Clinical Review & Education

JAMA | Review

Management of Acne Vulgaris

A Review
Dawn Z. Eichenfield, MD, PhD; Jessica Sprague, MD; Lawrence F. Eichenfield, MD

Multimedia
IMPORTANCE Acne vulgaris is an inflammatory disease of the pilosebaceous unit of the skin JAMA Patient Page page 2087
that primarily involves the face and trunk and affects approximately 9% of the population
worldwide (approximately 85% of individuals aged 12-24 years, and approximately 50% of CME Quiz at
jamacmelookup.com and CME
patients aged 20-29 years). Acne vulgaris can cause permanent physical scarring, negatively
Questions page 2072
affect quality of life and self-image, and has been associated with increased rates of anxiety,
depression, and suicidal ideation.

OBSERVATIONS Acne vulgaris is classified based on patient age, lesion morphology

(comedonal, inflammatory, mixed, nodulocystic), distribution (location on face, trunk, or
both), and severity (extent, presence or absence of scarring, postinflammatory erythema, or
hyperpigmentation). Although most acne does not require specific medical evaluation,
medical workup is sometimes warranted. Topical therapies such as retinoids (eg, tretinoin,
adapalene), benzoyl peroxide, azelaic acid, and/or combinations of topical agents are first-line
treatments. When prescribed as a single therapy in a randomized trial of 207 patients,
treatment with tretinoin 0.025% gel reduced acne lesion counts at 12 weeks by 63%
compared with baseline. Combinations of topical agents with systemic agents (oral Author Affiliations: Department of
antibiotics such as doxycycline and minocycline, hormonal therapies such as combination oral Dermatology, University of California
contraception [COC] or spironolactone, or isotretinoin) are recommended for more severe San Diego School of Medicine,
La Jolla (D. Z. Eichenfield, Sprague,
disease. In a meta-analysis of 32 randomized clinical trials, COC was associated with
L. F. Eichenfield); Division of Pediatric
reductions in inflammatory lesions by 62%, placebo was associated with a 26% reduction, and Adolescent Dermatology, Rady
and oral antibiotics were associated with a 58% reduction at 6-month follow-up. Isotretinoin Children's Hospital San Diego,
is approved by the US Food and Drug Administration for treating severe recalcitrant nodular San Diego, California
(D. Z. Eichenfield, Sprague,
acne but is often used to treat resistant or persistent moderate to severe acne, as well as acne L. F. Eichenfield); Department of
that produces scarring or significant psychosocial distress. Pediatrics, University of California
San Diego School of Medicine,
CONCLUSIONS AND RELEVANCE Acne vulgaris affects approximately 9% of the population La Jolla (L. F. Eichenfield).
worldwide and approximately 85% of those aged 12 to 24 years. First-line therapies are Corresponding Author: Lawrence F.
topical retinoids, benzoyl peroxide, azelaic acid, or combinations of topicals. For more severe Eichenfield, MD, University of
disease, oral antibiotics such as doxycycline or minocycline, hormonal therapies such as California San Diego and Rady
Children's Hospital, 3020 Children’s
combination oral conceptive agents or spironolactone, or isotretinoin are most effective.
Way, Mail Code 5092, San Diego, CA
92123 ([email protected]).
JAMA. 2021;326(20):2055-2067. doi:10.1001/jama.2021.17633 Section Editor: Mary McGrae
McDermott, MD, Deputy Editor.

A
cne vulgaris affects approximately 9% of the popu-
lation worldwide1 and approximately 85% of those aged Methods
12 to 24 years. 2 Acne also affects more than 50% of
people aged 20 to 29 years and approximately 43% of people The PubMed database and Cochrane Library were searched for
aged 30 to 39 years. 2 Approximately 18% of women and 8% English-language studies on acne vulgaris published from January 1,
of men develop acne after 25 years of age.3,4 Acne negatively 2010,toJune30,2021.Selectedmanuscriptsweremanuallyevaluated
affects quality of life and self-esteem, and it is associated with for additional relevant references. A total of 113 articles (basic science
increased risks of anxiety, depression, suicidal ideation, and articles and prospective and retrospective cohort trials) were included
physical scarring.5 in this review, including 21 randomized clinical trials, 8 meta-analyses,
Acne management is based on its pathogenesis as an inflam- 10systematicreviews,6clinicalguidelinesrelevanttothegeneralmedi-
matory disorder of the pilosebaceous unit. Acne can be effectively cal readership, 7 basic science mechanistic articles, 10 prospective co-
treated in almost all patients. Disease morphology, severity, and pa- hort studies, 22 retrospective cohort studies, and 29 reveiws.
tient characteristics including age, skin color, psychological burden
of disease, and patient motivation for treatment should be consid- Assessment and Pathogenesis
ered in treatment selection. This narrative review summarizes the Acne presents as comedones, papules, pustules, nodules, and sec-
diagnosis and treatment of acne. ondary signs including scars, erythema, and hyperpigmentation.

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 Clinical Review & Education Review Management of Acne Vulgaris

Figure 1. Classification of Acne by Morphology

Clinical Characteristic findings Representative lesions

categorization

Comedonal Closed (whiteheads) and open

(blackheads) comedones

Inflammatory Erythematous papules, pustules,

nodules, or cystlike nodular lesions

Mixed Both comedonal and inflammatory

lesions are present

Nodulocystic Predominance of large inflammatory

nodules or cystlike lesions, often
accompanied by scarring

Comedones are dilated hair follicles filled with keratin squamae, a common pathogenesis that involves 2 factors: sebaceous hyper-
bacteria, and sebum. Open comedones (blackheads) have a plasia due to androgen activity, altered follicular growth and differ-
pigmented dilated pilosebaceous orifice that contains oxidized sur- entiation, follicular colonization by the bacteria Cutibacterium acnes
face pigment, while closed comedones (whiteheads) appear as small (formerly Propionibacterium acnes), and inflammation.7 These patho-
white papules. Acne can be classified based on primary morphol- genic factors result in the formation of microcomedones, consist-
ogy (Figure 1). Inflammatory acne lesions have erythematous pap- ing of dilated hair follicles filled with keratin squamae, bacteria, and
ules, pustules, nodules, or cyst like lesions. A predominance of large sebum not visible to the naked eye. The microcomedone is consid-
inflammatory nodules or cyst like lesions, often accompanied by scar- ered the precursor for all clinical acne lesions, such as comedones
ring, is seen in nodulocystic acne. and inflammatory papules, though the exact process by which the
Acne is classified by age, beginning with neonatal acne and ex- microcomedone evolves into other acne lesions remains unclear.
tending past adolescence to adult acne. What has been termed C acnes, Staphylococcus epidermidis, and Malassezia form biofilms
neonatal acne is now considered to be a distinct entity called neo- within the pilosebaceous unit that can promote inflammation, com-
natal cephalic pustulosis, which begins between birth and the first edo formation, and antibiotic resistance.8 Wide variance exists in an-
weeks of life. It presents as superficial pustules rather than com- tibiotic susceptibility of C acnes strains worldwide, both geographi-
edones and may represent an inflammatory reaction to Malassezia cally and over time, with resistance patterns reflecting local clinical
species.6 Infantile (6 weeks to ⱕ1 year), midchildhood (1 year to <7 practice patterns. C acnes is frequently resistant to commonly used
years), preadolescent (ⱖ7 to ⱕ12 years or menarche), adolescent, topical antibiotics such as clindamycin and erythromycin.
and adult acne all manifest with acneiform lesions consisting of com- Although most acne does not require specific medical evalua-
edones, inflammatory papules, and pustules (Figure 1). They share tion, a medical workup is sometimes warranted. Acne may be the

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© 2021 American Medical Association. All rights reserved.

Management of Acne Vulgaris Review Clinical Review & Education

first sign of normal pubertal maturation, beginning at age 7 with

comedones on the forehead and central face. An evaluation for Box. Commonly Asked Questions About Acne Management
signs of precocious sexual maturation, virilization, and/or growth When should systemic therapy with oral antibiotics or hormones
abnormalities may be considered in infants with significant acne be prescribed for patients with acne?
and in children with acne onset between ages 1 to 7 years, since this For moderate to severe inflammatory acne, oral therapy with
may indicate an underlying systemic abnormality such as prema- antibiotics (such as doxycycline or minocycline) or hormonal
ture adrenarche and congenital adrenal hyperplasia.6,7 In a study of therapy (such as combination or contraceptives or
spironolactone) may be useful, generally with regimens of topical
premature adrenarche (puberty onset prior to 8 years in girls and 9
agents including benzoyl peroxide and topical retinoids. Oral
years in boys), acne and comedones occurred in 41 of 73 (56%)
isotretinoin is appropriate for severe acne or moderate acne that
prepubertal children.9 In preadolescent through adult patients, has not responded to other topical and systemic regimens.
endocrine abnormalities such as polycystic ovary syndrome (PCOS)
How should therapy for acne be selected?
can be considered when acne is unusually severe, poorly respon- Management is usually based on acne type, extent, anatomic
sive to treatment, or accompanied by signs of androgen excess location, and evidence of scarring and pigmentary changes.
such as hirsutism or menstrual irregularities. 10 In a study of Predominantly comedonal acne is usually treated with topical
treatment-resistant acne without menstrual disturbance, alopecia, retinoids, often with combinations of topical antimicrobials
or hirsutism, 86% of 29 patients had laboratory evidence of (eg, benzoyl peroxide), or alternative topicals. More pustular
inflammatory acne, extensive truncal acne, or acne associated
hyperandrogenism, and 36% were diagnosed with PCOS. 11,12
with scarring or significant dyspigmentation may benefit from
Truncal hirsutism and axillary acanthosis nigricans have been systemic therapies in addition to topical treatment. Nodular acne
shown to be the most reliable cutaneous markers of PCOS. 13 not responsive to systemic antibiotics or hormonal therapies and
Other endocrine abnormalities to consider include thyroid disease, moderate to severe acne of any morphology that does not
prolactin excess, nonclassical congenital adrenal hyperplasia, and respond to other treatments may be treated with isotretinoin.
virilizing tumors.10,14 A variety of drugs, such as corticosteroids, What are the common adverse effects of acne medications?
lithium, and cyclosporine, may induce or exacerbate acne and Many topical medications, including retinoids and benzoyl
should be considered in the setting of monomorphous papules, peroxide, can be associated with dryness or mild irritation.
unusual age of onset, atypical locations (eg, not face, chest, or Benzoyl peroxide is also associated with allergic contact
dermatitis, which manifests with edema, itching, and eczematous
back), and recent drug exposure.15
changes. Oral tetracycline derivatives may cause erosive
Assessment of acne severity is important for selecting therapy. esophagitis if ingested with inadequate water and may cause
Although there are numerous grading systems to define acne se- photosensitivity (more commonly with doxycycline) and
verity for research studies, there is no standardized system for induction of bacterial resistance with extended use. Rare and
clinical practice. Extent of disease, lesion morphology, presence or serious adverse effects can occur with oral antibiotics such as
absence of scarring and/or postinflammatory erythema, and hyper- hepatitis and lupus (with minocycline) and pseudotumor cerebri.
pigmentation should be noted. Acne may be predominantly on the
face, chest, back, or all of these areas, and may vary in severity by
body region. Acne severity and type can evolve over time; andro-
gen influences on adolescent and adult female acne are suggested Skin care, including the frequency of washing, types of cleans-
by inflammatory acne that fluctuates with the patient’s menstrual ers, and use of moisturizers and over-the-counter therapies can affect
cycle. Patients’ perspectives on their disease may not correlate with acne. For example, over-the-counter products with active ingredi-
physician assessments or published severity scales.16 ents that were previously available only as prescriptions (eg, ada-
palene) and other prescription and nonprescription agents that are
Management available online may affect acne and potentially complicate treat-
Acne treatment should be based on a comprehensive evaluation: a ment regimens through chemical incompatibility or skin irritation.
thorough patient history including assessment of prior therapy; re- Patients should be advised to practice gentle cleansing and avoid
sponse and sensitivity to medications; a full body examination to as- scrubs and exfoliating washes, which can cause irritation and re-
sess acne location, extent and lesion type, presence or absence of duce regimen adherence. A recent systematic review of 14 prospec-
scars or pigmentary changes; and patient expectations. The main tive studies with 671 participants concluded that few high-quality
strategies for acne management are based on physiological tar- data are available to identify which cleansers are most optimal for
gets: topical retinoids for comedolytic and keratolytic activity (mini- treating acne.17
mizing comedonal plugging), antibiotics for antimicrobial and anti- Topical therapies include retinoids, antibiotics, benzoyl perox-
inflammatory effects, hormonal therapies targeting sebaceous gland ide, and salicylic acid. Relatively few trials have compared these thera-
activity, and systemic isotretinoin affecting all of these targets (Box). pies to identify the most optimal first-line topical therapy for acne.14
Standard guidelines from the American Academy of Dermatology A recent systematic review and network meta-analysis of topical
and the American Academy of Pediatrics suggest topical agents such preparations for mild to moderate acne found no convincing evi-
as retinoids, benzoyl peroxide, and/or topical antibiotics as first- dence that topical treatments containing antibiotics as mono-
line treatment and combinations of topical agents with systemic therapy or in combination were more effective than those not con-
agents for more severe disease (Figure 2).6,7 Early and intensive treat- taining them. 18 Although there are few direct comparisons,
ment of acne can minimize physical effects such as scarring and psy- combination treatment with adapalene plus benzoyl peroxide ap-
chological effects. The treatment strategies shown in Figure 2 have pears to be more effective than either treatment alone, but the com-
not been validated in a randomized trial. bination may cause more adverse events, resulting in a slightly higher

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 Clinical Review & Education Review Management of Acne Vulgaris

Figure 2. Suggested Strategies for Management of Acne

Treatment for mild acne Treatment for moderate acne Treatment for severe acne
Topical benzoyl peroxide Topical combination therapya Topical combination therapya
or or + oral antibiotic
Topical retinoid Topical combination therapya or
or + oral antibiotic Topical combination therapya
Topical azelaic acid or + oral antibiotic
or Topical combination therapya + oral hormonal therapyd
Topical combination therapya + oral antibiotic or
+ oral hormonal therapyd Oral hormonal therapyd
If inadequate response or or
Oral hormonal therapyd Oral isotretinoin

Change topical medicationsb If inadequate response If inadequate response

or
Consider alternative topical
therapies (individually or Change topical medicationsb Add or change oral antibiotic
in combination) or or oral hormonal therapyd
Dapsone Add or change oral antibiotic or
Clascoteronec or oral hormonal therapyd Consider oral isotretinoin
Salicylic acid or
Sulfacetamide sulfur Consider oral isotretinoin

b
Stepped algorithm is based on disease severity, and it highlights initial and Indicates changing the topical antibiotic or retinoid type, concentration,
alternative management strategies. This algorithm has not been validated. formulation, or changing the combination of topical agents.
a c
Topical combination therapy includes retinoid + benzoyl peroxide, Prescribed only to patients aged 12 years or older.
retinoid + benzoyl peroxide + topical antibiotic, or benzoyl peroxide d
Indicates systemic hormonal therapy prescribed only to female patients.
+ topical antibiotic.

incidence of withdrawal than monotherapy.18 Patient education re- reduced by initiating treatment with lower-strength medication, ap-
garding acne pathophysiology and expectations about treatment ef- plying moisturizers, applying every other day instead of daily, slowly
fects and the time course for response are helpful to encourage increasing the dose as tolerated (eg, starting with application ev-
adherence.6 With effective therapy, some improvement is usually ery 2-3 days then increasing to daily),23 or using short-contact therapy
evident by 6 weeks, with maximum benefits typically observed af- (consisting of removing the therapy 30-60 minutes after applica-
ter 3 to 6 months. tion with a gentle cleanser).24 Patients should apply a small amount
Systemic therapies, which include oral antibiotics and hor- of medication (usually a pea size) to cover the entire face at night,
monal therapies (combined oral contraceptives [COCs] or spirono- rather than applying a small amount directly over acne lesions. Acne
lactone), are used in addition to topical agents, as an alternative for flaring after initiation of topical retinoids occurs in some individu-
moderate acne, or when there is inadequate response to topical als and may last up to 4 to 6 weeks. Retinoids can increase sun sen-
regimens.6,7 Isotretinoin is recommended for the treatment of se- sitivity, mitigated by use of a moisturizer with sunscreen.
vere nodular and treatment-resistant moderate acne, especially acne Topical tretinoin was the first retinoid approved for use in the
associated with physical scarring or psychosocial effects.7 United States. When prescribed as a single therapy, the nanogel
formulation of tretinoin 0.025% gel treatment reduced acne
Treatments lesion counts at 12 weeks by 63% compared with the conventional
Topical Retinoids topical tretinoin formulation in a phase 4- randomized trial of 207
Topical retinoids, either as monotherapy or in topical combination patients.25 Adapalene (the second FDA-approved retinoid) is pho-
products, are first-line therapies for acne.19 Retinoids are vitamin A tostable, unlike tretinoin, making it more resistant to change upon
derivatives that bind to retinoic acid receptors and retinoid X re- exposure to sunlight and allowing for daytime use.26 Adapalene
ceptors in the keratinocyte cytoplasm and translocate to the nucleus 0.1% gel has similar efficacy to that of tretinoin 0.025% gel,27 while
to initiate transcription changes. Retinoids stimulate epidermal cell adapalene 0.3% gel has a greater efficacy than adapalene 0.1%
proliferation, loosen connections among cells in the stratum cor- gel.28,29 Retinoids target 3 retinoic acid-receptor subtypes, α, β,
neum, accelerate elimination of sebum in sebaceous ducts, and pro- and γ; trifarotene is a γ-selective retinoid evaluated for both facial
mote microcomedone clearance.20 and truncal acne that has similar effects on inflammatory and non-
Four topical retinoids are approved by the US Food and Drug inflammatory acne lesions.30 However, few clinical trials have
Administration (FDA) to treat acne: tretinoin, adapalene, tazaro- directly compared topical retinoids for acne. When selecting a reti-
tene, and trifarotene. Different concentrations and topical formu- noid, a reasonable approach is to start with a formulation with
lations (which influence tolerability and efficacy) exist for each prod- lower potency such as adapalene 0.1%, and increase potency and
uct, and they are typically safe and effective. Different formulations concentration depending on tolerability and efficacy. Insurance
of these topical retinoids are approved for use in younger popula- coverage and costs to the patient are additional considerations.
tions (<12 years of age).21,22 Adapalene 0.1% gel has been approved for over-the-counter use
Approximately 30% of patients treated with topical retinoids to treat acne.
experience cutaneous irritation, consisting of burning, stinging, dry- Fetal malformations have been reported with systemic reti-
ness, and scaling with application.22 These adverse effects can be noids and topical retinoid use is not recommended in pregnancy.

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Management of Acne Vulgaris Review Clinical Review & Education

However, studies of women inadvertently exposed to topical treti- inflammatory properties.43 Studies have demonstrated safety and
noin during the first trimester of pregnancy showed no increase in efficacy in acne treatment, including in patients with glucose-6-
developmental anomalies.31 Although only a small amount of ada- phosphate dehydrogenase deficiency or sulfonamide allergy.44,45 The
palene is absorbed through the skin, studies of adapalene during most common application site reactions include erythema and dry-
pregnancy included a very small number of exposed pregnancies. ness, as well as temporary orange staining of the skin that occurs when
Therefore, better studied acne products, such as azelaic acid and benzoyl peroxide and topical dapsone are used concurrently.
topical clindamycin, are preferred for treatment in pregnancy. Azelaic acid is a dicarboxylic acid with mild keratolytic and antimi-
Tazarotene should be avoided during pregnancy, and women of crobial effects that reduces postinflammatory hyperpigmentation.46
child-bearing age should be counseled on possible risk of fetal mal- Topical antiandrogen creams, such as clascoterone 1%, have also been
formation and advised to take steps to prevent pregnancy while on developed for treatment of acne. Clascoterone is a novel topical andro-
these medications. gen receptor inhibitor that appears safe and effective in treating both
noninflammatory and inflammatory acne.47 Many topical fixed-dose
Topical Benzoyl Peroxide combination products of retinoids, antibiotics, and benzoyl peroxide
Topical benzoyl peroxide is among the most inexpensive and effec- have been FDA approved for acne treatment (Table 1).49 These prod-
tive acne therapies. Benzoyl peroxide penetrates the stratum cor- ucts simplify treatment regimens, thereby promoting adherence and
neum and enters the pilosebaceous unit where C acnes resides, gen- potentially improving treatment outcomes. One study showed an ad-
erating free radicals that damage the cell wall of pathogenic bacteria.32 herencerateof88%withacombinationtopicaltreatmentvs61%when
Inadditiontomildcomedolyticandanti-inflammatoryproperties,ben- the components were applied separately.50
zoyl peroxide limits the development of bacterial resistance to topi-
cal and oral antibiotics, and provides increased efficacy in compari- Oral Antibiotics
son with topical antibiotics alone (90% of patients using benzoyl Oral antibiotics are commonly used to induce relatively rapid con-
peroxide/topical clindamycin reported improvement at 12 weeks com- trol of moderate-to-severe inflammatory acne (within 1-2 months),
pared with 45% of patients using topical clindamycin alone).33-35 Since generally in combination with a topical retinoid and benzoyl perox-
benzoyl peroxide frequently causes dryness and erythema upon ini- ide (Table 2). Given concerns for increasing antibiotic resistance, clini-
tiation, there are many formulations and concentrations available.36 cal practice guidelines published by the American Academy of Der-
Allergic contact dermatitis has been reported in approximately 5% of matology and the American Academy of Pediatrics recommend
people treated for acne and may be considered in patients complain- avoiding use for longer than 3 to 4 months and monotherapy is not
ingofitchingandswellingduringbenzoylperoxideuse,incontrastwith recommended.6,7 Despite antibiotic stewardship initiatives for der-
localized dryness.37 Benzoyl peroxide can bleach clothing and rarely matologic conditions, a retrospective analysis from 2004-2013 found
hair. Use of benzoyl peroxide washes (similar to liquid cleansers), in- that the mean duration for antibiotic therapy remains long. Mean
stead of applying topical preparations for an extended time, may re- antibiotic prescription durations were approximately 192 days when
duce the likelihood of irritation.36 prescribed by dermatologists and approximately 213 days when pre-
scribed by nondermatologists.51,52 Among 97 patients with moder-
Topical Antibiotics ate to severe acne and undergoing combination therapy with an oral
Topical antibiotics reduce bacterial colonization of skin and fol- antibiotic, topical retinoid, and benzoyl peroxide, overall lesion
licles, and decrease inflammation by inhibiting the complement path- counts decreased by approximately 60% at 3 months compared with
ways and impairing neutrophil chemotaxis.38 They are more effec- baseline.53 Clinical improvement obtained with oral antibiotics may
tive for inflammatory acne lesions than comedones, but have some be maintained even after the antibiotics are discontinued by use of
effect on both types of lesions by reducing biofilm and subsequent topical retinoids and retinoid–benzoyl peroxide combinations.54,55
microcomedone formation. Bacterial antibiotic resistance with both The most commonly used oral antibiotics are tetracyclines,
topical and systemic antibiotic use has been reported as quickly as which decrease C acnes and have anti-inflammatory effects. The
6 weeks after start of monotherapy use; therefore monotherapy, es- second-generation tetracyclines, doxycycline and minocycline,
pecially topical, is generally not recommended.7,39 Concomitant ben- along with a relatively newly approved agent sarecycline,56 have a
zoyl peroxide with topical or oral antibiotics minimizes bacteria re- longer half-life allowing for once daily administration, the ability to
sistance and can be applied concurrently with topical antibiotics or be taken with food, and greater follicular penetration and bacterial
used as a wash prior to antibiotic application.34 resistance profiles as compared with oral erythromycin or
Three topical antibiotics, erythromycin, clindamycin, and mi- tetracycline.56-58 Unlike the broad-spectrum tetracyclines, doxycy-
nocycline, are FDA approved for acne therapy in children and adults. cline and minocycline, sarecycline is more narrow spectrum and
Most recently, minocycline 4% topical foam received FDA approval exhibits antibacterial activity against C acnes but has 16- to 32-fold
for treatment of patients with 9 or more years of moderate to se- reduced potency against enteric gram-negative bacteria based on
vere acne.40,41 comparisons of the minimum inhibitory concentration required to
inhibit the growth of 50% of organisms values, which may lead to
Other Topical Treatments less adverse effects on the gut microbiome.56 Common adverse
Salicylic acid has comedolytic effects and is available over the coun- effects of second-generation tetracyclines include gastrointestinal
ter in 0.5% to 2% strengths both as leave-on and wash-off products. symptoms such as nausea and vomiting. Photosensitivity (espe-
Sulfur shows mild antibacterial and keratolytic properties, and is of- cially with doxycycline) and pill esophagitis are reported adverse
ten combined with sodium sulfacetamide to mask its scent.42 Topi- effects, and counselling on protection against sunburn and main-
cal dapsone is a sulphone medication with antimicrobial and anti- taining an upright position for at least 1 hour after ingestion is

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 Clinical Review & Education Review Management of Acne Vulgaris

Table 1. Topical Treatments for Acne Vulgarisa

Pregnancy and lactation
Topical Formulation, dose, Predominant type recommendations
treatments and frequency Adverse effects of acne and precautions Additional information
Retinoids
Adapalene Cream or gel Erythema, dryness, Comedonal more than Risk of fetal harm is not Gel, 0.1% is the only
0.1% once nightly or irritation, inflammatory expected based on limited topical retinoid approved
photosensitivity, rare human data and insignificant by the US Food and Drug
0.3% once nightly allergic contact systemic absorption Administration for
dermatitis May use when breastfeeding over-the-counter use
Tazarotene Cream, foam, or gel Erythema, dryness, Comedonal more than Use alternative therapy during
0.05% once nightly or irritation, inflammatory pregnancy
photosensitivity, rare Avoid use on nipple while
0.1% once nightly allergic contact breastfeeding; otherwise, may
dermatitis use on other areas
Tretinoin Cream or gel Erythema, dryness, Comedonal more than Consider avoiding use especially Tretinoin cream and gel
0.025%, 0.05%, or 0.1% once irritation, inflammatory during the first trimester; risk formulations are
nightly or photosensitivity, rare of teratogenicity is low, based inactivated by
allergic contact on limited human data and concomitant use of
Microgel dermatitis minimal systemic absorption benzoyl peroxide
0.04%, 0.08% or 0.1% once May use when breastfeeding
nightly or
Lotion
0.05% once nightly
Trifarotene Cream Erythema, dryness, Comedonal more than Consider avoiding during Only topical retinoid
0.005% once nightly irritation, inflammatory pregnancy approved by the US Food
photosensitivity, rare Avoid use on nipple while and Drug Administration
allergic contact breastfeeding; otherwise, may for use on the chest
dermatitis use on other areas and back
Antibiotics
Erythromycin Foam, gel, or pad Irritation and allergic Inflammatory more May use during pregnancy High rates of
2% once daily contact dermatitis than comedonal May use while breastfeeding Cutibacterium acnes
resistance
Clindamycin Gel, lotion, or solution Irritation and allergic Inflammatory more May use during pregnancy
1% once daily or contact dermatitis than comedonal May use while breastfeeding
1% twice daily
Minocycline Foam Yellow discoloration of Inflammatory more May use during pregnancy
4% once daily fabric, yellow glare to than comedonal May use while breastfeeding
skin, headache
Hormonal
Clascoterone Cream Irritation; HPA-axis Same predominance No available data
1% twice daily suppression with large
application but was no
clinical evidence of
HPA-axis suppression
was observed in phase 2
or 3 trials48
Other
Azelaic acid Cream, gel, or suspension Irritation and Comedonal more than May use during pregnancy Some formulations are
10% or 15% once daily or hypopigmentation inflammatory May use while breastfeeding currently available for
over-the-counter use
10% or 15% twice daily
Benzoyl Bar soap, cream, foam, gel, Erythema, dryness, Same predominance May use during pregnancyc Available for
peroxide lotion or wash irritation, allergic May use while breastfeeding over-the-counter use
2%-10% once daily or contact dermatitis,
bleaching of fabrics
2%-10% twice daily
Dapsone Gel Irritation and allergic Inflammatory more May use during pregnancy Can cause orange
5% or 7.5% once daily or contact dermatitis than comedonal May use while breastfeeding discoloration of skin and
hair when used with
5% or 7.5% twice daily benzoyl peroxide
Salicylic acid Cream, gel, lotion, pad, or wash Irritation and allergic Comedonal more than May use during pregnancy Available for
0.5%-5% once daily contact dermatitis inflammatory Avoid use on nipple while over-the-counter use
breastfeeding; otherwise, may
use on other areas
Sulfa- Cream, foam, lotion, or Irritation and allergic Inflammatory more May use during pregnancyc Avoid in patients with
cetamide + suspension contact dermatitis than comedonal Caution advised while sulfa allergy or kidney
sulfur 8%/4% once or twice dailyb breastfeeding, although risk of disease
9%/4.5% once or twice dailyb infant harm is not expected
based on limited maternal
2%/10% once or twice dailyb or absorption
10%/5% once or twice dailyb

(continued)

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Management of Acne Vulgaris Review Clinical Review & Education

Table 1. Topical Treatments for Acne Vulgarisa (continued)

Pregnancy and lactation
Topical Formulation, dose, Predominant type recommendations
treatments and frequency Adverse effects of acne and precautions Additional information
Fixed-dose
combination
Benzoyl Gel Erythema, dryness, Inflammatory more May use during pregnancyc
peroxide + 5%/1% once dailyb irritation, allergic than comedonal May use while breastfeeding
clindamycin contact dermatitis,
3.75%/1.2% once dailyb or bleaching of fabrics
2.5%/1.2% once dailyb
Benzoyl Gel Erythema, dryness, Inflammatory more May use during pregnancyc
peroxide + 5%/3% once dailyb irritation allergic than comedonal May use while breastfeeding
erythromycin contact dermatitis, and
bleaching of fabrics
Adapalene + Gel Erythema, dryness, Same predominance Risk of fetal harm is not
benzoyl 0.1%/5% once dailyb or irritation, allergic expected based on limited
peroxide contact dermatitis, human data and insignificant
0.3%/5% once dailyb bleaching of fabrics systemic absorption
May use when breastfeeding
Tretinoin + Gel Erythema, dryness, Same predominance Consider avoiding use especially
clindamycin 0.025%/1.2% dailyb irritation, allergic during the first trimester; risk
contact dermatitis of teratogenicity is low based
on limited human data and
minimal systemic absorption
May use when breastfeeding
c
Abbreviation: HPA, hypothalamic-pituitary-adrenal. Some clinicians prescribe topical benzoyl peroxide and sodium
a
Table shows a representative list of products. Other topical formulations may sulfacetamide-sulfur during pregnancy; however, in-depth studies on the
exist alone or in compounded formulations. safety of benzoyl peroxide and sodium sulfacetamide-sulfur during pregnancy
b
are lacking.
With combination therapies, the first percent value indicates dosage for the
first drug, and the second percent value indicates dosage for the second drug.

appropriate. 59,60 Minocycline is also associated with adverse in acne. Because of the thromboembolic risk of COCs, the potential
effects such as urticaria (observed in approximately 1%-2% of benefits of COCs should be evaluated against the potential risks. Pa-
patients in acne trials), vestibular adverse effects, serum sickness– tients with risk factors for thromboembolic disease (migraine head-
like reactions, minocycline-induced hyperpigmentation (most com- aches, smoking, high blood pressure, older age) and people with a
monly a blue-greyish discoloration), drug reaction with eosinophilia family history of thromboembolic events may not be appropriate
and systemic symptoms, and autoimmune hepatitis (Table 2). candidates for COCs to treat acne.66 Potential adverse effects of
Rates of adverse effects such as photosensitivity, vestibular effects, COCs on growth and total bone density attainment should be con-
and gastrointestinal events were reported less in patients treated sidered in pediatric patients. Peak bone mineral density at the fem-
with sarecycline.61 oral neck and total hip is attained between 16 and 19 years in women.
In children younger than 8 years of age and in those with tetra- A recent meta-analysis of 7 prospective observational studies and
cycline allergies or other contraindications, alternative antibiotic 2 open-label randomized comparative trials of 1513 girls and young
agents, such as erythromycin, azithromycin, cephalexin, ampicillin women aged 12 to 19 years reported that combined hormonal con-
and trimethoprim/sulfamethoxazole may be used, though there traception was associated with a weighted mean difference of −0.02
are limited data on efficacy. Erythromycin is associated with in absolute spinal bone mineral density at 12 and 24 months as com-
C acnes resistance.62,63 pared with controls.67 Pediatric clinical practice guidelines advise
waiting more than 1 year after menarche to initiate COCs.6
Hormonal Treatment Spironolactone is an antiandrogenic diuretic that is effective
Hormonal therapy, using COCs and anti-androgens, such as spirono- against acne in female patients.68 It is more commonly used in adult
lactone, suppresses ovarian androgen production and blocks the ef- women and individuals with PCOS, but can be highly effective in pa-
fects of androgens on sebaceous glands, decreasing sebum produc- tients without hyperandrogenism69,70 and has been shown to have
tion and improving acne. Unlike intrauterine and implantable devices, similar effectiveness to oral antibiotics for acne.51,71,72 Spironolac-
COCs, through first-pass hepatic metabolism, increase sex hormone– tone can cause hyperkalemia and therefore, should be prescribed
binding globulin and decrease circulating androgen levels, particu- cautiously in patients with known kidney disease or those taking cer-
larly free testosterone.64 In a meta-analysis of 32 randomized clini- tain medications (eg, potassium-sparing diuretics); however, re-
cal trials, COCs were associated with reductions in inflammatory cent studies show the rate of hyperkalemia in healthy young women
lesions by 62%, placebo was associated with a 26% reduction, and taking spironolactone for acne is comparable to the baseline rate of
oral antibiotics were associated with a 58% reduction at 6-month hyperkalemia in this population.73,74 Due to potential feminization
follow-up.65 Several COCs containing norgestimate/ethinyl estra- of male fetuses, based on the mechanism of action and data from
diol, norethindrone acetate and ethinyl estradiol, and drospirenone/ animal reproduction studies,75 contraceptives are commonly pre-
ethinyl estradiol are FDA approved for the treatment of acne. There scribed concurrently to prevent pregnancy and for their concur-
are currently no data for use of drospirenone-only–containing pills rent antiandrogenic effects. Menstrual irregularities are a common

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 Clinical Review & Education Review Management of Acne Vulgaris

Table 2. Systemic Treatments for Acne Vulgaris

Systemic Predominant Pregnancy and lactation recommendations
treatments Frequency and dose Adverse effects type of acne and precautions
Antibioticsa
Ampicillin 1000 mg once daily or Gastrointestinal upset, allergic rashb Inflammatory May use during pregnancy
1500 mg once daily more than May use while breastfeeding
comedonal
Amoxicillin 250 mg twice daily or Gastrointestinal upset, allergic rashb Inflammatory May use during pregnancy
500 mg twice daily or more than May use while breastfeeding
comedonal
500 mg, 3 times/d
Azithromycin 500 mg 3 times/wk or Gastrointestinal upset, headache, Inflammatory May use during pregnancy
500 mg for 3 consecutive rare QT prolongation more than May use while breastfeeding
days every 10 days comedonal
Cephalexin 500 mg twice daily Gastrointestinal upset, vaginal Inflammtory May use during pregnancy
candidiasis, headache, transient more than May use while breastfeeding
elevation of liver enzymes comedonal
Doxycycline 50-100 mg once daily or Gastrointestinal upset, Inflammatory Avoid use during pregnancy; risk of fetal bone and
50-100 mg twice daily photosensitivity, pseudotumor more than teeth discoloration and enamel hypoplasia; possible
cerebri, elevated aminotransferases comedonal risk of fetal toxicity
Avoid breastfeeding if more than 3-wk treatment
duration
Minocycline 50-100 mg once daily or Gastrointestinal upset, pigment Inflammatory Avoid use during pregnancy; risk of fetal bone and
50-100 mg twice daily changes, dizziness, pseudotumor more than teeth discoloration and enamel hypoplasia; possible
cerebri, elevated aminotransferases, comedonal risk of fetal toxicity
serum sickness-like reaction, Avoid breastfeeding if more than 3-wk treatment
autoimmune hepatitis duration
Sarecycline 60 mg once daily Gastrointestinal upset, headache, Inflammatory Avoid use during pregnancy; risk of fetal bone and
for patients 33-54 kg rare dizziness, photosensitivity more than teeth discoloration and enamel hypoplasia; possible
100 mg once daily comedonal risk of fetal toxicity
for patients 55-84 kg or Avoid breastfeeding if more than 3-wk treatment
150 mg once daily duration
for patients 85-136 kg
Trimethoprim + 80 mg/400 mg once Gastrointestinal upset, vestibular Inflammatory With trimethoprim, consider alternative treatment
sulfamethoxazole dailyc symptoms, rare severe cutaneous more than during pregnancy; animal studies and limited human
reactions (Stevens-Johnson comedonal studies have shown risk of teratogenicity and fetal loss
syndrome and toxic epidermal With sulfamethoxazole, avoid use while breastfeeding
necrolysis) an infant with G6PD deficiency
With sulfamethoxazole, caution advised while
breastfeeding; possible risk of poor infant feeding
Combined oral
contraceptives +
hormonald
Norgestimate + Once dailye Gastrointestinal upset, mood Same Contraindicated during pregnancy
ethinyl estradiol changes, headache, hypertension, predominance Avoid use while breastfeeding from birth to 6 weeks
thrombo-embolism postpartum
Norethindrone Once dailye Gastrointestinal upset, mood Same Contraindicated during pregnancy
acetate + ethinyl changes, headache, hypertension, predominance Avoid use while breastfeeding from birth to 6 weeks
estradiol thrombo-embolism postpartum
Drospirenone + Once dailye Gastrointestinal upset, mood Same Contraindicated during pregnancy
ethinyl estradiol changes, headache, hypertension, predominance Avoid use while breastfeeding from birth to 6 weeks
thrombo-embolism postpartum
Hormonal
Spironolactone 25-100 mg once daily or Dizziness, menstrual irregularity, Same Avoid use in pregnancy; risk of fetal antiandrogen
25-100 mg twice daily breast tenderness, hyperkalemia predominance effects
May use while breastfeeding
Retinoid
Isotretinoinf 0.5-1 mg/kg per day Mucocutaneous dryness, Same Contraindicated during pregnancy; known risk of
hyperlipidemia, elevated predominance teratogenicity and fetal demise
aminotransferases, muscle and/or Use alternative therapy while breastfeeding
joint pain, night blindness,
pseudotumor cerebral,
mood changes
e
Abbreviation: G6PD, glucose-6-phosphate dehydrogenase. Only available at 1 dose level.
a f
Antibiotic treatments were prescribed more predominantly for inflammatory With isotretinoin, the US Food and Drug Administration requires a risk
acne than for comedonal acne. management program called iPledge, which requires clinician and patient
b
Type or description of allergic rash was not provided. (men and women) registration, signed consent, and monthly clinical
c
evaluation and counseling. In the iPledge program, individuals of childbearing
With combination therapies, the first percent value indicates dosage for the
potential are required to specify and confirm monthly 2 specific forms of
first drug, and the second percent value indicates dosage for the second drug.
contraception being used and are required to have monthly pregnancy tests.
d
Combined oral contraceptives + hormonal drugs were equally prescribed for
inflammatory acne and comedonal acne.

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Management of Acne Vulgaris Review Clinical Review & Education

adverse effect in women not taking combined COCs.70 Spironolac- disorders, emotional lability, anxiety disorders, and rarely suicidal
tone is associated with gynecomastia but is not associated with an ideation and completion, these reports should be considered in the
increased risk of breast or gynecological cancers.76,77 context of elevated rates of depression and suicide among patients
with acne.91 A recent cohort study of 443 814 patients treated with
Oral Isotretinoin isotretinoin reported lower rates of suicide in patients treated with
Isotretinoin is a highly efficacious systemic retinoid that is comedo- isotretinoin compared with the French general population (stan-
lytic, decreases sebum production, reduces abundance of C acnes dardized incidence ratio of 0.6).92 Patients should be educated
in sebaceous follicles, and has anti-inflammatory properties. Isotreti- about the teratogenic potential of the medication, as well as poten-
noin is FDA approved for treating severe recalcitrant nodular acne tial adverse effects and toxicities.6 A common misperception
but is often used to treat resistant or persistent moderate to severe regarding isotretinoin is an increased risk of developing inflamma-
acne, as well as acne producing scarring or significant psychosocial tory bowel disease.93,94 Several cohort studies and meta-analyses
distress.7 Isotretinoin is considered to have the potential to induce have not found an association of isotretinoin with increased risk of
acne remission, with a cumulative dose of 120 to 150 mg/kg as an inflammatory bowel disease. Antibiotic exposure may be an impor-
appropriate end point to reduce relapse. However, definitions of tant confounder, as antibiotic use is associated with higher rates of
clearance, relapse, and remission have differed between studies, pre- inflammatory bowel disease.95,96
venting conclusive recommendations regarding optimal dosing to
attain remission.78 Several studies have suggested maintaining treat- Diet and Acne
ment for at least 2 months after complete resolution of acne.79,80 The relationship between diet and acne has been controversial. In
Longer treatment courses (eg, >220 mg/kg) were associated with the middle of the twentieth century, certain foods were thought to
lower rates of relapse.81 Risk factors for relapse after isotretinoin use exacerbate acne; however, little high-quality evidence supports
include young age, male sex, and initial severity of acne.77 this assertion. Compelling evidence suggests that high glycemic–
Isotretinoin is teratogenic. In pregnancies in which the fetus is load diets may exacerbate acne.97,98 High glycemic–index foods
exposed to isotretinoin, the risk of spontaneous abortion is approxi- increase insulin and insulin-like growth factor 1 levels that can
mately 20%. The risk of isotretinoin embryopathy is approxi- induce lipogenesis and proliferation of keratinocytes and sebo-
mately 18% to 28%.82 The FDA requires a risk management pro- cytes, stimulate androgen synthesis, and decrease production of
gram, iPledge, which requires clinician and patient (male and female) sex hormone–binding globulin.99,100 Multiple studies have sug-
registration, signed consent, and monthly clinical evaluation and gested an association between dairy products and acne, particu-
counseling. On a monthly basis, the iPledge program requires indi- larly low-fat milk. A meta-analysis of 4 cohort studies and 9 case-
viduals of childbearing potential to specify and confirm use of 2 spe- control or cross-sectional studies of 71 819 participants, aged 9 to
cific forms of contraception to have monthly pregnancy tests. 60 years, showed an odds ratio of 1.16 of acne in milk drinkers, with
The most common adverse effects of oral isotretinoin per a stronger association with high milk intake (ⱖ2 cups a day) and a
treatment-month include xerosis (72.13%), cheilitis (94.25%), stronger association with skim milk.99,100 Because controlled, care-
dry eyes (29.49%), and myalgias (23.05%). 83 These adverse fully designed studies assessing dietary changes on acne severity
effects are dose dependent and reversible upon discontinuation of are limited, standard clinical guidelines do not offer specific recom-
isotretinoin. Due to the potential for elevated liver enzymes, hyper- mendations on diet.
triglyceridemia, and leukopenia, regular laboratory test monitoring
is often performed.84,85 However, guidelines recommend against Procedural Therapy
complete blood cell count monitoring.7 In a population study of Limited studies have assessed procedures such as laser and light de-
13 772 patients with acne, aged 13 to 50 years, and undergoing vices, chemical peels, and intralesional steroid injections. Although
treatment with oral isotretinoin, the cumulative incidence of new large, multicenter double-blinded control trials are lacking, smaller
laboratory abnormalities was 44% for triglyceride level, 31% for studies suggest that these modalities may improve acne and post-
cholesterol level, 11% for transaminase level, and was uncommon acne scarring.7,101,102 Of the current procedural modalities avail-
(ⱕ6%) for hematologic tests. Mild triglyceride and cholesterol able, photodynamic therapy has the largest supporting evidence,
abnormalities are common.86,87 Moderate to severe lipid and with a meta-analysis of 13 randomized clinical trials (701 partici-
transaminase abnormalities were generally transient and revers- pants) showing that photodynamic therapy was associated with a
ible. There is no current consensus regarding optimal frequency of mean percentage reduction in the inflammatory lesion count of
laboratory monitoring; however, more recent guidelines and 15.97%.102 Photodynamic therapy is a 2-stage treatment that com-
cohort studies recommend limiting evaluation to baseline labora- bines light energy delivered with a light device or laser with a topi-
tory studies (liver function tests, serum cholesterol, and triglycer- cally applied photosensitizing agent, most commonly aminolevu-
ides) plus periodic monitoring (eg, repeat monitoring for abnormal linic acid or methyl aminolevulinic acid, targeting pilosebaceous units
tests until normalized or once with attainment of goal dose).85,87 and C acnes, which innately produces photosensitizing porphyrins
Additional less-common but significant adverse effects associ- that induce selective toxicity of pilosebaceous units. Intralesional ste-
ated with isotretinoin are described in the drug’s package insert, roid injections (typically 0.05 mL of 2.5mg/mL triamcinolone in-
including skeletal effects (specifically, hyperostosis and premature jected with a 27- to 30-gauge needle) are effective for treating larger,
epiphyseal closure), potential for development of inflammatory nodular inflammatory or cystic lesions, as well as keloidal scars.103
bowel disease, and depression. However, definitive evidence of Acne scarring can cause significant and long-standing distress
causation is lacking.84,88-90 Although the drug’s package insert to patients. While inflammatory and nodulocystic acne have a
counsels extensively on psychiatric effects, including depressive greater propensity to scar, any type of acne lesion associated with

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 Clinical Review & Education Review Management of Acne Vulgaris

inflammation can cause scarring. Of the available medical therapies, oral antibiotics or oral isotretinoin can be used in moderate to
topical retinoids or retinoid-benzoyl peroxide combinations may re- severe acne. Postinflammatory hyperpigmentation treatment
duce the number of smaller acne scars and treat established acne includes topical retinoids, azelaic acid, and hydroquinone, as well as
scars.104 Other physical modalities such as chemical peels, intral- procedural therapy such as superficial chemical peels and low flu-
esional trichloroacetic acid application, surgical subcision and exci- ence Nd:YAG laser.110
sion,fractionatedablativecarbondioxidenonablativelasers,andother Treatment of acne fulminans, a rare subtype of severe inflam-
light-based devices are effective in treating acne scarring.105 matory acne with rapid development of painful erosions and hem-
orrhagic crusting sometimes associated with systemic symptoms,
Special Considerations can be very challenging and is beyond the scope of this review.111 Oral
Acne treatment during pregnancy can be challenging given the po- corticosteroids, initially dosed at 0.5 to 1 mg/kg per day for 2 to 4
tential adverse effect of therapeutic agents on fetal development.106 weeks and until lesion healing, may be useful for acute inflamma-
Generally, topical azelaic acid or salicylic acid can be used for tion. Treatment generally requires prolonged use of low doses of
noninflammatory comedonal acne. For mild inflammatory acne, isotretinoin with concomitant slow tapering of oral steroids and may
azelaic acid or salicylic acid can be combined with topical antibiot- be best managed by a specialist.
ics such as erythromycin and clindamycin. Some clinicians also use
topical benzoyl peroxide or sodium sulfacetamide-sulfur; although Limitations
high-quality studies on the safety of benzoyl peroxide and sodium This review has several limitations. First, the search strategy was
sulfacetamide-sulfur during pregnancy are lacking. For moderate to restricted to English-language publications and may have missed
severe inflammatory acne, an oral antibiotic such as ampicillin or relevant publications. Second, this report was not a systematic
amoxicillin,107,108 erythromycin (erythromycin base or erythromy- review of the acne vulgaris literature and quality of evidence was
cin ethylsuccinate), or cephalexin can be combined with azelaic acid not evaluated. Third, this report does not represent a comprehen-
and possibly benzoyl peroxide. Intralesional steroid injections can sive review of all clinical studies of acne therapies.
be used to treat large cystic lesions.
For individuals who are lactating, most topical acne medica-
tions are low risk; use of tazarotene should be avoided around the
Conclusions
nipple (Table 1). Short-term use of some oral antibiotics may be
acceptable.108 COCs should be avoided for at least 4 weeks post- Acne vulgaris affects approximately 9% of the population
partum. No specific recommendations are available for isotreti- worldwide7 and approximately 85% of those aged 12 to 24 years.
noin use in lactating individuals.106 First-line therapies are topical retinoids, benzoyl peroxide, azelaic
Postinflammatory hyperpigmentation is more common in acid, or combinations of topical medications. For more severe dis-
more richly pigmented skin types and may pose greater concerns ease, oral antibiotics such as doxycycline or minocycline, hormonal
than lesion clearance.109 Early intensive treatment of acne is indi- therapies such as combination oral conceptive agents or spirono-
cated to prevent cosmetic sequela. Systemic treatments including lactone, or isotretinoin are most effective.

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