KERATOLYTIC TREATMENTS FOR ACNE: AZELAIC ACID
Recently Howard Maibach and Ali Alikhan of respectively the Mayo Clinic and the University of California School of Medicine published a short review on keratolytic treatments for acne (A.Alikhan, H.Maibach, Cosm.Toil., 125,16,(2010)). In Maibach’s review the most frequently used anti-acne agents were reviewed.
Keratinocyte deviations in proliferation, adhesion and differentiation obstruct the infundibulum (the funnel-like passage of the sebaceous gland) and the sebaceous duct, paving the way for excessive sebum secretion, bacterial overgrowth such as Propionibacterium acnes (P.acnes), and inflammatory response due to release of bacterial and cellular products, i.e. sebum and keratin.
Keratolytic agents are believed to function by relaxing the cohesiveness of the stratum corneum (SC). This involves the disintegration of desmosomes (intercellular junctions that provide strong adhesion between cells) and hemi-desmosomes, which link keratinocytes and bind them to the extracellular matrix (ECM), respectively. Therefore, keratolytic agents modulate and correct abnormal follicular keratinization. The most frequently used keratolytic agents are:
• Benzoyl peroxide
• Retinoids (tretinoin, isotretinoin, tazarotene, adapalene)
• Azelaic acid
• Salicylic acid
• Glycolic acid, lactic acid, citric acid (and other α-hydroxycarboxylic acid)
These products are used either single or in combination with other ingredients, frequently in combination with antibiotics, more particularly clindamycin or erythromycin. Benzoyl peroxide and retinoids are allowed in the USA but strictly forbidden in the European Union as laid down in EU Commission Regulation 1223/2009. Salicylic acid is allowed but with restrictions. Azelaic acid and α-hydroxycarboxylic acid can be used without restrictions.
Azelaic acid, modifies epidermal keratinization, i.e. cytostatic; it combats both aerobic and anaerobic bacteria, reducing P.acnes proliferation; and exhibits anti-inflammatory activity. Azelaic acid affects differentiation of human keratinocytes by decreasing synthesis of the keratin filament aggregating protein filaggrin.
Cyanoacrylate skin surface biopsies have demonstrated significant reductions (> 50%) in comedo count after four months of twice-daily 20% azelaic acid treatment, when compared with the vehicle alone. Additionally, comedone reduction was similar in magnitude to that of 0.05% retinoic acid cream.1
A 12-week controlled study comparing 20% azelaic acid treatment, its maximum usage in prescription treatments, with a vehicle demonstrated that azelaic acid significantly improved mild to moderate acne. Azelaic acid treatment decreased inflammatory lesions by 72% and comedones by 55.6%. In addition, 64% of individuals treated with azelaic acid reported good to excellent improvement.2
Azelaic acid has demonstrated inflammatory and non-inflammatory acne reduction in numerous studies, even when compared with tretinoin, benzoyl peroxide, erythromycin and tetracycline.3,4 One study compared 20% azelaic acid to 0.05% tretinoin over one month to report statistically equivalent comedones and total lesion reduction, and similar overall improvement with azelaic acid. Azelaic acid also demonstrated less erythema, scaling and irritation-induced discontinuation in comparison with tretinoin.2
Another trial comparing 20% azelaic acid with 5.0% BPO demonstrated a more rapid initial effect with BPO but similar results for global response and inflammatory lesion reduction at four months; finally, azelaic acid demonstrated milder, more transient adverse events than BPO.5
Pooling together the results of four trials, Mackrides et al. determined that after six months of treatment, 65–85% of those treated with azelaic acid experienced a decrease of more than 50% in number of lesions and references as a “good to excellent clinical response.” Transient side effects lasting two to four weeks have been described. These include burning, erythema, dryness, scaling, pruritis and hypopigmentation Despite efficacy as a monotherapy, a large randomized trial demonstrated that azelaic acid functions better in combination.3
Subjects were randomized to a 12-week regimen of twice daily 20% azelaic acid cream, either as monotherapy or in combination with one of the following: 4% benzoyl peroxide gel twice daily, 1% clindamycin gel twice daily, 0.025% tretinoin cream once daily, or 3% erythromycin/ 5% benzoyl peroxide gel twice daily. All four regimens improved acne, achieving greater efficacy and patient satisfaction than azelaic acid monotherapy.
In combination with 3% erythromycin/5% BPO, 20% azelaic acid produced a marked and relatively expedient decrease in inflammatory lesions. At the end of 12 weeks, reduction in this group was similar to 20% azelaic acid/1% clindamycin, which was the most tolerable of all regimens. In non-inflammatory lesion treatment, however, azelaic acid with 4% BPO and azelaic acid with 0.025% tretinoin were most effective. The azelaic acid plus benzoyl peroxide regimen also achieved the highest patient ratings in overall therapeutic result.3
1. M.Barbareschi et al, The anticomedonic activity of azelaic acid investigated by means of scanning electron microscopy on horny layer biopsy, J.Dermatol. Treatment 2,55,(1991).
2. A.Katsambas, K Graupe and J Stratigos, Clinical studies of 20% azelaic acid cream in the treatment of acne vulgaris. Comparison with vehicle and topical tretinoin, Acta.Derm.Venereol.Suppl.(Stockh.) 143,35,(1989).
3. G.Webster, Combination azelaic acid therapy for acne vulgaris, J.Am.Acad.Der- matol, 43,47,(2000).
4. P.S.Mackrides, A.F.Shaughnessy, Azelaic acid therapy for acne, Am.Fam. Physician 54,2457,(1996).