Topical Acne Therapy Advances in 2011

Jessica Wilford, MD and Shannon Humphrey, MD, FRCPC, FAAD

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Introduction

Acne vulgaris is a common disorder of the pilosebaceous follicle with multiple pathogenic factors. While previous anti-acne treatment algorithms focused on antibiotics, the incidence of antibiotic resistance and the availability of more effective, well-tolerated topical agents have led to new treatment paradigms. The 2009 Global Alliance to Improve Outcomes in Acne guidelines1 recommend that mild to moderate acne is best treated with retinoid-based topical agents. In addition, acne is increasingly recognized as a chronic disorder with a pattern of recurring outbreaks and important social and psychological effects. Aggressive treatment of acne at clinical onset, followed by maintenance therapy, is recommended in order to reduce the duration of active acne and in turn decrease the likelihood of physical scarring and psychological impact.

Overview

Pathogenesis

• Four main pathogenic factors interact to cause acne:¹
  1. Abnormal follicular keratinization and desquamation
  2. Excess production of sebum
  3. Bacterial colonization of pilosebaceous duct by Propionibacterium acnes (P. acnes)
  4. Inflammation
• Hygiene, beyond gentle twice-daily cleansing, has a negligible effect on acne development or resolution.
• The evidence implicating diet in the pathogenesis of acne is inconclusive, but high glycemic diets and dairy may contribute.²
• Acne formation begins with the microcomedone, a clinically invisible lesion. Microcomedones then develop into visible acne lesions: comedones, papules, pustules, and nodules. The degree of inflammation is variable.

Prevalence and Diagnostic Features

• The pilosebaceous unit is found in highest concentrations on the face, chest, and back, explaining the clinical distribution of acne.
• About 80% of people between the ages of 11-30 years are affected2 and up to 50% of affected individuals continue to have acne as adults.¹
• Acne is characterized by polymorphous lesions:
  • Non-inflammatory – open and closed comedones
  • Inflammatory – papules, pustules, and nodules
• Acne can also be classified by severity:
  • Mild – comedonal and papular/pustular
  • Moderate – papular/pustular and nodular
  • Severe – scarring, acne conglobata or fulminans
• Acne is best approached as a chronic disease^1,3 because of its relapsing and recurring pattern, prolonged course, manifestation as acute outbreaks or slow onset, and psychological and social impacts. The psychological sequelae of acne may not correlate with disease severity.

Treatment Rationale

• Sixty percent of acne cases can be managed with acute therapy followed by topical maintenance treatment.¹
• The goal of therapy is to treat visible acne, then continue maintenance to prevent the formation of microcomedones.
• Treatment can prevent or reduce negative outcomes, such as scarring, hyperpigmentation, depression, anxiety, and social withdrawal.
• Treatment should target multiple pathogenic factors.
• The historical approach of using topical or systemic antibiotic monotherapy to target P. acnes contributes to antibiotic resistance.
• Topical therapy of a retinoid plus an antimicrobial (benzoyl peroxide, or benzoyl peroxide + antibiotic) targets 3 of the 4 pathogenic factors while avoiding systemic effects and antibiotic resistance.

Topical Treatment Options

• Level 1 evidence shows combination retinoid-based therapy is first-line for acne treatment and it targets 3 of the 4 pathogenic factors: P. acnes colonization, inflammation, and abnormal desquamation.¹
• Retinoids are comedolytic, anticomedogenic, and antiinflammatory.
• Benzoyl peroxide (BPO) is an antimicrobial agent that has some keratolytic effects and does not contribute to antibiotic resistance.
• Antibiotics have antimicrobial and anti-inflammatory effects, but they should be used in conjunction with BPO lotion, gel or wash to limit antibiotic resistance, and should not be used for maintenance therapy.
• New fixed-dose retinoid-based combination therapies are available.
  • Patient adherence is improved with once daily dosing of a single formula.
  • Retinoid-BPO formulations may be preferable over retinoid-antibiotic formulations because there is no risk of developing bacterial resistance.¹

New Fixed-dose Combination Acne Treatments

Adapalene-Benzoyl Peroxide Gel (Tactuo™)

• This new fixed-dose (adapalene 0.1%-BPO 2.5%) topical agent is the first retinoid-BPO combination formulation.
• Applied once daily.
• Three double-blind randomized controlled trials^4-6 including a total of 3855 acne patients compared the efficacy of adapalene-BPO with adapalene, BPO, and gel vehicle. All three studies showed statistically significant superior efficacy of the adapalene-BPO combination over the three comparison treatments in total or near total clearing of acne and reduction in total number of inflammatory and noninflammatory lesions.
• An analysis of these three studies demonstrates a synergistic effect beyond that attributable to each agent alone:⁷
  • 1.2% of patients discontinued due to adverse events
  • 21.6% of patients experienced adverse events including dryness, erythema, scaling, and stinging/burning
  • Adverse events had a mean rating of “below mild” and peaked at week 1, then improved

Clindamycin-Tretinoin Gel (Biacna®)

• A new clindamycin-tretinoin fixed-dose combination gel is available.
• Applied once daily.
• Two randomized, double-blind, controlled trials⁸ of 2219 subjects compared the combination clindamycin-tretinoin hydrogel with each agent alone and gel vehicle for the treatment of acne vulgaris. The studies both showed statistically significant superior efficacy of the clindamycintretinoin combination over either agent alone or vehicle in reducing the number of inflammatory and noninflammatory lesions and inducing near or total clearing of the skin, with good tolerance.
• This formulation should be not be used for maintenance therapy and use in conjunction with a BPO product is recommended to limit antibiotic resistance.¹

Systemic Treatment Considerations

• Patients with severe inflammatory acne will likely require
  systemic therapy.
• Patients with moderate acne may also need systemic therapy,
  after adherence to topical therapies is assessed.
• Investigation for endocrine causes of acne may be indicated
  in cases with atypical clinical presentation, cases that
  are particularly severe and treatment resistant, or those
  associated with systemic signs and symptoms of endocrine
  disturbance. In females patients, exclude polycystic ovary
  syndrome, adrenal or ovarian tumors, and congenital
  adrenal hyperplasia. In males, exclude congenital adrenal
  hyperplasia.
• Systemic therapies include:³
  • Oral antibiotic + topical retinoid ± BPO
  • Oral isotretinoin
  • Oral contraceptive/anti-androgen for female patients

Limiting Antibiotic Resistance

• Oral antibiotics can cause resistance in bacterial flora throughout the body, while topical antibiotics can cause resistance of skin flora at the treated site.
• Recommendations to limit antibiotic resistance:¹
  • Reserve oral antibiotics for moderate to severe acne
  • Topical and systemic antibiotics should always be combined with BPO and a topical retinoid
  • Limit antibiotic duration: assess response and continuing need at 6-12 weeks
  • If multiple courses of antibiotics are required avoid unnecessary antibiotic switches (use the same one each time if effective)
  • Use BPO along with antibiotics (BPO is an efficient bactericidal agent and will minimize development of bacterial resistance at sites of topical antibiotic therapy)
  • Avoid oral or topical antibiotic monotherapy for acute or maintenance therapy
  • Avoid concurrent oral and topical antibiotic therapy without the addition of BPO

Maintenance Therapy

• A topical retinoid ± BPO is first-line maintenance therapy1 because it effectively controls the formation of microcomedones, is well-tolerated, and does not contribute to antibiotic resistance.
• For patients with mild to moderately severe acne, regardless of the type of therapy used to treat the acute episode of acne, a retinoid-based topical maintenance regimen should be initiated once lesions have resolved. For patients with severe acne, a different approach may be required.¹
• Because of the complex interplay of acne pathogenic factors, maintenance therapy may need to be continued for months to years.
• Patients should be advised that acne might follow a chronic pattern of remissions and outbreaks, which are best managed with maintenance therapy to control the formation of microcomedones before acne lesions become visible.
• Regular follow-up visits at least every 6 months during maintenance therapy will allow for assessment of treatment response, side-effects, and adherence.

Conclusion

Acne is a very common skin disorder predominantly managed in the family practice setting. In conjunction with patient education and a strong therapeutic alliance, retinoid-based topical agents for acute and maintenance therapy, including strategies to limit antibiotic resistance, are effective for mild to moderately severe acne, with few adverse effects and improved quality of life for affected patients.

References

1. Thiboutot D, et al. J Am Acad Dermatol 60(5 Suppl):S1-50 (2009 May).
2. Bowe W, et al. J Am Acad Dermatol 63(1):124-41 (2010 Jul).
3. Gollnick H, et al. J Am Acad Dermatol 49(1 Suppl):S1-38 (2003 Jul).
4. Thiboutot DM, et al. J Am Acad Dermatol 57(5):791-9 (2007 Nov).
5. Gold LS, et al. Cutis 84(2):110-6 (2009 Aug).
6. Gollnick HPM, et al. Br J Dermatol 161(5):1180-9 (2009 Nov).
7. Tan J, et al. J Dermatolog Treat [Epub 2010 Jul 28].
8. Leyden JJ, et al. J Am Acad Dermatol 54(1):73-81 (2006 Jan).