Bolognia JL, Jorizzo JL, Schaffer JV. Acne Vulgaris.

J
Dermatology. 2012;1(3):545-558

Acne Vulgaris
Genetic Factors
The pathogenesis of acne is multifactorial, and the precise role of genetic predisposition is
uncertain. The number, size and activity of sebaceous glands is inherited. In addition, the
concordance rate for the prevalence and severity of acne among identical twins is extremely
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. However, because of the extremely high prevalence of acne, it is difficult
to attribute its presence exclusively to genetic factors.
Sebum Production
The sebaceous gland is controlled primarily by hormonal stimulation (see below). After the
first 6 months of life (when sebum production is relatively high), the rate decreases and
remains stable throughout childhood. At adrenarche, sebum production dramatically
increases. Although the overall composition of sebum is the same in persons with
or without acne, those with acne have variable seborrhea6.
Comedo Formation
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 of the follicle, the infundibulum. Comedo
formation occurs when the corneocytes, which are normally shed into the lumen of the
follicle and extruded through the follicular ostium, are retained and accumulate, leading to
hyperkeratosis. Increased cohesiveness of these cells is responsible for this phenomenon. The
ultrastructural components of the cell that are responsible for adhesiveness all play a role,
including lamellar granules, cell membranes, epidermal lipids, and intercellular cementing
substances. In addition to increased intercellular cohesiveness of the corneocytes, their
production is accelerated as well. This combination of increased cellular cohesion and
proliferation occurs in the proximal portion of the infundibulum, the infrainfundibulum, and
it creates a bottleneck phenomenon and subsequent microcomedo formation. In the
underlying follicular epithelium, keratohyaline granules are increased in size and number,
whereas lamellar granules and tonofilaments are decreased. As the comedo expands, the
sebaceous lobule undergoes regression. Because of the very narrow opening to the skin
surface, there is initially an accumulation of loosely packed shed keratinocytes and sebum.
With expansion of the comedo, the contents become closely packed, creating whorled
lamellar concretions. As the forces increase, rupture of the comedo wall with extrusion of the
immunogenic keratin and sebum occurs, with resultant inflammation.
Inflammatory Responses
Inflammation is not only the result of comedo rupture, as it is also seen early in acne lesion
formation. For example, in acne-prone sites, 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 neutrophils predominate (typical of early lesions), a suppurative pustule is formed.
Neutrophils also promote the inflammatory response by releasing lysosomal enzymes and
generating reactive oxygen species, and levels of the latter in the skin and plasma may
correspond with
INTRODUCTION
Acne vulgaris is a multifactorial disorder of the pilosebaceous unit. The clinical picture can
vary significantly, from mild comedonal acne to fulminant systemic disease. Although all age
groups may be affected by its many variants, acne is primarily a disorder of adolescence.
Acne has an undeniable psychosocial impact, and affected individuals have an increased
likelihood of self-consciousness, social isolation, depression and even suicidal ideation1.
Recent insights into the pathogenesis of acne have aided significantly in further defining the
subtypes of acne and establishing effective treatment regimens.
HISTORY
In the sixth century AD, the term “acne” was first used by the Emperor Justinian’s physician,
Aetius Amidenus. It was later translated from Greek into Latin, and through these translations
confusion arose regarding its original meaning2. The debate continues as to whether its origin
is from the Greek acme, meaning peak, or whether acne was actually the original term. Its use
became obsolete until the 1800s, when “acne” regained a place in medical dictionaries. In
1842, Erasmus Wilson separated acne simplex (acne vulgaris) from acne rosacea3.
EPIDEMIOLOGY
Acne vulgaris affects approximately 40–50 million individuals each year in the US alone,
leading to an estimated annual cost in the US of at least $2.5 billion. With a peak incidence
during adolescence, acne affects approximately 85% of young people between 12 and 24
years of age and is therefore a physiologic occurrence in this group. Although it is typically
thought of as a disease of youth, acne often continues to be problematic well into adulthood.
In a recent survey-based study, 35% of women and 20% of men reported having acne in their
30s, while 26% of women and 12% of men were still affected in their 40s4. Caucasian boys
and men have a tendency to have more severe nodulocystic disease than other groups.
Individuals at increased risk for the development of acne include those with an XYY
karyotype or endocrine disorders such as polycystic ovarian syndrome, hyperandrogenism,
hypercortisolism and precocious puberty. Patients with these conditions tend to have more
severe acne that is less responsive to standard therapy.
PATHOGENESIS
The development of acne involves a complex interaction of multiple factors, both internal and
external to the pilosebaceous apparatus. Appreciating the anatomy and physiology of this
unique structure is acne severity8. Influx of lymphocytes (predominately T-helper [Th] cells)
and foreign body-type giant cells, in addition to neutrophils, results in inflamed papules,
nodules and cysts. The type of inflammatory response also plays a role in the development of
scarring. Early, nonspecific inflammation results in less scarring than does a delayed, specific
inflammatory response9.
Propionibacterium acnes and the Innate
Immune System
Propionibacterium acnes contributes significantly to the pathogenesis of acne. These Gram-
positive, non-motile rods are found deep within the sebaceous follicle, along with P.
granulosum and, rarely, P. parvum. They are anaerobic/microaerophilic and naturally
produce porphyrins (primarily coproporphyrin III) that fluoresce with Wood’s lamp
illumination. The pathogenicity of these microorganisms stems from several of their
properties, including the release of enzymes that contribute to comedo rupture, lipases and
chemotactic factors, as well as stimulation of a host response (by inflammatory cells and
keratinocytes) that involves production of proinflammatory mediators and reactive oxygen
species. Increased numbers of P. acnes have been reported in acne patients, but their numbers
do not correlate with clinical severity10. Different strains of P. acnes have been shown to
induce varying degrees of sebocyte differentiation and proinflammatory cytokine/chemokine
reponses11. Interactions between the skin’s innate immune system and P. Acnes play an
important role in acne pathogenesis. One mechanism is via Toll-like receptors (TLRs), a class
of transmembrane receptors that mediates the recognition of microbial pathogens by immune
cells such as monocytes, macrophages and neutrophils as well as by keratinocytes (see Ch.
4). TLR2 (which recognizes lipoproteins and peptidoglycans) is found on the surface of
macrophages surrounding acne follicles, and P. acnes has been found to increase expression
of TLR2 and TLR4 on keratinocytes. P. acnes has been shown to stimulate the release of
proinflammatory mediators (e.g. IL-1α, IL-8, IL-12, tumor necrosis factor-α [TNF-α], matrix
metalloproteinases) through the TLR2 pathway12–14. IL-8 results in neutrophil recruitment,
the release of lysosomal enzymes and subsequent disruption of the follicular epithelium,
whereas IL-12 promotes Th1 responses (see Ch. 4). The degree to which IL-8, IL-12 and
interferon-γ production is augmented does not appear to depend upon the strain of P. acnes
that is present14,15. In contrast, certain strains of P. acnes may have an increased propensity
to upregulate expression of human β-defensin-2 by the pilosebaceous unit via a TLR-
dependent mechanism14,16. Beta-defensin-2 (production of which is also augmented by
sebum free fatty acids), cathelicidins (expressed by sebocytes with upregulation by P. acnes),
and other antimicrobial peptides such as psoriasin (see Ch. 4) work synergistically to protect
the pilosebaceous unit from P. acnes17,18. Histone H4, which is secreted in a holocrine
manner by sebocytes, also directly kills P. acnes and may function together with free fatty
acids to augment innate immune defenses19. Lastly, P. acnes can induce monocytes to
differentiate into two distinct innate immune cell subsets: (1) CD209+ macrophages
(development of which is promoted by tretinoin) that more effectively phagocytose and kill
P. acnes; and (2) CD1b+ dendritic cells that activate T cells and release proinflammatory
cytokines20.
Hormonal Influences
Hormonal effects on sebum secretion are key to the pathogenesis of acne. Androgens are
produced both outside the sebaceous unit, primarily from the gonads and adrenal glands, and
locally within the gland via the action of androgen-metabolizing enzymes such as3β-
hydroxysteroid dehydrogenase (HSD), 17β-HSD and 5α-reductase (Fig. 36.2). Androgen
receptors, found in the cells of the basal layer of the sebaceous gland and the outer root
sheath of the hair follicle, are responsive to testosterone and 5α-dihydrotestosterone (DHT),
the most potent androgens. DHT has a 5–10-fold greater affinity than testosterone for the
androgen receptor and is thought to be the principal androgen mediating sebum production.
The role of androgens in sebaceous gland activity begins during the neonatal period. From
birth until approximately 6–12 months of age, infant boys have elevated levels of luteinizing
hormone (LH), which stimulates testicular production of testosterone. In addition, both male
and female infants exhibit increased levels of dehydroepiandrosterone (DHEA) and DHEA
sulfate (DHEAS) secondary to a large, androgenproducing “fetal zone” in the adrenal gland
that involutes over the first year of life. Of note, sebaceous gland activity in infants is not due
to persistent maternal hormonal stimulation, as was previously hypothesized. Both testicular
and adrenal androgen production decrease substantially by 1 year of age and remain at a
stable nadir until adrenarche. With the onset of adrenarche (typically at 7–8 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 precursor for the synthesis of more potent
androgens within the sebaceous gland (see Fig. 36.2). The rise in serum levels of DHEAS in
prepubescent 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 0.035–0.050 mg 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:
● directly opposing the effects of androgens locally within the
sebaceous gland
● inhibiting the production of androgens by gonadal tissue via a
negative feedback loop whereby pituitary gonadotropin release is
inhibited
● regulating genes that negatively influence sebaceous gland growth
or lipid production.
Dietary Factors
The relationship between diet and acne remains a subject of controversy. Over the past
decade, observational studies have found that milk intake (especially skim milk) is positively
associated with acne prevalence and severity, and prospective studies have documented a link
between a high glycemic-load diet and acne risk23.
CLINICAL FEATURES
Acne is typically found in sites with well-developed sebaceous glands, most often the face
and upper trunk. Non-inflammatory acne is characterized by open and closed comedones
(Fig. 36.3). The histologic features of these follicular-based lesions are reflected in their
clinical appearance. Closed comedones (whiteheads) are generally small (~1 mm), skin-
colored papules with no apparent follicular opening or associated erythema. These lesions
may be subtle and better appreciated upon palpation, stretching or side-lighting of the skin
(Fig. 36.4). In contrast, open comedones (blackheads) are dome-shaped papules with a
conspicuous dilated follicular opening that is filled with an inspissated core of shed keratin
(Fig. 36.5). Melanin deposition and lipid oxidation within the debris may be responsible for
the black coloration. “Ice-pick”-type scarring sometimes results from comedones alone.
Inflammatory acne also originates with (micro)comedo formation, followed by the
development of papules, pustules, nodules and cysts of varying severity (Figs 36.6 & 36.7).
Erythematous papules typically range from 1 to 5 mm in diameter. Pustules tend to be
approximately equal in size and are filled with white pus and normal flora. As the severity of
lesions progresses, nodules form and become markedly inflamed, indurated and tender. The
cysts of acne are deeper and filled with a combination of pus and serosanguineous fluid. In
patients with severe nodulocystic acne, these lesions frequently coalesce to form large,
complex inflamed plaques that can include sinus tracts. Early treatment of acne is essential
for the prevention of lasting cosmetic disfigurement due to scarring. Erythema and
postinflammatory hyperpigmentation (Fig. 36.8) often persist after resolution of
inflammatory acne lesions. Although the pigmentary changes usually fade over many months
if the acne is brought under control, occasionally they can be permanent. Unfortunately,
pitted scars (Fig. 36.9) or hypertrophic 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 regardless of
androgen levels, hormonal therapy is often effective. A predominantly comedonal, adult-
onset form of acne that is associated with smoking has also been described24.
Acne fulminans
Acne fulminans is the most severe form of acne and is characterized by the abrupt
development of nodular and suppurative acne lesions in association with systemic
manifestations. This uncommon variant primarily affects boys 13–16 years of age. Patients
typically have mild to moderate acne prior to the onset of acne fulminans, when numerous
microcomedones suddenly erupt and become markedly inflamed. There is rapid coalescence
into painful, oozing, friable plaques with hemorrhagic crusts (Fig. 36.10). The face, neck,
chest, back and arms are all affected. Lesions tend to ulcerate and can lead to significant
scarring. Osteolytic bone lesions may accompany the cutaneous findings; the clavicle and
sternum are most commonly affected, followed by the ankles, humerus and iliosacral joints.
Systemic manifestations include fever, arthralgias, myalgias, hepatosplenomegaly and severe
malaise. The related synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO)
syndrome, which can present with acne fulminans, is discussed in detail in Chapter 26.
Erythema nodosum may also arise in association with acne fulminans. Laboratory
abnormalities vary and include an elevated ESR, proteinuria, leukocytosis and anemia.
Labora tory studies are not required to establish the diagnosis, but their evolution may
parallel the clinical course and response to therapy. Treatment of acne fulminans usually
includes oral corticosteroids and oral isotretinoin, often with initiation of the latter at a low
dose and/or after the acute inflammation subsides. Paradoxically, an acne fulminans-like flare
occasionally develops during the first few weeks of isotretinoin therapy for acne25, and this
may be avoided by starting with a low dose of isotretinoin (see Ch. 126). Additional
treatment options for acne fulminans include topical or intralesional corticosteroids, oral
antibiotics (generally of limited efficacy), TNF-α inhibitors and immunosuppressive agents
(e.g. azathioprine). Dapsone may be particularly beneficial in the treatment of acne fulminans
associated with erythema nodosum26.
Acne conglobata and associated conditions
Acne conglobata is a severe form of nodulocystic acne that may have an eruptive onset but
without systemic manifestations. This recalcitrant acne variant is part of the follicular
occlusion tetrad, along with dissecting cellulitis of the scalp, hidradenitis suppurativa and
pilonidal cysts (see Ch. 38). The association of sterile pyogenic arthritis, pyoderma
gangrenosum, and acne conglobata can occur in the context of an autosomal dominant
autoinflammatory disorder referred to as PAPA syndrome, which is caused by mutations in
the gene that encodes proline–serine–threonine phosphatase interacting protein 1 (PSTPIP1;
also known as CD2 antigen-binding protein 1 [CD2BP1])27. Dysfunction of CD2BP1, which
has a role in actin reorganization and interacts with the pyrin protein (defective in familial
Mediterranean fever), compromises the physiologic signaling required for maintenance of a
proper inflammatory response. The triad of acne conglobata, hidradenitis suppurativa and
pyoderma gangrenosum has also been described outside the setting of PAPA syndrome27a.
Of note, a possible association between nodulocystic acne and inflammatory bowel disease
may potentially confound links that have been observed between the latter disorder and acne
therapies such as tetracyclines and isotretinoin27,27b.
Solid facial edema
An unusual and disfiguring complication of acne vulgaris is solid facial edema (Morbihan’s
disease). Clinically, there is a distortion of the midline face and cheeks due to soft tissue
swelling. The woody induration may be accompanied by erythema. Impaired lymphatic
drainage and fibrosis (potentially induced by mast cells) in the setting of chronic
inflammation are thought to be involved in the pathogenesis of solid facial edema, and a
report of its occurrence in identical twins with acne suggests that genetic factors may also
have a role. Similar changes have been described in patients with rosacea and Melkersson–
Rosenthal syndrome. Although fluctuations in severity are common, solid facial edema does
not usually resolve spontaneously. Treatment with isotretinoin (0.2–1 mg/kg/day), alone or in
combination with ketotifen (1–2 mg/day; not available in the US) or prednisone (10–30
mg/day), for 4–5 months has been reported to be useful.
Acne mechanica
Acne mechanica occurs secondary to repeated mechanical and frictional obstruction of the
pilosebaceous outlet. Comedo formation is the result. Well-described mechanical factors
include rubbing by helmets, chin straps, suspenders and collars. A classic example of acne
mechanica is fiddler’s neck, where repetitive trauma from violin placement on the lateral
neck results in a well-defined lichenified, hyperpigmented plaque interspersed with
comedones. Linear and geometrically distributed areas of involvement should suggest acne
mechanica. Treatment is aimed at eliminating the inciting forces.
Acne excoriée des jeunes filles
Acne excoriée des jeunes filles, as the name implies, occurs primarily in young women.
Typical comedones and inflammatory papules are systematically excoriated in a ritualistic
manner, leaving crusted erosions that may scar (see Ch. 7). Linear erosions suggest
selfmanipulation, and an underlying psychiatric component should be considered. Individuals
with an anxiety disorder, obsessive–compulsive disorder or personality disorder are
particularly at risk. Antidepressants or psychotherapy may be indicated in such patients.
Drug-induced acne
Acne or eruptive acneiform lesions can be seen as a side effect of a number of medications .
An abrupt, monomorphous eruption of inflammatory papules and pustules is often observed
in druginduced Acne, in contrast to the heterogeneous morphology of lesions seen in acne
vulgaris. This explains why some clinicians use the term “folliculitis”. High-dose intravenous
or oral corticosteroids commonly induce characteristic acneiform eruptions with a
concentration of lesions on the chest and back (see Fig. 36.12). Steroid-induced acne (and
rosacea) can also result from the inappropriate use of topical corticosteroids on the face.
Inflamed papules and pustules develop on a background of erythema that favors the
distribution of corticosteroid application. Lesions eventually resolve following
discontinuation of the corticosteroid, although “steroid dependency” can lead to prolonged
and severe flares post-withdrawal (see Ch. 37). When a history of prescription medication use
is not elicited, a comprehensive review of all over-the-counter medications and supplements,
as well as recent medical procedures, may reveal the responsible agent.
Occupational acne, acne cosmetica and pomade acne
Exposure to insoluble, follicle-occluding substances in the workplace is responsible for
occupational acne (see Ch. 16). Offending agents include cutting oils, petroleum-based
products, chlorinated aromatic hydrocarbons, and coal tar derivatives. Comedones dominate
the clinical picture, with varying numbers of papules, pustules and cystic lesions distributed
in exposed as well as typically covered areas. Primarily comedonal facial acne (with a
predominance of closed comedones) can also develop in areas of skin chronically exposed to
follicleoccluding cosmetics (acne cosmetica) or hair products (pomade acne; favors forehead
and temples).
Chloracne
Chloracne, the term used to define occupational acne caused by exposure to chlorinated
aromatic hydrocarbons, develops after several weeks of exposure. The malar, retroauricular
and mandibular regions of the head and neck (see Fig 16.13), as well as the axillae and
scrotum, are 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; polybrominated 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) has been proposed as the etiology by
some investigators, leading to renaming of the disorder as “neonatal cephalic pustulosis”.
Additional support for this view comes from the clinical response to treatment with topical
imidazoles (e.g. ketoconazole 2% cream). The active sebaceous glands and high sebum
excretion rate in neonates (see Pathogenesis) 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 benign nature of this
eruption, parental reassurance alone is usually adequate. However, as noted previously,
therapy with topical imidazoles can be effective.
Infantile acne
If acne presents at 3–12 months of age (occasionally as late as 18–24 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 6–12 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 1–2 years and remains quiescent 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 acne. Oral
antibiotics (e.g. erythromycin, azithromycin) can be helpful for patients with a more severe
inflammatory component, and isotretinoin is occasionally required for recalcitrant or
nodulocystic presentations30.
Endocrinologic abnormalities
Although most patients with acne do not have overt endocrinologic abnormalities,
hyperandrogenism should be suspected in female patients with hirsutism (see Ch. 70) or
irregular menstrual periods, as well as in children who develop acne between 2 and 7 years of
age. Acne in such patients is often severe or more difficult to treat, and the onset can be fairly
abrupt. Other signs and symptoms of hyperandrogenism in women and children include
coarsening of the voice, a muscular habitus, androgenetic alopecia, clitoromegaly with
variable posterior labial fusion, and increased libido. Insulin resistance and acanthosis
nigricans can occur in association with hyperandrogenism in the HAIR-AN syndrome. These
patients are at increased risk for accelerated cardiovascular disease and diabetes mellitus, and
they should be followed by appropriate medical specialists. The evaluation of patients
suspected of having hyperandrogenism includes a thorough history and physical examination;
the age of the patient and pubertal status are also important parameters. Prepubertal boys and
girls and postpubertal women with signs of hyperandrogenism should undergo appropriate
evaluation. Laboratory studies should not be performed while the patient is taking oral
contraceptives. Initial tests should include serum levels of total and free testosterone,
DHEAS, and 17-hydroxyprogesterone. Patients with clinical signs and symptoms suggestive
of hypercortisolism should also have an AM serum cortisol level, and X-rays of the hand and
wrist to evaluate bone age should be obtained in prepubertal children. Understanding
pathways of hormone production is essential in the evaluation of hyperandrogenic states (see
Fig. 70.15). For example, an elevated serum DHEAS or 17-hydroxyprogesterone level
indicates an adrenal source of excess androgen production. The degree to which levels of
these hormones are increased is then useful in discerning an etiology. DHEAS values in the
range of 4000–8000 ng/ml or 17-hydroxyprogesterone levels >3 ng/ml may be indicative of
congenital adrenal hyperplasia. Defects in adrenal enzymes, most commonly 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 >8000 ng/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 syndrome (PCOS) is the most common condition associated with an
elevated serum testosterone, with levels typically ranging from 100 to 200 ng/dl. An
increased LH/FSH ratio (>2–3) 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 200 ng/dl, an ovarian tumor should be
considered.
Acneiform Eruptions
Epidermal growth factor receptor inhibitor-induced
papulopustular eruption
Inhibitors of epidermal growth factor receptor (EGFR/HER1) signaling represent an
expanding class of therapeutic agents currently being used for the treatment of solid tumors,
including head and neck squamous cell carcinoma and lung, colon and breast carcinoma.
Inhibitors include gefitinib, cetuximab, erlotinib, lapatinib and panitumumab, with a number
of tyrosine kinase inhibitors and monoclonal antibodies in clinical trials or under
development (Fig. 36.15). The incidence of acneiform eruptions due to EGFR inhibitors is
very high, e.g. up to 95% of patients treated with panitumumab; additional cutaneous side
effects of these agents are presented in Table 21.14. In some studies, the presence or severity
of the acneiform eruption had a positive correlation with treatment outcomes (e.g. response
rate and survival time). Patients present with an eruption of monomorphous follicular
pustules and papules involving the face, scalp and upper trunk, usually 1–3 weeks after
beginning treatment with an EGFR inhibitor (Fig 36.16). Secondary infection with
Staphylococcus aureus often occurs, with oozing and the formation of honey-colored crusts.
While frequently described as acneiform, histopathology reveals a pattern of folliculitis, with
intrafollicular collections of neutrophils and perifollicular lymphocytes. No comedonal
lesions are seen either microscopically or clinically, further differentiating this eruption from
acne vulgaris. In the oncology patient, the differential diagnosis includes corticosteroid-
induced acne, various forms of folliculitis (e.g. Pityrosporum, Demodex spp.), neutrophilic
eccrine hidradenitis and viralassociated trichodysplasia spinulosa. Because discontinuation of
the medication is not an option in a patient who is responding to therapy, multiple treatments
have been tried with variable success, including topical and oral antibiotics, topical and (for
severe eruptions) oral corticosteroids, and topical and oral retinoids; prophylaxis with oral
doxycycline or minocycline may also be of benefit.
Tropical acne
Tropical acne is a follicular acneiform eruption that results from exposure to extreme heat.
This can occur in tropical climates or secondary to scorching occupational environments, as
in furnace workers. Historically, tropical acne caused significant morbidity among military
troops. Markedly inflamed nodulocystic acne involving the trunk and buttocks is typically
seen, and secondary staphylococcal infection is a frequent complication. Treatment is often of
limited efficacy until the patient returns to a more moderate climate.
Radiation acne
Radiation acne is characterized by comedo-like papules occurring at sites of previous
exposure to therapeutic ionizing radiation. The lesions begin to appear as the acute phase of
radiation dermatitis starts to resolve. The ionizing rays induce epithelial metaplasia within the
follicle, creating adherent hyperkeratotic plugs that are resistant to expression.
Treatment
The most common side effect of topical retinoids is local irritation
resulting in erythema, dryness, peeling and scaling. Delivery systems
have been developed to permit a greater concentration of retinoid while
decreasing irritancy, primarily through controlled slow release (e.g.
tretinoin impregnated into inert microspheres or incorporated within
a polyolprepolymer). A pustular flare of acne occasionally occurs during
the initial 3–4 weeks of treatment with a topical retinoid. This resolves
spontaneously with continued usage. Thinning of the stratum corneum
and irritation may also increase the user’s susceptibility to sunburn.
Therefore, the use of sunscreens should be advised.
Tretinoin (all-trans-retinoic acid), a naturally occurring metabolite of
retinol, was the first topical comedolytic agent used for the treatment
of acne. Because tretinoin is photolabile, night-time application is recommended
to prevent early degradation. To decrease the potential for
irritation, treatment is often started with a lower-concentration cream
formulation of tretinoin and the strength later increased (or the vehicle
changed to a gel). Alternate-night to every-third-night application may
be necessary initially, with increased frequency as tolerated. Stepwise
increments are typically done at 3–4-week intervals.
Although epidemiologic studies have not shown an increased risk of
birth defects in infants of mothers using topical tretinoin during the
first trimester, sporadic case reports of birth defects have been published35,36.
Because of this and the fact that systemic retinoids are
known teratogens, the use of topical tretinoin in pregnancy is discouraged.
However, dietary intake of vitamin A has been shown to have a
greater influence on serum retinoid levels than facial application of
tretinoin37.
The synthetic retinoid adapalene is an aromatic naphthoic acid derivative
(see Fig. 126.1). In the skin, it primarily binds the retinoic acid
receptor γ (RARγ), whereas tretinoin binds to both RARα and RARγ.
Although animal studies have shown adapalene to have milder comedolytic
properties than tretinoin, it is also less irritating38. Unlike tretinoin,
adapalene is light-stable and resistant to oxidation by benzoyl
peroxide.
Tazarotene is a synthetic acetylenic retinoid that, once applied, is
converted into its active metabolite, tazarotenic acid. Like adapalene,
this metabolite selectively binds RARγ but not RARα or RXR (see Ch.
126). Both daily overnight application of tazarotene and short contact
therapy regimens have been used and shown to be effective in the treatment
of comedonal and inflammatory acne. Topical tazarotene has
been designated pregnancy category X, so contraceptive counseling
should be provided to all women of childbearing age who are prescribed
this medication.
Benzoyl peroxide and other topical antibacterial agents
Benzoyl peroxide is a potent bacteriocidal agent that reduces P. acnes
within the follicle. It also has mild comedolytic properties and is particularly
effective when used in combination with other therapies. In
contrast to topical antibiotics, microbial resistance to benzoyl peroxide
has not been reported. Many preparations for all skin types are available
in both over-the-counter and prescription formulations. These include
bar soaps, washes, gels, lotions, creams, foams and pads in concentrations
ranging from 2.5% to 10% as well as products that combine
benzoyl peroxide with clindamycin, erythromycin or adapalene. As
benzoyl peroxide is a bleaching agent, whitening of clothing and bedding
can occur. Development of contact dermatitis (irritant > allergic) to 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
available alone as well as in combination with benzoyl peroxide or a
retinoid. Clindamycin and erythromycin represent the two most commonly
utilized antibiotics and the formulations vary from creams and
gels to solutions and pledgets (see Ch. 127).
Azelaic acid is a naturally occurring dicarboxylic acid found in cereal
grains. It is available as a topical cream and gel, which have been shown
to be effective in inflammatory and comedonal acne. By inhibiting the
growth of P. acnes, azelaic acid reduces inflammatory acne. It also
reverses the altered keratinization of follicles affected by acne and thus
demonstrates comedolytic properties. The activity of azelaic acid
against inflammatory lesions may be greater than its activity against
comedones. Azelaic acid is applied twice daily and its use is reported
to have fewer local side effects than topical retinoids. In addition, it
may help to lighten postinflammatory hyperpigmentation.
Sodium sulfacetamide is a well-tolerated topical antibiotic that is
thought to restrict the growth of P. acnes through competitive inhibition
of the condensation of para-aminobenzoic acid with pteridine
precursors (see Ch. 127). It is formulated in a 10% lotion, suspension,
foam and cleanser, either alone or in combination with 5% sulfur.
Tinted formulations are also available.
Topical dapsone 5% gel is approved for the treatment of acne vulgaris.
Of note, a temporary yellow–orange staining of the skin and hair occasionally
occurs with concomitant use of topical dapsone and benzoyl
peroxide.
Other topical medications
Salicylic acid is a widely used comedolytic and mild anti-inflammatory
agent (see Ch. 153). It is also a mild chemical irritant that works in
part by drying up active lesions. Salicylic acid is available over the
counter in concentrations of up to 2% in numerous delivery formulations,
including gels, creams, lotions, foams, solutions and washes. Side
effects of topical salicylic acid include erythema and scaling.
Oral Treatments
Antibiotics
Oral tetracycline derivatives, especially doxycycline and minocycline,
and less often macrolides (e.g. erythromycin, azithromycin) are prescribed
for moderate to severe inflammatory acne unresponsive to
topical combinations. In this setting, the primary mechanism of action
of these agents is suppression of the growth of P. acnes, thereby reducing
bacterial production of inflammatory factors. However, several of
these antibiotics also possess intrinsic anti-inflammatory properties.
Details regarding the mechanisms of action, recommended dosages,
and side effects of tetracyclines and macrolides are reviewed in Chapter
127. Resistance of P. acnes to erythromycin and the three major tetracyclines
(tetracycline and doxycycline more so than minocycline) has
been reported. The enhanced efficacy of minocycline, a lipophilic derivative
of tetracycline, may be due to its greater penetration into the
sebaceous follicle; however, it is also associated with a higher incidence
of serious adverse events, including a minocycline-induced hypersensitivity
syndrome and autoimmune reactions (see Ch. 21). The latter
typically develop after many months to years of therapy and can
include hepatitis, a lupus erythematosus-like syndrome and cutaneous
polyarteritis nodosa (often associated with antineutrophil cytoplasmic
antibodies).
Hormonal therapy
Hormonal therapy is an established second-line treatment for female
patients with acne and can be very effective, irrespective of whether or
not the serum androgen levels are abnormal. Although women and girls
with acne may have higher serum levels of androgens than those
without acne, the levels in acne patients are often within the normal
range. Hormonal therapies seem to work best in adult women with
inflammatory papules and nodules that tend to flare in the week prior
to menstruation and involve the lower face and neck. These patients
often note little improvement in their acne despite multiple courses of
various oral antibiotics.
In such patients, hormonal therapy with oral contraceptives, which
block both ovarian and adrenal production of androgens, can be initiated and oral antibiotics
discontinued. The use of oral contraceptives is also
indicated for women of childbearing potential if treatment with spironolactone
is anticipated (see below). Because of the potential risks associated
with oral contraceptive use and the need for breast and pelvic
examinations, consultation with a gynecologist is recommended.
Most oral contraceptive formulations combine an estrogen with a
progestin in order to minimize the risk of endometrial cancer, which is
known to occur with unopposed estrogen administration. Although
progestins have intrinsic androgenic activity, second-generation,
low-androgenic progestins (e.g. ethynodiol diacetate, norethindrone,
levonorgestrel) have been developed. Newer, third-generation progestins
(e.g. desogestrel, norgestimate, gestodene [Europe]) have even less
androgenic activity than their predecessors, and other progestins (e.g.
drospirenone, cyproterone acetate, dienogest) have antiandrogenic
properties.
Three oral contraceptives are currently FDA-approved for the treatment
of acne, although others also have evidence of efficacy39 (Table
36.6). The first is a triphasic oral contraceptive composed of a
norgestimate–ethinyl estradiol (35 mcg) combination. The second contains
a graduated dose of ethinyl estradiol (20–35 mcg) in combination
with norethindrone acetate, while the third contains a stable dose of
ethinyl estradiol (20 mcg) plus drospirenone (3 mg) with a 24-day
dosing regimen. Side effects from oral contraceptives include nausea,
vomiting, abnormal menses, weight gain and breast tenderness; agents
containing drospirenone can lead to elevations in serum potassium
levels, but this is generally not clinically significant in otherwise healthy
individuals. Rare but more serious complications include hypertension
and thromboembolism (e.g. deep venous thrombosis, pulmonary embolism).
The increase in risk of the latter ranges from 2–4-fold with
levonorgestrel or norethindrone to 3.5–7-fold with desogestrel, drospirenone
and cyproterone acetate40,41; it is higher for women over the
age of 35 years, smokers and those with other prothrombotic risk
factors (e.g. hereditary thrombophilia)42.
The progestational antiandrogen cyproterone acetate is currently
marketed in Europe and Canada but is not available in the US. Its
anti-acne effects are mediated primarily through androgen receptor
blockade. The standard formulation combines cyproterone acetate (2 mg) with ethinyl
estradiol (35 or 50 mcg) in an oral contraceptive
formulation. This preparation is widely used in Europe as the treatment
of choice for sexually active women with hormonally responsive acne.
Singular formulations of cyproterone acetate are also available. Studies
have indicated that approximately 75–90% of patients treated with
doses of 50–100 mg daily (with or without ethinyl estradiol 50 mcg)
show substantial improvement43. Although similar efficacy has been
reported for the 2 mg cyproterone acetate dose in the oral contraceptive
formulation, higher doses (e.g. on days 5–14 of the menstrual cycle)
may be helpful in women with severe hyperandrogenism. The most
frequent side effects are breast tenderness, headache, nausea and irregular
menses; hepatotoxicity or thromboembolism represent uncommon
complications.
Spironolactone functions as both an androgen receptor blocker and
an inhibitor of 5α-reductase. In doses of 50–100 mg twice daily, it has
been shown to reduce sebum production and improve acne44. Side
effects are dose-related and include potential hyperkalemia, irregular
menstrual periods, breast tenderness, headache and fatigue. However,
hyperkalemia is rare in young healthy patients. Although breast tumors
have been reported in rodent models given spironolactone, this drug
has not been directly linked to the development of cancer in humans45.
Because it is an antiandrogen, there is a risk of feminization of a male
fetus if a pregnant woman takes this medication. The potential risk to
a fetus and the symptoms of irregular menstrual bleeding can be alleviated
by combining spironolactone with an oral contraceptive. Side
effects can also be minimized if therapy is initiated with a low dose
(25–50 mg/day). Effective maintenance doses range from 25 to 200 mg/
day. As with other hormonal therapies, a clinical response may take up
to 3 months.
Records were reviewed of 85 women treated with 50–100 mg daily
of spironolactone, administered either as a single agent or as an adjunct
to standard therapies46. The maximum length of treatment was 24
months. Clearing of acne occurred in 33% of women treated with lowdose
spironolactone, 33% had marked improvement, 27% showed
partial improvement and 7% showed no improvement. The treatment
was well tolerated, with 58% reporting no adverse effects. Menstrual
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, postural
hypotension and nausea. Slight elevations in serum potassium
(range 4.8–5.3 mEq/l) were identified in 13.7% of the 73 patients examined,
but this was not considered to be clinically significant. The following
benefits were noted in some patients: an improvement in
premenstrual syndrome, decreased facial oiliness, decreased metrorrhagia,
reduced endometriosis pain and increased libido. The results of
this study suggested that:
● most side effects of spironolactone are dose-dependent, including
menstrual irregularities (the most common side effect)
● CNS symptoms are also relatively common, but appear to be
unrelated to dose
● hyperkalemia may be measurable but is clinically insignificant in
the absence of cardiac or renal disease
● reductions in blood pressure are slight, but rarely can be associated
with orthostatic symptoms.
Flutamide, a nonsteroidal androgen receptor blocker that is approved
by the FDA for the treatment of prostate cancer, can also be an effective
treatment for acne in women at doses of 62.5–500 mg/day. In addition
to side effects similar to those of other antiandrogens (e.g. menstrual
irregularities, breast tenderness, risk of feminization of a male fetus),
severe dose-related hepatotoxicity occasionally occurs.
Isotretinoin
Since 1971, oral isotretinoin (13-cis-retinoic acid) has been available in
Europe for the treatment of acne. Twelve years later, the FDA approved
it for patients with severe, nodulocystic acne refractory to treatment,
including oral antibiotics. Over time, other clinical forms of acne have
also been shown to benefit greatly from the use of isotretinoin47. These
include significant acne that is unresponsive to therapy (including
oral antibiotics) and/or results in scarring, as well as Gram-negative
folliculitis, pyoderma faciale and acne fulminans. The mechanism of
action of isotretinoin, as well as dosing regimens, side effects and
monitoring protocols, are discussed in detail in Chapter 126.

Patients with acne are typically treated with an isotretinoin dose of

0.5–1 mg/kg/day (taken with a fatty meal to increase gastrointestinal
absorption), often with a lower dose during the first month of treatment
to prevent an initial acne flare and to allow the patient to adjust to
dose-dependent side effects. Reaching a cumulative dose of 120–150 mg/
kg (e.g. 4–5 months of treatment with 1 mg/kg/day) has been shown to
reduce the risk of relapse. However, a 6-month course of low-dose
isotretinoin (e.g. 0.25–0.4 mg/kg/day, 40–70 mg/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 nodulocystic
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 2–3
months is recommended before starting another course of therapy.
Scarred nodules and sinus tracts that represent sequelae from previously
active cystic acne are not isotretinoin-responsive but may improve
with surgical modalities, which are generally delayed at least 6–12
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 cheilitis,
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),
and female patients of childbearing potential must have at least one (in
the US, two) negative pregnancy test(s) before starting treatment and
practice effective contraception for 1 month prior to, during, and for 1
month after completing therapy. In the US, prescription of isotretinoin
requires all physicians and patients to register with a pregnancy risk
management program (iPLEDGE™), which mandates monthly office
visits for all patients (with counseling not to share the medication) and
monthly pregnancy testing for female patients with childbearing potential.
Isotretinoin therapy leads to elevated serum triglyceride levels in
25–50% of patients and may have side effects involving the musculoskeletal
system (most often myalgias), eyes, liver (occasionally elevated
transaminases); intestines (controversial link to inflammatory
bowel disease) and central nervous system (see Table 126.8 and Ch.
126). To date, no firmly established causal association with depression
or suicide attempts has been demonstrated.
Surgical Treatment
Comedo extraction can improve the cosmetic appearance of acne and
aid in therapeutic responsiveness to topical comedolytic agents. The
keratinous contents of open comedones may be expressed using a
comedo extractor. The Schamberg, Unna and Saalfield types of comedo
expressers are most commonly used. Nicking the surface of a closed
comedo with an 18-gauge needle or a #11 blade allows easier expression.
Extraction is especially beneficial for deep, inspissated and persistent
comedones. This procedure should be used in conjunction with a
topical retinoid or other comedolytic treatment for maximum benefit.
Comedo extraction should not be performed on inflamed comedones
or pustules because of the risk of scarring. Light electrocautery and
electrofulguration (see Ch. 140) have also been reported as effective
treatments for comedones. Electrofulguration has the added benefit of
not requiring the prior use of a topical anesthetic. In selected patients,
cryotherapy represents another surgical option for the treatment of
comedonal acne (see Ch. 138).
Photodynamic therapy utilizing topical 5-aminolevulinic acid together
with various light sources (e.g. blue, red, intense pulsed) or lasers (e.g. pulsed dye, 635 nm
red diode) as well as methyl aminolevulinate plus
red light have been successfully used to treat acne (see Ch. 135). In
addition, blue or intense pulsed light alone and lasers such as the pulsed
dye, the 1320 nm neodymium:YAG and especially the 1450 nm diode
may be of therapeutic benefit for inflammatory acne (see Ch. 137).
Intralesional injection of corticosteroid (triamcinolone acetonide
2–5 mg/ml) can quickly improve the appearance and tenderness of
deep, inflamed nodules and cysts. Larger cysts may require incision and
drainage prior to injection. The maximal amount of corticosteroid used
per lesion should not exceed 0.1 ml. The risks of corticosteroid injections
include hypopigmentation (particularly in darkly pigmented skin),
atrophy, telangiectasias, and needle tract scarring.
Low-concentration chemical peels are also beneficial for the reduction
of comedones. The α-hydroxy acids (including glycolic acid), salicylic
acid and trichloroacetic acid are the most common peeling agents.
These lipid-soluble comedolytic agents act by decreasing corneocyte
cohesion at the follicular opening and assist in comedo plug extrusion.
Such agents are generally well tolerated by most skin colors and types,
and they can be used by the patient at home or in the dermatologist’s
office. Higher-concentration glycolic acid peels (20–70%, depending on
the patient’s skin type) and the less predictable phenol peel may also
be performed in the office setting. Risks of chemical peels include irritation,
pigmentary alteration and scarring.
One of the most distressing consequences of acne vulgaris is scarring.
Surgical treatments should be aimed at the type of scarring present.
Laser resurfacing (fractional as well as traditional), dermabrasion and
deeper chemical peels seek to reduce the variability of the skin surface
and smooth out depressed scars that improve when the skin is stretched.
For discrete depressed scars, soft tissue augmentation can be temporarily
beneficial. Filler substances used include poly-L-lactic acid, calcium
hydroxylapatite and autologous fat (see Ch. 158). Punch grafting is an
option for patients with “ice-pick” scarring. Surgical subscision is also
a commonly used technique in the management of acne scars. For
larger hypertrophic scars, aggregated pitted scars and sinus tracts, fullthickness
surgical excision may result in improved scar placement and
a better cosmetic appearance.
James WD, Berger TG, Elston DM. Acne. Andrew’s Disease of
the skin clinical dermatology. 2011;11:228-234

Acne
Acne vulgaris
Clinical features
Acne vulgaris is a chronic inflammatory disease of the pilosebaceous
follicles, characterized by comedones, papules, pustules,
nodules, and often scars. The comedo is the primary
lesion of acne. It may be seen as a flat or slightly elevated
papule with a dilated central opening filled with blackened
keratin (open comedo or blackhead) (Fig. 13-1). Closed comedones
(whiteheads) are usually 1 mm yellowish papules that
may require stretching of the skin to visualize. Macrocomedones,
which are uncommon, may reach 3–4 mm in size. The papules
and pustules are 1–5 mm in size, and are caused by inflammation,
so there is erythema and edema (Fig. 13-2). They may
enlarge, become more nodular, and coalesce into plaques of
several centimeters that are indurated or fluctuant, contain
sinus tracts, and discharge serosanguinous or yellowish pus
(Fig. 13-3).
Patients will typically have a variety of lesions in various
states of formation and resolution. In light-skinned patients,
lesions often resolve with a reddish-purple macule that is
short-lived. In dark-skinned individuals, macular hyperpigmentation
results and this may last several months (Fig. 13-4).
Acne scars are heterogeneous in appearance. Morphologies
include deep, narrow ice-pick scars seen most commonly on
the temples and cheeks, canyon-type atrophic lesions on the
face (Fig. 13-5), whitish-yellow papular scars on the trunk and
chin, anetoderma-type scars on the trunk, and hypertrophic
and keloidal elevated scars on the neck and trunk.
Acne affects primarily the face, neck, upper trunk (Fig. 13-6),
and upper arms. On the face it occurs most frequently on the
cheeks, and to a lesser degree on the nose, forehead, and chin.
The ears may be involved, with large comedones in the concha,
cysts in the lobes, and sometimes pre- and retro-auricular
comedones and cysts. On the neck, especially in the nuchal
area, large cystic lesions may predominate.
Acne typically begins at puberty and is often the first sign
of increased sex hormone production. When acne begins at the
age of 8–12 years, it is frequently comedonal in character,
affecting primarily the forehead and cheeks. It may remain
mild in its expression with only an occasional inflammatory
papule. However, as hormone levels rise into the middle
teenage years, more severe inflammatory pustules and nodules
occur, with spread to other sites. Young men tend to have an
oilier complexion and more severe widespread disease than
young women. Women may experience a flare of their papulopustular
lesions a week or so before menstruation. Acne may
also begin in 20–35-year-old women who have not experienced
teenage acne. This acne frequently manifests as papules,
pustules, and deep painful persistent nodules on the jawline,
chin, and upper neck.
Acne is primarily a disease of the adolescent, with 85% of
all teenagers being affected to some degree. It occurs with greatest frequency between the
ages of 15 and 18 in both sexes.
Generally, involution of the disease occurs before age 25;
however, great variability in age at onset and of resolution
occurs. Around 12% of women and 3% of men will continue
to have clinical acne until 44 years of age. A few will have
inflammatory papules and nodules into late adulthood.
Neonatal acne is a common condition that develops a few
days after birth, has a male sex preponderance, and is characterized
by transient facial papules or pustules which usually
clear spontaneously in a few days or weeks (Fig. 13-7). Infantile
acne includes those cases that persist beyond the neonatal
period or have an onset after the first 4 weeks of life. The acne process can extend into
childhood, puberty, or adult life. In
prolonged cases, topical benzoyl peroxide, erythromycin, or
the retinoids may be effective. With more inflammatory
disease, oral erythromycin, 125 mg twice a day, or trimethoprim,
100 mg twice a day, may be added to topical medications.
Oral isotretinoin has been utilized in the infantile period
and is effective. Childhood acne may evolve from persistent
infantile acne or begin after age 2. It is uncommon and has a
male predominance. Grouped comedones, papules, pustules,
and nodules can occur alone or in any combination, usually
limited to the face (Fig. 13-8). The duration is variable, from a
few weeks to several years, and occasionally extends into more
severe pubertal acne. Often there is a strong family history of
moderately severe acne.
Pathogenesis
Acne vulgaris is exclusively a follicular disease, with the principle
abnormality being comedo formation. It is produced by
the impaction and distension of the follicles with a keratinous
plug in the lower infundibulum. The keratinous plug is caused
by hyperproliferation and abnormal differentiation of keratinocytes
of unknown causes. Androgens, alterations in lipid composition,
and an abnormal response to local cytokines are all
hypothesized to be important. Androgen stimulation of the
sebaceous glands is critical. Acne begins after sebum secretion
increases and women with hyperandrogenic states often manifest
acne, along with hirsutism and menstrual abnormalities.
Treatment directed at reducing sebaceous secretion, such as
isotretinoin, estrogens or antiandrogens, is effective in clearing
acne.
As the retained cells block the follicular opening, the lower
portion of the follicle is dilated by entrapped sebum. Disruption
of the follicular epithelium permits discharge of the follicular
contents into the dermis. The combination of keratin, sebum,
and microorganisms, particularly Propionibacterium acnes,
leads to the release of proinflammatory mediators and the accumulation of lymphocytes,
neutrophils, and foreign body
giant cells. This, in turn, causes the formation of inflammatory
papules, pustules, and nodulocystic lesions.
Additional factors may exacerbate acne or, in a predisposed
patient, cause the onset of acne. Comedogenic greasy or
occlusive products may induce closed comedones and at times
inflammatory lesions. Other types of cosmetics may initiate or
worsen acne, but acne cosmetica is uncommon as most cosmetics
are tested for comedogenicity.
Many types of mechanical or frictional forces can aggravate
existing acne. A common problem is the overexuberant
washing some patients feel may help rid them of their blackheads
or oiliness. A key feature of mechanical or frictional acne
is an unusual distribution of the acne lesions. Provocative
factors include chin straps, violins, hats, collars, surgical tape,
orthopedic casts, chairs, and seats. One acne patient who had
laser hair removal developed flares of inflammatory lesions
localized to the acne-prone sites after each laser session; the
legs and abdomen were spared. All the above factors are likely
to irritate the follicular epithelium and exacerbate the changes
that lead to comedogenesis and follicular rupture. Prophylactic
measures designed to interdict these various mechanical forces
are beneficial.
In all women or children with acne the possibility of a hyperandrogenic
state should be considered. In the former, the presence
of irregular menses, hirsutism, or androgenetic alopecia
increases the likelihood of finding clinically significant hyperandrogenism.
Additionally, gynecologic endocrine evaluation
may be indicated in women who have acne resistant to conventional
therapy, who relapse quickly after a course of
isotretinoin, or in whom there is a sudden onset of severe acne.
Screening tests to exclude a virilizing tumor include serum
dehydroepiandrosterone sulfate (DHEAS) and testosterone,
obtained 2 weeks before the onset of menses. DHEAS levels
may be very high in adrenal tumors (>800mcg/dl) or less dramatic
in congenital adrenal hyperplasia (400–800mcgm/dl).
Ovarian tumor is suggested by testosterone levels above
200 ng/dL. Many patients with late-onset congenital adrenal
hyperplasia will have normal levels of DHEAS. Although
17-hydroxyprogesterone and adrenocorticotropic hormone
(ACTH) stimulation tests have been used in this setting, the
baseline 17-hydroxyprogesterone may be normal in some
women with adult 21-hydroxylase deficiency, and ACTH stimulation
may result in overdiagnosis of the syndrome. It is not
clear that screening for adult-onset 21-hydroxylase deficiency
improves patient outcome. Patients with polycystic ovarian
syndrome (PCOS) may have a high serum testosterone level
(150–200 ng/dL) or an increase in the luteinizing hormone
(LH)/follicle stimulating hormone (FSH) ratio (>2–3), but
recent American College of Obstetricians and Gynecologists
(ACOG) guidelines suggest that laboratory and imaging
studies are best used to exclude a virilizing tumor. The diagnosis
of PCOS is made clinically by the presence of anovulation
(fewer than nine periods per year or periods >40 days apart)
and signs of hyperandrogenism, such as acne and hirsutism.
Acne neonatorum is explained by circulating maternal hormones,
whereas acne extending or developing after the neonatal
period may be a form of acne cosmetica, acne venenata,
drug-induced acne, or part of an endocrinologic disorder. In
the absence of any of these etiologies, qualitative or quantitative
alterations of cutaneous androgen, metabolism, or
increased end-organ sensitivity could be postulated as pathogenetic
mechanisms for preadolescent acne.

Treatment
General principles
It is important to take a complete historical record of prior
therapies, including all over-the-counter products. The dose,
timing, combinations, side effects, and response to interventions
should be obtained. Corticosteroids, anabolic steroids,
neuroleptics, lithium, and cyclosporine may worsen acne. A
family history of acne and, if present, its tendency to scarring
should be noted. Women should be queried regularly about
menstrual irregularities and hair growth in a male pattern, as
well as use of cosmetics.
Failure of treatment may be because of drug interactions,
coexisting conditions, or antibiotic resistance; however, the
most common and important cause is lack of adherence
to the treatment plan. Utilizing medications that are well
tolerated, have convenient dosing regimens, and are cosmetically
acceptable will help, but thorough patient education is
essential. Explaining how lesions form, and the expected
response to, and duration and possible side effects of treatment,
and giving clear unambiguous instructions are key.
Patients should be aware of the difference between active
inflammatory lesions and the purplish-red or hyperpigmented
macules of inactive resolved lesions. Topical application to the
entire affected area rather than to specific lesions should be
emphasized, and the fact that oral and topical medications
should be used daily as the treatment is preventative in nature
should be discussed.
A high glycemic diet may worsen acne, however the strength
of its influence is unknown. The authors do not counsel
patients to alter their diets. Scrubbing of the face increases
irritation and may worsen acne. Use of only the prescribed
medications and avoidance of potentially drying over-thecounter
products, such as astringents, harsh cleansers, or antibacterial
soaps, should be emphasized. Non-comedogenic
cosmetics are recommended, and pressed powders and oilbased
products should be avoided.
Medical therapy
Systemic and topical retinoids, systemic and topical antimicrobials,
and systemic hormonal therapy are the main therapeutic
classes of treatment available. Treatment guidelines are outlined
in Box 13-1.
Topical treatment
As all topical treatments are preventative, use for 6–8 weeks
is required to judge their efficacy. The entire acne-affected area
is treated, not just the lesions, and long-term usage is the rule.
In many patients, topical therapy may be effective as maintenance
therapy after initial control is achieved with a combination
of oral and topical treatment.
Topical retinoids It has long been appreciated that these
agents are especially effective in promoting normal desquamation
of the follicular epithelium; thus, they reduce comedones
and inhibit the development of new lesions. Additionally, they
have a marked anti-inflammatory effect, inhibiting the activity
of leukocytes, the release of proinflammatory cytokines and
other mediators, and the expression of transcription factors
and toll-like receptors involved in immunomodulation. They
also help penetration of other active agents. Thus, they should preferred
agents in maintenance therapy.
Tretinoin was the first of this group of agents to be used for
acne. Popular forms of tretinoin are 0.025% and 0.05% in a
cream base because these are less irritating than the gels and
liquids. Its incorporation into microspheres and a polyolprepolymer
also helps to limit irritation and make the product
more stable in the presence of light and oxidizers. Tretinoin
treatment may take 8–12 weeks before improvement occurs.
When patients are tolerating the medication and are slow to
respond, retinoic acid gel or solution may be utilized. Tretinoin
should be applied at night and is in pregnancy category C.
Adapalene is a well-tolerated retinoid-like compound,
which has efficacy equivalent to the lower concentrations
of tretinoin. As it is light-stable, it may be applied in either
the morning or the evening. It is in pregnancy category C.
Tazarotene is comparatively strong in its action, but also relatively
irritating. It should be applied once at night or every
other night, and as it is in pregnancy category X, contraceptive
counseling should be provided.
Initially utilizing retinoids on an every-other-night basis, or
using a moisturizer with them, may lessen their irritancy. They
are also particularly useful in patients with skin of color as
they may lighten postinflammatory hyperpigmentation.
Benzoyl peroxide Benzoyl peroxide has a potent antibacterial
effect. P. acnes resistance does not develop during use. Its
concomitant use during treatment with antibiotics will limit
the development of resistance, even if only given for short 2- to
7-day pulses. While it is most effective in inflammatory acne,
some studies have shown it to be comedolytic also. The wash
formulations may be utilized for mild trunkal acne when systemic
therapies are not required.
Treatment is usually once or twice a day. Benzoyl peroxide
may irritate the skin and produce peeling. Water-based formulations
of lowest strength are least irritating. Application
lessened to once a day or every other day will also help limit
this. Allergic contact dermatitis will rarely develop, suggested
by the complaint of itch rather than stinging or burning. It is
in pregnancy category C.
Topical antibacterials Topical clindamycin and erythromycin
are available in a number of formulations. In general,
they are well tolerated and are effective in mild to moderate
inflammatory acne. These topical products are in pregnancy
category B. Use of these topical antibiotics alone, however, is
not recommended because of increasing antibiotic resistance.
As mentioned above, concurrent therapy with benzoyl peroxide
will limit this problem. Concomitant use with a topical
retinoid will hasten the response and allow for more rapid
discontinuance of the antibiotic. Dapsone is available topically
in a gel formulation. Hemolytic anemia may occur and a
discoloration of the skin is not uncommon when benzoyl
peroxide is applied after topical dapsone. Additionally,
concomitant oral use of trimethoprim/sulfamethoxazole will
increase the systemic absorption of topical dapsone. It is in
pregnancy category C.
Sulfur, sodium sulfacetamide, resorcin, and salicylic acid
Although benzoyl peroxide, retinoids, and topical antibiotics
have largely supplanted these older medications, sulfur,
resorcin, and salicylic acid preparations are still useful and
moderately helpful if the newer medications are not tolerated.
They are frequently found in over-the-counter preparations.
Sulfacetamide–sulfur combination products are mildly effective
in both acne and rosacea. The latter should be avoided in
patients with known hypersensitivity to sulfonamides.
Azelaic acid This dicarboxylic acid is remarkably free from
adverse actions and has mild efficacy in both inflammatory
and comedonal acne. It may help to lighten postinflammatory
hyperpigmentation and is in pregnancy category B.
Combination topical therapy Several products are available
which combine antibiotics such as clindamycin and benzoyl
peroxide, or retinoids and either antibiotics or benzoyl peroxide.
In general these medications increase adherence, as they
require less frequent application of medication, and they may
also limit irritation compared with the cumulative topical
application of each product separately. However, they limit
flexibility and may cause more irritation than a single product
used alone.
Oral antibiotics
These agents are indicated for moderate to severe acne, in
patients with inflammatory disease in whom topical combinations
have failed or are not tolerated, for the treatment of chest,
back, or shoulder acne, or in patients in whom absolute control
is deemed essential, such as those who scar with each lesion
or develop inflammatory hyperpigmentation. It generally
takes 6–8 weeks to judge efficacy. Starting at a high dose and
reducing it after control is preferred. Working to maintain
control eventually with topical retinoids or retinoid–benzoyl
peroxide combination therapy is ideal; however, keeping
patients free of disease for 1–2 months before each decrease in
dosage is best to prevent flaring. Most courses of oral therapy
are of at least 3–6 months’ duration.
There is concern that oral antibiotics may reduce the effectiveness
of oral birth control pills. It is appropriate for this as
yet unproved (except with rifampin, which is not used for
acne) association to be discussed with patients and a second
form of birth control offered.
Tetracycline Tetracycline is the safest and cheapest choice,
and will give a positive response in many patients. It is usually
given at an initial dose of 250–500 mg 1–4 times a day, with
gradual reduction of the dose, depending on clinical response.
It is best taken on an empty stomach, at least 30 min before
meals and 2 h afterwards, which often limits dosage to twice tetracycline, reducing
absorption by as much as half.
Vaginitis or perianal itching may result from tetracycline
therapy in about 5% of patients, with Candida albicans usually
present in the involved site. The only other common side
effects are gastrointestinal symptoms such as nausea. To
reduce the incidence of esophagitis, tetracyclines should not
be taken at bedtime. Staining of growing teeth occurs, precluding
its use in pregnant women and in children under the age
of 9 or 10. Tetracycline should also be avoided when renal
function is impaired.
Doxycycline The usual dose is 50–100 mg once or twice a
day, depending on the disease severity. Photosensitivity reactions
are not uncommon with this form of tetracycline and can
be dramatic. Subantimicrobial-dose doxycycline, doxycycline
hyclate 20 mg, may be given twice daily. The advantage of
this is that the anti-inflammatory activity is being utilized
but no antibiotic resistance results because of the low dose.
A sustained-release 40 mg formulation is also available. These
low-dose preparations appear to be of low efficacy, however.
Minocycline Minocycline is the most effective oral antibiotic
in treating acne vulgaris. In patients whose P. acnes develops
tetracycline resistance, minocycline is an alternative. The usual
dose is 50–100 mg once or twice a day, depending on the
severity of disease. Its absorption is less affected by milk and
food than is that of tetracycline. Vertigo may occur and beginning
therapy with a single dose in the evening may be prudent.
An extended-release preparation is also available, which limits
the vestibular side effects. Pigmentation in areas of inflammation,
of oral tissues, in postacne osteoma or scars, in a photodistributed
pattern, on the shins, in the sclera, nailbed, ear
cartilage, teeth, or in a generalized pattern may also be
seen (Fig. 13-9). Additionally, lupus-like syndromes, a hypersensitivity
syndrome (consisting of fever, hepatitis, and
eosinophilia), serum sickness, pneumonitis, and hepatitis
are uncommon but potentially serious adverse effects of
minocycline.
Erythromycin For those who cannot take tetracyclines
because of side effects or in pregnant women requiring oral
antibiotic therapy, erythromycin may be considered. The efficacy
is low. Side effects are mostly gastrointestinal upset;
vaginal itching is a rare occurrence. The initial dose is 250–
500 mg 2–4 times a day, reduced gradually after control is
achieved. Erythromycin may increase blood levels of other
drugs metabolized by the cytochrome P450 system.
Clindamycin Past experience has shown clindamycin to
give an excellent response in the treatment of acne; however,
the potential for the development of pseudomembranous
colitis and the availability of retinoids has limited its use. The
initial dose is 150 mg three times a day, reduced gradually as
control is achieved.
Fig. 13-9 Minocycline-induced blue pigmentation of the teeth and
nails.
Other antibiotics Sulfonamides are occasionally prescribed;
however, the potential for severe drug eruptions limits their
use. Trimethoprim–sulfamethoxazole (Bactrim, Septra), in
double-strength doses twice a day initially, is effective in many
cases unresponsive to other antibiotics. Trimethoprim alone,
300 mg twice a day, is also useful. Amoxicillin, in doses from
250 mg twice daily to 500 mg three times a day, is also an
alternative and may be useful in pregnancy as it falls into
pregnancy category B. Dapsone has been used in severe acne
conglobata, but is rarely used today. Isotretinoin is favored.
Bacterial resistance P. acnes antimicrobial resistance has
become a clinically relevant problem. Erythromycin and clindamycin
resistance is widespread and usually presents simultaneously.
Once P. acnes becomes resistant to tetracycline, it is
also resistant to doxycycline, so if lack of efficacy due to prolonged
oral therapy with one of them is suspected, a switch to
minocycline is necessary. While concomitant use of benzoyl
peroxide will help limit cutaneous drug resistance problems,
it is now appreciated that Staphylococcus aureus in the nares,
streptococci in the oral cavity, and enterobacteria in the gut
may also become resistant, and close contacts, including treating
dermatologists, may harbor such drug-resistant bacteria.
Strategies to prevent antibiotic resistance include limiting the
duration of treatment, stressing the importance of adherence
to the treatment plan, restricting the use of antibiotics to
inflammatory acne, encouraging retreatment with the same
antibiotic unless it has lost its efficacy, avoiding the use of
dissimilar oral and topical antibiotics at the same time, and
using isotretinoin if unable to maintain clearance without oral
antibacterial treatment.
Hormonal therapy
Hormonal interventions in women may be beneficial in the
absence of abnormal laboratory tests. The work-up for the
woman with signs of hyperandrogenism, such as acne, menstrual
irregularities, hirsutism, or androgenetic alopecia, is
presented above. Women with normal laboratory values often
respond to hormonal therapy. Results take longer to be seen
with these agents, with first evidence of improvement often
not apparent for 3 months and continued improved response
seen for at least 6 months. Particularly good candidates for
hormonal treatment include women with PCOS, late-onset
adrenal hyperplasia, or another identifiable endocrinologic
condition; and women with late-onset acne, severe acne, acne
that has not responded to other oral and topical therapies, or
acne that has relapsed quickly after isotretinoin treatment.
Women with acne primarily located on the lower face and
neck, and deep-seated nodules that are painful and longlasting,
are often quite responsive to hormonal intervention Oral contraceptives These agents block
both adrenal and
ovarian androgens. Ortho Tri-Cyclen, Estrostep, Alesse,
Yasmin, and Yaz are examples of birth control pills that
have beneficial effects on acne. Both the physician and the
patient should be familiar with the adverse reactions associated
with oral contraceptives, such as nausea, vomiting,
abnormal menses, melasma, weight gain, breast tenderness,
and rarely thrombophlebitis, pulmonary embolism, and
hypertension.
Spironolactone As pregnancy while on antiandrogen treatment
will result in feminization of a male fetus, spironolactone
is usually prescribed in combination with oral
contraceptives. It may be effective in doses from 25–200 mg/
day. Most women will tolerate a starting dose of 50–100 mg/
day. Most also tolerate 150 mg per day but many will have
side effects at 200 mg per day. Side effects are dose-dependent
and include breast tenderness, headache, dizziness, lightheadedness,
fatigue, irregular menstrual periods, and diuresis. In
a study by Shaw in patients treated with 50–100 mg/day,
hyperkalemia was measurable, but in the absence of renal
or cardiac disease was clinically insignificant. In his series, a
third of patients cleared, a third had marked improvement, a
quarter showed partial improvement, and 7% had no response.
Spironolactone is often used with other topical or oral acne
therapy. Several months of treatment are usually required to
see benefit.
Dexamethasone Dexamethasone, in doses from 0.125 to
0.5 mg given once at night, reduces androgen excess and may
alleviate cystic acne. Corticosteroids are effective in the treatment
of adult-onset adrenal hyperplasia, but antiandrogens
are also used increasingly in this setting.
Prednisone Although steroids may produce steroid acne,
they are also effective anti-inflammatory agents in severe and
intractable acne vulgaris. In severe cystic acne and acne conglobata,
corticosteroid treatment is effective; however, side
effects restrict its use. It is generally only given to patients with
severe inflammatory acne during the first few weeks of treatment
with isotretinoin, for initial reduction of inflammation,
and to reduce isotretinoin-induced flares.
Other hormonal agents Finasteride, flutamide, estrogen,
gonadotropin-releasing agonists, and metformin (by decreasing
testosterone levels) have all been shown to have a beneficial
effect on acne but due to side effects, expense, or other
considerations are not commonly used.
A
Fig. 13-11 A, Severe back acne before
isotretinoin. B, Response to treatment.
B
Oral retinoid therapy
Isotretinoin This drug is approved only for severe cystic
acne: however, it is useful in less severe forms of acne so as to
prevent the need for continuous treatment and the repeated
office visits that many patients require. It was a consensus of
experts that oral isotretinoin treatment is warranted for severe
acne, poorly responsive acne that improves by less than 50%
after 6 months of therapy with combined oral and topical
antibiotics, acne that relapses off oral treatment, scars, or acne
that induces psychological distress. Additionally, other agreed
indications were Gram-negative folliculitis, inflammatory
rosacea, pyoderma faciale, acne fulminans, and hidradenitis
suppurativa.
This retinoid is a reliable remedy in nearly all acne patients
(Fig. 13-11). The dose is 0.5–1 mg/kg/day in one or two daily
doses. For severe trunkal acne in patients who tolerate higher
doses, treatment may be given in doses up to 2 mg/kg/day.
In practice, most patients are started at a 20–40 mg dose so as
to avoid an early flare, and then increased to 40–80 mg/day
so as to limit side effects, which generally are dose-related.
Doses as low as 0.1 mg/kg/day are very nearly as effective as
the higher doses in clearing acne; the disadvantage is that they
are less likely to produce a prolonged remission even after 20
weeks of treatment. To obtain the greatest chance of a prolonged
remission, patients should receive 120–150 mg/kg
over the treatment course. An easy way to calculate the total
dose needed is to multiply the weight in kilograms by 3. The
product is the total number of 40 mg capsules needed to reach
the low end of the dosage spectrum.
The major advantage of isotretinoin is that it is the only acne
therapy that is not open-ended (i.e. that leads to a remission,
which may last many months or years). Approximately 40–
60% of patients remain acne-free after a single course of
isotretinoin. Approximately one-third of the relapsing patients
will need only topical therapy, the others oral treatments.
Many patients in the latter category prefer to be retreated with
isotretinoin due to its reliable efficacy and ability to predict
side effects, as they will be similar to those experienced in the
first course. In Azoulay et al’s study, fully 26% of isotretinointreated
patients received a second course within a 2-year
period.
Some subsets of patients tend to relapse more often. In
patients under 16, 40% need a second course of isotretinoin within 1 year and 73% within 2
years. Adult women and
patients with mild acne tend to relapse more often and more
quickly than severely affected 17- to 22-year-olds. While
patients’ tolerance and response to repeated courses are similar
to their experience with the first course, adult women who
relapse may be better managed with hormonal therapies, and
mild acne treated with standard therapy.
In adult acne patients, who frequently tolerate the side
effects of isotretinoin less well, lower doses and/or intermittent
therapy is possible. Goulden et al studied 80 adult acne
patients whom they treated with 0.5 mg/kg/day for 1 week
in every 4 over a period of 6 months. Acne resolved in 88%
and 39% relapsed after 1 year. Seukeran and Cunliffe treated
nine patients aged 56–75 years with 0.25 mg/kg/day for
6 months. All patients cleared and all but one remained clear
36 months later.
Patient education is critical in isotretinoin therapy. Its most
serious adverse effect is the risk of severe damage to the fetus
if it is given during pregnancy. Retinoid embryopathy is a
well-defined syndrome characterized by craniofacial, cardiovascular,
central nervous system, and thymus abnormalities.
It is of the utmost importance that a woman of child-bearing
potential follows closely the recommendations clearly outlined
in extensive material provided by the manufacturer. The
use of consent forms, contraception education, and unequivocal
documentation of the absence of pregnancy through
monthly laboratory testing are important components of a
Food and Drug Administration (FDA)-mandated verification
program designed to prevent pregnancy during treatment.
Women should not become pregnant until off medication for
at least 1 month. The drug is not mutagenic and there is no
risk to a fetus conceived while the male partner is taking the
drug.
Another major area of educational emphasis concerns the
psychological effects of the medication. Reports of depression,
psychosis, suicidal ideation, suicide, and attempted suicide
have prompted numerous studies of the mental health of
patients taking isotretinoin. While the usual outcome is an
improvement of mood because of the clearance of the disease,
and only one of the many large-scale population-based studies
has found evidence of an elevated incidence of depression,
there are a small number of patients who have developed
depression and have positive dechallenge and rechallenge
tests. Close monitoring for depression, fully educating the
patient, and enlisting the help of a roommate or family member
to look for changes in mood are all methods used to assess the
psychological status of the patient on isotretinoin.
Inflammatory bowel disease (IBD) is a third concern. Patients
with this condition have been successfully treated with
isotretinoin without flaring, new onset of IBD in patients
exposed to isotretinoin is of concern. The age of onset of IBD
overlaps with the age at which acne will frequently be treated
with isotretinoin and antibiotics. A review of Medwatch cases
revealed 85 cases with new-onset IBD in isotretinoin users.
Three cases improved off isotretinoin and then relapsed on
re-exposure. Most did not improve or resolve with discontinuation
of the medicine, with seven requiring surgery. Studies
investigating a possible association of IBD and isotretinoin or
tetracycline class antibiotics are ongoing. Some have reported
significant associations, but results are either contradictory or
are unverified.
Other side effects of isotretinoin are dose-dependent and
generally not serious. Dry lips, skin, eyes, and oral and nasal
mucosa occur in up to 90% of patients. These can be treated
with moisturization. Dryness of the nasal mucosa leads to
colonization by S. aureus in 80–90% of treated subjects. Skin
abscesses, staphylococcal conjunctivitis, impetigo, facial cellulitis,
and folliculitis may result. Such colonization may be
avoided by the use of bacitracin ointment applied to the anterior
nares twice a day during isotretinoin therapy. Arthralgias
may occur but, like other side effects, do not require interruption
of therapy unless severe. Monitoring of serum lipids is
carried out, as some patients will develop hypertriglyceridemia.
This may be controlled by avoidance of smoking and
alcohol, and by following a diet that is low in fat. It should be
realized that patients who develop this complication, and their
families, are at risk for the development of the metabolic
syndrome.
Liver function tests should be checked at regular intervals,
depending on patient risk factors and the dose utilized.
Intralesional corticosteroids
Intralesional corticosteroids are especially effective in reducing
inflammatory nodules. Kenalog-10 (triamcinolone acetonide
10 mg/mL) is best diluted with sterile normal saline
solution to 2.5 mg/mL. Injecting less than 0.1 mL directly into
the center of the nodule will help safeguard against atrophy
and hypopigmentation.
Physical modalities
Local surgical treatment is helpful in bringing about quick
resolution of the comedones, although many clinicians wait
until after 2 or more months of topical retinoids to extract
those that remain. The edge of the follicle is nicked with a No
11 scalpel blade and the contents of the comedo are expressed
with a comedo extractor. Scarring is not produced by this
procedure. Light electrode desiccation is an alternative. In
isotretinoin-treated patients, macrocomedones present at
weeks 10–15 may be expressed, since they tend to persist
throughout therapy.
The use of photodynamic therapy and various forms of
light, laser, or radiofrequency energy is under investigation. It
is clear that there is an ability to destroy sebaceous glands or
kill P. acnes with such interventions; however, the methods to
deliver such treatments in an efficient, cost-effective, safe, relatively
painfree, and practical manner are evolving. These treatments
will be a welcome addition as they have the potential
to provide care without the concerns associated with systemic
drugs. More studies of larger patient populations with appropriate
controls are needed to evaluate their place in the spectrum
of acne treatments.
Complications
Even with the excellent treatment options available, scarring
may occur. This may be quite prominent and often results
from the cystic type of acne, although smaller lesions may
produce scarring in some individuals. Pitted scars, widemouthed
depressions, and keloids, primarily seen along the
jawline and chest, are common types of scarring (Fig. 13-12).
These may improve spontaneously over the course of a year
or more. Many treatment options are available. Chemical
peeling, ablative, nonablative, and vascular laser treatments,
skin needling or rolling, dermabrasion, scar excision, subcision,
punch grafts alone or followed by dermabrasion or laser
smoothing, intralesional corticosteroids or fluorouracil, fractionated
laser resurfacing, fat transfer, and the use of filler
substances are among the procedures reported to be effective
in improving the appearance.
Other complications from acne are prominent residual
hyperpigmentation, especially in darker-skinned patients;
pyogenic granuloma formation, which is more common in
acne fulminans and in patients treated with high-dose isotretinoin;
osteoma cutis, which consists of small, firm papules
resulting from long-standing acne vulgaris; and solid facial

Gawkrodger DJ, Ardern-Jones MR. Dermatology an

illustrated colour text: Acne. 2012;5:64-65
Acne
Acne is a chronic inflammation of the pilosebaceous units,
producing comedones, papules, pustules, cysts and scars.
It affects nearly every adolescent. Acne has an equal sex
incidence and tends to affect women earlier than men,
although the peak age for clinical acne is 18 years in both
sexes. Acne results from:
n increased sebum excretion – seborrhoea (greasy skin)
n pilosebaceous duct hyperkeratosis and comedone
formation
n colonization of the duct with Propionibacterium acnes
n release of inflammatory mediators (including cytokines).
In acne, the androgen-sensitive pilosebaceous unit (p. 4)
shows a hyper-responsiveness that results in increased
sebum excretion. Factors in sebum induce comedones, and
P. acnes initiates inflammation through chemical mediators
inducing enzymes (e.g. lipase) and prostaglandins (Fig. 1).

Clinical presentation
Comedones are either open
(blackheads: dilated pores with black
plugs of melanin-containing keratin)
or closed (whiteheads: small creamcoloured,
dome-shaped papules). They
appear at about the age of 12 years
and evolve into inflammatory papules
(Fig. 2), pustules or cysts (Fig. 3). The
sites of predilection – the face,
shoulders, back and upper chest
– have many sebaceous glands. The
severity of acne depends on its extent
and the type of lesion, with cysts being
the most destructive.
Acne usually persists until the early
twenties, although in a few patients,
particularly women, the disease
continues into the fifth decade. Scars
may follow healing, especially of cysts
or abscesses. Scars may be ‘ice-pick’,
atrophic (Fig. 4) or keloidal.
Some variants of acne are seen:
n Acné excoriée: due to squeezing,
affects depressed or obsessional
young women.
n Chloracne: caused by systemic
toxicity of certain aromatic
halogenated industrial chemicals.
n Conglobate: a mass of burrowing
abscesses and sinuses with scarring.
n Cosmetic: pomade and cosmeticinduced
comedonal and papular
acne (mainly seen in the USA).
n Drug-induced: by systemic steroids,
androgens and topical steroids.
n Infantile: mostly found on the faces
of male infants; cause unknown.
n Physical: occlusion by the back of a
wheelchair or on a violinist’s chin. Complications and differential
diagnosis
Embarrassment, social withdrawal and
depression are important sequelae of
acne. These can improve with effective
treatment. The rare and severe acne
fulminans, seen in adolescent males, is
associated with fever, arthritis and
vasculitis. Long-term antibiotic
treatment may induce a Gram-negative
folliculitis.
Rosacea can usually be differentiated
from acne (see below). Bacterial
folliculitis is more acute than acne, but
the two may coexist.
Management
Treatment depends on the type and
extent of acne and the patient’s
psychological state. ‘Over-the-counter’
creams have often already been used.
Local treatment is adequate for mild
acne and is used with systemic drugs
for more severe cases.
n Benzoyl peroxide (Panoxyl, Brevoxyl)
cream or gel, applied twice a day,
works by reducing the number of
P. acnes. It may cause irritation,
contact allergy and bleach clothing.
n Tretinoin (Retin-A gel) is good at
reducing the number of comedones,
but may be irritant.
n Antibiotics, e.g. clindamycin alone
(Dalacin T) or with benzoyl peroxide
(Duac), erythromycin alone
(Stiemycin) or with zinc (Zineryt),
can be used for mild or moderately
severe acne.

n Other topical agents, e.g. azelaic acid,

isotretinoin and adapalene.
Oral treatment with antibiotics,
retinoid or hormones is prescribed for
moderate or severe acne, acné excoriée
and in depressed patients.
Antibiotics
The first-line systemic antibiotic drug
is oxytetracycline, 500 mg twice daily
(taken half an hour before food with
water), given for a minimum of
4 months. Tetracyclines are
contraindicated in children and in
pregnancy, and may cause Candida
albicans infection or photosensitivity.
Lymecycline (Tetralysal, 408 mg daily)
and doxycycline (Vibramycin, 100 mg
once daily) are alternative tetracyclines
that are better absorbed.
Erythromycin (500 mg twice daily)
and trimethoprim are second-choice
antibiotics. Women on oral
contraceptives who take an antibiotic
are advised that, if diarrhoea develops,
additional contraception is needed for
the rest of the menstrual cycle.
Antiandrogen
The combination of an antiandrogen
and an oestrogen (co-cyprindiol–
cyproterone acetate, 2 mg, and
ethinylestradiol, 35 mcg: Dianette) is
used in females (not males) with
moderate to severe acne that is resistant
to conventional therapy. The
antiandrogen suppresses sebum
production. Co-cyprindiol is given for
6–12 months and is also a contraceptive.
Retinoid
Isotretinoin (Roaccutane), which
reduces sebum excretion, inhibits P.
acnes and is anti-inflammatory, is a
very effective treatment for acne. It is
used if acne is severe or unresponsive
to conventional treatment, or if acne
relapses quickly once antibiotics are
stopped. A course lasts 4 months and
requires the monitoring of liver
function and fasting lipids. Isotretinoin
is teratogenic. Women given the drug
must not be pregnant and need to
take the oral contraceptive throughout
treatment and for the month before
and after. Side-effects include cracked
lips, dry skin, nose bleeds, hair loss,
muscle aches and mood change.
Other therapies
Acne cysts may require injection with
triamcinolone acetonide (a steroid), or
sometimes excision or cryotherapy.
Comedones can be removed using an
extractor. Diet has no effect on acne.
Rosacea
Rosacea is a chronic inflammatory
facial dermatosis characterized by
erythema and pustules. The cause of
rosacea is unknown. Histologically,
dilated dermal blood vessels, sebaceous
gland hyperplasia and an inflammatory
cell infiltrate are seen. Sebum excretion
is normal.
Clinical presentation
Rosacea has an equal sex incidence.
Although commonest in middle age, it
also affects young adults and the
elderly. The earliest symptom is
flushing. Erythema, telangiectasia,
papules, pustules (Fig. 5) and,
occasionally, lymphoedema involve the
cheeks, nose, forehead and chin.
Rhinophyma, hyperplasia of the
sebaceous glands and connective tissue
of the nose (Fig. 5), and eye
involvement by blepharitis and
conjunctivitis are complications.
Sunlight and topical steroids
exacerbate the condition. Rosacea
persists for years, but usually responds
well to treatment. Rosacea lacks the
comedones of acne and occurs in an
older age group. Contact dermatitis,
photosensitive eruptions, seborrhoeic
dermatitis and lupus erythematosus
often involve the face but are more
acute or scaly, or lack pustules.
Management
Topically, metronidazole 0.75% cream
(Rozex) or azelaic acid may be helpful.
If this is ineffective, the usual oral
treatment is oxytetracycline, initially
1 g daily, reducing to 250 mg daily
after a few weeks and continued for
2–3 months. Erythromycin is an
alternative. Repeated treatment is often
needed. Isotretinoin can be used but is
less effective than in acne. Plastic
surgery is required for rhinophyma.

Weller R, Hunter H, Mann M. Clinical Dermatology. 2015;5:156-166

Sebaceous and Sweat
Gland Disorders
Sebaceous glands
Most sebaceous glands develop embryologically from
hair germs, but a few free glands arise from the epidermis.
Those associated with hairs lie in the obtuse angle
between the follicle and the epidermis (see Figure 13.1).
The glands themselves are multilobed and contain cells
full of lipid, which are shed whole (holocrine secretion)
during secretion so that sebum contains their remnants
in a complex mixture of triglycerides, free fatty acids, wax
esters, squalene and cholesterol. Sebumis discharged into
the upper part of the hair follicle. It lubricates and waterproofs
the skin, and protects it from drying; it is also
mildly bacteriocidal and fungistatic. Sebaceous follicles
are most commonly found on the face, behind the ears,
and on the upper chest and back. Free sebaceous glands
not associated with hair follicles may be found in the
eyelid (meibomian glands),mucous membranes (Fordyce
spots), nipple, peri-anal region and genitalia.
Androgenic hormones, especially dihydrotestosterone,
stimulate sebaceous gland activity. Human sebaceous
glands contain 5α-reductase, 3α- and 17α-hydroxysteroid
dehydrogenase, which convert weaker androgens to dihydrotestosterone,
which in turn binds to specific receptors
in sebaceous glands, increasing sebumsecretion. The
sebaceous glands react tomaternal androgens for a short
time after birth, and then lie dormant until puberty when
a surge of androgens produces a sudden increase in sebum
excretion and sets the stage for acne.
Acne
Acne is a disorder of the pilosebaceous apparatus characterized
by comedones, papules, pustules, cysts and
scars.
Prevalence
Nearly all teenagers have some acne (acne vulgaris). It
affects the sexes equally, starting usually between the ages
of 12 and 14 years, tending to be earlier in females. The
peak age for severity in females is 16–17 and inmales 17–
19 years. Variants of acne are much less common.
Cause
Acne vulgaris
Many factors combine to cause acne (Figure 12.1), characterized
by chronic inflammation around pilosebaceous
follicles.
_ Sebum over-production. Sebum excretion is increased.
However, this alone need not cause acne; patients with
acromegaly, or with Parkinson’s disease, have high sebum
excretion rates but no acne. Furthermore, sebum excretion
often remains high long after the acne has gone
away.
_ Hormonal. Androgens (from the testes, ovaries,
adrenals and sebaceous glands themselves) are the main
stimulants of sebum excretion, although other hormones
(e.g. thyroid hormones and growth hormone) have
minor effects too. Those castrated before puberty, or with
androgen insensitivity, never develop acne. In acne, the
sebaceous glands respond excessively to what are usually
normal levels of these hormones (increased target organ
sensitivity). This may be caused by 5α-reductase activity
being higher in the target sebaceous glands than in other
parts of the body. Fifty per cent of females with acne have
slightly raised free testosterone levels – usually because
of a low level of sex hormone binding globulin rather
than a high total testosterone – but this is still only a
fraction of the concentration inmales, and its relevance is
debatable. _ Poral occlusion. Both genetic and environmental factors
(e.g. some cosmetics) cause the epithelium to overgrow
the follicular surface. Follicles then retain sebum that
has an increased concentration of bacteria and free fatty
acids. Rupture of these follicles is associated with intense
inflammation and tissue damage, mediated by oxygen free
radicals and enzymes such as elastase, released by white
cells.
_ Increased bacterial colonization. Propionibacterium
acnes, a normal skin commensal, plays a pathogenic
part. It colonizes the pilosebaceous ducts, breaks down
triglycerides releasing free fatty acids, and induces the
ductal epithelium to secrete pro-inflammatory cytokines
via activation of Toll-like receptor 2 (TLR2) pathway.
Activated neutrophils release lysosomal enzymes which
lead to follicular rupture. The release of follicular content
results in a foreign body reaction which furthers the
inflammatory reaction.
_ Genetic. The condition is familial in about half of those
with acne. There is a high concordance of the sebum
excretion rate and acne in monozygotic, but not dizygotic,
twins. Further studies are required to determine the precise
mode of inheritance.
_ Diet. Recent systematic reviews of diet on acne suggest
that dairy products (particularly milk) and high glycaemic
load may be associated with increased risk and
severity of acne. Prospective studies are needed to determine
if a low glycaemic diet and reduced dairy intake may
help acne.
Presentation
Common type
Lesions are confined to the face, shoulders, upper chest
and back. Seborrhoea (a greasy skin; Figure 12.2) is often
present. Open comedones (blackheads), because of the
plugging by keratin and sebum of the pilosebaceous orifice,
or closed comedones (whiteheads), caused by overgrowth
of the follicle openings by surrounding epithelium,
are always seen. Inflammatory papules, nodules
and cysts occur (Figures 12.3 and 12.4), with one or two
types of lesion predominating.Depressed or hypertrophic
scarring and post-inflammatory hyperpigmentation can
follow.
Conglobate (gathered into balls; from the Latin globus
meaning ‘ball’) is the name given to a severe form of
acne with all of the above features as well as abscesses thick serosanguinous fluid or pus. On
resolution, it leaves
deeply pitted or hypertrophic scars, sometimes joined
by keloidal bridges. Although hyperpigmentation is usually
transient, it can persist, particularly in those with an
already dark skin. Psychological depression is common in
persistent acne, which need not necessarily be severe.
Variants of acne
_ Neonatal acne. This occurs inmore than 20%of healthy
newborn babies between 2 weeks to 3 months of age. It
may follow transplacental stimulation of a child’s sebaceous
glands by maternal androgens.
_ Infantile acne. This rare type of acne is present at 3–
6 months of age and typically resolves in 12 months. It
is more common in males and may last up to 3 years.
Its morphology is like that of common acne and it may
Figure 12.4 Conglobate acne with inflammatory nodules,
pustulocystic lesions and depressed scars.
Figure 12.5 Late-onset acne in a woman. Often localized to the
chin.
be the forerunner of severe acne in adolescence. Maternal
hormones have a minor role at this age. Rather, the
immature infantile adrenal gland produces elevated dehydroepiandrosterone
(DHEA) and delayed maturation of
the gonadal feedback system results in increased levels of
luteinizing hormone (LH), follicle-stimulating hormone
(FSH) and testosterone.
_ Late onset. This occurs mainly in women and is often
limited to the chin and jawline (Figure 12.5).Nodular and
cystic lesions predominate. It is stubborn and persistent.
_ Acne fulminans. Acne fulminans is a rare variant in
which conglobate acne is accompanied by fever, joint
pains and a high erythrocyte sedimentation rate (ESR).
_ Mechanical. Excessive scrubbing, picking or the rubbing
of chin straps or a fiddle (Figure 12.6) can rupture
occluded follicles.
_ Tropical. Heat and humidity are responsible for this
variant, which affects Caucasoids with a tendency to acne.
This occurs mainly on the trunk and may be conglobate.
Sweat causes follicular occlusion by causing the perifollicular
epidermis to swell.
_ Excoriated. This is most common in young girls.
Obsessional picking or rubbing leaves discrete denuded
areas.
_ Exogenous. Tars, chlorinated hydrocarbons, oils and
oily cosmetics may induce comedone formation or precipitate
inflammation around vellous hair follicles. Suspicion
should be raised if the distribution is odd or if comedones
predominate (Figure 12.7).
_ Drug-induced (Figure 12.8). Corticosteroids, androgenic
and anabolic steroids, gonadotrophins, oral contraceptives,
lithium, iodides, bromides, antituberculosis
and anticonvulsant therapy can all cause an acneiform
rash. Follicular acneiform eruption has commonly been
reported in patients receiving inhibitors of the epidermal growth factor receptor (EGF-R).
Suspicion should be
raised when acne, dominated bymonomorphous papulopustules
rather than comedones, appears suddenly in a
non-teenager and coincides with the prescription of a
drug known to cause acneiform lesions.
_ Follicular occlusion tetrad. Severe nodulocystic acne can
be associated with dissecting cellulitis of the scalp, suppurative
hidradenitis and pilonidal cysts.
_ Polycystic ovarian syndrome. Consider this in obese
females with oligomenorrhoea or secondary amenorrhoea
or infertility. Glucose intolerance, dyslipidaemia,
hirsutism and hypertension may be other features. Acne
accompanying the polycystic ovarian syndrome is caused
by modestly raised circulating androgen levels.
_ Congenital adrenal hyperplasia. Hyperpigmentation,
ambiguous genitalia, history of salt-wasting in childhood
and a Jewish background are all clues to this rare diagnosis
caused by 21-hydroxylase deficiency.
_ Androgen-secreting tumours. These cause the rapid
onset of virilization (clitoromegaly, deepening of voice,
breast atrophy, male pattern balding and hirsutism) as
well as acne.
Course
Acne vulgaris clears by the age of 23–25 years in 90% of
patients, but some 5% of women and 1% of men still need
treatment in their thirties or even forties. Investigations
None are usually necessary. Cultures are occasionally
needed to exclude a pyogenic infection, an anaerobic
infection or Gram-negative folliculitis. Only a few laboratories
routinely culture P. acnes and test its sensitivity to
antibiotics.
Any acne, including infantile acne, which is associated
with virilization, needs investigation to exclude
an androgen-secreting tumour of the adrenals, ovaries
or testes, and to rule out congenital adrenal hyperplasia
caused by 21-hydroxylase deficiency. Tests should
then include the measurement of plasma levels of
total and free testosterone, sex hormone binding globulin,
LH, FSH, DHEA sulfate, androstenedione, 17-
hydroxyprogesterone, urinary free cortisol and, depending
on the results, ultrasound examination or computed
tomography scan of the ovaries and adrenals. Female
patients should not be taking the oral contraceptive pill
when these hormone levels are measured. Congenital
adrenal hyperplasia is associated with high levels of 17-
hydroxyprogesterone, and androgen secreting tumours
with high androgen levels.
Polycystic ovarian syndrome is characterized by modestly
elevated testosterone, androstenedione and DHEA
sulfate levels, a reduced sex hormone binding level and
an LH : FSH ratio of greater than 2.5 : 1. Pelvic ultrasound
may reveal multiple small ovarian cysts, although some
patients with acne have ovarian cysts without biochemical
evidence of the polycystic ovarian syndrome.
Differential diagnosis
Rosacea (see Rosacea) affects older individuals. Comedones
are absent, the papules and pustules occur only
on the face and the rash has a centrofacial erythematous
background. Pyogenic folliculitis can be excluded by
culture. Hidradenitis suppurativa (see Hidradenitis suppurativa)
is associated with acne conglobata, but attacks
the axillae and groin. Pseudofolliculitis barbae and acne
keloidalis nuchae, caused by ingrowing hairs, occur on the
necks and scalps of men with curly facial hair and clears
up if shaving is stopped. Always suspect cosmetic acne,
especially in post-adolescent women with acne limited to
the face.
Treatment
Acne frequently has marked psychological effects. Even
mild acne can have significant impact on self-esteem and
quality of life.Anoptimistic approach is essential, and regular
encouragement worthwhile.
Occasionally, an underlying cause (seeVariants of acne)
is found; this should be removed or treated.
At some time most teenagers try antiacne preparations
bought fromtheir pharmacist. Local treatment is the standard
of care for most patients with comedo-papular acne,
although both local and systemic treatments are needed
for pustulocystic scarring acne (Figure 12.9).
Local treatment (Formulary 1, p. 405)
1 Regular gentle cleansing with soap and water should be
encouraged, to remove surface sebum.
2 Salicylic acid is widely available as an over-the-counter
acne treatment; it is a mild comedolytic agent.
3 The antibacterial agent benzoyl peroxide is applied only
at night initially, but can be used twice daily if this does
not cause too much dryness and irritation. It is most
effective for inflammatory lesions and is not affected by propionibacterial antibiotic
resistance. It is wise to start
with a 2.5 or 5% preparation, moving up to 10% if necessary.
Benzoyl peroxide bleaches coloured materials, particularly
towels and flannels.
4 The vitamin A (retinol) analogues (tretinoin,
isotretinoin, adapalene, tazarotene) normalize follicular
keratinization, down-regulate TLR 2 expression
and reduce sebum production. Retinoids are especially
effective against comedones. Patients should be warned
about skin irritation (start with small amounts) and
photosensitivity. Concomitant eczema is usually a contraindication
to their use. Tretinoin can be prescribed as
a lotion, cream or gel. Patients with oily skin may prefer
gels which are drying, while those with sensitive skin
tend to prefer the more emollient creams. Newer preparations
(in the United States) use microspheres (Retin-A
micro) or specially formulated bases (Avita, Avage) that
minimize irritation. The weakest preparation should
be used first, and applied every 2–3 nights, increasing
frequency after several weeks as tolerated. Sometimes,
after a week or two, it will have to be stopped temporarily
because of irritation. The combination of benzoyl peroxide
in the morning and tretinoin at night has many
advocates.
_ Isotretinoin 0.05% is made up in a gel base (not available
in United States) and applied once or twice daily. It
irritates less than the same concentration of tretinoin.
_ Adapalene (0.1% gel) is a retinoid-like drug indicated
for mild tomoderate acne.Comparedwith tretinoin, it
is a milder comedolytic but also better tolerated.
_ Tazarotene (0.1% gel), applied once daily, was found
in one study to be more effective than tretinoin (0.1%
microsponge).
Topical retinoids should not be prescribed for pregnant
woman with acne.
5 Azelaic acid is bacteriocidal for P. acnes: it is also antiinflammatory
and inhibits the formation of comedones by
reducing the proliferation of keratinocytes. It should be
applied twice daily. It is often used in darker skin patients
as it may help to lighten post-inflammatory hyperpigmentation.
6 Topical antibiotics include topical clindamycin, erythromycin
and sulfacetamide (Formulary 1, p. 405) but
antibacterial resistance of P. acnes is a growing problem,
with most erythromycin-resistant strains being crossresistant
to clindamycin. Combining antibiotics with benzoyl
peroxide reduces P. acnes numbers and the likelihood
of resistant strains emerging (Formulary 1, p. 405).
The addition of zinc acetate complex to erythromycin
enhances the anti-inflammatory effect of the antibiotic.
7 Topical dapsone 5% gel is a newer option for treating
acne. It is safe in patients with a deficiency in glucose-6-
phosphate dehydrogenase.
8 Cosmetic camouflage help some patients, especially
females, whose scarring is unsightly. Cover-ups also
obscure post-inflammatory pigmentation. A range of
makeup is available in the United Kingdom and the
United States (Formulary 1, p. 399).
Systemic treatment (Formulary 2, p. 411)
Antibiotics
Theprevalenceof antibiotic-resistant P. acnes, particularly
to erythromycin, is rising even in patients never previously
exposed to it. As well as reducing P. acnes numbers,
antibiotics also have a direct anti-inflammatory effect
so will continue to be beneficial, but wherever possible
they should be used in combination with topical benzoyl
peroxide or retinoids to limit colonization by antibioticresistant
bacteria.
Tetracyclines
_ An average starting dosage for an adult of oxytetracycline
or tetracycline is 500 mg twice daily, but up to
1.5 g/day may be needed in resistant cases. The antibiotic
should not be used for less than 3 months and may
be needed for a year or two, or even longer. It should be
taken on an empty stomach, 1 hour before meals or 4
hours after food, as the absorption of these tetracyclines
is decreased bymilk, antacids and calcium, iron and magnesium
salts. The dosage should be tapered in line with
clinical improvement, an average maintenance dosage
being 250–500 mg/day. Even with long courses, serious
side-effects are rare, although candidal vulvovaginitismay
force a change to a narrower spectrum antibiotic such as
erythromycin.
_ Doxycycline, 100 mg once or twice daily, is a cheaper
alternative tominocycline, butmore frequently associated
with phototoxic skin reactions. A new low dose preparation
(40mg; Oracea,United States) is given once daily and
inhibits acne by stopping inflammation in and around the
pilosebaceous follicles without apparently affecting the
bacterial flora of the vagina or elsewhere.
_ Minocycline, 50 mg twice or 100 mg once daily (in
a modified release preparation), has the same efficacy
as other tetracyclines. Absorption is not significantly
affected by food or drink. It carries the risk of causing a
lupus-like syndrome and also pigmentation, and is thus
not recommended as a first-line treatment.

Tetracyclines should not be taken in pregnancy or by

children under 9 years as they are deposited in growing
bone and developing teeth, causing stained teeth and
dental hypoplasia. Rarely, the long-termadministration of
minocycline causes a greyish pigmentation, like a bruise,
especially on the faces of those with actinic damage and
over the shins.
Erythromycin (dosage as for oxytetracycline) is the
next antibiotic of choice but is preferable to tetracyclines
in women who might become pregnant. Its major
drawbacks are nausea and the widespread development
of resistant Propionibacteria, which leads to therapeutic
failure.
Trimethoprim is used with or without sulfamethoxazole
by some as a third-line antibiotic for acne, when
a tetracycline and erythromycin have not helped. White
blood cell counts should be monitored. Ampicillin is
another alternative.

Hormonal treatment
Hormonal therapy can be very effective for female
patients with acne, even if their serumandrogen levels are
normal. They tend to work best in adultwomenwith persistent
inflammatory papules involving the chin and jawline
who report flares around their menstrual cycle.
Co-cyprindiol, a combined antiandrogen–oestrogen
treatment (Dianette: 2 mg cyproterone acetate and
0.035 mg ethinylestradiol), is available in many countries
and may help persistent acne in women. Monitoring is as
for any patient on an oral contraceptive pill (OCP), and
further contraceptivemeasures are unnecessary. The incidence
of venous thrombo-embolism is higher than for
the low dose OCP, and the course should not go on for
more than 3 months after the acne has cleared, at which
point the drug should be replaced by a low oestrogen/low
progestogen oral contraceptive. These drugs are not for
males.
A number of combined oral contraceptives have been
shown to improve acne. They reduce ovarian androgen
synthesis and, by increasing sex hormone binding globulin,
reduce free testosterone levels and sebum production.
Ethinyl estradiol 35 μg/norgestimate (Ortho Tri-
Cyclen) and ethinyl estradiol 20–35 μg/norethindrone
acetate (Estrostep) have been approved for use in acne in
the United States.
Spironolactone blocks the androgen receptor and
inhibits 5α-reductase, thus reducing sebum production.
It may be added to the OCP after 3 months if there
has been an inadequate response. The usual dose is 25–
100 mg/day with food. In older patients, or those with
concomitantmedical problems, serumelectrolytes should
be checked as it may cause hyperkalaemia. Pregnancy
should be avoided as there is a risk of causing abnormalities
of the fetal male genitalia.
Isotretinoin (13-cis-retinoic acid; Formulary 2, p. 422)
is an oral retinoid that inhibits sebum excretion, the
growth of P. acnes and acute inflammatory processes. The
drug is usually reserved for severe nodulocystic acne,
unresponsive to the measures outlined above. It is routinely
given for 4–6 months, in a dosage of 0.5–2 mg/kg
body weight/day. Young men with truncal acne may
require higher dosage while patients with side effectsmay
benefit from a lower daily dose given over a longer period
of time. Patients with severe acne may notice a flare on
initiation of isotretinoin, but this effect is usually short
lived and the drug can be continued. A lower starting
dose and concomitant administration of prednisone may
prevent severe flares during the first few months. It is
because of its early side effects that some dermatologists
start isotretinoin in a low dose (e.g. 20 mg/day) and then
work up to the target dose if no significant side effects
are reported at review during the first month of treatment.
The goal is to achieve a total cumulative dose of
120–150 mg/kg to reduce the risk of relapse. A full blood
count, liver function tests and fasting lipid levels should
be checked before the start of the course, and then 1 and 4
months after starting the drug. The drug seldomhas to be
stopped, although abnormalities of liver function rarely
limit treatment.
Isotretinoin is highly teratogenic: various national programmes
(iPledge in the USA, Pregnancy Prevention Programme
in UK) have been instituted to reduce the risk
of women becoming pregnant while taking isotretinoin.
Tests for pregnancy are carried out monthly while the
drug is being taken, and only a single month’s supply of the drug should be prescribed at a
time, on receipt of
a negative pregnancy test. The recommendations in the
United States are especially stringent. Patient, physician
and dispensing pharmacy must all be registered with the
iPLEDGE programme and, as in the United Kingdom,
prescriptions are given 1 month at a time on receipt of a
negative pregnancy test. Two separate effective forms of
birth control must be used at the same time for at least 1
month before starting isotretinoin, throughout treatment
and for 1 month after stopping it. Treatment should start
on day 3 of the patient’s next menstrual cycle following a
negative pregnancy test.
Depression, sometimes leading to suicide, is a rare
accompaniment of treatment although causality has yet
to be confirmed in a large controlled study. Nevertheless,
patients and their family doctors should be warned about
thepossible appearanceorworseningof depressionbefore
starting a course of isotretinoin, and patients should be
asked to sign a document that indicates that the issue of
adverse psychiatric events has been discussed. A review of
signs and symptoms of depression and suicidal ideation
should be performed at every visit and the drug should be
stopped immediately if there is any concern. This potentially
severe accompaniment of isotretinoin treatment has
to be balanced against its remarkable efficacy in severe
acne. Isotretinoin has been available in Europe for the
treatment acne since 1971 and the lives of most patients
with conglobate acne have been transformed after successful
treatment with isotretinoin.
Other side effects of isotretinoin include dry skin, dry
and inflamed lips and eyes, nosebleeds, facial erythema,
muscle aches, hyperlipidaemia and hair loss; these are
reversible and often tolerable, especially if the acne is
doing well. Rarer and potentiallymore serious side effects
include changes in night-time vision, pseudotumor cerebri,
pancreatitis, hepatotoxicity, blood dyscrasias, hyperostosis
and hearing loss. Early review appointments (e.g.
at 1 and 2 weeks into treatment) are comforting to both
patient and doctor. A useful ‘avoidance list’ for patients
taking isotretinoin is given in Table 12.1.
Physical treatment
Epidermabrasion with gritty soaps peel off more of the
stratum corneum than they open comedones, may cause
irritation and are not generally recommended.
Chemical peels are a useful adjunct to medical acne
treatment. The comedolytic effects include decreasing
corneocyte cohesion at the follicular opening and assisting
in comedo plug extrusion. β-hydroxy acids (salicylic
acid, β-lipohydroxy acid; LHA) are more efficacious because of their lipophilicity, which
preferentially target
the lipid-filled sebaceous follicles.
For deep persistent comedones, extraction with an 18-
gauge needle or No. 11 blade and a comedo extractormay
aid in their rapid resolution. This can be used in conjunction
with topical retinoids.
Cysts can be incised and drained with or without a
local anaesthetic. Intralesional injections of 0.1mL triamcinolone
acetonide (2.5–10mg/mL) hasten the resolution
of stubborn cysts, but can leave atrophy.
Treatment with light and laser therapies
Light and laser treatments offer an alternative for patients
who are refractory to traditional topical therapy, cannot
tolerate side effects from systemic therapy, have concerns
about antibiotic resistance or are adverse to prescription
medication. Light and laser treatments reduce acne by
photoactivation of porphyrins naturally produced by P.
acnes, leading to reduction in the growthof P. acnes. These
treatments have been shown to have short-termimprovements
over placebo in small trials, although more robust
controlled trials comparing light with conventional treatments
need to be carried out. The combination of red and
blue lightmay provide some benefit in mild inflammatory
acne.Current studies using intense pulsed light (IPL) have
led tomixed results. Some studies suggest IPL may reduce others have shown benefit in non-
inflammatory lesions
only. Pulsed dye 585 nm laser has been tried with some
benefit, but there are no data on long-term outcomes.
Photodynamic therapymay reduce acne lesion count, but
results are no better than topical retinoids, and the side
effects (redness, swelling, pain and exfoliation) may limit
its use.
Acne scar treatment
Scarring caused by acne is often bothersome to patients
but treatment can be challenging. Acne scarring can be
classified based on colour and texture and treatment
modalities including topical, surgical and laser therapy
used to improve their appearance (Figure 12.10).
Colour
Erythema from dilated capillaries is not uncommon after
inflammatory acne lesions. This generally resolves over
time but pulsed dye laser (PDL, 585 or 595 nm) can safely
reduce vascularity by targeting oxyhaemoglobin within
red blood cells. IPL has also been shown to reduce erythema
but must be used with caution in patients with
darker skin types.
Post-inflammatory hyperpigmentation is particularly
common after acne in darker skinned individuals. This
often improves with time, but sun avoidance and the
use of hydroquinone can help to speed resolution. Various
lasers, including short pulse Q-switched lasers (ruby
694 nm, alexandrite 755 nm and Nd:YAG 1064 nm) are
useful for treating skin pigmentation.
Texture
Elevated or hypertrophic scars can be treated with topical
and intralesional corticosteroids. Recent studies have
shown beneficial effects of fractionated ablative lasers
in softening elevated scars by ablating channels of condensed
collagen that contribute to the scar’s thickness.
Atrophic scars such as ice-pick and boxcar scars can be
treated with surgical excision, dermabrasion, lasers and
dermal fillers. Deeply bound rolled acne scars are best
treated with surgical subcisions to loosen the tethering
effect.
Dermabrasion helps to smooth out depressed scars by
blending in the transition between the indentation and
surrounding normal tissue. A high-speed rotating wire
brush planes down to a bleeding dermis. Dermabrasion
should not be carried out if there are any active lesions and
does not help depressed ‘ice-pick’ scars, which may best
be removed with a small punch. Unsightly hyperpigmentation
may follow in darker skins. Microdermabrasion is
well tolerated but its effects are usually transient.
Skin resurfacing with fractionated ablative lasers is
rapidly replacing confluent ablative CO2 and erbium
resurfacing as the best treatment for post-acne scarring.
The procedure, which should be delayed until the acne
is quiescent, is usually performed under local anaesthesia.
Unlike traditional confluent ablative laser, fractionated
laser creates microscopic columns of thermal
injury on the skin, causing skin tightening and collagen
remodelling while reducing the amount of time for
re-epithelization.
Collagen or hyaluronic acid dermal fillers can be
injected into depressed scars to temporarily improve
their appearance. Patients with a history of any autoimmune
disorder are excluded from this treatment. Shallow
atrophic lesions do better than discrete ‘ice-pick’ scars.
The procedure is expensive and has to be repeated every
6 months as the filler is reabsorbed.
 Chowdhury M, Katugampola RP, Finlay AY. Dermatology
at a Glance: Acne Vulgaris.2013:35-37
Acne vulgaris
This is the most common skin disease affecting teenagers. It is
associated with significant impact on psychological well-being. A
disease of the pilosebaceous unit in the skin, pathogenesis of acne
is multi-factorial (Fig 14.4) and includes the following:
• Hyperkeratinisation of the epidermis in the infundibulum of the
hair follicles.
• Shedding and accumulation of keratinocytes within the lumen
of the infundibulum.
• Stimulation of increased sebum production by androgen hormones.
• Proliferation of Propionibacterium acnes, a Gram-positive anaerobic
bacterium, within the pilosebaceous units.
• Because of the narrow openings into the skin surface, the shed
corneocytes, sebum and P. acnes accumulate within the pilosebaceous
units which subsequently rupture.
• This leads to dermal inflammation, mainly consisting of neutrophils
(early and late stages) and T-helper lymphocytes (late
stages).
• Up-regulation of genes coding inflammatory cytokines including
matrix metalloproteinases and interleukin-8.
Diagnosis is made clinically based on the types of lesions
described below and the distribution of the rash characteristically
affecting the face, back and shoulders to varying extents. Different
stages of clinical severity exist, corresponding to the stages of
pathogenesis described above:
• Comedones (Figure 14.5) are non-inflamed early lesions of
acne. Closed comedones (‘white-heads’) are small, approximately 1–2 mm skin-coloured
papules. Open comedones (‘black-heads’)
are papules with a central keratin plug consisting of shed keratin.
Comedones can lead to subtle ice-pick scars.
• Papules and pustules (Figure 14.6) develop with the onset of
inflammation. These erythematous lesions often lead to scarring.
• Nodules and cysts are associated with marked inflammation and
tenderness and lead to scarring (Figures 14.7 and 14.8).
Complications of acne include the following:
• Scarring ranging from subtle pitted (‘ice-pick’) to keloid scars
(Figure 14.9).
• Psychological distress due to the disease itself and subsequent
scarring.
The aim of treatment is disease control and prevention of scarring
(Table 14.3). Choice of treatment(s) depends on the stage of
clinical severity:
• Mild comedones ± few papules: topical benzoyl peroxide ±
topical antibiotic (e.g. clindamycin), topical retinoid.
• Moderately severe acne with papules and pustules with mild scarring:
the above topical treatment with a 3-month course of oral
antibiotic (e.g. erythromycin, oxytetracycline, doxycycline). In
female patients, an anti-androgen combined with oestrogen in the
form of the oral contraceptive pill can be used (e.g. Dianette®
containing 2 mg cyproterone acetate + 35 μg ethinylestradiol).
• Severe acne with papules, pustules, nodules, cysts and scarring:
oral isotretinoin 0.5–1 mg/kg/day for 4–6 months. Isotretinoin
is a retinoid and is teratogenic; therefore females of child-bearing
age commenced on isotretinoin should be counselled and must use
a reliable mode of contraception (e.g. oral contraceptive pill, intrauterine
contraceptive device).
In treatment resistant acne, consider possible underlying
cause(s):
• Polycystic ovarian syndrome in females
• Ingestion or injection of anabolic steroids.

Jain Sima. Dermatology Illustrated Study Guide and

Comprehensive Board Review: Acne and Related
Conditions. 2012:78-82
ACNE AND RELATED CONDITIONS
A. ACNE VULGARIS AND SPECIAL FORMS (Tables 3-1 , 3-2 )
Acne Vulgaris
• Infl ammation of the pilosebaceous unit (PSU) causing comedones,
papulopustules and nodules
• Four key pathogenic factors
o Abnormal follicular keratinization
• ↑ Corneocyte cohesiveness and proliferation
o Propionibacterium acnes ( P. acnes ) in sebum
• Gram + anaerobic rod, resident fl ora in follicle but acne patients
with higher concentration
• Naturally produces p orphyrins (coproporphyrin III), which is the
target of light-based acne therapy
• Secretes lipases which cleave lipids in sebum into pro-infl ammatory
free fatty acids (FFAs), which are both comedogenic and chemotactic
• Binds/activate t oll-like receptor 2 (TLR2)
o Infl ammation
• ↑ IL-1 , IL-8, and TNF-a through TLR-2 pathway
o Hormonal effect on sebum due to androgens
• ↑ Sebum production due to androgen-stimulated sebaceous glands
• Androgen receptors present on basal layer of sebaceous gland and
ORS of hair follicle; respond to most potent androgen, dihydrotestosterone
(DHT), and testosterone (latter produced by gonads and
can be converted to DHT via 5 a -reductase )
• Dehydroepiandrosterone sulfate (DHEA-S): weak androgen
produced by adrenal glands
• Microscopic precursor lesion: microcomedo
• May present with non-infl ammatory comedones (open/closed), infl ammatory
papules, pustules, ± nodules
• Histology: follicular distension often with ruptured PSU and accompanying
brisk infl ammatory response, ± foreign body reaction with multinucleated
giant cells