Rosacea: Update on Management and Emerging Therapies

Robyn S. Fallen MD; Melinda Gooderham MD, MSc, FRCPC

Disclosures

Skin Therapy Letter. 2012;17(10) 

In This Article

Treatment

Topical pharmacotherapeutic options include azelaic acid, erythromycin, metronidazole or sodium sulfacetamide 10% + sulfur 5%.[11] As in the management of other dermatological conditions, vehicle selection for topical rosacea preparations is an important consideration. The choice of lotion, cream, gel or foam can influence efficacy, compliance, and tolerability, which is especially relevant for these patients who often have heightened skin sensitivity, but is beyond the scope of this review.[12] In patients with moderate to severe papulopustular subtype or ocular involvement, systemic therapy is often required and includes doxycycline, erythromycin, metronidazole, minocycline, tetracycline, or, in select severe cases, low-dose isotretinoin.[11] Laser, light-based therapies and surgical interventions may also be warranted in select patient populations.[13] Recent research has added low-dose doxycycline to the therapeutic armamentarium and two additional treatments, ivermectin and alpha-adrenergic receptor antagonists, hold promise for the future. This article will review the topical and systemic options for the management of cutaneous manifestations of rosacea with a focus on emerging therapies.

Topical Metronidazole

Topical metronidazole has been used in the treatment of rosacea since the 1950s. It has demonstrated greater efficacy compared to placebo in multiple trials with both statistically significant and clinically important results.[14] There is no statistically significant difference between the two concentrations of topical metronidazole (0.75% or 1%) and it has also been shown to be effective in maintaining remission.[14] Among available topical therapies metronidazole has also been proposed as the most costeffective regimen, which may be an important consideration for some patients.[15]

Topical Azelaic Acid

Azelaic acid is a naturally occurring saturated dicarboxylic acid approved for the treatment of mild to moderate rosacea. Patients using azelaic acid showed an improvement of 70-80% in their rosacea compared with 50–55% in the placebo group.[14] Azelaic acid 15% gel administered once daily has demonstrated equivalent efficacy to twice daily application, although the recommended dosing is twice daily.[16]

Metronidazole versus Azelaic Acid

In two studies comparing topical metronidazole and azelaic acid, there was no statistically significant difference between the treatment groups with respect to patient-assessed outcomes.[17,18] However, in the split-face comparison clinical trial by Maddin, patients favored the outcome of azelaic acid.[19] In both the Maddin and Elewski et al trials, the investigators were of the opinion that treatment with azelaic acid was more effective than metronidazole.[17,19]

Subantimicrobial Low-dose Oral Doxycycline

Tetracyclines (pregnancy category D) have been a mainstay of rosacea therapy for more than half a century.[3] However, a clear bacterial pathogen has not been implicated in the pathophysiology of rosacea.[20] Furthermore, standard antimicrobial dosing may affect endogenous flora and risks the development of antibiotic resistant strains. Antibiotic stewardship is advocated in all medical disciplines in hopes of preserving efficacy for the management of bacterial infections.[21] In light of these considerations, tetracyclines also have numerous anti-inflammatory properties thought to be responsible for their efficacy in the management of rosacea. They suppress neutrophil migration and chemotaxis, inhibit angiogenesis and the activation, proliferation and migration of lymphocytes, block production of matrix metalloproteinases (MMPs), and upregulate anti-inflammatory cytokines.[22,23]

Anti-inflammatory, low-dose doxycycline 40 mg capsules, formulated as 30 mg immediate-release and 10 mg delayedrelease beads and dosed once daily, provide a subantimicrobial dose that reduces the inflammatory response without producing drug concentrations required to treat bacterial diseases, thus avoiding concerns regarding selective pressures generating microbial resistance.[24] The efficacy of oral doxycycline 40 mg capsules once daily in the treatment of adults with rosacea was demonstrated in two large, randomized, double-blind, placebocontrolled, multicenter trials. Assessed after 16 weeks of therapy, doxycycline 40 mg provided a significantly greater reduction in the total inflammatory lesion count (primary endpoint) than placebo.[25] Furthermore, doxycycline 40 mg was associated with a rapid onset of action, with a significantly greater decrease in lesion count than placebo by first follow-up at 3 weeks in both studies.[25] Interestingly, maximum anti-inflammatory effects appear to be achieved with doxycycline 40 mg capsules once daily. In a small, randomized, double-blind trial, no additional improvement in rosacea symptoms was achieved with oral doxycycline 100 mg once daily.[26] The treatment was generally well-tolerated by patients; adverse events (experienced by approximately 4% of patients) were of mild to moderate intensity, with headache, nasopharyngitis and gastrointestinal side effects reported most frequently.[25] No photosensitivity was observed, although tetracyclines as a class of medications have been associated with this effect.[25] Doxycycline 40 mg capsules have been demonstrated as safe and effective monotherapy for rosacea in both males and females and in patients of all skin types.[27,28] Furthermore, patientrated measures report improvement in symptoms, reduction in the interference of symptoms with life activities, and satisfaction with treatment.[29] Combination therapy with doxycycline 40 mg plus either azelaic acid gel 15% or metronidazole gel 1% were also safe, efficacious and well-tolerated.[30,31]

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