Recent Advances in Acne Pathogenesis

Implications for Therapy

Shinjita Das; Rachel V. Reynolds

Disclosures

Am J Clin Dermatol. 2014;15(6):479-488. 

In This Article

Acne Treatment

The therapeutic ladder for acne management ranges from topical to oral agents, with more recent advances in the development of physical modalities, including radiofrequency, PDT, and laser treatments.

Topical Retinoids

Topical retinoids (first-generation all-trans retinoic acid [tretinoin] and third-generation adapalene and tazarotene) are the therapeutic cornerstone for acne comprising mild comedonal and inflammatory papules.[63] By binding to nuclear membrane retinoic acid receptors (RARs), they normalize follicular keratinocyte differentiation and cohesion of corneocytes to promote comedolysis and inhibit comedogenesis.[64] Specifically, tretinoin binds all three RARs with moderate affinity (RAR-α, β, γ); adapalene preferentially binds RAR-β, γ; and tazarotene has highest affinity for RAR-β. Furthermore, adapalene also downregulates 5-lipoxygenase, leukotriene production, and AP-1 transcription factor (thus inhibiting MMP-mediated tissue destruction and scarring).[65] Adapalene also plays an anti-inflammatory role by inhibiting neutrophil chemotaxis. Both tretinoin and adapalene inhibit monocyte expression of TLR2 and have been demonstrated to prevent release of oxygen free radicals by neutrophils.[66,67] Topical retinoids can facilitate percutaneous absorption of benzoyl peroxide and topical antibiotics.

Topical Antibacterial Agents

  • Benzoyl peroxide causes bacterial oxidation and is bactericidal. Of note, benzoyl peroxide does not induce bacterial resistance.

  • Clindamycin and erythromycin are the two most commonly prescribed topical antibiotics with coverage against Staphylococcus aureus and P. acnes. They function by binding the 50S ribosomal subunit and inhibit protein synthesis. Concomitant use with benzoyl peroxide can limit development of bacterial resistance.

  • Azelaic acid inhibits mitochondrial activity and DNA synthesis.

  • Dapsone inhibits dihydropteroate synthetase and nucleic acid synthesis.

  • Sodium sulfacetamide also inhibits bacterial dihydropteroate synthetase.

Oral Antibiotics

Oral antibiotics are useful for moderate to severe inflammatory acne refractory to topical therapy. They exhibit their effects via both antimicrobial and direct anti-inflammatory properties. Specifically, antibiotics have been shown to inhibit bacterial lipase, down-regulate inflammatory cytokines, prevent neutrophil chemotaxis, and inhibit MMPs.[68–70]

  • Tetracyclines (doxycycline and minocycline, in particular, which bind 30S ribosomal subunit) are the most frequently prescribed oral antibiotics for acne. Lowdose tetracyclines (e.g. doxycycline 20 mg twice daily) are recommended for anti-inflammatory effect and to minimize the risk of antibiotic resistance.[71]

  • Macrolides, such as erythromycin and azithromycin, are also utilized, as they suppress P. acnes proliferation within the follicle. They are implemented as secondline agents after tetracycline antibiotics.

Oral Hormonal Treatment

Hormonal therapy may benefit women with signs of hyperandrogenism (premenstrual flares, jawline distribution, hirsutism, and presentation or worsening of acne in adulthood). Oral contraceptives inhibit ovarian and adrenal production of androgens and most contain both estrogen and progestin to reduce the risk of endometrial cancer. The three US FDA-approved oral contraceptives for acne treatment include norgestimate-ethinyl estradiol, ethinylestradiol with norethindrone, and ethinyl estradiol with drospirenone.[72,73] Newer formulations also show antiandrogen effects. Spironolactone, which has dual function through androgen receptor blockade and inhibition of 5αreductase, can reduce sebum production and improve acne.[73,74] Flutamide (FDA-approved for the treatment of prostate cancer) is a non-steroidal androgen receptor blocker that has also been effective, but cost and hepatotoxicity significantly limit its use.[75] Outside of the USA, clinicians can prescribe anti-androgen cyproterone acetate at low dosage (2 mg/day) or higher dosage (50 mg/day) combined with estrogen; of note, patients on higher-dosage cyproterone acetate should be monitored for hepatotoxicity.

Oral Retinoids

Isotretinoin (13-cis-retinoic acid) is FDA-approved for treatment-resistant severe, nodulocystic acne and exerts an in vitro anti-androgen effect through inhibition of the 3αhydroxysteroid activity of retinol dehydrogenase. While 13-cis-retinoic acid does not directly bind any of the nuclear retinoic acid receptors, its metabolites are thought to bind RAR and retinoid X receptor (RXR). The RAR-RXR heterodimer then binds the retinoid ligand and transcriptionally regulates genes involved in inhibition of inflammation, promotion of follicular keratinocyte differentiation, and decrease in sebaceous gland activity. RAR-RXR can also antagonize AP-1, which limits activation of MMPs that cause tissue destruction and acne scarring.[76–79]

Isotretinoin exerts anti-sebocyte effect through a unique non-retinoid receptor mechanism that recruits neutrophil gelatinase-associated lipocalin (NGAL), which can induce apoptosis in sebocytes during isotretinoin treatment. Interestingly, an increase in NGAL after isotretinoin treatment occurs before decreases in sebum production and P. acnes. Ongoing research will elucidate mechanisms by which NGAL mediates the isotretinoin effect.[80] Another recent study noted that isotretinoin impacts the antimicrobial peptide expression in acne lesions. Specifically, isotretinoin therapy was associated with reduced expression of cathelicidin, HβD2, lactoferrin, psoriasin, and koebnerisin; however, only cathelicidin and koebnerisin levels normalized after a full 6-month course of treatment. Isotretinoin was noted to have no impact on other antimicrobial peptides, including granulysin, perforin, and dermcidin, among others. These findings raise the possibility of specifically targeting antimicrobial peptides in the treatment of acne.[81]

Devices for Acne Treatment

Most acne treatments provide short-term clearance, and isotretinoin is the only medication that offers the best chance at long-term remission. However, the burden of monitoring programs for teratogenicity and the risk of adverse effects have prompted continued research to identify other treatments. Increasing antibiotic resistance is another important factor in seeking new treatment approaches.[82,83] Radiofrequency, light, and laser devices are active areas of research and development. Of note, randomized double-blinded clinical trials with sufficient numbers of patients and with comparisons of devices with standard therapies (topical and systemic drugs) are lacking. Furthermore, data are limited regarding frequency of relapses after treatment with devices. It is not possible to evaluate the real benefit of medical devices, and at this time these devices should be viewed as useful adjuncts to established therapies rather than as standalone treatment options.

Radiofrequency Devices. Non-ablative radiofrequency devices use radio waves to heat the dermis and subcutaneous tissue while sparing the epidermis. Initially designed to improve skin laxity, radiofrequency devices have recently been studied in the treatment of inflammatory acne. High temperatures are thought to kill bacteria and shrink sebaceous glands. While preliminary studies show promise, the study samples were small.[84–87] More recently, fractional radiofrequency treatment with insulated microneedles targeting the middermis has shown promise in treating inflammatory acne lesions.[86] Common side effects include pinpoint bleeding at the sites of treatment, pain, and redness. Unlike lasers, radiofrequency treatments do not cause hyperpigmentation (no epidermal heating), and thus may be a viable option for patients with darker skin types.

Light and Laser Treatments for Acne. Non-Coherent Light Sources: Non-coherent light sources harness the photochemical effect of visible or ultraviolet light on endogenous bacterial porphyrins to produce free radicals and reactive oxygen species that can cause membrane damage to P. acnes (major porphyrin is protoporphyrin IX). The optimal wavelengths for killing P.acnes in this manner are in the blue light region (400–420 nm).

Intense pulse light (IPL) provides non-coherent pulses of visible light (longer wavelength than blue light) that are thought to penetrate deeper into the follicle to photoactivate P. acnes porphyrins.[88] Efficacy data are conflicting, and newer devices combine IPL source with suction devices ('photopneumatic' devices) with some improved efficacy.[89] Major limitations include lack of properly controlled evaluation.

Blue light treatment is FDA-approved for acne treatment. Initial studies demonstrated that 8 weeks of blue light therapy for acne can reduce the number of inflammatory, but not comedonal, acne lesions (patients should continue a topical retinoid).[90] Others have reported improvement of acne on the face and trunk with broadspectrum green and violet wavelengths.[91] The FDA recently approved the use of narrow-band light sources for home-use laser devices.

PDT utilizes exogenous photosensitizers that preferentially absorb into the pilosebaceous unit and enhance the effect of light treatments. Because aminolevulinic acid (ALA) and methyl-aminolevulinate (M-ALA) are only FDA-approved for treatment of actinic keratoses, their application in acne treatment is considered off-label. PDT requires at least 70–90 min incubation of photosensitizer on the skin, followed by exposure to either blue (415 nm, ALA) or red (635 nm, M-ALA) light. The longer wavelength of red light penetrates deeper into the dermis where sebaceous glands reside (500–1,000 μm) and thus offers better efficacy.[92,93]

Variations of PDT include 'high dose' (optimized to target the sebaceous glands but with more side effects) and 'low dose' (gentler parameters with fewer side effects but less effective). There can be 40–70 % improvement in inflammatory lesions lasting 3–6 months, with further improvement noted on repeat treatment. PDT can cause significant inflammatory side effects, including pain, post-procedure photosensitivity, and phototoxic effect (edema, blistering—downtime for 7–10 days post-procedure).[94] This side effect profile may be tolerable for patients with moderate to severe acne who have failed or want to avoid isotretinoin, do not want to receive an oral contraceptive, or are planning to become pregnant.

Lasers for Acne Treatment: Pulsed-dye lasers (PDL) cause selective photothermolysis of dilated blood vessels within acne lesions. While there is no direct effect on P. acnes or sebum production, the soluble factor transforming growth factor (TGF)-β (a cytokine involved in wound healing) is up-regulated after non-ablative PDL therapy. TGF-β seems to mediate an anti-inflammatory effect that manifests as a global improvement in acne appearance rather than limited to the treated site. The lack of high-quality controlled trials have made it difficult to interpret conflicting reports of PDL efficacy.[95,96]

Mid-infrared lasers gained attention when the 1,450 nm diode laser was shown to damage sebaceous glands in a rabbit ear model and in ex vivo human skin.[97] Photothermolysis at the level of the sebaceous gland and alteration in follicular hyperkeratinization may play a role. A preliminary split-back randomized controlled trial showed significant decrease in acne lesion counts compared with control sites.[97] In follow-up studies, most of the patients were concomitantly receiving either an oral or topical acne regimen during the laser treatment.[98] A subsequent splitface study in 38 subjects showed no benefit using the Revised Acne Grading scale. However, global improvement in acne was observed, again suggesting the role of a soluble factor (not identified in the paper).[99]

More recently, Sakamoto et al.[101] have spear-headed efforts to utilize selective photothermolysis of lipids within sebaceous glands. Anderson et al.[100] have identified 1,210 and 1,720 nm as wavelengths where the absorption coefficient of lipid exceeds that of water. In vitro studies of fresh porcine skin samples have demonstrated selective thermal damage to fat but not overlying skin near the 1,210 nm wavelength. Furthermore, artificially prepared sebum has absorption peaks near 1,210, 1,728, 1,760, 2,306, and 2,346 nm.[101] These data suggest the potential for sebum to be targeted as a chromophore in the selective photothermolysis of sebaceous glands. Preliminary studies (ex vivo specimens of skin) have shown that 1,700 nm for 100–135 ms pulse durations selectively target sebaceous glands without damage to the epidermis or dermis. Studies are underway to further characterize these observations.

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