The highly visible nature of rosacea can have a huge psychological impact on sufferers. So what can pharmacists do to help them? 

 

 

Rosacea is defined as a chronic, relapsing, inflammatory condition that affects the central portion of facial skin. More frequently seen in fair-skinned individuals of Celtic or Northern European heritage, rosacea occurs more commonly in women (although men tend to experience more severe disease) and in those between 30 and 50 years of age.

A system for classifying rosacea defines four sub-types (see box) although, in practice, aspects of each sub-type will 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:

• Flushing (transient erythema)
• Non-transient erythema
• Papules and pustules
• Telangiectasia (visible blood vessels).

Secondary features such as oedema, phymatous changes and ocular involvement may also be present. The condition often progresses from a “pre-rosacea” phase, characterised by transient erythema, to episodes of repeated and then permanent flushing and inflammation. The erythema associated with rosacea can last up to 10 minutes (which allows for a distinction with flushing due to embarrassment).

The skin of patients with rosacea becomes extremely sensitive and can be rough with scaling. Sufferers often complain of having “sensitive skin” and of experiencing a burning or stinging sensation after using many topical products.

 

Pathophysiology

The precise cause of rosacea remains unclear but inheritable factors have a part to play – as many as 30 per cent of sufferers having a family history of rosacea. Typically, rosacea patients cite increased temperature, ingestion of hot drinks, alcohol, spicy foods and exposure to both cold and hot weather as potential trigger factors. These triggers, inducing flushing and a burning/ stinging sensation, suggest that the cause is related to aberrant changes within the innate immunity and neurovascular systems.

The innate immune system within the skin detects and responds to the dangers posed by various environmental factors (e.g. noxious chemicals, microbes, UV radiation) through activation of toll-like receptors (TLR). These receptors are able to identify foreign molecules and initiate an inflammatory response.

One group of compounds produced in response to activation of TLRs are antimicrobial peptides known as cathelicidins and one particular cathelicidin (LL-37) has been extensively studied.

The cathelicidins have multiple roles in the skin 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. Rosacea skin also contains higher levels of kallikrein 5, the enzyme that produces cathelicidin, as well as the matrix metalloproteinase enzymes that induce production of kallikrein 5.

For over 50 years there has been speculation that the Demodex folliculorum mite has a role to play in the pathophysiology of rosacea. Demodex is an arachnid mite, less than 1mm in length, which lives in the pilosebaceous follicles of facial skin and feeds on sebum and skin cells.

Rosacea sufferers have an over-sensitive innate immune system

Skin biopsies show that about 10 per cent of people with healthy skin are colonised with Demodex and the prevalence increases with age. For instance, 69 per cent of people between 30 and 50 years of age – the commonest age range in which rosacea first presents – have demodex infestation. Furthermore, the density of mites in the skin of rosacea sufferers is 10 times greater than in people without the condition.

While the precise role of the mite in rosacea has never been determined, recent studies suggest that Bacillus oleronius, a bacterium that resides in the digestive tract of the mite, may be a trigger. Microbiologist Dr Kevin Kavanagh suggests that as the mite dies, it releases bacteria and that bacterial antigens stimulate neutrophil recruitment and subsequently trigger the inflammatory response seen in rosacea.

The bacterium probably has a symbiotic relationship with the mite so that once killed, the mite population also diminishes. It is well established that rosacea gradually returns once antibiotic therapy ceases and Dr Kavanagh speculates that, as the mite population is re-established, the levels of B. oleronius again increases, leading to a rosacea relapse.

Dermatologist and rosacea expert, Dr Alison Layton, thinks it likely that Demodex could be both a risk factor and trigger for rosacea since it is rare in the absence of Demodex.

In summary, it appears that rosacea sufferers have an over-sensitive innate immune system which, in turn, leads to an abnormal response to environmental triggers. This heightened response induces greater than usual levels of the pro-inflammatory, antimicrobial cathelicidin LL-37, which gives rise to the vascular changes observed. Unfortunately, many of these vascular changes are irreversible; hence the occurrence of persistent erythema and telangiectasia.

Acne rosacea on the cheek of the face of a 44-year-old female patient

Treatment of rosacea

Papulopustular rosacea

Currently available treatments for rosacea are directed at managing sub-type 2 (papulopustular rosacea). Mild to moderate disease, defined as only a small number of papules and pustules, is normally managed with topical antibiotic agents such as metronidazole or azelaic acid. Other agents that have been used include topical clindamycin, tretinoin cream and benzoyl peroxide.

In more severe cases where there are a larger number of papules and pustules, treatment usually requires oral antibiotics such as tetracycline or oxytetracycline (500mg twice daily), both of which are licensed for the treatment of rosacea. Doxycycline (100mg daily) and lymecycline (408mg daily) are currently not licensed but are often used as alternatives.

The mode of action of antibiotics is due to their antiinflammatory rather than bactericidal effects. For example, antibiotics are known to up-regulate anti-inflammatory cytokines, block neutrophil migration/chemotaxis and the production of matrix metalloproteinase enzymes.

A 2011 Cochrane review of rosacea interventions concluded that there was “some evidence to support the effectiveness of topical metronidazole, azelaic acid and doxycycline (40mg) in the treatment of moderate to severe rosacea”. There is also some evidence that combining oral and topical therapies (e.g. doxycycline and azelaic acid) is more effective at bringing a flare under control more rapidly.

While oral therapies reduce lesion counts and the associated inflammation, they are less effective at resolving the persistent erythema.

Rhinophyma

Rhinophymatous rosacea does not respond to oral therapy and usually requires surgical intervention, although isotretinoin (an unlicensed use) can be helpful in the early stages.

Ocular rosacea

Ocular rosacea is initially managed with lid hygiene measures such as a hot compress applied to the eyelid margins.

Additionally, mild cleansing solutions, such as dilute baby shampoo, can be applied to the eyelids to remove debris. Patients often have dry eyes, so artificial tear solutions should be applied frequently throughout the day. An ointment-based product can be used at night. More severe disease can be managed with oral tetracyclines.

Self-care in rosacea

It is important that patients are aware of the potential triggers for rosacea and try to avoid these wherever possible. It is useful for patients to keep a diary to help identify and therefore minimise exposure to potential triggers. All patients should use a high factor, broad spectrum sunscreen every day and those with very dry skin should be advised to experiment with hypoallergenic emollients to help relieve the dryness.

Pharmacy teams can support people to self-manage their skin conditions

New and emerging therapies in rosacea

Studies suggest that ETR (sub-type 1) is the commonest presentation of rosacea, affecting more than 70 per cent of patients. Despite this, ETR has been the most difficult form of rosacea to treat and general advice has centred on avoiding triggers, which is not always possible.

Brimonidine tartrate 0.5% (Mirvaso) is a highly selective alpha-2-adrenoceptor agonist indicated for the treatment of the persistent facial erythema due to rosacea (i.e. ETR). The drug has been available for many years as an eye-drop (Alphagan) and Mirvaso was launched in April 2014.

The site of action for brimonidine is the adrenoceptors in the smooth muscle vasculature, as studies show that vasoconstriction is mediated via alpha-receptors, in particular post-synaptic alpha- 2-adrenoceptors. Although the vasodilatation of small vessels is permanent (hence the persistent erythema), the vasoconstriction induced by alpha-agonists offers a potential means of managing the erythema.

Efficacy data for brimonidine comes from several studies in which the extent of erythema was assessed using a five-point scale ranging from clear (0) to severe (5). The results showed that 28 per cent of patients experienced a one-point reduction on the scale after 30 minutes and one-third achieved a two-point reduction after three hours. 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.

Topical ivermectin

Data from phase III clinical trials suggest that a new topical treatment containing the arcaricidal agent, ivermectin, may be a useful treatment for papulopustular rosacea. The drug kills demodex mites and studies using a single dose of oral ivermectin have met with some success in rosacea. Full results are expected to be published later this year.

Conclusion

Rosacea is a common and psychologically disabling condition. Current treatments for the papulopustular form are effective but the introduction of Mirvaso to manage the erythematous sub-type is to be welcomed. As research continues to understand the mechanisms through which rosacea develops, it is likely that a wider range of effective treatments will become available in the future.