Evidence-Based Recommendations for the Diagnosis and Treatment of Pediatric Acne
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SUPPLEMENT ARTICLE
Evidence-Based Recommendations for the Diagnosis
and Treatment of Pediatric Acne
AUTHORS: Lawrence F. Eichenfield, MD,a Andrew C.
Krakowski, MD,a Caroline Piggott, MD,a James Del Rosso, abstract
DO,b Hilary Baldwin, MD,c Sheila Fallon Friedlander, MD,a
INTRODUCTION: Acne vulgaris is one of the most common skin con-
Moise Levy, MD,d Anne Lucky, MD,e Anthony J. Mancini, MD,f
Seth J. Orlow, MD, PhD,g Albert C. Yan, MD,h Keith K. Vaux, ditions in children and adolescents. The presentation, differential di-
MD,i Guy Webster, MD, PhD,j Andrea L. Zaenglein, MD,k,l and agnosis, and association of acne with systemic pathology differs by
Diane M. Thiboutot, MDl age of presentation. Current acknowledged guidelines for the diag-
aDivision of Pediatric and Adolescent Dermatology, Rady nosis and management of pediatric acne are lacking, and there are
Children’s Hospital, San Diego and Departments of Pediatrics and variations in management across the spectrum of primary and spe-
Medicine (Dermatology), University of California, San Diego, San
Diego, California; bSection of Dermatology, Valley Hospital
cialty care. The American Acne and Rosacea Society convened a panel
Medical Center, Las Vegas, Nevada; cDepartment of Dermatology, of pediatric dermatologists, pediatricians, and dermatologists with
SUNY Downstate Medical Center, Brooklyn, New York; dPediatric/ expertise in acne to develop recommendations for the management
Adolescent Dermatology, Dell Children’s Medical Center, Austin,
of pediatric acne and evidence-based treatment algorithms.
Texas, Department of Dermatology, UT Southwestern Medical
School, Dallas, Texas and Departments of Pediatrics and METHODS: Ten major topic areas in the diagnosis and treatment of
Dermatology, Baylor College of Medicine, Houston, Texas; pediatric acne were identified. A thorough literature search was per-
eDepartments of Dermatology and Pediatrics, University of
Cincinnati College of Medicine and Cincinnati Children’s Hospital formed and articles identified, reviewed, and assessed for evidence
Medical Center, Cincinnati, Ohio; fDepartments of Pediatrics and grading. Each topic area was assigned to 2 expert reviewers who de-
Dermatology, Northwestern University Feinberg School of veloped and presented summaries and recommendations for critique
Medicine and Division of Dermatology, Ann & Robert H. Lurie
Children’s Hospital of Chicago; gThe Ronald O. Perelman
and editing. Furthermore, the Strength of Recommendation Taxonomy,
Department of Dermatology, New York University School of including ratings for the strength of recommendation for a body of
Medicine, New York, New York; hSection of Pediatric Dermatology, evidence, was used throughout for the consensus recommendations
Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
for the evaluation and management of pediatric acne. Practical
and Departments of Pediatrics and Dermatology, Perelman
School of Medicine at the University of Pennsylvania; evidence-based treatment algorithms also were developed.
iDivision of Pediatrics and Hospital Medicine, Rady Children’s
RESULTS: Recommendations were put forth regarding the classifica-
Hospital, San Diego, California and Department of Pediatrics,
University of California, San Diego, California; jDepartment of tion, diagnosis, evaluation, and management of pediatric acne, based
Dermatology, Jefferson Medical College, Thomas Jefferson on age and pubertal status. Treatment considerations include the use
University, Philadelphia, Pennsylvania; kDepartment of of over-the-counter products, topical benzoyl peroxide, topical
Dermatology, The Pennsylvania State University College of
Medicine; and lDepartment of Pediatrics, Penn State Hershey
retinoids, topical antibiotics, oral antibiotics, hormonal therapy, and
Children’s Hospital, Hershey, Pennsylvania isotretinoin. Simplified treatment algorithms and recommendations
KEY WORDS are presented in detail for adolescent, preadolescent, infantile, and
pediatric acne, acne treatment, combination acne therapy, neonatal acne. Other considerations, including psychosocial effects
retinoids, benzoyl peroxide, bacterial resistance, isotretinoin, of acne, adherence to treatment regimens, and the role of diet and
hormonal therapy, acne guidelines, acne algorithm, neonatal
acne, infantile acne, mid-childhood acne, preadolescent acne, acne, also are discussed.
American Acne and Rosacea Society, AARS CONCLUSIONS: These expert recommendations by the American Acne
(Continued on last page)
and Rosacea Society as reviewed and endorsed by the American Acad-
emy of Pediatrics constitute the first detailed, evidence-based clinical
guidelines for the management of pediatric acne including issues of
special concern when treating pediatric patients. Pediatrics 2013;131:
S163–S186
PEDIATRICS Volume 131, Supplement 3, May 2013 S163
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Acne vulgaris is one of the most com- American Acne and Rosacea Society, Each topic area was assigned to 2 ex-
mon skin conditions in children and a nonprofit organization promoting pert reviewers, who developed and
adolescents. Although often considered research, education, and improved presented an in-depth summary and
a disease of teenagers, in whom the care of patients with acne and rosacea. recommendations for further critique
prevalence is reported to be from 70% The expert panel was charged with and editing. The Strength of Recom-
to 87%,1 12 years of age is no longer developing recommendations for the mendation (SOR) Taxonomy ratings for
considered the lower end of the age management of pediatric acne and the recommendation for a body of evi-
range for acne onset.2 A study by Lucky evidence-based treatment algorithms. dence is noted throughout the article.4
et al3 revealed acne lesions in 78% of A member of the expert panel served as This taxonomy addresses the quality,
365 girls ages 9 to 10. In addition, acne liaison to the American Academy of quantity, and consistency of evidence
and other acneiform (acnelike) con- Pediatrics and as part of the recom- and allows authors to rate individual
ditions occur at different ages, in- mendation writing group. studies or bodies of evidence. The tax-
cluding neonates, infants, and young onomy emphasizes the use of patient-
children, and may be associated with METHODS oriented outcomes that measure
differential diagnoses or systemic pa- changes in morbidity or mortality. The
The expert panel identified special
thology that differs from teenagers. authors reviewed the bodies of evi-
issues in the diagnosis and treatment of
dence for each of the recommenda-
There are issues of special concern in acne and acneiform conditions in pe-
treatment of preadolescents with acne. tions and assigned one of the following
diatric patients across various ages.
SOR: an A-level recommendation is
The majority of clinical trials for acne Ten major topic areas were specified by
based on consistent and good-quality
medications are conducted in patients the panel (Table 1). A thorough English-
patient-oriented evidence; a B-level
12 years of age or older. As a result, language literature search was perfor-
recommendation is based on inconsis-
there is little published evidence re- med for each topic area, and identified
tent or limited-quality patient-oriented
garding the safety and efficacy of many articles were reviewed utilizing a
evidence; and a C-level recommenda-
acne medications in pediatric patients. patient-centered approach to grading
tion is based on consensus, usual
Furthermore, the treatment of acne evidence available to the expert panel.4
practice, opinion, disease-oriented ev-
often involves use of several medi- Relevant clinical trial registries and
idence, or case series for studies of
cations that target either different types data filed with the Food and Drug Ad-
diagnosis, treatment, prevention, or
of acne lesions, different factors in- ministration (FDA) were included in the
screening. This article summarizes the
volved in the pathogenesis of acne, or data review.
resultant consensus recommenda-
different degrees of acne severity. Po-
tions for the evaluation and diagnosis
tential interactions between medi-
of pediatric acne, as well as a series of
cations can add another layer of TABLE 1 Topic Areas Researched and
Discussed by Expert Panel treatment algorithms to assist health
complexity to the management of acne
Pediatric Acne Categorization and Differential care practitioners in the management
in pediatric patients, as can concerns and treatment of acne in pediatric
Diagnosis of Acne
about systemic side effects and impact patients.
Evaluation of Pediatric Acne by Age/Classification
of medications on growth and de- Evidence-based Treatment Review for Pediatric
velopment. The psychosocial impact of Acne
acne can be significant, as can issues of • OTC products CATEGORIZATION AND
• BP treatment
adherence to treatment regimens. • Topical retinoids, antibiotics, and fixed-dose
DIFFERENTIAL DIAGNOSIS OF
Currently, detailed, acknowledged guide- combination products PEDIATRIC ACNE
• Oral antibiotics: age-related issues, safety, and
lines for the diagnosis and manage- resistance Both age and form of presentation are
ment of acne in pediatric patients are • Isotretinoin pediatric patients with severe acne relevant to the diagnosis of pediatric
lacking. Recognizing the need to ad- • OC use and hormonal therapy acne. Although there is some overlap in
Pediatric Acne Treatment Considerations
dress special issues regarding the age and presentation of acneiform
• Previous treatment history
diagnosis and treatment of acne in • Costs conditions, the consensus of the panel
children of various ages, a panel of • Ease of use/regimen complexity and adherence regarding relevant age categories is
experts consisting of pediatric der- • Vehicle selection
presented in Table 2. These ranges are
• Active scarring
matologists, pediatricians, and der- • Side effects approximate. In girls, age of onset of
matologists with expertise in acne was • Psychosocial impact menarche may be a better delineating
convened under the auspices of the • Diet point between preadolescence and
S164 EICHENFIELD et al
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SUPPLEMENT ARTICLE
TABLE 2 Expert Panel Consensus: Pediatric cheeks, chin, eyelids, and forehead, but mass.12 Should workup for a hormonal
Acne Categorized by Age
the scalp, neck, and upper chest and anomaly be considered, a pediatric
Acne Type Age of Onset back may be involved.8 Its pathogene- endocrinology referral and/or bone
Neonatal Birth to #6 wk sis may involve colonization with age and serologic evaluation of follicle-
Infantile 6 wk to #1 y
Mid-childhood 1 y to ,7 y
Malassezia species, a normal com- stimulating hormone, luteinizing hormone,
Preadolescent $7 to #12 y or menarche mensal of infant skin, or may represent testosterone, and dehydroepiandros-
in girls an inflammatory reaction to a yeast terone sulfate levels are recommended.
Adolescent $12 to #19 y or after overgrowth at birth.8,10 NCP is typically No further workup is necessary for the
menarche in girls
mild and self-limited, and reassuring majority of cases in the absence of
the parents is usually the only man- hormonal abnormalities. It is also im-
adolescence. In general, acne is un- agement needed. If lesions are nu- portant to distinguish true infantile
complicated by systemic disease, but merous, 2% ketoconazole cream may acne from other similar cutaneous
in some cases it may be a cutaneous reduce fungal colonization.11 New- lesions, because there is some evidence
manifestation of underlying pathology. borns also may present with or develop that infantile acne predisposes to more
It is essential to have a broad un- transient neonatal pustular melanosis, severe adolescent acne.13 Infantile acne
derstanding of acne at different ages with pustules on the chin, neck, or may be treated with topical antimicro-
and to be aware of the differential di- trunk. Within 24 hours, these pustules bial agents; topical retinoids; noncycline
agnoses for each age group. Table 3 rupture, leaving hyperpigmented mac- antibiotics, such as erythromycin; and,
presents a differential diagnosis for ules with a rim of faint white scale.10 occasionally, isotretinoin, though all are
acne in each age group.5–7 Workup is Consensus Recommendation: without FDA indication for use in this
based on age and physical findings.6 age group.
Neonates may have true acne, al-
The physical examination should focus Consensus Recommendation:
though many self-limited papulo-
on type and distribution of acne
pustular eruptions also occur on Most infantile acne is self-limited
lesions, height, weight, growth curve,
the faces of neonates. In infants and not associated with underlying
and possible blood pressure abnor-
and younger children (,7 years endocrine pathology. However, in
malities. Signs of precocious sexual
of age) with significant acne vulga- patients with additional physical
maturation or virilization should prompt
ris, evaluation for signs of sexual signs of hormonal abnormality,
workup and/or a referral to a pediatric
precocity, virilization, and/or growth a more extensive workup and/or
endocrinologist.8
abnormalities that may indicate an referral to a pediatric endocrinol-
Consensus Recommendation: underlying systemic abnormality ogist may be appropriate. (SOR: C).
Acneiform eruptions from the neo- (endocrinologic diseases, tumors,
natal period through adolescence gonadal/ovarian pathology) and ap- Mid-Childhood Acne
may be broadly categorized by age propriate workup and/or referral to
Mid-childhood acne presents primarily
and pubertal status. a pediatric endocrinologist may be
on the face with a mixture of comedones
warranted. (SOR: C).
and inflammatory lesions.10 Children
between the ages of 1 and 7 years,
Neonatal Acne Infantile Acne however, do not normally produce
Neonatal acne is estimated to affect up Infantile acne may begin at ∼6 weeks of significant levels of adrenal or gonadal
to 20% of newborns.9 The major con- age and last for 6 to 12 months or, androgens; hence, acne in this age
troversy in this age group is whether rarely, for years. It is more common in group is rare. When it does occur, an
the lesions truly represent acne or one boys and presents with comedones as endocrine abnormality should be sus-
of a number of heterogeneous pap- well as inflammatory lesions, which pected. A workup by a pediatric endo-
ulopustular acneiform conditions typi- can include papules, pustules, or oc- crinologist is usually warranted to rule
cally without comedones, such as casionally nodular lesions. Physical out adrenal or gonadal/ovarian pa-
neonatal cephalic pustulosis (NCP) or examination should include assess- thology including the presence of
transient neonatal pustular melanosis. ment of growth including height, androgen-secreting tumors. Increased
Although rare, some neonates may weight, and growth curve; testicular bone age and accelerated growth, as
present with androgen-driven come- growth and breast development; pres- evidenced by deviation from standard-
donal and inflammatory acne.8,10 NCP ence of hirsutism or pubic hair; clito- ized age-appropriate growth curves,
pustules are usually confined to the romegaly; and increased muscle are important indicators of the effects
PEDIATRICS Volume 131, Supplement 3, May 2013 S165
Downloaded from by guest on October 29, 2015TABLE 3 Differential Diagnosis of Acne in than 8 years of age because of the risk Consensus Recommendation:
Younger Pediatric and Adolescent
Patients
of damage to developing bones and Preadolescent (7–12 years) acne is
tooth enamel. Hormonal therapy could common and may precede other
Adolescent (∼12–18 y of age)
be used if warranted by endocrinologic signs of pubertal maturation. Workup
Corticosteroid-induced acne
Demodex folliculitis
pathology.8 beyond history and physical is gen-
Gram-negative folliculitis Consensus Recommendation: erally unnecessary unless there
Keratosis pilaris
Malassezia (pityrosporum) folliculitis Mid-childhood acne is very uncom- are signs of androgen excess, PCOS,
Papular sarcoidosis mon and should warrant an endo- or other systemic abnormalities.
Perioral dermatitis crinologic workup for causes of (SOR: B).
Pseudofolliculitis barbae
Tinea faciei hyperandrogenism. (SOR: C).
Preadolescent ($7 to #12 y of age)
Acne venenata or pomade acne (from the use Preadolescent Acne PEDIATRIC ACNE CLASSIFICATION
of topical oil-based products)
It is not uncommon for acne vulgaris to AND SEVERITY ASSESSMENT
Angiofibromas or adenoma sebaceum
Corticosteroid-induced acne occur in preadolescents, as a result of In general, treatment of pediatric acne
Flat warts normal adrenarche and testicular/ vulgaris is similar to acne treatment in
Keratosis pilaris
Milia
ovarian maturation. Acne may be the older adolescents and adults and is
Molluscum contagiosum first sign of pubertal maturation.8 In based on acne pathophysiology. The
Perioral dermatitis fact, with the trend toward earlier age pathogenesis of acne involves the in-
Syringomas
of onset of adrenarche and menarche, terplay of 4 factors: sebaceous hyper-
Mid-Childhood (1–7 y of age)
Adrenal tumors there appears to be a downward shift plasia under the influence of increased
Congenital adrenal hyperplasia in the age at which acne first appears. androgen levels, alterations in follicular
Cushing syndrome Preadolescent acne is characterized by growth and differentiation, colonization
Gonadal tumors
Ovarian tumors a predominance of comedones on the of the follicle by Propionibacterium
PCOS forehead and central face (the so- acnes (P acnes), and consequent im-
Premature adrenarche called “T-zone”) with relatively few in- mune response and inflammation.15
True precocious puberty
Any Age
flammatory lesions.10 Early pre- A useful clinical categorization of acne
Acne venenata or pomade acne (from the use of sentation may include comedones of is based on predominate morphology:
topical or oil-based products) the ear. comedonal with closed and open
Bilateral nevus comedonicus
Chlorinated aromatic hydrocarbons (chloracne) History and physical examination are comedones (“whiteheads” and “black-
Corticosteroids (topical, inhaled, and oral) the most important parts of the as- heads”); inflammatory, with erythema-
Demodicidosis sessment in this age group. Further tous papules, nodules, or cystlike
Facial angiofibromas (tuberous sclerosis)
Flat warts workup is generally unnecessary un- nodular lesions; or mixed, where both
Infections (bacterial, viral, and fungal) less there are signs of excess andro- types of lesions are present. The micro-
Keratosis pilaris gens.7 Polycystic ovary syndrome comedo is the not-clinically-apparent
Medication-Induced (anabolic steroids,
dactinomycin, gold, isoniazid, lithium, phenytoin,
(PCOS) or another endocrinologic ab- precursor of both comedonal and in-
and progestins) normality may be considered when the flammatory lesions. It is a product of hy-
Milia acne is unusually severe, accompanied peractive sebaceous glands and altered
Miliaria
by signs of excess androgens, or is follicular growth and differentiation.
Molluscum contagiosum
Periorificial dermatitis unresponsive to treatment.14 Pelvic ul- Reduction in existing microcomedones
Rosacea trasound is not considered useful for and prevention of the formation of new
Adapted from Tom and Friedlander6 and Krakowski and diagnosis of PCOS because it is non- ones is central to the management of
Eichenfield.7
specific. all acne lesions.16
Treatment of uncomplicated pre- Comedones form as a result of in-
of excess androgens. In addition to treat- adolescent acne is comparable to that creased cell division and cohesiveness
ments to address androgen-secreting of acne in older age groups, as dis- of cells lining the follicular lumen. When
tumors or congenital adrenal hyper- cussed later. It is important in this age these cells accumulate abnormally, mix
plasia, the treatment of mid-childhood group to elicit the patient’s level of with sebum, and partially obstruct the
acne is similar to that of adolescent concern regarding his or her acne, follicular opening, they form a closed
acne except that oral tetracyclines are which may not always be concordant comedo (whitehead). If the follicular
usually not an option in children younger with parental concern. opening is larger, the keratin buildup is
S166 EICHENFIELD et al
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more visible and can darken to form an treatment as patients may not recog- Although no single acne treatment,
open comedo (blackhead). Follicular nize the improvement or think they apart from isotretinoin, addresses all 4
colonization with P acnes leads to in- have scarring. Effective and early pathogenic factors, it is now clear that
flammation via the production of inflam- treatment is essential to prevent many of the medications traditionally
matory mediators and the formation of scarring as well as postinflammatory used to treat acne actually act by more
inflammatory papules and pustules. changes and to limit the long-term than 1 mechanism. In addition to tar-
Nodular acne is characterized by a physical and psychological impact of geting the largest number of patho-
predominance of large inflammatory acne. genic factors, the approach to pediatric
nodules or pseudocysts and is often It has been repeatedly demonstrated acne should be to use the least ag-
accompanied by scarring or the pres- that acne can have a significant adverse gressive regimen that is effective while
ence of sinus tracts when adjacent impact on quality of life, and that the avoiding regimens that encourage the
nodules coalesce. level of distress may not correlate di- development of bacterial resistance.
Acne severity may be classified clini- rectly with acne severity.18,19 In 1 study, Educating a patient (and parents) about
cally as mild, moderate, or severe based assessments using several quality of reasonable expectations of results and
on the number and type of lesions and life instruments revealed deficits for discussing management of treatment-
the amount of skin involved. Although acne patients who did not correlate related side effects can maximize
there are numerous grading systems by with clinical assessments of severity.20 both compliance and efficacy.
which to define acne severity, there is no Reported social, psychological, and Numerous medications are available to
agreed-upon standard, and interpre- emotional symptoms were as severe as treat acne. Design of an effective regi-
tation is subjective. Many grading sys- those reported by individuals with men is facilitated by an increased un-
tems are most useful for research chronic medical conditions such as derstanding of the mechanisms of
purposes. For clinical purposes, sim- chronic asthma, epilepsy, diabetes, and action, the side effect profile, and the
plicity is key. Typically, patients’ as- back pain or arthritis. Adolescents, in indications and contraindications of
sessments do not correlate well with particular, may be insecure about their key antiacne agents discussed later.
either those of physicians or published appearance and vulnerable to peer
severity scales.17 The panel noted that opinions. Because social functioning OVER-THE-COUNTER TREATMENT
severity scales frequently overemphasize and quality-of-life decrements may not OPTIONS
inflammatory lesions. For example, in correlate with disease severity, even
Nationwide television commercials and
some research settings, a patient mild acne may be more troubling to
magazine ads abound with over-the-
might be classified as having mild young patients than they are willing to
counter (OTC) products. Although largely
acne because he or she has only a few admit.21
untested in controlled clinical trials,
inflammatory lesions in the presence Consensus Recommendation: many of these products are considered
of hundreds of closed comedones. In Acne can be categorized as pre- somewhat effective, particularly for
such cases, the patient (and the phy- dominately comedonal, inflamma- patients with mild acne. Those which
sician) is more likely to consider his tory, and/or mixed. Presence or have been tested include salicylic acid-
or her acne to be severe. Determin- absence of scarring, PIH, or ery- containing topical products and many
ation of severity can be modified by thema should be assessed. Sever- benzoyl peroxide (BP) products de-
extent of involvement and scarring as ity may be broadly categorized as scribed in further detail later. Salicylic
well. mild, moderate, or severe. (SOR: A). acid has revealed some efficacy in acne
Although some acne may resolve with- trials, although when tested head-to-
out residual changes, inflammatory head with other topicals, particularly BP,
acne may result in the formation of APPROACH TO PEDIATRIC ACNE it is generally less effective.22,23 Nonpre-
significant scars. In darker skin, post- THERAPY scription, nonbenzoyl-peroxide-containing
inflammatory hyperpigmentation (PIH) The therapeutic objectives in acne are products appear to be somewhat ef-
is common. Residual erythema can oc- to treat as many age-appropriate fective for the treatment of acne, espe-
cur as well. These changes are most pathogenic factors as possible by re- cially mild acne, though there is limited
often reversible but can take many ducing sebum production, preventing published evidence supporting their
months to fully resolve. Recognizing the formation of microcomedones, efficacy in the treatment of acne.
these as secondary changes is impor- suppressing P acnes, and reducing in- Sulfur, sodium sulfacetamide, and
tant when determining the efficacy of flammation to prevent scarring. resorcinol are active ingredients in
PEDIATRICS Volume 131, Supplement 3, May 2013 S167
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ucts. Sulfur exhibits mild antibacterial neum and enter the pilosebaceous unit nificantly reduce bacterial load, but data
and keratolytic properties.24 Because where P acnes resides. It acts via the are lacking. However, they can be effec-
of sulfur’s distinctive odor, it is often generation of free radicals that oxi- tive if left on the skin for the duration
combined with sodium sulfacetamide dize proteins in the P acnes cell wall. recommended by the manufacturer.
to mask the scent.25 It is often used in It also has been shown to have mild Consensus Recommendations:
adult female acne because of its fa- comedolytic36 and antiinflammatory BP is generally regarded as a safe
vorable tolerability.26,27 Resorcinol also properties.37,38 BP helps limit the de- and effective medication that may
has mild antimicrobial properties and velopment of P acnes resistance to be used as monotherapy or in top-
is typically formulated in a 2% con- antibiotics and also provides increased ical combination products for mild
centration in combination with 5%
efficacy in combination with retinoids.39,40 acne or in regimens of care for
sulfur.
So far, antibiotic resistance to BP has acne of all types and severities.
One common acne myth is that poor not been reported.41–44 (SOR: A).
hygiene and improper cleansing cause
Although issues regarding genotoxicity BP may minimize development of
acne.21,28 The role of facial cleansing in
have been raised in the past, BP has now antibiotic-resistant P acnes when
acne is to remove makeup, dirt, and
been labeled as “GRASE” (generally used with topical or systemic anti-
excess oil.29 Use of the wrong, too
regarded as safe and effective) by the biotics. (SOR: C).
harsh cleanser can disrupt skin bar-
FDA, and all topical monotherapy
rier, increase transepidermal water
products have been made available OTC PRESCRIPTION TREATMENT
loss, encourage bacterial coloniza-
since 2011. Labeling includes advice to OPTIONS: SINGLE AGENTS
tion, promote comedones, and cause
avoid the eyes, lips, and mouth. The
symptoms of burning and stinging.30,31 Topical Retinoids
product can cause bleaching of hair
Typically, twice-daily washing with a
and clothing, and risk of increased Topical retinoids, as monotherapy and
gentle soap-free, pH-balanced cleanser
sunburn and the need for photo- in topical combination products, are
is recommended. Antibacterial washes,
protection also are mentioned. BP fre- used routinely for the treatment of acne
other than BP, have not been shown to
quently causes dryness, erythema, and vulgaris. Their safety and efficacy are
be useful in the treatment of acne.
peeling upon initiation of treatment. well documented in large pivotal trials
Facial toners can decrease oiliness and Starting with lower concentrations (eg, that included pediatric patients ranging
remove makeup and traces of dirt. They 2.5%) and utilizing more emollient from 12 to 18 years of age. Sub-
are a common component of several vehicles if needed can help alleviate sequently, because acne routinely
prepackaged combination acne treat- these discomforts. Allergic contact presents in patients younger than 12
ment regimens. Patients should be cau- dermatitis to BP occurs in 1 in 500 years of age, topical retinoids are
tious not to overuse facial toners people and should be considered if widely used off-label in this age group.
becausetheycanbeirritating.Ifirritation a patient complains of itching and Tretinoin gel 0.05% (Atralin, Coria Lab-
occurs, this will adversely affect the swelling of the eyes. oratories, Fort Worth, TX) is FDA-
tolerability of acne medications. approved for use in children $10 years of
BP is available in a variety of for-
Another common acne myth is that use mulations and in concentrations rang- age,46 and adapalene and benzoyl per-
of cosmetics worsens acne. On the ing from 2.5% to 10%. There is some oxide gel 0.1%/2.5% (Epiduo, Galderma
contrary, use of concealing oil-free, evidence that higher concentrations do Laboratories, LP, Fort Worth, TX) is in-
noncomedogenic makeup can im- not increase efficacy but are more ir- dicated for ages 9 and older. Adapalene
prove patient quality of life and does not ritating. However, the back may be gel, tretinoin gel, and tretinoin micro-
worsen the severity of acne.32,33 Use of a “special site” circumstance, where sphere gel have been investigated in
cosmetics in patients with acne has not increasing concentration or prolonged both open-label and blinded studies in
been shown to delay treatment re- contact leads to increased efficacy.45 children under 12 years of age.47–49
sponse either. Formulations include a variety of topi- Retinoids normalize desquamation of
BP has been shown to be the most cal leave-on preparations as well as the follicular epithelium, thus preventing
widely studied of OTC products and has washes that permit patients to remove the formation of new microcomedones,
shown to be one of the most versatile, BP from the skin, reducing the possi- precursors to both comedonal and in-
safe, inexpensive, and effective acne bility of bleaching of clothing, bedding, flammatory lesions, and also promote
therapies.34,35 Its lipophilic nature per- or towels.38 It has been suggested that the clearing of existing microcomedones.50
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In addition, some topical retinoids TABLE 4 Formulations and Concentrations of Topical Retinoids
also have direct antiinflammatory Retinoid Formulationa Strength, % Pregnancy Category
activity.43,51,52 At present, 3 topical Tretinoin Cream 0.025, 0.05, 0.1 C
retinoids (tretinoin, adapalene, and Gel 0.01, 0.025
Gel (micronized) 0.05
tazarotene) are available by pre- Microsphere gel 0.04, 0.1
scription in the United States. Each is Polymerized cream 0.025
available in a variety of formulations Polymerized gel 0.025
Adapalene Cream 0.1 C
and concentrations (Table 4).53 Their
Gel 0.1, 0.3
most common adverse effects include Solution 0.1
burning, stinging, dryness, and scal- Lotion 0.1
ing.15 These effects may be reduced by Tazarotene Gel 0.05, 0.1 X
Cream 0.05, 0.1
initiating treatment with the lowest
Adapted from Imahiyerobo-Ip and Dinulos.52
strength, typically sufficient to treat a Numerous generic retinoids are available. Branded products are available under the following trade names: Atralin, Avita,
mild acne, or by recommending regular and Retin-A Micro for tretinoin; Differin for adapalene; and Tazorac for tazarotene.
use of a moisturizer. Patients should be
instructed not to spot-treat but rather to
use a pea-size amount to cover the en- are extremely rare in the literature, in a study of 215 women accidentally ex-
tire face. In patients with sensitive skin, a 16-week study of 12 infants with in- posed to topical tretinoin during the
therapy can be initiated with thrice- fantile acne (mean age, 12.6 months), first trimester of pregnancy, Jick et al57
weekly application, increasing to daily 0.1% adapalene cleared both come- showed no difference in developmental
use as tolerated.48 donal and inflammatory lesions in anomalies compared with 430 age-
a median of 3.4 months with side effects matched controls. Tretinoin and ada-
Tolerability may be further improved by
that did not require discontinuation, palene have a pregnancy category C
the use of a noncomedogenic moistur-
underscoring the reported high toler- and tazarotene a category X rating.
izer that includes a sunscreen.15,38 Top- ability of adapalene.47 Tazarotene is an
ical tretinoin was the first retinoid Consensus Recommendation:
effective topical retinoid, but it is used
approved for use in the United States. It Topical retinoids (tretinoin, adapa-
less often as a first-line agent for acne
is available in a variety of vehicles such lene, tazarotene) may be used as
because of concerns regarding tolera-
as a micronized gel or a polymerized monotherapy or in combination
bility; it is also known to be more irri-
cream for increased tolerability. In a products and in regimens of care
tating.56
12-week open-label study of 40 patients for all types and severities of acne
In the absence of significant systemic in children and adolescents of all
with mild/moderate acne ages 8 to 12
absorption of the active ingredients, the ages. (SOR adolescents: A; SOR pre-
years (mean age, 10.7 years), tretinoin
possibility of intolerability remains the adolescents and younger: B).
microsphere gel 0.04% produced a sig-
primary safety issue. However, older
nificant decrease in Evaluator’s Global
girls who may be of childbearing po-
Severity Score (P , .001) from baseline Antibiotics/Antimicrobials
tential are often of the age group
to week 12, with 75% of participants Although acne is not an infection,
treated with topical retinoids. Naturally
graded as almost clear or mild. Skin antibiotics reduce P acnes colonization
circulating endogenous retinoids are
irritation occurred in 35% of the of the skin and follicles. They are ef-
present in the plasma of normal healthy
patients but was mild in most cases and fective in acne both by inhibiting bac-
girls as a result of dietary consumption
improved by study’s end.48
of foods such as fish, carrots, sweet terial protein synthesis38 and by
Other topical retinoid alternatives potatoes, and red peppers. Continuous decreasing inflammation via inhibition
to tretinoin include adapalene and daily dosing of tretinoin 0.1% cream, of bacterial proinflammatory media-
tazarotene. Adapalene, a distinct reti- tazarotene 0.1% gel, and adapalene tors and decreasing neutrophil che-
noid that is generally well tolerated, is 0.1% gel has been shown to only slightly motaxis.58,59
available in cream, gel, and lotion increase the mean maximum plasma The alarming increase in P acnes re-
formulations.53,54 Adapalene is photo- levels of circulating retinoids in most sistance to both topical and systemic
stable, including in fixed-combination patients. In 1 study, serum retinoid antibiotics used to treat acne not only
with BP.55 levels were found to be more heavily renders these drugs less effective
Although studies regarding the use of influenced by dietary intake than by against acne but may also influence
topical retinoids in pediatric patients topical application of tretinoin. In commensal bacteria in both the acne
PEDIATRICS Volume 131, Supplement 3, May 2013 S169
Downloaded from by guest on October 29, 2015patient and his or her environment.60 (administered as 1 tablet daily) is FDA most common with oral doxycycline.73–75
Resistance may occur with both ap- approved for the treatment of moder- The former can be circumvented with
propriate and incorrect use of anti- ate to severe inflammatory acne vul- appropriate photoprotection, and the
biotics.58 garis that is not predominantly nodular latter by ingestion with a large glass
in patients $12 years of age.62 Both of water, maintaining an upright posi-
Topical Antibiotics immediate-release doxycycline and tion for at least 1 hour after ingestion,
Topical antibiotic monotherapy is not immediate-release minocycline have and use of an enteric-coated formula-
recommended because of both its slow listed the indication in their FDA- tion.76 Although rare, drug hypersensi-
onset of action and the greater likeli- approved labeling of adjunctive use tivity syndrome (DHS), Stevens-Johnson
hood of the development of bacterial for severe acne, although this was not syndrome, or lupuslike syndrome (LLS)
resistance. If topical or oral antibiotic based on formal submission for FDA may occur with administration of
treatment is to be prolonged more than approval for either drug.63,64 The com- minocycline. DHS presents early after
a few weeks (as is usually the case in monly used oral antibiotics for children initiation of minocycline therapy, usu-
acne treatment), topical BP should be older than 8 years are tetracycline ally within the first 2 to 8 weeks,
added to optimize efficacy via its non- derivatives, including tetracycline, commonly with flulike symptoms (ie,
specific antimicrobial activity and re- doxycycline, and minocycline. Although fever, malaise), diffuse exanthemlike
duce the emergence of less sensitive erythromycin was used successfully in erythema, facial edema, cervical lymph-
P acnes variants.60 It has even been the past, the worldwide prevalence of adenopathy, and elevated hepatic en-
suggested that, if antibiotic therapy is P acnes resistance to erythromycin zymes (especially transaminases),
maintained for more than 3 months, has led to decreased use of this agent, although other organs may be in-
a BP washout should occur between both orally and topically, for acne.60,65,66 volved with interstitial inflammation
courses, although no large studies Comparative studies are limited, but (eg, pneumonitis, nephritis, and thy-
have addressed this recommenda- the second-generation tetracyclines, roiditis).77,78
tion.15 doxycycline and minocycline, are pre- Minocycline-associated LLS, which is
Use of topical antibiotics in fixed- ferred because of pharmacokinetic commonly reversible, generally devel-
combination products containing BP advantages allowing for once-daily ops after chronic exposure (ie, many
may help reduce the emergence of administration in most cases, greater months to years), and often presents
antibiotic-resistant strains of bacteria. lipophilicity that is believed to augment with malaise, distal polyarthralgias
In the case of the fixed-combination of follicular penetration, and lower prev- with or without polyarthritis, and, more
tretinoin and clindamycin, concomitant alence of resistant P acnes strains as rarely, autoimmune hepatitis.78–80 Most
use of BP is recommended. compared with tetracycline.15,67,68 For cases of minocycline-associated LLS do
Consensus Recommendation: children under 8 years of age and not have skin eruptions, although rare
Topical antibiotics (clindamycin, those with tetracycline allergies, al- reports have revealed superficial vas-
erythromycin) are not recommen- ternative oral antibiotic agents, in- culitis such as cutaneous polyarteritis
ded as monotherapy because of cluding erythromycin, azithromycin, nodosa. A positive antinuclear antibody
slow onset of action and predictable and trimethoprim/sulfamethoxazole, test is often present, although not always
emergence of antibiotic-resistant should be used very judiciously be- diagnostic or predictive of minocycline
bacterial organisms. (SOR: C). If cause of the potential risk for severe LLS, along with other autoantibodies.
topical antibiotic treatment is to adverse reactions, such as toxic epi- The autoantibody profile may be highly
be prolonged for more than a few dermal necrolysi.69–72 Table 5 sum- variable among cases of minocycline-
weeks, topical BP should be added, marizes the dosages, adverse events, associated LLS. When present, p-anca
or used in combination products. and precautions regarding the use of positivity is believed to strongly sup-
(SOR: C). the most frequently used oral anti- port the diagnosis. Presence of antihi-
biotics for treatment of inflammatory stone antibody is not required to
Oral Antibiotics acne.69 confirm the diagnosis of LLS and may
Interestingly, with the exception of The panel agreed that education and not be detected in some cases. Finally,
extended-release minocycline, use of monitoring related to potential adverse within the first few weeks of minocy-
oral antibiotics in acne is not FDA ap- events is important with oral antibiotic cline treatment, physicians should con-
proved.61 Extended-release minocy- therapy for acne. Photosensitivity (pho- sider the rare risk of serumsicknesslike
cline dosed at 1 mg/kg per day totoxicity) and “pill esophagitis” are reaction.78 Cutaneous and/or mucosal
S170 EICHENFIELD et al
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TABLE 5 Oral Antibiotics Used for Treatment of Moderate-to-Severe Acne Vulgaris
Antibiotic Recommended Dosage Potential Adverse Effects Comments
a
Doxycycline 50–100 mg QD or BID; Gastrointestinal upset especially pill Can be taken with meals, take with large glass
150 mg QD esophagitis (reduced with enteric coated of water and maintain upright position $1 h
formulation); photosensitivity (especially in to decrease risk of esophagitis; optimize
doses of $100 mg daily); staining of photoprotection especially in sunny season
forming tooth enamel (if given #8 y of age); or with known increased outdoor exposure;
vaginal candidiasis; BIH (rare). avoid in children who have not developed
set of permanent teeth; monitor for blurred
vision, severe headaches sometimes with
nausea and/or vomiting.
Erythromycinb 250–500 mg QD-BID Gastrointestinal upset; drug-drug interactions High prevalence of antibiotic-resistant P acnes.
such as increase in carbamazepine serum
levels → toxicity.
Tetracycline 500 mg BID Fixed drug eruption; gastrointestinal Ingest on empty stomach preferable;
symptoms; staining of forming tooth enamel absorption is decreased if taken with iron,
(if given #8 y of age); vaginal candidiasis; calcium, or many other metal ions found in
BIH (rare). vitamins/supplements, dairy products
(including milk, yogurt); avoid in children
who have not developed set of permanent
teeth; avoid in renal or hepatic disease;
monitor for blurred vision, severe
headaches sometimes with nausea and/or
vomiting.
Minocycline (immediate release) 50–100 mg QD-BID Cutaneous and/or mucosal hyperpigmentation Can be taken with meals; warn patient about
of skin and mucosal sites (oral, sclera, dizziness/vertigo (suggest initial doses be
conjunctiva); bone may be affected in some given when at home and not driving to
cases; DHS (systemic) often with hepatitis assess if patient susceptible to these
and/or pneumonitis (most often will occur effects); avoid in children who have not
within the first 1–2 mo); hepatitis developed set of permanent teeth; monitor
(hypersensitivity [tends to occur more for malaise, flulike symptoms, diffuse
acutely early in treatment course] or erythema with facial swelling, respiratory
autoimmune [more often to occur with complaints suggestive of drug
more chronic use of several months to hypersensitivity especially within the first
years]); LLS; Stephens-Johnson syndrome; few months after starting therapy;
vestibular toxicity (tends to occur within the discontinue therapy if this side effect
first few days after starting therapy); suspected; monitor for malaise, distal
staining of forming tooth enamel (if given arthralgias with or without arthritis
#8 y of age); vaginal candidiasis; BIH (rare). especially with more prolonged use of
several months to years suggestive of LLS;
monitor for pigmentary changes on skin
especially face, trunk, legs, and scars;
monitor for blue or gray discoloration of
sclera, oral mucosa, nail beds; monitor for
blue discoloration of acne scars; some cases
maybe persistent even with discontinuation;
monitor for blurred vision, severe
headaches sometimes with nausea and/or
vomiting.
Minocycline extended-release tablets 1 mg/kg QD Same potential reactions as above although Same as above except lower incidence of acute
(available since 2006) above side effects reported predominantly vestibular side effects with weight-based
with immediate-release formulations dosing (1 mg/kg per day); not yet known if
(available since 1971); lower incidence of other potential side effects reduced with
acute vestibular side effects with weight- weight-based dosing of the extended-
based dosing (1 mg/kg per day). release formulation; less accumulation of
minocycline over time due to
pharmacokinetic properties of extended-
release formulation; may possibly correlate
with decreased risk of cutaneous or
mucosal hyperpigmentation if dosed
properly by patient weight.
PEDIATRICS Volume 131, Supplement 3, May 2013 S171
Downloaded from by guest on October 29, 2015TABLE 5 Continued
Antibiotic Recommended Dosage Potential Adverse Effects Comments
Trimethoprim/ sulfamethoxazole 160–800 mg BID Severe cutaneous eruptions (toxic epidermal Not generally recommended for use as first or
necrolysis, Stevens-Johnson syndrome); second-line agent for acne; to be used
bone marrow suppression (anemias, judiciously in selected refractory cases;
neutropenia, and thrombocytopenia); obtain complete blood cell count at baseline
hypersensitivity reactions; drug eruptions and periodically thereafter; additional
(rash); fixed drug eruption. caution in patients with history of anemia
(megaloblastic types); may warrant
hematologic consultation if use of this agent
highly considered.
BID, twice daily; QD, once daily. Adapted from Tan,69 Gollnick et al,15 and Del Rosso and Kim.70
a Enteric-coated and double-scored 150 mg tablet available; double-scored tablet provides 50 mg/unit (tablet can be administered whole or broken into total of 3 segments).
b Use of lower dose for maintenance therapy based on anecdotal experience or clinical impression and not by large-scale clinical trials.
hyperpigmentation may occur in some also referred to as pseudotumor cerebri. Second-generation tetracyclines
patients treated with minocycline and A high index of suspicion is warranted (doxycycline, minocycline) are some-
appears to correlate with cumulative if headache and visual disturbances, times preferred to tetracycline be-
drug exposure over time in most sometimes accompanied by nausea cause of ease of use, fewer problems
cases reported with use of immediate- and/or vomiting, are noted to detect BIH with absorption with food and min-
release minocycline formulations av- early because persistence can lead to erals in vitamins and other supple-
ailable since 1971.81–83 Weight-based severe loss of vision, which may be ments, and less-frequent dosing.
dosing of minocycline (1 mg/kg per permanent.88 (SOR: C).
day) using the extended-release tablet In the past 20 years, P acnes has be- Patients should be educated and
formulation once daily, available since come less sensitive to oral and topi- monitored for potential adverse
mid-2006, may potentially reduce the cal antibiotics because of increasing events when utilizing oral antibiot-
risk of hyperpigmentation as both the selection pressure arising from their ics for acne. (SOR: B).
peak serum level and total drug ex- widespread usage.60,66,70,89 However,
posure are diminished as compared strategies listed in Table 6 can mini- Topical Dapsone
with immediate-release minocycline mize the potential for the de- Dapsone, a synthetic sulfone, has anti-
formulations; however, continued phar- velopment of resistance to antibiotics microbial and antiinflammatory effects;
macosurveillance is warranted to con- when used to treat acne, especially as however, its activity in the treatment
firm this preliminary observation.84 the duration of therapy is often pro-
Face, trunk, legs, oral mucosa, sclera, longed over months. Recent studies
and nail beds should be examined pe- have revealed that the use of sys-
riodically. TABLE 6 Strategies to Optimize Oral
temic antibiotics for acne treatment Antibiotic Therapy in Acne Vulgaris
Acute vestibular adverse events (ie, also may be associated with an in-
crease in resistant coagulase-negative Use in moderate or severe inflammatory acne
vertigo, dizziness) that sometimes vulgaris in combination with a topical regimen
occur in patients treated with mino- staphylococci and a possible in- that includes BP.
cycline develop early after initiation of creased risk of upper respiratory Avoid antibiotic monotherapy when using either an
tract infection; however, further oral or topical antibiotic agent for acne vulgaris.
treatment and are reversible with Discontinue (or taper) within 1 to 2 mo once new
discontinuation of therapy.85–87 Weight- studies are needed to evaluate the inflammatory acne lesions have stopped
based dosing of extended release- true clinical implications of these po- emerging.
minocycline (1 mg/kg once daily) has tential risks.60,90 Incorporate a topical retinoid into the regimen
early to augment overall therapeutic benefit and
been reported to reduce the risk for Consensus Recommendations: prepare for discontinuation of oral agent with
development of acute vestibular ad- Oral antibiotics are appropriate goal of maintaining control with topical
program; may also use BP-containing
verse events as compared with a daily for moderate-to-severe inflamma- formulation with topical retinoid for
dose up to threefold higher.61 tory acne vulgaris at any age. Tet- maintenance of control of acne.
A rare central nervous system-related racycline derivatives (tetracycline, If retreatment is needed, use the same oral
antibiotic that was previously effective in the
side effect associated with use of tet- doxycycline, and minocycline) should past.
racycline, doxycycline, or minocycline is not be used in children younger than Adapted from Gollnick et al,15 Leyden,50 and Del Rosso and
benign intracranial hypertension (BIH), 8 years of age. (SOR: B). Kim.70
S172 EICHENFIELD et al
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of acne as a topical agent is not believed tretinoin use in acne treatment of sociation between excessive intake of
to be related to P acnes reduction.91 adolescents and preadolescents and vitamin A with the incidence of frac-
Recently, a 5% dapsone gel was ap- agrees that it may be used in younger tures. In evaluating isotretinoin spe-
proved in the United States for acne patients with severe, refractory, and cifically, 1 small prospective cohort
treatment. It was evaluated in two 12- scarring acne. study associated isotretinoin with
week randomized, double-blind, phase Its most common side effects include minimal-to-mild bone demineralization
3 trials in patients aged 12 and older dry, chapped skin and lips, dry eyes, and at specific sites (such as Ward’s tri-
with mild, moderate, or severe acne.92 myalgias. Nose bleeds secondary to angle of the femur), but revealed that
The 3010 subjects used dapsone 5% dryness also are common. These effects these effects may be reversible.113 Ad-
gel twice daily or vehicle gel. A com- are generally reversible upon discon- ditional data from small prospective
bined analysis revealed a statistically tinuation of the drug. Some patients cohort114 and case control studies115,116
significant reduction in noninflam- may experience increases in serum have, however, documented no mea-
matory and inflammatory lesions by triglycerides and changes in liver surable changes in bone mineralization
week 12 compared with vehicle (P , enzymes. Both fasting serum lipids and markers. These changes were not as-
.001). Treatment response was rapid, liver function tests should be obtained sociated with increased risk of frac-
with statistically significant inter- at baseline and monitored periodically tures in those treated with isotretinoin
group differences in lesion count at thereafter. A major adverse effect of at the standard doses and durations
4 weeks. Adverse events were com- isotretinoin and a public health concern used for acne.
parable between dapsone gel and is its teratogenic potential. For this Hyperostoses are thought to occur with
vehicle gel and rarely led to discon- reason, the FDA mandated in 2007 the somewhat greater frequency among
tinuation. implementation of a computerized risk those who received long-term systemic
Available studies demonstrate that management program (iPledge), which retinoid therapy for disorders of kera-
topical dapsone is most effective registers all isotretinoin patients, phy- tinization. Hyperostosis during retinoid
against inflammatory lesions, with ef- sicians, pharmacies, and manufac- use has been most strongly associated
ficacy enhanced more when combined turers and ensures monthly monitoring with long-term therapy or chemo-
with a topical retinoid as compared of pregnancy status in females of prevention, appears to be dose- and
with BP.92,93 The safety of 5% dapsone childbearing potential. duration-dependent, is often asymp-
gel applied twice daily has been dem- Three of the most significant and con- tomatic, and may resolve spontane-
onstrated in patients who are glucose troversial groups of adverse effects ously. Overall, this phenomenon
6 phosphate dehydrogenase-deficient attributed to isotretinoin and de- appears to be uncommon among those
and in patients who are sulfonamide scribed in the drug’s package insert receiving isotretinoin for acne vulgaris.
allergic.94–96 The most common application- are skeletal issues; potential for de- Premature epiphyseal closure in as-
site reactions consisted of erythema velopment of inflammatory bowel sociation with retinoid therapy appears
and dryness that were similar be- disease (IBD); and mood changes, de- to be a rare event and may occur in an
tween groups. A temporary orange pression, suicidal ideation, and sui- asymmetric or generalized fashion.
staining of the skin can occur when cide, which are addressed in greater Only a single case has been reported in
BP and topical dapsone are used detail because of their relevance in association with isotretinoin adminis-
together. pediatric patients.98 tered for acne.117 Other cases have
primarily been reported as a conse-
Oral Isotretinoin in Severe Acne Bone Effects quence of isotretinoin therapy for
disorders of keratinization118 or neu-
Oral isotretinoin targets all of the The interaction between retinoids and
roblastoma.113,119
pathophysiologic factors involved in skeletal homeostasis is complex. Ani-
acne typically producing excellent mal studies have indicated that exces-
results.15 A recent consensus con- sive intake of retinoids can have IBD
ference on its use recommends inhibitory effects on both osteoblast There are conflicting data on the po-
a starting dose of 0.5 mg/kg per day and osteoclast activity that may pose tential association between isotretinoin
for the first 4 weeks to avoid initial a theoretical risk for fractures or hy- and IBD. In available published reports,
flares, increasing to the full dosage of perostosis.99–112 Well-designed clinical 21 patients with preexisting IBD who
1 mg/kg per day.97 The panel concurs studies involving human subjects have subsequently receive isotretinoin have
with this recommendation for iso- generated conflicting data on the as- been reported to tolerate the drug;
PEDIATRICS Volume 131, Supplement 3, May 2013 S173
Downloaded from by guest on October 29, 20154 experienced worsening of IBD symp- jority of patients prescribed isotretinoin studies (2 prospective, 1 case-control,
toms during therapy, suggesting that treatment have been on extended an- and 1 cohort study) evaluated iso-
the majority of patients with IBD who tibiotic therapy and that previous an- tretinoin use and depressive symp-
received isotretinoin have largely tol- tibiotic use may be an important toms.135,136 Although none of these
erated isotretinoin for acne.107,120–128 confounding variable in the relation- additional studies identified a positive
The occurrence of IBD after exposure to ship between IBD and isotretinoin. association between isotretinoin use
isotretinoin has been reported. These Furthermore, a potential link between and depression, 2 of them indicated
are composed of case reports or small IBD and inflammatory acne itself can- that as acne improved, quality of life
case series (N = 18); a systematic re- not be excluded. improved137 and depressive symp-
view of FDA MedWatch Data129 high- toms and suicidal ideation actually
lighting 85 identified cases, of which 62 Mood Disorders decreased.138
were deemed highly probable or The evidence regarding an association In summary, case reports and case
probable; and 1 large case-control between isotretinoin use and mood series have identified patients who
study involving 8189 cases of IBD, disorders is primarily anecdotal, with developed depressive symptoms while
which included 24 cases that had re- the original case series of 24 patients receiving or after isotretinoin therapy,
ceived isotretinoin.130 In this case- reported by Hazen comprising the and 1 study utilizing positron emission
control study, only ulcerative colitis reported experience on this linkage. tomography has documented changes
was associated with previous iso- One open-label study compared acne in cerebral metabolism in patients re-
tretinoin use, and increasing cumula- patients recalcitrant to antibiotics to ceiving isotretinoin therapy. Epidemio-
tive dose or duration to isotretinoin those receiving isotretinoin, and iden- logic studies, however, do not currently
was associated with an elevated risk of tified changes in brain metabolism in support a causative association be-
ulcerative colitis (1.5 odds ratio in- the orbitofrontal cortex, which are tween isotretinoin and depression, and
crease per 20 mg increase in dose, and thought to partially mediate depressive acne severity itself is a predictor of
5.63 overall increased odds ratio in symptoms.133 However, the numbers of mental health issues and suicidal ide-
association with longer duration). patients studied were small (N = 28), ation. Ongoing vigilance and surveil-
and those receiving isotretinoin had lance of patients for mood changes
At the same time, a case-control study
more severe acne, which could corre- while on isotretinoin therapy seem
evaluating a Manitoba IBD Epidemiology
late with more severe depressive reasonable, but the data appear reas-
Database revealed no evidence for an
symptoms independent of the iso- suring.
association between IBD and iso-
tretinoin. Indeed, in a large cross-
tretinoin use131; in addition, a system- Consensus Recommendation:
sectional questionnaire-based study
atic literature-based search of case
of 3775 adolescents between 18 and 19 Isotretinoin is recommended for
reports, case series, and clinical trials severe, scarring, and/or refractory
years of age who suffered from acne,
likewise revealed no evidence for an acne in adolescents and may be
those with more severe acne were
association.132 used in younger patients. (SOR
more than twice as likely to have
An association between IBD (in partic- mental health issues and 1.8 times adolescents: A; SOR preadolescents
ular, ulcerative colitis) and isotretinoin, more likely to have suicidal ideation. In and younger: C). Extensive counsel-
therefore, may potentially exist, al- fact, ∼1 in 4 adolescents with signifi- ing, particularly regarding the
though if it does, it appears to affect cant acne were noted to have mental avoidance of pregnancy as well
a small subset of patients. The phe- health issues. A systematic review by as careful monitoring of potential
nomenon appears to be rare, seems to Marqueling and Zane134 identified 6 side effects and toxicities, is rec-
be idiosyncratic, and, at present, there prospective studies and 3 retrospec- ommended.
are no identifiable clinical character- tive studies that involved at least 20
istics that can currently a priori predict patients, studied depressive symptoms PRESCRIPTION TREATMENT
this type of response. The association is in human subjects as primary data, OPTIONS: TOPICAL FIXED-DOSE
also fraught with confounding factors, and used epidemiologic techniques. In COMBINATION THERAPIES
since the highest age of IBD onset this analysis, there was no apparent Numerous topical fixed-dose combina-
overlaps the age when patients develop increase in depression diagnoses or tion products, including BP/clindamycin,
severe acne and when isotretinoin is symptoms when baseline was com- BP/adapalene, BP/erythromycin, and
typically used. In addition, it was noted in pared with after treatment with iso- tretinoin/clindamycin, are currently FDA
a study by Margolis et al114 that the ma- tretinoin. Four subsequent additional approved for pediatric patients 12 years
S174 EICHENFIELD et al
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