image of silk fabric and dry skin

Robyn S. Fallen1 MD and Melinda Gooderham2 MD, MSc, FRCPC

1McMaster University, Hamilton, ON, Canada
2Skin Centre for Dermatology and Skin Laser Clinic, Peterborough, ON, Canada

ABSTRACT

Rosacea is a common chronic skin disorder that has significant impact on the self-esteem and quality of life of affected individuals. Currently understood as an inflammatory condition that occurs in the context of an altered innate immune response, 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 improvement in quality of life. Standard topical treatments include metronidazole and azelaic acid, although many other agents and regimens have been presented. Subantimicrobial/antiinflammatory dose oral doxycycline was US FDA approved in 2006 for the management of rosacea, but Health Canada clearance was only recently granted for this indication. Furthermore, renewed research interest has led to the development of other emerging therapies including topical ivermectin, brimonidine and oxymetazoline that hold promise for patients suffering from this condition.

Key Words:
erythema, inflammation, rosacea, telangiectasia

Introduction

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

Given that up to a third of patients have a family history of rosacea and the increased prevalence among individuals of Northern European descent, an underlying genetic predisposition may help explain these patterns.3 While the etiology of rosacea remains unclear and despite clinical heterogeneity, basic science has developed a possible unified understanding of the condition 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.

Furthermore, although the intricacies of the relationship between psychological factors and rosacea remains to be elucidated, 75% of affected patients report low self-esteem, with a significant odds ratio of 4.81 for a 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, importantly, the improvement in these psychological indices that can occur with treatment.9

Once rosacea is diagnosed, patients should be reassured of the benign, but chronic, nature of the condition. Counseling should be directed toward the identification and avoidance of triggers, diligent photoprotection, concealing cosmetics and proper skin care.3,10 It is also prudent to review medications to identify, and discontinue if possible, those that may exacerbate flushing such as beta blockers.3

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

Emerging Therapies

Ivermectin cream (CD5024)

An agent currently under investigation is CD5024 1% cream, which is a new topical formulation of the acaricidal compound, ivermectin.32 Although the exact pathophysiology is yet to be elucidated, one well-known hypothesis for the etiology of rosacea is the presence of Demodex mites in the pilosebaceous unit of affected individuals.33 Reports have been published on cutaneous demodicidosis responding to oral ivermectin and topical permethrin, but data is lacking on the topical application of ivermectin alone.34

There are currently three Phase III studies ongoing, one comparing CD5024 1% cream to metronidazole cream 0.75% (ClinicalTrials.gov identifier NCT01493947) and two similar studies comparing CD5024 1% cream to azelaic acid 15% gel with an initial randomized controlled phase for 12 weeks, and a comparator extension phase for 40 weeks (ClinicalTrial.gov identifiers NCT01494467 and NCT01493687).35-37 The projected trial completion date is August 2013.

Adrenergic Receptor Antagonists: Brimonidine and Oxymetazoline

Novel therapies to treat the erythema associated with rosacea are under development and have the potential to fill a void in the arsenal of rosacea therapeutics. 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.38

Brimonidine tartrate, an alpha-2 agonist also known as CD07805/47, has been shown in a two part dose-finding Phase II 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.39 In part B of the study, two dosages (0.18% and 0.5%) of the gel was compared to vehicle over a 4 week period in 269 subjects. No tachyphylaxis, aggravation of symptoms or rebound erythema was observed. The majority of adverse effects were skin-related and mild and transient in nature. The 0.5% gel once daily was significantly more effective according to both patient and clinician assessments (≥ two-grade improvement) and is the dose that has gone forward in Phase III clinical development to confirm safety and efficacy.38 Results of the Phase III randomized controlled trials are anticipated to be released in the fourth quarter of 2012.

Oxymetazoline or AGN-199201, 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.40 It has been formulated into a cream and is currently in clinical development for the treatment of erythematotelangiectatic rosacea (ClinicalTrials.gov identifier NCT 01579084).41

Other Treatments

  • Available for more than 50 years, topical sodium sulphacetamide 10% + sulphur 5% has also been demonstrated to significantly reduce inflammatory lesions and facial erythema compared to vehicle.42 However, the quality of studies evaluating this therapy have been generally poor.14
  • Systemic isotretinoin has also been used off-label in the treatment of patients with severe rosacea. A randomized, double-blind, non-inferiority trial comparing the use of different dosages of oral isotretinoin to both doxycycline or placebo found isotretinoin 0.3 mg/kg to be an effective therapy with a similar safety profile as for the treatment of acne.43
  • Various topical regimens including an antibiotic and tretinoin preparations have been proposed. A recent randomized, doubleblind, placebo-controlled study assessing a combination gel of clindamycin phosphate 1.2% + tretinoin 0.025% found no difference in papule/pustule count, but mild improvement in the telangiectatic component of rosacea was observed.44
  • Although not FDA approved for the management of rosacea, a randomized, double-blind, vehicle-controlled trial has demonstrated the efficacy of once daily topical benzoyl peroxide 5%/clindamycin 1% gel in patients with moderate to severe rosacea.45 Common adverse events include pruritus, burning, and bleaching of hair/clothing.
  • In a randomized, controlled, single-blind, split-face trial of patients with erythematotelangiectatic rosacea, both pulsed dye laser and intense pulsed light treatments were found to have similar efficacy and safety.46,47
  • An open-label uncontrolled trial of the calcineurin inhibitor pimecrolimus 1% cream suggests it is effective and welltolerated for mild to moderate inflammatory rosacea.48 A small, single-centre randomized study found pimecrolimus 1% cream to be as effective as metronidazole 1% cream.49
  • The use of oral zinc sulfate has also been proposed for the management of rosacea. However, a randomized, doubleblind trial of 220 mg zinc sulfate dosed twice daily showed no difference in magnitude of improvement between subjects receiving zinc therapy versus placebo.50
  • 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 products that may be used by patients such as niacinamide, feverfew, turmeric, colloid.al oatmeal and quassia extract.51,52

Conclusion

With the advent of novel therapeutic options for the treatment of rosacea such as subantimicrobial anti-inflammatory dose doxycycline, ivermectin and the alpha-adrenergic receptor antagonists, there is renewed interest in the study of this chronic inflammatory condition. There is ongoing need for well-designed, high-quality studies of widely used treatments for rosacea including isotretinoin, sodium sulphacetamide/sulphur, and light-based therapies, as well as comparative studies, given the emergence of new treatments. Lifestyle interventions such as avoidance measures for triggering factors, the use of sunscreen, dietary changes and patient education are additional areas of needed research. It would be beneficial for outcomes in future trials to be based on validated, standardized scales assessing both efficacy and improvement in quality of life. Where possible, therapeutic decision-making should take into account high-level evidence and be guided by clinical experience, individual patient characteristics and preferences until further evidence is available.

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