Topical vs Systemic Treatments: Rosacea Lesion Reduction Compared

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Although the pathogenesis of rosacea is still unclear, researchers behind a recent study believe it to be multifactorial, involving dysregulation of the innate immune system and the neurovascular system. For the formation of inflammatory lesions (ILs; papules and pustules) in rosacea, Demodex folliculorum have been recognized due to 98.6% of rosacea patients with ILs having densities of the mites.¹ At high densities, the mite’s inherent immunogenicity may overwhelm the immunosuppressive mechanisms, causing inflammation and the appearance of ILs.

With rosacea primarily affecting the central face region, researchers noted it is typically associated with substantial psychosocial impact, with many patients experiencing reduced self-esteem, anxiety, and social withdrawl.² Given this impact, the review aimed to determine the effectiveness of topical and systemic therapies in reducing IL count.³

Included Criteria

In total, 264 unique articles were identified during the extensive search, with 43 included in the final review. Of the 43 included, researchers stated that 40 were randomized controlled trials (RCTs) and 3 were uncontrolled trials, all including 18,347 patients with rosacea. 

Treatment Methods

The review reported the following results from the 43 included studies:

Adapalene was reported by 1 study in a 0.1% topical formula to be applied once daily. Researchers found a mean 83.5% reduction in ILs among 27 patients, representing a 1.75-fold reduction over placebo or vehicles.

Two formulations of azelaic acid were investigated by 7 different studies among 1999 patients: 15% and 20%. The 20% formulation led to a 74.7% reduction in inflammatory lesions (ILs), while the 15% formulation resulted in a 61.3% reduction. Both were more effective than topical placebo, with reductions of 1.56-fold and 1.28-fold, respectively.

A 5% benzoyl peroxide and 1% clindamycin topical formulation resulted in a 72.7% reduction in ILs among 52 patients, representing a 1.52-fold improvement over placebo.

A study on clarithromycin at 500 mg 3 times daily showed a 71.2% reduction in ILs among 20 patients, achieving a 2.58-fold improvement compared to systemic placebo.

Doxycycline, administered at 40 mg daily, resulted in a 49.5% reduction in ILs among 450 patients throughout 4 studies, which was a 1.79-fold improvement over systemic placebo.

Isotretinoin doses ranged from 10 to 50 mg daily, with an average reduction in ILs of 87.5% in 3 different studies among 221 patients, representing a 3.17-fold reduction over systemic placebo.

A 1% ivermectin topical formulation applied once or twice daily led to a 79% reduction in ILs in 6 studies among 2408 patients, providing a 1.65-fold improvement over topical placebo.

A total of 16 studies spanning 2583 patients featured Metronidazole in 0.75% and 1% formulations applied once or twice daily showed a 70.6% and 67.2% reduction in ILs, respectively. The reductions were 1.48-fold and 1.41-fold over topical placebo.

Minocycline, both topical (1.5% and 3%) and oral (20 mg to 45 mg daily), demonstrated varied efficacy. Topical 1.5% reduced ILs by 45.9%, while 3% reduced by 53.2%. Oral doses of 20 mg showed a 53.2% reduction, and higher doses of 40-45 mg led to an 81.6% reduction in ILs.

A 5% permethrin topical formulation applied twice daily achieved a 66.5% reduction in ILs among 39 patients, a 1.39-fold improvement over topical placebo.

A 1% pimecrolimus topical formulation applied twice daily resulted in an 80.3% reduction in ILs among 70 patients, offering a 1.68-fold improvement over topical placebo.

Sarecycline, administered at a once-daily weight-based dose, resulted in an 80% reduction in ILs among 72 patients, a 2.90-fold improvement over systemic placebo.

A topical formulation of sodium sulfacetamide 10% and sulphur 5% resulted in an 80% reduction in ILs among 75 patients, representing a 1.67-fold improvement over topical placebo.

Conclusion

The review found that systemic treatments achieved greater reductions in IL count compared to topical ones; however, they suggested this is mainly due to the greater effectiveness of systemic placebos compared to topical vehicle formulations. Isotretinoin emerged to researchers as the most effective systemic treatment, significantly reducing ILs through its effects on sebum production and pilosebaceous units. Doxycycline was also found to be effective due to its anti-inflammatory properties and modulation of various inflammatory factors.

Among topical treatments, ivermectin showed the greatest reduction in ILs due to its acaricidal and anti-inflammatory effects, though researchers stated it may cause transient exacerbations due to mite death. Metronidazole, azelaic acid, and minocycline were also reported to demonstrate efficacy with different mechanisms. The review stated combination therapies, such as doxycycline and ivermectin, have shown promising results, including faster onset of action.⁴ Given the variability in patient response and the chronic nature of rosacea, researchers suggested further investigation is needed to explore the effectiveness of combination treatments and their impact on disease remission.

References

1. Forton FM, De Maertelaer V. Two consecutive standardized skin surface biopsies: An improved sampling method to evaluate demodex density as a diagnostic tool for rosacea and demodicosis. Acta Derm Venereol. 2017;97(2):242-248. doi:10.2340/00015555-2528
2. Huynh TT. Burden of disease: The psychosocial impact of rosacea on a patient's quality of life. Am Health Drug Benefits. 2013;6(6):348-354.
3. Geng RSQ, Sood S, Hua N, et al. Efficacy of treatments in reducing inflammatory lesion count in rosacea: A systematic review. J Cutan Med Surg. May 28, 2024. doi:10.1177/12034754241253195
4. Schaller M, Kemény L, Havlickova B, et al. A randomized phase 3b/4 study to evaluate concomitant use of topical ivermectin 1% cream and doxycycline 40-mg modified-release capsules, versus topical ivermectin 1% cream and placebo in the treatment of severe rosacea [published correction appears in J Am Acad Dermatol. 2021 May;84(5):1506. doi: 10.1016/j.jaad.2020.01.031]. J Am Acad Dermatol. 2020;82(2):336-343. doi:10.1016/j.jaad.2019.05.063