Download Educational Objectives Noah S. Scheinfeld, JD, MD CONTINUING EDUCATION CREDIT

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Acne: A Review of Diagnosis and Treatment
Noah S. Scheinfeld, JD, MD
Educational Objectives
After reviewing this article, readers should be able to:
Choose the most effective therapy for the non-inflammatory and inflammatory manifestations of acne.
Describe the role that hormonal imbalance plays in the
etiology of acne.
Identify the mechanism of action of the topical and oral
therapies for acne.
Abstract
Acne vulgaris (acne) is probably the most common dermatological complaint in the U.S. Acne has a range of presentations and manifestations, thus apparently
comprising many disease states. Although
acne is not an infectious disease, specimens of bacteria such as Propionibacterium acnes, Propionibacterium granulosum, and Staphylococcus epidermidis can be
obtained for culture from the eruptions of
acne. Other common associations of acne include hormonal
imbalances and follicular hyperkeratinization.
Therapies for acne are varied. The most cost-effective treatment option is benzoyl peroxide; for comedonal acne, the most
effective therapy consists of retinoids. Isotretinoin remains the
most potent therapy. Other treatments include oral and topical antibiotics, topical sulfur agents, topical azelaic acid, and
oral contraceptives.
Introduction
Acne vulgaris (acne) affects almost all humans at some
point in their lives. Acne is the most common condition treated
by American dermatologists. Approximately seven million
new cases are diagnosed each year in the U.S.1–34 The cost of
prescription and over-the-counter (OTC) medications exceeds
Dr. Scheinfeld is Assistant Clinical Professor in the Department
of Dermatology at Columbia University and a dermatologist in
private practice. He can be reached at 30 Central Park South,
Suite 2D, New York, New York 10019 (212-991-6490).
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• June 2007 • Vol. 32 No. 6
$1 billion annually.
Acne engenders substantial psychosocial morbidity. A study
from England notes that people with severe acne have a higher
rate of unemployment than those with clearer skin.2 Other
studies have indicated an adverse impact on social relationships. Teenagers with acne are at an increased risk of depression (odds ratio, 2.04), anxiety (odds ratio, 2.3), and suicide
attempts (odds ratio, 1.83).16
Acne commonly afflicts people between adolescence and the
end of life. It is more common in boys than in girls during puberty (ages 10 to 12).30 Between the ages of 21 and 45 years,
acne is more common in women than in men of a similar age.
In one community-based study from the United Kingdom, the
estimated prevalence of facial acne was 14% in adult women
between 26 and 44 years of age.24 By age 45 years, 5% of both
men and women still experience a range of acne lesions; however, comedones are common in the elderly, even independent of solar elastosis.
In a study of hospitalized patients in
geriatric wards, Kumar and Marks found
a prevalence rate of 26% for senile comedones.33 Acne rarely occurs in prepubescent children as a result of an endocrinopathy; more commonly, it occurs in neonates as a
transient eruption caused by circulating maternal hormones.
Stages of Acne
Morphologically, acne is divided into inflammatory and noninflammatory subtypes that can overlap. Papules, pustules,
and nodules characterize inflammatory lesions; comedones
(open and closed) characterize non-inflammatory lesions.35
Acne is graded on a scale of mild, moderate, and severe, with
intermediate grades and severe variants:35
• Mild acne can present simply with comedonal or mild
papulopustular lesions, with or without the presence of a
few papulopustules.
• Moderate acne presents with numerous comedones, few
to numerous pustules, and few small nodules, without
residual scarring.
• In severe acne, papulopustules are numerous, many nodules appear, inflammation is manifested, and scarring is
present.
• Very severe acne is characterized by sinus tracts, grouped
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comedones, numerous deeply located nodules, and severe
inflammation and scarring.
Mild or moderate non-inflammatory acne can be treated
with topical retinoids. Non-inflammatory acne of a moderateto-severe or greater grade is best treated with oral isotretinoin
(Accutane, Roche).
Inflammatory acne of any grade can benefit from the use of
topical benzoyl peroxide (e.g., Benzac, Galderm; Benzagel,
Aventis). The initial treatment of mild inflammatory acne can
be OTC benzoyl peroxide without the need for intervention by
a medical doctor. Mild inflammator y acne that does not
respond to benzoyl peroxide can benefit from a variety of topical treatments.
For moderate comedonal and mild-to-moderate papulopustular acne, combination therapy with either benzoyl peroxide or topical retinoids plus topical antibiotics such as
erythromycin (e.g., Akne-Mycin, DPT Laboratories) or clindamycin phosphate (Cleocin T, Pfizer) has proved effective. Six
to eight weeks should be allowed for most treatments to work
before the regimen is altered.36
Moderate inflammatory acne is best treated with oral medications that include antibiotics, oral contraceptives for female
patients, and isotretinoin for patients who have not responded
to other oral medications.37,38
Clinical Presentation
As a polymorphic disease with non-inflammatory and inflammatory aspects, acne has a wide spectrum of clinical manifestations,1 including papules, pustules, open or closed comedones, and/or cysts. Most men and women with acne manifest
a mixture of non-inflammatory and inflammatory lesions; however, some patients have predominantly one type of lesion or
the other type.18
The lesions appear in characteristic locations and possess
a typical appearance. Acne is most commonly manifested on
the face, chest, and back; it can appear on the lower back as
well. It usually spares the neck, the scalp, and the skin behind
the ears.
Comedones are typically present only on the face, whereas
papules and pustules of acne can appear on the face, chest, and
back. Milia and cysts, although distinct from acneiform eruptions, commonly occur with these eruptions.
Common symptoms include pain, tenderness, and erythema
in the areas where acne cysts and swollen skin are present. In
particular, these cysts, if inflamed, can be painful. In some
cases, acne appears to be related to excess sebum production
and oily skin.
Differential Diagnosis
The differential diagnosis of acne includes gram-negative folliculitis, perioral dermatitis, sebaceous hyperplasia, syringoma,
tuberous sclerosis (adenoma sebaceum), trichoepithelioma,
Demodex folliculitis, bacterial folliculitis, and papular sarcoidosis. The diseases that most closely resemble acne, but are
said to be distinguishable from it, include:
• gram-negative folliculitis: occurs after months of therapy
with tetracycline (e.g., Sumycin, Par); responds only to
sulfa antibiotics, such as sulfamethoxazole/trimethoprim
(Bactrim, Women First) or isotretinoin; and is the type
from which gram-negative pathogens can be obtained for
culture20
• rosacea: classically defined as a facial eruption lacking
comedones
• perioral dermatitis: thought to be a variation of rosacea
• acneiform drug eruptions: most commonly associated with
epidermal growth factor blockers but related, at a lower
incidence, to lithium and phenytoin (Dilantin, Pfizer)
• eosinophilic pustular folliculitis: most closely associated
with HIV infection in the U.S. but not uncommon in the
Japanese population
Acne can occur in tandem with other eruptions and can
result in scarring that lasts beyond its resolution. It can overlap with acne rosacea or seborrheic dermatitis.19 It can also be
concurrent with gram-negative folliculitis; the latter may be
manifested following months of therapy with antibiotics (typically tetracyclines). Acne can leave behind hypertropic scars,
pitted (“icepick”) scars, sinus tracts, keloids, and atrophic
scars.
In men of color, pseudofolliculitis is a common sequela of
acne in the beard area. In old age, people who had acne in earlier life and experienced actinic damage can manifest
Favre–Racouchot syndrome. The relationship of the syndrome
to acne is unclear.
Biofilm and Enzymatic Tools of P. acnes
To understand the mechanisms, utility, and basis of the cornerstones of topical therapy—retinoids and benzoyl—it is important to comprehend the organism P. acnes.39
P. acnes resides within the pilosebaceous unit in a biofilm.
An important factor in the persistence and effect of P. acnes is
its ability to form such a biofilm, including the production of
an exopolymer that is similar in appearance to the polysaccharide intercellular adhesin of S. epidermidis. This glycocalyx
polymer forms a protective exoskeleton and may be an important immunogenic agent that feeds the inflammation that sometimes is associated with acne. 8 This biofilm functions as a physical barrier that prevents the elevation of concentrations of
antimicrobial agents proximate to the bacteria sufficient to
hinder the bacteria.8 The role of biofilm probably explains the
parameters of successful treatment of acne, including:8
• the need for prolonged courses of oral antibiotics.
• the lack of consistent clinical relevance of the presence
of P. acnes resistant to antibiotics to treatment with oral
antibiotics.
• isotretinoin’s capacity to cure acne.
• the mechanisms that underlie the effectiveness of benzoyl
peroxide, including its generation of free radicals, when
it is placed on the skin.
P. acnes possesses other means of engendering acne. The
organism can produce active enzymes and inflammator y
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mediators that can contribute to acne’s progression, including
smooth-muscle contracting substances, lipases, proteases,
hyaluronate lyase, and phosphatase.21 Lipases can convert
triglycerides in sebum to free fatty acids; this increases
the clumping of P. acnes in the follicles, thereby facilitating an
increase in the number of bacteria.
Etiology
Follicular hyperkeratinization underlies the development
of comedones, the characteristic acne lesion.22 Although many
patients believe that acne stems from a failure to clean the face
effectively and sufficiently, researchers have noted it is a failure of the skin and the pores to slough off dead skin cells.23
Hyperkeratinization is related to the presence of P. acnes in the
follicles as it unleashes its enzymatic armamentarium and
hides behind the biofilm.23
Comedones can be open (blackheads), or closed (whiteheads). Retinoids that normalize follicularization are the most
effective therapy for acne. Preparations include topical retinoids such as tretinoin (all-trans retinoic acid) (e.g., Retin-A,
Ortho) and oral retinoids such as isotretinoin (Accutane).
Acne also involves neutrophil pathology and inflammation.
The pustules of acne are filled with neutrophils, which damage
the follicle and which are associated with erythema. Because
acne is characterized by neutrophils—the “foot soldiers” of
inflammation—antibiotics that have anti-inflammatory activity
may be used. Examples include tetracyclines, macrolides (e.g.,
Biaxin, Abbott), minocycline (Minocin, Wyeth), doxycycline
(e.g., Vibramycin, Pfizer) at full and submicrobial doses,
azithromycin (Zithromax, Pfizer), and erythromycin (e.g.,
Akne-Mycin).
Acne is related to hormonal imbalances. Androgen levels in
patients with acne are higher than in controls; people with androgen insensitivity syndrome do not develop acne.25 Acne
flares during a woman’s menstrual period, and it may also affect men who take anabolic steroids. It responds to the use of
medications that work to “even out” hormonal levels, such as
oral contraceptives (e.g., norgestimate/ethinyl estradiol
[Ortho Tri-Cyclen, Ortho-McNeil]) or substances that block
female hormones (e.g., spironolactone [Aldactone, Pfizer]).
As a hormonal disease, acne, particularly in women, is
related to excess androgen and is strongly associated with polycystic ovary syndrome (PCOS).26 If patients have irregular
menstrual periods and acne, an investigation is recommended
to determine the cause of the excess androgen. Sex hormone–
secreting tumors, congenital adrenal hyperplasia, and other
endocrine diseases marked by excess androgen can result in
acne. Men who take testosterone or anabolic steroid supplements also tend to develop acne.
A variety of miscellaneous mechanisms are associated with
acne. On the cellular level, acne has been found to be related
to defects in T-cell receptors.3 It is a disease of autoimmunity
of sorts in which the body seems to respond to itself with inflammation. Some authors have linked an intake of fatty foods29
to the occurrence of acne, but this association remains controversial. Smoking may be a clinically important contributory
factor to the prevalence and severity of acne.31
Topical applications of a variety of substances have been
linked to the development of acne. Chloracne, which may be
considered to be an acneiform eruption rather than a true
manifestation of acne, can be associated with topical exposure
to halogens or oils. Examples of halogens include bromides
(present in cough syrups and asthma medications), chlorides,
fluoride, and iodides (in salt or seafood). Women sometimes
develop acne on areas of the face that are covered by hair as
well as by oils or pomades for the hair. Mechanics tend to have
acne because of the use of oils in their work.
Acne can also result from oral medications (Table 1).40
Lithium is a potent inducer of neutrophils and can cause and
exacerbate acne.32 Epidermal growth factor blockers are linked
to an acneiform eruption, whose severity parallels clinical
effect, which histologically is a folliculitis.
Topical and oral preparations that induce or worsen acne
include corticosteroids, which can cause steroid acne; this
may be characterized by monomorphous dome-shaped
papules on the chest. Steroid acne is often encountered in
patients with collagen–vascular diseases or with neurological pathology that requires protracted courses of oral
corticosteroids (in particular, potent ones such as dexamethasone).
Acne excoriée (pathological or compulsive picking at the
skin) commonly occurs in young women who pick at scattered acne papules, which are converted into scars; this is as
much a psychological disease as a physical disease. Treatment involves selective serotonin reuptake inhibitors (SSRIs)
to relieve the urge to pick and isotretinoin to erase all traces
of acne that are exacerbated by picking.28
Table 1 Classes and Types of Medications That Can Cause Acne
Antipsychotic
Agents
Trazodone
(Deseryl)
Haloperidol
(Haldol)
Lithium
Amineptine
(Survector)
(off-patent)
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Hormones
Anticonvulsants
Antibiotics
Elemental
Agents
Estrogens
Phenytoin
(Dilantin)
Lamotrigine
(Lamictal)
Isoniazid
Halogens
Anabolic-androgenic
steroids
Corticosteroids
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Chemotherapy
Imatinib mesylate
(Gleevec)
Gefitinib (Iressa)
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Table 2 Therapies for Acne
Topical
Antibiotics
Topical
Non-antibiotics
and
Non-retinoids
Oral
Antibiotics
Topical Retinoids
Oral
Non-antibiotics
Herbals,
Vitamins,
Minerals
Clindamycin 1%
lotion, gel, sol, pad
(Cleocin)
Azelaic acid 20%
Tetracycline 500 mg Tazarotene cream
Oral contraceptives
cream (Azelex);
b.i.d. (Sumycin)
gel (Tazorac, Avage) (Ortho Tri-Cyclen)
Azelaic acid 15% gel
(Finacea)
Nicotinamide
1.5 g q.d. divided
in two or three
doses (Nicomide)
Erythromycin
ointment 2%
(Akne-Mycin)
Sodium sulfacetamide 10%/sulfur
5% combination lotion, cream, pads,
short contact
preparation,
cleanser (Novacet,
Sulface)
Doxycycline
50–100 mg b.i.d.
(Vibramycin)
Combination of
nicotinamide
750 mg, zinc 25 mg,
copper 1.5 mg, and
folic acid 0.5 mg
b.i.d.
Sodium sulfacetamide 10%
lotion
Minocycline 50–100 Adapalene cream,
mg b.i.d. (Minocin)
gel (Differin)
Benzoyl peroxide
5%/clindamycin 2%
combination gel,
pad (BenzaClin)
Benzoyl peroxide
Benzoyl peroxide
5%/erythromycin
gel, wash q.d.–b.i.d.
3% combination gel, (Benzac, Benzagel)
pad (Benzamycin)
Topical dapsone 5%
gel (Aczone)
Doxycycline, submicrobial dose,
20 mg b.i.d. or
40 mg q.d.
Extended-release
minocycline HCl
(Solodyn) 45, 90, or
135 q.d.
Sulfamethoxazole/
trimethoprim
double-strength
b.i.d. (Bactrim)
Azithromycin 250
mg t.i.w.–q.d.
(Zithromax)
Tretinoin cream, gel, Isotretinoin 0.5–2
solution (Retin-A)
mg/kg q.d. for 5–12
months; 10 or 20
mg for six months
(Accutane)
Oral zinc gluconate
200 mg q.d.–b.i.d.
Tretinoin 0.025%/
clindamycin
phosphate 1% gel
(Velac: not yet
approved)
Ocimum gratissimum
oil (basil) (topical)
Tretinoin 0.025%/
clindamycin
phosphate 1.2% gel
(Ziana)
Melaleuca alternifolia
(tea tree oil)
(topical)
Clarithromycin 250
mg, 333 mg, 500 mg
b.i.d.–q.d. (Biaxin)
Erythromycin
250–500 mg
b.i.d.–q.i.d.
q.d. = once daily; b.i.d. = twice a day; t.i.d = three times a day; t.i.w. = three times a week; q.i.d. = four times a day; mg = milligram; pad = pledget;
sol = solution.
Treatment
Topical Therapies
Therapies for acne are varied4 and include proper cleaning
regimens, topical agents, oral antibiotics, oral retinoids, and
oral hormonal therapies. Available treatments are outlined in
Table 2.
The skin of patients with acne can be easily irritated by topical agents that are used to treat the condition. The use of mild,
non-drying cleaning products and non-comedogenic moisturizers may help reduce this irritation.
All topical medications dry the skin to some extent, and
patients should be warned about this. They should be advised
to use the medications as tolerated.
For example, the topical medication can be used for 15
minutes at a time and then washed off. The time can be
increased as tolerated, or the agent can be used every other
day or every third day, with the frequency to be increased as
tolerated.
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Antibiotics
The use of a topical agent is usually the best place to start
treatment. The simplest and most cost-effective agent is benzoyl peroxide if it is tolerated.41 Bacterial resistance to benzoyl
peroxide has not been noted.42 This agent can be used as a
leave-on product or as a wash. It is available over the counter
and by prescription in various topical forms, including pledgets,
soaps, washes, lotions, creams, and gels. It is also available as
part of combination products that also contain clindamycin
(e.g., BenzaClin) or er ythromycin (e.g., Benzamycin). It
ranges in strength from 2.5% to 10%. However, more so than
other topical acne treatments, benzoyl peroxide can induce allergic contact dermatitis.41
Proactiv is an FDA-approved, OTC brand of benzoyl peroxide that has achieved prominence because of aggressive
direct-to-consumer marketing. This benzoyl peroxide/sulfur
combination can be more soothing for patients than traditional
benzoyl peroxide products. It is available as a cleanser, toner,
and repairing solution. The possibility of increased tolerability,
its advertising campaign, and the basic effectiveness of benzoyl
peroxide against acne have made Proactiv one of the most
successful acne treatments ever, in terms of dollar volume.43
Other acne medications include topical antibiotics whose
active agent is erythromycin or clindamycin. Topical metronidazole, which is commonly used to treat rosacea, is not indicated for treating acne. These agents, like their oral counterparts, are particularly effective against inflammatory acne and
acne related to P. acnes responds to topical or oral antibiotics.
The FDA has approved dapsone 5% gel (Aczone, QLT USA)
to treat acne after glucose-6-phosphate dehydrogenase (G6PD)
levels are assessed, as required in the product’s boxed warning. A phase 4 post-approval trial is currently ongoing with the
goal of having the restriction removed. In a study of patients
with G6PD deficiency, the gel was found to be safe and effective in substantially decreasing inflammator y acneiform
lesions.34
Antibiotics do not abate comedones, and bacterial resistance
to antibiotics may develop. The development of resistance is
reduced if topical antibiotics are used in combination with
benzoyl peroxide.
Topical Retinoids
For mild acne, it is best to start with topical medications,
which should be given for six to eight weeks. A first-line treatment for comedonal, non-inflammatory acne involves the use
of topical retinoids (e.g., Retin-A) , such as tretinoin, adapalene
(Differin, Galderma), and tazarotene (e.g., Allergan’s Tazorac
and Avage).36–38,40–42
Topical retinoids have comedolytic and anti-inflammatory
properties. They increase epidermal differentiation and help
normalize and abate follicular hyperproliferation and hyperkeratinization. Topical retinoids are the only medications that
abate open and closed comedones; they decrease the quantity
of micro-comedones, comedones, and inflammatory papules
and pustules.
Retinoids are effective as monotherapy, or they can be combined with topical regimens that include antibiotics and benzoyl peroxide. Topical retinoids can also be used in conjunction with oral antibiotics.
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Topical retinoids should be applied to clean, dry skin once
daily. If they cause irritation, they can be applied every other
day or every third day if irritation occurs with daily use. Some
physicians have advocated the use of short-contact regimens
with tazarotene, which is applied to the face for 5 to 20 minutes
and is then removed by washing. Skin irritation, skin flaking
and peeling, and redness of the skin can be linked to the use
of topical retinoids.
Mild, non-drying skin cleaners and non-comedogenic moisturizers may help reduce this irritation.27 Alternate-day dosing
may be used if irritation persists. Topical retinoids thin the stratum corneum, and they can be associated with sun sensitivity.
New developments in retinoids include a combination product of tretinoin 0.025% and clindamycin phosphate 1.2% in a gel
(Ziana, Medicis). Ziana is indicated for the topical treatment
of acne in patients 12 years of age and older.
According to trials, adapalene 0.3% gel (Differin) might be
superior to its 0.1% gel predecessor.44
A product combining tretinoin 0.025% and clindamycin phosphate 1% in a hydrogel base (Velac, Connetics) has not yet
come to market.
Additional Topical Agents
Other topical agents include azelaic acid, either as a cream
(Azelex, Allergan) or a gel (Finacea, Intendis), used once a day.
Products that contain sulfur in different forms are soothing and
somewhat effective for treating acne, rosacea, and seborrheic
dermatitis.
Oral Therapies
Antibiotics
Oral antibiotics are effective in the treatment of acne,
particularly when acne is related to inflammation or P. acnes
infection.4 As previously stated, the antibiotics are useful for
moderate and severe grades of inflammatory acne because of
their anti-inflammatory properties.
Tetracyclines. Tetracyclines are commonly used to treat
acne. Some authors think that more lipophilic antibiotics and
antibiotics with less P. acnes resistance, such as minocycline
(Minocin), are more effective than tetracycline. Others claim
that there is no clear proof that minocycline is superior to
tetracycline. Because tetracyclines stain the teeth, they should
not be used in children.
Doxycycline. A new development in the role of oral antibiotics for acne treatment is the use of submicrobial doses of
doxycycline (Vibramycin). These doses have only anti-inflammatory rather than antibiotic activity, and they have been
shown to be equivalent to higher antimicrobial doses.
Er ythromycin. Oral erythromycin has been a mainstay of
anti-acne treatment.4,11 P. acnes resistance to erythromycin
has greatly reduced its utility in acne therapy.
Azithromycin. Azithromycin (Zithromax) has been suggested as an effective acne treatment, and it might be more useful than erythromycin because of its longer half-life, greater
anti-inflammatory activity, wider coverage of gram-negative
organisms, and fewer gastrointestinal adverse effects. Irreversible deafness has been reported after the use of low-dose
azithromycin in healthy patients, but the handful of cases suggests that this side effect is rare.
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Sulfa agents. Trimethoprim/sulfamethoxazole (Bactrim),
given as a double-strength tablet twice a day, can be effective;
it often works when other antibiotics fail. It is useful in treating gram-negative folliculitis, a mimic of acne that does not
respond to tetracycline or macrolides but does respond to
isotretinoin and trimethoprim/sulfamethoxazole.
The most common adverse side effect is a maculopapular
eruption; rare side effects include Stevens–Johnson syndrome,
hepatitis, and toxic epidermal necrolysis.
The combination of methotrexate plus trimethoprim/
sulfamethoxazole can be fatal. If patients are taking methotrexate for psoriasis or rheumatoid arthritis or if they intend
to use methotrexate as an abortifacient and they seek treatment of acne, these drugs should not be prescribed together.
For many dermatologists, these possible adverse effects make
trimethoprim/sulfamethoxazole a third-line therapy for acne.
Oral Contraceptives
Oral contraceptives are effective in women for acne that is
related to androgen excess or that waxes and wanes with their
menstrual periods. These agents increase sex hormone–binding globulin; this decreases circulating free testosterone,
thereby abating acne in some cases. Combination birth control tablets have shown efficacy in the treatment of acne vulgaris. Spironolactone (Aldactone), which may also be used in
the treatment of acne vulgaris, binds the androgen receptor
and reduces androgen production.
Oral Retinoids (Isotretinoin)
Isotretinoin (Accutane), a systemic retinoid, is the single
most effective agent for the treatment of acne of all types.5,6 It
normalizes epidermal differentiation and inhibits sebum excretion permanently by 70%. Isotretinoin also works as an antiinflammatory agent. However, it is not a panacea; one study
found that 7.2% of patients with acne did not respond to
isotretinoin therapy.45
Some dermatologists find that dispensing enough isotretinoin to achieve a cumulative dose of 120 to 150 mg/kg is
the optimal way to use this agent for acne; they prefer that
isotretinoin 1 mg/kg be given in a divided dose twice a day for
five months or that therapy be initiated at a dose of 0.5 mg/kg
per day for four weeks and increased as tolerated until a dose
of 1 mg/kg daily is achieved. Other experts advocate the lowdose regimens of isotretinoin involving six months of treatment
with 20 mg/day, noting that such dosing has a low incidence
of severe side effects and is less expensive than higher-dose
regimens.46
As a rule, a single course of isotretinoin at a cumulative
dose of 120 to 150 mg/kg should cure acne in two-thirds of
patients. A side effect from the continued use of isotretinoin,
however, is a condition known as diffuse idiopathic skeletal
hyperostosis (DISH). For this reason, some physicians order
a radiographical skeletal baseline examination if repeated
courses of isotretinoin are considered. Patients should be
warned of the rare possibility of the occurrence of DISH before therapy is begun.
Isotretinoin is a teratogen, and fertile women must be
informed of this fact. In the U.S., isotretinoin may be distributed only if patients, physicians, and pharmacists participate
in the iPledge program.47 Before pharmacists may distribute
the product, patients must enroll in this program and a negative pregnancy test in fertile women must be confirmed.
Isotretinoin does not seem to have a negative effect on
mood. Some reports suggest that it increases the incidence of
depression, but larger studies have not borne this out. Children
exposed to high doses of isotretinoin are at risk for premature
epiphyseal closure, whereas adults maintaining long-term
therapy have an increased tendency to develop hyperostosis
and other changes in bones. In any case, physicians must
counsel women regarding contraception, and two negative
pregnancy test results are required before therapy can be initiated. These test results must be confirmed monthly.
For all patients, a baseline laboratory examination should
also include assessments of cholesterol, triglyceride, and
hepatic transaminase levels as well as a complete blood count.
Although an increase of isotretinoin has been shown to raise
triglyceride levels in well-documented cases, its adverse effects
on the liver are less well defined and certainly less common.
In cases of acne fulminans, isotretinoin can worsen acne initially. Coadministration with corticosteroids at the beginning
of therapy can be useful in severe cases to prevent the initial
flaring of acne.
Nutritional Supplements
Vitamins and minerals have been used to treat acne. Pharmacological doses of nicotinamide tablets (e.g., Nicomide,
DUSA/Sirius), 1.5 g/day, given in divided doses two or three
times a day, have been used often in combination with zinc, copper, and folic acid.17 Oral and topical zinc have also been advocated, but strong evidence of its effect needs to be established.
Other Treatments
For variations of acne, other therapies can be attempted.
Triamcinolone. Cysts of acne respond within a day after
injections with triamcinolone acetonide (Kenalog, Apothecon)
at a concentration of 2 to 3 mg/mL, although atrophy can
result temporarily. Recently, lasers and light sources have
been advocated, but controlled studies are lacking and such
treatments are expensive.48
Psychotropic medications. Acne excoriée is characterized
by excessive scratching or picking of normal skin or skin with
minor surface irregularities. It is most common in young
women who pick at scattered acne papules, which are turned
into scars. The compulsion is best treated with antidepressants
or antipsychotic medications combined with isotretinoin. Medications that can be used include the selective serotonin reuptake inhibitors (SSRIs) as first-line psychiatric agents (e.g.,
Zoloft, Paxil, or Prozac). If the obsessive–compulsive disability is severe, low-dose risperidone (Risperdal, Janssen)
2 mg or olanzapine (Zyprexa, Eli Lilly) 2.5 mg can be helpful.
It may be advisable for patients to seek out psychological
assistance or counseling in these cases.49,50
Surger y. Acne surger y involves the extraction of comedones. Open comedones are pores that contain keratin plugs
with black tops (blackheads). Closed comedones are pores
containing keratin plugs with white tops that may be more
firmly embedded than open comedones (whiteheads). Comedones are not usually inflamed, but they can be.51
Vol. 32 No. 6 • June 2007 •
P&T® 345
CONTINUING EDUCATION CREDIT
How Long Should Therapy Continue?
Acne naturally waxes and wanes, and the use of therapy can
be instituted and discontinued as needed. After the inflammation is controlled with oral antibiotics, acne can often be controlled with topical retinoids and benzoyl peroxide for long
periods. Long-term therapy with minocycline beyond six
months carries an increased risk of pigmentary deposition.52
Many acne patients continue with an antibiotic for more than
a year without adverse effects.52
Isotretinoin can “cure” acne in many cases, although up to
20% to 25% of patients need to be re-treated for optimal results.53,54 Topical retinoids have anti-aging effects on the skin;
thus, long-term therapy, if tolerated, can be seen as desirable.
Role of the Pharmacist
Pharmacists play an important role in acne treatment. They
must be aware of the side effects of acne medications and the
potential interactions of acne medications with other agents,
in particular methotrexate and sulfamethoxazole/trimethoprim. Pharmacists are active participants in the iPledge program and must use an online database to disburse isotretinoin.55
Many patients with acne never see a physician, and they
often seek advice from a pharmacist about therapy. In an
Australian study by Yeatman et al.,56 70% of the 315 consumers
inter viewed were purchasing OTC products, and 50%
purchased prescription items. Of the OTC products, 42% were
originally recommended by the pharmacy staff members and
18% were recommended by doctors. More than one-third of
consumers buying OTC products described symptoms to the
pharmacy staff, and in about 50% of cases, they spoke to the
pharmacy assistant. Pharmacists must be aware of different
OTC preparations, including benzoyl peroxide, salicylic acid,
sulfur, and sodium sulfacetamide, all of which are available in
concentrations of 2% or more.57
Conclusion
Acne continues to be one of the most common diseases in
the U.S. Treatments have greatly improved the quality of life
for patients. In particular, isotretinoin has been useful in severe
cases. However, the new iPledge program has limited the ease
of prescribing medications. Submicrobial doses of doxycycline, topical dapsone, and adapalene 0.3% cream are promising new modalities.
Acne is a disease with substantial morbidity that can be
ameliorated with treatment and that requires the partnership
of the patient, physician, and pharmacist to achieve its greatest effectiveness.
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CONTINUING EDUCATION CREDIT
32. Chan HH, Wing Y, Su R, et al. A control study of the cutaneous
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Dapsone Gel Study Group. Two randomized studies demonstrate
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best treatment for mild to moderate acne? J Fam Pract 2006;55:
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passim.
38. Goulden V. Guidelines for the management of acne vulgaris in
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39. Leyden JJ. Current issues in antimicrobial therapy for the treatment of acne. J Eur Acad Dermatol Venereol 2001;15(Suppl
3):51–55.
40. Plewig G, Jansen T. Acneiform dermatoses. Dermatology 1998;196:
102–107.
41. Scheinfeld NS. 10 misadventures in treating acne. Skin Aging
2005;13(8):48–50.
42. Gollnick H, Schramm M. Topical drug treatment in acne. Dermatology 1998;196(1):119–125.
43. Burkhart CG, Burkhart CN. Treatment of acne vulgaris without
antibiotics: Tertiary amine-benzoyl peroxide combination vs. benzoyl peroxide alone (Proactiv Solution). Int J Dermatol 2007;
46:89–93.
44. Thiboutot D, Pariser DM, Egan N, et al, the Adapalene Study
Group. Adapalene gel 0.3% for the treatment of acne vulgaris:
A multicenter, randomized, double-blind, controlled, phase III
trial. J Am Acad Dermatol 2006;54:242–250.
45. Goulden V, Layton AM, Cunlif fe WJ. Long-term safety of
isotretinoin as a treatment for acne vulgaris. Br J Dermatol 1994;
131:360–363.
46. Amichai B, Shemer A, Grunwald MH. Low-dose isotretinoin in the
treatment of acne vulgaris. J Am Acad Dermatol 2006;54:644–646.
47. Cheetham TC, Wagner RA, Chiu G, et al. A risk management
program aimed at preventing fetal exposure to isotretinoin:
Retrospective cohort study. J Am Acad Dermatol 2006;55:442–448.
48. Ortiz A, Van Vliet M, Lask GP, Yamauchi PS. A review of lasers
and light sources in the treatment of acne vulgaris. J Cosmet Laser
Ther 2005;7:69–75.
49. Fried RG, Wechsler A. Psychological problems in the acne patient.
Dermatol Ther 2006;19(4):237–240.
50. Eichenfield LF, Fried RG, Taylor SC, et al. Acne and your pediatric
patient: A round-table discussion of treatment modalities and
other factors. Cutis 2005;76(5 Suppl):5–24.
51. Jansen T, Grabbe S, Plewig G. Clinical variants of acne. Hautarzt
2005;56(11):1018–1026.
52. Smith K, Leyden JJ. Safety of doxycycline and minocycline:
A systematic review. Clin Ther 2005;27(9):1329–1342.
53. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for
acne: Results of a multicenter dose-response study. J Am Acad
Dermatol 1984;10(3):490–496.
54. Stainforth JM, Layton AM, Taylor JP, Cunliffe WJ. Isotretinoin for
the treatment of acne vulgaris: Which factors may predict the need
for more than one course? Br J Dermatol 1993;129:297–301.
55. Doshi A. The cost of clear skin: Balancing the social and safety
costs of iPLEDGE with the efficacy of Accutane (isotretinoin).
Seton Hall Law Rev 2007;37(2):625–660.
56. Yeatman JM, Kilkenny MF, Stewart K, Marks R. Advice about
management of skin conditions in the community: Who are the
providers? Australas J Dermatol 1996 (37 Suppl 1):S46–S47.
57. Akhavan A, Bershad S. Topical acne drugs: Review of clinical properties, systemic exposure, and safety. Am J Clin Dermatol 2003;
4:473–492. Conflict of Interest (COI) Statement
Dr. Scheinfeld has no relationships to disclose.The
content of this article has been reviewed under Jefferson’s
Continuing Medical Education COI Policy.
Vol. 32 No. 6 • June 2007 •
P&T® 347
CONTINUING EDUCATION CREDIT
Continuing Education Questions for Physicians and Pharmacists
P&T ® 2007;32(6):340–347
ACPE Program # 079-999-07-018-H04
Expiration Date: June 30, 2008
TOPIC: Acne: A Review of Diagnosis and Treatment
CME Accreditation
This activity has been planned and implemented in accordance with the Essential Areas
and Policies of the Accreditation Council for Continuing Medical Education (ACCME)
through the joint sponsorship of Jefferson Medical College and MediMedia USA, Inc.
Jefferson Medical College of Thomas Jefferson University, as a member of the Consortium for Academic Continuing Medical
Education, is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. All faculty/authors participating in continuing medical education activities sponsored by Jefferson Medical College are expected to disclose to the activity audience any real or apparent conflict(s) of interest related to the content
of their article(s). Full disclosure of these relationships appears on the last page of the article.
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This CME activity is designed to assist physicians and other health care professionals who are P&T committee members in
making formulary decisions. Its goal is to increase participants’ ability to recognize and treat important medical problems.
Jefferson Medical College designates this continuing medical education activity for a maximum of one Category 1 credit
toward the Physician’s Recognition Award (PRA) of the American Medical Association. Each physician should claim only
those credits that he/she actually spent in the educational activity.
This credit is available for the period of one year from the date of publication.
Although forms will be processed when received, certificates for CME credits will be issued every six months, in February
and August. Interim requests for certificates can be made by contacting the Jefferson Office of Continuing Medical Education
at (215) 955-6992 or by going online to http://jeffline.tju.edu/jeffcme/.
Continuing Pharmacy Education Credit
The Department of Health Policy, Thomas Jefferson University Hospital, is approved by the Accreditation Council
for Pharmacy Education (ACPE) as a provider of continuing pharmacy education and complies with the
Criteria for Quality for continuing pharmacy education programming. This program (079-999-07-018-H04) is acceptable for 1.0 hour of continuing education credit (0.1 CEUs) in states that recognize ACPE-approved providers. Statements of
Credit indicating hours/CEUs will be mailed within six to eight weeks to participants who completed this activity and submitted a completed evaluation with payment.
How to Apply for CE Credit
1. Each CE article is prefaced by learning objectives for participants to use to determine whether the article relates to their
individual learning needs.
2. Read the article carefully, paying particular attention to the tables and other illustrative materials.
3. Complete the questions and fill in the answers on the evaluation form on the next page.
4. Complete the CE Registration and Evaluation Form. Type or print your full name and address in the space provided, and
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5. Payment of $10 per exam is required for processing and maintenance of records. Make checks payable to P&T®. This
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6. Send the completed form, answer sheet, and $10 payment to:
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Attn: Continuing Education Credit
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date, this article will no longer be designated for credit and forms cannot be processed.
348 P&T®
• June 2007 • Vol. 32 No. 6
CONTINUING EDUCATION CREDIT
Continuing Education Questions for Physicians and Pharmacists
TOPIC: Acne: A Review of Diagnosis and Treatment
APCE Program # 079-999-07-018-H04
CE Evaluation: Select the one best answer to each of the following questions, and record your response on the
examination answer sheet. Complete the additional requested information. Forward the answer sheet, with appropriate payment, to the Department of Health Policy,Thomas Jefferson University Hospital, at the address indicated.
A certificate of completion will be mailed within six to eight weeks of receipt of your exam/payment. (A minimum
test score of 70% is required.)
Multiple Choice
6.
Which of the following is true regarding the role of
over-the-counter medications in the management
of acne?
a. Doxycycline is the most cost-effective treatment.
b. Oral OTC medications are the most common and
effective treatment.
c. Patients should not combine OTC medications and prescription medication for acne.
d. Benzoyl peroxide is the simplest and most cost-effective
treatment if tolerated.
7.
Which of the following patients are poor
candidates for OTC medications for acne?
a. patients with only comedones on the face
b. patients with papules, pustules, and comedones on the
face
c. patients with papules and pustules on the face
d. patients with papules, pustules, and cysts on the face,
chest, neck, and back
8.
When counseling acne patients who have chosen to
use isotretinoin for acne management, which of the
following statement(s) is/are correct?
a. Patients should be warned of the rare possibility of the
occurrence of diffuse idiopathic skeletal hyperostosis
(DISH).
b. Patients are required to confirm a negative pregnancy
test before pharmacists may distribute isotretinoin.
c. A cumulative dose of 120 to 150 mg/kg is the optimal
way to use isotretinoin for acne.
d. all of the above
9.
Oral contraceptives are effective in both women
and men for acne that waxes and wanes
periodically.
a. True
b. False
Select the one correct answer.
1.
Which of the following is correct regarding the
epidemiology of acne?
a. Acne occurs primarily in men in their later years.
b. Acne occurs most commonly in women in the postmenopausal phase.
c. Acne is the least common dermatological condition in
the U.S.
d. Acne affects almost all humans at some point in their
lives, and approximately seven million new cases are
diagnosed each year in the U.S.
2.
Pharmacists are often on the front lines of care for
acne patients seeking relief.
a. True
b. False
3.
Which of the following is correct in regard to the
clinical presentation of acne?
a. comedones on the face
b. papules and pustules of the face, chest, and back
c. pain, tenderness, and erythema around cysts
d. all of the above
4.
Which of the following is/are associated with an
increased risk of developing (worsening) acne?
a. menstrual period and hormonal imbalances
b. fatty foods
c. oral medications (i.e., trazodone, haloperidol, estrogen,
phenytoin)
d. all of the above
5.
The nonpharmacological management of acne may
include which of the following?
a. isotretinoin
b. tetracycline
c. doxycycline
d. benzoyl peroxide
10. Which of the following is the rare side effect of
trimethoprim/sulfamethaxazole?
a. red man syndrome
b. Stevens–Johnson syndrome
c. Franconi syndrome
d. Raynaud syndrome
Vol. 32 No. 6 • June 2007 •
P&T® 349
Pharmacy and Therapeutics
CE Registration and Evaluation Form
Date of publication: June 2007
Title: Acne: A Review of Diagnosis and Treatment
Authors: Noah S. Scheinfeld, JD, MD
Submission deadline: June 30, 2008
ACPE Program # 079-999-07-018-H04
A Peer-Reviewed Journal for Managed Care
and Hospital Formulary Management
Registration
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2 hr
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Date _______________
Answer Sheet
Please fill in the box next to the letter corresponding to the correct answer
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350 P&T®
• June 2007 • Vol. 32 No. 6