What is the clinical evidence and mechanism of action supporting the use of azelaic acid for treating rosacea?

Azelaic Acid for Rosacea: Clinical Evidence and Mechanism of Action

Azelaic acid is a well-established, effective first-line treatment for papulopustular rosacea with strong clinical evidence demonstrating 51-58% reduction in inflammatory lesions and 44-46% improvement in erythema through its anti-inflammatory effects on the cathelicidin pathway. 1, 2

Mechanism of Action

Azelaic acid works through several mechanisms to improve rosacea symptoms:

1. Anti-inflammatory activity:

   • Primarily exerts anti-inflammatory effects by targeting the cathelicidin pathway, which is upregulated in rosacea-affected skin 1
   • Downregulates the cathelicidin pathway based on both in vitro and in vivo studies 3
   • Reduces reactive oxygen species, contributing to its anti-inflammatory properties 4

2. Antimicrobial properties:

   • Possesses antimicrobial activity against Propionibacterium acnes and Staphylococcus epidermidis 5
   • May inhibit microbial cellular protein synthesis 5

3. Normalization of keratinization:

   • Produces an anticomedonal effect 5
   • Reduces stratum corneum thickness, decreases keratohyalin granule size and number, and reduces filaggrin in epidermal layers 5
   • This action may contribute to decreased microcomedo formation 5

Clinical Evidence

Efficacy Data

1. FDA Approval Studies:

   • Two pivotal 12-week, double-blind, randomized, vehicle-controlled studies with 664 total subjects 6
   • Inflammatory lesion count reductions: 58% vs 40% (vehicle) in study 1 (p=0.0001) and 51% vs 39% (vehicle) in study 2 (p=0.0208) 6
   • Erythema improvement: 44% vs 29% (vehicle) in study 1 (p=0.0017) and 46% vs 28% (vehicle) in study 2 (p=0.0005) 6
   • Investigator Global Assessment success (clear, minimal, or mild final result): 61% and 62% with azelaic acid vs 40% and 48% with vehicle 6

2. Treatment Guidelines Recognition:

   • Recommended by both the American Academy of Dermatology and British Journal of Dermatology as a first-line therapy for mild to moderate papulopustular rosacea 2
   • Demonstrated baseline lesion reduction from 17.5 and 17.8 to 6.8 and 8.9 at 12 weeks in clinical trials 1
   • Achieved 51% and 46% IGA success rates in two large studies 1

3. Novel Formulations:

   • A 2021 study of a novel 15% azelaic acid formulation combined with 1% dihydroavenanthramide D showed significant reduction in IGA scores (median from 3 to 1) and inflammatory lesion counts (median from 8 to 1) after 8 weeks 7
   • Azelaic acid 15% foam has shown efficacy with favorable tolerability and lower incidence of sensory adverse effects 3

Pharmacokinetics

• Approximately 3-5% of applied dose penetrates into stratum corneum, with up to 10% reaching epidermis and dermis 5
• Only about 4% is systemically absorbed 5
• Negligible cutaneous metabolism occurs after topical application 5
• Half-life is approximately 12 hours after topical dosing 5
• Primarily excreted unchanged in urine, with some β-oxidation to shorter chain dicarboxylic acids 5

Clinical Application

Dosing and Administration

• FDA-approved as 15% gel for twice-daily application 6, 8
• Treatment duration of 12 weeks is recommended, though continued improvement may occur beyond this period 2
• Allow 6-12 weeks to demonstrate full efficacy before considering treatment failure 2

Safety and Tolerability

• Generally well-tolerated with mild and transient local irritation 8
• Common side effects include burning, stinging, itching, and scaling 8
• Suitable for all skin types 8
• Does not induce epidermal permeability barrier impairment 3
• Proper skin care can reduce neurosensory adverse effects 3

Comparative Efficacy

• Appears to produce quicker onset of clinical effect than metronidazole when either is used with subantimicrobial dose doxycycline 3
• Both azelaic acid and metronidazole are effective when used in combination with doxycycline for papulopustular rosacea 3

Treatment Considerations

Combination Therapy

• Can be effectively combined with oral doxycycline 40mg modified-release for moderate to severe papulopustular rosacea 2
• Combination approaches target complementary inflammatory pathways 2

Long-term Management

• Continuing topical treatment after successful initial therapy helps maintain remission 2
• Should be incorporated with sun protection, gentle cleansers, and trigger avoidance for optimal outcomes 2

Azelaic acid 15% gel represents a valuable first-line treatment option for rosacea with established efficacy, safety, and multiple beneficial mechanisms of action targeting the underlying inflammatory pathways of the disease.