Combination Therapy for Acne Vulgaris

J. Rao, MD, FRCPC

Division of Dermatology and Cutaneous Sciences, University of Alberta, Edmonton, Canada

The Disease

• Acne vulgaris is a complex skin disorder of the pilosebaceous unit affecting almost all people at some point in their lifetime, especially among people aged 15–24 years.
• Acne can be physically and emotionally scarring, causing significant psychosocial morbidity and reducing self esteem.
• All forms of acne involve one or more of these pathophysiologic factors:
  • Hyperkeratinization of the follicular epithelium with comedone formation
  • Increased sebum production
  • Bacterial proliferation of Propionibacterium acnes (P. acnes)
  • Local immune hypersensitivity causing inflammation.
• Acne may be classified according to predominance of specific skin lesions:
  • Comedonal (non-inflammatory) – mild
  • Papular (inflammatory) – mild-to-moderate
  • Pustular (inflammatory) – moderate
  • Nodulocystic – severe
• This order also follows increasing severity, with cutaneous scarring as the ultimate result.

Make a Diagnosis

Existing therapies for acne can be divided into one of the following categories:

1. Physical or mechanical modalities
   • Includes comedone extraction and other forms of acne surgery, chemical peels, and microdermabrasion.
2. Light-based therapy
   • Includes laser treatment, the usage of noncoherent light sources and photodynamic therapy
3. Topical or systemic medications
   • Includes retinoids, antibiotics, benzoyl peroxide, and hormonal therapy.
   • Two major categories based on primary mechanism of action:
     • Antimicrobials: reduce P. acnes growth
     • Comedolytics: reduce and/or prevent comedone formation
4. Formulations (i.e., gel vs. cream) may decrease sebum production.

Combination Therapy

• It is necessary to address all pathophysiologic factors of acne for effective treatment.
• Most medications do not act against all four major pathophysiologic features of acne.
• Combination therapy with a few logically chosen agents has a greater chance of addressing more pathophysiologic factors in acne development.
• Other benefits of combination therapy:
  • Some combinations have demonstrated synergy (i.e., the combined effect is better than that seen by the individual agents).
  • Potential to decrease individual drug doses and exposure times
  • Potential to reduce and prevent antibiotic resistance
  • Potential cost-savings by reducing the use of expensive medications.

Recommendations for Treatment

• Topical and systemic agents are the mainstay of acne therapy and maintenance.
• Physical and light-based modalities should be used as second-line or adjunctive therapy.
• Hormonal therapies may be used as second choice or adjunctive therapy in women with contributing androgenic factors for acne.
• Choose agents with different, but complementary mechanisms of action (e.g., antimicrobial + comedolytic agent).
• Tolerability is related to compliance; choose agents with a good tolerability profile.
• Topical retinoids alone, or in combination with other medications, should be considered first-line therapy for both inflammatory and non-inflammatory acne.
  • Includes adapalene, tazarotene, tretinoin, and tretinoin gel microsphere.
  • Use early for best results.
  • Inhibits microcomedone formation, which is the precursor lesion in acne.
  • Clears mature comedones.
  • Improves inflammatory lesions.
  • Has synergistic effects with oral or topical antibiotics.
  • Induces remission of acne in maintenance therapy.
• Antibiotics are adjunctive therapy in inflammatory acne.
  • Oral antibiotics include minocycline, doxycycline, tetracycline, trimethoprim-sulfamethoxazole, and erythromycin.
  • Topical antibiotics include clindamycin and erythromycin.
  • Use only as long as necessary and combine with topical retinoids.
  • Antibiotics should not be used as monotherapy in order to prevent resistance and target more pathophysiologic factors.
  • Minimize duration of therapy to prevent resistance and side-effects.
  • If there is need to continue antimicrobials, use benzoyl peroxide or benzoyl peroxide/antibiotic combinations.

Recommendations for Maintenance

Acne Medications and Pregnancy

Some acne medications must not be used by women who
are pregnant or lactating, or who may become pregnant
because of the potential harm to a fetus or breastfed infant.
These medications include:

• Hormonal therapy
  • Estrogen and derivatives, flutamide, spironolactone

  Oral and topical isotretinoin

  • Established teratogenicity

  Oral tetracyclines

  • Tetracycline, doxycycline, minocycline
  • Dental discoloration noted

  Oral sulfonamides

  • Trimethoprim-sulfamethoxazole
  • Theoretical risk of teratogenicity, anemia, jaundice

  Topical retinoids

  • Adapalene, tazarotene, tretinoin
  • Theoretical risk of teratogenicity

Conclusion

Acne vulgaris remains a therapeutic challenge, in large part due to its multifactorial pathophysiology. Evidence for improved and quicker efficacy with safety and longer remission has been noted with combination therapies.