Redness in Rosacea: Still an Unmet Medical Need

Miami Beach, FL—Although there are effective treatments for rosacea, none of the currently available topical or oral medications directly target the persistent generalized facial erythema (ie, redness) that is a primary characteristic of the condition, according to Diane S. Berson, MD, Dermatologist at the Iris Cantor Women’s Health Center, NewYork-Presbyterian/Weill Cornell Medical Center.

“Many products claim to have ‘antiredness’ ingredients, including those sold over the counter and those sold in doctor’s offices. In reality, they may help to some degree, but they do not target vasodilatation,” Dr Berson said in her discussion of rosacea at the 2013 American Academy of Dermatology (AAD) annual meeting. “Currently, all we really have for our patients with redness are office-based procedures, such as laser treatments.”

The skin of patients with rosacea contains blood vessels that are dilated and that secrete proinflammatory factors.  The ability to target and constrict those vessels (ie, vasoconstriction) would prevent the leakage of these proinflammatory mediators and thus reduce the redness inherent in the condition now known as erythematotelangiectatic rosacea (ETR), she explained.

“Two basic things are happening with ETR at the molecular level: chronic inflammation and flushing, which is a vasodilatory phenomenon,” Dr Berson said.  Patients with rosacea have an altered innate immunity (ie, an exaggerated immune reaction to triggers). Light, heat, certain foods, Demodex mites, and other factors stimulate the expression of proinflammatory factors (ie, cytokines, matrix metalloproteinases). This produces chronic inflammation while there is simultaneous vascular hyperactivity. In rosacea, Dr Berson said, “You get vasodilatation, neovascularization, flushing, and redness.”

Topical Agents on the Horizon
None of the agents that are currently approved by the US Food and Drug Administration (FDA) are vasoconstrictors that are able to address the redness of rosacea, although some may exert anti-inflammatory properties, Dr Berson pointed out.

Two new topical agents that are now in clinical trials should help fill this unmet medical need, she noted. Brimonidine tartrate 0.5% gel, which has completed phase 2 and phase 3 clinical trials (details for the phase 3 trial discussed below), is a selective alpha-2 adrenergic receptor agonist; as an ophthalmologic preparation, brimonidine (Alphagan) is currently used for glaucoma.

Brimonidine tartrate 0.5% gel stimulates the vasculature of the smooth muscles lining the blood vessels of the skin, thereby causing vasoconstriction. The onset is less than 30 minutes, the maximum effect is observed in 4 to 6 hours, and the efficacy persists for 12 hours, Dr Berson noted.

“If the patient applies this in the morning, she can have decreased redness all day,” she emphasized.

Telangiectasia, however, is unaltered, because these tiny capillaries lack smooth muscle. There is also no change in inflammatory lesions as a result of this treatment; however, these problems are managed by other available products. Tachyphylaxis is absent, meaning that there is no diminishing effect over time and no rebound worsening. “When the patient discontinues treatment, she will eventually return to baseline but will not look worse,” Dr Berson maintained.

The second agent, oxymetazoline cream, is a selective alpha-1 agonist that is a component of many topical decongestants that are currently in phase 2 testing. Oxymetazoline has also demonstrated a prompt onset of action.

“We anticipate FDA approval of these agents, and this will be very helpful for our patients with the ETR form of rosacea,” she said.

Erythema of Rosacea Responds to Investigational Brimonidine TartrateGel
At the AAD meeting, researchers reported good results with topical brimonidine tartrate gel 0.5% in a controlled study led by Joseph F. Fowler, Jr, MD, Clinical Professor of Dermatology, University of Louisville, and President, North American Contact Dermatitis Group.

In this phase 3 trial, “once-daily brimonidine tartrate gel 0.5% provided significantly greater efficacy and a faster onset of action (30-minute effect) compared with the vehicle gel (ie, placebo) for the topical treatment of facial erythema of rosacea, and adverse events were overall similar to vehicle gel,” Dr Fowler reported.

Brimonidine tartrate is a highly selective alpha-adrenergic receptor agonist with potent subcutaneous vasoconstrictive activity.

These data are from a large, phase 3, multicenter, randomized, double-blind, parallel-group, vehicle (placebo)-controlled study of 325 individuals with rosacea. Patients had moderate-to-severe erythema according to the clinician’s erythema assessment and the patient’s self assessment, which are both 5-point scales (0 = clear). The patients were randomized to brimonidine tartrate gel 0.5% or to placebo, applied once daily for 8 weeks, which included a 4-week treatment phase and a 4-week follow-up phase.

Patients were assessed on days 1, 15, and 29, and at weeks 6 and 8 during follow-up. Treatment was considered successful if it led to a 2-grade improvement on both outcome measures at each time point.

At the end of the treatment phase, the brimonidine tartrate gel 0.5% led to significantly greater 1- and 2-grade improvements on the clinician’s erythema assessment and patient’s self assessment compared with vehicle gel (both P <.001). The clinicians observed no loss of efficacy during the 4-week treatment phase. “The superiority of brimonidine tartrate gel 0.5% was demonstrated throughout the study,” Dr Fowler noted.

Based on the clinician’s erythema assessment and patient’s self-assessment on day 29, a 1-grade improvement was achieved by 57% of the patients receiving brimonidine gel versus 30% of those receiving placebo (P <.001); a 2-grade improvement was observed in 23% of the patients receiving brimonidine gel versus <1% of patients receiving placebo (P <.001).

Brimonidine gel also had a significantly faster onset of action—as early as 30 minutes after the first application. With brimonidine, 28% of the patients achieved a 1-grade improvement within 30 minutes of the first application compared with 7% of placebo-treated patients (P <.001).

Adverse events reported in this trial were comparable: 11.6% for brimonidine and 5.3% for placebo. The most frequent side effects with brimonidine were worsening of erythema (N = 5), itching (N = 4), skin irritation (N = 3), and flushing (N = 3). Most events were transient, dermatologic, and mild, and usually did not require discontinuation of treatment. No abnormal changes in blood pressure, heart rate, or laboratory parameters were reported in this trial.

DemodexMites In Focus
Frank Powell, MD, Acting Director and Chairman of the Board of Directors at the University College Dublin Charles Institute of Dermatology, Ireland, discussed at the AAD meeting the long-standing and evolving hypothesis that Demodex folliculorum (ie, mites) are pathogenic in patients with rosacea, citing recent studies that explore this concept.

Using confocal laser scanning microscopy on 25 patients with rosacea and 25 matched controls, researchers recently identified a mean number of mites of 165 per 8 × 8–mm area compared with 35 mites in controls. The corresponding mean numbers of mites per follicle were 0.7 and 0.1, respectively.¹ In a 2010 meta-analysis of 48 publications, the pooled odds ratio for developing rosacea in persons with Demodex infestation was 7.57; the degree of infestation played a more important role than did the mite infestation rate, Zhao and colleagues concluded.² “The degree is what is important,” Dr Powell said. “Normal controls also have mites in the skin.”

In 2012, Forton suggested that the inflammatory process of papulopustular rosacea appears to be a consequence of the proliferation of Demodex.³ Her research supports the hypothesis that a specific (innate or acquired) immune defect against Demodex allows the proliferation of the mite, and this is followed by a second stage in which mites penetrate into the dermis and the immune system is suddenly stimulated; this gives rise to an exaggerated immune response against Demodex, resulting in the papules and pustules of the rosacea.

“We all haveDemodex in our skin,” Dr Powell noted. “We probably don’t want to get rid of Demodex, because they may be doing something positive, but we want to reduce the population.” Although Dr Powell said that he personally does not use antimite treatments, they have been shown to be effective.

References

1. Sattler EC, et al. Noninvasive in vivo detection and quantification of Demodex mites by confocal laser scanning microscopy. Br J Dermatol. 2012;167:1042-1047.
2. Zhao YE, Wu LP, Peng Y, Cheng H. Retrospective analysis of the association between Demodex infestation and rosacea. Arch Dermatol. 2010;146:896-902.
3. Forton FM. Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. J Eur Acad Dermatol Venereol. 2012;26:19-28.