchae
clinical lesion. Early lesions, microcomedones, demon-
■ Keratosis pilaris
strate a dilated follicle with a narrow follicular orifice
■ Neurotic excoriations/factitial
filled with shed keratinocytes. Closed comedones show ■ Lupus miliaris disseminatus faciei
increased distension of the follicle, creating a cystic ■ Neonatal acne
space that contains eosinophilic keratinous debris, hair, ■ Sebaceous hyperplasia
and bacteria. Open comedones show enlarged follicular ■ Milia
ostia, with atrophic or absent sebaceous glands. Only ■ Transient neonatal pustular melanosis
mild perivascular inflammation is present at this stage. Always Rule Out
As the cystic structure enlarges, its contents begin ■ Closed comedonal acne
to infiltrate the dermis, inducing an inflammatory ■ Acne due to systemic agents (eg, corticosteroids)
response with neutrophils. If the lesion does not ■ Contact acne (eg, occupational acne)
resolve, it may develop a foreign body granulomatous ■ Chloracne
reaction or scarring. ■ Open comedonal acne
■ Acne caused by systemic agents
■ Contact acne
■ Chloracne
DIFFERENTIAL DIAGNOSIS ■ Inflammatory acne
■ Acne caused by systemic agents
Although one type of lesion may predominate, acne ■ Staphylococcal folliculitis
vulgaris is diagnosed by a variety of acne lesions (com- ■ Gram-negative folliculitis
edones, pustules, papules, and nodules) on the face, ■ Eosinophilic folliculitis
back, or chest (Table 78-1). The diagnosis is usually ■ Furuncle or carbuncle
straightforward, but inflammatory acne may be con- ■ Angiofibromas of tuberous sclerosis
fused with folliculitis, rosacea, or perioral dermatitis. ■ Neonatal acne
Patients with tuberous sclerosis and facial angiofibro- ■ Candidal infections

mas have been misdiagnosed as having recalcitrant

midfacial acne. Facial flat warts or milia are occasion-
ally confused with closed comedones. congenital adrenal hyperplasia, and adrenal and ovar-
As discussed earlier, acne can be seen in associa- ian neoplasms often have accompanying acne.
tion with endocrinologic abnormalities. Patients with Variants of acne, as reviewed in Chap. 80, must also
hyperandrogenism may have acne plus other stigmata be differentiated from typical acne vulgaris to guide
of increased androgen levels (ie, hirsutism, deepened treatment. These types of acne include neonatal acne,
voice, irregular menses). Endocrinologic disorders such infantile acne, midchildhood acne, acne fulminans,
1400 as PCOS (including hyperandrogenism, insulin resis- acne conglobata, acne with solid facial edema, and
tance, acanthosis nigricans [HAIR-AN] syndrome), acne excoriée des jeunes filles.

Kang_CH078_p1391-1418.indd 1400 07/12/18 4:23 pm

 Several less common acneiform eruptions can be
confused with acne vulgaris. These mimickers include
predict risk for development of moderate to severe
acne.109 Furthermore, prepubescent females with com-
14
medication-induced acne, halogen acne, chloracne, edonal acne and females with high DHEAS levels are
acne mechanica, tropical acne, radiation acne, and more likely to develop severe or long-standing nodu-
other miscellaneous acneiform disorders that are dis- lar acne.110
cussed in Chap. 80.

CLINICAL COURSE AND MANAGEMENT

Tailoring a patient’s acne regimen with the knowl-
PROGNOSIS edge of the pathogenesis of acne and the mechanism
of action of the available acne treatments will ensure
The typical age of onset of acne vulgaris varies consid-
maximum therapeutic response. Treatment regimens
erably. It may start as early as 8 years of age or it may
should be initiated early and be sufficiently aggressive
not appear until the age of 20 years or even later. The
to prevent permanent sequelae. Often multiple treat-

Chapter 78 :: Acne Vulgaris

course generally lasts several years and is followed by
ments are used in combination so as to combat the
spontaneous remission in most cases. Although the
various factors in the pathogenesis of acne (Table 78-2).
condition clears in the majority of patients by their
The mechanism of action of the most common treat-
early 20s, some have acne extending well into the third
ments for acne can be divided in the following catego-
or fourth decades of life. The extent of involvement
ries as they relate to the pathophysiology:
varies, and spontaneous fluctuations in the degree of
involvement are the rule rather than the exception. 1. Correct the altered pattern of follicular keratinization.
In women, there is often variation in relation to the 2. Decrease sebaceous gland activity.
menstrual cycle, with a flare just before the onset of 3. Decrease the follicular bacterial population, par-
menstruation, especially in those older than 30 years of ticularly P. acnes.
age.108 Family history, body mass index, and diet may 4. Exert an antiinflammatory effect.

TABLE 78-2
Treatment Algorithm for Acne Vulgaris
MILD MODERATE SEVERE
PAPULAR OR PAPULAR OR CONGLOBATA OR
COMEDONAL PUSTULAR PUSTULAR NODULAR FULMINANS

First Topical retinoid or Topical retinoid + Oral antibiotic + Oral antibiotic + topical Oral isotretinoin ± oral
combinationa topical antimicrobial topical retinoid ± retinoid ± BPO corticosteroids
or combinationa BPO or combinationa
Second Topical dapsone Topical dapsone or Oral antibiotic + Oral isotretinoin or oral High-dose oral
or azelaic acid or azelaic acid or salicylic topical retinoid ± antibiotic + topical antibiotic + topical
salicylic acid acid BPO or combinationa retinoid ± BPO–azelaic retinoid + BPO or
acid or combinationa combinationa
Female — — + Oral contraceptive– + Oral contraceptive– + Oral contraceptive–
antiandrogen antiandrogen antiandrogen
Additional Comedone Comedone extraction, Comedone extraction, Comedone extraction; Intralesional cortico-
options extraction Laser or light therapy, laser or light ther- intralesional cortico- steroid, laser or light
photodynamic apy, photodynamic steroid, laser or light therapy, photody-
therapy therapy therapy, photodynamic namic therapy
therapy
Refractory to Check compliance Check compliance
treatment Exclude gram-negative
folliculitis
Females: exclude PCOS,
adrenal or ovarian
tumors, CAH
Males: exclude ECAH
Maintenance Topical retinoid Topical retinoid ± BPO, Topical retinoid ± BPO, Topical retinoid ± BPO, or
± BPO, or or combinationa or combinationa combinationa
combinationa
a
Manufactured combination products include benzoyl peroxide (BPO)–erythromycin, BPO–clindamycin, adapalene–BPO, and tretinoin–clindamycin.
CAH, congenital adrenal hyperplasia; PCOS, polycystic ovarian syndrome.
Adapted from Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to improve outcomes in acne. J Am Acad Dermatol. 1401
2003;49(1Suppl):S1.

Kang_CH078_p1391-1418.indd 1401 07/12/18 4:23 pm

14 LOCAL THERAPY
the expression of genes involved in cell proliferation,
differentiation, melanogenesis, and inflammation.111,112
The result is modification of corneocyte accumulation
CLEANSING and cohesion and inflammation. Thus, retinoids have
both comedolytic and antiinflammatory properties.112
The importance of cleansing in the treatment of acne is Tretinoin is commercially available in several
generally intuitive. Twice-daily washing with a gentle strengths and formulations. Having both potent com-
cleanser followed by the application of acne treatments edolytic and antiinflammatory properties, it is widely
may encourage a routine and therefore better compli- used. In general, all retinoids can be contact irritants,
ance. Overcleansing or use of harsh alkaline soaps are with alcohol-based gels and solutions having the
likely to increase the skin’s pH, disrupt the cutaneous greatest irritancy potential. Some newer formulations
lipid barrier, and compound the irritancy potential of use a microsphere delayed-delivery technology (Retin
many topical acne treatments. Use of a syndet (syn- A Micro 0.04%, 0.08% or 0.1% gel) or are incorpo-
thetic detergent) will allow cleansing without disrup- rated within a polyolprepolymer (PP-2; Avita cream)
Part 14

tion of the skin’s normal pH. Medicated cleansers, to decrease the irritancy potential of tretinoin while
containing benzoyl peroxide, salicylic acid, or sulfur, allowing greater concentration of medication. Advis-
offer convenience as a wash and are excellent for hard- ing patients to apply tretinoin on alternate nights dur-
to-reach areas such as the back. ing the first few weeks of treatment can help ensure
::

greater tolerability. Patients must also be cautioned

Acneiform Disorders

about sun exposure because of thinning of the stratum

TOPICAL MEDICATIONS corneum, especially those with any irritant reaction.
(SEE TABLE 78-3) Regular use of a sunscreen should be advised. The
comedolytic and antiinflammatory properties of topi-
Retinoids: Retinoids are defined by their ability cal retinoids make them ideal for maintenance therapy
to bind to and activate retinoic acid receptors (RARs) of acne. Generic tretinoin is inactivated by concomitant
and in turn activate specific gene transcription result- use of benzoyl peroxide and is photolabile. Therefore,
ing in a biologic response. Some have chemical struc- patients should be counseled to apply tretinoin at bed-
tures similar to tretinoin (all-trans-retinoic acid), but time and not at the same time as benzoyl peroxide.
they may be entirely dissimilar, such as adapalene or Adapalene is a synthetic retinoid widely marketed
tazarotene, and still potentiate a retinoid effect. In gen- for its greater tolerability. It specifically targets the
eral, the binding of these agents to nuclear RAR affects RARγ receptor. It is both photostable and can be used

TABLE 78-3
Commonly Available Prescription Acne Preparations—Topical
GENERIC TRADE VEHICLE CONCENTRATION SIZE

Retinoids—Topical
Tretinoin Retin-A Cream 0.025%, 0.05%, 0.1% 20 g, 45 g
Gel 0.01%, 0.025% 15 g, 45 g (0.025% only)
Liquid 0.05% 28 mL
Retin-A micro Gel with microsponge 0.04%, 0.1% 20 g, 45 g
50-g pump
Avita Cream 0.025% 20 g, 45 g
Gel 0.025% 20 g, 45 g
Refissa Cream 0.05% 40 g
Tretin-X Cream 0.025%, 0.05%, 0.1% 35 g (kit with cleanser)
Gel 0.025%, 0.1% 35 g (kit with cleanser)
Generic Cream 0.025%, 0.05%, 0.1% 20 g, 45 g
Gel 0.01%, 0.025%, 0.05% 15 g, 45 g
Adapalene Differin Cream 0.1% 15 g, 45 g
Gel 0.1%, 0.3% 15 g, 45 g
Lotion 0.1% 2 oz
Generic Gel 0.1% 45 g
Tazarotene Tazorac Cream 0.1% 30 g, 60 g
Gel 0.1% 30 g, 60 g
Fabior Foam 0.1% 50 g, 100 g
Retinoid Combinations—Topical
Tretinoin–clindamycin Ziana Gel 0.025%/1.2% 30 g, 60 g
Veltin Gel 0.025%/1.2% 30 g, 60 g
1402
Adapalene–benzoyl peroxide Epiduo Gel 2.5%/0.1%, 2.5%/0.3% 45 g

(Continued)

Kang_CH078_p1391-1418.indd 1402 07/12/18 4:23 pm

 TABLE 78-3
14
Commonly Available Prescription Acne Preparations—Topical (Continued)
GENERIC TRADE VEHICLE CONCENTRATION SIZE

Antimicrobials—Topical
Benzoyl peroxide Benzac AC Gel 2.5%, 5%, 10% 60 g
Wash 2.5%, 5%, 10% 240 mL (2.5%), 226 mL
Benzac W Gel 2.5%, 5%, 10% 60 g
Wash 5%, 10% 226 mL
Benzashave Cream 5%, 10% 113.4 g
Benziq LS Gel 5.25% 50 g
Wash 5.25% 175 g
Brevoxyl Gel 4%, 8% 42.5 g
Creamy wash 4%, 8% 170 g (kit with cleanser)

Chapter 78 :: Acne Vulgaris

BenzEFoam Foam 5.3%, 9.8% 60 g, 100 g
Clinac Gel 7% 45 g
Desquam-E Gel 2.5%, 5%, 10% 42.5 g
PanOxyl Creamy wash 4% 6 oz
Foamy wash 10% 5.5 oz
Triaz Gel 3%, 6%, 9% 42.5 g
Cleanser 3%, 6%, 9% 6 oz, 12 oz
Pads 3%, 6%, 9% 1 g (30 or 60/box)
Foaming cloths 3%, 6%, 9% 3.2 g (30 or 60/box)
ZoDerm Cleanser 4.5%. 6.5%, 8.5% 400 mL
Pads 4.5%. 6.5%, 8.5% 6 mL (30/box)
Hydrating wash 5.75% 400 mL
Generic Gel 5%, 10% 45 g, 60 g, 90 g
Wash 2.5%, 5%, 10% 142 g, 227 g
Erythromycin Generic Gel 2% 30 g, 60 g
Ointment 2% 25 g
Solution 2% 60 mL
Pledget 2% (60/box)
Clindamycin Cleocin T Gel 1% 30 g, 60 g
Lotion 1% 60 mL
Solution 1% 30 mL, 60 mL
Pledget 1% (60/box)
Evoclin Foam 1% 50 g, 100 g
Clindagel Gel 1% 40 mL, 75 mL
ClindaMax Gel 1% 30 g, 60 g
Lotion 1% 60 mL
Clindets Pledget 1% 60 s
Generic Gel 1% 30 g, 60 g
Lotion 1% 30 g, 60 g
Solution 1% 30 g
Dapsone Aczone Gel 5%, 7.5% 30 g, 60 g, 90 g
Benzoyl peroxide–erythromycin Benzamycin Gel 5%/3% 46.6 g, 60/box
Benzamycin Gel Pak
Generic Gel 5%/3% 23.2 g, 46.6 g
Benzoyl peroxide/clindamycin BenzaClin Gel 5%/1% 25 g, 50 g
50-g pump
Duac Gel 5%/1% 45 g
Acanya Gel 2.5%/1.2% 50 g
Generic Gel 5%/1% 50 g
Benzoyl peroxide/hydrocortisone Vanoxide HC Lotion 5%–0.5% 25 mL
Miscellaneous
Sodium sulfacetamide Klaron Lotion 10% 4 oz
Ovace Foam 10% 70 g
Wash 10% 6 oz, 12 oz, 16 oz
Sodium sulfacetamide/sulfur Avar Emollient cream 10%–5% 45 g, 2 oz
Generic Suspension (cleanser) 8%–4%, 9%–4%, 10%–5% 6 oz, 12 oz
Foam 10%–5% 60 g60/box
Topical pad 10%–5% 1403
Azelaic acid Finacea Gel 15% 50 g
Azelex Cream 20% 30 g, 50 g

Kang_CH078_p1391-1418.indd 1403 07/12/18 4:23 pm

14 in conjunction with benzoyl peroxide without degra-
dation. Adapalene 0.1% gel has been shown in clini-
likely in patients who are treated concurrently with
benzoyl peroxide123; therefore, the combination of
cal trials to have greater or equal efficacy to tretinoin these two products is preferable over monotherapy
0.025% gel with greater tolerability.113,114 It is available with topical antibiotics. Topical dapsone 5% and 7.5%
at a 0.1% concentration in both a nonalcohol gel and gel is the most recently approved topical antibiotic
cream and as a 0.3% gel. The 0.3% adapalene gel has for acne. With twice-daily application, topical dap-
been shown to have similar efficacy to tazarotene 0.1% sone has shown better efficacy in controlling inflam-
gel with increased tolerability.115 A combination topical matory lesions (58%) versus noninflammatory lesions
agent containing adapalene (0.1% or 0.3%) and 2.5% (19%).124,125 Unlike oral dapsone, topical dapsone is safe
benzoyl peroxide is also available.116,117 Adapalene for use even in patients with a glucose-6-phosphate
0.1% gel is the only retinoid recently made available dehydrogenase (G6PD) deficiency.126 It is generally
by the U.S. Food and Drug Administration (FDA) for well tolerated but should not be applied concomitantly
over-the-counter (OTC) treatment of acne in those with benzoyl peroxide, or it may impart an orange
12 years and older.118 color on the skin.127 As of submission of this chapter, a
Part 14

Tazarotene, also a synthetic retinoid, exerts its action phase II clinical trial with topical minocycline 1% and
through its metabolite, tazarotenic acid, which in turn 4% foam for the treatment of moderate to severe acne
inhibits the RARγ receptor. It is a potent comedolytic has been published and shows promising results.128
agent and has been shown to be more effective than
Salicylic Acid:
::

tretinoin 0.025% gel and tretinoin 0.1% microsphere Salicylic acid is a ubiquitous ingre-
dient found in OTC acne preparations (gels and washes)
Acneiform Disorders

gel.119,120 Both the 0.1% cream and gel formulations are

approved for the treatment of acne, as well as a 0.1% in concentrations ranging from 0.5% to 2%. This lipid-
foam for the chest and back. The irritant properties soluble β-hydroxy acid has comedolytic properties but
of tazarotene can be minimized by the use of short- somewhat weaker than those of a retinoid. Salicylic
term contact therapy. In this regimen, the medication acid also causes exfoliation of the stratum corneum
is applied for 5 minutes and then washed off with a through decreased cohesion of the keratinocytes. Mild
gentle cleanser. The use of tazarotene is not recom- irritant reactions may result. It is generally considered
mended for use during pregnancy (formerly Preg- less effective than benzoyl peroxide.
nancy Category X classification), and female patients Azelaic Acid: Azelaic acid is available by prescrip-
of childbearing age should be adequately counseled, tion in a 20% cream or 15% gel. This dicarboxylic acid
with consideration of obtaining a negative pregnancy has both antimicrobial and comedolytic properties129
test result before initiation of therapy. It is also a competitive inhibitor of tyrosinase and
Benzoyl Peroxide: Benzoyl peroxide prepara- thus may decrease postinflammatory hyperpigmenta-
tions are among the most common topical medications tion.130 It is generally well tolerated, although transient
prescribed by dermatologists and are also readily avail- burning can occur, and is considered safe in pregnancy.
able OTC. Benzoyl peroxide is a powerful antimicrobial
Sulfur, Sodium Sulfacetamide, and Res-
agent, markedly reducing the bacterial population via
orcinol: Products containing sulfur, sodium sul-
release of free oxygen radicals.121 It also has mild com-
facetamide, and resorcinol, once favored treatments
edolytic properties. Benzoyl peroxide preparations are for acne, are still found in several OTC and prescrip-
available in creams, lotions, gels, washes, foams, and tion niche formulations. Sulfonamides are thought to
pledgets in a variety of concentrations ranging from have antibacterial properties through their inhibition
2.5% to 10%. Products that are left on the skin, such as of para-aminobenzoic acid (PABA), an essential sub-
gels, are generally considered more effective, but data stance for P. acnes growth.131 Sulfur also inhibits the
are lacking. Benzoyl peroxide can produce significant
formation of free fatty acids and has presumptive ker-
dryness and irritation and can bleach clothing and
atolytic properties. It is often combined with sodium
hair. Higher concentrations are not necessarily more
sulfacetamide to enhance its cosmetic tolerability due
efficacious and can cause increased irritation. Allergic
to sulfur’s distinctive odor. Resorcinol is also indicated
contact dermatitis has been uncommonly reported. Of
for use in acne for its antimicrobial properties. It is gen-
significance, bacteria are unable to develop resistance
erally found in a 2% concentration in combination with
to benzoyl peroxide, making it the ideal agent for com-
5% sulfur.
bination with topical or oral antibiotics.122
An overview of topical agents for acne treatment is
Topical Antibiotics: Erythromycin and clindamy- outlined in Table 78-3.
cin have historically been the most commonly used
topical antibiotics for the treatment of acne. How-
ever, over the past few decades, the estimated global
incidence rate of P. acnes resistance to antibiotics has
SYSTEMIC THERAPY
increased from 20% (in 1978) to 62% (in 1996). In par-
ticular, high resistance to erythromycin has resulted ANTIBIOTICS AND ANTIBACTERIAL
in significant reduction in its use in recent years with
preferential use of clindamycin. These two agents have
AGENTS
1404 also been used in combination preparations with ben- Tetracyclines: Broad-spectrum antibiotics are
zoyl peroxide. The development of resistance is less widely used in the treatment of inflammatory acne.

Kang_CH078_p1391-1418.indd 1404 07/12/18 4:23 pm

 The tetracyclines are the most commonly used anti-
biotics in the treatment of acne. Although the oral
also, tetracyclines have been reported to inhibit skel-
etal growth in fetuses. Therefore, they should not be
14
administration of tetracyclines does not alter sebum administered to pregnant women, especially after the
production, it does decrease the concentration of fourth month of gestation, and are not recommended
free fatty acids while the esterified fatty acid con- for use in children younger than 9 years of age in the
tent increases. Free fatty acids are inflammatory, and treatment of acne.
their level is an indication of the metabolic activ-
ity of P. acnes and its secretion of proinflammatory Macrolides: Because of the prevalence of eryth-
products. This reduction in free fatty acids may be romycin-resistant strains of P. acnes, the use of oral
through suppression of P. acnes and may take several erythromycin is generally limited to pregnant women
weeks to become evident. Therefore, several weeks or children. Azithromycin has been used more often
of therapy are often required to observe maximal for acne, typically at dosages of 250 to 500 mg orally
clinical benefit. The effect, then, is one of preven- three times weekly.134 Azithromycin undergoes hepatic
tion; the individual lesions require their usual time metabolism with GI upset and diarrhea as the most
common side effects.

Chapter 78 :: Acne Vulgaris

to undergo resolution. Decreases in free fatty acid
formation also have been reported with erythromy-
cin, demethylchlortetracycline, clindamycin, and Tr i m e t h o p r i m – S u l f a m e t h ox a zo l e :
minocycline. Trimethoprim–sulfamethoxazole combinations are
Doxycycline and minocycline are the most com- also effective in acne. In general, because the poten-
monly used tetracycline derivatives for the treat- tial for side effects is greater with their use, they
ment of acne. They have the distinct advantage that should be used only in patients with severe acne who
they can be taken with food with minimal impaired do not respond to other antibiotics. GI upset and
absorption. Doxycycline is administered in dosages cutaneous hypersensitivity reactions are common.
of 50 to 100 mg twice daily. Its major disadvantage Serious adverse reactions, including the Stevens-
is the potential risk of photosensitivity reactions, Johnson syndrome–toxic epidermal necrolysis spec-
including photo-onycholysis, and patients may need trum and aplastic anemia, have been described. If
to be switched to another antibiotic during summer trimethoprim–sulfamethoxazole is used, the patient
months. Gastrointestinal (GI) upset is another com- should be monitored for potential hematologic sup-
mon side effect; it can be minimized if medication is pression monthly.
taken with food.
Cephalexin: Cephalexin, a first-generation ceph-
Minocycline is given in divided doses at a level of
alosporin, has been shown in vitro to kill P. acnes.
100 to 200 mg/day. Patients taking minocycline should
However, because it is hydrophilic and not lipo-
be monitored carefully because the drug can cause
philic, it penetrates poorly into the pilosebaceous
blue-black pigmentation, especially in acne scars,
unit. Success with oral cephalexin135 is most likely
as well as the hard palate, alveolar ridge, and ante-
caused by its antiinflammatory rather than antimi-
rior shins. Vertigo has occasionally been described.
crobial properties. Because of the risk of promoting
Minocycline-induced autoimmune hepatitis and a
the development of bacterial resistance, particularly
systemic lupus erythematosus–like syndrome have
to Staphylococcus spp., the authors discourage the use
been reported during minocycline therapy, but these
of cephalexin for acne.
side effects are very rare.132,133 Of note, patients who
develop lupus-like reactions can be safely switched to Clindamycin and Dapsone: Less commonly
an alternative tetracycline. Serum sickness–like reac- used antibiotics include clindamycin and dapsone.
tions and drug reaction with eosinophilia and systemic Oral clindamycin had been used more readily in the
symptoms (DRESS) syndrome have also been reported past, but because of the risk of pseudomembranous
with minocycline use. colitis, it is now rarely used systemically for acne.
Tetracycline is usually given initially in dosages It is still commonly used topically, however, often
of 500 to 1000 mg/day. Higher doses of up to 3500 in combination with benzoyl peroxide. Dapsone
mg/day have been used in severe cases, but prudent (see Chap. 187), a sulfone often used for cutaneous
monitoring of liver function is warranted. Tetracycline neutrophilic disorders, may be beneficial in severe
should be taken on an empty stomach, 1 hour before or markedly inflammatory acne and select cases of
2 hours after meals, to promote absorption; thus, com- resistant acne. It is used at doses of 50 to 100 mg
pliance by adolescents with its administration can be daily for 3 months. G6PD levels should be examined
challenging. GI upset is the most common side effect, before initiation of therapy, and regular monitor-
with esophagitis and pancreatitis possible. Uncom- ing for hemolysis and liver function abnormalities
mon side effects include hepatotoxicity, hypersensitiv- is warranted. Although not as reliably effective as
ity reactions, leukocytosis, thrombocytopenic purpura, isotretinoin, it is relatively low cost and should be
and pseudotumor cerebri. considered in severe cases when isotretinoin is not
Tetracyclines should be used with caution in patients an option.
with renal disease because they may increase uremia.
Tetracyclines have an affinity for rapidly mineralizing Antibiotics and Bacterial Resistance: Anti-
tissues and are deposited in developing teeth, where biotic resistance is a growing concern worldwide 1405
they may cause irreversible yellow-brown staining; and should be suspected in patients unresponsive to

Kang_CH078_p1391-1418.indd 1405 07/12/18 4:23 pm

14 appropriate antibiotic therapy after 6 weeks of treat-
ment. Increasing propionibacterium resistance has
of ethinyl estradiol (20–35 µg) in combination with
norethindrone acetate (1 mg).141 Yaz contains ethi-
been documented to all macrolides and tetracyclines nyl estradiol (20 ug) and the antiandrogen drospire-
commonly used in the treatment of acne. A prevalence none (3 mg). Drospirenone is a 17 α-spironolactone
rate of 65% was documented in one study performed derivative that has both antimineralocorticoid and
in the United Kingdom.136 Overall, resistance is high- antiandrogenic properties, which may improve estrogen-
est with erythromycin and lowest with the lipophilic related weight gain and bloating.141 An oral contra-
tetracyclines, doxycycline, and minocycline.63 The least ceptive containing a low dose of estrogen (20 µg) in
resistance is noted with minocycline. To prevent resis- combination with levonorgestrel (Alesse) has also
tance, prescribers should avoid antibiotic monother- demonstrated efficacy in acne.142 Side effects from oral
apy, limit long-term use of antibiotics, and combine contraceptives include nausea, vomiting, abnormal
usage with benzoyl peroxide whenever possible.137 menses, weight gain, and breast tenderness. Rare but
Recent guidelines recommend limiting the duration more serious complications include thrombophlebitis,
of oral antibiotic therapy in acne to 3 to 6 months to pulmonary embolism, and hypertension. With the use
Part 14

reduce risk of resistance.138 of oral contraceptives containing estrogen and pro-

gestin rather than estrogen alone, side effects such
as delayed menses, menorrhagia, and premenstrual
HORMONAL THERAPY cramps are uncommon. However, other side effects
::

The goal of hormonal therapy is to counteract the such as nausea, weight gain, spotting, breast tender-
Acneiform Disorders

effects of androgens on the sebaceous gland. This ness, amenorrhea, and melasma can occur.
can be accomplished with antiandrogens, or agents Glucocorticoids: Because of their antiinflamma-
designed to decrease the endogenous production of tory activity, high-dose systemic glucocorticoids may
androgens by the ovary or adrenal gland, including be of benefit in the treatment of acne. In practice, their
oral contraceptives, glucocorticoids, or gonadotropin- use is usually restricted to severely involved patients,
releasing hormone (GnRH) agonists. often overlapping with isotretinoin to limit any poten-
Oral Contraceptives: Oral contraceptives can tial flaring from at the start of treatment. Furthermore,
improve acne by four main mechanisms. First, they because of the potential side effects, these drugs are
decrease the amount of gonadal androgen produc- ordinarily used for limited periods of time, and recur-
tion by suppressing LH production. Second, they rences after treatment are common. Prolonged use
decrease the amount of free testosterone by increas- may result in the appearance of steroid acne. Gluco-
ing the production of sex hormone binding globu- corticoids in low dosages are also indicated in female
lin. Third, they inhibit the activity of 5-α reductase patients who have an elevation in serum DHEAS
activity, preventing the conversion of testosterone associated with an 11- or 21-hydroxylase deficiency
to the more potent DHT. Last, progestins that have or in other individuals with demonstrated androgen
an antiandrogenic effect can block the androgen excess. Low-dose prednisone (2.5 mg or 5 mg) or dexa-
receptors on keratinocytes and sebocytes. The third- methasone can be given orally at bedtime to suppress
generation progestins—gestodene (not available in adrenal androgen production.106 The combined use of
the United States), desogestrel, and norgestimate— glucocorticoids and estrogens has been used in recalci-
have the lowest intrinsic androgenic activity.139 Two trant acne in women based on the inhibition of sebum
progestins have demonstrated antiandrogenic prop- production by this combination.143 The mechanism
erties: (1) cyproterone acetate (not available in the of action is probably related to a greater reduction of
United States) and (2) drospirenone. There are three plasma androgen levels by combined therapy than is
oral contraceptives currently FDA approved for the produced by either drug alone.
treatment of acne: (1) Ortho Tri-Cyclen, (2) Estrostep, Gonadotropin-Releasing Hormone Ago-
and (3) Yaz (Table 78-4). Ortho Tri-Cyclen is a tripha- nists: GnRH agonists, such as leuprolide (Lupron),
sic oral contraceptive comprised of a norgestimate act on the pituitary gland to disrupt its cyclic release of
(180, 215, 250 mg)–ethinyl estradiol (35 µg) combina- gonadotropins. The net effect is suppression of ovar-
tion.140 In an effort to reduce the estrogenic side effects ian steroidogenesis in women. These agents are used
of oral contraceptives, preparations with lower doses in the treatment of ovarian hyperandrogenism. GnRH
of estrogen (20 µg) have been developed for the treat- agonists have demonstrated efficacy in the treatment
ment of acne. Estrostep contains a graduated dose of acne and hirsutism in female patients both with and
without endocrine disturbance.144 However, their use
is limited by their side effect profile, which includes
menopausal symptoms and bone loss.
TABLE 78-4
U.S. Food and Drug Administration–Approved Antiandrogens: Spironolactone is an aldo-
Oral Contraceptives for Acne in Women sterone antagonist and functions in acne as both an
androgen-receptor blocker and inhibitor of 5-α reduc-
Ortho Tri-Cyclen (norgestimate + ethinyl estradiol) tase. In dosages of 50–100 mg twice a day, it has been
Estrostep (norethindrone acetate + ethinyl estradiol)
1406 shown to reduce sebum production and to improve
Yaz (drospirenone + ethinyl estradiol)
acne.145 Side effects include diuresis, potential

Kang_CH078_p1391-1418.indd 1406 07/12/18 4:23 pm

hyperkalemia, irregular menstrual periods, breast
tenderness, headache, and fatigue. Combining spi-
United States with the initiation of the iPledge pro-
gram in 2006 to ensure that pregnancy-prevention
14
ronolactone treatment with an oral contraceptive can procedures are followed.
alleviate the symptoms of irregular menstrual bleed- The mechanism of action of isotretinoin is not com-
ing. Although hyperkalemia is a risk of spironolac- pletely known. The drug produces profound inhibi-
tone, this risk has shown to be minimal, even when tion of sebaceous gland activity, and this undoubtedly
spironolactone is administered with other aldoste- is of great importance in the initial clearing.154,155 In
rone antagonists (eg, drospirenone-containing oral some patients, sebaceous gland inhibition continues
contraceptives).146 A recent study evaluating the use- for at least 1 year, but in the majority of patients, sebum
fulness of routine potassium monitoring in healthy production returns to normal after 2 to 4 months.154
young female patients taking spironolactone for acne Thus, this action of the drug cannot be used to explain
showed that the rate of hyperkalemia was equivalent the long-term remissions. The P. acnes population is
to that of the general population and therefore rou- also decreased during isotretinoin therapy, but this
tine monitoring is of low utility.147 As an antiandro- decrease is generally transient.155,156 Isotretinoin has

Chapter 78 :: Acne Vulgaris

gen, there is a risk of feminization of a male fetus if no inhibitory effect on P. acnes in vitro. Therefore, the
a pregnant woman takes this medication. Long-term effect on the bacterial population is probably indirect,
studies in rats receiving high doses of spironolactone resulting from the decrease in intrafollicular lipids
demonstrated an increased incidence of adenomas on necessary for organism growth. Isotretinoin also has
endocrine organs and the liver, resulting in a black box antiinflammatory activity and probably has an effect
warning by the FDA (http://www.drugs.com/pro/ on the pattern of follicular keratinization. These effects
aldactone). The potential for spironolactone to induce also are temporary, and the explanation for long-term
estrogen-dependent malignancies still remains con- remissions remains obscure.
troversial. However, the available data suggest that Given the ubiquitous distribution of RAR, isotreti-
there is no definitive documented association between noin almost always causes side effects, mimicking
breast carcinoma and spironolactone ingestion after those seen in the chronic hypervitaminosis A syn-
more than 30 years of data on spironolactone.148,149 drome.157 In general, the severity of side effects tends
Cyproterone acetate is a progestational antiandro- to be dose dependent. The most common side effects
gen that blocks the androgen receptor. It is combined are related to the skin and mucous membranes. Chei-
with ethinyl estradiol in an oral contraceptive formu- litis of varying degrees is found in virtually all cases.
lation that is widely used in Europe for the treatment Other side effects that are likely to be seen in more than
of acne. Cyproterone acetate is not available in the 50% of patients are dryness of the mucous membranes
United States. and skin. An eczematous eruption is occasionally seen,
Flutamide, an androgen receptor blocker, has been particularly in cold, dry weather. Thinning of hair and
used at doses of 250 mg twice a day in combination granulomatous paronychial lesions are less common.
with oral contraceptives for treatment of acne or hir- Ophthalmologic findings include xerophthalmia, night
sutism in females.150 Liver function tests should be blindness, conjunctivitis, keratitis, and optic neuritis.
monitored because cases of fatal hepatitis have been Corneal opacities and hearing loss (both transient and
reported.151 Pregnancy should be avoided. Use of flu- persistent) have also been reported with isotretinoin
tamide in the treatment of acne may be limited by its use. Pseudotumor cerebri, also known as benign intra-
side effect profile. cranial hypertension, is evidenced by severe headache,
nausea, and visual changes. The risk of pseudotu-
mor cerebri may be increased with concomitant use
of tetracyclines and isotretinoin; therefore, these two
ISOTRETINOIN medications should not be used together without care-
ful prior consideration. If symptoms suggest benign
(SEE CHAP. 185) intracranial hypertension, prompt neurologic evalu-
ation for evidence of papilledema is required. Vague
The use of the oral retinoid isotretinoin has revo- complaints of headache, fatigue, and lethargy are also
lutionized the management of treatment-resistant frequent.
acne.152 It is approved for use in patients with severe The relationship between isotretinoin use and psy-
recalcitrant nodular acne. However, it is commonly chiatric effects is currently being examined. Risks
used in many other acne scenarios, including any sig- of depression, suicide, psychosis, and aggressive or
nificant acne that is unresponsive to treatment with violent behavior are all listed as possible side effects.
oral antibiotics and acne that results in significant Although no clear mechanism of action has been
physical or emotional scarring. Isotretinoin is also established, some evidence for biologic plausibility
effective in the treatment of gram-negative folliculitis, does exist. Psychiatric adverse events are described
pyoderma faciale, and acne fulminans.153 The remark- with high-dose vitamin A and etretinate. Also, reti-
able aspects of isotretinoin therapy are the complete noids have the demonstrated ability to enter the
remission in almost all cases and the longevity of the central nervous system (CNS) of rats and mice. And
remission, which lasts for months to years in the great finally, there are documented case reports and studies
majority of patients. However, because of its terato- linking isotretinoin use to depression in certain indi- 1407
genicity, its use has become highly regulated in the viduals.158 A meta-analysis of nine studies looking at
14 the possible link between isotretinoin and depression
found that the incidence of depression in patients on
Other laboratory abnormalities that have been
reported with isotretinoin use are an elevated erythro-
isotretinoin ranged from 1% to 11%.159 The authors cyte sedimentation rate and platelet count. Alterations
importantly pointed out that this range is similar to in the red blood cell parameters with decreased white
control group patients taking oral antibiotics. Another cell counts can occur. White blood cells in the urine
author examining case-control studies on isotretinoin have rarely been linked to isotretinoin use. Most labo-
and depression found the relative risk to range from ratory changes are mild and spontaneously resolve
0.9 to 2.7 with wide confidence intervals.160 Some stud- upon discontinuation of medication use.
ies demonstrate that patients taking isotretinoin have Laboratory monitoring while patients are taking
an overall improvement in mood.161 Retinoids have not isotretinoin includes obtaining a baseline complete
been shown to activate genes to induce behavioral or blood count, liver function tests and lipid panel, with
psychiatric changes. Nor is there evidence demonstrat- the greatest attention paid to following serum triglyc-
ing functionality of retinoid signaling pathways in the eride levels. Baseline values for serum triglycerides
mature CNS. Large population-based studies have not should be obtained and repeated at 4 and 8 weeks of
Part 14

supported causality. As dermatologists are often on therapy. If the values are normal at 8 weeks, there is no
the front line seeing adolescents at risk for depression, need to repeat the test during the remaining course of
careful screening of adolescents is particularly needed therapy unless there are risk factors. If serum triglyc-
because the risk of depression in this population is 10% erides increase above 500 mg/dL, the levels should be
::

to 20%.162 monitored frequently. Levels above 700 to 800 mg/dL

Acneiform Disorders

GI symptoms are generally uncommon, but nau- are a reason for interrupting therapy or treating the
sea, esophagitis, gastritis, and colitis can occur. Acute patient with a lipid-lowering drug. Eruptive xantho-
hepatitis is rare, but liver function studies should mas or pancreatitis can occur at higher serum triglyc-
be regularly monitored because elevations in liver eride levels.
enzymes can occur in 15% of patients, sometimes A recent study evaluating the characteristics of lab
necessitating dose adjustments. Elevated levels of abnormalities in 515 patients who underwent isotret-
serum triglycerides occur in approximately 25% of inoin therapy for acne reported clinically insignifi-
patients taking isotretinoin. This elevation, which is cant leukopenia (1.4%) or thrombocytopenia (0.9%),
dose related, typically occurs within the first 4 weeks infrequent transaminitis (1.9%) with the most signifi-
of treatment and is often accompanied by an overall cant elevations occurring with triglyceride (19.3%)
increase in cholesterol with a decrease in the high- and cholesterol (22.8%) levels. Recommendations
density lipoprotein levels. The effect of this transient for otherwise healthy patients with normal baseline
alteration on overall coronary artery health is unclear. labs are to repeat laboratory studies after 2 months
Acute pancreatitis is a rare complication that may or taking isotretinoin therapy, and if results are normal,
may not be related to triglyceride levels. There are no further testing may be required. Routine com-
case reports documenting a potential link between plete blood count monitoring was also found to be
isotretinoin and new-onset or flared inflammatory unnecessary.167
bowel disease (IBD). However, a study that critically The greatest concern during isotretinoin therapy
examined these case reports found no grounds for is the risk of the drug being administered dur-
a causal relationship between isotretinoin use and ing pregnancy and thereby inducing teratogenic
IBD.163 A recent population-based case-control study effects in the fetus.168,169 The drug is not mutagenic;
found that patients with IBD were no more likely its effect is on organogenesis. Therefore, the pro-
to have used isotretinoin than those without IBD.164 duction of retinoic embryopathy occurs very early
Patients with a family history of IBD and those with in pregnancy, with a peak near the third week of
a preexisting IBD should be counseled regarding the gestation.168,169 A significant number of fetal abnor-
possibility of isotretinoin-induced IBD. malities have been reported after the use of isotreti-
Isotretinoin has effects on bone mineralization as noin. For this reason, it should be emphasized that
well. A single course of isotretinoin was not shown isotretinoin should be given only to patients who
to have a significant effect on bone density.165 How- have not responded to other therapy. Furthermore,
ever, chronic or repeated courses may result in sig- women who are of childbearing age must be fully
nificant osteopenia. Osteoporosis, bone fractures, informed of the risk of pregnancy. The patient must
and delayed healing of bone fractures have also been use two highly effective contraception techniques
reported. The significance of reported hyperostosis is such as the use of an oral contraceptive and con-
unclear, but the development of bony hyperostoses doms with a spermicidal jelly. Contraception must
after isotretinoin therapy is more likely in patients be started at least 1 month before isotretinoin ther-
who receive the drug for longer periods of time and apy. Female patients must be thoroughly counseled
in higher dosages, such as for disorders of keratini- and demonstrate an understanding of contraception
zation.166 Serial bone densitometry should be done in techniques before starting isotretinoin. Two forms of
any patient on long-term isotretinoin. Myalgias are contraception should be used throughout the course
the most common musculoskeletal complaint, seen of isotretinoin and for 1 month after stopping treat-
in 15% of patients. In severe cases, creatine phos- ment. No more than 1 month’s supply of isotretinoin
1408 phokinase levels should be evaluated for possible should be given to a female patient so that she can
rhabdomyolysis. be counseled on a monthly basis on the hazards of

Kang_CH078_p1391-1418.indd 1408 07/12/18 4:23 pm

 pregnancy during isotretinoin therapy. A pregnancy
test must be repeated monthly. Abstinence as the PROCEDURES
14
sole form of birth control should only be allowed in
special instances. Because the drug is not mutagenic,
there is no risk to a fetus conceived by a man who is
ACNE SURGERY
taking isotretinoin. Although it may seem obvious, it Acne surgery, a mainstay of therapy in the past used
is important to remind men who are taking isotreti- for the removal of comedones and superficial pus-
noin not to give any of their medication to female tules, aids in bringing about involution of individual
companions under any circumstances or to donate acne lesions. However, with the advent of comedo-
blood while taking the medication. lytic agents, such as topical retinoids, its use is pri-
The recommended daily dosage of isotretinoin is marily restricted to patients who do not respond to
in the range of 0.5 to 1 mg/kg/day. A cumulative comedolytic agents. Even in these patients, the come-
weight-based dosing formula may also be used with dones are removed with greater ease and less trauma
a total dose of 120 to 150 mg/kg of isotretinoin dur- if the patient is pretreated with a topical retinoid for

Chapter 78 :: Acne Vulgaris

ing a course of therapy.170 This dosing regimen is of 3 to 4 weeks. Acne surgery should not be performed
particular use in patients who have variable dosages at home because inaccurate placement of the com-
or interrupted periods of treatment because achiev- edo extractor may rupture the follicle and incite an
ing the total dose will ensure the greatest chance inflammatory reaction. The Unna type of comedo
of long-term remission. Because back and chest extractor, which has a broad flat plate and no narrow
lesions show less of a response than facial lesions, sharp edges, is preferable. The removal of open com-
dosages as high as 2 mg/kg/day may be necessary edones is desirable for cosmetic purposes but does
in patients who have very severe truncal involve- not significantly influence the course of the disease.
ment. Patients with severe acne, particularly those In contrast, closed comedones should be removed
with granulomatous lesions, often develop marked to prevent their rupture. Unfortunately, the orifice
flares of their disease when isotretinoin is started. of closed comedones is often very small, and usu-
Therefore, the initial dosing should be low, even ally the material contained within the comedo can
below 0.5 mg/kg/day. These patients often need be removed only after the orifice is gently enlarged
pretreatment for 1 to 2 weeks with prednisone with a 25- or 30-gauge needle, lancet, or other suitable
(40–60 mg/day), which may have to be continued sharply pointed instrument. Cotton-tipped applica-
for the first 2 weeks of therapy. A typical course of tors are also useful to gently extract follicular content
isotretinoin is 20 weeks, but the length of the course after the orifice is opened.
of treatment is not absolute; in patients who have
not shown an adequate response, therapy can be
extended. Additional improvement may be seen for SUBCISION
1 to 2 months after discontinuation, so that com-
plete clearance may not be a necessary endpoint for Subcision is a minor surgical procedure used for treat-
determining when to discontinue therapy. Low-dose ment of depressed scars and is most effective for roll-
regimens, 0.1 to 0.4 mg/kg/day, have shown effi- ing acne scars (distensible, depressed scars with gentle
cacy. However, with such dosages, the incidence of sloping edges). This method involves the use of a small
relapses after therapy is greater. Approximately 10% hypodermic needle that is inserted into the periphery
of patients treated with isotretinoin require a second of a scar with the sharp edges maneuvered under the
course of the drug. The likelihood for repeat therapy defect to loosen the fibrotic adhesions, which results
is increased in patients younger than 16 to 17 years in release of the tethered scar to the underlying subcu-
of age. It is standard practice to allow at least 2 to taneous tissue and collagen formation during wound
3 months between courses of isotretinoin. healing. Subcision has a reported success rate of 50%
in the treatment of rolling scars.174

DIET INTRALESIONAL INJECTION OF

CORTICOSTEROIDS
Several articles suggesting a role for diet in acne
exist.171,172 A recent review of these studies concluded Intralesional injection of corticosteroids can dramati-
that there may be some link between milk and acne cally decrease the size of deep nodular lesions. The
as well as between high-glycemic index foods and injection of 0.05 to 0.25 mL per lesion of a triamcino-
acne.173 Yet overall, the implications of these studies are lone acetonide suspension (2.5–10 mg/mL) is recom-
not clear, and the role of chocolate, sweets, milk, high- mended as the antiinflammatory agent. This is a very
glycemic index foods, and fatty foods in patients with useful form of therapy in patients with nodular acne
acne requires further study. There is no evidence to or for particularly persistent nodular lesions. A major
support the value of elimination of these foods. How- advantage is that it can be done without incising or
ever, restricting a food firmly thought by the patient draining the lesions, thus avoiding the possibility of
to be a trigger is not harmful as long as the patient’s scar formation. Hypopigmentation, particularly in 1409
nutritional well-being is not compromised. darker-skinned patients, and atrophy are risks.

Kang_CH078_p1391-1418.indd 1409 07/12/18 4:23 pm

14 CHEMICAL PEELS enhanced, narrowband (407–420 nm) blue light known
as ClearLight (Lumenis) is currently FDA approved
Superficial chemical peels can be performed as an for the treatment of moderate inflammatory acne.187
adjuvant to the pharmacologic treatment of facial Red light may also be beneficial because it penetrates
acne or in patients with contraindications for other deeper into the dermis and has greater antiinflamma-
treatment modalities (eg, pregnancy). Superficial tory properties but causes less photoactivation of the
peels aim to remove the stratum corneum, enhancing porphyrins. Therefore, the combination of blue and
physiologic cell turnover.175 The most common peel- red light may prove the most beneficial. Treatments
ing agents for use in acne are the α-hydroxy acids should be given twice weekly for 15-minute sessions
such as glycolic acid and trichloroacetic acid (TCA), for the face alone and 45 minutes for the face, chest,
β-hydroxy acid such as salicylic acid, and combina- and back. A multicenter study has shown that 80% of
tion peels including Jessner solution. Glycolic acid patients treated with the ClearLight for 4 weeks had
reduces hyperkeratinization by decreasing cohesion a 60% reduction in acne lesions. There was a gradual
of corneocytes at low concentrations and promoting return of lesions over 3 to 6 months.190
Part 14

desquamation and epidermolysis at higher concen- The most consistent improvement in acne after light
trations,176 with one study of 80 patients reporting treatment has been demonstrated with photodynamic
glycolic acid peels effective at improving comedonal, therapy.191 Photodynamic therapy involves the topical
papulopustular, and nodulocystic acne variants.177 application of aminolevulinic acid (ALA) 1 hour before
::

Salicylic acid is a lipophilic agent that also decreases exposure to a low-power light source. These sources
Acneiform Disorders

corneocyte cohesion and promotes desquamation of include the pulsed-dye laser, intense pulsed light, or a
the stratum corneum. Whereas low concentrations broadband red light source. The topical ALA is taken
of salicylic acid are found in daily acne cleansers, up by the pilosebaceous unit and metabolized to proto-
concentrations of 20% to 30% are typically used for porphyrin IX.192 The protoporphyrin IX is targeted by
superficial peels, and similar to glycolic acid, have the light and produces singlet oxygen species, which
been reported to reduce the number of inflamma- then damage the sebaceous glands.193 Several studies
tory and noninflammatory acne lesions.178 The most using ALA-PDT maintained clinical improvement for
common side effects of chemical peels include ery- up to 20 weeks.194,195
thema, xerosis, exfoliation, burning, and increase in Although lasers are beginning to find a role in the
photosensitivity. treatment of acne, the authors consider them inferior
to the traditional medical treatments. They work by
emitting minimally divergent, coherent light that can
PHOTOTHERAPY AND LASERS be focused over a small area of tissue. The pulsed KTP
laser (532 nm) has demonstrated a 35.9% decrease in
Various forms of phototherapy are under investiga- acne lesions when used twice weekly for 2 weeks.
tion for their use in treating acne vulgaris.179 Ultravio- Although there was no significant decrease in P. acnes,
let (UV) light has long been thought to be beneficial there was significantly lower sebum production even
in the treatment of acne. Up to 70% of patients report at 1 month.196 The pulsed-dye laser (585 nm) can
that sun exposure improves their acne.180 This reported also be used at lower fluences to treat acne. Instead
benefit may be attributable to camouflage by UV radi- of ablating blood vessels and causing purpura, a
ation–induced erythema and pigmentation, although lower fluence can stimulate procollagen production
it is likely that the sunlight has a biologic effect on the by heating dermal perivascular tissue.193 The benefi-
pilosebaceous unit and P. acnes. Although UVB can cial effects of a single treatment can last 12 weeks.197
also kill P. acnes in vitro, UVB penetrates poorly to the Some of the nonablative infrared lasers, such as the
dermal follicle, and only high doses causing sunburn 1450- and 1320-nm laser, have shown to be helpful
have be shown to improve acne.181,182 UV radiation in improving acne.198,199 These lasers work by causing
may have antiinflammatory effects by inhibiting cyto- thermal damage to the sebaceous glands. The concur-
kine action.183 Twice-weekly phototherapy sessions are rent use of a cryogen spray device protects the epider-
needed for any clinical improvement. The therapeutic mis while the laser causes necrosis of the sebaceous
utility of UV radiation in acne is superseded by its car- gland.200 In a pilot study, 14 of 15 patients treated
cinogenic potential.179,184-187 with the 1450-nm laser had a significant reduction in
Other types of phototherapy for acne treatment inflammatory lesions that persisted for 6 months. The
use porphyrins. Treatment of acne with phototherapy 1320-nm Nd:YAG (neodymium-doped yttrium alu-
works either by activating the endogenous porphyrins minum garnet) and the 1540 erbium glass lasers have
of P. acnes or by applying exogenous porphyrins. Cop- also been demonstrated to improve acne.201 Multiple
roporphyrin III is the major endogenous porphyrin treatments are needed with either of these lasers to
of P. acnes. Coproporphyrin III can absorb light at the lessen acne lesions. These treatments tend to be pain-
near-UV and blue light spectrum of 415 nm.188 Irradia- ful and show a gradual modest improvement, limit-
tion of P. acnes with blue light leads to photoexcitation ing their utility.
of endogenous bacterial porphyrins, singlet oxygen One of the newer uses of light for treating acne is
production, and subsequent bacterial destruction.189 A with a photopneumatic device (Isolaz, Solta Medical).
1410 visible light source—blue, red, or both—may be used to This photopneumatic device has a handpiece that
excite the endogenous porphyrins. The high-intensity, applies negative pressure (ie, suction) to the skin and

Kang_CH078_p1391-1418.indd 1410 07/12/18 4:23 pm

 then delivers a broadband-pulsed light (400–1200 nm).
The suction is used to unplug the infundibulum of
better safety profile in treating acne scars, particu-
larly in darker skin types population (Fitzpatrick
14
the pilosebaceous unit, and the light is delivered to skin types IV–VI), compared with more conven-
activate the P. acnes porphyrins, thus releasing sin- tional resurfacing modalities.216 It has been shown
glet oxygen species. Patients treated with this device that microneedling can be combined with various
may experience some posttreatment erythema or adjuvant treatments, including platelet-rich plasma,
purpura. Results are modest and temporary, and the vitamin C, and glycolic acid, to enhance the clinical
device is best for inflammatory lesions.202,203 Although improvement of atrophic acne scars.217,218
the light-based treatments are beneficial in that they
avoid some of the side effects of the oral medications,
the cost of these light and laser treatments tends to be FILLERS
prohibitive. The injection of dermal fillers to improve acne scars
Lasers, however, can be useful for the treatment of is based on soft tissue augmentation. Hyaluronic acid
acne scars.204 Pulsed-dye lasers help improve persis- fillers are nonpermanent fillers that stimulate collagen

Chapter 78 :: Acne Vulgaris

tent erythema from acne lesions and atrophic scars. production and are a safe and effective treatment for
Fractional photothermolysis lasers are approved for acne scars including atrophic scars. A stronger stimu-
the treatment of acne scars by the FDA, and stud- lation of collagen production is seen with semiperma-
ies support improvement of various acne scars. The nent or biostimulatory fillers, such as poly-L-lactic acid
use of 1550-nm fractional photothermolysis two to (PLL) and calcium hydroxylapatite, and permanent
six times in a 1-month interval showed the majority fillers.219,220
of patients achieving a 50% to 75% improvement in Acne scars can be permanent and have a long-
facial and back acne scarring, and some patients had lasting impact on patients who have acne, even after
greater than 75% in acne scarring. No adverse effects active lesions resolve. In general, multiple and combi-
were found including in patients with Fitzpatrick nation treatments using various available modalities
Skin types III to V.205 Another study showed a clinical can improve acne scars and address patients’ physical
improvement averaged 51% to 75% in nearly 90% of and psychological concerns.
patients after three monthly laser treatments,206 and a
long-term improvement can be seen.207 Ablative CO2
and fractional CO2 lasers have also been shown to
improve acne scars,208 but adverse effects can be more
common and should be used with caution, particu-
ACNE THERAPY IN
larly in darker skin types. PREGNANCY
Acne vulgaris is a common problem encountered by
DERMABRASION pregnant and lactating women. During pregnancy,
acne may worsen as a result of a rise in serum mater-
Dermabrasions are used less now since the develop-
nal androgen levels. Inflammatory lesions tend to be
ment of new lasers, lights, and other devices. Derm-
more common than noninflammatory lesions, often
abrasion is useful in treating larger atrophic scars,209,210
with involvement of the trunk. Patients with a his-
but because physical removal of uninvolved skin must
tory of acne are more prone to developing acne during
occur to reach the deeper scarred areas, this treat-
pregnancy.221 Because pregnant or lactating women are
ment is less favored given the prolonged recovery and
often excluded from clinical trials, current evidence is
increase in risk of complications. In particular, there
limited to animal studies, retrospective studies, and
is a greater chance of discoloration of skin in darker-
case reports. As a general rule, topical agents are
skinned patients (Fitzpatrick types IV–VI). Micro-
safer than oral medications for use during pregnancy
dermabrasion, however, has fewer adverse effects and
and lactation because systemic absorption is lower.222
can be used safely in most patients.211
Listed in Table 78-5 is a summary of common acne
medications used and their safety in pregnancy. Of
MICRONEEDLING note, although benzoyl peroxide and salicylic acid are
considered Pregnancy Category C, recent changes in
Nonablative radiofrequency microneedling is a pregnancy labeling of drugs suggest that more topi-
relatively novel technique for the treatment of both cal medications may be used during pregnancy, and
inflammatory acne lesions and acne scars. Micronee- although inadequate human data may be available, the
dling is a minimally invasive procedure that uses fine risk of fetal harm is not expected based on expected
needles to puncture the epidermis. The mechanism of limited systemic absorption. No reports of teratogenic-
action is primarily by reduction of sebaceous gland ity have been associated with either medication. For
activity and remodeling of dermis through ther- the retinoids, adapalene is categorized as “may use
mal stimulation.212,213 The microwounds created also during pregnancy,” but tretinoin is “consider avoiding
stimulate the release of growth factors and induce use during pregnancy,” and tazarotene is “use alterna-
collagen production.214,215 The epidermis remains rela- tive during pregnancy” (Epocrates [2016], Dx version
tively intact, therefore healing quickly and helping 16.11 [mobile application software]). Safety in lactation 1411
to limit adverse events. It has been shown to have a may be different from that in pregnancy. For example,

Kang_CH078_p1391-1418.indd 1411 07/12/18 4:23 pm

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Part 14

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::

New Progestins. Obstet Gynecol. 1993;81:1034-1047. isotretinoin. J Am Acad Dermatol. 2001;45:515-519.

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14
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Chapter 78 :: Acne Vulgaris

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Z Naturforsch C. 1987;42:123-128.

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14 213. Lee SJ, Goo JW, Shin J, et al. Use of fractionated
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microneedling with distilled water in the treatment
Part 14
::
Acneiform Disorders

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