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Rosacea: Update on Management and Emerging Therapies

Robyn S. Fallen, MD1 and Melinda Gooderham, MD, MSc, FRCPC2

1McMaster University, Hamilton, ON, Canada
2Skin Centre for Dermatology and Skin Laser Clinic, Peterborough, ON, Canada
Article adapted from: Fallen RS, Gooderham M. Rosacea: update on management and emerging therapies.
Skin Therapy Lett. 2012 Nov-Dec;17(10):1-4.

Introduction

Rosacea is a common chronic skin disorder that has significant impact on the self-esteem and quality of life of affected individuals. It is currently understood as an inflammatory condition that occurs in the context of an altered innate immune response, hence, the available topical and systemic therapies function as immunomodulators to restore cutaneous homeostasis. The goals of therapy include reduction of papules, pustules, erythema and physical discomfort with improved quality of life. Standard topical treatments include azelaic acid and metronidazole, although many other agents and regimens have been presented. Subantimicrobial low-dose oral doxycycline is a recently approved therapeutic option for the management of rosacea. Additionally, several emerging therapies are on the horizon.

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Overview of Rosacea

  • Rosacea is a chronic skin disorder characterized by facial erythema, telangiectasia, inflammatory papules and pustules with intermittent episodes of exacerbation and remission.
  • There are four generally accepted clinical subtypes which have been described by the National Rosacea Society: erythematotelangiectatic, papulopustular, phymatous, and ocular.1
    • Two variants, granulomatous and neurogenic, have also been presented.1,2
  • Affecting approximately 10% of the general population, rosacea is more prevalent in women, although impacted men often have more disfiguring skin changes.3
  • Patients often present between 30 and 50 years of age but manifestations can occur throughout the life course.4
  • Up to one-third of patients have a family history of rosacea.
    • There is an increased prevalence among individuals of Northern European descent, supporting an underlying genetic predisposition.3
  • While the etiology of rosacea remains unclear and despite clinical heterogeneity, basic science has developed a possible unified understanding of rosacea as an inflammatory disorder in the context of an altered innate immune response.5
  • It is proposed that environmental changes, which may include UV light exposure, hormone balances and microbe challenges (by pathogens such as Demodex folliculorum), are sensed by pattern recognition receptors of the immune system. Subsequent signaling induced effector molecules such as reactive oxygen species, cytokines, cathelicidin and chemokines may then modify dermal structure through vascular changes, collagen degeneration, lymphohistiocytic infiltration and neutrophil recruitment, which may perpetuate this response.6,7
  • Given this model, it is clear why most current therapies attempt to modulate various points of this inflammatory cascade.

Psychosocial Impact

  • Although the relationship between psychological factors and rosacea remains to be determined, 75% of affected patients report low self-esteem with a significant odds ratio of 4.81 for diagnosed depressive disorder in this population compared to the general population.8
  • The use of validated assessment tools has demonstrated the impact of rosacea on quality of life and the improvement that can occur with treatment.9

Patient Education

  • Once rosacea is diagnosed patients should be reassured of the benign but chronic nature of the condition.
  • Counselling should be directed toward the identification and avoidance of triggers, diligent photoprotection, concealing cosmetics, and proper skin care.3
  • It is also prudent to review medications to identify, and discontinue if possible, those that may exacerbate flushing, such as beta blockers.3

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Treatment Overview

  • Topical pharmacotherapeutic options include azelaic acid, erythromycin, metronidazole or sodium sulfacetamide 10% + sulfur 5%.10
  • As in the management of other dermatological conditions, the choice of vehicle for topical rosacea preparations is also an important consideration.
  • The choice of lotion, cream, gel or foam can influence efficacy, compliance, and tolerability, which is especially relevant for patients who often have heightened skin sensitivity.11
  • 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.10
  • Laser, light-based therapies and surgical interventions may also be warranted in select patient populations.12
  • 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 focuses on approved therapies for the management of the cutaneous manifestations of rosacea.

Topical Metronidazole

  • Topical metronidazole has demonstrated greater efficacy compared with placebo in multiple trials, with both statistically significant and clinically important results.13
  • There is no statistically significant difference between the two concentrations of topical metronidazole (0.75% or 1%). It has also been shown to be effective in maintaining remission.13
    • Topical metronidazole is available in a 0.75% gel, lotion, and cream format for twice daily use and a 1% cream and gel for once daily use.
    • Once daily dosing of 1% metronidazole cream appears to be as effective as twice daily dosing.14
  • A recent systematic review of nine trials demonstrated the efficacy of topical metronidazole versus placebo.15,16
    • A reduction in inflammatory lesions and erythema scores was observed, including improvement in physician’s global evaluation and patient-assessed measures.
    • No benefits were noted for telangiectasia in these studies, however, a study by Tan et al, showed improvement in telangiectasiae scores as well as erythema and inflammatory lesion counts using a 1% metronidazole cream with a sun protection factor of 15.17
  • Given its favourable efficacy and tolerability profile, topical metronidazole will continue to play an important role in the management of rosacea.
  • Metronidazole has also been proposed as the most costeffective topical regimen, which may be an important consideration for some patients.18

Topical Azelaic Acid

  • Azelaic acid (AzA) is a naturally occurring saturated dicarboxylic acid approved for the treatment of mild to moderate rosacea.
  • It can be found in dietary sources (e.g., whole grains), lacks toxicity, is non-teratogenic and non-mutagenic.19
  • It has multiple biologic activities including antiinflammatory, anti-keratinizing and anti-bacterial effects. In rosacea, its therapeutic properties are derived via inhibition of reactive oxygen species produced by neutrophils.20
  • A 15% gel formulation is available for the treatment of rosacea. A 20% cream formulation is approved in the US for acne vulgaris.
  • The 15% gel, although formulated to a lower concentration than the cream, is significantly more bioavailable than the cream because of an optimized aqueous gel vehicle.
  • Patients using AzA had an improvement of 70-80% in their rosacea compared with 50-55% in the placebo group.13
  • AzA 15% gel administered once daily has demonstrated equivalent efficacy to twice daily application, although recommended dosing is twice daily.21
  • Two pivotal phase 3 trials have shown that AzA 15% gel applied twice daily for 12 weeks was superior when compared with the vehicle in the treatment of papulopustular rosacea.22
    • In these studies, a mean reduction in inflammatory lesion counts and improvements in erythema scores were observed in AzA-treated group vs. placebo.
  • There was no improvement in telangiectasia severity in any study of AzA for rosacea.
  • Studies have shown that AzA is a safe and effective treatment for papulopustular rosacea and has a favourable tolerability profile.

Topical Metronidazole versus Azelaic Acid

  • Two studies comparing topical metronidazole and AzA found no statistically significant difference between the treatment groups with respect to patient-assessed outcomes.23,24
  • However, in the split-face comparison clinical trial by Maddin patients favoured the outcome of AzA.25
  • In both the Maddin and Elewski et al trials, the investigators were of the opinion that treatment with AzA was more effective than metronidazole.23,25

Subantimicrobial Low-dose Oral Doxycycline

  • Tetracyclines (pregnancy category D) have numerous antiinflammatory properties thought to be responsible for their efficacy in the management of rosacea.26,27 However, a clear bacterial pathogen has not been implicated in rosacea pathophysiology.28
  • Standard antimicrobial dosing may affect endogenous flora and risks the development of antibiotic resistant strains.
  • Subantimicrobial, low-dose doxycycline 40 mg capsules, formulated as 30 mg immediate-release and 10 mg delayed-release 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.29
  • 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, placebo-controlled, multicenter trials.30
    • Assessed after 16 weeks of therapy, doxycycline 40 mg provided a significantly greater reduction in the total inflammatory lesion count than placebo.
    • The treatment was generally well-tolerated by patients; adverse events (approximately 4% of patients) were of mild to moderate intensity, with headache, nasopharyngitis and gastrointestinal side effects reported most frequently.
    • No photosensitivity was observed, although tetracyclines as a class of medications have been associated with this effect.
  • Combination therapy with doxycycline 40 mg plus either AzA gel 15% or metronidazole gel 1% were also safe, efficacious and well-tolerated.31,32

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Emerging Therapies

Ivermectin Cream

  • Ivermectin cream is a new 1% cream formulation of the acaricidal compound, ivermectin, and is currently under investigation.33
  • One hypothesis for the etiology of rosacea is the presence of Demodex mites in the pilosebaceous unit of affected individuals and although the association is well known, the pathophysiology is yet to be elucidated. Reports have been published on cutaneous demodicidosis responding to oral ivermectin and topical permethrin but data are lacking on the topical application of ivermectin alone.34

Adrenergic Receptor Antagonists: Brimonidine and Oxymetazoline

  • The adrenergic receptor antagonists brimonidine tartrate and oxymetazoline, which have potent vasoconstrictive activity and anti-redness capabilities, are currently found in eye drops for glaucoma and a nasal decongestant spray, respectively.
  • Brimonidine tartrate, an alpha-2 agonist, has been shown in a two part dose-finding, phase 2 study to be safe and efficacious in reducing the erythema of rosacea. A single application of the 0.5% gel reduced erythema between 30 minutes to 12 hours as measured with an objective chromameter.35 No tachyphylaxis, aggravation of symptoms or rebound erythema was observed. The majority of adverse effects were skin-related and mild and transient in nature.
  • Oxymetazoline, a potent alpha-1 and partial alpha-2 receptor agonist, has been shown in case reports to be an effective agent for reducing facial erythema.36 It has been formulated into a cream and is currently in clinical development for the treatment of erythematotelangiectatic rosacea.

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Other Treatments with Limitations in the Evidence

  • Topical sodium sulphacetamide 10% + sulphur 5%
  • Systemic isotretinoin
  • Topical antibiotic + tretinoin
  • Topical benzoyl peroxide 5% + clindamycin 1% gel
  • Pulsed dye laser or intense pulsed light
  • Pimecrolimus 1% cream
  • Oral zinc sulfate

Due to the chronic nature of the condition, patients frustrated with medical therapy may turn to marketed botanicals and herbal remedies in hopes of improved control. Although there is a paucity of data surrounding the effects of these cosmeceuticals, the prudent clinician should be aware of additional products that may be used by patients such as niacinamide, feverfew, turmeric, colloidal oatmeal and quassia extract.37

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Conclusion

The chronic course of rosacea requires early intervention and continuous management to treat visible symptoms, control disease progression, and mitigate psychosocial impact. Disease subtype and patient-specific characteristics (including preferences) will guide therapeutic decisions, which may involve a combination of therapies. Generally, topical therapy is first-line, but in moderate to severe cases, or those with ocular involvement, systemic therapy may be necessary. Patient education regarding the triggers of rosacea, proper skin care, photoprotection, and camouflaging cosmetics are also useful nonpharmacologic strategies.

References

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