¹Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Windsor Clinical Research, Windsor, ON, Canada
³Western University, Schulich School of Medicine, Windsor, ON, Canada

Conflict of interest:
Cindy Kang and Monica Shah have no conflicts of interest to disclose. Jerry Tan has been a consultant, investigator and/or speaker for Almirall, Bausch, Boots/Walgreens, Cipher, Galderma, L’Oréal, Promius, Sun and Vichy. Disclaimers: This manuscript is an original submission. Views expressed in the submitted article are our own and not official positions of our institutions.

Abstract:
The diagnosis and classification of rosacea has been modified to reflect presenting features. On exclusion of differentials, the diagnosis of rosacea is based on the presence of either (1) phymatous changes, or (2) centrofacial persistent erythema. In their absence, diagnosis can be established by presence of any two of: flushing/transient erythema, papules and pustules, telangiectases, or ocular manifestations. Management of rosacea depends on presenting feature(s), their severity, and impact. General management includes gentle skin care, sun protection, and trigger avoidance. Evidence-based treatment recommendations include topical brimonidine and oxymetazoline for persistent erythema; topical azelaic acid, ivermectin, metronidazole, minocycline and oral doxycycline, tetracycline and isotretinoin for papules and pustules; vascular lasers and light devices for telangiectases; and omega-3 fatty acids and cyclosporine ophthalmic emulsion for ocular rosacea. While surgical or laser therapy can be considered for clinically noninflamed phyma, there are no trials on their utility. Combination therapies include topical brimonidine with topical ivermectin, or topical metronidazole with oral doxycycline. Topical metronidazole, topical ivermectin, and topical azelaic acid are appropriate for maintenance therapy. In conclusion, the updated phenotype approach, based on presenting clinical features, is the foundation for current diagnosis, classification, and treatment of rosacea.

Key Words:
alpha-adrenergic agonist, anti-parasitic, antibiotic, diagnosis, dicarboxylic acid, erythema, laser therapy, management, phenotype approach, phyma, retinoids, rosacea, telangiectasia

Table of Content:

1. Introduction
2. Quality of Evidence
3. Diagnosis
4. Evaluation and Differential Diagnosis
5. Associated Comorbidities
6. Management
7. Conclusion

Introduction

Rosacea is a chronic inflammatory dermatosis affecting the centrofacial region (cheeks, chin, nose, and central forehead), with a prevalence of 5.5% of the adult population.¹ While rosacea has been considered to primarily affect fair-skinned individuals, this may be due to difficulty in detecting facial redness in darker skin types. Nevertheless, rosacea patients of Asian, Hispanic, or African ancestry have been described in literature.² Women are more likely to develop rosacea, however, when present in men, the disease tends to be more severe.³ The typical age of onset is after 30 years old;^4,5 however, ocular rosacea can occur as early as 22 months of age.⁶ Pediatric rosacea is rare and is usually associated with a family history of the condition.^6,7 Ocular manifestations of rosacea occur in more than 50% of rosacea patients.⁸

There are several flare triggers in patients with rosacea including temperature changes, heat, cold, exercise, ultraviolet radiation, spicy food, and alcoholic beverages.⁹ Microbes have also been implicated in the pathophysiology of rosacea, including Demodex species, Bacillus oleronius, Staphylococcus epidermidis, Helicobacter pylori, and Bartonella quintana.¹⁰ The immune system, neurogenic inflammation, and vascular hyperreactivity are central to the pathophysiology of rosacea. Specifically, innate immune system activation via toll-like receptor 2 (TLR2), transient receptor potential (TRP) ion channels, and proinflammatory cytokines contribute to clinical manifestations of rosacea.¹¹

Rosacea has a significant impact on the emotional, social, and occupational wellbeing of affected individuals. Due to the altered facial features characterising this disease, patients with rosacea frequently experience stigmatization. Consequently, they can suffer from depression and anxiety and tend to avoid social situations.¹²

The phenotype approach establishes diagnosis and management based on the presenting features of the individual.¹³ While previously classified according to subtypes, each potentially comprising multiple signs and symptoms, this nomenclature should be abandoned as it limits the ability to study, evaluate, and treat individual features.¹³ The phenotype approach more accurately addresses patient features and can facilitate focused treatment on those of greatest severity and impact.¹³ Thus, this review provides an overview of the updated phenotype approach in the diagnosis and management of rosacea.

Quality of Evidence

The PubMed database was searched for systematic reviews, meta-analyses, and guidelines on the diagnosis, classification, and management of rosacea, with a focus on phenotypes. Key words included “rosacea” and “diagnosis” or “classification” or “management” or “guidelines” or “treatment”. There were no limits on age, sex, or nationality or year of publication. Only studies published in English on human subjects were included.

Diagnosis

The diagnosis of rosacea is clinical and based on specific features according to the ROSacea COnsensus expert panel (ROSCO)¹³ and the National Rosacea Society (NRS).¹⁴ On clinical exclusion of other conditions with similar presenting features, the diagnosis of rosacea is established with either: (1) phymatous changes, or (2) centrofacial persistent erythema (Table 1).^13,15 In their absence, diagnosis can be established by the presence of any two of the following major features: flushing/transient erythema, papules and pustules, telangiectases (Table 1), or ocular rosacea (Table 2).^13,15 Minor features, such as burning, stinging, dry sensation of the skin, or edema are not diagnostic of rosacea (Table 1).¹⁵ The diagnosis of rosacea in darker skin types (Fitzpatrick phototypes V and VI) is difficult as erythema and telangiectasia may not be readily visible, and a high level of suspicion based on minor features is required. A less common variant of rosacea is granulomatous rosacea, with multiple brown, yellow, or red cutaneous papules of uniform size. Occasionally, skin biopsy may be useful for diagnostic support.¹³

Table 1: Descriptions of cutaneous rosacea features by consensus

Consensus of an expert panel of 19 dermatologists from Argentina (n = 1), Brazil (n = 1), Canada (n = 1), France (n = 1), Germany (n = 2), India (n = 1), Italy (n = 1), the Netherlands (n = 1), Qatar (n = 1), Singapore (n = 1), South Africa (n = 1), the U.K. (n = 1) and the U.S.A. (n = 6); and two ophthalmologists from Germany (n = 1) and the U.S.A (n = 1). Some panellists abstained when their clinical expertise did not extend to a particular subject.
Reprinted from Schaller M. et al., 2019, Br J Dermatol, 176, p. 1273.¹⁵

Table 2: Descriptions of ocular rosacea features

Note that these are recommendations rather than consensus due to n = 2. Both ophthalmologists voted ‘Agree’ or ‘Strongly agree’ to the descriptions.
Consensus of an expert panel of 19 dermatologists from Argentina (n = 1), Brazil (n = 1), Canada (n = 1), France (n = 1), Germany (n = 2), India (n = 1), Italy (n = 1), the Netherlands (n = 1), Qatar (n = 1), Singapore (n = 1), South Africa (n = 1), the U.K. (n = 1) and the U.S.A. (n = 6); and two ophthalmologists from Germany (n = 1) and the U.S.A (n = 1). Some panellists abstained when their clinical expertise did not extend to a particular subject.
Reprinted from Schaller M. et al., 2019, Br J Dermatol, 176, p. 1274.¹⁵

Evaluation and Differential Diagnosis

Differential diagnoses of rosacea depend on the clinical feature(s) present (Table 3). Examples include contact dermatitis, photodermatitis, seborrheic dermatitis, and systemic lupus erythromatous for facial erythema; perimenopausal flushing, emotional flushing, carcinoid syndrome, and mastocytosis for flushing; and acne vulgaris and folliculitis for papules and pustules.¹⁶ Exclusion of mimics can be established by taking an adequate history, performing a directed physical evaluation for distinguishing features, and further testing as required.

Table 3: Differential diagnoses of rosacea

Information from Asai et al., 2016,¹⁶ Ogé et al., 2015,¹⁹ Scheinfeld et al., 2010,⁵⁵ and Izikson et al., 2006.⁵⁶

Associated Comorbidities

Associations between rosacea and metabolic, cardiovascular, gastrointestinal (GI), neurologic, and psychiatric diseases have been established (Table 4).¹⁷ Some of these share common innate inflammatory elements with rosacea, such as macrophage and macrophage-derived mediators, reactive oxygen species, matrix metalloproteinases, interleukin-1b (IL-1b), and tumor-necrosis-factor (TNF).¹⁸

Table 4: Rosacea and associated comorbidities

CI = confidence interval, N/A = not available, OR = odds ratio, P = probability

Management

The goals of rosacea treatment are to reduce the severity of features and the frequency and intensity of flares.¹³ General management includes routine skin care: gentle cleansers, moisturizers, sun protection, and avoidance of triggers.^16,19 Specific treatments should be targeted at clinical features (Table 5 on pages 7-8). If multiple features are present, combination treatment should be considered.¹⁶ The phenotype approach allows for such feature-based treatment according to the severity and impact of the presentation.²⁰ An updated systematic review of rosacea treatment based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, is outlined below (Table 5).²¹

Table 5: Treatment recommendations and certainty of evidence

CI = confidence interval, Er:YAG = erbium-doped yttrium aluminium garnet, I2 = heterogeneity, IPL = intense pulsed light, MD = mean difference, MR = modified release, N/A = not available, Nd:YAG = neodymium-doped yttrium aluminum garnet, NNTB = number needed to benefit, NNTH = number needed to harm, PDL = pulsed dye laser, P = probability, RCT = randomized controlled trial, RR = relative risk
Information from van Zuuren et al., 2019.²¹

Flushing/Transient Erythema

No randomized controlled trials available.

Persistent Erythema

Evidence to support the efficacy and safety in transient reduction of persistent erythema was derived from two randomized vehicle-controlled trials for topical brimonidine 0.33% gel²² and topical oxymetazoline 1% cream.^23,24 Quality of evidence for efficacy was reported as high-certainty for brimonidine 0.33% gel and moderate-certainty for oxymetazoline 1% cream.²¹ Adverse event frequency was similar to vehicle for both brimonidine²² (moderate-certainty evidence)²¹ and for oxymetazoline^23,24 (moderate-certainty evidence).²¹ In both, there is ongoing concern about the potential risk of worsening erythema with repeated use.^25,26

Papules and Pustules

Dicarboxylic Acids

Topical azelaic acid 15% foam twice daily is a safe and effective treatment for papules and pustules^27,28 (high-certainty evidence)²¹ with an adverse event frequency similar to vehicle^27,28 (moderate-certainty evidence)²¹ according to two randomized vehicle-controlled trials.^27,28

Another randomized controlled trial showed that azelaic acid 15% gel may be more effective in reducing mean nominal lesion count than metronidazole 0.75% gel²⁹ (moderate-certainty evidence).²¹ These differences, however, were not reproducible and were considered to be unimportant.^30,31

Antiparasitics

Topical ivermectin 1% cream once daily is more effective in the treatment of papules and pustules compared to vehicle³² (high-certainty evidence),²¹ and compared to metronidazole 0.75% cream twice daily³³ (moderate-certainty evidence).²¹ Adverse event rates for topical ivermectin were similar compared to vehicle³² (moderate-certainty evidence)²¹ and topical metronidazole.³³

Retinoids

In two randomized controlled trials, low-dose oral isotretinoin 0.25 mg/kg and low-dose oral isotretinoin 0.30 mg/kg were more effective than placebo³⁴ (high-certainty evidence)²¹ and oral doxycycline (100 mg for 14 days, then tapered to 50 mg)³⁵ (moderate-certainty evidence),²¹ respectively. The frequency of adverse events was higher for isotretinoin compared to placebo³⁴ (moderate-certainty evidence),²¹ but similar to oral doxycycline³⁵ (moderate-certainty evidence).²¹

Antibiotics

Several randomized vehicle- or placebo-controlled trials demonstrated the efficacy of topical metronidazole 1% cream,^36-38 topical minocycline 1.5% and 3% foam,³⁹ oral doxycycline 40 mg modified-release (MR),⁴⁰ and oral tetracycline 250 mg twice daily^41,42 in the treatment of papules and pustules. The quality of evidence for efficacy was moderate-certainty for the first three treatments, but low-certainty for oral tetracycline.²¹ Adverse event frequency was similar to vehicle/placebo for topical metronidazole^36-38 (moderate-certainty evidence),²¹ oral doxycycline,⁴⁰ and oral tetracycline,^41,42 but higher than vehicle for topical minocycline39 (moderate-certainty evidence).²¹ Topical clindamycin 1% cream or gel was found to be no more effective than vehicle for any outcome⁴³ (low-to-moderate certainty evidence).²¹ Compared to oral doxycycline 40 mg MR, oral minocycline 100 mg is similarly effective⁴⁴ (moderate-certainty evidence)²¹ with no differences in the rate of adverse events⁴⁴ (low-certainty evidence).²¹ Compared to oral doxycycline 100 mg, oral azithromycin 500 mg three times a week then tapered is similarly effective in reducing lesion counts⁴⁵ (very low-certainty evidence).²¹ Finally, 40 mg MR doxycycline is as effective as 100 mg with fewer side effects.⁴⁶

Telangiectases

There is low-to-moderate certainty evidence that long pulsed dye laser (PDL), neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, and intense pulsed light (IPL) therapy reduce telangiectasia.²¹

Clinically Non-inflamed Phyma

Physical modalities, such as ablative laser surgery using carbon dioxide or erbium-doped yttrium aluminium garnet (Er:YAG) modalities, electrosurgery, or cryosurgery, may improve clinically noninflamed phyma.¹⁶ However, it is difficult to determine their effectiveness due to the lack of evaluation by randomized controlled trials.^16,21

Clinically Inflamed Phyma

While there are no randomized controlled trials evaluating the efficacy of treatments for clinically inflamed phyma, oral doxycycline or oral isotretinoin are still recommended.^16,21

Ocular Rosacea

One randomized placebo-controlled trial supported omega-3 fatty acids (180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid) one capsule twice daily⁴⁷ (moderate-certainty evidence)²¹ in the treatment of ocular rosacea. Another randomized controlled trial supported cyclosporine ophthalmic emulsion 0.05% twice daily versus artificial tears⁴⁸ (low-certainty evidence)²¹ and versus oral doxycycline 100 mg twice daily for the first month followed by 2 months once daily⁴⁹ (low-certainty evidence).²¹ For the cyclosporine ophthalmic emulsion, there were no differences in the rate of adverse events compared to artificial tears (low-certainty evidence).²¹ For severe ocular rosacea or when there is diagnostic uncertainty, referral to an ophthalmologist should be arranged.²¹

Combination Therapies

Treatment combinations may address several different clinical features of rosacea. For example, compared to vehicle, topical brimonidine 0.33% gel with topical ivermectin 1% cream can effectively reduce both erythema and papules and pustules.⁵⁰ Compared to metronidazole 1% gel alone, metronidazole 1% gel with oral doxycycline 40 mg MR can reduce lesion counts to a greater extent.⁵¹

Finally, randomized controlled trials reported no difference in efficacy between oral minocycline 45 mg with or without topical azelaic acid 15% gel⁵² (moderate-certainty evidence)²¹ or between topical clindamycin phosphate 1.2% with tretinoin 0.025% gel compared to placebo⁵³ (moderate-certainty evidence).²¹ However, in the latter, there was a higher rate of adverse events in the topical clindamycin/tretinoin group compared to placebo (moderate-certainty evidence).²¹

Maintenance Therapies

Topical metronidazole 0.75% gel, ivermectin 1% cream, and azelaic acid 15% gel are reported as effective and safe for maintenance therapy of papules and pustules.^21,54

Conclusion

The diagnosis and classification of rosacea has evolved to a phenotype approach to accurately address the clinical features presenting in an individual and to advance epidemiological and clinical trials research.¹³ This review details the rosacea phenotype approach to diagnosis and classification, and summarizes current evidence-based treatment recommendations for individual features. There is no singularly effective treatment for all features of rosacea. There is an unmet need for high quality investigations for treatment of inflamed phyma, flushing/transient erythema, and ocular rosacea.

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Conflicts of Interest:
PJW has no conflicts to disclose. MHB has no conflicts to disclose. NS has been a principal investigator and received research grant from Bayer, and has acted as consultant and/or received honoraria from Allergan, Celgene, Cutera, Cynosure, Eclipse, Endo, EndyMed, Galderma, Nutraceutical Wellness, Venus Concept.

ABSTRACT
Approximately 16 million Americans have rosacea, an inflammatory cutaneous disorder with central facial erythema, papules, pustules, telangiectasia, flushing, and swelling being among the more commonly recognized features. Overexpression of cathelicidin peptide LL-37 has been implicated in the pathophysiology of rosacea. Azelaic acid has been found to inhibit the pathologic expression of cathelicidin, as well as the hyperactive protease activity that cleaves cathelicidin into LL-37. Given these findings, a small prospective, open-label, interventional trial was undertaken to assess the effects of azelaic acid 15% gel on inflammatory lesions of papulopustular rosacea in a real-world setting. Use of azelaic acid was associated with a significant reduction in inflammatory lesions, which persisted beyond the active treatment phase. Overall, azelaic acid 15% gel is an appropriate initial topical therapy for the treatment of moderate facial rosacea. 

Key Words:
atopic dermatitis, biologics, dupilumab, eczema, Th2 related inflammation

Introduction

Rosacea is a common chronic cutaneous disorder that is estimated to affect close to 10% of Americans in the community setting.¹ It is characterized by central facial erythema, papules, pustules, telangiectasia, flushing, and swelling. The precise pathogenesis of rosacea remains unclear. Dysregulation of the innate immune system, overgrowth of commensal skin organisms, and aberrant neurovascular signaling have been implicated in the pathophysiology of rosacea.²

The facial skin of rosacea patients has been documented to exhibit increased baseline expression of cathelicidin antimicrobial peptide, LL-37 (the active form of cathelicidin), and kallikrein 5 (KLK5), the protease responsible for cleaving cathelicidin into LL-37.³ In rosacea skin, KLK5 also cleaves cathelicidin into other abnormal peptide fragments. These forms of LL-37 are pro-inflammatory and stimulate angiogenesis, contributing to the clinical manifestations of rosacea. In addition, increased expression of toll-like receptor 2 (TLR2), a pattern recognition receptor, has been identified.⁴ This may contribute to the enhanced inflammatory responses to exogenous trigger factors seen in rosacea.

Azelaic acid, a naturally occurring, saturated, straight-chained, 9-carbon atom dicarboxylic acid, is used topically for the treatment of papulopustular rosacea (PPR). Azelaic acid has been shown to have anti-inflammatory activity through reduction of the cathelicidin pathway that is upregulated in facial skin of patients with rosacea. In vitro studies performed using murine or human skin showed that azelaic acid directly inhibits KLK5 in cultured keratinocytes, KLK5 gene expression, TLR2 expression, and cathelicidin and LL-37 formation.^5,6 An in vivo study conducted in patients with PPR showed reduction in cathelicidin and KLK5 activity after treatment with azelaic acid 15% gel applied twice daily.⁵Azelaic acid also has known antimicrobial, antioxidant, and anti-keratinization effects.⁷

Clinical trials have shown that azelaic acid 15% gel is an effective and safe first-line topical monotherapy for patients with PPR.⁸ Exposure to azelaic acid 15% gel has been associated with statistically significant reductions in inflammatory lesions of rosacea.⁹ However, there is a lack of data in the literature on the use of azelaic acid 15% gel outside a clinical trial setting, in real-world clinical practice. The objective of this study was, therefore, to assess the effectiveness of azelaic acid 15% gel when used as monotherapy for the treatment of mild to moderate PPR in a real-world setting.

Methods

This prospective, open-label, interventional study enrolled 20 subjects with PPR. Individuals aged 18 years or older with mild to moderate facial rosacea (as classified by Investigator Global Assessment [IGA]) and who had between 2 and 50 inflammatory facial lesions (papules or pustules) were eligible for participation. Patients with moderate or severe rhinophyma, ocular rosacea requiring topical or systemic antibiotics, or a history of hypersensitivity to any component of the gel were excluded. To prevent any carry-over effects of other medications, patients underwent an adequate washout according to drug type. Concomitant use of any treatments with effects in rosacea was prohibited for the duration of the study.

Subjects were instructed to apply azelaic acid 15% gel (Finacea Gel®) topically to the face twice daily for 12 weeks. They were also advised to avoid known rosacea triggers as much as possible. Clinical evaluations were made at baseline, weeks 4 and 12, and at 4 weeks after completion of active treatment (week 16). Effectiveness endpoints included inflammatory lesion counts, the IGA of rosacea severity, and participant’s subjective evaluation of rosacea improvement. Adverse events were also monitored.

Findings

Treatment with azelaic acid 15% gel was associated with a statistically significant reduction in all lesions types, and the reduction in lesions persisted beyond the treatment period. There was a significant decrease in mean total inflammatory lesion count at all study visits compared to baseline. The greatest decrease was observed at week 12, the conclusion of active treatment, with a difference of -3.4 from baseline (P<0.05). The difference in mean lesion count between week 16 and baseline was -2.4. This reduction in lesions 4 weeks after treatment discontinuation remained significant relative to baseline (P<0.05) (Figure 1).

Most subjects perceived a change in their facial skin over the course of azelaic acid treatment. At week 12, 47% of patients self-reported a moderate to significant improvement while 31% reported a mild improvement (Figure 2).

At the baseline visit, the IGA of rosacea was documented as “moderate” or “mild” for the majority of patients. IGA scores improved at each visit, with all visits showing a significant improvement when compared to the IGA at baseline (P<0.05). By week 16, the majority of IGA scores had become ratings of “almost clear” or “mild” (Figure 3).

Overall, azelaic acid 15% gel was safe and well-tolerated. Adverse events were limited to mild itching and stinging that did not require a disruption of treatment or any additional intervention. No subjects discontinued participation in the study for any reason.

Discussion

Data regarding the effectiveness of therapeutics is typically derived from rigorously administered, randomized, controlled phase 3 trials for FDA approval. While these studies are essential to document the efficacy of topical drugs, it is not always possible to predict the therapeutic benefits of a topical treatment used in the real-world setting.

Azelaic acid 15% gel resulted in a significant reduction in inflammatory lesion counts after 4 weeks of treatment in this study, and IGA scores showed clear improvement in the majority of patients. The effectiveness of azelaic acid 15% gel increases as treatment duration increases. Most patients reported that they had experienced improvement, with none reporting worsening of their condition since the start of the study.

The main limitations of this study were the small sample size, the short study duration, and a single center trial. Further investigations will be needed to observe the long-term efficacy and safety of azelaic acid 15% gel. Additional work is needed to determine patient preference and changes in quality of life associated with use of azelaic acid 15% gel. Future directions may also include real-world effectiveness of azelaic acid 15% gel applied once daily and when used in combination with other agents such as metronidazole.

Conclusion

This study confirms the benefits of azelaic acid 15% gel for the management of mild to moderate PPR in a real-world setting. Treatment with azelaic acid 15% gel applied twice daily to the face was associated with a significant reduction in inflammatory lesions and elicited an effect that persisted beyond the active treatment phase.

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Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Conflicts of Interest:
CZ has no conflicts to disclose.

ABSTRACT
A triad approach to the treatment of acne and rosacea has been recommended. This integrated management approach includes patient education, selection of therapeutic agents, and initiation of an appropriate skin care regime. Proper skin care in patients undergoing treatment of both acne and rosacea includes use of products formulated for sensitive skin that cleanse, moisturize and photoprotect the skin. Both acne and rosacea are associated with epidermal barrier dysfunction, which can be mitigated by suitable skin care practices. Appropriate skin care recommendations for patients with acne and rosacea will be discussed.

Key Words:
acne, emollients, rosacea, photoprotection, skin barrier dysfunction, sunscreen, topical, transepidermal water loss

Acne

Acne vulgaris is the most common skin disease seen in dermatology office practice. Optimal management includes, in addition to selection of an appropriate therapeutic regimen, patient education and integration of proper skin care. Providing instructions on skin care and cosmetics to female acne patients improves quality of life compared to patients to whom no instructions are given.¹

Acne is associated with impaired epidermal barrier function.² Decreased stratum corneum hydration and reduced free sphingosine and total ceramide, indicative of an impaired stratum corneum intercellular lipid membrane, has been demonstrated in patients with acne. Although sebum excretion is increased in acne patients, alteration in the lipid composition of acne skin may further impair barrier function. Moreover, medications used to treat acne can alter stratum corneum integrity and function. An increase in transepidermal water loss has been shown with use of benzoyl peroxide, likely due to damage to the stratum corneum.³ Treatment with topical retinoids results in enhanced desquamation, reducing stratum corneum thickness and function. Use of appropriate skin care products in patients being treated for acne has been shown to increase adherence to pharmacological treatment and improve treatment outcomes.⁴

Cleansing

Although the majority of acne patients believe that suboptimal skin care and dirt on the skin contribute to acne,⁵ there are little scientific data to guide our recommendations regarding cleansing of acne prone skin.

The optimal frequency of cleansing is unclear, but most dermatologists recommend twice daily washing with a mild cleanser. One small study of males with mild to moderate acne compared the effect of face washing with a gentle cleanser once, twice or four times daily on acne severity.⁶ Although no statistically significant differences were noted between the groups, significant improvement in both open comedones and total inflammatory lesions were seen in the group washing twice daily. Worsening of acne was observed in the study group who washed once a day, whereas washing four times daily did not adversely affect acne severity.

Although more frequent facial cleansing may not aggravate acne, aggressive scrubbing of the involved areas should be avoided to prevent irritation and trauma to underlying comedones, leading to increased inflammation.

Moisturizing

As acne prone skin is associated with epidermal barrier dysfunction which can be aggravated by acne medications, regular use of an emollient is an importance part of acne therapy. Use of a noncomedogenic and nonacnegenic moisturizer is typically recommended. However, due to difficulties in testing for both comedogenicity and acnegenicity, including variability in individual patient susceptibility to acne formation, ensuring that a product will not trigger acne in a particular patient can be difficult.⁷

Sun Protection

Sun protection should also be recommended to acne patients.⁸ A systemic review found no convincing evidence that natural sunlight improves acne, although such studies are inherently difficult to conduct.⁹ Several oral acne treatments, including doxycycline and isotretinoin, are potentially photosensitizing.¹⁰ The US Food and Drug Administration official labelling for medications containing benzoyl peroxide and topical retinoids advises sun avoidance,^11,12 although no effect on ultraviolet Binduced erythema was shown with use of either benzoyl peroxide or adapalene in one study¹³. In addition to providing sun protection, the emollient component of the sunscreen may improve epidermal barrier function. Finally, sun protective measures may prevent or minimize postinflammatory hyperpigmentation, particularly in patients with higher skin types.¹⁴

Rosacea

TAs is the case with acne, proper skin care is an important component of the management of rosacea. A triad approach to rosacea care has been suggested, which includes treatment, patient education regarding triggers, and advice as to appropriate skin care and cosmetics.¹⁵ In a questionnaire sent to over 7000 individuals registered in the Canadian Rosacea Awareness Program, respondents expressed a strong interest in receiving more information on skin care, makeup and psychological aspects of rosacea.¹⁶

The involved skin of rosacea has been shown to exhibit increased transepidermal water loss due to impaired epidermal barrier function.¹⁷ Rosacea prone skin is also hyper-reactive; cutaneous insult results in prolonged vasodilation, exhibited clinically as facial erythema. Furthermore, the presence of an impaired stratum corneum barrier increases the irritancy of skin care products by enhancing penetration into the skin. Hence, skin care practices that optimize barrier function should be recommended.

Cleansing

Although skin cleansing is an important component of general skin care, surfactants contained in skin cleansers can weaken epidermal barrier function by disrupting proteins and lipids in the stratum corneum.¹⁸ Given the fact that patients with rosacea have impaired barrier function and a higher susceptibility to irritants, including sodium lauryl sulphate, mild cleansing is important.

The type of surfactant in the cleanser as well as its hydrogen ion concentration (pH) are major factors contributing to the irritant potential of a cleanser.¹⁸ Mild cleansers include synthetic detergents (syndets) and lipid-free cleansers. Syndet liquid cleansers or bars contain synthetic detergents and less than 10% soap. They have a favorable pH (5.5-7) and provide effective cleansing with less irritation potential than true soaps. Lipid-free cleansers have a neutral or slightly acidic pH. They are effective cleansers that leave a moisturizing film on the skin but do not lather.

Studies have shown benefits of mild cleansing in patients with rosacea. In a 4-week randomized, double-blind study of 70 patients with moderate rosacea who were using metronidazole 1% gel, subjects were instructed to use either a soap bar or a mild syndet bar. Use of the syndet cleanser reduced dryness, burning, stinging and itching compared to use of the soap bar.¹⁹

In addition to recommending an appropriate cleanser, physicians should advise rosacea patients to wash with lukewarm water, as hot water causes vasodilation and increased facial erythema. Mechanical trauma to the skin should also be minimized, including avoidance of granular exfoliants.

Astringents and toners, which are typically applied after cleansing, should likewise be avoided, as they tend to increase erythema and remove desirable oil from the skin.

Moisturizing

Use of appropriate moisturizers has several potential benefits in the management of rosacea. As rosacea skin has been shown to have increased transepidermal water loss, use of an emollient may improve barrier function and reduce dryness. Improved barrier function may also lead to reduced skin sensitivity and improved tolerance of topical medications.²⁰

Regarding choice of emollient, those containing potential irritants such as urea, glycolic acid, lactic acid, menthol and camphor should be avoided. Although the barrier dysfunction associated with rosacea may potentially increase allergenicity of skin care products, minimal data is available on the prevalence of contact allergy in rosacea patients.²¹ However, as fragrances can cause both irritant and allergic reactions, fragrance-free products should be recommended. Cream type moisturizers are generally preferred over thin lotions and gels.

Sun Protection

Daily sun protection is an important component of rosacea management. Sun exposure is a common trigger of acute flares of rosacea, and chronic photodamage may also contribute to the pathogenesis of rosacea.²² Acute ultraviolet light may aggravate rosacea by stimulating proinflammatory peptide production, reducing cutaneous antioxidant reserves, and increasing production of reactive oxygen species.²³ However, finding a welltolerated sunscreen can be difficult for rosacea patients. Selecting a cream based product containing an inorganic ultraviolet light filter and a silicone derivative, such as dimethicone orcyclomethicone, may reduce the likelihood of irritation.

Conclusion

Optimal management of both acne and rosacea includes initiation of an appropriate skin care regimen. This entails providing patients with advice regarding appropriate cleansing, moisturizing, and photoprotecting of the affected areas. Providing recommendations regarding skin care has been shown to improve quality of life in female acne patients and to be an unmet need in patients with rosacea. Integration of appropriate skin care in this patient population will improve barrier dysfunction and tolerability of prescribed therapy, leading to improved adherence and better treatment outcomes.

References

1. Matsuoka Y, Yoneda K, Sadahira C, et al. Effects of skin care and makeup under instructions from dermatologists on the quality of life of female patients with acne vulgaris. J Dermatol. 2006 Nov;33(11):745-52.
2. Thiboutot D, Del Rosso JQ. Acne vulgaris and the epidermal barrier. J Clin Aesthet Dermatol. 2013 Feb;6(2):18-24.
3. Weber SU, Thiele JJ, Han N, et al. Topical alpha-tocotrienol supplementation inhibits lipid peroxidation but fails to mitigate increased transepidermal water loss after benzoyl peroxide treatment of human skin. Free Radic Biol Med. 2003 Jan;34(2):170-6.
4. De Lucas R, Moreno-Arias G, Perez-Lopez M, et al. Adherence to drug treatments and adjuvant barrier repair therapies are key factors for clinical improvement in mild to moderate acne: the ACTUO observational prospective multicenter cohort trial in 643 patients. BMC Dermatol. 2015 Sept;15:17.
5. Tan JK, Vasey K, Fung KY. Beliefs and perceptions of patients with acne. J Am Acad Dermatol. 2001 Mar;44(3):439-45.
6. Choi JM, Lew VK, Kimball AB. A single-blinded, randomized, controlled clinical trial evaluating the effect of face washing on acne vulgaris. Pediatr Dermatol. 2006 Sept-Oct;23(5):421-7.
7. Draelos ZD. Cosmetics in acne and rosacea. Semin Cutan Med Surg. 2001 Sept;20(3):209-14.
8. Bowe WP, Kircik LH. The importance of protoprotection and moisturization in treating acne vulgaris. J Drugs Dermatol. 2014 Aug;13(suppl 7):s89-s94.
9. Magin P, Pond D, Smith W, et al. A systemic review of the evidence for ‘myths and misconceptions’ in acne management: diet, face-washing and sunlight. Fam Pract. 2005 Feb;22(1):62-70.
10. Drucker AM, Rosen CF. Drug-induced protosensitivity: culprit drugs, management and prevention. Drug Saf. 2011 Oct; 34(10):821-37.
11. Acanya® (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/2.5%, for topical use [Prescribing information]; revised February 2014. Valeant Pharmaceuticals, Bridgewater, NJ. Available at: http://www.acanyagel.com/ AcanyaPumpPI_FINAL.pdf. Accessed March 20, 2017.
12. Tazorac® (tazarotene) cream, 0.05% and 0.1%, for topical use [Prescribing information]; revised December 2013. Allergan, Inc., Irvine, CA. Available at: https://www.allergan.com/assets/pdf/tazorac_cream_pi. Accessed March 20, 2017.
13. Cetiner S, Ilknur T, Ozkan S. Phototoxic effects of topical azelaic acid, benzoyl peroxide and adapalene were not detected when applied immediately before UVB to normal skin. Eur J Dermatol. 2004 Jul-Aug;14(4):235-7.
14. Molinar VE, Taylor SC, Panya AG. What’s new in objective assessment and treatment of facial hyperpigmentation? Dermatol Clin. 2014 Apr;32(2):123-35.
15. Elewski BE, Draelos Z, Dreno B, et al. Rosacea-global diversity and optimized outcome: proposed international consensus from the rosacea international expert group. J Eur Acad Dermatol Venereol. 2011 Feb;25(2):188-200.
16. Shear NH, Levine C. Needs survey of Canadian rosacea patients. J Cutan Med Surg. 1999 Apr;3(4):178-81.
17. Dirschka T, Tronnier H, Folster-Holst R. Epithelial barrier function and atopic diathesis in rosacea and perioral dermatitis. Br J Dermatol. 2004 Jun;150(6):1136-41.
18. Farris PK. Skin care based on science: improving outcomes in rosacea. Cosmetic Dermatol. 2012 Feb;25(2):72-8.
19. Subramanyan K, Johnson AW. Role of mild cleansing in the management of sensitive skin. Poster presented at the American Academy of Dermatology 61st Annual Meeting. San Francisco, CA, Mar 21-16, 2003.
20. Del Rosso JQ. The use of moisturizers as an integral component of topical therapy for rosacea: clinical results based on the assessment of skin characteristics study. Cutis. 2009 Aug;84(2):72-6.
21. Jappe U, Schafer T, Schnuch A, et al. Contact allergy in patients with rosacea: a clinic-based, prospective epidemiological study. J Eur Acad Dermatol Venereol. 2008 Nov;22(10):1208-14.
22. Del Rosso JQ. Adjunctive skin care in the management of rosacea: cleansers, moisturizers, and photoprotectants. Cutis. 2005 Mar;75(Suppl 3):17-21.
23. Del Rosso JQ. Advances in understanding and managing rosacea: part 1: connecting the dots between pathophysiological mechanisms and common clinical features of rosacea with emphasis on vascular changes and facial erythema. J Clin Aesthet Dermatol. 2012 Mar;5(3):16-25.

¹Wayne State University, Detroit, MI, USA
²Mediprobe Research Inc., London, ON, Canada
³Department of Medicine, University of Toronto School of Medicine, Toronto, ON, Canada
⁴Henry Ford Medical Center, Department of Dermatology, Detroit, MI, USA

ABSTRACT
The etiology of papulopustular rosacea (PPR) is not well understood yet appears to involve both the innate and adaptive immune response in addition to possible infestation with Demodex mites. Current treatments for PPR consist mainly of antibiotics. Ivermectin cream 1%, a new topical treatment for PPR, possesses both anti-inflammatory and anti-parasitic properties. After 12 weeks of treatment, subjects treated with ivermectin cream 1% had significantly greater reductions in PPR symptoms and enhanced diseaserelated quality of life improvements compared to subjects who received vehicle. Furthermore, PPR symptoms continued to improve with prolonged treatment (40 weeks). Ivermectin cream 1% offers a multi-pronged approach to combat the complex pathophysiology of rosacea.

Key Words:
anti-parasitic, avermectin, Demodex, erythema, inflammation, insecticide, papulopustular rosacea, Rosiver®, Soolantra®,
topical ivermectin

Introduction

Rosacea is a chronic inflammatory condition affecting the central facial skin of the cheeks, nose, chin and forehead. Rosacea typically affects females approximately 30 years of age and increases in severity throughout the lifespan.¹ The exact cause of rosacea is unknown and its pathogenesis is not well understood.^2,3 Innate and adaptive immune responses, vascular abnormalities, dermal microorganism imbalances, and environmental factors may interact to produce chronic inflammation and the development of fibrosis.² Four subtypes of rosacea have been identified: 1) erythematotelangiectatic rosacea, 2) papulopustular rosacea (PPR), 3) phymatous rosacea, and 4) ocular rosacea²; yet, whether these represent a distinct variation or a continuum of disease severity remains a matter of debate.² PPR, previously known as acne rosacea, is characterized by erythema, telangiectasia, papules, pustules, edema, and sometimes pain, stinging or burning.⁴ Patients report that symptoms are a cause of low self-esteem, as they are a source of shame, embarrassment, and physical discomfort.⁵ Treatment is strongly encouraged to moderate the detrimental effect on patient quality of life (QoL) and to prevent the condition from worsening. Few therapeutic alternatives exist for the treatment of PPR. There is some evidence supporting the efficacy of azelaic acid, topical metronidazole and sub-antimicrobial dose doxycycline in the treatment of moderate to severe rosacea, although it remains unclear which agent is most effective.⁶

Ivermectin is derived from avermectin, a class of broadspectrum anti-parasitic agents isolated from the fermentation of Streptomyces avermitilis.⁷ Ivermectin possesses both antiparasitic and anti-inflammatory properties and has been shown to reduce the number of Demodex mites in demodicidosis and blepharitis and to inhibit the production of lipopolysaccharide inflammatory cytokines, such as tumor necrosis factor-alpha and interlukin (IL)-1b, while upregulating the production of the anti-inflammatory cytokine IL-10.⁸ Because PPR is recognized as an inflammatory condition whose pathogenesis may involve parasitic infestation with Demodex mites, vehicle-controlled and active comparator trials were undertaken to evaluate the efficacy and safety of topical ivermectin 1% cream in the treatment of PPR.

Pivotal Phase 3 Studies

Two pivotal phase 3 trials assessed the efficacy and safety of ivermectin cream 1% for moderate to severe PPR.⁹ These trials were part of a larger study comprised of a second long-term active comparator trial10 and a 4 week follow-up safety study. The pivotal phase 3 studies were identically designed multicenter, randomized, double-blind, vehicle-controlled trials that enrolled participants aged 18 years or older with moderate to severe PPR and 15-70 inflammatory facial lesions.⁹ Subjects were randomized in a 2:1 ratio to receive either ivermectin 1% cream or vehicle cream for 12 weeks. Participants were instructed to apply their respective cream to the face once daily at bedtime while avoiding the upper and lower eyelids and lips. Participants were also asked to avoid known rosacea triggers, such as specific foods and environments, whenever possible. Evaluations occurred at baseline and at weeks 2, 4, 8 and 12. Co-primary efficacy outcomes for this study included the percentage of participants who achieved an Investigator Global Assessment (IGA) of “clear” or “almost clear” and mean change in inflammatory lesion counts between groups at week 12. Other efficacy outcomes were percent change in inflammatory lesion counts from baseline, subjective assessment of rosacea improvement, and QoL scores on the Dermatology Life Questionnaire Index (DLQI) and the Rosacea Quality of Life Index (RosaQoL™). Adverse events (AEs) and laboratory parameters (hematology and blood chemistry) were also monitored.

Study 1 enrolled 683 participants and Study 2 enrolled 688 participants, the majority of whom were female (Study 1: 68.2% and Study 2: 66.7%) and approximately 50 years of age on average. Participants in Study 1 had an average of 30.9 lesions, while subjects in Study 2 had an average 32.9 inflammatory lesions at baseline. The proportion of participants with an IGA of ‘severe’ was 18% and 24.1% in Studies 1 and 2, respectively. There were no differences in DLQI scores between treatment groups at baseline.

Efficacy results are presented in Table 1. In both studies, a significantly higher percentage of participants who received ivermectin 1% had an IGA of ‘clear’ or ‘almost clear’ at week 12 compared to vehicle (P<0.001) and the significant difference between active and control arms was noted at week 4 (10.9% and 11.8% vs. 5.6% and 5.7%, respectively; P The mean difference in inflammatory lesion counts between ivermectin 1% and vehicle from baseline to week 12 was -8.13 and -8.22 for Studies 1 and 2, respectively (ivermectin 1% vs. vehicle, both P<0.001). There was also a significant difference in the median reduction in lesion count from baseline between the ivermectin 1% and vehicle groups (both studies P<0.001) observed as early as week 2. In both studies, a significantly higher proportion of participants who received ivermectin 1% cream reported improvement of their rosacea symptoms as ‘excellent’ or ‘good’ compared to participants who received vehicle (P<0.001). QoL scores also improved in the ivermectin 1% groups compared to vehicle at the end of 12 weeks. In both studies, a significantly greater proportion of participants in the ivermectin 1% group (approximately 53%) than the vehicle group (approximately 35%) considered their rosacea had no effect on their QoL (P<0.001). Improvement in RosaQoL scores was also significantly higher for ivermectin 1% compared to vehicle (-0.64 ± 0.7 and -0.60 ± 0.6 vs. -0.35 ± 0.5 in both vehicle groups; P=0.001 for Studies 1 and 2).

For Studies 1 and 2, no serious treatment-related AEs were reported in either the ivermectin 1% cream or vehicle groups. Burning (1.8% for ivermectin 1% cream and 2.6% for vehicle) was the most commonly reported treatment-related AE in Study 1, while pruritus and dry skin were the most commonly reported treatment-related AEs in Study 2 (pruritus: 0.7% vs. 0% and dry skin: 0.7% vs. 0.9% for ivermectin 1% cream vs. vehicle). Furthermore, treatment-related AEs with active drug were less than with vehicle alone. Laboratory tests showed no clinically significant abnormalities.

Ivermectin 1% Cream vs. Azelaic Acid 15% Gel

Ivermectin 1% cream was then evaluated against azelaic acid 15% gel in a 40 week extension study.¹⁰ In this continuation of the pivotal phase 3 trials, participants with PPR originally assigned to ivermectin 1% cream once daily in the 12-week study continued to be treated as such and participants initially randomized to vehicle were switched to azelaic acid 15% gel twice daily for 40 weeks. Efficacy was assessed at 4 week intervals using the IGA. Safety assessments were comprised of documentation of AEs, tolerability signs and symptoms, and laboratory tests.

Six hundred and twenty-two and 683 participants enrolled in the 40-week extension studies (see previous section for participant demographics). The efficacy of ivermectin 1% cream increased over time as IGA scores of ‘clear’ and ‘almost clear’ increased from 38.4% to 71.1% by the end of Study 1 and from 40.1% to 76% by the end of Study 2; 59.4% and 57.9% of participants who received azelaic acid had an IGA of ‘clear’ or ‘almost clear’ by the end of Studies 1 and 2, respectively. No statistical comparisons were made because of the differing treatments lengths between the ivermectin 1% and azelaic acid 15% groups. Furthermore, because the ivermectin group had already been treated with ivermectin for 3 months, while the azaleic acid group had previously received vehicle, baseline factors may not have been comparable between groups.

The incidence of treatment-related AEs in the ivermectin 1% cream and azelaic acid 15% gel groups was 1.9% vs. 6.7% and 2.1% vs. 5.8% in Studies 1 and 2, respectively. No severe or serious AEs were deemed related to ivermectin 1% cream in Studies 1 or 2 and no serious AEs were considered related to azelaic acid 15% gel in either study; however, 1 severe case of skin irritation was considered related to azelaic acid in Study 2. In Study 1, 4 participants in the azelaic acid group and 5 in the ivermectin group discontinued the study as a result of AEs. In Study 2, 5 participants in the azelaic acid group and 3 in the ivermectin group discontinued the study due to AEs. None of the AEs in either study were considered related to ivermectin 1% cream; however, in the azaleic acid group, 3 AEs in Study 1 and 4 AEs in Study 2 were considered related to azaleic acid (Study 1: skin irritation, eye and skin irritation, and skin pain and burning; Study 2: skin irritation, skin burning, skin discomfort, and skin burning and pruritus).

Ivermectin 1% Cream vs. Metronidazole 0.75% Cream

Another phase 3, investigator-blinded, randomized trial conducted in Europe explored the efficacy and safety of ivermectin 1% cream compared to metronidazole 0.75% cream for the treatment of moderate to severe PPR (Table 2).¹ Nine-hundred and sixty-two participants age 18 years or older with moderate or severe PPR and presenting with 15-70 facial lesions were randomized 1:1 to receive either ivermectin 1% cream (n=478) once daily or metronidazole 0.75% gel (n=484) twice daily for 16 weeks. Treatments were applied to the entire face, avoiding the upper and lower eyelids and lips. Participants were also asked to avoid known rosacea triggers. Study visits were at baseline and at weeks 3, 6, 9, 12 and 16. Efficacy endpoints included inflammatory lesion counts, the IGA, participants’ subjective evaluation of rosacea improvement, and the DLQI. The safety evaluation consisted of AE assessments over the course of the study, as well as local tolerance and laboratory parameters.

At baseline, the majority of participants had moderate rosacea (16.7% severe) with an average 32.5 inflammatory lesions. Participants had a mean age of 52 years and were primarily female (65.2%). In terms of efficacy at week 16, ivermectin was significantly more effective than metronidazole 0.75% cream in reducing the percentage of inflammatory lesions (83% vs. 73.7%; P<0.001) with a significant difference between the two treatments observed at week 3. The IGA of disease severity was also significantly better for ivermectin 1% cream compared to metronidazole 0.75%, with 84.9% of the ivermectin 1% cream and 75.4% of the metronidazole 0.75% cream groups rated as ‘clear’ or ‘almost clear’ at week 16 (P<0.001), with the greatest difference in IGA noted at week 12. Approximately 86% of the ivermectin group rated their global improvement as ‘excellent’ or ‘good’ compared to 74.8% in the metronidazole 0.75% group. Although the DLQI scores were similar between treatment groups at baseline (6.93 and 6.05 for ivermectin and metronidazole, respectively), participants treated with ivermectin 1% cream showed a greater improvement in QoL as indicated by a reduction in their DLQI scores (-5.18 vs. -3.92; P<0.01).

A similarly low proportion of participants experienced a treatment-related AE (1.9% in the ivermectin 1% cream group and 2.5% in the metronidazole 0.75% group). The most common treatment-related AE was skin irritation experienced by 3 and 4 participants in the ivermectin 1% cream and metronidazole 0.75% cream groups, respectively. Three participants in the ivermectin 1% cream group discontinued the study because of skin irritation and hypersensitivity, while 10 participants in the metronidazole 0.75% cream group discontinued the study due to skin irritation, allergic dermatitis, aggravation of rosacea, erythema, pruritus and feeling hot. Worsening of local tolerance parameters from baseline was more pronounced in
the metronidazole 0.75% group than the ivermectin 1% cream group for stinging/burning (15.5% vs. 11.1%), dryness (12.8% vs. 10%), and itching (11.4% vs. 8.8%). No clinically significant abnormalities in laboratory parameters were found.

Discussion

Ivermectin 1% cream is markedly more effective than vehicle in reducing inflammatory lesions of rosacea as it results in a significant reduction in lesion counts after only 2 weeks of treatment and produces substantially greater improvements in IGA ratings of ‘clear’ or ‘almost clear’ as early as week 4.⁹ The efficacy of ivermectin 1% cream increases with prolonged treatment as evidenced in the 40 week trials.¹⁰ Also, when compared to the standard treatment for PPR, metronidazole 0.75% cream, topical ivermectin was markedly superior to metronidazole in terms of reducing inflammatory lesions and IGA ratings.¹ Ivermectin 1% cream had a significantly greater positive impact on patient QoL compared to vehicle or metronidazole 0.75%.^1,9 Ivermectin 1% cream was well-tolerated and demonstrated a favorable safety profile across phase 3 studies, with skin irritation being the most common treatmentrelated AE.

In phase 3 trials, ivermectin 1% cream produced greater objective and subjective outcomes and improvements in disease-specific QoL over vehicle and an active comparator. Topical ivermectin represents a novel approach to the treatment of PPR that appears to confer superior efficacy and tolerability as compared to current treatment options, while offering the added convenience of once daily dosing. Since ivermectin possesses both anti-parasitic and anti-inflammatory properties, its effectiveness in treating PPR may be attributed to its ability to combat several pathogenic factors linked to the condition. Further studies are needed to elucidate the contribution of the anti-parasitic versus the antiinflammatory modes of action of ivermectin.

References

1. Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2015 Apr;172(4):1103-10.
2. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004 Sep;51(3):327-41.
3. Diamantis S, Waldorf HA. Rosacea: clinical presentation and pathophysiology. J Drugs Dermatol. 2006 Jan;5(1):8-12.
4. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013 Dec;69(6 Suppl 1): S15-26.
5. van der Linden MM, van Rappard DC, Daams JG, et al. Health-related quality of life in patients with cutaneous rosacea: a systematic review. Acta Derm Venereol. 2015 Apr 15;95(4):395-400.
6. van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011 Oct;165(4):760-81.
7. Merck & Co. Inc. Stromectal (ivermectin) tablets [Internet]. 2010 [cited 2015 Feb 20].
8. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogenactivated protein kinase activation pathway. Fundam Clin Pharmacol. 2009 Aug;23(4):449-55.
9. Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014 Mar;13(3):316-23.
10. Stein Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled,investigator-blinded trials. J Drugs Dermatol. 2014 Nov;13(11):1380-6.

¹Faculty of Medicine, University of Alberta, Edmonton, AB, Canada
²Division of Dermatology & Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, AB, Canada
³Toronto Dermatology Centre, Toronto, ON, Canada

ABSTRACT

Rosacea is a common, chronic cutaneous condition that affects the face. Two topicals and one oral medication are currently approved for the treatment of rosacea, including azelaic acid, metronidazole, and sub-antimicrobial dose of doxycycline. Identification of subtypes can help guide treatment strategies. It is essential for psychosocial implications of rosacea to be considered and conservative management, such as nonpharmacologic routine skin care, must form an important part of the overall care. Recently, new insights into the pathophysiology of rosacea have led to the emergence of etiologically oriented treatments. Ivermectin, an acaricidal agent that has been shown to be effective against rosacea refractory to other therapies, is currently in Phase 3 trials. Brimonidine, which was US FDA approved last year and recently sanctioned by Health Canada, has filled an essential therapeutic void in the targeted treatment of diffuse facial erythema.

Key Words:
alpha-2 adrenergic receptor agonists, anti-bacterial agents, antiparasitic agent, erythema, inflammation, rosacea, telangiectasia

Introduction

Rosacea is a common chronic cutaneous condition that primarily affects the central facial area, including the cheeks, nose, eyes, chin, and forehead.¹ Primary cutaneous manifestations include sensitive skin, flushing, persistent erythema, papules, pustules, and telangiectases. Although symptoms may wax and wane in the short-term, rosacea is slowly progressive in the long-term for many patients.²

The National Rosacea Society has classified rosacea into four main subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular.³ Progression from one subtype to another is possible.⁴ Proper identification of subtypes may help guide therapeutic strategies.

Rosacea affects up to 10% of the general population and onset is typically between the ages of 30 and 50 years.⁵ It is especially common in light-skinned individuals of Northern European descent,⁶ with women more frequently affected,⁵ but men are more prone to develop thickening and distorting phymatous skin changes, especially of the nose. Although infrequent, some cases have been diagnosed in darker skin types; however, underdiagnosis and low reported incidence may be attributable to sampling bias and decreased visibility of clinical signs (e.g., erythema and telangiectasias).⁷

The pathophysiology is multifactorial and currently not fully understood. Multiple factors have been proposed to play a role, including vascular abnormalities, gastrointestinal disorders, matrix degeneration, pilosebaceous gland abnormalities, microbial activity, and altered innate immune response.^8,9 A new understanding of rosacea pathogenesis is emerging and alongside it the development of novel agents that target specific pathogenic factors and the symptoms they induce.

Rosacea can create psychosocial burdens, such as embarrassment, anxiety, and low self-esteem that adversely affect quality of life. These negative impacts should be taken into consideration when treating rosacea patients.^10,11 Conservative measures, such as trigger avoidance, proper skin care, and the use of camouflaging cosmetics and photoprotection should also be incorporated in the management plan.¹²

Conventional Therapies

Topical Metronidazole

Metronidazole was first shown to be an effective treatment against rosacea in the 1980s.¹³ Despite being an antibacterial and antiprotozoal agent, metronidazole’s therapeutic benefits in rosacea are mostly derived through its anti-inflammatory and antioxidant effects.¹⁴ Multiple trials have demonstrated that topical metronidazole significantly decreases the number of inflammatory lesions and reduces erythema compared to placebo, is generally well tolerated, has a low incidence of adverse effects, and is effective in maintaining remission.^15-18 Importantly, different formulations of metronidazole have been demonstrated to have similar efficacy, regardless of vehicle type (cream, gel, or lotion) or concentration (0.75% or 1%).^19-21 Once-daily dosing was also confirmed to be similarly effective as twice-daily application.^19,22 In addition, when combined with a sun protection factor 15 sunscreen, metronidazole may reduce the development of facial telangiectasia.²³ Of note, topical metronidazole is a pregnancy category B medication.

Topical Azelaic Acid

Azelaic acid is a naturally occurring dicarboxylic acid approved in the last decade for the treatment of mild to moderate rosacea.²⁴ Mostly applied as a 15% gel or a 20% cream, azelaic acid can attribute its efficacy to anti-inflammatory, anti-keratinizing, and antibacterial effects.²⁴ Multiple trials have demonstrated that azelaic acid is more effective than placebo at reducing the number of inflammatory lesions and degree of erythema.^25-27 The pooled rates of patients showing marked improvements with azelaic acid treatment were 70-80%, compared with 50-55% in the placebo group.²⁸ Azelaic acid also has a relatively low incidence of adverse effects, with burning, stinging, and irritation being the most commonly reported.²⁶ The incidence of side effects is greater with azelaic acid compared with metronidazole, but these effects are generally mild and transient.²⁹ Although the conventional regimen is twice-daily application of azelaic acid, once-daily dosing has been found to be equally effective.³⁰ Further studies are needed to support the use of azelaic acid as a maintenance therapy.²⁸ It is listed as a pregnancy B category medication.

Tetracyclines

Off-label use of oral antibiotics has been recognized for more than 50 years as an effective treatment for rosacea. Therapeutic benefits of tetracyclines in rosacea are primarily a consequence of their anti-inflammatory rather than antibacterial mechanisms, as there is insufficient evidence to support a bacterial infection in disease pathogenesis.³¹ Tetracycline-family antibiotics should particularly be considered in the presence of ocular rosacea, which typically affects greater than 50% of patients with rosacea. Tetracyclines, which are contraindicated in pregnant women, are the most frequently used class of antibiotics and are most effective against inflammatory papules and pustules.

Second-generation tetracyclines, including minocycline and in particular doxycycline, are especially safe and effective oral therapies for rosacea. Unlike the parent tetracycline, they have greater bioavailability,³² rapid onset of action, and can be taken with food, which minimizes gastrointestinal side effects. Additionally, second-generation tetracyclines only require oncedaily dosing, which may improve compliance. Most importantly, they are effective at a sub-antimicrobial dose, thereby avoiding disruption of the endogenous flora and, of global importance, the propagation of antibacterial resistance.³³

Recently, two Phase 3, multicenter, randomized, double-blinded, placebo-controlled clinical trials³³ demonstrated that a subantimicrobial dose of 40 mg doxycycline administered daily to patients with moderate to severe rosacea significantly reduced total inflammatory papule and pustule counts compared with placebo after 16 weeks of treatment, with significant improvements observed at 3 weeks. Prevalence of adverse effects was low and only marginally higher than placebo, with nasopharyngitis (4.8%), diarrhea (4.4%), and headaches (4.4%) being the most commonly reported. There were no cases of photosensitivity or vaginal candidiasis. A separate study demonstrated that the efficacy of 40 mg doxycycline is comparable to that of 100 mg doxycycline in rosacea.³⁴ Subantimicrobial dose of 40 mg doxycycline is approved in both US and Canada for the treatment of rosacea. In contrast, minocycline is not approved for this indication and has five times greater rates of adverse effects compared with doxycycline, with the most commonly reported being hyperpigmentation, hepatotoxicity, and drug-induced lupus.³⁵

Further study is needed to investigate the effectiveness of combination therapy with sub-antimicrobial dose of doxycycline and topical metronidazole, which has been shown in a small-scale study to induce a faster onset of action and be more effective at clearing inflammatory lesions compared with metronidazole alone.³⁶

New and Emerging Therapies

Topical Ivermectin

Several topical acaricidal agents (permethrin 5%, crotamiton 10%, and ivermectin 1%) have been studied for the treatment of rosacea, all of which primarily target Demodex folliculorum and Demodex brevis mites. The potential etiological role of these mites in rosacea has been debated for many years.⁹ There is renewed interest in Demodex mites due to recent studies that demonstrated antigenic proteins produced by a Demodexisolated bacterium (Bacillus oleronius) may aggravate the inflammatory responses in papulopustular and ocular rosacea,³⁷ as well as in erythematotelangiectatic rosacea.³⁸ This pathogenic scenario implicating the bacterium rather than the Demodex mites themselves may explain the efficacy of antibacterial therapies in rosacea.

Numerous case reports^39-41 have been published on the successful treatment of rosacea with topical acaricidal agents refractory to other therapies, however, data from controlled, randomized trials are lacking. Phase 3 randomized clinical trials studying the impact of topical ivermectin 1% cream in rosacea are underway, which compare its efficacy and safety with metronidazole 0.75% cream and azelaic acid 15% gel.^42-44 Results are expected to be available in the near future.

Topical Brimonidine and Oxymetazoline

Diffuse and persistent facial erythema has long been a clinical challenge in rosacea therapy.⁵ One contributing factor to diffuse facial erythema is abnormal cutaneous vasomotor responses, which leads to enlarged superficial facial blood vessels.⁴⁵ Importantly, however, these blood vessels remain responsive to vasoactive stimuli, hence, the growing interest in alpha (α)-2 adrenergic receptor agonists as a therapeutic option to manage the nontransient erythema.⁴⁵

Brimonidine tartrate 0.33% gel, approved by the US FDA in August 2013 and by Health Canada in February 2014, is the latest addition to the treatment armamentarium and the first topical agent approved for the treatment of facial erythema of rosacea. Brimonidine (initially available in prescription eye drops for the treatment of glaucoma) is a highly selective α-2 adrenergic receptor agonist with potent vasoconstrictive activity.⁴⁶

In two Phase 3 randomized, double-blind pivotal trials, topical brimonidine tartrate (BT) gel 0.5% once-daily was found to be significantly more effective than vehicle over a 4 week treatment period.⁴⁷ In the two trials, approximately 24.82% of the patients using BT gel 0.5% (vs. 9.76%; p<0.05) were assessed on day 29 to have at least a two-grade improvement by both clinicians and patients over 12 hours after drug application, with peak improvements observed at 3 and 6 hours. Noticeable improvement (one-grade based on Clinician’s Erythema Assessment and Patient’s Self-Assessment) was observed (28.2% vs. 5.9%; p<0.01) as early as 30 minutes after the first application on day 1. Adverse events were mildly elevated in the active treatment group, but events were mostly skin-related, transient, and mild, with the most commonly reported being worsening of erythema (5.1%), pruritus (5.0%), skin irritation (1.2%), and worsening of rosacea (1.1%). There was no evidence of tachyphylaxis, rebound, or aggravation of telangiectasia or inflammatory lesions. Additionally, recently published data from a 12-month, multicenter, open-label study reported sustained efficacy with no incidence of tachyphylaxis in the long-term treatment of moderate to severe erythema of rosacea.⁴⁸

Phase 2 clinical trial for another promising α-adrenergic receptor agonist, called oxymetazoline, has recently been completed.⁴⁹ Results should be available in the near future.

Other Therapies

Topical sodium sulfacetamide 10% with sulfur 5% has been used for more than 50 years for its clinical efficacy and safety in the treatment of rosacea, although its mechanism of action is not well understood. In an 8-week study, sulfacetamide 10% with sulfur 5% has been shown to significantly reduce inflammatory lesions (78% vs. 36%; p<0.001) and facial erythema (83% vs. 31%; p<0.001) compared to vehicle.⁵⁰ However, studies evaluating this therapy are limited and generally of poor quality.²⁸

Oral isotretinoin can be used off-label for the treatment of more severe or persistent cases of papulopustular rosacea and may help slow or halt the progression of rhinophyma. In a large scale, randomized, double-blind, 12-week study comparing different doses of isotretinoin to doxycycline and placebo in the treatment of rosacea, isotretinoin 0.3 mg/kg demonstrated non-inferiority to doxycycline (p=0.00001) and was well tolerated.⁵¹ However, isotretinoin should only be prescribed with close monitoring and, particularly in women with childbearing potential, an appropriate contraception strategy is essential due to its teratogenic potential.

Laser and light therapies have been used successfully for many years to treat the vascular manifestations of rosacea. In a randomized, controlled, single-blind, split-face trial, both pulsed dye laser and intense pulse light modalities were found to be effective, with similar efficacy, in reducing erythema and telangiectasia in patients with erythematotelangiectatic rosacea.⁵²

In a double-blind, randomized, vehicle-controlled, 12-week clinical trial,⁵³ off-label use of topical benzoyl peroxide 5% with clindamycin 1% once-daily was shown to be effective in reducing papule and pustule count in patients with rosacea compared to vehicle alone (71.3% vs. 19.3%; p=0.0056). Adverse events were only mildly elevated in the treatment group, with localized burning and itching being the most commonly reported.

Pimecrolimus 1% cream was demonstrated in an open-labeled, uncontrolled, 4-week trial to be effective and well tolerated in the treatment of rosacea.⁵⁴ Adverse events were transient and mild, which included local burning, itching, dryness, and stinging.

Conclusion

There are numerous treatment options available for rosacea, however, only a handful of agents are substantiated with quality research. If available, therapeutic decision-making should be guided by high-level evidence and patient-specific factors, such as rosacea subtype, severity, treatment expectations, tolerance, cost, and previous response to therapy. Topical azelaic acid and metronidazole are considered safe and efficacious first-line therapies. Sub-antimicrobial dose of doxycycline is the best research-supported oral therapeutic option and can be used to treat moderate to severe forms of papulopustular or ocular rosacea, or in patients who may be more adherent on a systemic regimen. Low-dose isotretinoin or surgical interventions may be indicated for the phymatous type. Light and laser-based therapies can play a major clinical role in the treatment of the telangiectatic component. The novel therapy, brimonidine, provides targeted treatment of facial diffuse erythema of rosacea. A comprehensive treatment plan must also incorporate non-drug strategies aimed at quality of life improvements and include trigger avoidance, proper daily skin care, camouflaging and photoprotection. Further research is needed on the effectiveness of combination treatments, isotretinoin, sulfacetamide, light-based options, and newly emergent agents compared with conventional therapies.

References

1. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004 Sep;51(3):327-41; quiz 42-4.
2. Powell FC. Clinical practice. Rosacea. N Engl J Med. 2005 Feb 24;352(8):793- 803.
3. Wilkin J, Dahl M, Detmar M, et al. Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2004 Jun;50(6):907-12.
4. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2002 Apr;46(4):584-7.
5. Gupta AK, Chaudhry MM. Rosacea and its management: an overview. J Eur Acad Dermatol Venereol. 2005 May;19(3):273-85.
6. Jansen T, Plewig G. Rosacea: classification and treatment. J R Soc Med. 1997 Mar;90(3):144-50.
7. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013 Dec;69(6 Suppl 1):S27-35.
8. Gallo R, Drago F, Paolino S, et al. Rosacea treatments: What’s new and what’s on the horizon? Am J Clin Dermatol. 2010;11(5):299-303.
9. Layton A, Thiboutot D. Emerging therapies in rosacea. J Am Acad Dermatol. 2013 Dec;69(6 Suppl 1):S57-65.
10. Aksoy B, Altaykan-Hapa A, Egemen D, et al. The impact of rosacea on quality of life: effects of demographic and clinical characteristics and various treatment modalities. Br J Dermatol. 2010 Oct;163(4):719-25.
11. Wolf JE, Jr., Del Rosso JQ. The CLEAR trial: results of a large community-based study of metronidazole gel in rosacea. Cutis. 2007 Jan;79(1):73-80.
12. Gooderham M. Rosacea and its topical management. Skin Therapy Lett. 2009 Feb;14(2):1-3.
13. Nielsen PG. Treatment of rosacea with i% metronidazole cream. A doubleblind study. Br J Dermatol. 1983 Mar;108(3):327-32.
14. Narayanan S, Hunerbein A, Getie M, et al. Scavenging properties of metronidazole on free oxygen radicals in a skin lipid model system. J Pharm Pharmacol. 2007 Aug;59(8):1125-30.
15. Dahl MV, Katz HI, Krueger GG, et al. Topical metronidazole maintains remissions of rosacea. Arch Dermatol. 1998 Jun;134(6):679-83.
16. Breneman DL, Stewart D, Hevia O, et al. A double-blind, multicenter clinical trial comparing efficacy of once-daily metronidazole 1 percent cream to vehicle in patients with rosacea. Cutis. 1998 Jan;61(1):44-7.
17. Bleicher PA, Charles JH, Sober AJ. Topical metronidazole therapy for rosacea. Arch Dermatol. 1987 May;123(5):609-14.
18. Rowe-Jones DC, Peel AL, Kingston RD, et al. Single dose cefotaxime plus metronidazole versus three dose cefuroxime plus metronidazole as prophylaxis against wound infection in colorectal surgery: multicentre prospective randomised study. BMJ. 1990 Jan 6;300(6716):18-22.
19. Yoo J, Reid DC, Kimball AB. Metronidazole in the treatment of rosacea: do formulation, dosing, and concentration matter? J Drugs Dermatol. 2006 Apr;5(4):317-9.
20. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol. 1999 Jun;40(6 Pt 1):961-5.
21. Dahl MV, Jarratt M, Kaplan D, et al. Once-daily topical metronidazole cream formulations in the treatment of the papules and pustules of rosacea. J Am Acad Dermatol. 2001 Nov;45(5):723-30.
22. Jorizzo JL, Lebwohl M, Tobey RE. The efficacy of metronidazole 1% cream once daily compared with metronidazole 1% cream twice daily and their vehicles in rosacea: a double-blind clinical trial. J Am Acad Dermatol. 1998 Sep;39(3):502-4.
23. Tan JK, Girard C, Krol A, et al. Randomized placebo-controlled trial of metronidazole 1% cream with sunscreen SPF 15 in treatment of rosacea. J Cutan Med Surg. 2002 Nov-Dec;6(6):529-34.
24. Fitton A, Goa KL. Azelaic acid. A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs. 1991 May;41(5):780-98.
25. Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from two vehicle-controlled, randomized phase III studies. J Am Acad Dermatol. 2003 Jun;48(6):836-45.
26. Carmichael AJ, Marks R, Graupe KA, et al. Topical azelaic acid in the treatment of rosacea. J Dermatolog Treat. 1993;4(suppl):S19-S22.
27. Bjerke R, Fyrand O, Graupe K. Double-blind comparison of azelaic acid 20% cream and its vehicle in treatment of papulo-pustular rosacea. Acta Derm Venereol. 1999 Nov;79(6):456-9.
28. van Zuuren EJ, Kramer S, Carter B, et al. Interventions for rosacea. Cochrane Database Syst Rev. 2011(3):CD003262.
29. Colon LE, Johnson LA, Gottschalk RW. Cumulative irritation potential among metronidazole gel 1%, metronidazole gel 0.75%, and azelaic acid gel 15%. Cutis. 2007 Apr;79(4):317-21.
30. Thiboutot DM, Fleischer AB, Jr., Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008 Jun;7(6):541-6.
31. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol. 2004 Oct;51(4):499-512; quiz 3-4.
32. Maibach H. Second-generation tetracyclines, a dermatologic overview: clinical uses and pharmacology. Cutis. 1991 Nov;48(5):411-7.
33. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007 May;56(5):791-802.
34. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008 Jun;7(6):573-6.
35. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther. 2005 Sep;27(9):1329-42.
36. Sanchez J, Somolinos AL, Almodovar PI, 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 Nov;53(5):791-7.
37. Lacey N, Delaney S, Kavanagh K, et al. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Br J Dermatol. 2007 Sep;157(3): 474-81.
38. O’Reilly N, Menezes N, Kavanagh K. Positive correlation between serum immunoreactivity to Demodex-associated Bacillus proteins and erythematotelangiectatic rosacea. Br J Dermatol. 2012 Nov;167(5):1032-6.
39. Allen KJ, Davis CL, Billings SD, et al. Recalcitrant papulopustular rosacea in an immunocompetent patient responding to combination therapy with oral ivermectin and topical permethrin. Cutis. 2007 Aug;80(2):149-51.
40. Forstinger C, Kittler H, Binder M. Treatment of rosacea-like demodicidosis with oral ivermectin and topical permethrin cream. J Am Acad Dermatol. 1999 Nov;41(5 Pt 1):775-7.
41. Karincaoglu Y, Bayram N, Aycan O, et al. The clinical importance of demodex folliculorum presenting with nonspecific facial signs and symptoms. J Dermatol. 2004 Aug;31(8):618-26.
42. Galderma. Randomized, double-blind, parallel-group, vehicle-controlled, dose-finding study investigating the pharmacodynamics and safety of three concentrations of CD07805/47 topical gel (0.07%, 0.18%, and 0.50%), applied in subjects with moderate to severe erythematotelangiectatic rosacea. In: ClinicalTrials.gov, Identifier: NCT00989014. Last updated September 19, 2013. Available at: http://clinicaltrials.gov/ct2/show/NCT00989014. Accessed: March 9, 2014.
43. Galderma. A phase 3 randomized, double blind, 12 week vehicle controlled, parallel group study assessing the efficacy and safety of CD5024 1 % cream versus vehicle cream in subjects with papulopustular rosacea, followed by a 40 week investigator blinded extension comparing the long term safety of CD5024 1% cream versus azelaic Acid 15 % gel. In: ClinicalTials.gov, Identifier: NCT01493687. Last updated January 27, 2014. Available at: http://clinicaltrials.gov/ct2/show/NCT01493687?term=NCT01493687&rank=1. Accessed: March 10, 2014.
44. Galderma. Efficacy and safety of CD5024 1% cream versus metronidazole 0.75% cream in subjects with papulopustular rosacea over 16 weeks treatment, followed by a 36-week extension period (ATTRACT).In: ClinicalTrials.gov, Identifier: NCT01493947. Last updated December 20, 2013. Available at: http://clinicaltrials.gov/ct2/show/NCT01493947?term=NCT01493947&rank=1. Accessed: March 9, 2014.
45. Del Rosso JQ. Advances in understanding and managing rosacea: part 2: the central role, evaluation, and medical management of diffuse and persistent facial erythema of rosacea. J Clin Aesthet Dermatol. 2012 Mar;5(3):26-36.
46. Rahman MQ, Ramaesh K, Montgomery DM. Brimonidine for glaucoma. Expert Opin Drug Saf. 2010 May;9(3):483-91.
47. Fowler J, Jr., Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehiclecontrolled pivotal studies. J Drugs Dermatol. 2013 Jun 1;12(6):650-6.
48. Moore A, Kempers S, Murakawa G, et al. Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of a 1-year open-label study. J Drugs Dermatol. 2014 Jan;13(1):56-61.
49. Allergan. Safety and tolerability of AGN-199201 in patients with erythema associated with rosacea. In: Clinical Trials.gov, Identifier: NCT01579084. Last updated September 12, 2013. Available at: http://clinicaltrials.gov/ct2/show/NCT01579084?term=NCT01579084&rank=1. Accessed: March 10, 2014.
50. Sauder DN, Miller R, Gratton D, et al. The treatment of rosacea: the safety and efficacy of sodium sulfacetamide 10% and sulfur 5% lotion (Novacet) is demonstrated in a double-blind study. J Dermatolog Treat. 1997;8(2):79-85.
51. Gollnick H, Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treatment of rosacea – doxycycline- and placebo-controlled, randomized clinical study. J Dtsch Dermatol Ges. 2010 Jul;8(7):505-15.
52. Neuhaus IM, Zane LT, Tope WD. Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Dermatol Surg. 2009 Jun;35(6):920-8.
53. Breneman D, Savin R, VandePol C, et al. Double-blind, randomized, vehiclecontrolled clinical trial of once-daily benzoyl peroxide/clindamycin topical gel in the treatment of patients with moderate to severe rosacea. Int J Dermatol. 2004 May;43(5):381-7.
54. Kim MB, Kim GW, Park HJ, et al. Pimecrolimus 1% cream for the treatment of rosacea. J Dermatol. 2011 Dec;38(12):1135-9.

¹Faculty of Medicine, University of Alberta, Edmonton, AB
²Division of Dermatology and Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, AB
³Toronto Dermatology Centre, Toronto, ON

Introduction

Rosacea is a common, chronic cutaneous condition that affects the face. Several topical medications are currently approved for the treatment of rosacea, including azelaic acid and metronidazole. Systemic therapy utilizing a sub-antimicrobial dose of doxycycline is also effective in treating rosacea. Identification of subtypes can help guide treatment strategies. Psychosocial implications of rosacea must be considered and conservative management, such as skin care, must form an important part of the overall care. Recently, new insights into the pathophysiology of rosacea have led to the emergence of etiologically oriented treatments, including the newly approved brimonidine gel 0.33% (Onreltea™).

Background

• Rosacea is a common chronic cutaneous condition that primarily affects the central facial area, including the cheeks, nose, eyes, chin and forehead.¹
• Primary cutaneous manifestations include sensitive skin, flushing, persistent erythema, papules, pustules and telangiectases.
• Although symptoms may wax and wane in the short-term, rosacea is slowly progressive in the long-term for many patients.²
• The National Rosacea Society has classified rosacea into four main subtypes: ³
  1. Erythematotelangiectatic
  2. Papulopustular
  3. Phymatous
  4. Ocular
• Progression from one subtype to another is possible.⁴ Proper identification of subtypes may help guide therapeutic strategies.
• Rosacea affects up to 10% of the general population and the onset is typically between the ages of 30 and 50 years.⁵
• It is especially common in light-skinned individuals of northern European descent, with women more frequently affected.^5,6 However, men are more prone to develop thickening and distorting phymatous skin changes, especially of the nose.
• While rosacea was considered rare in people of colour, a recent increase in case reports documenting rosacea in patients with Fitzpatrick Skin Types IV-VI, suggests that it is more common in darker skinned individuals than previously thought, and may have been under-recognized and unreported in the dermatology literature.^7,8
• Rosacea pathophysiology is multifactorial and currently not fully understood. Factors proposed to play a role include vascular abnormalities, gastrointestinal disorders, matrix degeneration, pilosebaceous gland abnormalities, microbial activity, and altered innate immune response.^9,10
• Rosacea can create psychosocial burdens, such as embarrassment, anxiety and low self-esteem, and adversely affect quality-of-life, which should be taken into consideration when treating these patients.^11,12 Conservative measures, such as trigger avoidance, proper skin care, camouflaging cosmetics, and photo-protection should also be incorporated into the management plan.¹³

Conventional Therapies

Topical Metronidazole

• Metronidazole (Noritate® 1% Cream, Dermik; MetroGel 1%, Metrocream™ 0.75% Cream, Metrolotion® 0.75% Lotion, Metrogel® 0.75% gel), first demonstrated efficacy against rosacea in the 1980s.¹⁴
• Despite being an antibacterial and antiprotozoal agent, metronidazole confers its therapeutic efficacy mostly through its anti-inflammatory and antioxidant effects.¹⁵
• Multiple trials have demonstrated that topical metronidazole significantly decreases the number of inflammatory lesions and reduces erythema compared to placebo; is generally well tolerated; has a low incidence of adverse effects; and is effective in maintaining remission.^16-19
• Importantly, different formulations of metronidazole have demonstrated similar efficacy, regardless of vehicle type (cream, gel, or lotion) or concentration (0.75% or 1%).^20,22
• Once- and twice-daily applications have similar efficacy.^20,23
• Metronidazole 1% has demonstrated less cumulative potential for irritation over a 21-day period, (similar to that of white petrolatum) compared with metronidazole gel 0.75%.²⁴
• When combined with sunscreen SPF 15, metronidazole may reduce development of facial telangiectasia.²⁵
• Topical metronidazole is a pregnancy category B medication.

Topical Azelaic Acid

• Azelaic acid (Finacea®) is a naturally occurring dicarboxylic acid approved in the last decade for the treatment of mild to moderate rosacea.²⁶
• Mostly applied as a 15% gel or a 20% cream, azelaic acid has anti-inflammatory, antikeratinizing, and antibacterial effects.²⁶
• Multiple trials have demonstrated that azelaic acid is more effective than placebo at reducing the number of inflammatory lesions and degree of erythema.^27-29 The pooled rates of patients showing marked improvements with azelaic acid treatment were 70-80%, compared to 50-55% with placebo.³⁰
• Azelaic acid also has a relatively low incidence of adverse effects, with burning, stinging and irritation being the most commonly reported.²⁸ However, data from Colon et al, show that azelaic acid gel 15% caused significantly more irritation than white petrolatum when administered over a 21-day period, as well as both concentrations of metronidazole (p<.0001 for all comparisons).²⁴
• Although the conventional regimen is twice-daily application, once-daily dosing has been found to be equally effective.³¹
• Further studies are needed to support the use of azelaic acid as a maintenance therapy.³⁰
• It is currently a pregnancy B category medication.

Tetracycline

• While not indicated for the treatment of rosacea, oral antibiotics have been recognized for the past 50 years as an effective treatment and are thought to exert their therapeutic effects primarily via anti-inflammatory rather than antibacterial mechanisms.³²
• Because the role of micro-organisms in rosacea pathogenesis remains unclear, the use of antibiotics at standard doses is not an ideal approach.
• However, the tetracycline-family of antibiotics is effective in treating ocular rosacea, which typically affects greater than 50% of patients with rosacea.
• Tetracyclines are the most frequently used class of antibiotics with greatest efficacy against inflammatory papules and pustules.
• Tetracyclines are contraindicated in pregnant women.
• Second-generation tetracyclines, including minocycline and in particular doxycycline, are especially safe and effective oral therapies for rosacea.
• Unlike the parent, second generation tetracyclines have greater bioavailability, rapid onset of action, and can be taken with food, which minimizes gastrointestinal side effects.³³
• Second-generation tetracyclines require once-daily dosage, which may improve compliance.
• Most importantly, they are effective at a sub-antimicrobial dose, which avoids disruption of the endogenous flora and, of global importance, the propagation of antibacterial resistance.³⁴
• Recently, two phase 3, multicenter, randomized, doubleblind, placebo-controlled clinical trials demonstrated that a daily sub-antimicrobial dose of 40 mg doxycycline (Apprilon™), administered to patients with moderate to severe rosacea, significantly reduced total inflammatory papule and pustule counts compared with placebo after 16-weeks treatment, with significant improvements evident at 3 weeks.³⁴
• Prevalence of adverse effects was low and only marginally higher than placebo, with nasopharyngitis (4.8%), diarrhea (4.4%) and headaches (4.4%) being the most commonly reported.
• No cases of photosensitivity or vaginal candidiasis occurred.
• A separate study demonstrated that the effectiveness of 40 mg doxycycline is comparable to that of 100 mg doxycycline in rosacea but with a lower incidence of gastrointestinal side effects.³⁵

New Therapies

Brimonidine

• Diffuse facial erythema has long posed an unmet need in rosacea management.⁵
• One contributing factor is abnormal cutaneous vasomotor responses, which leads to persistently enlarged facial blood vessels.³⁶ These blood vessels remain responsive to vasoactive stimuli, hence the growing interest in α2-adrenergic receptor agonists as a possible therapeutic option.³⁶
• Brimonidine 0.33% gel (Mirvaso™), approved by FDA in August 2013, is the latest addition to the therapeutic armamentarium and the first topical agent approved for the treatment of facial erythema of rosacea. This formulation was recently approved by Health Canada with the trade name Onreltea®, for the topical treatment of facial erythema of rosacea in adults 18 years of age or older.¹² (*Notethe literature refers to both brimonidine gel 0.33% and brimonidine tartrate gel 0.5%. This is the same product and the terms are interchangeable.)
• Brimonidine is a highly selective α2-adrenergic receptor agonist with potent vasoconstrictive activity and is also found in prescription eye drops for the treatment of glaucoma.³⁷
• In two phase 3 randomized, double-blind pivotal trials, topical brimonidine tartrate gel 0.5% once daily was significantly more effective than vehicle over a 4-week treatment period.³⁸ In the two trials, approximately 24.82% of the patients using brimonidine tartrate gel 0.5% versus (vs.) 9.76%; p<0.05) on day 29 were assessed to have at least a two-grade improvement by both clinicians and patients over 12 hours after drug application, with peak improvements observed at 3 and 6 hours (Fig. 1 and 2).
• Noticeable improvement (one-grade Clinician’s Erythema Assessment and 5 point Patient Self Assessessment Scale) was observed (28.2% vs. 5.9%; p<0.01) as early as 30 minutes after the first application on day one.
• Adverse events were mildly elevated in the treatment group but were largely cutaneous, transient and mild, with the most commonly reported being worsening of erythema (5.1%), pruritus (5.0%), skin irritation (1.2%), and rosacea (1.1%).
• There was no evidence of tachyphylaxis, rebound, or aggravation of telangiectasia or inflammatory lesions.
• Data from a 12-month, multi-center, open-label study also show no incidence of tachyphylaxis, with efficacy maintained over the long-term.³⁹

Figure 1: Baseline

Figure 2: 3 hours post-Brimonidine treatment

Other Therapies

• Topical sodium sulfacetamide 10% with sulfur 5% has been used for over 50 years for its clinical efficacy and safety in the treatment of rosacea, although its mechanism of action is not well understood.
• In an 8-week study, sulfacetamide 10% with sulfur 5% has been shown to significantly reduce inflammatory lesions (78% vs. 36%; p<0.001) and facial erythema (83% vs. 31%; p<0.001) compared to vehicle.^4,40 Studies evaluating this therapy, however, are limited and generally of poor quality.³⁰
• Laser and light therapies have been used successfully for many years to treat the vascular manifestations of rosacea.
• In a randomized, controlled, single-blind, split-face trial, both pulsed dye laser and intense pulse light were found to be effective, with similar efficacy in reducing erythema and telangiectasia in patients with erythematotelangiectatic rosacea.⁴¹

Conclusion

Therapeutic decision-making in the treatment of rosacea should be guided by high-level evidence, where available, and will depend on subtype, severity, patient expectations, tolerance, budget and previous therapy used. Topical azelaic acid and metronidazole are considered safe and efficacious first-line therapies. A sub-antimicrobial dose of doxycycline is the best research-supported oral therapeutic indicated for the treatment of rosacea and provides a safe and convenient option for patients who prefer oral to topical therapy. Light and laserbased therapies play a major clinical role in the treatment of the telangiectatic component. The promising novel therapy, brimonidine, fills a much-needed niche in the targeted treatment of facial diffuse erythema of rosacea.

References

1. Crawford GH, et al. J. Am Acad Dermatol. 2004:(51); 327-341; quiz 342-324,
   doi:10.1016/j.jaad.2004.03.030.
2. Powell FC, N Eng J Med. 2005;(352):793-803.
3. Wilkin J, et al. J Am Acad Dermatol. 2004;(50):907-912.
4. Wilkin J, et al. J Am Acad Dermatol. 2002;(46):584-587.
5. Gupta AK, et al. J Eur Acad Dermatol Venereol. 2005;(19):273-285.
6. Jansen T, et al. J R Soc Med. 1997;(90):144-150.
7. Jayawant SS, et al. J Dermatol Treatment. 2008;(19):267-273.
8. Sanchez J, et al. J Am Acad Dermatol. 2005;(53):791-797.
9. Gallo R, et al. Am J Clin Dermatol. 2010;(11):99-303.
10. Layton A, et al. J. Am. Acad. Dermato. 2013;(69):S57-65.
11. Aksoy B, et al. Br J Dermatol. 2010;(163):719-725.
12. Wolf JE, Jr. et al. Cutis. 2007;(79):73-80.
13. Gooderham M, Skin therapy letter. 2009;(14):1-3.
14. Nielsen PG, Br J Dermatol. 1983;(108):327-332.
15. Narayanan S, et al. JPharm Pharmacol. 2007;(59):1125-1130.
16. Dahl MV, et al. Arch Dermatology. 1988;(134):679-683.
17. Breneman DL, et al. Cutis. 1988;(61):44-47.
18. Bleicher PA, et al. Arch. Dermatol. 1987;(123):609-614.
19. Rowe-Jones DC, et al. BMJ. 2009;(300):18-22.
20. Yoo J, et al. J Drugs Dermatol. 2006; (5):317-319.
21. Maddin SA. J Am Acad Dermatol. 1999; (40):961-965.
22. Dahl M V, et al. J Am Acad Dermatol. 2001;(45):723-730.
23. Jorizzo J L, et al. J. Am Acad Dermatol. 1998;(39):502-504.
24. Colon L E, et al. Cutis. 2007;79:317-321.
25. Tan JK, et al. J Cutan Med Surg. 2002;(6):529-534.
26. Fitton A, et al. Drugs. 1991;(41):780-798.
27. Thiboutot D, et al. J Am Acad Dermatol. 2003;(48):836-845.
28. Carmichael AJ, et al. J. Dermatol Treat. 1993;(4):S19-S22.
29. Bjerke R, et al. Acta dermato-venereologica. 1999;(79):456-459.
30. van Zuuren EJ, et al. 2011. The Cochrane database of systematic reviews, CD003262, doi:10.1002/14651858.CD003262.pub4.0
31. Thiboutot DM, et al. J Drugs Dermatol. 2008; (7):541-546.
32. Pelle MT, et al. J Am Acad Dermatol. 2004;(51):499-512.
33. Maibach H. Cutis. 1991;(48):411-417.
34. Del Rosso JQ, et al. J Am Acad Dermatol. 2007;(56):791-802.
35. Del Rosso JQ, et al. J Drugs Dermatol. 2008;(7):573-576.
36. Del Rosso JQ. J Clin Aesthet Dermatol. 2012;(5):26-36.
37. Rahman MQ, et al. Expert Opin Drug Saf. 2010;(9):483-491.
38. Fowler J Jr, et al. J Drugs Dermatol. 2012;(12):650-656.
39. Moore A, et al. J Drugs Dermatol. 2014;13(1):56-61.
40. Sauder DN, et al. J Dermatol Treat. 1997;(8):79-85.
41. Neuhaus IM,et al. Dermatol Surg. 2009;(35):920-928.

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.

References

1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002 Apr;46(4):584-7.
2. Scharschmidt TC, Yost JM, Truong SV, et al. Neurogenic rosacea: a distinct clinical subtype requiring a modified approach to treatment. Arch Dermatol. 2011 Jan;147(1):123-6.
3. Baldwin HE. Diagnosis and treatment of rosacea: state of the art. J Drugs Dermatol. 2012 Jun;11(6):725-30.
4. Leaute-Labreze C, Chamaillard M. [Paediatric rosacea]. Ann Dermatol Venereol. 2007 Oct;134(10 Pt 1):788-92.
5. Del Rosso JQ, Gallo RL, Kircik L, et al. Why is rosacea considered to be an inflammatory disorder? The primary role, clinical relevance, and therapeutic correlations of abnormal innate immune response in rosacea-prone skin. J Drugs Dermatol. 2012 Jun;11(6):694-700.
6. Yamasaki K, Gallo RL. The molecular pathology of rosacea. J Dermatol Sci. 2009 Aug;55(2):77-81.
7. Webster GF. Rosacea. Med Clin North Am. 2009 Nov;93(6):1183-94.
8. Gupta MA, Gupta AK, Chen SJ, et al. Comorbidity of rosacea and depression: an analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey–Outpatient Department data collected by the U.S. National Center for Health Statistics from 1995 to 2002. Br J Dermatol. 2005 Dec;153(6):1176-81.
9. Aksoy B, Altaykan-Hapa A, Egemen D, et al. The impact of rosacea on quality of life: effects of demographic and clinical characteristics and various treatment modalities. Br J Dermatol. 2010 Oct;163(4):719-25.
10. Del Rosso JQ. The use of moisturizers as an integral component of topical therapy for rosacea: clinical results based on the Assessment of Skin Characteristics Study. Cutis. 2009 Aug;84(2):72-6.
11. Gooderham M. Rosacea and its topical management. Skin Therapy Lett. 2009 Feb;14(2):1-3.
12. Jackson JM, Pelle M. Topical rosacea therapy: the importance of vehicles for efficacy, tolerability and compliance. J Drugs Dermatol. 2011 Jun;10(6):627-33.
13. Little SC, Stucker FJ, Compton A, et al. Nuances in the management of rhinophyma. Facial Plast Surg. 2012 Apr;28(2):231-7.
14. van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011 Oct;165(4):760-81.
15. Thomas K, Yelverton CB, Yentzer BA, et al. The cost-effectiveness of rosacea treatments. J Dermatolog Treat. 2009;20(2):72-5.
16. Thiboutot DM, Fleischer AB, Jr., Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008 Jun;7(6):541-6.
17. Elewski BE, Fleischer AB, Jr., Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol. 2003 Nov;139(11):1444-50.
18. Wolf JE, Jr., Kerrouche N, Arsonnaud S. Efficacy and safety of once-daily metronidazole 1% gel compared with twice-daily azelaic acid 15% gel in the treatment of rosacea. Cutis. 2006 Apr;77(4 Suppl):3-11.
19. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol. 1999 Jun;40(6 Pt 1):961-5.
20. Mays RM, Gordon RA, Wilson JM, et al. New antibiotic therapies for acne and rosacea. Dermatol Ther. 2012 Jan-Feb;25(1):23-37.
21. Chon SY, Doan HQ, Mays RM, et al. Antibiotic overuse and resistance in dermatology. Dermatol Ther. 2012 Jan-Feb;25(1):55-69.
22. Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines. Dermatol Clin. 2007 Apr;25(2):133-5, v.
23. Korting HC, Schollmann C. Tetracycline actions relevant to rosacea treatment. Skin Pharmacol Physiol. 2009;22(6):287-94.
24. McKeage K, Deeks ED. Doxycycline 40 mg capsules (30 mg immediaterelease/ 10 mg delayed-release beads): anti-inflammatory dose in rosacea. Am J Clin Dermatol. 2010;11(3):217-22.
25. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007 May;56(5):791-802.
26. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008 Jun;7(6):573-6.
27. Del Rosso JQ, Preston NJ, Caveney SW, et al. Effectiveness and safety of modified-release doxycycline capsules once daily for papulopustular rosacea monotherapy results from a large community-based trial in subgroups based on gender. J Drugs Dermatol. 2012 Jun;11(6):703-7.
28. Alexis AF, Webster G, Colon LE, et al. Effectiveness and safety of doxycycline 40 mg monotherapy for the treatment of rosacea in skin type subgroups. J Am Acad Dermatol. 2012 Apr;66(4):AB50.
29. Johnson SM, LeVine P. Self-reported treatment impressions and satisfaction of papulopustular rosacea patients treated with doxycycline, USP, 40 mg capsules. J Drugs Dermatol. 2011 Dec;10(12):1376-81.
30. Del Rosso JQ, Bruce S, Jarratt M, et al. Efficacy of topical azelaic acid (AzA) gel 15% plus oral doxycycline 40 mg versus metronidazole gel 1% plus oral doxycycline 40 mg in mild-to-moderate papulopustular rosacea. J Drugs Dermatol. 2010 Jun;9(6):607-13.
31. Bhatia ND, Del Rosso JQ. Optimal management of papulopustular rosacea: rationale for combination therapy. J Drugs Dermatol. 2012 Jul;11(7):838-44.
32. UK Medicines Information. New drugs online report for ivermectin.
33. Forton FM. Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. J Eur Acad Dermatol Venereol. 2012 Jan;26(1):19-28.
34. Forstinger C, Kittler H, Binder M. Treatment of rosacea-like demodicidosis with oral ivermectin and topical permethrin cream. J Am Acad Dermatol. 1999 Nov;41(5 Pt 1):775-7.
35. Galderma. A phase 3 randomized, double blind, 12 week vehicle controlled, parallel group study assessing the efficacy and safety of CD5024 1 % cream versus vehicle cream in subjects with papulopustular rosacea, followed by a 40 week investigator blinded extension comparing the long term safety of CD5024 1% cream versus azelaic Acid 15 % gel. In: ClinicalTials.gov, Identifier: NCT01493687. Last updated June 12, 2012. Available at: http:// clinicaltrials.gov/ct2/show/NCT01493687?term=NCT01493687&rank=1. Accessed: October 2, 2012.
36. Galderma. A phase 3 randomized, double blind, 12 week vehicle controlled, parallel group study assessing the efficacy and safety of CD5024 1 % cream versus vehicle cream in subjects with papulopustular rosacea, followed by a 40 week investigator blinded. extension comparing the long term safety of CD5024 1% cream versus azelaic acid 15 % gel. In: ClinicalTials.gov, Identifier: NCT01494467. Last updated June 25, 2012. Available at: http://clinicaltrials. gov/ct2/show/NCT01494467. Accessed: October 2, 2012.
37. Galderma. Efficacy and safety of CD5024 1% cream versus metronidazole 0.75% cream in subjects with papulopustular rosacea over 16 weeks treatment, followed by a 36-week extension period (ATTRACT). In: ClinicalTrials.gov, Identifier: NCT01493947. Last updated September 5, 2012. Available: http:// clinicaltrials.gov/ct2/show/NCT01493947?term=NCT01493947&rank=1. Accessed: October 2, 2012.
38. Fowler J, Jarratt M, Moore A, et al. Once-daily topical brimonidine tartrate gel 0.5% is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies. Br J Dermatol. 2012 Mar;166(3):633-41.
39. Galderma. Randomized, double-blind, parallel-group, vehicle-controlled, dose-finding study investigating the pharmacodynamics and safety of three concentrations of CD07805/47 topical gel (0.07%, 0.18%, and 0.50%), applied in subjects with moderate to severe erythematotelangiectatic rosacea. In: ClinicalTrials.gov, Identifier: NCT00989014. Last updated July 24, 2012. Available at: http://clinicaltrials.gov/ct2/show/NCT00989014. Accessed: September 25, 2012.
40. Shanler SD, Ondo AL. Successful treatment of the erythema and flushing of rosacea using a topically applied selective alpha1-adrenergic receptor agonist, oxymetazoline. Arch Dermatol. 2007 Nov;143(11):1369-71.
41. Bikowski J. Rosacea therapy: current approaches and future directions. Pract Dermatol. 2012 Jul:31-2.
42. Korting HC, Schollmann C. Current topical and systemic approaches to treatment of rosacea. J Eur Acad Dermatol Venereol. 2009 Aug;23(8):876-82.
43. Gollnick H, Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treatment of rosacea – doxycycline- and placebo-controlled, randomized clinical study. J Dtsch Dermatol Ges. 2010 Jul;8(7):505-15.
44. Chang AL, Alora-Palli M, Lima XT, et al. A randomized, double-blind, placebocontrolled, pilot study to assess the efficacy and safety of clindamycin 1.2% and tretinoin 0.025% combination gel for the treatment of acne rosacea over 12 weeks. J Drugs Dermatol. 2012 Mar;11(3):333-9.
45. Breneman D, Savin R, VandePol C, et al. Double-blind, randomized, vehiclecontrolled clinical trial of once-daily benzoyl peroxide/clindamycin topical gel in the treatment of patients with moderate to severe rosacea. Int J Dermatol.2004 May;43(5):381-7.
46. Neuhaus IM, Zane LT, Tope WD. Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Dermatol Surg. 2009 Jun;35(6):920-8.
47. Kassir R, Kolluru A, Kassir M. Intense pulsed light for the treatment of rosacea and telangiectasias. J Cosmet Laser Ther. 2011 Oct;13(5):216-22.
48. Kim MB, Kim GW, Park HJ, et al. Pimecrolimus 1% cream for the treatment of rosacea. J Dermatol. 2011 Dec;38(12):1135-9.
49. Koca R, Altinyazar HC, Ankarali H, et al. A comparison of metronidazole 1% cream and pimecrolimus 1% cream in the treatment of patients with papulopustular rosacea: a randomized open-label clinical trial. Clin Exp Dermatol. 2010 Apr;35(3):251-6.
50. Bamford JT, Gessert CE, Haller IV, et al. Randomized, double-blind trial of 220 mg zinc sulfate twice daily in the treatment of rosacea. Int J Dermatol. 2012 Apr;51(4):459-62.
51. Emer J, Waldorf H, Berson D. Botanicals and anti-inflammatories: natural ingredients for rosacea. Semin Cutan Med Surg. 2011 Sep;30(3):148-55.
52. Ferrari A, Diehl C. Evaluation of the efficacy and tolerance of a topical gel with 4% quassia extract in the treatment of rosacea. J Clin Pharmacol. 2012 Jan;52(1):84-8.

Peterborough, ON, Canada

Introduction

Many options exist for the treatment of rosacea, including topical and systemic therapy, laser and light-based therapies, and surgical procedures. A classification system for rosacea identifies four subtypes, which may help guide therapeutic decision-making. Standard topical treatment agents include metronidazole, azelaic acid, and sulfacetamide-sulfur. Second-line therapies include benzoyl peroxide, clindamycin, calcineurin inhibitors, and permethrin. Rosacea can contribute to lower self-esteem and have significant psychosocial implications, such as stress at work and social isolation. This can have a significant impact on quality of life and should be taken into consideration when treating these patients.

Prevalence

• Rosacea is a common chronic skin disorder that is thought to affect approximately 14% of women and 6% of men.¹
• All ethnicities can be affected, but rosacea is most prevalent in fair-skin individuals of northwest European descent.
• Initial diagnosis most frequently occurs between the ages of 30-50 years.
• Although rosacea prevalence is higher in women, there is a much greater incidence of severe telangiectasias and rhinophyma (red, bulbous nose) in men, especially in patients presenting with advanced disease.

Diagnostic Features

Rosacea is a chronic relapsing inflammatory skin disorder characterized by facial flushing, persistent erythema, telangiectasia (dilated superficial blood vessels), and inflammatory papules and pustules affecting the central face (across the cheeks, nose, or forehead). The ears, scalp, neck, and chest are less commonly involved.

The National Rosacea Society has described a classification system based on four main subtypes and one variant.²

Subtype 1: Erythematotelangiectatic

• Characterized by flushing, persistent central facial erythema, and telangiectasia of the cheeks and around the nose.
• Central facial edema, stinging, burning, pruritus, and roughness, scaling, and a history of flushing alone are also common.

Subtype 2: Papulopustular

• Characterized by persistent central facial erythema with transient papules or pustules or both.
• Papules and pustules can also occur in the perioral, perinasal, or periocular regions.
• There is a resemblance to acne vulgaris, except that comedones (whiteheads and blackheads) are absent, hence, the term “acne rosacea” is sometimes used.
• Rosacea and acne can coexist, therefore, patients can present simultaneously with comedones, papules and/or pustules.
• This subtype has often been seen after or in combination with subtype 1.
• Burning and stinging sensations may be reported by patients; telangiectasias may be present, but obscured by persistent erythema, papules, or pustules.

Subtype 3: Phymatous

• Common features include thickening skin, irregular surface nodularities, and enlargement.
• Phymatous rosacea most commonly affects the nose (rhinophyma), but the chin, forehead, cheeks, and ears can also be involved.
• This subtype frequently occurs after or in combination with subtypes 1 or 2.
• Patients may also exhibit persistent erythema, telangiectases, papules, and/or pustules.

Subtype 4: Ocular

• Diagnosis of this subtype is considered when a patient exhibits or reports one or more of the following symptoms: watery or bloodshot appearance, foreign body sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, telangiectasia, or lid and periocular erythema.
• Recurrent staphylococcal infection manifesting as styes are common.
• Patients can experience impaired vision, requiring ophthalmologic consultation.
• Most frequently, signs and symptoms of ocular rosacea present concurrently with those affecting the skin.
• Ocular signs and symptoms may precede cutaneous manifestations and vice versa.

One Variant: Granulomatous

• This is a rare variation of rosacea that is characterized by hard papules or nodules ranging in colour from yellow, brown, or red.
• The lesions exhibit less inflammation and are typically found on relatively normal-appearing skin of the cheeks and periorificial areas.

Treatment Overview

Treatment starts with making a proper diagnosis, including subtyping. Following this, conservative measures such as trigger avoidance, proper skin care, camouflaging cosmetics, and photoprotection should be discussed in detail with patients. The goals of therapy include the reduction of papules, pustules, erythema, physical discomfort, and an improvement in quality of life. Topical pharmacotherapeutic options include azelaic acid, metronidazole, sulfacetamide 10% + sulfur 5%, clindamycin 1% + benzoyl peroxide 5% gel, clindamycin, and erythromycin. For patients with moderate to severe papulopustular rosacea or those with ocular involvement, systemic therapy is often prescribed – therapeutic options include tetracycline, minocycline, doxycycline, erythromycin, metronidazole, or in severe cases, low dose isotretinoin. The telangiectatic component does not respond to either oral or topical medications, and is best treated with laser and light-based therapies. Surgical intervention may be required for the phymatous subtype. Therapeutic choices will depend on patient expectations, tolerance, previous therapies used, rosacea subtype, and severity.

Azelaic Acid

Azelaic acid (AzA) is a newer therapeutic option that is available for the treatment of rosacea. Although it received regulatory approval in Canada in 2004, AzA has only recently become commercially available in June 2010. AzA is a naturally occurring dicarboxylic acid that can be found in dietary sources, such as whole grains.³ It lacks toxicity, is non-teratogenic and non-mutagenic.⁴ It has multiple biologic effects including anti-inflammatory, anti-keratinizing, and anti-bacterial activities. The likely mechanism of action in the treatment of rosacea is via inhibition of reactive oxygen species produced by neutrophils.⁴

• A novel 15% gel formulation is available for the treatment of rosacea. A 20% cream formulation is approved in the U.S. for acne vulgaris, but it is not currently available in Canada.
• 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.

Multiple reviews have been published examining the use of AzA in rosacea.^3,5,6

• Two pivotal phase III 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.⁷
  • In these studies, a mean reduction in inflammatory lesion counts and improvements in erythema scores were observed in AzA-treated group vs. placebo.⁷
• A 15-week study, comparing the twice daily use of AzA 15% gel to metronidazole 0.75% gel also showed a significant benefit for AzA over metronidazole.⁸

Metronidazole

Metronidazole has been the mainstay of topical rosacea treatment. It is a nitroimidazole antibiotic whose mechanism of action in rosacea is not well established, but it appears to work through an anti-inflammatory mechanism.^12,13 Metronidazole is the most widely used topical agent for rosacea.

• Available as a 0.75% gel, lotion, and cream 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
• It is generally well tolerated and has a low incidence of adverse effects.^12,13
• A recent systematic review of 9 trials demonstrated the efficacy of topical metronidazole vs. placebo.^5,15 Most of these studies used 0.75% metronidazole and ranged from 8-9 weeks in duration with one trial lasting 6 months.
  • A reduction in inflammatory lesions and erythema scores were noted, as was an improvement in physician’s global evaluation and patient-assessed measures when these were available.^5,15
  • 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 (SPF) of 15.¹⁶
• Although data is limited, two studies have demonstrated that topical metronidazole may be as effective as oral tetracycline in reducing the inflammatory component of rosacea.^17,18
• The efficacy of topical metronidazole is constant regardless of the formulation, strength, and frequency of application.¹²
• Metronidazole also plays a role in maintenance therapy for rosacea, either with or without prior concomitant systemic antibiotic treatment.¹²
• Given its high efficacy and tolerability, it will continue to play an important role in the management of rosacea.

Sodium Sulfacetamide + Sulfur

• An older treatment that has gained new popularity is sodium sulfacetamide 10% + sulfur 5%, which is used to treat acne, rosacea, and seborrheic dermatitis.¹³
• It is available in multiple formulations as a lotion, cream, gel, or cleanser.^9,13
• The mechanism of action is not well understood, but the sulfacetamide has anti-bacterial properties, and the sulfur component confers anti-fungal, anti-demodectic, and keratolytic effects.

Other Therapies

• Many other topical treatments have been reported and are being used for rosacea. Some are effective, but are not yet approved for use in rosacea. Further investigation is needed to determine their role in the topical armamentarium of rosacea therapy.

• Combination clindamycin 1% + benzoyl peroxide 5% gel, which is approved for use in acne vulgaris, has shown promise in the treatment of rosacea. A double-blind, randomized controlled trial using this formulation once daily showed a significant reduction in inflammatory lesion count, erythema severity, and overall rosacea severity. The treatment was well tolerated.¹⁹
• Topical antibiotics (e.g., clindamycin lotion or cream) have shown benefit in the topical treatment of rosacea, but evidence supporting its use is lacking.
• The calcineurin inhibitors, tacrolimus and pimecrolimus, have been investigated for use in papulopustular rosacea because of their anti-inflammatory effects. Early reports indicate improvement from tacrolimus in the treatment of steroid-induced rosacea.20 However, while three studies have demonstrated a reduction in erythema associated with rosacea, neither tacrolimus nor pimecrolimus had any benefit over vehicle with respect to lesion counts.^21-23
• Topical retinoids have also been used to treat rosacea, but the true efficacy has not been established. Their use is limited by their irritant potential, and investigators suggested that better tolerated agents, such as adapalene, could be considered.13
• Topical steroids are sometimes used on a short-term basis for the severe inflammatory component, but long-term side-effects and exacerbating potential limit their use in this chronic condition.¹³
• Permethrin 5% cream, which is proposed to work because of its anti-parasitic effects, may target Demodex mites, a potential cause of rosacea.¹³

Self-Care Tips

Cleansers

• Due to hypersensitivity of the skin, limit face washing to twice daily. Cleansing can offer a cooling effect that temporarily relieves sensations of burning and itching.
• Select gentle, mild skin cleansers with non-sensitizing ingredients (i.e., free of fragrances and preservatives).
• Avoid the use of washing implements (e.g., sponge, brush, wash cloth), especially those with a rough surface that can further aggravate the skin.
• Allow skin to dry before applying either a moisturizer or medication.

Moisturizers

• The regimented use of a suitable moisturizer is essential for managing rosacea. If left untreated, dry skin can cause further discomfort, resulting in burning, tightness, itching, and stinging.
• Recommendations cannot be generalized, since each person with rosacea can react differently to the same product. Water-based moisturizers may be less likely to induce sensitivity reactions.
• Seborrheic dermatitis is a common concurrent skin condition, appearing as a red and scaly rash on the scalp, eyelids, eyebrows, sides of the nose, and behind the ears. Patients with rosacea can have dry scaly skin secondary to the dermatitis, so no amount of moisturizing will help the scaling until the inflammation is first controlled by medication.

Sunscreens

• The sun is one of the most common triggers of rosacea flare-ups, therefore, selecting a suitable non-oily broad spectrum sunscreen with SPF of at least 15 to 30 is recommended.
• The most effective protection against UV radiation is sun avoidance, e.g., by limiting exposure, or at least direct exposure during peak times, and by wearing appropriate clothing and hats.
• Maintaining proper sun protection is essential, because the heat of the sun and UV exposure can aggravate the skin and result in increased redness and long-term damage to blood vessels.

Cosmetic Camouflage

• Makeup can be a useful cosmetic tool to conceal the symptoms of rosacea.
• Foundations or concealers with a green tint are helpful for camouflaging redness, blood vessels, and blemishes.
• Avoid powder formulations on dry, flaky skin, as these products can collect in areas of dryness and worsen the appearance of skin.

Conclusion

Because of its chronic, inflammatory nature, rosacea requires continuous management. Treatment can be tailored to the subtype and may involve a combination of therapies. Patients should first be counseled on the triggers of rosacea, proper skin care, photoprotection, and camouflaging cosmetic options. Topical therapy is usually first-line, but in moderate-to-severe cases, or those with ocular involvement, systemic therapy may be required. Laser or light-based treatments and surgical procedures can offer added benefit. Many topical agents are available for the treatment of rosacea, and the erythematotelangiectatic and papulopustular variants usually respond most favourably. The Cochrane Collaboration Review of interventions for rosacea concludes there is good evidence that topical azelaic acid and metronidazole are both safe and effective treatments. Other treatment options also include sulfacetamide 10%-sulfur 5%, benzoyl peroxide 5%-clindamycin 1%, or clindamycin alone.

References

1. Berg M, et al. Acta Derm Venereol 69(5):419-23 (1989).
2. Wilkin J, et al. J Am Acad Dermatol 46(4):584-7 (2002).
3. Gupta AK, et al. Int J Dermatol 46(5):533-8 (2007).
4. Breathnach AS. Medial Hypothesis 52(3):221-6 (1999).
5. van Zuuren EJ, et al. J Am Acad Dermatol 56(1):107-15 (2007).
6. Liu RH, et al. Arch Dermatol 142(8):1047-52 (2006).
7. Thiboutot D, et al. J Am Acad Dermatol 48(6):836-45 (2003).
8. Elewski BE, et al. Arch Dermatol 139(11):1444-50 (2003).
9. Bikowski JB, et al. J Drugs Dermatol 3(3):251-61 (2004).
10. Maddin S. J Am Acad Dermatol 40(6 Pt 1):961-5 (1999).
11. Thiboutot DM, et al. J Drugs Dermatol 7(6):541-6 (2008).
12. McLellan KJ, et al. Am J Clin Dermatol 1(3):191-9 (2000).
13. Nally JB, et al. J Drugs Dermatol 5(1):23-6 (2006).
14. Jorizzo JL, et al. J Am Acad Dermatol 39(3):502-4 (1998).
15. van Zuuren EJ, et al. Cochrane Database Syst Rev (3):CD003262. DOI:10.1002/14651858.CD003262.pub3 (2005).
16. Tan JKL, et al. J Cutan Med Surg 6(6):529-534 (2002).
17. Nielsen PG. Br J Dermatol 109(1):63-5 (1983).
18. Veien NK, et al. Cutis 38(3):209-10 (1986).
19. Breneman D, et al. Int J Dermatol 43(5):381-7 (2004).
20. Goldman D. J Am Acad Dermatol 44(6):995-8 (2001).
21. Bamford J, et al. J Am Acad Dermatol 50(1):107-8 (2004).
22. Karabulut AA, et al. J Eur Acad Dermatol Venereol 22(6):729-34 (2008).
23. Weissenbacher S, et al. Br J Dermatol 156(4):728-32 (2007).

Peterborough, ON, Canada

ABSTRACT
Many options exist for the treatment of rosacea, including topical and systemic therapies, laser and light-based therapies, and surgical procedures. A classification system for rosacea identifies 4 subtypes (i.e., erythematotelangiectatic, papulopustular, phymatous, and ocular), which may help guide therapeutic decision-making. The goals of therapy include reduction of papules, pustules, erythema, physical discomfort, and an improvement in quality of life. Standard topical treatment agents include metronidazole, azelaic acid, and sodium sulfacetamide-sulfur. Second line therapies include benzoyl peroxide, clindamycin, calcineurin inhibitors, and permethrin.

Key Words:
rosacea; topical therapy; systemic therapy; laser

Rosacea is a chronic relapsing skin disorder characterized by facial flushing, persistent erythema, telangiectasia, and inflammatory papules and pustules affecting the central face.
The National Rosacea Society has described a classification system based on 4 main subtypes: erythematotelangiectatic, papulopustular, phymatous, ocular, and one variant, i.e.,
granulomatous.¹ Rosacea can contribute to lower self-esteem and have significant psychosocial implications, e.g., stress at work and social isolation.² This can have a significant impact on quality of life and should be taken into consideration when treating these patients.

Treatment starts with making a proper diagnosis, including identification of subtype. Following this, conservative measures, such as trigger avoidance, proper skin care, camouflaging cosmetics, and photoprotection should be discussed in detail. Topical pharmacotherapeutic options include: azelaic acid (Finacea® Gel, Intendis/Bayer),
clindamycin, clindamycin 1%-benzoyl peroxide 5% gel (BenzaClin®, sanofi-aventis; Duac®, Stiefel), erythromycin, metronidazole (MetroCream®, MetroLotion®, MetroGel®, Rozex® Gel, Galderma; Noritate®, Dermik), or sodium sulfacetamide 10% + sulfur 5% (Plexion®, Medicis; Rosac® Cream, Stiefel; Rosula® Lotion, Doak Dermatologics; Sulfacet-R®, Novacet® Lotion, Perrigo). For patients with moderate-to-severe papulopustular rosacea or those with ocular involvement, systemic therapy is often prescribed and options include doxycycline, erythromycin, metronidazole, minocycline, tetracycline, or in severe cases, low dose isotretinoin. The telangiectatic component does not respond to either oral or topical therapy, and is best treated with laser and light-based therapies. Surgical intervention may be required for the phymatous subtype. Therapeutic choices will depend on patient expectations, tolerance, previous therapies used, rosacea subtype, and severity. This article will focus on topical therapies for rosacea.

Azelaic Acid (AZA)

AZA is a newer therapeutic option for the treatment of rosacea. It was approved by the US FDA in 2002, the European Union in 2003, and in Canada in 2004, although it has only recently become commercially available in Canada. AZA is a naturally occurring dicarboxylic acid that can be found in dietary sources, such as whole grains.³ It lacks toxicity, is nonteratogenic and nonmutagenic.⁴ It has multiple biologic effects including anti-inflammatory, antikeratinizing and antibacterial activities. The likely mechanism of action is via inhibition of reactive oxygen species produced by neutrophils.⁴

A novel 15% gel formulation (Finacea®, Intendis/Bayer) is available for the treatment of rosacea, in addition to a 20% cream formulation approved for use in 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. Multiple reviews have been published examining the use of AZA in rosacea.^3,5,6 Two pivotal phase III trials have shown that AZA 15% gel, applied twice daily for 12 weeks, was superior when compared with the vehicle for patients with papulopustular rosacea.⁷ A mean reduction in inflammatory lesion counts ranged from 51%-58% in the AZA group, compared with 39%-40% in the vehicle group. Improvement in erythema scores ranged from 44%-46% in patients treated with AZA, compared with 28%-29% in the vehicle group.⁷ In a 15-week study, AZA 15% gel applied twice daily also showed significant benefit over metronidazole 0.75% gel.⁸ In these studies, the use of AZA 15% gel led to a mean reduction in inflammatory lesion counts ranging from 51%–73% and a reduction of erythema severity ranging from 44%–56%. The number of patients achieving success, as defined by the investigator global assessment, ranged from 61%–69%.^7-9

A split-face study by Maddin10 comparing AZA 20% cream with metronidazole 0.75% cream, showed a reduction in inflammatory lesions of 78.5% and 69.4%, respectively. There was also a reduction in erythema of 25.5% and 18.7% for AZA and metronidazole, respectively. Both treatments led to a significant reduction in inflammatory lesions over 15 weeks, but the difference between treatments was not significant.10 Of note, the physician rating of global improvement was significantly higher on the side treated with AZA at both weeks 9 and 15.¹⁰ In the comparative studies, AZA had a greater potential to cause irritation than the metronidazole, which included facial skin signs and symptoms. However, these events were reported as mild to moderate and transient in nature.⁸ There was no improvement reported in telangiectasia severity in any study of AZA for rosacea.

The dosing recommendation for AZA 15% gel is a twice daily application. However, Thiboutot et al. found once daily dosing to be as effective as twice daily.¹¹ Research has shown that AZA when used as a treatment for papulopustular rosacea is a safe and effective and exhibits a favorable tolerability profile.

Metronidazole

Metronidazole has been the mainstay of topical rosacea treatment. It is a nitroimidazole antibiotic whose mechanism of action in rosacea is not well established, but appears to work through an anti-inflammatory mechanism.^12,13 It is the most widely used topical agent for rosacea and is available in a 0.75% gel, lotion, and cream format for twice daily use, and a 1% cream or gel for once daily use. Jorizzo et al.¹⁴ found that once daily dosing of 1% metronidazole cream was as effective as twice daily dosing. It is generally well tolerated and has a low incidence of adverse effects.^12,13 A recent review by the Cochrane Collaboration¹⁵ and a condensed version of this work by van Zuuren et al.5, summarizes 9 “high and intermediate quality” trials, which show clear evidence that topical metronidazole is significantly more effective than vehicle alone. Most of these studies used 0.75% metronidazole and ranged from 8-9 weeks in duration, with 1 trial lasting 6 months. A reduction in inflammatory lesions and erythema scores were noted, as was an improvement in physician’s global evaluation, and patient-assessed measures when these were
available.^5,15 No benefits were noted for the 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 SPF ^15.16

Although data are limited, 2 studies have shown that topical metronidazole may be as effective as oral tetracycline in reducing the inflammatory component of rosacea.^17,18 Efficacy of metronidazole is constant regardless of the formulation, strength, and frequency of application.12 This drug also plays a role in maintenance therapy, either with or without prior concomitant systemic antibiotic therapy.¹² Given its high efficacy and tolerability, it will continue to play an important role in the management of rosacea.

Sodium Sulfacetamide 10% + Sulfur 5%

Sodium sulfacetamide 10% + sulfur 5% is an older treatment that has gained new popularity. It is used to treat acne, rosacea, and seborrheic dermatitis,13 and is available in
multiple formulations as a lotion, cream, gel, or cleanser.^9,13 The mechanism of action is not well understood, but the sulfacetamide has antibacterial properties, and the sulfur component confers antifungal, antidemodectic, and keratolytic effects.¹⁹ Two studies, one comparing the sodium sulfacetamide-sulfur combination with the vehicle and another comparing it with metronidazole 0.75% gel, showed a significant reduction in both inflammatory lesion counts and erythema scores in papulopustular rosacea.^19,20

Other Therapies

Many other topical treatments for rosacea have been reported. Some are effective, but are not yet approved. Further investigation is needed to determine their potential role in the topical armamentarium of rosacea therapy.

• Topical antibiotics (e.g., clindamycin lotion or cream) have shown benefit, but evidence supporting their use is lacking.
• The calcineurin inhibitors, tacrolimus (Protopic®, Astellas Pharma) and pimecrolimus (Elidel®, Novartis), have been investigated for use in papulopustular rosacea because of their anti-inflammatory effects. Early reports suggested benefit from tacrolimus in the treatment of steroid-induced rosacea.²¹ However, while 3 studies have demonstrated a reduction in erythema associated with rosacea, neither tacrolimus nor pimecrolimus had any benefit over vehicle with respect to lesion counts.^22-24
• Clindamycin 1%-benzoyl peroxide 5% gel, which is approved for use in acne vulgaris, has shown promise for rosacea therapy. A double-blind, randomized controlled trial using this once daily formulation showed a significant reduction in inflammatory lesion count, erythema severity, and overall rosacea severity. The treatment was well tolerated.²⁵
• Permethrin 5% cream, which is proposed to work because of its anti-parasitic effects, may target Demodex mites, a potential cause of rosacea.13 This formulation was compared in 1 study with the vehicle and with metronidazole 0.75% gel, and was found to be superior to the vehicle and equal in efficacy to metronidazole.²⁶
• Topical retinoids have been used to treat rosacea, but the true efficacy has not been established. Their use is limited by their irritant potential. Nally and Berson13 suggested that better tolerated agents, e.g., adapalene, should be considered.
• Topical steroids are sometimes used on a short-term basis for the severe inflammatory component, but long-term side-effects and exacerbating potential limit their use in this chronic condition.¹³
• There is anecdotal evidence of 4 patients with erythematotelangiectatic rosacea who were treated successfully with oxymetazoline, a topically applied selective á1-adrenergic receptor agonist. The impressive results of this treatment warrant further study.^27,28

Conclusions

Because of its chronic, inflammatory nature, rosacea requires continuous management. Treatment can be tailored to the subtype and may involve a combination of therapies. Patients should first be counseled on the triggers of rosacea, proper skin care, photoprotection, and camouflaging cosmetic options. Topical therapy is usually first line, but in moderate to- severe cases, or those with ocular involvement, systemic therapy may be required. Laser or light-based treatments and surgical procedures can offer added benefit. Many topical agents are available for the treatment of rosacea, and the erythematotelangiectatic and papulopustular variants usually respond most favorably. There is good evidence that topical AZA and metronidazole are both safe and effective treatments. Other treatment options also include sodium sulfacetamide 10%-sulfur 5%, benzoyl peroxide 5%-clindamycin 1%, or clindamycin alone.

References

1. Wilkin J, Dahl M, Detmar M, et al. Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol 50(6):907-12 (2004 Jun).
2. National Rosacea Society. What is rosacea? Available at: www.rosacea.org. Accessed January 20, 2009.
3. Gupta AK, Gover MD. Azelaic acid (15% gel) in the treatment of acne rosacea. Int J Dermatol 46(5):533-8 (2007 May).
4. Breathnach AS. Azelaic acid: potential as a general antitumoural agent. Med Hypothesis 52(3):221-6 (1999 Mar).
5. van Zuuren EJ, Gupta AK, Gover MD, et al. Systematic review of rosacea treatments. J Am Acad Dermatol 56(1):107-15 (2007 Jan).
6. Liu RH, Smith MK, Basta SA, et al. Azelaic acid in the treatment of papulopustular rosacea: a systematic review of randomized controlled trials. Arch Dermatol 142(8):1047-52 (2006 Aug).
7. Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from 2 vehicle-controlled, randomized phase III studies. J Am Acad Dermatol 48(6):836-45 (2003 Jun).
8. Elewski BE, Fleischer AB, Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol 139(11):1444-50 (2003 Nov).
9. Bikowski JB, Goldman M. Rosacea: where are we now? J Drugs Dermatol 3(3):251-61 (2004 May-Jun).
10. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol 40(6 Pt 1):961-5 (1999 Jun).
11. Thiboutot DM, Fleischer AB, Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol 7(6):541-6 (2008 Jun).
12. McClellan KJ, Noble S. Topical metronidazole: a review of its use in rosacea. Am J Clin Dermatol 1(3):191-9 (2000 May-Jun).
13. Nally JB, Berson DS. Topical therapies for rosacea. J Drugs Dermatol 5(1):23-6 (2006 Jan).
14. Jorizzo J, Lebwohl M, Tobey RE. The efficacy of metronidazole 1% cream once daily compared with metronidazole 1% cream twice daily and their vehicles in rosacea: A double-blind clinical trial. J Am Acad Dermatol 39(3):502-4 (1998).
15. van Zuuren EJ, Graber MA, Hollis S, et al. Interventions for rosacea. Cochrane Database Syst Rev 20(3):CD003262 (2005 Jul 20).
16. Tan JKL, Girard C, Krol A, et al. Randomized placebo-controlled trial of metronidazole 1% cream with sunscreen SPF 15 in treatment of rosacea. J Cutan Med Surg 6(6): 529-34 (2002 Nov-Dec).
17. Nielsen PG. A double blind study of 1% metronidazole cream versus systemic oxytetracycline therapy for rosacea Br J Dermatol 109(1):63-5 (1983 Jul).
18. Veien NK, Christiansen JV, Hjorth N, et al. Topical metronidazole in the treatment of rosacea. Cutis 38(3):209-10 (1986 Sep).
19. Sauder DN, Miller R, Gratton D, et al. The treatment of rosacea: the safety and efficacy of sodium sulfacetamide 10% and sulfur 5% lotion (Novacet) is demonstrated in a double-blind study. J Dermatolog Treat 8(2):79-85 (1997).
20. Lebwohl M, Medansky RS, Russo CL, et al. The comparative efficacy of sodium sulfacetamide 10% /sulfur 5% (Sulfacet-R®) lotion and metronidazole 0.75% (Metrogel®) in the treatment of rosacea. J Geriatr Dermatol 3(5):183-5 (1995).
21. Goldman D. Tacrolimus ointment for the treatment of steroid-induced rosacea: a preliminary report. J Am Acad Dermatol 44(6):995–8 (2001 Jun).
22. Bamford JT, Elliott BA, Haller IV. Tacrolimus effect on rosacea. J Am Acad Dermatol 50(1):107-8 (2004 Jan).
23. Karabulut AA, Izol Serel B, Eksioqlu HM. A randomized, single-blind, placebo-controlled, split-face study with pimecrolimus cream 1% for papulopustular rosacea. J Eur Acad Dermatol Venereol 22(6):729-34 (2008 Jun).
24. Weissenbacher S, Merkl J, Hildebrandt B, et al. Pimecrolimus cream 1% for papulopustular rosacea: a randomized vehicle-controlled double-blind trial. Br J Dermatol 156(4):728-32 (2007 Apr).
25. Breneman D, Savin R, VandePol C, et al. Double-blind, randomized, vehicle-controlled clinical trial of once-daily benzoyl peroxide/clindamycin topical gel in the treatment of patients with moderate to severe rosacea. Int J Dermatol 43(5):381-7 (2004 May).
26. Koçak M, Ya¡gli S, Vahapo¡glu G, et al. Permethrin 5% cream versus metronidazole 0.75% gel for the treatment of papulopustular rosacea: a randomized double-blind placebo-controlled study. Dermatology 205(3):265-70 (2002).
27. Shanler SD, Ondo AL. Successful treatment of the erythema and flushing of rosacea using a topically applied selective alpha1-adrenergic receptor agonist, oxymetazoline. Arch Dermatol 143(11):1369-71 (2007 Nov).
28. Shanler S, Ondo A. Successful treatment of the erythema and flushing of rosacea using a topically applied selective .1-adrenergic receptor agonist, oxymetazoline (Abstract). J Am Acad Dermatol 58(2):AB9 (2008 Feb).

The major goals of rosacea treatment are to:

• Understand the condition
• Identify and avoid the factors that cause flushing for you and that flare your rosacea
• Control the active symptoms and signs of rosacea
• Achieve optimum maintenance of this condition and its complications
• Understand that this is a chronic condition

Self Help:

1) Aggravating factors – These factors can increase your core body temperature:

• Exposure to weather – sun, cold, wind
• Hot food, hot drinks, and alcohol
• Exercise (you should exercise in cool surroundings and avoid dehydration)
• Medications (you should avoid vasodilating drugs, that is, drugs that expand your blood vessels, and topical steroids)
• Cosmetics (you should avoid greasy, drying, or perfumed products)

2) Daily skin care:

• Avoid hot water, loofahs, and rough towels
• Avoid toners, exfoliating agents, and astringents
• Dandruff – Rosacea frequently coexists with sebhorreic dermatitis or dandruff

3) Cosmetics:

Cosmetic cover-up:

• Anti-redness cream, awaits fuller evaluation – Rosacure® is a silymarin extract that claims to reduce the facial redness in rosacea.

4) Patient Support Groups

Medical Treatment:

• For mild rosacea, topical therapy is always the first choice
• When rosacea is more severe, topical therapy must often be combined with oral treatment
• Creams and oral antibiotics are not effective in treating the flushing of the face, or the broken blood vessels