Re-evaluating Treatment Targets in Acne Vulgaris: Adapting to a New Understanding of Pathophysiology

June 2014 | Volume 13 | Issue 6 | Supplement Individual Articles | 57 | Copyright © June 2014

Leon H. Kircik MD

Indiana University School of Medicine, Indianapolis, IN
Icahn School of Medicine at Mount Sinai, New York, NY
Physicians Skin Care, PLLC, Louisville, KY

“non-inflammatory lesions” (microcomedo, open and closed comedones) are actually inflammatory in nature. More supporting evidence is that lipid peroxide levels, which are also a marker of inflammation, are elevated in early comedones and microcomedones, as well as in all subsequent acne lesions.4
Inflammation persists throughout the course of lesion development and resolution. Persistent inflammatory hyperpigmentation and erythema are evidence of the inflammatory processes occurring throughout the acne lesion cycle.9 Kang et al confirmed that acne scars are mediated by inflammation.1 Additionally,10 inflammatory genes are upregulated in the skin of acne patients.10 Researchers showed a prominent role of matrix metalloproteinases, inflammatory cytokines, and antimicrobial peptides in acne lesions. Some of those biomarkers, such as IL-1 and integrins, may be involved with prelesional inflammation early on in the disease process.11
The conventional teaching that the microcomedone is the mother of all acne lesions is losing its validity. The notion of sequencing of all inflammatory lesions from so-called “non-inflammatory” lesions is being replaced by the new concept of inflammatory lesions possibly rising from normal appearing skin, scar, or just erythematous macules. With computer assisted alignment and tracking of acne lesions, Do et al were able to demonstrate that 28% of all inflammatory lesions arise directly from visibly normal skin.6 This means that 28% of papules and pustules did not follow comedones as was conventionally considered.
New research into the P. acnes microbiome confirms that the bacteria is not infective; in fact, certain strains of P. acnes were enriched in healthy skin, while other strains were more likely to be associated with the development of acne.12 Two phylogenetically distinct types of P. acnes have been identified: type 1 and type 2. Type I is subdivided into type 1A, type 1B, and type 1C.12-13 Type 1A P. acnes isolates have been reported as predominant in AV and, of the various subtypes, they have the greatest effect on antimicrobial peptides and proinflammatory cytokine production.10,12-13

Reconsidering Therapeutic Targets

Systemic antibiotics used in acne therapy are known to confer anti-inflammatory effects, and mostly anti-inflammatory actions appear to account for the efficacy of antibiotics in acne therapy. 14 In light of documented antibiotic resistance associated with antibiotics used to treat acne,15-16 guidelines for acne management published in the last decade discourage long-term use of antibiotics and emphasize the use of topical antimicrobials and retinoids.17 Remarkably, evidence shows that oral antibiotics remain the most commonly prescribed treatments for acne, accounting for 41% of all prescriptions written for acne.18 A 2009 update of the recommendations emphasizes the use of oral or topical antibiotics in combination with benzoyl peroxide (BPO),19 avoiding the use of oral or topical antibiotics as monotherapy, concurrent use of oral and topical antibiotics, and discontinuation of antibiotics when there is only slight or no improvement. The guidelines also highlight the critical role of topical retinoids in long-term acne maintenance treatment. Benzoyl peroxide is a potent oxidizing agent that generates reactive oxygen species that physically destroy the bacteria. In addition to antimicrobial properties, BPO is also shown to have comedolytic and antiinflammatory effects.19
Benzoyl peroxide’s efficacy as a monotherapy was traditionally considered to be limited; however, the agent is readily used in fixed-dose combinations with antibiotics or topical retinoids, providing documented benefit.20-22 Like BPO, retinoids are being shown to have multiple effects. While the anti-comedogenic effect is the hallmark of topical retinoids, we now know that they also have anti-inflammatory properties.21 The fixed combination formulation of adapalene 0.1% and BPO 2.5% has established efficacy, safety, and tolerability.23-24 Pooled analysis from 3 double-blind controlled trials of similar design including 3,855 subjects shows that adapalene/BPO gel has synergistic effects. The fixed combination of adapalene 0.1%/ BPO 2.5% has early anti-inflammatory benefits. Synergy was observed for reduction in inflammatory lesions through week 4 and for non-inflammatory lesions through week 8.25
Acne vulgaris is a chronic disorder, suggesting a need for continuous and long-term use of antibiotics. Yet such antibiotic use contributes to the major health problem of antibiotic resistance and poses a great challenge to maintenance treatment of the disease. In the past, Thiboutot et al had shown positive results for adapalene 0.1% gel in maintenance therapy of severe acne after stopping doxycycline,26 and Leyden et al had similarly shown that tazarotene 0.1% gel plus minocycline is not better than minocycline alone in sustaining acne improvement.27
In view of this above challenge, adapalene 0.1%/BPO 2.5% gel has been studied in long-term management of severe acne after stopping 3 months’ use of oral antibiotics. A randomized, vehicle-controlled, multicenter, double-blind study evaluated the efficacy and safety of the fixed-dose combination adapalene 0.1%/BPO 2.5% gel with doxycycline hyclate 100mg once daily in the treatment of severe AV for the first 12 weeks, followed by just topical treatment vs vehicle for 6 months. A total of 459 participants were randomized in a 1:1 ratio to receive oral doxycycline hyclate 100mg once daily and either adapalene/BPO or