Management of facial flushing in rosacea

Rosacea can be defined as a chronic, relapsing inflammatory condition that affects the central portion of facial skin. The condition is thought to affect up to 10% of the population and is more commonly experienced by fair-skinned individuals of Celtic or Northern European heritage.(1)

Rosacea occurs more frequently in women (although men tend to experience more severe disease) and in those aged between 30 and 50 years. A system for classifying rosacea was developed in 2002 and revised in 2004.(2) This defines four sub-types that are shown in Box 1; in practice, aspects of each of the sub-types can be present to varying degrees in the same patient. Irrespective of the sub-type, a diagnosis of rosacea is made in patients having one or more of the following primary features:

Secondary features such as a burning or stinging sensation, oedema, phymatous changes and ocular involvement may also be present. The highly visible nature of rosacea has a huge psychological impact on sufferers. In a survey by the National Rosacea Society (in the US) of 603 patients, 76% stated that rosacea led to a reduction in self-confidence and self-esteem, while 69% had experienced embarrassment because of their condition.(3)

The precise cause of rosacea remains unclear and given the different sub-types it is likely that the cause is multifactorial. Inheritable factors are important and a family history is reported in as many as 30% of sufferers. Patients with rosacea cite potential trigger factors as increased temperature, ingestion of hot drinks, alcohol, spicy foods and exposure to both cold weather and ultraviolet (UV) radiation. These triggers lead to increased flushing and a sensation of burning or stinging in the skin and have led to the suggestions that the cause is related to aberrant changes within the innate immunity and neurovascular systems. The innate immune system in the skin detects and responds to the dangers posed by various environmental factors, for example, noxious chemicals, microbes, UV radiation, etc, through activation of toll-like receptors (TLR). These receptors identify foreign molecules and initiate an inflammatory response. One group of compounds produced in response to activation of TLRs are the cathelicidins and one particular cathelicidin, LL-37, has been extensively studied. The cathelicidins are endogenous antimicrobial peptides with multiple roles including induction of cellular inflammation, angiogenesis (increased vascularity) and stimulation of pro-inflammatory cytokines. Higher than normal levels of cathelicidin have been found in the skin of patients with rosacea and injection of cathelicidin fragments into mouse skin results in a rosacea-like dermatitis.4 Furthermore, rosacea skin also contains higher levels of kallikrein 5, the enzyme that produces cathelicidin,(5) LL-37, as well as the matrix metalloproteinase enzymes, which induce production of kallikrein 5.

Taken together, these observations suggest that rosacea patients have an oversensitive innate immune system, which, in turn, leads to an abnormal response to environmental triggers. The heightened response induces greater than usual levels of the pro-inflammatory, anti-microbial, cathelicidin, LL-37, which evokes further downstream events that ultimately give rise to the vascular changes observed. Unfortunately, many of the vascular changes are irreversible, hence the occurrence of persistent erythema and telangiectasia.

Most of the currently available oral and topical treatments for rosacea are directed at managing sub-type 2, that is papulopustular rosacea. Commonly used therapies include topical antibiotics such as metronidazole or azelaic acid, with more severe cases requiring oral antibiotics such as doxycycline. While these therapies reduce lesion counts and the associated inflammation, they are less effective at resolving the persistent erythema.

Rhinphyma rosacea usually requires surgical intervention although isotretinoin (unlicensed use) can be helpful in the early stages. Ocular rosacea can also be managed to some extent with oral antibiotics.

Studies suggest that erythematotelangiectatic rosacea (ETR) (sub-type 1) is the most common presentation of rosacea and affects more than 70% of patients.(6,7) Despite this, ETR has been the most difficult form to treat. General advice has centred on avoidance of trigger factors in addition to the need for daily sunscreen use and a recommendation to use a high water content moisturiser to minimise the effect of burning or irritation. Nevertheless, this approach rarely leads to a satisfactory resolution of symptoms for most patients. Several treatments for ETR have been used with varying degrees of success. Beta-blockers, which exert vasoconstrictor effects, have met with limited success due to the problems of hypotension and bradycardia. Nonetheless, recently it was shown that carvedilol could be successfully used to treat a small number of patients with persistent erythema unresponsive to other therapies.(8) Other options have included the pre-synaptic centrally acting a-blocker, clonidine, at a dose of 50µg twice daily. However, this is an unlicensed use and there is no clinical trial evidence to support its use in rosacea. Other treatment options have included the use of lasers.(9)

In recent years, several case reports have suggested a role for a1-adrenergic agonists. Case reports on the use of oxymetazoline 0.05% solution and xylometazoline 0.05% appeared in the literature in 2007. A nasal solution of oxymetazoline was applied to patients’ facial erythema that reduced one hour after application and continued to improve over the next two to three hours with the effect lasting several hours.(10) The mode of action is related to the vasoconstrictor action of oxymetazoline, although some evidence suggests that the drug also exerts an anti-inflammatory action.(11)

The possible usefulness of vasoconstrictor a-agonists prompted the search for other potential agents in the treatment of ETR. To date only one product, Mirvaso^®, has received a licence.

Brimonidine tartrate 0.5% (Mirvaso^®) is a highly selective a2-adrenoceptor agonist indicated for the treatment of the persistent facial erythema due to rosacea, that is, ETR. The drug has been available for many years as an eye-drop (Alphagan^®) for the management of raised intraocular pressure associated with either open-angle glaucoma or ocular hypertension. The drug was launched in the UK in April 2014 but has been available in the US since September 2013.

The site of action for brimonidine is the adrenoceptors in the smooth muscle vasculature, and studies suggest that vasoconstriction is mediated via a-receptors, in particular post-synaptic a2-adrenoceptors.12 As discussed above, though the vasodilatation of small vessels is permanent (hence the persistent erythema), the vasoconstriction induced by a-blockers offers a potential means of managing the erythema.

Efficacy data for brimonidine come from several studies. Two dose-ranging Phase II randomised, double-blind controlled trials (presented in the same paper) included 304 patients with moderate to severe, persistent facial erythema.(13) In addition, a second trial (again incorporating two separate studies)(14) included 553 patients. Finally, 449 patients were included in a 12-month open-label safety trial(15) although only 279 (62.1%) were retained for 12 months. Both studies(13,14) included only patients with ETR rosacea and excluded those with papulopustular disease or, if present, those with minimal inflammatory lesions. However, the open-label trial included patients (29%) who were prescribed concomitant topical or oral therapy for rosacea.

During the trials, assessment of erythema was based on two scales: a clinician erythema assessment and a patient self-assessment. Both tools utilised a 5-point scale ranging from 0 (clear) to 4 (severe). A 1-point change in either scale was noticeable and therefore deemed clinically relevant. Skin colouration was also independently measured using a chromameter, which provides an objective assessment of skin colour. The degree of telangiectasia was assessed using a 5-point scale ranging from clear (0) to severe (4). All trials enrolled patients with moderate to severe erythema, defined as a value of 3 to 4 on each erythema scale. Patients applied Mirvaso® once a day and assessments were made at baseline, after 30 minutes and then hourly over the next 12 hours.

The primary outcome measure was a 2-point change in erythema score, which was assessed after 29 days of treatment. A summary of the results obtained from two of the trials(14) is shown in Table 1. During the study, it was found that Mirvaso^® had a relatively fast onset of action. Thirty minutes after application on the first day, 27.9% (n=129) of patients experienced a 1-point change in erythema score in study A compared with 28.4% (n=148) in study B.(14) The maximum effect of the drug was observed between two and eight hours after administration and while erythema returned after 12 hours, it did not reach baseline values.(13 )

In the 12-month study, small (and presumably non-significant) reductions in mean telangiectasia and inflamed lesions scores were recorded.

A summary of the adverse events noted during the 12-month open-label study with brimonidine 0.5% are shown in Table 2.

A particular concern with the use of a-agonists in the management of nasal congestion is the potential for tachyphylaxis (loss of effect) and a rebound (worsening of erythema) effect on cessation of therapy. In the study by Fowler et al,(14) it was observed that at week 8 (four weeks after cessation of treatment) 2.1% of patients in the treatment group experienced a worsening of erythema scores relative to their baseline (pre-treatment) values.

The manufacturer recommends a maximum dosage of 1g/day, divided into pea size amounts and applied to the forehead, both cheeks, nose and chin. The product is available as a 30g tube costing £33.69, which is 30 days’ treatment.

Many health professionals and patients appreciate that until recently there has been no effective treatment for the persistent erythema associated with ETR. Based on the current evidence and until other treatments become available, Mirvaso® represents an important development in the management of this common and distressing condition.