The characteristic rosacea symptoms often overlap, so drug therapy should be tailored to the individual symptomatology. This is one of the Key Messages of the current ROSCO recommendations. Combination therapies are frequently used in clinical practice and have also often been shown to be superior to monotherapy in various studies, as shown in a recent secondary analysis.
Rosacea is a common chronic inflammatory skin condition that mostly affects adults. According to epidemiological data, about 80% of rosacea patients are over 30 years old [1,2]. Modern therapy for rosacea is based on the phenotype of the disease rather than the individual subtypes. This is one of the key messages of the ROSacea Consensus (ROSCO) Panel in an update of recommendations published in 2020 [1]. This classificatory change is based on the fact that the earlier subtype classification did not sufficiently reflect the manifestations observed in practice, since in reality the symptoms often overlap. Therefore, treatment should be primarily based on the symptoms of the disease. These are primarily persistent erythema, “flushing”, telangiectasia, papules with/without pustules, phymatous changes of the skin, and ocular manifestations [2]. In conjunction with the revision of the classification criteria, the ROSCO panel also adjusted the evidence-based recommendations for first-line therapy. These were summarized in an article published last year in DERMATOLOGIE PRAXIS [3].
In order to expand the treatment spectrum and achieve optimized efficacy, combining different drug substances is a proven strategy. What is the evidence base in this regard? This was one of the questions that van Zuuren et al. [4] in their secondary analysis. The research team came across several randomized trials that had evaluated the use of ivermectin, doxycycline, brimonidine, and metronidazole as sole therapy or in combination with a second agent. These are drugs that are routinely used in Switzerland (Table 1) .
Topical ivermectin plus oral doxycycline.
A study published in 2020 evaluated the combined use of topical ivermectin and oral doxycycline 40 mg with altered drug release. Both substances primarily relieve inflammation. A randomized, investigator-blinded phase IIIb/IV trial evaluated treatment with ivermectin 1% cream plus oral modified-release doxycycline versus ivermectin 1% cream plus placebo in 273 subjects with severe rosacea (IGA 4) [5]. After 23 weeks, both treatment regimens resulted in a reduction in the number of lesions, but combination therapy proved to be more effective (80.3% vs. 73.6%; p=0.032). Moreover, the combined application showed a faster onset of action. As early as week 4, significantly more study participants achieved IGA 0 (11.9% vs 5.1%; p=0.043) and complete (100%) lesion regression (17.8% vs 7.2%; p=0.006). Both treatment groups experienced improvements in erythema, stinging sensations, burning of the skin, and “flushing” and ocular manifestations. And in all study conditions, only a few adverse effects were reported.
Topical brimonidine plus topical ivermectin.
Topical brimonidine, which primarily reduces erythema, and topical ivermectin, which is used to reduce inflammatory lesions, are common treatment options for rosacea. In a randomized-controlled double-blind study of 190 subjects with moderate to severe rosacea (IGA score 3-4 on a scale of 0-4), the combination of brimonidine 0.33% gel in the morning and ivermectin 1% cream in the evening was studied [6]. The first group (n=49) was treated with the combination therapy for 12 weeks, and the second group (n=46) received brimonidine placebo in the morning and ivermectin 1% cream in the evening during the first 4 weeks. Subsequently, this subsample was treated with brimonidine 0.33% gel in the morning and ivermectin 1% cream in the evening for 8 weeks. In the third group (n=95), brimonidine placebo was used in the morning and ivermectin placebo in the evening throughout the 12 weeks.
The results were published in 2017 and showed that more subjects in the first group achieved an IGA score of 0 or 1 compared to the placebo groups (55.8% vs. 36.8%; p=0.007) [6]. The benefits of the combination of brimonidine plus ivermectin emerged as early as week 4 with an IGA success rate of 22.4%. Group 2, which was treated with ivermectin only (without brimonidine) for the first 4 weeks, achieved an IGA success rate of 13% and the placebo group 9.5%. The reduction in erythema and inflammatory lesions, as well as the subjectively perceived improvements reported by patients, support the added value of combined treatment of brimonidine gel plus ivermectin cream compared with monotherapy.
Topical metronidazole plus doxycycline.
In a randomized, double-blinded trial with 72 study participants, the combination of modified-release doxycycline plus topical metronidazole 1% gel (1×/d) was compared with monotherapy of topical metronidazole 1% gel (1×/d) in patients with mild to moderate rosacea [7]. The combined treatment resulted in significantly better reduction of inflammatory lesions compared with monotherapy. This effect was already evident at week 4 and remained significant until week 12 (13.86 vs 8.47 lesions; p=0.002). At week 12, outcomes in terms of IGA scores and erythema were significantly better in the treatment arm with combination therapy.
Similar results were produced by another double-blind, also randomized, study comparing doxycycline 20 mg plus metronidazole 0.75% gel twice daily with metronidazole 0.75% and placebo in 40 rosacea patients over a 16-week period [8]. In summary, the combined treatment strategy was shown to be superior to monotherapy in both studies.
Literature:
- Schaller M, et al: Recommendations for rosacea diagnosis, classification and management: update from the global ROSacea COnsensus 2019 panel. British Journal of Dermatology 2020; 182(5): 1269-1276.
- Reinholz M, et al: Pathogenesis and clinic of rosacea as key for symptom-oriented therapy. JDDG 2016; 14(S6): https://doi.org/10.1111/ddg.13139_g
- Peter M: Rosacea: the new phenotype-based diagnosis has proven its worth. DERMATOLOGY PRACTICE 2020; 30(5): 42-45.
- van Zuuren EJ, et al: Rosacea: New Concepts in Classification and Treatment. Am J Clin Dermatol 2021. https://doi.org/10.1007/s40257-021-00595-7
- Schaller M, 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. J Am Acad Dermatol 2020; 82: 336-343.
- Gold LS, et al: Treatment of rosacea with concomitant use of topical ivermectin 1% Cream and brimonidine 0.33% gel: a randomized, vehicle-controlled study. J Drugs Dermatol 2017; 16: 909-916.
- Fowler JF Jr: Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, usp monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. J Drugs Dermatol 2007; 6: 641-645.
- Sanchez J, et al: A randomized, double-blind, placebo-controlled trial of the combined effect of doxycycline hyclate 20-mg tablets and metronidazole 0.75% topical lotion in the treatment of rosacea. J Am Acad Dermatol 2005; 53: 791-797.
- Swissmedics: Drug Information, www.swissmedicinfo.ch (last accessed 05/18/2021).
DERMATOLOGIE PRAXIS 2021; 31(3): 40-41
