Rosacea: An Introduction

Medical treatment of rosacea with emphasis on topical therapies

Monthly Focus: Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis

Medical treatment of rosacea with emphasis on topical therapies

James Q Del Rosso Department of Dermatology, Univenity uf Nevada Schw[ uf Medicine, La~ Vega~, Nevada, USA

Due to the development and release of newer topical formulations, the diagnosis and treatment of rosacea has received renewed attention over the past 3 - 5 years both in the literature and at medical 5ymposia. Rosacea is a very common facial dermatosis. In the Us, rosacea is estimated to affect> 14 million people, predominantly adults with - 60% of cases diagnosed before the age of 50 [1]. A frustrating aspect of the disease is its inherent chronicity punctuated with periodsof exacerbation and relative remission. A variety of subtypes have been identified which correlate with clinical presentation. Although the pathogenesis of rosacea is poorly understood, multiple topical agents are available. The efficacy of topical therapy for rosacea relatesprimarily to reduct ion in inflammatory lesions (papules, pustules), decreased intensity of erythema, a reduction in the number and intensity of flares and amelioration of 5ymptoms, which may include stinging, pruritus and burning. The list of main topical agents utilised for the treatment of rosacea include metronidazole, sulfacetamide-sulfur, azelaic acid and topical antibiotics (clindamycin, erythromycin). Depending on the severity at initial presentation, topical therapy may be combined with 5ystemic antibiotic therapy (e.g., oral tetracycline derivative). Newer therapeutic choices primarily involve improved vehicle formulations, which demonstrate favourable skin tolerability and cosmetic elegance.

Keywords: antibiotics, dennatosis, erythema, rosacea, therapy

Expert Opin. Pharmacother. (2004) 5(1 ):5-1 3

1. Introduction

The diagnosis of rosacea is made based on clinical presentation. Characteristic clinical features include centrofacial erythema, papules, pustules and linear telangiectasias [2]. Rosacea is a chronic disorder, characterised by a persistent background of centrofacial erythema. Several flare factors or 'tripwires' are recognised, including heat, sunlight, ingestion of hot liquids (oral-thermal flushing), alcohol ingestion and hot spicy foods [3,4]. Although individuals of any racial background may develop rosacea, Caucasians are most commonly affected, especially those of Celtic or Scandinavian origin [3]. Some patients affected by rosacea develop phymas, which are bulbous proliferations of sebaceous hyperplasia, sometimes with fibrosis. The most commonly encountered phymatous proliferation affects the distal nose (rhinophyma). Fortunately, phymas are relatively uncommon compared to the overall prevalence of rosacea, affecting males more often than females. A noncutaneous feature of rosacea seen in 30 - 50% of patients is associated with ocular disease (conjunctivitis, blepharitis, keratitis). Rosacea may adversely impact the quality of life with many patients expressing negative effects on emotional well being, interpersonal relationships and employment interactions. With effective treatment, patients often relate improvements in their quality oflife [5].

2. Pathogenesis, clinical presentation and disease progression

Our limited and fragmented understanding of the pathogenesis of rosacea has resulted in the slow development of new compounds specifically targeted against pathways involved in formation of the disease. Several features of rosacea are independently apparent, including the inflammatory-, vascular-, sebaceous- and ocular components [3,6]. However, how these components are unified is not known (Figure 1) [3,4.6]. The pathogenic significance of sunlight exposure and photodamage in rosacea has been recognised, with sunlight identified as the most common rosacea flare factor [3,6]. Chronic sunlight (ultraviolet light) exposure and photodamage induces alteration and degradation of perivascular collagen and elastic tissue producing loss of structural and functional integrity of cutaneous microvasculature [3,6]. Abnormalities associated with rosacea, which are related to chronic photodamage include stimulation of angiogenesis, dilatation and increased capacity of facial vasculature, release of reactive oxygen species, leakage of inflammatory cells and mediators, release of protease enzymes from activated neutrophils and macrophages, extravasation of proteins and increase in vascular endothelial growth factor [3,6-8]. An interrelationship between cutaneous microvasculature and vascular lability with inflammatory cells, such as neutrophils, production of reactive oxygen species, inflammatory mediators and degradative enzymes, has been proposed [6]. Other suggested associations with the pathogenesis of rosacea have included follicular proliferation of Demodex mites and concommitant gastrointestinal Helicohacter pylori infection [3,4,6]. Although Demodex spp. mite proliferation may induce a rosaceaform facial eruption, its overall relationship to the development of rosacea remains controversial.

The potential association of H. pylori infection with rosacea is also controversial [3,9,10]. The individual components of rosacea exhibit clinical correlations. Erythema, papules, pustules and oedema reflect the inflammatory component. Erythema, flushing, telangiectasia and oedema correlate with the vascular component. Phymas reflect the sebaceous component and the ocular component is composed of conjunctivitis, blepharitis and keratitis (Figure 1). A classification scheme for rosacea differentiates subtypes of the disease [2]. Prerosacea - characterised by intermittent flushing and erythema - is the earliest stage of the disease. The term prerosacea is actually a misnomer. In fact, such patients have rosacea, but have not yet developed persistent clinical features. The vascular rosacea subtype presents as persistent facial erythema, fine, linear telangiectasias, mild facial oedema and complete or near complete absence of inflammatory lesions. This form of rosacea has been referred to as erythematotelangiectatic rosacea. The subtype of inflammatory rosacea exhibits persistent facial erythema, telangiectasias, moderate-to-severe oedema and multiple papules and/or pustules. Hyperplastic rosacea is characterised by facial erythema, marked sebaceous hyperplasia and phymas, with or without the presence of inflammatory lesions. The term subtype is preferred over stage, as there is currently no definitive evidence of progression from one subtype to another.

3. Treatment goals and expectations

Unlike acne vulgaris, patients presenting with rosacea have little preconceived notions regarding the nature of their condition or its treatment. As a result, the clinician is confronted with the responsibility of informing the patient concerning the chronicity of rosacea and the importance of compliance

with therapy. It is also important to emphasise reasonable expectations with therapy as the condition is not curable; long-term therapy is required to sustain control of rosacea [1,5]. The goals of treatment are to modify exacerbating flare factors, decrease facial erythema, reduce the number of papules and pustules and maintain remission. The time course of initial response may require 1 - 3 months. Inflammatory lesion reduction and erythema may be substantially improved, however, a background of facial erythema may be chronically persistent ('rouge complexion') and occasional flares may occur. As the clinical signs of rosacea are reduced by therapy whilst associated symptoms tend to dissipate. Preexisting telangiectasias and phymas are not responsive to topical treatment with metronidazole, azelaic acid, sulfacetamidesulfur or antibiotic therapy, requiring the use of physical modalities for effective treatment [1,5].

4. Available topical therapies

The primary topical agents currently available for the treatment of rosacea are metronidazole, 10% sulfacetamide 5% sulfur (sulfacetamide-sulfur), azelaic acid, topical clindamycin and topical erythromycin [1,5]. Multiple vehicle formulations are available, allowing for correlation for different skin types and personal preferences.

4.1 Metronidazole Topical metronidazole has been proven to be effective and safe for the treatment of rosacea. Although the mechanism of action is not well understood, anti-inflammatory and antioxidant properties appear to playa role [11]. The efficacy of metronidazole application does not appear to relate to antimicrobial activity [12]. Systemic absorption of metronidazole after topical application appears to be negligible [12].

4.1.1 Efficacy Since its release in 1989, topical metronidazole has been the predominant first-line topical agent for the treatment of rosacea. Multiple studies, inclusive of vehicle-controlled, randomised, blinded trials and split-face examinations have evaluated the efficacy of 0.75% metronidazole and 1 % formulations in patients with inflammatory rosacea in > 500 actively-treated adult patients. Study durations have generally ranged 7 - 12 weeks, with some as long as 15 weeks [1,5,12-14]. Topical metronidazole has consistently demonstrated statistically significant superiority compared to the vehicle [1,5,12]. By study end point, inflammatory lesion reduction after use of topical metronidazole ranged 48 - 65%, exceeding vehicle use in individual studies over a range of 20 - 50%; significant reductions in erythema were also documented [1,5,12]. Most studies also noted statistically significant symptom reduction with improvements reported in 54 - 88% of patients treated with metronidazole [12]. Clinical evidence of improvement has been reported to occur as early as 3 weeks after starting therapy with further improvement

noted with continued use [12-14]. An 8-week, double-blind trial demonstrated equivalent efficacy in patients treated with either 1 % metronidazole cream or oxytetracycline 500 mg/day p.o. [15]. Similar results were also noted in a 9-week double-blind study evaluating 0.75% metronidazole gel versus oral oxytetracycline 500 mg daily [16]. At the study end point, complete clearance was achieved in 75% of patients treated with topical metronidazole and 66% of patients treated with oxytetracycline. Studies comparing results with topical metronidazole and tetracycline 500 - 750 mg/day p.o. suggest comparable efficacy after 4and 8 weeks of therapy with oral treatment demonstrating a tendency to produce a more rapid onset of effect [17,18].

4.1.2 Tolerability and safety Topical metronidazole including gel, lotion and cream formulations have demonstrated excellent tolerability, especially considering the skin sensitivity and hyperirritability associated with rosacea. The most commonly noted adverse events were local tolerability reactions, described as itching, stinging, dryness or burning, reported in < 2% of patients [12]. The conspicuous absence of systemic side effects associated with topical metronidazole use is likely to be related to negligible systemic absorption. Cutaneous toxicity studies indicate that topical metronidazole does not induce phototoxicity, photocontact allergy or contact sensitivity [12]. A topical emulsion formulation of metronidazole is currently in development.

4.1.3 Effect of vehicle formulation Two 12-week, investigator-blinded trials established comparable efficacy with 0.75% metronidazole gel, cream and lotion formulations [19,20].

4.1.4 Impact of application frequency A 12-week, investigator-blinded study comparing 0.75% and 1 % metronidazole applied once-daily demonstrated comparable efficacy [14]. Both formulations were well-tolerated.

4.1.5 Maintenance of remis90n A two-phase trial demonstrated statistically significant superiority of topical metronidazole over vehicle in maintaining remission of rosacea [21]. After an initial 12-week, open-phase of concurrent therapy with 0.75% metronidazole gel twicedaily and tetracycline 1000 mg/day p.o., responsive patients were transferred to a 6-month, blinded trial. This second phase evaluated the continued use of topical therapy alone with either metronidazole or vehicle. In the group of patients treated with topical metronidazole, remission was sustained in 77% of patients versus 58% in the vehicle arm.

4.2 Sulfacetamide-sulfur Sulfacetamide-sulfur lotion has been used in dermatology since 1956, initially for the treatment of acne vulgaris, then subsequently for seborrheic dermatitis and rosacea [22,23]. Over time, advances in formulation science has resulted in the

development of improved vehicles allowing for greater cosmetic elegance, lessened irritation potential and little to no malodour (related to the sulfur component) [5]. Several vehicles exist, including lotions, creams, a topical suspension and both fragranced and non-fragranced cleanser formulations. Sulfacetamide-sulfur has enjoyed a rebirth in the US with six new formulations released over the past 3 - 4 years. Although the mechanism of action of sulfacetamide-sulfur in rosacea is not known, anti-inflammatory benefit has been reported based on clinical studies and long-term experience [1,5].

4.2.1 Efficacy of leave-on formulations An 8-week, vehicle-controlled, blinded, study of sulfacetamidesulfur lotion applied twice-daily for rosacea demonstrated significant reduction in inflammatory lesion counts and facial erythema [24]. In the active treatment study arm, a 65 and 78% reduction in inflammatory lesion counts at weeks 4 and 8, respectively, was demonstrated. The comparative response in the vehicle group was 44 and 36% decrease in lesion counts at weeks 4 and 8, respectively. A 66 and 83% reduction in facial erythema at weeks 4 and 8 was observed in the group treated with sulfacetamide-sulfur compared to a 33 and 31 % reduction at weeks 4 and 8 in the vehicle arm, respectively. An 8-week, open evaluation of sulfacetamide-sulfur lotion applied twice-daily for rosacea reported an 81 and 43% mean reduction in inflammatory lesion counts and mean reduction in erythema, respectively, compared to baseline [25]. Comparable efficacy between sulfacetamide-sulfur lotion and 0.75% metronidazole gel was demonstrated in an 8-week, investigator-blinded trial [26]. Sulfacetamide-sulfur formulations are especially helpful in patients presenting with simultaneous seborrheic dermatitis and rosacea, a relatively common finding often referred to as rosacea-seborrhoea overlap [1,5].

4.2.2 Efficacy of cleanser formulations Sulfacetamide-sulfur cleansers are generally used as adjunctive therapy in combination with other topical and/or systemic agents used to treat rosacea and are also helpful in patients who present with rosacea-seborrhoea overlap [1,5]. An 8-week, investigator-blinded study of sulfacetamide-sulfur cleanser used twice-daily with and without 0.75% metronidazole gel reported statistically significant reduction in papule counts, erythema and overall severity of rosacea in both study groups [27]. Maximal response was observed using the combination of both active agents. Similar results were observed in a 4-week open-trial using a fragrance-free sulfacetamide-sulfur cleanser formulation in combination with topical metronidazole [27].

4.2.3 Tolerability and safety Overall, currently available sulfacetamide-sulfur leave-on formulations are associated with favourable safety and tolerability profiles. Occasionally patients may experience application sites reactions, such as facial dryness, erythema or pruritus; reactions are often mild and transient and tend to decrease over time [24,25]. Facial dryness appears to be the most

common noted reaction, especially early during therapy and generally improves with continued therapy or with emollient use. Trials evaluating patient tolerability and acceptability with the cleanser formulations used as monotherapy or in combination with topical metronidazole noted favourable assessments of tolerability and product aesthetics [1,5,27]. Noncutaneous adverse reactions have not generally been associated with topical sulfacetamide-sulfur formulations [1,5,24-26]. Although the true risk is uncertain, topical sulfacetamide-sulfur is best avoided in patients with a history of allergy or hypersensitivity to sulfonamides or sulfur.

4.3 Azelaic acid Azelaic acid is a naturally-occurring dicarboxylic acid, which has been used for the treatment of acne vulgaris as a 20% cream formulation. Preliminary studies with 20% azelaic acid cream have demonstrated efficacy for the treatment of rosacea [13,28,29]. The proposed anti-inflammatory mechanism of azelaic acid for rosacea is believed to be related at least partially to the inhibition of neutrophil-mediated reactive oxygen species [30]. Additional research allowed for the development of a 15% gel vehicle of azelaic acid, shown in vitro to produce greater percutaneous penetration of active drug despite a lower concentration [31]. Further research evaluating azelaic acid for the treatment of rosacea used the 15% concentration in the aqueous gel vehicle [32].

4.3.1 Efficacy Two parallel, double-blind, vehicle-controlled, 12-week trials evaluated a twice-daily application of 15% azelaic acid gel in the treatment of adult patients with moderate papulopustular rosacea [32]. The studies evaluated therapy with the active drug in 333 patients. In both studies, statistically significant superiority of 15% azelaic acid over the vehicle alone was demonstrated. Greater per cent reductions in mean inflammatory lesion counts were observed in the azelaic acid study arms in both trials; the first trial demonstrated 58 versus 40% and the second trial 51 versus 39% for azelaic acid versus vehicle, respectively. Improvement in erythema was noted in 44 and 46% of azelaic acidtreated patients and in 29 and 28% of vehicle-treated patients in the first and second trial, respectively. Improvement in efficacy parameters was noted within the first 4 weeks of treatment and continued throughout the 12-week duration ofthe study. A double-blind, comparative trial evaluated the efficacy of 15% azelaic acid gel versus 0.75% metronidazole gel in 251 patients [33]. Both agents were applied twice-daily over a duration of 15 weeks. Mean per cent reduction in inflammatory lesion counts was 72.7 and 55.8% in the azelaic acid and the metronidazole group, respectively. The nominal reduction in mean number of lesions was a decrease of 12.9 and 10.7 lesions with azelaic acid and metronidazole, respectively. Reduction in facial erythema was noted in 56 and 42% of patients treated with azelaic acid and metronidazole, respectively. Progressive improvement in efficacy parameters was observed throughout the 15-week trial in azelaic acid-treated patients.

4.3.2 Tolerability and safety Due to the particulate nature of azelaic acid, mild transient sensory symptoms may be noted upon application in some patients. In the controlled, parallel trials, 38% of patients experienced symptoms of burning, stinging or itching with 70% of this subset reporting these reactions as transient and mild-to-moderate in intensity [32]. Only 5% of patients in both studies discontinued the use of 15% azelaic acid gel due to adverse events compared to 1 and 2% in vehicle-treated patients. Cutaneous adverse effects resulted in reduction in application frequency to once-daily or temporary discontinuation of treatment for a few days in 10.2% of patients. Persistent and severe symptoms of stinging and burning were reported in only 0.6% of patients treated with azelaic acid, accounting for the high patient retention rate in both studies. In a comparative trial of 15% azelaic acid gel versus 0.75% metronidazole gel, local tolerability was rated as good or excellent in 87 and 96% of azelaic acid and metronidazole-treated patients, respectively [33]. Facial adverse reactions of burning, stinging and pruritus, most rated as mild or moderate, were reported in 25.8 and 7% of azelaic acid and metronidazoletreated patients, respectively [33]. As with the other topical agents discussed earlier, non cutaneous or systemic adverse effects have not been associated with azelaic acid use.

4.4 Other reported topical therapies Limited data are available on the use of topical antibiotics for the treatment of rosacea. Topical clindamycin or erythromycin are generally used as secondary options or adjunctive therapy in the treatment of rosacea [5]. A twice-daily application of either agent has been shown to be effective [34,35]. In most patients with rosacea, the use of an aqueous-based gel or lotion is preferred over an alcohol-based solution or gel in order to reduce the potential for irritation and erythema. Sporadic reports of rosacea treatment have been published with benzoyl peroxide, sulfur, tretinoin, permethrin, bifonazole and ketoconazole [36]. The clinical benefit of sulfur and permethrin may in some cases relate to reduction is Demodex spp. mites.

5. Current best practices

The management of rosacea in volves the rational selection and compliant use of pharmacological treatment coupled with thorough patient education regarding the chronicity of the disorder, the intermittent nature of exacerbations, appropriate general skin care practices, photoprotection, modification of flare factors, achievable treatment expectations and compliance. The chronicity of rosacea, periodic exacerbations, flare factors and reasonable treatment expectations were reviewed earlier.

5.1 General skin care It is important that patients with rosacea be instructed on the type of general skin care products they should use (such as nonmedicated cleansers and moisturisers) and which they

should avoid [5]. General facial cleansers should be used gently without vigorous rubbing. Alcohol or acetone-based cleansers and astringents are best avoided as they frequently induce irritation and erythema. Abrasive formulations or those containing exfoliants, such as glycolic acid or salicyclic acid, are also not recommended. A soap-free cleanser, usually in the form of a gentle synthetic detergent ('syndet') bar or liquid may be used. After application of medications, a moisturiser may be used if there are signs of dryness, such as fine scaling. There has been some suggestion that patients with rosacea are affected by the impairment of epidermal barrier function, further supporting the potential value of emollient use [3]. A gentle emollient with proper balance of humectant and occlusive properties that is cosmetically elegant is most appropriate. Where applicable, compatibility with facial makeup is very significant. Moisturisers containing special additives, such as retinol and glycol acid, are best avoided. In patients with marked facial erythema, makeup with appropriate erythemamasking ability may be helpful. In many cases, the services of an aesthetician are needed to appropriately individualise the selection of makeup, carefully match skin tone and educate the patient on the proper application technique to create a natural appearance, maximising erythema camouflage.

5.2 Sunscreen use and photoprotection Daily protection from ultraviolet light is a vital component of rosacea therapy. Avoidance of intense and incidental ultraviolet radiation exposure as best as possible by avoiding midday sunlight, staying in shaded areas, wearing of a broad-rimmed hat, avoidance of natural and artificial tanning and through consistent use of sunscreens is strongly recommended. As discussed earlier, sunlight exposure is a major rosacea 'tripwire' and chronic photodamage is believed to be a major pathogenic factor in the development of rosacea. Many moisturiser formulations also contain sunscreens, allowing for application of one product to achieve two goals. Use of a 'broad spectrum' sunscreen formulation capable of filtering both ultraviolet type A and ultraviolet type B wavelengths, with a sun protection factor (SPF) rating of at least SPF 15 is suggested.

5.3 Compliance It is critical to the success of therapy that patients understand the importance of compliance with their entire treatment programme, including use of medications and proper follow-up to evaluate the response to therapy. Depending on the severity of disease, the initial medication regimen may utilise monotherapy or a combination of agents. Education on the proper use of medications is very significant. In general, initial improvement and control of rosacea may require a time period of 1 - 3 months. Depending on response, adjustments in treatment may be warranted. Once adequate control is achieved, maintenance therapy generally requires, at minimum, the use of a topical agent due to the chronicity of the disease. In order to achieve reasonable long-term control of rosacea, strict compliance with proper skin care techniques,

avoidance of flare factors, photoprotection and medication use is necessary on a continued basis.

5.4 Rational selection of pharmacological therapy Effective pharmacological treatment of rosacea requires rational selection among the multiple agents that are available [1,5]. A variety of approaches may be used as there is no universally accepted algorithm. The initial selection of medications is based on the severity of disease (Figure 2). Topical therapy may be effectively used alone in milder cases of rosacea. In patients with moderate-to-severe disease, most dermatologists use a combination of topical therapy and oral antibiotic therapy. The question of which topical agent is to be used initially is a relatively open choice, especially if there has been no prior exposure to any of the available agents that may serve to direct in favour of, or against, previously used therapy. Poor compliance or inadequate duration of use are common factors in treatment failure. In addition, as currently available topical agents and oral antibiotics primarily decrease the inflammatory component, features related to the vascular component of rosacea often do not improve to the same extent. As a result, many patients perceive that treatment is inadequate due to limited comprehension of the selective effects of pharmacotherapy. Other than the use of sulfacetamide-sulfur cleansers as adjunctive therapy, there is a paucity of data on the use combination topical therapy for rosacea. The major oral antibiotics used for the treatment of rosacea are the oral tetracyclines (tetracycline, doxycycline, minocycline) [37,38]. Oral macrolides such as erythrmomycin or clarithromycin, may be used as secondary choices if necessary. Tetracycline is generally initiated at a dosage of 500 mg b.i.d. Doxycyline and minocycline are generally used at a dosage of 100 - 200 mg/day [38]. After an adequate duration of disease control has been achieved, generally over a 3 - 4-month period, the oral antibiotic may be discontinued with continuation of topical therapy alone for maintenance. Another option is to taper to half the initial antibiotic dose, whilst continuing

with topical treatment. If disease control continues with the combination therapy, the clinician may elect to discontinue the antibiotic a few months later and maintain control of disease with continued topical therapy. Oral antibiotic therapy may be reinitiated if significant exacerbation occurs, which does not reverse with continued use of topical therapy alone. For mild-to-moderate rosacea, compliant use of topical monotherapy (e.g., metronidazole, sulfacetamide-sulfur, azelaic acid) is frequently successful in achieving reasonable control of rosacea [1,5]. As explained earlier, an appropriate therapeutic trial for a given topical agent is 3 months. Most patients will exhibit some degree of improvement within the first 3 - 6 weeks of treatment. If topical monotherapy fails, an oral antibiotic may be added.

6. Expert opinion

As with the therapy for any disease, clinicians appreciate the availability of multiple options in their armamentarium when treating rosacea. Regardless of disease severity, topical therapy is an important component of both initial treatment and maintenance therapy. As explained above, oral antibiotic therapy is indicated in combination with topical treatment in cases of greater severity. Which topical agent should be used first? Which topical agent is best? Clinical studies and 'real world' experience suggest that topical metronidazole, sulfacetamide-sulfur and azelaic acid are all effective options. Based on the long and established track record of efficacy and safety with topical metronidazole, clinicians utilising this form of treatment may see no reason to divert to another agent as their first-line choice. Others may elect to vary the topical agent which they prescribe initially in order to evaluate whether or not they appreciate therapeutic differences between metronidazole, sulfacetamide-sulfur and azelaic acid. In clinical practice, there are some patients who respond better to one agent or another for unknown reasons. At present, it is not possible to predict if an individual patient will respond better to a specific topical agent. In patients with mild-to-moderate rosacea, when topical monotherapy fails, an oral antibiotic may be added. Although data are limited, anecdotal experience suggests that the combination of two 'first-line' topical agents may provide significant additive benefit. When combination topical therapy proves to be successful, oral antibiotic therapy may be circumvented. The author has observed effective combination topical therapy with metronidazole used in combination with a sulfacetamide-sulfur 'leave on' formulation. A rapid onset of efficacy may be noted within a few weeks along with a significant reduction in erythema, papules and pustules. The combined use of a sulfacetamide-sulfur cleanser and either topical metronidazole or azelaic acid also appears to augment a reduction in erythema and decrease in inflammatory lesions. The comparative 15-week study between 15% azelaic acid gel and 0.75% metronidazole gel suggests greater efficacy with azelaic acid for rosacea in terms of inflammatory lesion

reduction and decrease in erythema [33]. Statistically significant greater improvement in parameters such as reductions in lesion counts and erythema were noted in the group treated with azelaic acid. On the other hand, some authorities have pointed out that the mean nominal decrease in lesions reflects a reduction difference of only 2.2 lesions by the end of the study. Based on currently available studies including the comparative trial, the tolerability profile of metronidazole appears to be more favourable than with azelaic acid. It is the overall experience of the author that both agents achieve reasonable control of rosacea if consistently used and that both are welltolerated by most patients. It is important, however, that patients treated with azelaic acid be educated to expect a sensation of transient tingling or mild stinging shortly after application. Over time, additional experience will ultimately determine whether or not differences in efficacy or tolerability between metronidazole formulations and 15% azelaic acid gel are appreciated by clinicians based on 'real world' experience. Results reported in the 'controlled environment' of clinical trials do not always translate to clinical results observed after widespread practice experience. Another observation in the comparative trial suggests that a plateau effect in efficacy exists with topical metronidazole after 8 weeks of therapy [33]. In this study, 15% azelaic acid gel produced progressive improvement in efficacy parameters over the 15-week duration of the study. Other studies with topical 0.75% metronidazole gel, lotion and cream formulations and 1 % metronidazole cream used over a duration range of 12 - 15 weeks, including two European trials inclusive of 100 and 114 patients treated with active drug, have not suggested a plateau effect in efficacy with metronidazole [12-14,39-41]. With all of the available topical agents, studies evaluating prolonged duration of therapy over several months or longer would be helpful in better defining long-term therapeutic response patterns. Regardless of the agent used, it is likely that a peak effect is achieved after a defined period of time in each individual patient, with chronic use required to sustain clinical benefit. Maintenance topical therapy is mandatory to maximise control of rosacea as 25% of patients relapse within 1 month of stopping active treatment, approximately one-half to twothirds exhibit recurrence within 6 months and 70% recur within 4 years without use of maintenance therapy [42]. As mentioned earlier, clinical trials and experience have demonstrated that telangiectasias are not responsive and erythema is only partially responsive to the topical agents reviewed previously [1,5]. There has been some suggestion that topical retinoid therapy may reduce erythema and telangiectasia associated with rosacea. An evaluation of 23 females treated with 0.05% retinaldehyde cream applied once-daily

for 6 months demonstrated reduction in erythema in 75% of patients after 5 months and decrease in isolated telangiectasia in 46% of patients after 6 months [43]. Clinical assessments and evaluation by spectrophotometry were used to determine responses to treatment. The direct anti-inflammatory activity of topical retinoids and their ability to reduce clinical and histological effects of chronic photodamage may potentially correlate with effective treatmen t of rosacea. However, at presen t, data are too limited to substantiate a definitive role for topical retinoid therapy for rosacea. Further research is needed to determine their efficacy and tolerability for this disease state. The importance of photoprotection as a component of rosacea has been emphasised above. Unfortunately, many rosacea patients report susceptibility to irritation after sunscreen application. Sunscreens containing dimethicone and cyclomethicone as components of the vehicle formulation exhibit a lessened tendency for irritation in patients with rosacea [44]. A new avenue of research and clinical study for the treatment of acne and rosacea is the use of sub antimicrobial doses of doxycycline. The ability of tetracyclines to reduce inflammation using doses lower than what are needed to produce an antibiotic effect is valuable, especially as eradication of commensal organisms and production of antibiotic-resistant bacterial strains are circumvented [45,46]. Reduction in doxycycline-associated adverse reactions is an additional benefit with use of lower dosing. Decreased inflammation occurs via a reduction in matrix metalloproteinase activity, cytokine downregulation and anticollagenolytic activity [45]. Doxycycline 20 mg b.i.d. has been shown to be subantimicrobial with demonstrated efficacy in the treatment of acne [46]. A preliminary 8-week, open-label study evaluated the efficacy of doxycyline 20 mg b.i.d. used as monotherapy for rosacea [45]. After an average duration of 4 weeks, significant reduction in inflammatory lesion counts were noted, with some patients demonstrating complete clearance. A 50% reduction in erythema was also observed. Additional studies are needed to further evaluate this intriguing approach to treatment of inflammatory skin disorders such as rosacea. Patients and clinicians both benefit from the multiple topical agents and vehicle choices that are available for the treatment of rosacea. The development of an individualised treatment programme, inclusive of thorough patient education, avoidance or modification of flare factors, use of proper skin care techniques and product selection, consistent avoidance of sunlight and photoprotection and rational selection and adjustment of pharmacological therapy, provides a high likelihood of treatment success. Additional research including further evaluation of sub antimicrobial doxycycline therapy is welcome and will hopefully provide viable treatment options.

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