Rosacea: a symptom-based approach to management Edward Seaton MA, MRCP

Rosacea: a symptom-based approach to management Edward Seaton MA, MRCP VM Rosacea is a common skin condition of unknown aetiology. Dr Seaton describes the recommended management of the vascular and inflammatory symptoms. Figure 1. with features of persistent erythema and inflammatory papules and pustules; azelaic acid gel is the first-line topical treatment Rosacea is a chronic skin disease usually affecting the convex surfaces of the face in which a pattern of symptoms occurs, including facial flushing, erythema, telangiectasia, inflammatory papules or pustules and swelling (phymomas). It used to be thought that patients progressed from a propensity to flushing, through persistent erythema, to inflammation and eventually to phymomatous change, but it is now recognised that very different subtypes of rosacea exist, perhaps representing separate conditions altogether, and that most patients do not follow this strict progression. Incidence Rosacea is common, although the exact prevalence is unknown. It is commoner in fair-skinned (Celtic and northern European) races and very rare in black people. It accounts for 1-3 per cent of dermatology consultations in Sweden. Women are more commonly affected than men, although rhinophyma is uncommon in females. Rosacea usually starts between the ages of 30 and 50. Aetiology The cause of rosacea is unknown, but several factors have been proposed. Abnormal vascular reactivity Prominent flushing is a common feature in rosacea. Patients have an elevated resting facial blood flow that also increases abnormally in reaction to warming. It has been suggested that rosacea www.escriber.com Prescriber 5 April 2008 15

prolonged flushing dietary, environmental and emotional triggers persistent erythema sparing concavities burning, stinging and pain telangiectasias no inflammatory lesions persistent erythema sparing concavities flushing inflammatory papules and pustules tissue swelling as late event persistent swelling of nose, chin, forehead, cheeks or ears prominent pores thickened skin nodular, moonscape-like appearance as late event commoner in men itch, burning, stinging, dryness or watering blepharoconjunctivitis, chalazion or hordeolum may occur keratitis or visual disturbance if severe Table 1. Subtypes of rosacea patients have a primary error in control of vascular tone and that secondary leakiness of vasculature promotes inflammatory papules and swelling. However, reproducible abnormalities of vascular neurotransmission have not been identified. Alteration of the dermis by climactic insults Rosacea is commoner in the fair skinned, is rare on body sites that are normally clothed, and facial erythema is seen in those exposed to chronic heat. These observations suggest that environmental, climactic insults may be important. Exposure to ultraviolet light damages dermal elastin and collagen, and in rats causes blood vessel tortuosity. It has been suggested that sluggish blood flow in tortuous vessels might cause pooling of inflammatory mediators and vasoactive agents. Microbial organisms Demodex folliculorum is a mite that inhabits the skin of almost all humans. It has been proposed as a causative organism in rosacea because: abnormally high numbers of Demodex are found in patients with papulopustular rosacea an apparently associated inflammatory response can be seen in some biopsy specimens rosacea occurs in middle age and Demodex colonisation increases with age. However, topical rosacea treatments do not alter Demodex numbers and erythematotelangiectatic rosacea (ETR) patients have normal levels of colonisation. Historical textbooks suggested a link between rosacea and dyspepsia. However gastritis or Helicobacter pylori colonisation is not consistently associated with rosacea. Improvements noted with H. pylori eradication therapy are likely related to the antibiotics themselves rather than the organism s elimination. Chemicals and ingested agents Despite popular belief, there is no demonstrable causative link between alcohol and rosacea or rhinophyma, although it may precipitate flushing attacks in rosacea patients. Clinical features A working party of the American National Rosacea Society has suggested four subclassifications (see Table 1). The ETR subtype is characterised by symptoms of vascular rosacea, that is to say prolonged flushing (lasting many minutes), persistent erythema and telangiectasia. Scaling and roughness may also occur. Such patients typically describe stinging, discomfort or pain during flushing attacks or after applying topical products. Flushing attacks are commonly induced by alcohol, hot drinks, spicy food, exercise, cold or hot weather and hot baths or showers. Caffeine itself does not induce flushing. Erythema affects the convexities of the face and spares the perioral and periocular concavities, giving an appearance of ski-goggle sunburn. The papulopustular rosacea (PPR) subtype is the classical description of rosacea. It presents with a combination of vascular and inflammatory signs. Patients have persistent erythema, with striking periocular sparing, but also inflammatory papules and pustules, which may appear in crops. Comedones (blackheads and whiteheads) are not a feature. Skin oedema may occur in longstanding disease. Chronic oedema and tissue hyperplasia can occur de novo, or as an uncommon complication of other forms of rosacea. Men are much more commonly affected. Rhinophyma is the commonest type, but the forehead, chin, cheeks, eyelids and ears can also be affected. Clinically thickened, swollen and sometimes craggy moonscape-like nodular skin with prominent pores is seen. 16 Prescriber 5 April 2008 www.escriber.com

Ocular involvement in rosacea is often overlooked but probably occurs in 50 per cent of patients. Direct questioning of patients may reveal symptoms of ocular itch, irritation, burning, dryness or watering and occasionally pain or visual disturbance. On examination blepharoconjunctivitis, chalazia, hordeola (styes) and rarely keratitis may be seen. VM Differential diagnosis While classical PPR provides little diagnostic difficulty, the red face often presents a diagnostic problem even for experienced dermatologists. Seborrhoeic dermatitis, acne, contact allergic dermatitis, lupus erythematosus, Jessner s lymphocytic infiltrate, cutaneous lymphoma carcinoid syndrome, lupus pernio (sarcoidosis), squamous or basal cell carcinoma and angiosarcoma may mimic rosacea or rhinophyma. Patients should be referred to a dermatologist if there is diagnostic doubt. Treatment (see Table 2) When determining which treatment to select for rosacea, it is best to consider separately both vascular and inflammatory symptoms and signs as well as the presence of ocular involvement and swelling. By doing this, it is possible to select the most appropriate treatment for your patient. In general pharmacological treatments are useful for inflammatory disease but disappointing for vascular rosacea, which responds better to physical treatments such as intense pulsed light and lasers. Very few randomised controlled trials (RCTs) of rosacea therapies have been conducted. General measures Patients may find it useful to keep a diary to identify trigger factors Figure 2. Electrosurgery is an effective treatment for rhinophyma for flushing episodes, such as hot drinks or certain foods. Uncomfortable flushing can often be relieved by a simple moisturiser, eg aqueous cream, kept in the fridge and applied to sooth symptoms when they occur. Moisturisers are often helpful to control discomfort in rosacea and should be used in place of soaps for washing, but patients may need to try several before finding one that does not sting. Camouflage creams are very useful and can be expertly blended to suit patients skin type by the British Red Cross Camouflage Service, which runs clinics in many dermatology departments. Some clinicians suggest that sunscreen be regularly applied to prevent sunlight-induced exacerbations, but rosacea patients often have trouble finding a sunscreen that is comfortable and cosmetically acceptable. It is worth reassuring patients that progression to rhinophyma is unusual. The most effective therapies for persistent erythema are light www.escriber.com Prescriber 5 April 2008 19

drugs usually ineffective diary to identify triggers moisturiser as soap substitute fridge-cooled moisturiser for painful flushing cosmetic camouflage very helpful intense pulsed light highly effective topical azelaic acid first line (once daily, build up to twice daily) topical metronidazole alternative oral antibiotics for more severe disease or for rapid response second-generation tetracyclines, eg lymecycline, first line erythromycin alternative continue oral antibiotics for 2-3 months at least combine with topical azelaic acid azelaic acid for maintenance repeat courses of oral antibiotics often needed most patients do not request treatment electrosurgery and/or laser resurfacing effective oral isotretinoin useful for swelling in papulopustular rosacea artificial tears topical metronidazole gel oral second-generation tetracyclines consider referral to ophthalmologist Table 2. Recommended management of rosacea based. Intense pulsed light therapy involves irradiation of the skin with high-intensity broadspectrum light, causing thermal damage to superficial vasculature, and probably also inducing remodelling of dermal collagen. Approximately 90 per cent of patients will experience improvement after three or four treatments, although short-lived worsening of erythema and bruising can occur. Pulsed-dye lasers can also be used to treat persistent erythema and telangiectasias. Unfortunately drugs are not often useful for vascular rosacea. Topical therapies are ineffective for the prevention of flushing. Oral propranolol, clonidine or mirtazapine have been prescribed to control flushing, but their use is unlicensed and evidence largely anecdotal. Until recently, topical and systemic antibiotics were the mainstay of treatment for PPR. The efficacy of these agents is explained by their anti-inflammatory rather than any antibacterial effects. Recently a 15 per cent azelaic acid hydrogel formulation (Finacea) has become available as a novel nonantibiotic topical treatment. Metronidazole is available in several formulations (0.75-1 per cent) for the topical treatment of rosacea. Metronidazole has demonstrated benefits over placebo in several RCTs and compares well with twice-daily oral tetracycline 250mg. Topical erythromycin and clindamycin can also be effective (although unlicensed). Azelaic acid is a naturally occurring dicarboxylic acid that inhibits production of reactive oxygen species by neutrophils. A recent RCT comparing 15 per cent azelaic acid gel twice daily with 0.75 per cent metronidazole gel demonstrated at least therapeutic equivalence, and probable superiority, of azelaic acid after eight weeks. Approximately one-quarter of azelaic acid patients experience short-lived stinging and 4 per cent discontinued the trial because of this. Patients can be advised to apply azelaic acid once daily for the first few weeks to improve tolerability. The increasing global prevalence of multiantibiotic-resistant micro-organisms means that antibiotic prescribing should be judicious, particularly for noninfectious diseases. For this reason, 15 per cent azelaic acid should probably be the first-line topical treatment for rosacea. Systemic antibiotics are generally reserved for patients who fail to respond to topical therapies or for those who require a rapid response. Oxytetracycline and tetracycline (250mg twice daily) can be effective, but most dermatologists use a second-generation tetracycline as first-line systemic treatment, eg lymecycline 408mg once or twice daily or doxycycline 100mg once daily. These agents have better bioavailability, can be taken with food and have longer half-lives than first-generation tetracyclines. Minocycline can cause irreversible pigmentation of the skin and is probably best avoided. Doxycycline can cause cutaneous photosensitivity. 20 Prescriber 5 April 2008 www.escriber.com

The macrolides, erythromycin (500mg twice daily), clarithromycin (250mg once or twice daily) and azithromycin (250mg once or twice daily) are also effective, as is metronidazole (200mg twice daily). Antibiotic courses should be continued for at least two to three months and should be combined with topical azelaic acid if possible, which can be continued afterwards to provide maintenance. Concomitant use of different oral and topical antibiotics is best avoided. Repeated courses of oral antibiotics are often required. Oral isotretinoin has also been used in PPR, but its superiority over conventional therapy has not been demonstrated. Many patients with advanced rhinophyma will not request treatment. If required electrosurgery is an effective approach, in which the excess tissue is removed with a cutting and coagulating electrode and the nose then allowed to heal by granulation. Resurfacing laser therapy can also be used. Patients with extensive PPR and early phymatous change may improve with oral isotretinoin. Mild ocular rosacea may respond to simple measures including artificial tears and application of topical metronidazole gel to the eyelids, but systemic tetracycline is Acne Support Group (also helps rosacea patients). PO Box 9, Newquay, Cornwall, TR9 6WG. Tel: 0870 870 2263; website (mostly acne focused): www.m2w3.com/ acne. British Association of Dermatologists. Patient information leaflet available online: www.bad. org.uk/public/leaflets/rosacea.asp. American National Rosacea Society. Patient information available at www.rosacea.org. Table 3. Sources of patient information the most effective treatment. If troublesome, referral to an ophthalmologist is advisable. Special situations: rosacea in pregnancy Severe flares of rosacea can sometimes occur in pregnancy. Topical metronidazole and oral erythromycin are not known to be harmful to the fetus, but tetracyclines are contraindicated. Manufacturers advise avoidance of azelaic acid because of insufficient data. Conclusion Treatment of rosacea can be rewarding, but it should be directed at the subtype of disease. Patients with inflammatory papules and pustules often respond well to topical 15 per cent azelaic acid or 0.75-1 per cent metronidazole, while oral tetracyclines are useful for those who fail to respond and patients with ocular symptoms. Persistent erythema and telangiectasia respond to light and laser therapy, while electrosurgical shave excision can be performed for severe rhinophyma. However, the differential diagnosis of the red face is broad and referral to a dermatologist should be considered if there is diagnostic doubt or therapeutic failure. Further reading A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea. Results of a randomized trial. Elewski BE, Fleischer AB, Pariser DM. Arch Dermatol 2003;139: 1444-50. Rosacea. Powell FC. New Eng J Med 2005;352:793-803. Rosacea: I. Etiology, pathogenesis and subtype classification. Crawford GH, Pelle MT, James WD. J Am Acad Dermatol 2004;51:327-41. Rosacea II. Therapy. Pelle MT, Crawford GH, James WD. J Am Acad Dermatol 2004;51:449-512. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. Wilkin J, Dahl M, Detmar M, et al. 2002;46:584-7. Systematic review of rosacea treatments. Van Zuuren EJ, Gupta AK, Gover MD, et al. J Am Acad Dermatol 2007;56:107-15. Dr Seaton is a consultant dermatologist at the Royal Free Hospital, London 22 Prescriber 5 April 2008 www.escriber.com