Therapies to Improve the Cosmetic Symptoms of Rosacea

Rosacea is a commonly encountered chronic inflammatory skin disease that affects an estimated 16 million Americans and exhibits a particular predilection for the convexities of the central face (eg, forehead, cheeks, nose, chin).^1,2 The pathophysiology of rosacea remains poorly understood despite the relatively high prevalence of the disease and substantial ongoing research.³ The current paradigm suggests a complex multifactorial interplay involving aberrations of the innate and adaptive immune system, neurovascular dysregulation, blood and lymphatic vessel changes, genetic predispositions, and overgrowth of commensal organisms such as Demodex.³ Additionally, a variety of external factors may exacerbate clinical symptoms (eg, UV radiation, heat exposure, spicy food, alcohol, stress).

The diagnosis of rosacea is made clinically and rarely requires histologic confirmation. Although rosacea can present with a wide range of clinical features that often wax and wane over time, a near universal finding is diffuse centrofacial erythema.⁴ This centrofacial redness may symptomatically worsen during a flare period, causing flushing, but it often persists nontransiently between flares as background erythema. Other variable findings of rosacea include the presence of telangiectases, edema, plaques, phymatous changes, dry skin, ocular manifestations, and inflammatory lesions in the form of papules and pustules.⁵ Patients also may report a stinging or burning sensation in affected areas. It is important to note that most patients will only exhibit some of these clinical features and that symptoms often vary in the timing of their emergence or regression.⁵ A classification system has been developed for rosacea that categorizes the disease into 4 subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) and one variant (granulomatous).⁶ These categories are determined by the grouping of clinical features present, but it is not uncommon for patients to exhibit clinical manifestations of more than 1 subtype.⁷

The detrimental cosmetic effects of rosacea are obvious given its chronic nature and tendency to affect highly visible areas such as the face. As such, rosacea can have a devastating impact on patients’ quality of life.⁸ Patients with rosacea have been reported to have higher incidence rates of low self-esteem, embarrassment, social anxiety, and depression as compared to the rest of the population. Effective treatment, however, can improve cosmetic appearance and mitigate the negative psychosocial impacts of the disease.⁸

Treatment of rosacea focuses on relieving cosmetic symptoms, as no curative therapy currently exists. Treatment comes in a wide variety of forms, including topical medications, systemic pharmacologic therapies, light-based modalities, and procedural interventions. Choice of therapy should be determined on a case-by-case basis as guided by the clinical features present, and combination or sequential therapies often are required to achieve optimal cosmetic results. In this article, we review both existing and emerging treatments of rosacea and assess their ability to improve the cosmetic symptoms of rosacea (Table).

Skin Care

Proper skin care is an important aspect of treatment for all patients with rosacea and thus includes the use of over-the-counter cleansers, moisturizers, and sunscreens.⁹ The choice of skin care products is an important consideration given the often hypersensitive skin of rosacea patients. Moisturizers and cleansers should have an acidic to neutral pH, similar to normal skin. They should not contain emulsifiers that strip moisture from the skin or protective lipids and proteins from the stratum corneum.¹⁰ Moisturizers without irritants, abrasives, or allergens should be used following skin cleansing. Protection from UV radiation with sunscreen, ideally with a sun protection factor greater than 30, is particularly important, as it can prevent UV-induced rosacea flares as well as photodamage that can cause additional erythema and telangiectasia.⁴ Rosacea patients also may find green-tinted makeup to be useful in concealing areas of erythema.⁸

Topical Therapy

Currently, there are only 5 US Food and Drug Administration (FDA)–approved topical medications for the treatment of rosacea: metronidazole (MTZ) gel 0.75% and 1%, azelaic acid (AzA) gel 15%, sodium sulfacetamide (SS) 10%–sulfur 5% lotion and cream, brimonidine tartrate (BT) gel 0.5%, and the most recently approved ivermectin (IVM) cream 1%.⁷ Metronidazole, AzA, and SS primarily are used to treat the inflammatory papules and pustules of rosacea, while BT is used to treat persistent background erythema. The exact mechanisms of action by which MTZ, AzA, and SS treat rosacea are unclear, but they are thought to reduce inflammation and/or immune response. Metronidazole and AzA both have demonstrated favorable safety profiles and significant (P<.05) efficacy over vehicle in reducing inflammatory lesions in numerous well-controlled randomized clinical studies.^4,11,12 There is some evidence that AzA may be more effective than MTZ; one 15-week multicenter, double-blind, randomized, parallel-group study demonstrated that twice-daily AzA gel 15% showed significant superiority (P=.02) over twice-daily MTZ gel 0.75% in improving the inflammatory lesions and erythema of rosacea.¹³ Sodium sulfacetamide also has shown good efficacy in the treatment of inflammatory lesions and performed significantly better (P=.04) than MTZ according to one multicenter, investigator-blinded, randomized, parallel-group study,¹⁴ but the overall evidence is not as strong as MTZ and AzA.^4,11,15 The most common adverse effect for MTZ, AzA, and SS is application-site irritation, but overall most patients report good tolerance to these topical medications.⁴ Azelaic acid is unique in that patients may report stinging, tingling, or burning after application, but these effects are not associated with visible skin changes and usually are transient, generally remitting after 1 to 2 weeks.⁴

Brimonidine tartrate is a highly selective α₂-adrenergic receptor agonist whose mechanism of action in the treatment of rosacea is thought to involve vasoconstriction of superficial skin vasculature and to a lesser extent anti-inflammatory effects.¹⁶ In a double-blind, randomized, vehicle-controlled phase 3 trial, application of BT gel 0.5% once daily for 4 weeks demonstrated significant efficacy over vehicle (P<.001) in treating persistent nontransient facial erythema in 553 adult patients with 2 or fewer papulopustular lesions as evaluated over 12 hours on days 1, 15, and 29.¹⁷ Notably, a substantial difference in cosmetic appearance was observed in another study as early as 30 minutes after the first gel application on day 1.¹⁸ The results of this phase 3 trial¹⁷ mirrored those of the phase 2 dose-optimization and safety studies of similar design.¹⁸ In addition to another long-term, 1-year, open-label study,¹⁹ both phase 2 and 3 studies have shown favorable safety profiles with no reports of tachyphylaxis, rebound erythema, or aggravation of other disease features such as telangiectases or inflammatory lesions.^17,18 Recently, however, there have been some reports of considerable rebound erythema with BT use and thus patients should be made aware of this possibility.^20,21 Case reports of successful treatment of background erythema and flushing with other topically applied adrenergic receptor modifiers such as oxymetazoline and xylometazoline have been published in the literature,^22,23 but additional research will be necessary to validate these claims.

Ivermectin, a decades-old antiparasitic, has recently shown promising results as a treatment of rosacea patients with moderate to severe papulopustular lesions. Its therapeutic effect is believed to be mediated by its activity against Demodex, a natural skin mite that has been found at increased concentrations in a subset of patients with rosacea, as well as by its natural anti-inflammatory properties.²⁴ In 2 identically designed, randomized, double-blind, controlled trials of IVM cream 1% applied once daily for 12 weeks, a significantly larger proportion of patients in the IVM groups achieved an investigator global assessment of clear or almost clear as compared to vehicle (IVM: 38.4% and 40.1%, respectively; vehicle: 11.6% and 18.8%, respectively; P<.001). Both trials also demonstrated that IVM was significantly superior to vehicle in the reduction of inflammatory lesion counts measured at week 12 as compared to baseline (IVM: 76.0% and 75.0%, respectively; vehicle: 50.0% and 50.0%, respectively; P<.001).²⁴ An extension of these original trials demonstrated long-term safety with up to 52 weeks of topical IVM use and reported a low incidence rate of adverse effects, most commonly transient skin burning, pruritus, and dryness. Notably, the incidence rate of these adverse effects was lower than a comparison group receiving AzA gel 15% once daily.²⁵ Once-daily application of IVM cream 1% also has recently demonstrated superiority over twice-daily MTZ cream 0.75% for 16 weeks in a phase 3 investigator-blinded, randomized, parallel-group study. The IVM group was significantly superior to MTZ in the reduction of inflammatory lesions as compared to baseline (83.0% vs 73.7%) and in the number of participants who achieved an investigator global assessment score of clear or almost clear (84.9% vs 75.4%)(both P<.001).²⁶ There also is limited evidence for the use of other antiparasitic topical medications such as crotamiton 10% and permethrin 5%, but such agents frequently cause irritation and may not be well tolerated in rosacea patients.^27-29

There are a variety of other non–FDA-approved topical medications that have been used with varying success in the literature, including cyclosporine, macrolides, benzoyl peroxide, retinoids, and calcineurin inhibitors such as tacrolimus and pimecrolimus. Evidence for the use of these medications generally is limited to a few studies with small numbers of patients and will not be discussed further in this article.^4,11,30 These agents, however, may be useful in select cases when first-line regimens have failed and also may be good targets for future research.