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ADNEXAL DISEASES SECTION 6

Acne Vulgaris
Andrea L Zaenglein and Diane M Thiboutot
36
vital to understanding the pathogenesis of acne (Fig. 36.1) and essential
Synonym: Acne for formulating effective treatment regimens. The structure and func-
tion of sebaceous glands are reviewed in detail in Chapter 35, and Table
35.4 summarizes their roles in acne.

Key features Genetic Factors


A multifactorial disorder of the pilosebaceous unit The pathogenesis of acne is multifactorial, and the precise role of
Significant psychologic and economic impact genetic predisposition is uncertain. The number, size and activity of
sebaceous glands is inherited. In addition, the concordance rate for the
Clinically characterized by comedones, papules, pustules, cysts and
prevalence and severity of acne among identical twins is extremely
scarring
high. It is a widely held belief that acne (including nodulocystic acne)
runs in families, and an association between moderate to severe acne
and a family history of acne has been observed in several studies5.
INTRODUCTION However, because of the extremely high prevalence of acne, it is difficult
to attribute its presence exclusively to genetic factors.
Acne vulgaris is a multifactorial disorder of the pilosebaceous unit. The
clinical picture can vary significantly, from mild comedonal acne to Sebum Production
fulminant systemic disease. Although all age groups may be affected by
The sebaceous gland is controlled primarily by hormonal stimulation
its many variants, acne is primarily a disorder of adolescence. Acne has
(see below). After the first 6 months of life (when sebum production is
an undeniable psychosocial impact, and affected individuals have an
relatively high), the rate decreases and remains stable throughout child-
increased likelihood of self-consciousness, social isolation, depression
hood. At adrenarche, sebum production dramatically increases.
and even suicidal ideation1. Recent insights into the pathogenesis of
Although the overall composition of sebum is the same in persons with
acne have aided significantly in further defining the subtypes of acne
or without acne, those with acne have variable seborrhea6.
and establishing effective treatment regimens.
Comedo Formation
HISTORY One of the first steps in the production of acne is the formation of the
microcomedo. This begins in the keratinized lining of the upper portion
In the sixth century AD, the term acne was first used by the Emperor
of the follicle, the infundibulum (Fig. 36.1A). Comedo formation occurs
Justinians physician, Aetius Amidenus. It was later translated from
when the corneocytes, which are normally shed into the lumen of the
Greek into Latin, and through these translations confusion arose
follicle and extruded through the follicular ostium, are retained and
regarding its original meaning2. The debate continues as to whether its
accumulate, leading to hyperkeratosis. Increased cohesiveness of these
origin is from the Greek acme, meaning peak, or whether acne was
cells is responsible for this phenomenon. The ultrastructural compo-
actually the original term. Its use became obsolete until the 1800s,
nents of the cell that are responsible for adhesiveness all play a role,
when acne regained a place in medical dictionaries. In 1842, Erasmus
including lamellar granules, cell membranes, epidermal lipids, and
Wilson separated acne simplex (acne vulgaris) from acne rosacea3.
intercellular cementing substances.
In addition to increased intercellular cohesiveness of the corneocytes,
EPIDEMIOLOGY their production is accelerated as well. This combination of increased
cellular cohesion and proliferation occurs in the proximal portion of
Acne vulgaris affects approximately 4050 million individuals each year the infundibulum, the infrainfundibulum, and it creates a bottleneck
in the US alone, leading to an estimated annual cost in the US of at phenomenon and subsequent microcomedo formation. In the underly-
least $2.5 billion. With a peak incidence during adolescence, acne ing follicular epithelium, keratohyaline granules are increased in size
affects approximately 85% of young people between 12 and 24 years of and number, whereas lamellar granules and tonofilaments are decreased.
age and is therefore a physiologic occurrence in this group. Although As the comedo expands, the sebaceous lobule undergoes regression
it is typically thought of as a disease of youth, acne often continues to (Fig. 36.1B,C). Because of the very narrow opening to the skin surface,
be problematic well into adulthood. In a recent survey-based study, 35% there is initially an accumulation of loosely packed shed keratinocytes
of women and 20% of men reported having acne in their 30s, while and sebum. With expansion of the comedo, the contents become closely
26% of women and 12% of men were still affected in their 40s4. Cau- packed, creating whorled lamellar concretions. As the forces increase,
casian boys and men have a tendency to have more severe nodulocystic rupture of the comedo wall with extrusion of the immunogenic keratin
disease than other groups. and sebum occurs, with resultant inflammation (Fig. 36.1C,D).
Individuals at increased risk for the development of acne include
those with an XYY karyotype or endocrine disorders such as polycystic Inflammatory Responses
ovarian syndrome, hyperandrogenism, hypercortisolism and precocious
Inflammation is not only the result of comedo rupture, as it is also
puberty. Patients with these conditions tend to have more severe acne
seen early in acne lesion formation. For example, in acne-prone sites,
that is less responsive to standard therapy.
the number of CD4+ T cells and levels of interleukin-1 (IL-1) have been
shown to be increased perifollicularly prior to hyperkeratinization7. The
type of inflammatory response determines the clinical lesion seen. If
PATHOGENESIS neutrophils predominate (typical of early lesions), a suppurative pustule
The development of acne involves a complex interaction of multiple is formed. Neutrophils also promote the inflammatory response by
factors, both internal and external to the pilosebaceous apparatus. releasing lysosomal enzymes and generating reactive oxygen species,
and levels of the latter in the skin and plasma may correspond with
545
Appreciating the anatomy and physiology of this unique structure is
SECTION

6 PATHOGENESIS OF ACNE
adnexal diseases

A B C D

Epidermis

Sebaceous
lobule

Follicular
epithelium

Early comedo Later comedo Inflammatory papule/pustule Nodule/cyst


Infundibulum Accumulation of shed keratin Propionibacterium acnes Marked inflammation
hyperkeratosis and sebum proliferation Scarring
corneocyte cohesiveness Formation of whorled lamellar Sebaceous lobule regression
Androgen stimulation concretions Mild inflammation
of sebum secretion Corneocyte
Sebum
P. acnes

Fig. 36.1 Pathogenesis of acne.

acne severity8. Influx of lymphocytes (predominately T-helper [Th] whereas IL-12 promotes Th1 responses (see Ch. 4). The degree to
cells) and foreign body-type giant cells, in addition to neutrophils, which IL-8, IL-12 and interferon- production is augmented does not
results in inflamed papules, nodules and cysts. The type of inflamma- appear to depend upon the strain of P. acnes that is present14,15.
tory response also plays a role in the development of scarring. Early, In contrast, certain strains of P. acnes may have an increased propen-
nonspecific inflammation results in less scarring than does a delayed, sity to upregulate expression of human -defensin-2 by the piloseba-
specific inflammatory response9. ceous unit via a TLR-dependent mechanism14,16. Beta-defensin-2
(production of which is also augmented by sebum free fatty acids),
Propionibacterium acnes and the Innate cathelicidins (expressed by sebocytes with upregulation by P. acnes),
and other antimicrobial peptides such as psoriasin (see Ch. 4) work
Immune System synergistically to protect the pilosebaceous unit from P. acnes17,18.
Propionibacterium acnes contributes significantly to the pathogenesis Histone H4, which is secreted in a holocrine manner by sebocytes, also
of acne. These Gram-positive, non-motile rods are found deep within directly kills P. acnes and may function together with free fatty acids
the sebaceous follicle, along with P. granulosum and, rarely, P. parvum. to augment innate immune defenses19. Lastly, P. acnes can induce
They are anaerobic/microaerophilic and naturally produce porphyrins monocytes to differentiate into two distinct innate immune cell subsets:
(primarily coproporphyrin III) that fluoresce with Woods lamp illumi- (1) CD209+ macrophages (development of which is promoted by tretin-
nation. The pathogenicity of these microorganisms stems from several oin) that more effectively phagocytose and kill P. acnes; and (2) CD1b+
of their properties, including the release of enzymes that contribute to dendritic cells that activate T cells and release proinflammatory
comedo rupture, lipases and chemotactic factors, as well as stimulation cytokines20.
of a host response (by inflammatory cells and keratinocytes) that
involves production of proinflammatory mediators and reactive oxygen Hormonal Influences
species. Increased numbers of P. acnes have been reported in acne Hormonal effects on sebum secretion are key to the pathogenesis of
patients, but their numbers do not correlate with clinical severity10. acne. Androgens are produced both outside the sebaceous unit,
Different strains of P. acnes have been shown to induce varying degrees primarily from the gonads and adrenal glands, and locally within the
of sebocyte differentiation and proinflammatory cytokine/chemokine gland via the action of androgen-metabolizing enzymes such as
reponses11. 3-hydroxysteroid dehydrogenase (HSD), 17-HSD and 5-reductase
Interactions between the skins innate immune system and P. acnes (Fig. 36.2). Androgen receptors, found in the cells of the basal layer of
play an important role in acne pathogenesis. One mechanism is via the sebaceous gland and the outer root sheath of the hair follicle, are
Toll-like receptors (TLRs), a class of transmembrane receptors that responsive to testosterone and 5-dihydrotestosterone (DHT), the
mediates the recognition of microbial pathogens by immune cells such most potent androgens. DHT has a 510-fold greater affinity than
as monocytes, macrophages and neutrophils as well as by keratinocytes testosterone for the androgen receptor and is thought to be the principal
(see Ch. 4). TLR2 (which recognizes lipoproteins and peptidoglycans) androgen mediating sebum production.
is found on the surface of macrophages surrounding acne follicles, and The role of androgens in sebaceous gland activity begins during the
P. acnes has been found to increase expression of TLR2 and TLR4 on neonatal period. From birth until approximately 612 months of age,
keratinocytes. P. acnes has been shown to stimulate the release of infant boys have elevated levels of luteinizing hormone (LH), which
proinflammatory mediators (e.g. IL-1, IL-8, IL-12, tumor necrosis stimulates testicular production of testosterone. In addition, both male
factor- [TNF-], matrix metalloproteinases) through the TLR2 and female infants exhibit increased levels of dehydroepiandrosterone
pathway1214. IL-8 results in neutrophil recruitment, the release of lyso- (DHEA) and DHEA sulfate (DHEAS) secondary to a large, androgen-
546 somal enzymes and subsequent disruption of the follicular epithelium, producing fetal zone in the adrenal gland that involutes over the first
CHAPTER

PATHWAYS OF C19 STEROID METABOLISM 36

Acne Vulgaris
3b-HSD
DHEA Androstenedione

Aromatase 17b-HSD
Estrone

Testosterone
17b-HSD
Aromatase 5a-reductase

Estradiol Dihydrotestosterone
Androstanediols
(DHT) 3b- and
3a-HSDs

Fig. 36.2 Pathways of C19 steroid metabolism. Dehydroepiandrosterone


(DHEA) is a weak androgen that is converted to the more potent testosterone
by 3-hydroxysteroid dehydrogenase (HSD) and 17-HSD. 5-reductase then
Fig. 36.3 Comedonal acne vulgaris. On the cheek, there are open and closed
converts testosterone to dihydrotestosterone (DHT), the predominant
comedones as well as postinflammatory hyperpigmentation.
hormonal effector on the sebaceous gland. Both DHEA and testosterone can
be metabolized to estrogens by the enzyme aromatase. The sebaceous gland
expresses each of these enzymes.

year of life. Of note, sebaceous gland activity in infants is not due to Fig. 36.4 Closed
persistent maternal hormonal stimulation, as was previously hypo comedones highlighted
thesized. Both testicular and adrenal androgen production decrease by side lighting. Courtesy,
substantially by 1 year of age and remain at a stable nadir until Ronald P Rapini, MD.
adrenarche.
With the onset of adrenarche (typically at 78 years of age, usually
heralding menarche by several years), circulating levels of DHEAS begin
to rise due to adrenal production. This hormone can serve as a precur-
sor for the synthesis of more potent androgens within the sebaceous
gland (see Fig. 36.2). The rise in serum levels of DHEAS in prepubesc
ent children is associated with an increase in sebum production and
the initial development of comedonal acne21.
Little is known about the physiologic role of estrogens in modulating
sebum production. Any estrogen given systemically in sufficient
amounts will decrease sebum production. However, the dose of estrogen
required to suppress sebum production is greater than the dose required
to suppress ovulation. Although acne may respond to treatment with
lower-dose oral contraceptives containing 0.0350.050mg of ethinyl
estradiol or its esters, higher doses of estrogen are often required to
demonstrate a reduction in sebum secretion22. As with androgens, it is
not known whether circulating estrogens or locally produced estrogens
are important in modulating sebum secretion. Estrogens may act by
several mechanisms, including: (~1mm), skin-colored papules with no apparent follicular opening or
l directly opposing the effects of androgens locally within the associated erythema. These lesions may be subtle and better appreci-
sebaceous gland ated upon palpation, stretching or side-lighting of the skin (Fig. 36.4).
l inhibiting the production of androgens by gonadal tissue via a In contrast, open comedones (blackheads) are dome-shaped papules
negative feedback loop whereby pituitary gonadotropin release is with a conspicuous dilated follicular opening that is filled with an
inhibited inspissated core of shed keratin (Fig. 36.5). Melanin deposition and
l regulating genes that negatively influence sebaceous gland growth lipid oxidation within the debris may be responsible for the black
or lipid production. coloration. Ice-pick-type scarring sometimes results from comedones
alone.
Dietary Factors Inflammatory acne also originates with (micro)comedo formation,
followed by the development of papules, pustules, nodules and cysts of
The relationship between diet and acne remains a subject of contro- varying severity (Figs 36.6 & 36.7). Erythematous papules typically
versy. Over the past decade, observational studies have found that milk range from 1 to 5mm in diameter. Pustules tend to be approximately
intake (especially skim milk) is positively associated with acne preva- equal in size and are filled with white pus and normal flora. As the
lence and severity, and prospective studies have documented a link severity of lesions progresses, nodules form and become markedly
between a high glycemic-load diet and acne risk23. inflamed, indurated and tender. The cysts of acne are deeper and filled
with a combination of pus and serosanguineous fluid. In patients with
CLINICAL FEATURES severe nodulocystic acne, these lesions frequently coalesce to form
large, complex inflamed plaques that can include sinus tracts.
Acne is typically found in sites with well-developed sebaceous glands, Early treatment of acne is essential for the prevention of lasting cos-
most often the face and upper trunk. Non-inflammatory acne is char- metic disfigurement due to scarring. Erythema and postinflammatory
acterized by open and closed comedones (Fig. 36.3). The histologic hyperpigmentation (Fig. 36.8) often persist after resolution of inflam-
features of these follicular-based lesions are reflected in their clinical matory acne lesions. Although the pigmentary changes usually fade 547
appearance. Closed comedones (whiteheads) are generally small over many months if the acne is brought under control, occasionally
SECTION

6
Fig. 36.7 Severe cystic
acne. This form is best
treated with low doses of
adnexal diseases

isotretinoin initially, to
avoid precipitating a
flare.

Fig. 36.5 Open comedones in a patient with scarring cystic acne.

Fig. 36.8
Postinflammatory
hyperpigmentation
secondary to acne. Such
pigmentary changes
are most common in
patients with darker skin
colors.

Fig. 36.6 Inflammatory acne vulgaris. Papules, obvious pustules, and atrophic
scars are present.

they can be permanent. Unfortunately, pitted scars (Fig. 36.9) or hyper-


trophic scars (most commonly on the trunk; see Fig. 98.5) are often
sequelae of nodulocystic acne.

Acne Variants
Post-adolescent acne
Inflammatory acne persisting beyond 25 years of age is most common
in women, tends to flare during the week prior to menstruation, and
typically features tender, deep-seated papulonodules on the lower third
of the face, jawline and neck24. Approximately one-third of affected
women have other signs of hyperandrogenism (see below), but regard-
less of androgen levels, hormonal therapy is often effective. A predomi-
nantly comedonal, adult-onset form of acne that is associated with Fig. 36.9 Ice-pick scarring secondary to acne.
smoking has also been described24.

Acne fulminans
Acne fulminans is the most severe form of acne and is characterized Osteolytic bone lesions may accompany the cutaneous findings; the
by the abrupt development of nodular and suppurative acne lesions in clavicle and sternum are most commonly affected, followed by the
association with systemic manifestations. This uncommon variant ankles, humerus and iliosacral joints. Systemic manifestations include
primarily affects boys 1316 years of age. Patients typically have mild fever, arthralgias, myalgias, hepatosplenomegaly and severe malaise.
to moderate acne prior to the onset of acne fulminans, when numerous The related synovitis, acne, pustulosis, hyperostosis and osteitis
microcomedones suddenly erupt and become markedly inflamed. There (SAPHO) syndrome, which can present with acne fulminans, is dis-
is rapid coalescence into painful, oozing, friable plaques with hemor- cussed in detail in Chapter 26. Erythema nodosum may also arise in
548 rhagic crusts (Fig. 36.10). The face, neck, chest, back and arms are all association with acne fulminans. Laboratory abnormalities vary and
affected. Lesions tend to ulcerate and can lead to significant scarring. include an elevated ESR, proteinuria, leukocytosis and anemia. Labora-
CHAPTER

36
Fig. 36.10 Acne
fulminans. Inflamed,
friable papulopustules

Acne Vulgaris
and plaques with
erosions, oozing and
formation of granulation
tissue. Courtesy, Julie V
Schaffer, MD.

Fig. 36.11 Solid facial edema due to acne vulgaris. There is soft tissue
swelling in the central portion of the face.

tory studies are not required to establish the diagnosis, but their evolu- fluctuations in severity are common, solid facial edema does not usually
tion may parallel the clinical course and response to therapy. resolve spontaneously. Treatment with isotretinoin (0.21mg/kg/day),
Treatment of acne fulminans usually includes oral corticosteroids and alone or in combination with ketotifen (12mg/day; not available in
oral isotretinoin, often with initiation of the latter at a low dose and/ the US) or prednisone (1030mg/day), for 45 months has been
or after the acute inflammation subsides. Paradoxically, an acne reported to be useful28,29.
fulminans-like flare occasionally develops during the first few weeks of
isotretinoin therapy for acne25, and this may be avoided by starting with Acne mechanica
a low dose of isotretinoin (see Ch. 126). Additional treatment options
Acne mechanica occurs secondary to repeated mechanical and frictional
for acne fulminans include topical or intralesional corticosteroids, oral
obstruction of the pilosebaceous outlet. Comedo formation is the
antibiotics (generally of limited efficacy), TNF- inhibitors and immuno
result. Well-described mechanical factors include rubbing by helmets,
suppressive agents (e.g. azathioprine). Dapsone may be particularly
chin straps, suspenders and collars. A classic example of acne mechanica
beneficial in the treatment of acne fulminans associated with erythema
is fiddlers neck, where repetitive trauma from violin placement on the
nodosum26.
lateral neck results in a well-defined lichenified, hyperpigmented plaque
interspersed with comedones. Linear and geometrically distributed
Acne conglobata and associated conditions areas of involvement should suggest acne mechanica. Treatment is
Acne conglobata is a severe form of nodulocystic acne that may have aimed at eliminating the inciting forces.
an eruptive onset but without systemic manifestations. This recalci-
trant acne variant is part of the follicular occlusion tetrad, along with Acne excorie des jeunes filles
dissecting cellulitis of the scalp, hidradenitis suppurativa and pilonidal
cysts (see Ch. 38). Acne excorie des jeunes filles, as the name implies, occurs primarily
The association of sterile pyogenic arthritis, pyoderma gangrenosum, in young women. Typical comedones and inflammatory papules are
and acne conglobata can occur in the context of an autosomal dominant systematically excoriated in a ritualistic manner, leaving crusted
autoinflammatory disorder referred to as PAPA syndrome, which is erosions that may scar (see Ch. 7). Linear erosions suggest self-
caused by mutations in the gene that encodes prolineserinethreonine manipulation, and an underlying psychiatric component should be
phosphatase interacting protein 1 (PSTPIP1; also known as CD2 considered. Individuals with an anxiety disorder, obsessivecompulsive
antigen-binding protein 1 [CD2BP1])27. Dysfunction of CD2BP1, which disorder or personality disorder are particularly at risk. Antidepressants
has a role in actin reorganization and interacts with the pyrin protein or psychotherapy may be indicated in such patients.
(defective in familial Mediterranean fever), compromises the physio-
logic signaling required for maintenance of a proper inflammatory Drug-induced acne
response. The triad of acne conglobata, hidradenitis suppurativa and Acne or eruptive acneiform lesions can be seen as a side effect of a
pyoderma gangrenosum has also been described outside the setting of number of medications (Table 36.1). An abrupt, monomorphous erup-
PAPA syndrome27a. Of note, a possible association between nodulo- tion of inflammatory papules and pustules is often observed in drug-
cystic acne and inflammatory bowel disease may potentially confound induced acne (Figs 36.12 & 36.13), in contrast to the heterogeneous
links that have been observed between the latter disorder and acne morphology of lesions seen in acne vulgaris. This explains why some
therapies such as tetracyclines and isotretinoin27,27b. clinicians use the term folliculitis.
High-dose intravenous or oral corticosteroids commonly induce char-
Solid facial edema acteristic acneiform eruptions with a concentration of lesions on the
An unusual and disfiguring complication of acne vulgaris is solid facial chest and back (see Fig. 36.12). Steroid-induced acne (and rosacea) can
edema (Morbihans disease). Clinically, there is a distortion of the also result from the inappropriate use of topical corticosteroids on the
midline face and cheeks due to soft tissue swelling (Fig. 36.11). face. Inflamed papules and pustules develop on a background of ery-
The woody induration may be accompanied by erythema. Impaired thema that favors the distribution of corticosteroid application. Lesions
lymphatic drainage and fibrosis (potentially induced by mast cells) in eventually resolve following discontinuation of the corticosteroid,
the setting of chronic inflammation are thought to be involved in the although steroid dependency can lead to prolonged and severe flares
pathogenesis of solid facial edema, and a report of its occurrence in post-withdrawal (see Ch. 37). When a history of prescription medica-
identical twins with acne suggests that genetic factors may also have tion use is not elicited, a comprehensive review of all over-the-counter
a role. Similar changes have been described in patients with rosacea medications and supplements, as well as recent medical procedures, 549
and MelkerssonRosenthal syndrome (see Table 36.2). Although may reveal the responsible agent (see Table 36.1).
SECTION
Occupational acne, acne cosmetica and pomade acne
6 CAUSES OF DRUG-INDUCED ACNE
Exposure to insoluble, follicle-occluding substances in the workplace is
Common Uncommon responsible for occupational acne (see Ch. 16). Offending agents
adnexal diseases

include cutting oils, petroleum-based products, chlorinated aromatic


Anabolic steroids (danazol, testosterone) Azathioprine
hydrocarbons, and coal tar derivatives. Comedones dominate the clini-
Bromides* Cyclosporine
Corticosteroids (see Fig. 36.12) Disulfiram
cal picture, with varying numbers of papules, pustules and cystic
Corticotropin Phenobarbital lesions distributed in exposed as well as typically covered areas. Prima-
EGFR inhibitors (see Fig. 36.16) Propylthiouracil rily comedonal facial acne (with a predominance of closed comedones)
Iodides Psoralen + ultraviolet A can also develop in areas of skin chronically exposed to follicle-
Isoniazid (see Fig. 36.13) IQuinidine occluding cosmetics (acne cosmetica) or hair products (pomade acne;
Lithium Vitamins B6 and B12 favors forehead and temples).
Phenytoin
Progestins (see text) Chloracne
*Found in sedatives, analgesics and cold remedies.
Chloracne, the term used to define occupational acne caused by expo-
Found in contrast dyes, cold/asthma remedies, kelp and combined vitaminmineral
supplements. sure to chlorinated aromatic hydrocarbons, develops after several weeks
of exposure. The malar, retroauricular and mandibular regions of the
Table 36.1 Causes of drug-induced acne. EGFR, epidermal growth factor head and neck (see Fig 16.13), as well as the axillae and scrotum, are
receptor. most commonly afflicted with small cystic papules and nodules. The
extremities, buttocks and trunk are variably involved. Cystic lesions
can heal with significant scarring, and recurrent outbreaks may occur
for many years following exposure. The following agents, found in
electrical conductors and insulators, insecticides, fungicides, herbicides
and wood preservatives, have all been implicated: polychlorinated
naphthalenes, biphenyls, dibenzofurans and dibenzodioxins; polybro-
minated naphthalenes and biphenyls; tetrachloroazobenzene; and
tetrachloroazoxybenzene.
Prevention of exposure is integral to the safety of at-risk employees.
Initial management is aimed at vigorous removal of chemical agents at
the time of exposure. Topical or oral retinoids and oral antibiotics may
be beneficial therapeutic interventions.

Neonatal acne (neonatal cephalic pustulosis)


Neonatal acne occurs in more than 20% of healthy newborns (see Ch.
34). Lesions usually appear at about 2 weeks of age and generally resolve
within the first 3 months of life. Small, inflamed papulopustules (but
typically not comedones) arise primarily on the cheeks and nasal bridge,
but the forehead, chin, neck and upper trunk can also be involved (see
Fig. 34.5).
The pathogenesis of neonatal acne has been the subject of debate.
An inflammatory response to Malassezia spp. (e.g. sympodialis, furfur)
Fig. 36.12 Acneiform eruption secondary to high-dose dexamethasone. has been proposed as the etiology by some investigators, leading to
Abrupt eruption of monomorphous follicular papules and pustules on the renaming of the disorder as neonatal cephalic pustulosis. Additional
trunk. support for this view comes from the clinical response to treatment
with topical imidazoles (e.g. ketoconazole 2% cream). The active seba-
ceous glands and high sebum excretion rate in neonates (see Pathogen-
esis) are also thought to play a role. The substantial decline in sebum
production after the first few months of life helps to explain the limited
period of susceptibility to neonatal acne. Given the transient and
Fig. 36.13 Drug-
benign nature of this eruption, parental reassurance alone is usually
induced acne due to
isoniazid. Courtesy, Kalman adequate. However, as noted previously, therapy with topical imidazoles
Watsky, MD. can be effective.

Infantile acne
If acne presents at 312 months of age (occasionally as late as 1824
months), it is classified as infantile (Fig. 36.14). In contrast to neonatal
acne, comedo formation is prominent and pitted scarring can develop.
Deep cystic lesions and suppurative nodules are occasionally seen. The
pathogenesis of infantile acne reflects the androgen production intrinsic
to this stage of development (see Pathogenesis), including elevated
levels of LH stimulating testicular production of testosterone in boys
during the first 612 months of life (with levels transiently equivalent
to those during puberty) and elevated levels of DHEA produced by the
infantile adrenal gland in both boys and girls. These androgen levels
normally decrease substantially by 12 months of age and remain at
nadir levels until adrenarche.
Infantile acne typically resolves within 12 years and remains quies-
cent until around puberty. In unusual cases, however, infantile-onset
acne may persist into adolescence. Topical retinoids (e.g. tretinoin,
adapalene) and benzoyl peroxide are first-line treatments for infantile
550 acne. Oral antibiotics (e.g. erythromycin, azithromycin) can be helpful
for patients with a more severe inflammatory component, and
CHAPTER
an adrenal source of excess androgen production. The degree to
which levels of these hormones are increased is then useful in dis- 36
cerning an etiology. DHEAS values in the range of 40008000ng/ml

Acne Vulgaris
or 17-hydroxyprogesterone levels >3ng/ml may be indicative of con-
genital adrenal hyperplasia. Defects in adrenal enzymes, most com-
monly 21-hydroxylase or (less often) 11-hydroxylase, lead to this
condition. Patients with severe deficiencies of these enzymes become
symptomatic during infancy, whereas those with partial deficiencies
present in adolescence. If the serum DHEAS is >8000ng/ml, with or
without an elevated testosterone level, an adrenal tumor should be
suspected.
If the testosterone levels (total and free) are elevated and the DHEAS
level is relatively normal, an ovarian source is likely. Polycystic ovary
A syndrome (PCOS) is the most common condition associated with an
elevated serum testosterone, with levels typically ranging from 100 to
200ng/dl. An increased LH/FSH ratio (>23) is also commonly observed.
Symptoms of PCOS include irregular menstrual periods, hirsutism,
obesity, insulin resistance and reduced fertility (see Fig. 70.11). When
levels of serum testosterone exceed 200ng/dl, an ovarian tumor should
be considered.

Apert syndrome
Also known as acrocephalosyndactyly type I, Apert syndrome is an
autosomal dominant disorder that features disfiguring synostoses of the
bones of the hands and feet, vertebral bodies and cranium. Affected
individuals have an increased incidence of severe (frequently nodulo-
cystic), early-onset acne with a more widespread distribution than in
classic acne, often involving the entire extensor aspects of the arms,
buttocks and thighs31. Acne in patients with Apert syndrome also tends
to be highly resistant to therapy, although isotretinoin has been reported
B to be beneficial. Other cutaneous findings in this disorder can include
marked seborrhea, nail anomalies (e.g. a single nail for the second
Fig. 36.14 Infantile acne. Presentations can range from scattered
through fourth digits), and diffuse pigmentary dilution of the hair and
papulopustules (A) to multiple coalescing papulonodules and inflammatory
cysts (B). If the latter child failed to improve with a topical retinoid plus an oral skin. Of note, Apert syndrome results from activating mutations in the
antibiotic, consideration would be given to oral isotretinoin. Courtesy, Kalman FGFR2 gene, which encodes fibroblast growth factor receptor 2; mosai-
Watsky, MD. cism for the same FGFR2 mutations has been found to underlie
acneiform/comedonal nevi (see Ch. 62). FGFR2 signaling has been
shown to have effects on follicular keratinocyte proliferation, sebaceous
lipogenesis and inflammatory cytokine production, and it may be asso-
ciated with a nuclear deficiency of the forkhead box O1 (FoxO1) tran-
scription factor.
isotretinoin is occasionally required for recalcitrant or nodulocystic
presentations30.
Acneiform Eruptions
Endocrinologic abnormalities Epidermal growth factor receptor inhibitor-induced
Although most patients with acne do not have overt endocrinologic papulopustular eruption
abnormalities, hyperandrogenism should be suspected in female Inhibitors of epidermal growth factor receptor (EGFR/HER1) signaling
patients with hirsutism (see Ch. 70) or irregular menstrual periods, as represent an expanding class of therapeutic agents currently being used
well as in children who develop acne between 2 and 7 years of age. for the treatment of solid tumors, including head and neck squamous
Acne in such patients is often severe or more difficult to treat, and the cell carcinoma and lung, colon and breast carcinoma. Inhibitors include
onset can be fairly abrupt. Other signs and symptoms of hyperandro- gefitinib, cetuximab, erlotinib, lapatinib and panitumumab, with a
genism in women and children include coarsening of the voice, a number of tyrosine kinase inhibitors and monoclonal antibodies in
muscular habitus, androgenetic alopecia, clitoromegaly with variable clinical trials or under development (Fig. 36.15). The incidence of
posterior labial fusion, and increased libido. Insulin resistance and acneiform eruptions due to EGFR inhibitors is very high, e.g. up to 95%
acanthosis nigricans can occur in association with hyperandrogenism of patients treated with panitumumab; additional cutaneous side effects
in the HAIR-AN syndrome. These patients are at increased risk for of these agents are presented in Table 21.14. In some studies, the pres-
accelerated cardiovascular disease and diabetes mellitus, and they ence or severity of the acneiform eruption had a positive correlation
should be followed by appropriate medical specialists. with treatment outcomes (e.g. response rate and survival time).
The evaluation of patients suspected of having hyperandrogenism Patients present with an eruption of monomorphous follicular pus-
includes a thorough history and physical examination; the age of the tules and papules involving the face, scalp and upper trunk, usually 13
patient and pubertal status are also important parameters. Prepubertal weeks after beginning treatment with an EGFR inhibitor (Fig 36.16).
boys and girls and postpubertal women with signs of hyperandrogenism Secondary infection with Staphylococcus aureus often occurs, with
should undergo appropriate evaluation. Laboratory studies should not oozing and the formation of honey-colored crusts. While frequently
be performed while the patient is taking oral contraceptives. Initial tests described as acneiform, histopathology reveals a pattern of folliculitis,
should include serum levels of total and free testosterone, DHEAS, and with intrafollicular collections of neutrophils and perifollicular lymph
17-hydroxyprogesterone. Patients with clinical signs and symptoms ocytes. No comedonal lesions are seen either microscopically or clini-
suggestive of hypercortisolism should also have an AM serum cortisol cally, further differentiating this eruption from acne vulgaris.
level, and X-rays of the hand and wrist to evaluate bone age should be In the oncology patient, the differential diagnosis includes
obtained in prepubertal children. corticosteroid-induced acne, various forms of folliculitis (e.g. Pityrospo-
Understanding pathways of hormone production is essential in the rum, Demodex spp.), neutrophilic eccrine hidradenitis and viral-
evaluation of hyperandrogenic states (see Fig. 70.15). For example, an associated trichodysplasia spinulosa. Because discontinuation of the 551
elevated serum DHEAS or 17-hydroxyprogesterone level indicates medication is not an option in a patient who is responding to therapy,
SECTION

6
Fig. 36.15 Epidermal growth factor receptor (EGFR)
EPIDERMAL GROWTH FACTOR RECEPTOR SIGNAL TRANSDUCTION AND INHIBITION BY ANTICANCER AGENTS signal transduction and inhibition by anticancer
agents.
adnexal diseases

Anti-EGFR monoclonal antibodies:


cetuximab
panitumumab
nimotuzumab
EGF, zalutumumab
TGF necitumumab

EGFR

TK
Tyr P Tyr Tyr P Tyr
Tyr Tyr
Tyr
Tethered Extended and Active upon Tethered and Inactive
inactive dimerization dimerization unable to bind TK domain
configuration competent ligand or extend
upon ligand
binding
Tyrosine kinase inhibitors:
EGF, epidermal growth factor erlotinib afatinib
EGFR, EGF receptor gefitinib neratinib
TGF, transforming growth factor lapatinib vandetanib
TK, tyrosine kinase

A B

Fig. 36.16 Acneiform eruptions due to epidermal growth factor receptor inhibitors. A,B Numerous monomorphous follicular pustules and crusted papules on
the face of two patients treated with erlotinib. A, Courtesy, Julie V Schaffer, MD.

multiple treatments have been tried with variable success, including Historically, tropical acne caused significant morbidity among military
topical and oral antibiotics, topical and (for severe eruptions) oral cor- troops. Markedly inflamed nodulocystic acne involving the trunk and
ticosteroids, and topical and oral retinoids; prophylaxis with oral doxy- buttocks is typically seen, and secondary staphylococcal infection is a
cycline or minocycline may also be of benefit. frequent complication. Treatment is often of limited efficacy until the
patient returns to a more moderate climate.
Tropical acne
Tropical acne is a follicular acneiform eruption that results from expo- Radiation acne
552 sure to extreme heat. This can occur in tropical climates or secondary Radiation acne is characterized by comedo-like papules occurring at
to scorching occupational environments, as in furnace workers. sites of previous exposure to therapeutic ionizing radiation. The lesions
CHAPTER
begin to appear as the acute phase of radiation dermatitis starts to
resolve. The ionizing rays induce epithelial metaplasia within the
respond to antibiotic therapy. They eventually resolve spontaneously,
after an average of 11 months, without treatment33. 36
follicle, creating adherent hyperkeratotic plugs that are resistant to

Acne Vulgaris
expression.
Childhood flexural comedones
This recently described entity is characterized by discrete, double-
Pseudoacne of the transverse nasal crease orifice comedones localized to the axillae and, less commonly, the
The transverse nasal crease is a horizontal anatomical demarcation line groin34. The majority of patients have a single lesion and the average
found in the lower third of the nose which corresponds to the separa- age at diagnosis is 6 years, with boys and girls equally affected. A small
tion point between the alar cartilage and the triangular cartilage. Milia, subset of cases are familial. There is no association with other signs of
cysts and comedones can line up along this fold (Fig. 36.17A)32. These hidradenitis suppurativa, acne vulgaris or precocious puberty. In most
acne-like lesions are not hormonally responsive and arise during early cases, the flexural comedones are discovered incidentally in patients
childhood prior to the onset of puberty. Treatment consists of surgical presenting with other dermatologic concerns such as molluscum
expression as needed. contagiosum.

Idiopathic facial aseptic granuloma


This chronic, painless, solitary nodule with an acneiform appearance PATHOLOGY
can develop on the cheeks of young children (mean age, 3.8 years)33.
Histopathologic examination of acne lesions demonstrates the stages
Multiple lesions are uncommon. Histopathologic evaluation reveals a
of acnegenesis that parallel the clinical findings (see Fig. 36.1). In
dermal lymphohistiocytic infiltrate with foreign body-type giant cells.
early lesions, microcomedones are seen. A mildly distended follicle
Cultures are typically negative (70% of patients) and the lesions do not
with a narrowed follicular opening is impacted by shed keratinocytes.
The granular layer at this stage is prominent. In closed comedones,
the degree of follicular distension is increased and a compact cystic
structure forms. Within the cystic space, eosinophilic keratinaceous
debris, hair, and numerous bacteria are present. Open comedones
have broad, expanded follicular ostia and greater overall follicular
distension. The sebaceous glands are typically atrophic or absent. A
mild perivascular mononuclear cell infiltrate circles the expanding
follicle.
As the follicular epithelium distends, the cystic contents inevitably
begin to rupture into the dermis (Fig. 36.18). The highly immunogenic
cystic contents (keratin, hair and bacteria) induce a marked inflamma-
tory response. Neutrophils first appear, creating a pustule. As the lesion
matures, foreign body granulomatous inflammation engulfs the follicle
and end-stage scarring can result.
In acne fulminans, there is massive inflammation with varying
degrees of overlying necrosis. Comedones are rarely observed. Severe
scarring may be seen in resolving lesions.

Fig. 36.18 Histology of


an inflamed comedo.
A
There is disruption of the
pilosebaceous unit and
secondary inflammation.
Courtesy, Ronald P Rapini, MD.

Fig. 36.17 Disorders in the differential diagnosis of comedonal acne vulgaris.


A Pseudoacne of the transverse nasal crease in a young child. Note the milia
and comedones located along this anatomical demarcation line. B Trichostasis
spinulosa. Multiple vellus hairs and keratinous debris are found within the 553
dilated follicular orifices. A, Courtesy, Julie V Schaffer, MD. B, Courtesy, Judit Stenn, MD.
SECTION

6 DIFFERENTIAL DIAGNOSIS open comedones are clustered in the lateral malar region in Favre
Racouchot disease (see Ch. 87) or appear in a linear array in nevus
Although classic acne vulgaris is usually easily recognized clinically, the comedonicus (see Chs 62 and 109). If multiple vellus hairs are seen
adnexal diseases

differential diagnosis of acneiform eruptions is broad and depends upon arising from a dilated follicular orifice (in association with keratinous
the age of onset, lesional morphology and location (Table 36.2). During debris), trichostasis spinulosa is the likely diagnosis (Fig. 36.17B). The
the neonatal period, acne must be differentiated from other common most common location is the nose.
dermatoses. Sebaceous hyperplasia occurs in the majority of healthy Angiofibromas and appendageal tumors of follicular origin, e.g. tri-
neonates, presenting as transient yellowish papules on the cheeks, nose choepitheliomas, trichodiscomas and fibrofolliculomas, often present
and forehead. Miliaria rubra is also very common during the neonatal as multiple facial papules (see Ch. 111). They are typically non-
period, when overheating and bundling can cause temporary obstruc- inflammatory, and, in the case of trichoepitheliomas, lesions are con-
tion of the eccrine ducts that leads to formation of small inflammatory centrated in the nasolabial folds. Non-inflammatory, closed cystic
papulopustules. Small, white milia often appear on the cheeks and nose papules and nodules on the central chest and back characterize steato-
of neonates, but they generally resolve within a few months. cystoma multiplex (see Ch. 110). This autosomal dominant disorder
Predominantly comedonal acne vulgaris needs to be differentiated must be differentiated from a similar clinical condition, eruptive vellus
from comedonal eruptions caused by follicular occlusion or friction, hair cysts. These smaller cysts may become inflamed and, as the name
including pomade and occupational acne, acne cosmetica and acne implies, contain multiple vellus hairs that can be easily visualized
mechanica (see above); history as well as location can help to make the histologically.
diagnosis of these forms of contact acne. Sebaceous hyperplasia, a The follicle-based inflammatory papules and pustules of acne vulgaris
very common finding in adults, is relatively uncommon in adolescents. must be distinguished from the many forms of folliculitis, including
These yellowish, lobulated papules arise primarily on the forehead and staphylococcal, Gram-negative, and eosinophilic variants (see Ch. 38).
cheeks. In folliculitis, the lesions are typically monomorphous and comedones
A solitary enlarged comedo is better classified as a dilated pore of are not present. Gram-negative folliculitis can complicate acne vulgaris
Winer; rarely it represents a large-pore basal cell carcinoma. Multiple treated with oral antibiotics for a prolonged period. The inflammatory

DIFFERENTIAL DIAGNOSIS OF ACNE

ACNE VULGARIS COMEDONAL


Closed Open
Milia Contact acne (see above)
Osteoma cutis Acne exacerbated by systemic corticosteroids or anabolic steroids
Sebaceous hyperplasia Trichostasis spinulosa (see Fig. 36.17B)
Syringomas FavreRacouchot disease
Trichoepitheliomas* Nevus comedonicus
Trichodiscomas, fibrofolliculomas Basaloid follicular hamartoma syndrome
Eruptive vellus hair cysts, steatocystoma multiplex Familial dyskeratotic comedones
Colloid milia Radiation-induced comedones
Acne exacerbated by systemic corticosteroids or anabolic steroids Dilated pore of Winer (single lesion)
Contact acne (occupational, pomade, cosmetica, mechanica; chloracne) Follicular spines (in settings such as viral-associated trichodysplasia spinulosa,
Follicular mucinosis type VI pityriasis rubra pilaris, multiple myeloma, demodicosis, follicular
mucinosis and lithium therapy)
ACNE VULGARIS INFLAMMATORY
Rosacea Keratosis pilaris
Perioral dermatitis Viral-associated trichodysplasia spinulosa (also referred to as viral-associated
Folliculitis culture-negative (normal flora), staphylococcal, Gram-negative, trichodysplasia of immunosuppression)
eosinophilic, Pityrosporum, Demodex spp. (adults > children) Lupus miliaris disseminatus faciei
Acne/acneiform eruptions due to topical or systemic corticosteroids, anabolic Psychogenic (neurotic) excoriations, factitial lesions
steroids or other medications (e.g. lithium, EGFR inhibitors; see Table 36.1) Follicular mucinosis, follicular mycosis fungoides
Pseudofolliculitis barbae, acne keloidalis nuchae Tinea faciei
Furuncle/carbuncle Molluscum contagiosum (especially inflamed lesions)
Neutrophilic dermatoses and neutrophilic eccrine hidradenitis Angiofibromas
NEONATAL ACNE (NEONATAL CEPHALIC PUSTULOSIS)
Sebaceous hyperplasia Candidal infections
Milia Papulopustular eruption of hyper-IgE syndrome
Miliaria rubra (especially pustular variant) Vesiculopustular eruption of transient myeloproliferative disorder
SOLID FACIAL EDEMA SECONDARY TO ACNE VULGARIS
Solid facial edema secondary to rosacea Angioedema (lasts <2448 hours), C1 esterase inhibitor deficiency (lasts 4272
MelkerssonRosenthal syndrome, sarcoidosis (e.g. Heerfordts syndrome), hours), blepharochalasis/Ascher syndrome
lepromatous leprosy Sweets syndrome or cellulitis more abrupt onset
Lymphoma (B- or T-cell), leukemia cutis, angiosarcoma Superior vena cava syndrome
Scleromyxedema, myxedema, self-healing (juvenile) cutaneous mucinosis Lymphatic malformation
Autoimmune connective tissue disease (e.g. dermatomyositis, lupus Other trichinosis, primary systemic amyloidosis, pachydermoperiostosis
erythematosus, Stills disease)
*Early or small-sized.

In the differential diagnosis of cystic lesions of the trunk.

Can also lead to rosacea-like picture (see Ch. 38).

Often in the setting of HIV infection and/or other immunocompromised states.
554
Table 36.2 Differential diagnosis of acne. EGFR, epidermal growth factor receptor.
CHAPTER
Topical Treatments
lesions typically appear on the central face (including the upper lip) and
cheeks as well as on the upper trunk and, in the case of Pseudomonas
Topical retinoids
36
(hot tub) folliculitis, on the lower trunk. Eosinophilic folliculitis

Acne Vulgaris
usually occurs in the setting of HIV infection and is markedly The anti-acne activity of topical retinoids involves normalization of
pruritic. follicular keratinization and corneocyte cohesion, which aids in the
Pseudofolliculitis barbae and acne keloidalis nuchae most often affect expulsion of existing comedones and prevents the formation of
men of African descent (see Ch. 38). The papular component of rosacea new ones. Topical retinoids also have significant anti-inflammatory
favors the malar region, chin and forehead; the presence of telangiecta- properties and thus may be used as monotherapy for acne with both
sias, an absence of comedones and a history of easy flushing can aid comedonal and mild inflammatory components. In addition, concur-
in diagnosis (see Ch. 37). Rosacea typically occurs at a later age than rent use of a topical retinoid can enhance the efficacy of benzoyl per-
acne, but both can develop in a single individual. Prolonged use of oxide and topical antibiotics by increasing the penetration of the latter
topical corticosteroids on the face may lead to rosacea-like lesions or medications into the sebaceous follicle. Topical retinoids used for acne
perioral/periorificial dermatitis, and patients treated with oral corticos- include tretinoin, adapalene, tazarotene and (in some countries)
teroids can develop an eruption of monomorphous papulopustules that isotretinoin (see Ch. 126); topical products that combine tretinoin or
favors the trunk (steroid folliculitis; see Fig. 36.12). This can occur adapalene with clindamycin, or adapalene with benzoyl peroxide, are
at any age and resolves upon discontinuation of the corticosteroid. also available.
Lastly, psychogenic (neurotic) excoriations and factitial dermatitis con-
centrated on the face, chest and back can mimic acne, particularly acne
excorie des jeunes filles. Linearity and the lack of a clinically detectable
HISTORY AND PHYSICAL EXAMINATION OF THE ACNE PATIENT
primary lesion are clues.
History Physical examination

TREATMENT Sex Skin type (e.g. oily versus dry)


Age Skin color/phototype
A thorough history and physical examination are key to developing an Motivation Distribution of acne
appropriate and maximally effective treatment plan (Table 36.3). The Lifestyle/hobbies Face (e.g. T-zone, cheeks, jawline)
physician should review with the patient all prescription and over-the- Occupation Neck, chest, back, upper arms
Current and previous treatments Overall degree of involvement (mild,
counter medications used for acne or other conditions, and note the
Use of cosmetics, sunscreens, moderate or severe)
clinical responsiveness to them. A review of cosmetics, sunscreens, cleansers, moisturizers Lesion morphology
cleansers and moisturizers is also helpful. In female patients, a men- Menstrual history Comedones
strual and oral contraceptive history is important in determining hor- Medications Inflammatory papules
monal influences on acne. On physical examination, careful note Corticosteroids Pustules
should be taken of lesion morphology, including the presence of come- Oral contraceptives Cysts
dones, inflammatory lesions, nodules and cysts. Secondary changes Anabolic steroids Sinus tracts
such as scarring and postinflammatory pigmentary changes are also Other (e.g. lithium, EGFR inhibitors; Scarring
see Table 36.1) Pitted
important clinical findings. The patients skin color and type can influ-
Concomitant illnesses Hypertrophic
ence the chosen formulation of a topical medication. Patients with oily
skin tend to prefer the more drying gels and lotions, whereas those with Atrophic
drier skin types may prefer creams. Postinflammatory pigmentary changes
Common therapies for the treatment of acne are listed in Tables 36.4 Table 36.3 History and physical examination of the acne patient. EGFR,
and 36.5. epidermal growth factor receptor.

TREATMENT OF ACNE VULGARIS

Mild Moderate Severe


Comedonal Papular/pustular Papular/pustular Nodular Conglobata/fulminans

First line Topical retinoid Topical retinoid + topical Oral antibiotic + topical Oral antibiotic + topical Oral isotretinoin (may require
antimicrobial* retinoid BPO retinoid BPO concurrent oral corticosteroid,
esp. for acne fulminans)
Second line Alternative topical retinoid Alternative topical retinoid Alternative oral antibiotic Oral isotretinoin Dapsone
Azelaic acid + alt. topical antimicrobial + alt. topical retinoid Alternative oral antibiotic High-dose oral antibiotic +
Salicylic acid Azelaic acid BPO/azelaic acid + alt. topical retinoid topical retinoid + BPO
Salicylic acid BPO/azelaic acid
Topical dapsone
Options for Oral contraceptive/ Oral contraceptive/ Oral contraceptive/
female patients antiandrogen antiandrogen antiandrogen
Surgical options Comedo extraction Comedo extraction Comedo extraction Intralesional corticosteroid
Intralesional corticosteroid
Refractory to Exclude Gram-negative Exclude Gram-negative
treatment folliculitis folliculitis
Female patient: exclude adrenal or ovarian dysfunction
Exclude use of anabolic steroid or other acne-exacerbating medications
Maintenance Topical retinoid BPO Topical retinoid BPO Topical retinoid BPO
*Antibiotic (e.g. clindamycin, erythromycin or sodium sulfacetamide) and/or BPO.

Tetracycline derivatives.

e.g. azithromycin or trimethoprimsulfamethoxazole.

Table 36.4 Treatment of acne vulgaris. Lack of response should also lead the clinician to consider non-compliance with treatment or another diagnosis. In
general, monotherapy with a topical or oral antibiotic should be avoided. alt, alternative; BPO, benzoyl peroxide. Adapted from Gollnick H, Cunliffe W, Berson D, etal. J Am Acad 555
Dermatol. 2003;49(1 Suppl):S137.
SECTION

6 COMMON THERAPIES FOR ACNE VULGARIS


benzoyl peroxide is also possible, and should be suspected in patients
who develop marked erythema with its use.
Topical antibiotics are widely used for the treatment of acne and are
Topical therapy Systemic therapy
adnexal diseases

available alone as well as in combination with benzoyl peroxide or a


Benzoyl peroxide (1) Oral minocycline (1) retinoid. Clindamycin and erythromycin represent the two most com-
Antibiotics Oral doxycycline (1) monly utilized antibiotics and the formulations vary from creams and
Clindamycin (1) Oral tetracycline (1) gels to solutions and pledgets (see Ch. 127).
Erythromycin (1) Oral erythromycin (1) Azelaic acid is a naturally occurring dicarboxylic acid found in cereal
Sodium sulfacetamide/sulfur (1) Oral azithromycin (1)
Oral contraceptives (1)
grains. It is available as a topical cream and gel, which have been shown
Retinoids (1) to be effective in inflammatory and comedonal acne. By inhibiting the
Salicylic acid (2) Oral spironolactone (1)
Azelaic acid (1) Oral isotretinoin (1) growth of P. acnes, azelaic acid reduces inflammatory acne. It also
Dapsone (1) reverses the altered keratinization of follicles affected by acne and thus
demonstrates comedolytic properties. The activity of azelaic acid
Table 36.5 Common therapies for acne vulgaris. Key to evidence-based against inflammatory lesions may be greater than its activity against
support: (1) prospective controlled trial; (2) retrospective study or large case
comedones. Azelaic acid is applied twice daily and its use is reported
series; (3) small case series or individual case reports.
to have fewer local side effects than topical retinoids. In addition, it
may help to lighten postinflammatory hyperpigmentation.
The most common side effect of topical retinoids is local irritation Sodium sulfacetamide is a well-tolerated topical antibiotic that is
resulting in erythema, dryness, peeling and scaling. Delivery systems thought to restrict the growth of P. acnes through competitive inhibi-
have been developed to permit a greater concentration of retinoid while tion of the condensation of para-aminobenzoic acid with pteridine
decreasing irritancy, primarily through controlled slow release (e.g. precursors (see Ch. 127). It is formulated in a 10% lotion, suspension,
tretinoin impregnated into inert microspheres or incorporated within foam and cleanser, either alone or in combination with 5% sulfur.
a polyolprepolymer). A pustular flare of acne occasionally occurs during Tinted formulations are also available.
the initial 34 weeks of treatment with a topical retinoid. This resolves Topical dapsone 5% gel is approved for the treatment of acne vulgaris.
spontaneously with continued usage. Thinning of the stratum corneum Of note, a temporary yelloworange staining of the skin and hair occa-
and irritation may also increase the users susceptibility to sunburn. sionally occurs with concomitant use of topical dapsone and benzoyl
Therefore, the use of sunscreens should be advised. peroxide.
Tretinoin (all-trans-retinoic acid), a naturally occurring metabolite of
retinol, was the first topical comedolytic agent used for the treatment Other topical medications
of acne. Because tretinoin is photolabile, night-time application is rec- Salicylic acid is a widely used comedolytic and mild anti-inflammatory
ommended to prevent early degradation. To decrease the potential for agent (see Ch. 153). It is also a mild chemical irritant that works in
irritation, treatment is often started with a lower-concentration cream part by drying up active lesions. Salicylic acid is available over the
formulation of tretinoin and the strength later increased (or the vehicle counter in concentrations of up to 2% in numerous delivery formula-
changed to a gel). Alternate-night to every-third-night application may tions, including gels, creams, lotions, foams, solutions and washes. Side
be necessary initially, with increased frequency as tolerated. Stepwise effects of topical salicylic acid include erythema and scaling.
increments are typically done at 34-week intervals.
Although epidemiologic studies have not shown an increased risk of Oral Treatments
birth defects in infants of mothers using topical tretinoin during the
first trimester, sporadic case reports of birth defects have been pub- Antibiotics
lished35,36. Because of this and the fact that systemic retinoids are Oral tetracycline derivatives, especially doxycycline and minocycline,
known teratogens, the use of topical tretinoin in pregnancy is discour- and less often macrolides (e.g. erythromycin, azithromycin) are pre-
aged. However, dietary intake of vitamin A has been shown to have a scribed for moderate to severe inflammatory acne unresponsive to
greater influence on serum retinoid levels than facial application of topical combinations. In this setting, the primary mechanism of action
tretinoin37. of these agents is suppression of the growth of P. acnes, thereby reduc-
The synthetic retinoid adapalene is an aromatic naphthoic acid deriv- ing bacterial production of inflammatory factors. However, several of
ative (see Fig. 126.1). In the skin, it primarily binds the retinoic acid these antibiotics also possess intrinsic anti-inflammatory properties.
receptor (RAR), whereas tretinoin binds to both RAR and RAR. Details regarding the mechanisms of action, recommended dosages,
Although animal studies have shown adapalene to have milder comedo- and side effects of tetracyclines and macrolides are reviewed in Chapter
lytic properties than tretinoin, it is also less irritating38. Unlike tretin- 127. Resistance of P. acnes to erythromycin and the three major tetra-
oin, adapalene is light-stable and resistant to oxidation by benzoyl cyclines (tetracycline and doxycycline more so than minocycline) has
peroxide. been reported. The enhanced efficacy of minocycline, a lipophilic deriv-
Tazarotene is a synthetic acetylenic retinoid that, once applied, is ative of tetracycline, may be due to its greater penetration into the
converted into its active metabolite, tazarotenic acid. Like adapalene, sebaceous follicle; however, it is also associated with a higher incidence
this metabolite selectively binds RAR but not RAR or RXR (see Ch. of serious adverse events, including a minocycline-induced hypersensi-
126). Both daily overnight application of tazarotene and short contact tivity syndrome and autoimmune reactions (see Ch. 21). The latter
therapy regimens have been used and shown to be effective in the treat- typically develop after many months to years of therapy and can
ment of comedonal and inflammatory acne. Topical tazarotene has include hepatitis, a lupus erythematosus-like syndrome and cutaneous
been designated pregnancy category X, so contraceptive counseling polyarteritis nodosa (often associated with antineutrophil cytoplasmic
should be provided to all women of childbearing age who are prescribed antibodies).
this medication.
Hormonal therapy
Benzoyl peroxide and other topical antibacterial agents Hormonal therapy is an established second-line treatment for female
Benzoyl peroxide is a potent bacteriocidal agent that reduces P. acnes patients with acne and can be very effective, irrespective of whether or
within the follicle. It also has mild comedolytic properties and is par- not the serum androgen levels are abnormal. Although women and girls
ticularly effective when used in combination with other therapies. In with acne may have higher serum levels of androgens than those
contrast to topical antibiotics, microbial resistance to benzoyl peroxide without acne, the levels in acne patients are often within the normal
has not been reported. Many preparations for all skin types are available range. Hormonal therapies seem to work best in adult women with
in both over-the-counter and prescription formulations. These include inflammatory papules and nodules that tend to flare in the week prior
bar soaps, washes, gels, lotions, creams, foams and pads in concen to menstruation and involve the lower face and neck. These patients
trations ranging from 2.5% to 10% as well as products that combine often note little improvement in their acne despite multiple courses of
benzoyl peroxide with clindamycin, erythromycin or adapalene. As various oral antibiotics.
556 benzoyl peroxide is a bleaching agent, whitening of clothing and bedding In such patients, hormonal therapy with oral contraceptives, which
can occur. Development of contact dermatitis (irritant > allergic) to block both ovarian and adrenal production of androgens, can be initiated
CHAPTER
and oral antibiotics discontinued. The use of oral contraceptives is also
indicated for women of childbearing potential if treatment with spironol-
(2mg) with ethinyl estradiol (35 or 50mcg) in an oral contraceptive
formulation. This preparation is widely used in Europe as the treatment 36
actone is anticipated (see below). Because of the potential risks associ- of choice for sexually active women with hormonally responsive acne.

Acne Vulgaris
ated with oral contraceptive use and the need for breast and pelvic Singular formulations of cyproterone acetate are also available. Studies
examinations, consultation with a gynecologist is recommended. have indicated that approximately 7590% of patients treated with
Most oral contraceptive formulations combine an estrogen with a doses of 50100mg daily (with or without ethinyl estradiol 50mcg)
progestin in order to minimize the risk of endometrial cancer, which is show substantial improvement43. Although similar efficacy has been
known to occur with unopposed estrogen administration. Although reported for the 2mg cyproterone acetate dose in the oral contraceptive
progestins have intrinsic androgenic activity, second-generation, formulation, higher doses (e.g. on days 514 of the menstrual cycle)
low-androgenic progestins (e.g. ethynodiol diacetate, norethindrone, may be helpful in women with severe hyperandrogenism. The most
levonorgestrel) have been developed. Newer, third-generation progestins frequent side effects are breast tenderness, headache, nausea and irregu-
(e.g. desogestrel, norgestimate, gestodene [Europe]) have even less lar menses; hepatotoxicity or thromboembolism represent uncommon
androgenic activity than their predecessors, and other progestins (e.g. complications.
drospirenone, cyproterone acetate, dienogest) have antiandrogenic Spironolactone functions as both an androgen receptor blocker and
properties. an inhibitor of 5-reductase. In doses of 50100mg twice daily, it has
Three oral contraceptives are currently FDA-approved for the treat- been shown to reduce sebum production and improve acne44. Side
ment of acne, although others also have evidence of efficacy39 (Table effects are dose-related and include potential hyperkalemia, irregular
36.6). The first is a triphasic oral contraceptive composed of a menstrual periods, breast tenderness, headache and fatigue. However,
norgestimateethinyl estradiol (35mcg) combination. The second con- hyperkalemia is rare in young healthy patients. Although breast tumors
tains a graduated dose of ethinyl estradiol (2035mcg) in combination have been reported in rodent models given spironolactone, this drug
with norethindrone acetate, while the third contains a stable dose of has not been directly linked to the development of cancer in humans45.
ethinyl estradiol (20mcg) plus drospirenone (3mg) with a 24-day Because it is an antiandrogen, there is a risk of feminization of a male
dosing regimen. Side effects from oral contraceptives include nausea, fetus if a pregnant woman takes this medication. The potential risk to
vomiting, abnormal menses, weight gain and breast tenderness; agents a fetus and the symptoms of irregular menstrual bleeding can be allevi-
containing drospirenone can lead to elevations in serum potassium ated by combining spironolactone with an oral contraceptive. Side
levels, but this is generally not clinically significant in otherwise healthy effects can also be minimized if therapy is initiated with a low dose
individuals. Rare but more serious complications include hypertension (2550mg/day). Effective maintenance doses range from 25 to 200mg/
and thromboembolism (e.g. deep venous thrombosis, pulmonary embo- day. As with other hormonal therapies, a clinical response may take up
lism). The increase in risk of the latter ranges from 24-fold with to 3 months.
levonorgestrel or norethindrone to 3.57-fold with desogestrel, dros- Records were reviewed of 85 women treated with 50100mg daily
pirenone and cyproterone acetate40,41; it is higher for women over the of spironolactone, administered either as a single agent or as an adjunct
age of 35 years, smokers and those with other prothrombotic risk to standard therapies46. The maximum length of treatment was 24
factors (e.g. hereditary thrombophilia)42. months. Clearing of acne occurred in 33% of women treated with low-
The progestational antiandrogen cyproterone acetate is currently dose spironolactone, 33% had marked improvement, 27% showed
marketed in Europe and Canada but is not available in the US. Its partial improvement and 7% showed no improvement. The treatment
anti-acne effects are mediated primarily through androgen receptor was well tolerated, with 58% reporting no adverse effects. Menstrual
blockade. The standard formulation combines cyproterone acetate irregularities occurred in 17.5%, and symptoms of lethargy, fatigue,
dizziness or headache (CNS symptoms) were reported in 16%. Less
common side effects included breast tenderness, a diuretic effect, pos-
COMMONLY USED ORAL CONTRACEPTIVES tural hypotension and nausea. Slight elevations in serum potassium
(range 4.85.3mEq/l) were identified in 13.7% of the 73 patients exam-
Oral contraceptive Estrogen mcg/Progestin mcg ined, but this was not considered to be clinically significant. The fol-
FDA-APPROVED FOR ACNE VULGARIS lowing benefits were noted in some patients: an improvement in
Ortho Tri-Cyclen Ethinyl estradiol 35/norgestimate 180, 215, 250 premenstrual syndrome, decreased facial oiliness, decreased metror-
rhagia, reduced endometriosis pain and increased libido. The results of
Estrostep Ethinyl estradiol 20, 30, 35/norethindrone 1000
this study suggested that:
Yaz, Loryna and Ethinyl estradiol 20/drospirenone 3000 l most side effects of spironolactone are dose-dependent, including
Beyaz*
menstrual irregularities (the most common side effect)
CLINICAL DATA TO SUPPORT USE l CNS symptoms are also relatively common, but appear to be

Alesse Ethinyl estradiol 20/levonorgestrel 100 unrelated to dose


l hyperkalemia may be measurable but is clinically insignificant in
Diane-35 Ethinyl estradiol 35/cyproterone acetate 2000
the absence of cardiac or renal disease
Yasmin, Syeda, Ethinyl estradiol 30/drospirenone 3000 l reductions in blood pressure are slight, but rarely can be associated
Zarah and Safyral*
with orthostatic symptoms.
Natazia Estradiol valerate 1000, 2000, 3000/dienogest 2000, 3000
Flutamide, a nonsteroidal androgen receptor blocker that is approved
NO/INSUFFICIENT CLINICAL DATA by the FDA for the treatment of prostate cancer, can also be an effective
Demulen Ethinyl estradiol 35, 50/ethynodiol diacetate 1000 treatment for acne in women at doses of 62.5500mg/day. In addition
Desogen Ethinyl estradiol 35/desogestrel 150 to side effects similar to those of other antiandrogens (e.g. menstrual
irregularities, breast tenderness, risk of feminization of a male fetus),
Mircette Ethinyl estradiol 20, 10/desogestrel 150
severe dose-related hepatotoxicity occasionally occurs.
Ortho-Cept Ethinyl estradiol 35/desogestrel 150
Ortho-Cyclen Ethinyl estradiol 35/norgestimate 250 Isotretinoin
Ortho-Novum 7/7/7 Ethinyl estradiol 35/norethindrone 500, 750, 1000 Since 1971, oral isotretinoin (13-cis-retinoic acid) has been available in
Ortho-Novum 10/11 Ethinyl estradiol 35/norethindrone 500, 1000 Europe for the treatment of acne. Twelve years later, the FDA approved
it for patients with severe, nodulocystic acne refractory to treatment,
Ortho Tri-Cyclen Lo Ethinyl estradiol 25/norgestimate 180, 215, 250
including oral antibiotics. Over time, other clinical forms of acne have
Ovcon-35 Ethinyl estradiol 35/norethindrone 400 also been shown to benefit greatly from the use of isotretinoin47. These
TriPhasil Ethinyl estradiol 35, 50/levonorgestrel 50, 75, 125 include significant acne that is unresponsive to therapy (including
*Also contains levomefolate calcium for protection against neural tube defects. oral antibiotics) and/or results in scarring, as well as Gram-negative

Not available in the US. folliculitis, pyoderma faciale and acne fulminans. The mechanism of
action of isotretinoin, as well as dosing regimens, side effects and 557
Table 36.6 Commonly used oral contraceptives. monitoring protocols, are discussed in detail in Chapter 126.
SECTION

6 Patients with acne are typically treated with an isotretinoin dose of Fig. 36.19 Impetigo in a
0.51mg/kg/day (taken with a fatty meal to increase gastrointestinal patient treated with
absorption), often with a lower dose during the first month of treatment isotretinoin. Multiple
adnexal diseases

to prevent an initial acne flare and to allow the patient to adjust to serous crusts are evident.
dose-dependent side effects. Reaching a cumulative dose of 120150mg/
kg (e.g. 45 months of treatment with 1mg/kg/day) has been shown to
reduce the risk of relapse. However, a 6-month course of low-dose
isotretinoin (e.g. 0.250.4mg/kg/day, 4070mg/kg cumulative) can be
effective in the treatment of moderate acne, with fewer side effects and
improved patient satisfaction48. Subsets of patients who are less likely
to respond to isotretinoin and/or more likely to require multiple courses
of treatment include adolescents under 16 years of age who have nodu-
locystic acne, individuals with endocrine abnormalities, and women
with less severe acne. Considering that improvement may continue for
several months after discontinuing isotretinoin, a hiatus of at least 23
months is recommended before starting another course of therapy.
Scarred nodules and sinus tracts that represent sequelae from previ-
ously active cystic acne are not isotretinoin-responsive but may improve
with surgical modalities, which are generally delayed at least 612
months after completing isotretinoin therapy to avoid the possible risk
of atypical healing or scarring responses.
The most common adverse effects of isotretinoin involve the skin
and mucous membranes and are dose-dependent. These include cheili-
tis, dryness of the oral and nasal mucosa, generalized xerosis and skin
fragility. With the institution of isotretinoin therapy, induction of an
acne fulminans-like flare, formation of excessive granulation tissue,
and cutaneous infections (in particular with Staphylococcus aureus) can
also occur (Fig. 36.19).
Teratogenicity is a serious potential complication (see Table 126.7),
pulsed dye, 635nm red diode) as well as methyl aminolevulinate plus
and female patients of childbearing potential must have at least one (in
red light have been successfully used to treat acne (see Ch. 135). In
the US, two) negative pregnancy test(s) before starting treatment and
addition, blue or intense pulsed light alone and lasers such as the pulsed
practice effective contraception for 1 month prior to, during, and for 1
dye, the 1320nm neodymium:YAG and especially the 1450nm diode
month after completing therapy. In the US, prescription of isotretinoin
may be of therapeutic benefit for inflammatory acne (see Ch. 137).
requires all physicians and patients to register with a pregnancy risk
Intralesional injection of corticosteroid (triamcinolone acetonide
management program (iPLEDGE), which mandates monthly office
25mg/ml) can quickly improve the appearance and tenderness of
visits for all patients (with counseling not to share the medication) and
deep, inflamed nodules and cysts. Larger cysts may require incision and
monthly pregnancy testing for female patients with childbearing poten-
drainage prior to injection. The maximal amount of corticosteroid used
tial. Isotretinoin therapy leads to elevated serum triglyceride levels in
per lesion should not exceed 0.1ml. The risks of corticosteroid injec-
2550% of patients and may have side effects involving the muscu-
tions include hypopigmentation (particularly in darkly pigmented skin),
loskeletal system (most often myalgias), eyes, liver (occasionally ele-
atrophy, telangiectasias, and needle tract scarring.
vated transaminases); intestines (controversial link to inflammatory
Low-concentration chemical peels are also beneficial for the reduction
bowel disease) and central nervous system (see Table 126.8 and Ch.
of comedones. The -hydroxy acids (including glycolic acid), salicylic
126). To date, no firmly established causal association with depression
acid and trichloroacetic acid are the most common peeling agents.
or suicide attempts has been demonstrated.
These lipid-soluble comedolytic agents act by decreasing corneocyte
cohesion at the follicular opening and assist in comedo plug extrusion.
Surgical Treatment Such agents are generally well tolerated by most skin colors and types,
Comedo extraction can improve the cosmetic appearance of acne and and they can be used by the patient at home or in the dermatologists
aid in therapeutic responsiveness to topical comedolytic agents. The office. Higher-concentration glycolic acid peels (2070%, depending on
keratinous contents of open comedones may be expressed using a the patients skin type) and the less predictable phenol peel may also
comedo extractor. The Schamberg, Unna and Saalfield types of comedo be performed in the office setting. Risks of chemical peels include irrita-
expressers are most commonly used. Nicking the surface of a closed tion, pigmentary alteration and scarring.
comedo with an 18-gauge needle or a #11 blade allows easier expres- One of the most distressing consequences of acne vulgaris is scarring.
sion. Extraction is especially beneficial for deep, inspissated and persist- Surgical treatments should be aimed at the type of scarring present.
ent comedones. This procedure should be used in conjunction with a Laser resurfacing (fractional as well as traditional), dermabrasion and
topical retinoid or other comedolytic treatment for maximum benefit. deeper chemical peels seek to reduce the variability of the skin surface
Comedo extraction should not be performed on inflamed comedones and smooth out depressed scars that improve when the skin is stretched.
or pustules because of the risk of scarring. Light electrocautery and For discrete depressed scars, soft tissue augmentation can be temporar-
electrofulguration (see Ch. 140) have also been reported as effective ily beneficial. Filler substances used include poly-L-lactic acid, calcium
treatments for comedones. Electrofulguration has the added benefit of hydroxylapatite and autologous fat (see Ch. 158). Punch grafting is an
not requiring the prior use of a topical anesthetic. In selected patients, option for patients with ice-pick scarring. Surgical subscision is also
cryotherapy represents another surgical option for the treatment of a commonly used technique in the management of acne scars. For
comedonal acne (see Ch. 138). larger hypertrophic scars, aggregated pitted scars and sinus tracts, full-
Photodynamic therapy utilizing topical 5-aminolevulinic acid together thickness surgical excision may result in improved scar placement and
with various light sources (e.g. blue, red, intense pulsed) or lasers (e.g. a better cosmetic appearance.

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559
CHAPTER

36

Acne Vulgaris
Infantile acne. Multiple open and closed comedones, papules and atrophic
scarring. Courtesy of Holly Gunn MD.

559.e1