Acne vulgaris

Acne vulgaris is a chronic skin condition that most commonly affects adolescents and young adults, but it can occur at any age. The etiology of acne is multifactorial: genetic predisposition, hormonal effects on sebum production, bacterial colonization with Cutibacterium acnes, and/or keratin plugs from follicular hyperkeratosis. Acne manifests as noninflammatory comedonal acne and/or inflammatory acne, e.g., papules and/or nodules that are often located on the face, shoulders, upper chest, and back. History and physical examination are usually sufficient for diagnosis. Diagnostic studies are only indicated for differential diagnosis or if an underlying medical condition is suspected, e.g., polycystic ovary syndrome (PCOS). Prompt pharmacological treatment is recommended to prevent complications of acne. Treatment is based on the severity of acne and the type of lesion; options include topical and systemic medications.

• Prevalence: the most prevalent chronic skin condition in the US, affecting ∼ 50 million people ^[1][2]
• Age of onset: typically by 11–12 years, with symptoms usually disappearing around 20–30 years of age ^[3]
• Sex: more common in male individuals during adolescence; , but more common in women during adulthood

Epidemiological data refers to the US, unless otherwise specified.

Causes of acne vulgaris

• Genetic predisposition ^[4]
• Hormonal factors
  • ↑ Androgens during puberty → increased production of sebum by sebaceous glands
  • In women: menstrual cycle
• Follicular hyperkeratosis: Higher keratinocyte activity and decreased keratinocyte shedding in pilosebaceous units leads to the formation of comedones.
• Bacterial colonization with Cutibacterium acnes; (formerly known as Propionibacterium acnes) → inflammatory reactions with formation of papules, nodules, pustules, and/or cysts

Risk factors for acne vulgaris

• External factors, e.g.: ^[2]
  • Climate ^[5]
  • Drugs (e.g., anabolic steroids, progestin-only contraception, corticosteroids)
  • Food ^[6]
  • Stress
  • Tobacco smoke
  • Cosmetics
• Underlying endocrine conditions, e.g.: ^[1]
  • Insulin resistance
  • Obesity
  • Polycystic ovary syndrome
  • Congenital adrenal hyperplasia (CAH)

• Commonly found in areas with sebaceous glands (predilection sites: face, shoulders, upper chest, and back)
• Noninflammatory acne: comedonal acne
  • Open comedones (“blackheads”): dark, open portion of sebaceous material
  • Closed comedones (“whiteheads”): closed small round lesions that contain whitish material (sebum and shed keratin)
• Inflammatory acne: Affected areas are red and can be painful.
  • Papular/pustular acne: papules, pustules that arise from comedones
  • Nodulocystic acne (> 5 mm in diameter)
    • Commonly affects the back and neck
    • Severe form: acne conglobata (associated with cysts and abscesses)
• Severity ^[1][2][7][8]
  • Mild acne
    • Few comedones
    • Inflammatory papules and/or pustules may be present.
  • Moderate acne
    • Several comedones and inflammatory papules and pustules
    • Some nodules may be present.
  • Severe acne: extensive skin involvement
    • Mulitple comedones
    • Inflammatory papules and pustules
    • Nodules and/or cysts (i.e., nodulocystic acne) may be present.

Patients with inflammatory acne are at risk for scarring. ^[8]

References:^[9]

Acne fulminans ^[10][11]

Acne fulminans is a rare, severe form of acne that is characterized by painful ulcerative skin lesions and systemic inflammatory symptoms.

Epidemiology

• Rare disease (approx. 200 documented cases)
• Age of onset: 13–22 years
• ♂ > ♀ (3:1)
• Mainly individuals of northern European descent

Etiology

• Adverse effect of isotretinoin (most common)
• Idiopathic

Clinical features

• Primary lesions
  • Acute onset
  • Large, painful nodules, plaques, and ulcers with hemorrhagic crusts
  • Most commonly located on the trunk
• Systemic manifestations
  • Fever
  • Myalgia
  • Weight loss
  • Arthralgia, arthritis
  • Rarely hepatosplenomegaly, erythema nodosum, septic osteomyelitis

Diagnostics

• ↑ CRP, ↑ ESR
• Leukocytosis, thrombocytosis, anemia
• ↑ Liver enzymes

Treatment ^[10][12]

• Refer urgently to dermatology.
• Discontinue isotretinoin if lesions develop while taking this medication.
• Initiate monotherapy with systemic corticosteroids for at least 2–4 weeks.
• Once lesions have improved, continue systemic corticosteroids while initiating low-dose isotretinoin.
• Patients with treatment resistance : Consider cyclosporine, biologics (e.g., infliximab, anakinra), or dapsone.

• Acne vulgaris is usually a clinical diagnosis.
• Consider diagnostic studies if an underlying pathology or alternative diagnosis is suspected, e.g.: ^[1]
  • Hyperandrogenism: Perform diagnostics for hyperandrogenism; if abnormal, refer to endocrinology.
  • Concern for bacterial infection (e.g., refractory acne or suspected skin and soft tissue infections): Swab lesions for bacterial culture.

Routine testing for C. acnes is not recommended because it does not alter management. ^[1]

• Skin and soft tissue infections ^[1]
  • Gram-negative folliculitis (caused by, e.g., Klebsiella or Serratia)
  • Pityrosporum folliculitis
  • Staphylococcal skin infections
• Hidradenitis suppurativa
• Pseudofolliculitis barbae
• Perioral dermatitis
• Miliaria

The differential diagnoses listed here are not exhaustive.

Approach ^[1][2][13]

• Perform a thorough clinical evaluation and address any underlying risk factors for acne vulgaris.
• Provide supportive care instructions.
• Start initial therapy based on acne severity.
• Manage patient expectations.
  • It may take 4–6 weeks for the affected skin to start improving and ≥ 2 months for resolution. ^[14]
  • Trial and error is often required to find the best regimen.
• Reassess therapy response and provide ongoing management of acne as indicated.
• Consider referral to a dermatologist for:
  • Moderate to severe acne
  • Recalcitrant acne
  • Significant scarring

Early pharmacological treatment is recommended to prevent acne complications. ^[13]

Supportive care ^[1][2][13]

• Provide general skin care instructions. ^[13]
  • Use a gentle facial cleanser and avoid excessive cleaning and scrubbing (e.g., with exfoliants). ^[1]
  • Avoid skin care products (e.g., moisturizers, cosmetics) that are comedogenic.
  • Do not pick at acne lesions.
• For individuals with endocrine-related acne (e.g., due to PCOS, obesity), recommend maintaining a healthy BMI.
• Dietary restrictions and supplements (e.g., fish oil) are not supported by current evidence. ^[1]

Overview of pharmacological therapy ^[1][2]

The preferred initial treatment regimen is based on the lesion type and severity of acne.

Isotretinoin and oral tetracycline antibiotics should not be prescribed concurrently as both can cause medication-induced intracranial hypertension. ^[1][2]

Procedural interventions ^[1][2]

Although there is insufficient evidence on the efficacy of procedural interventions, they may be considered by a dermatologist.

• Intralesional steroids: for inflammation and pain caused by nodules
• Chemical peels or comedo extraction: for comedonal acne
• Lasers and light therapy (e.g., photodynamic therapy): for comedonal acne or moderate to severe inflammatory acne

General principles

• Topical treatments are used to treat all stages of acne.
• A mixture of topical therapies is often required; use of fixed combination products may improve adherence.
• When prescribing, consider the following to optimize therapy : ^[1][13][15]
  • Medication concentration
  • Type of topical formulation (e.g., gel, lotion)
  • Duration of skin contact

Topical retinoids ^[1][2]

• Retinoids are vitamin A derivatives with an anti-inflammatory and comedolytic effect.
• Used as monotherapy for comedonal acne or adjunctive therapy for acne of any severity
• Applied at night as some preparations are not photostable and all retinoids can cause photosensitivity

Commonly used agents ^[1]

• Tazarotene ^[1][2]
• Adapalene alone or in combination with benzoyl peroxide ^[1][2]
• Tretinoin alone or in combination with clindamycin ^[1][2]

Benzoyl peroxide can inactivate tretinoin; advise patients not to apply both products at the same time unless using a fixed combination product. ^[1]

Topical retinoids are contraindicated during pregnancy. ^[1][2]

Topical antibiotics for acne ^[1][2]

• Help manage acne through both a bactericidal and anti-inflammatory effect
• Used as an adjunctive therapy for acne

Commonly used agents

• Preferred: clindamycin alone or in combination with benzoyl peroxide ^[1][2]
• Alternative: erythromycin alone or in combination with benzoyl peroxide ^[1][2]

Avoid using topical antibiotics as monotherapy and limit the length of therapy to 12 weeks to prevent the development of drug-resistant bacteria.

Other topical agents ^[1][2][13]

• Consider as monotherapy treatment for mild acne or adjunctive treatment for moderate acne
• Options include: ^[1][2]
  • Benzoyl peroxide ^[1][2][13]
  • Azelaic acid ^[2][13]
  • Dapsone ^[1][2]
  • Clascoterone ^[13]

There is limited evidence to support the use of certain topical medications such as salicylic acid, niacinamide, and sulfacetamide/sulfur for the treatment of acne. ^[1][2]

General principles ^[1][2]

• Indicated for moderate to severe inflammatory acne
• Always combine with topical treatments (i.e., benzoyl peroxide or a retinoid) to:
  • Decrease antibiotic resistance
  • Increase efficacy
• Limit treatment to < 4 months to prevent antibiotic resistance. ^[1][2][13]

Recommended antibiotics ^[1][2]

• First line: tetracyclines
  • Minocycline
  • Doxycycline
  • Tetracycline
• Alternative: macrolides
  • Azithromycin (off-label) ^[13]
  • Erythromycin (off-label) ^[1]

Alternative oral antibiotics (e.g., cephalosporins, penicillins, or trimethoprim/sulfamethoxazole) are not recommended for treating acne because of limited evidence, but can be considered if preferred regimens are not tolerated or acceptable (e.g., during pregnancy). ^[1]

Always combine oral antibiotics with topical therapy and limit treatment duration to < 4 months to prevent antibiotic resistance. ^[1][2][13]

General principles

• Medications with an antiandrogenic effect (e.g., COCPs and aldosterone antagonists) can help female individuals with inflammatory acne.
• Choice of antiandrogenic treatment is based on:
  • Patient preference
  • Presence of contraindications to hormonal contraception
• Glucocorticoids can be used for select indications in patients of both sexes.

Combined oral contraceptive pill (COCP) ^[1][2]

• Can be used alone or in combination with other acne therapies
• Prior to initiation, exclude contraindications and discuss adverse effects of hormonal contraception.

Indications

• Acne in patients seeking contraception
• Consider in female individuals of reproductive age with acne and: ^[2]
  • Symptoms of hyperandrogenism
  • Symptoms that worsen with menstruation
  • Limited response to other acne therapies

FDA-approved COCPs for the treatment of acne ^[1][2][13]

• Triphasic norgestimate/ethinyl estradiol
• Triphasic norethindrone acetate/ethinyl estradiol/ferrous fumarate
• Drospirenone/ethinyl estradiol
• Drospirenone/ethinyl estradiol/levomefolate

Users of progestin-only contraception often report worsening of acne. It is unclear what impact the new progestin-only pill containing drospirenone, an antiandrogenic progestin, has on hormonal acne. ^[16][17]

Aldosterone antagonists

• Spironolactone (off label) can be used for hormonal acne. ^[1][13]
• Can be used in combination with COCP or as an alternative for patients with contraindications to hormonal contraception.
• Evidence on efficacy is limited but side effects are usually mild at lower doses.
  • Hyperkalemia is rare in young women with normal hepatic and renal function. ^[1]
  • Menstrual irregularities can be reduced by concurrent use of COCP. ^[18]

Contraception is generally recommended for women of reproductive age who are taking spironolactone, which can have antiandrogenic effects on a developing fetus (e.g., feminization of a male fetus). ^[1]

Glucocorticosteroids ^[1][2]

• Indicated for use as an adjunctive therapy in certain scenarios:
  • Patients with adrenal hyperandrogenism
  • When initiating oral isotretinoin to prevent acne fulminans-like eruptions or flares of acne fulminans
  • Severe nodulocystic acne during pregnancy (see “Acne in pregnancy”)
• Consider referral to a dermatologist for management.

Oral glucocorticoid therapy can decrease the risk of acne fulminans-like eruptions in patients starting isotretinoin therapy. ^[1][2]

Acne can worsen with rapid titration of glucocorticosteroids; avoid long-term treatment to minimize the side effects of glucocorticoid therapy. ^[1]

General principles ^[1][2]

• Isotretinoin is a systemic vitamin A derivative.
• Decreases the concentration of C. acnes and inflammation by decreasing sebum production and promoting comedolysis ^[2]

Indications ^[1][2]

• Severe; , nodular, recalcitrant acne
• Moderate acne requiring therapy escalation

Contraindications

• Absolute contraindications include:
  • Pregnancy
  • Female individuals of reproductive age not using contraception ^[2]
  • Breastfeeding
• Relative contraindications include:
  • Hyperlipidemia
  • Risk factors for hyperlipidemia
  • Liver disease

Avoid oral isotretinoin during pregnancy and in female individuals of reproductive age not using contraception because of the risk of teratogenesis. ^[2]

Initiating isotretinoin therapy ^[1][2][19]

• Discuss risks and benefits of therapy with patients.
• Explain the mandatory iPLEDGE risk management program and enroll the patient.
• One month prior to treatment for patients who can become pregnant:
  • Perform the first of two serum and/or urine pregnancy tests to confirm the patient is not pregnant.
  • Provide counseling on contraception options and risk for birth defects.
  • Initiate two methods of contraception. ^[1][19]
    • One approved form of primary contraception ^[19]
    • One approved form of secondary barrier contraception ^[19]
  • Repeat the pregnancy test after at least 30 days of using two approved forms of contraception, prior to starting isotretinoin. ^[19]
• Obtain baseline liver chemistries, cholesterol, and triglycerides.
• Stop any medications that may interact with isotretinoin, e.g., oral tetracyclines. ^[20]
• Based on the severity of acne, select the appropriate starting dose of isotretinoin. ^[1][2]
• Consider prescribing an oral glucocorticosteroid (e.g., prednisone ) when starting isotretinoin.
• Advise patients not to donate blood : ^[19]
  • During treatment
  • For at least one month after treatment

Enrollment in the online iPLEDGE program is required for all patients, prescribers, and pharmacists dealing with isotretinoin to prevent cases of fetal retinoid syndrome. ^[1][2]

Ongoing management of isotretinoin therapy ^[1][2][19]

• Schedule monthly follow-up to:
  • Assess for adverse effects of isotretinoin, e.g., acne fulminans
  • Confirm contraceptive use ^[19]
  • Perform a pregnancy test; if pregnancy occurs, discontinue isotretinoin immediately.
  • Issue a new 30-day supply of isotretinoin ^[19]
• For patients with severe acne, uptitrate isotretinoin after one month.
• Monitor liver chemistries, cholesterol, and triglycerides at least once during treatment. ^[21]
• Treatment duration is usually 15–20 weeks to attain a cumulative dose of 120–150 mg/kg. ^[1]
• After treatment is complete:
  • Start maintenance therapy for acne. ^[22][23]
  • For patients who can become pregnant: ^[19]
    • Perform a pregnancy test.
    • Advise continuation of contraception precautions for at least one month.
    • At one month, repeat the pregnancy test; if negative, contraception can be discontinued.

Patients planning to conceive should discontinue treatment at least one month prior to conception.

Cytopenias can occur with isotretinoin use, but there is insufficient evidence to recommend routine monitoring of complete blood counts. ^[1]

Adverse effects of isotretinoin ^[1][2]

• Dermatological: dry skin, cheilitis, alopecia, acne fulminans
• Metabolic
  • ↑ Triglycerides, ↑ cholesterol, ↑ glucose
  • ↑ AST, ↑ ALT
  • Acute pancreatitis
• Hematologic: cytopenias, venous thromboembolism
• Neurological: medication-induced intracranial hypertension, psychiatric disorders, hearing impairment
• Ophthalmic: corneal opacities, decreased night vision
• Musculoskeletal: arthralgia, osteoporosis, delayed bone healing, premature epiphyseal closure
• Nonspecific symptoms: headaches, fatigue
• Drug interactions (e.g., with tetracyclines or contraceptives)
• Possible delayed wound healing after elective procedures (e.g., dermabrasion for acne scarring) ^[1]

Fetal retinoid syndrome ^[24]

• Congenital CNS defects
  • Hydrocephalus
  • Microcephaly
  • Cerebellar and cortical defects
  • Cranial nerve deficits
• Cardiac conditions: congenital heart disease (e.g., great vessel anomalies)
• Congenital craniofacial anomalies (i.e., dysmorphic features)
  • Microtia
  • Microphthalmia
  • Cleft palate
• Other
  • Thymic hypoplasia
  • PTH deficiency

Individuals taking oral isotretinoin should be monitored for symptoms of suicidal ideation and inflammatory bowel disease, even though there is insufficient evidence of an association. ^[1][2]

• Perform a clinical evaluation after 4–8 weeks to assess the patient's response to treatment. ^[2]
• If treatment response is poor :
  • Assess treatment adherence and consider adjusting the current treatment regimen. ^[1]
  • If further adjustments do not help, consider referring to a dermatologist for management.
• If there is improvement, consider transitioning to maintenance therapy for acne, e.g. : ^[2][23]
  • Mild acne: topical retinoid
  • Moderate acne: topical retinoid PLUS topical benzoyl peroxide
  • Severe acne: combination of a topical retinoid, topical benzoyl peroxide, and an antibiotic (topical or oral)

Following the initiation of an acne medication regimen, it typically takes 4–6 weeks to notice clinical improvement and at least 2–3 months to see clearing. ^[14]

• Secondary bacterial infections
• Postinflammatory erythema
• Hyperpigmentation
• Scarring
• Psychological distress ^[1][25]

We list the most important complications. The selection is not exhaustive.

Acne in infants

Neonatal cephalic pustulosis ^[26][27][28]

• Epidemiology: affects up to 20% of infants ^[26]
• Pathophysiology: unclear; thought to result from an overgrowth of the fungal species Malassezia
• Clinical presentation: : onset in the first few weeks of life of a papulopustular rash without comedones
• Treatment
  • Self-limited disease, treatment not usually required
  • Topical antifungals (e.g., ketoconazole) can speed up resolution.

Infantile acne ^[26][27]

• Epidemiology
  • More common in boys
  • Affects < 2% of children. ^[26]
• Clinical presentation
  • Age of onset: ≥ 3 months
  • Papulopustular rash, closed comedones
  • Severe cases can develop nodules and cysts
  • Can last 1–2 years
  • May cause scarring, especially in children with darker skin
• Treatment
  • Topical treatments, e.g., benzoyl peroxide, erythromycin, azelaic acid, and retinoids
  • In severe cases, consider systemic therapy with oral erythromycin or isotretinoin.

Neonatal cephalic pustulosis resolves without treatment, but infantile acne requires treatment to prevent scarring. ^[26]

Acne in pregnancy ^[13][29]

• Pregnancy-related changes in maternal androgens can alleviate or worsen acne.
• Inflammatory acne is more common than noninflammatory acne; the trunk is often affected.
• Follow standard treatment of acne by severity using agents that are safe in pregnancy.

Agents safe to use during pregnancy ^[13][29][30]

• Topical agents
  • Azelaic acid
  • Benzoyl peroxide ^[13]
  • Antibiotics
• Certain systemic antibiotics
  • Macrolides: erythromycin, azithromycin
  • Penicillins: ampicillin, amoxicillin
  • Cephalosporins: e.g., cephalexin

Agents to be used with caution during pregnancy ^[13][29]

Only use the following medications if the potential benefit outweighs the potential or unknown risks to the fetus.

• Topical agents
  • Clascoterone
  • Dapsone
• Systemic agents
  • Trimethoprim/sulfamethoxazole ^[29]
  • Corticosteroids: Reserve use for acne fulminans and severe nodulocystic acne during second and third trimesters. ^[13]
• Intralesional corticosteroids ^[29]

Agents to avoid during pregnancy ^[13]

The following agents are contraindicated in women who are pregnant or planning pregnancy.

• Topical agents: retinoids
• Systemic agents
  • Tetracyclines
  • Hormonal therapies (spironolactone, COCP)
  • Retinoids