Acne vulgaris is a common disorder of the pilosebaceous unit that causes comedones, papules, pustules, and nodules on the face, chest, and back. It predominately affects adolescents but may be present in patients through 30 years old or older (Zaenglein, Graber, & Thiboutot, 2012).
The pathogenesis of acne involves the following four key elements: (a) follicular epidermal hyperproliferation, (b) excess sebum production, (c) inflammation, and (d) Propionibacterium acnes (Zaenglein et al., 2012). Treatment is typically based on the type of acne that is diagnosed. However, regardless of the morphology, topical retinoids are often involved in the first-line treatment either as monotherapy or in combination with topical or oral antibiotics or benzoyl peroxide (Zaenglein et al., 2012). Topical dapsone, azelaic acid, and salicylic acid are used as alternatives to retinoids.
Topical antibacterials such as erythromycin are not recommended as monotherapy for acne vulgaris. Azelaic acid is a safe and appropriate monotherapy treatment option for acne vulgaris. Azelaic acid is a dicarboxylic acid that is thought to alter follicular epidermal hyperproliferation, inflammation, and Propionibacterium acnes, but not excess sebum production (Allergan, Inc., 2003; Zaenglein et al., 2012).
MECHANISM OF ACTION
The mechanism of action of azelaic acid is not well understood. However, in vitro, it possesses antimicrobial activity against Propionibacterium acnes and Staphylococcus epidermidis, most likely through microbial cellular protein synthesis inhibition (Allergan, Inc., 2003). Microcomedones and comedones can arise because of hyperkeratinization. Azelaic acid produces an anticomedonal effect by decreasing the amount of hyperkeratinization (Allergan, Inc., 2003). Biopsies have shown a decrease in stratum corneum thickness, keratohyalin granules, and filaggrin in patients treated with azelaic acid cream (Allergan, Inc., 2003). Azelaic acid also competitively inhibits tyrosinase, an enzyme involved in the conversion of tyrosine to melanin (Figure 1). Last, its mechanism of action also includes the inhibition of DNA synthesis and mitochondrial enzymes, thereby inducing direct cytotoxic effects on the melanocyte (Sarkar et al., 2016). Therefore, azelaic acid is thought to decrease postinflammatory hyperpigmentation (Zaenglein et al., 2016).
USES IN PRACTICE
Topical azelaic acid is Food and Drug Administration (FDA) approved for mild-moderate inflammatory acne vulgaris under the brand name Azelex as 20% cream (Allergan, Inc., 2003). It is also FDA approved for mild-to-moderate papulopustular rosacea under the brand name Finacea as 15% gel and 15% foam (Bayer HealthCare Pharmaceuticals Inc., 2015). At this time, azelaic acid is not approved for any other subtype of rosacea. In clinical studies for azelaic acid gel 15% (Finacea), there was some reduction of erythema noted in patients treated for papulopustular rosacea, but no specific clinical trials were performed to study erythema in rosacea in the absence of papules and pustules (Bayer HealthCare Pharmaceuticals Inc., 2015). Azelaic acid is also used off-label for the treatment of hyperpigmentation disorders, including melasma, due to its inhibition of tyrosinase (Figure 1; Mazurek & Pierzchala, 2016).
PHARMACOKINETICS
Topical azelaic acid has a bioavailability of up to 10% in the epidermis and dermis (Allergan, Inc., 2003). Approximately 4% of azelaic acid cream or gel is absorbed systemically after topical application (Allergan, Inc., 2003; Bayer HealthCare Pharmaceuticals Inc., 2015). Azelaic acid is a saturated dicarboxylic acid (HOOC-(CH2)7-COOH) found in many foods, including animal products and whole grains. It may undergo some beta-oxidation to shorter-chain dicarboxylic acids, but it is predominately excreted in its original form in urine (Allergan, Inc., 2003). The half-life of topical azelaic acid is approximately 12 hours, and the patient should apply it to the area of concern twice daily. Favorable results are typically seen within 4 weeks in patients with acne vulgaris and within 12 weeks in patients with papulopustular rosacea (Allergan, Inc., 2003; Bayer HealthCare Pharmaceuticals Inc., 2015).
ADVERSE EFFECTS
Mild, transient adverse effects have been reported with topical azelaic acid. Adverse effects of the 15% gel (Finacea gel) used for rosacea include burning/stinging/tingling (29%), pruritis (11%), scaling/dry skin (8%), and erythema/irritation (4%; Bayer HealthCare Pharmaceuticals Inc., 2015). Adverse effects of the 20% cream (Azelex) used for acne vulgaris are similar but less commonly noted in the clinical trials. They include pruritus, burning, stinging, and tingling in 1%-5% of patients and erythema, dryness, rash, peeling, irritation, dermatitis, and contact dermatitis in less than 1% of patients (Allergan, Inc., 2003). Clinical trials of the 15% foam (Finacea foam) reported similar adverse reactions. All three formulations of topical azelaic acid mention that hypopigmentation has been reported and recommend monitoring for this in patients with dark complexions, as this has not been well studied in this population. Azelaic acid can also cause ocular and mucous membrane irritation; thus, contact should be avoided (Bayer HealthCare Pharmaceuticals Inc., 2015). It should be noted that hypersensitivity reactions to azelaic acid or its components have also been reported.
ALTERNATIVES
Currently, there are no other known drugs with the same mechanism of action as azelaic acid. On the other hand, there are many other drugs that can be used in the treatment of acne vulgaris, such as topical and oral retinoids, oral and topical antibiotics, benzoyl peroxide, topical dapsone, salicylic acid, photodynamic therapy, lasers, and peels. Antibiotics develop resistance when not used in combination with benzoyl peroxide and therefore should not be used as monotherapy. Azelaic acid is an effective monotherapy for acne vulgaris in pregnant women (Chien, Qi, Rainer, Sachs, & Helfrich, 2016).
WARNINGS AND PRECAUTIONS
Hypersensitivity reactions have been reported with the use of azelaic acid. It should be avoided in patients with known hypersensitivity reactions to azelaic acid or its components. Hypopigmentation has been reported with the use of azelaic acid as well. Skin should be monitored for signs of hypopigmentation, especially in patients with dark complexions. In addition, contact with the eyes, mouth, and other mucous membranes should be avoided.
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