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Advances in the topical treatment of acne and rosacea
From: Journal of Drugs in Dermatology | Date: 9/1/2004 | Author: Ceilley, Roger I.
Acne and rosacea are common skin diseases which may present similarly and both involve inflammation. Both can result in significant cosmetic impairment and lead to quality of life decrements if not optimally treated. The conventional approach for both diseases involves the use of topical therapy to treat inflammatory lesions in combination, when needed, with a systemic or topical antibiotic. An important issue in the management of both diseases at present is the need to reduce antibiotic usage due to the increasing problem of bacterial resistance. One of the emerging treatment paradigms that is becoming increasingly useful as an antibiotic-sparing strategy is the use of procedural therapies in combination with medical management. Such procedural modalities include lasers, intense pulsed light (IPL), and photodynamic therapies (PDT). Topical regimens are used pre-treatment and following physical modalities for maintenance of remission. Acne vulgaris and rosacea are two common skin diseases that may be challenging to diagnose and treat. Both can be cosmetically disfiguring to those afflicted with them and both can result in significant psychosocial impairment. Acne and rosacea are frequently discussed together, because their clinical presentation has a certain degree of overlap. Both are at least partly inflammatory disorders and both present with papules and pustules. Rosacea was once considered a form of acne. However, increasing understanding of the pathogenesis of acne and the new classification of subtypes of rosacea have permitted clinicians to diagnose these two skin diseases with more precision and to target therapies to specific aspects of their underlying pathophysiology. This is especially true in the case of acne, whose pathogenesis is well delineated, versus rosacea where less of its etiology and pathogenesis are known. Advances in the understanding of these diseases have led to much more effective therapies. Accordingly, the psychosocial and quality of life decrements that patients with these two diseases suffered in the past have been greatly reduced. An important new paradigm in the management of acne and rosacea is the use of appropriate combinations of topical, systemic and light or laser-based therapies to optimize clinical, but also cosmetic, results. Recently, the Global Alliance to Improve Outcomes in Acne published a set of consensus guidelines. The guidelines were evidence-based where possible and included input from numerous countries around the world. Their goal was to provide a comprehensive overview of acne therapy to "form the basis for more uniform therapeutic strategies throughout the world, enhanced patient compliance and more effective use of healthcare resources (1)." Perhaps one of the most important advances in the management of acne has been the discovery of the role of vitamin A derivatives and other molecules that can interact with retinoid receptors. There are presently three topical agents--tretinoin, adapalene and tazarotene--that are active at retinoid receptors and can combat acne at its most proximal stage--the formation of the microcomedo. In February 2002, a committee within the National Rosacea Society established a standard classification system for rosacea (2). The Committee delineated primary and secondary features of rosacea as well as subtypes that comprise clusters of primary and secondary features that tend to manifest together. The new system is intended to facilitate the diagnosis and treatment of rosacea as well as communication among researchers, healthcare providers, insurers, patients and the general public (2). This paper will review relevant findings in the pathophysiology and topical treatment of acne and rosacea in the context of both the consensus recommendations of the Global Alliance to Improve Outcomes in Acne and the New Standard Classification of Rosacea. Acne is the most common of skin disorders. It affects 35%-85% of adolescents (3). A community-based study showed that 12% of women older than 25 had clinical acne and that this rate of prevalence did not decrease until after 44 years of age (4). Despite its wide prevalence, acne is a cause of great distress among many of its sufferers. A consensus of the Global Alliance to Improve Outcomes in Acne was that the increasing understanding of acne pathophysiology should guide its treatment. According to the guidelines, the primary pathophysiologic features in acne are: 1) excessive sebum production under androgenic stimulation, 2) abnormal desquamation of the follicular epithelium leading to the formation of the microcomedo and the creation of an environment conducive to bacterial growth, 3) proliferation of Propionibacterium acnes (P. acnes) and, 4) inflammation leading to the formation of papules and pustules (Table 1). The treatment of acne should target as many of these factors as possible. Excessive sebum production: At pubarche, increasing levels of androgens, the major sebotrophic hormones, begin to drive an increase in sebum production. However, while androgenic stimulation is important in the pathogenesis of acne, the typical acne patient does not have significant endocrine abnormalities. Hormonal therapy is not indicated in the initial management of mild to moderate acne, although females who require oral contraception may be candidates for anti-androgen therapy early in the course of treatment. Abnormal desquamation of the follicular epithelium: In acne, keratinocytes, hyperproliferate and accumulate within the sebaceous follicle. As these abnormally desquamated cells accumulate in the sebaceous follicle, they lead to microcomedo formation. The microcomedo, is the precursor to all acne lesions and is present in 80% of acne papules but is invisible to the unaided eye (5). However, as the already clogged follicle begins to fill with lipids, bacteria and cell fragments, the microcomedo progresses to open or closed comedones (blackheads and whitehead, respectively), both of which are non-inflammatory lesions. If P. acnes proliferates, inflammatory mediators are generated and inflammatory papules and pustules occur. Bacterial proliferation: The microenvironment of the follicle in acne is conducive to colonization with P. acnes. This leads to inflammation and the production of the visible papules and pustules with which acne patients typically present to dermatologists. Inflammation: Inflammation in acne occurs as a result of humoral and cellular immune reactions to P. acnes proliferation. It has been suggested that changes in sebum production or composition irritate infundibular keratinocytes leading to the release of interleukin 1a (IL-1a) (6). In addition, CD4 lymphocytes and neutrophils migrate to the follicle (5,7). Rupture of the follicular duct leads to the extravasation of lipids, corneocytes and bacteria into the dermis, causing further inflammation (8). Using the above four-part model of acne pathophysiology, it is possible to design a rational approach to the management of the disease. Figure 1 shows the activity of the different classes of anti-acne therapies on each of these components of the disease process. The Consensus Guidelines state that combination therapy should be started as early as possible in all acne patients, except those requiring oral isotretinoin, so as to attack two or more pathogenic factors. Table 2 summarizes the recommendations for initial therapy in different stages and levels of acne severity. Mild comedonal acne with minimal inflammatory lesions should be treated with topical retinoids. Acne with a predominantly inflammatory component should be treated with a topical retinoid plus benzoyl peroxide (BP) with or without topical antibiotics. Moderate to severe acne should be treated with a topical retinoid and BP plus oral antibiotics. Females with moderate and severe acne can also be treated with oral contraceptives as an androgen-reduction strategy, especially if they require birth control. Oral isotretinoin should be used in severe and refractory acne, including severe nodular or conglobate acne. Patients who are unresponsive to other therapies may be treated with hormonal therapy (primarily for females) and oral isotretinoin (1). Consensus Recommendations and Rationales Topical Retinoids Should Be First-Line Therapy in Acne An important paradigm in the treatment of acne is the early use of topical retinoids. Topical retinoids have multiple anti-acne actions. Retinoids target the microcomedo, the earliest precursor to all acne lesions. Formerly, therapy was not initiated until visibly apparent lesions had formed. The ability of retinoids to inhibit microcomedo formation prevents their progression to closed and open comedones and inflammatory lesions. The rationale for the use of topical retinoids from the start of therapy is that they can achieve a parallel reduction in both noninflammatory and inflammatory lesions. Initially, it was believed that retinoids were effective only against noninflammatory lesions, but research indicates that topical retinoids possess both direct and indirect anti-inflammatory activity (9). Adapalene has been shown to produce greater reductions in noninflammatory, inflammatory and total lesion counts than tretinoin after 12 weeks of therapy (10). Figure 2 shows the mechanism of action of topical retinoids. They reverse abnormal desquamation by increasing normal turnover of the follicular epithelium as well as cellular differentiation and maturation (11). This action prevents the blockage and distension of the follicle with epithelial cells and sebum which leads to microcomedo formation and provides an ideal environment for bacterial colonization. Bacteria colonizing the blocked follicle digest sebum lipids and release lipases which hydrolyze triglycerides into free fatty acids. Free fatty acids are comedogenic and irritate the follicular wall, leading to rupture and further irritation and inflammation of the surrounding dermis. It has been shown that adapalene, like antibiotics, decreases free fatty acid levels in microcomedones which may be one mechanism of adapalene's anti-inflammatory activity (1,12,13). Topical retinoids interfere with the interaction of P. acnes exoproducts and toll-like receptor-2 (TLR-2) which is a specific "pathogen recognition receptor." This probably occurs through the reduction of TLR-2 surface membrane expression as well as by interference with the follicular microclimate conducive to bacterial proliferation. In addition, topical retinoids inhibit activation of the activator protein-1 (AP-1) transcription factor pathway which is believed to be a component of acne inflammation and scarring. This may relate to retinoids' ability to reduce inflammation and may correlate with a decreased risk of acne scarring (14,15). In contrast to the early experience with first-generation tretinoin formulations, the newer generation of retinoids do not result in an initial acne flare early in the treatment course. A dramatic decrease in inflammatory lesions may be visible earlier with adapalene than with other retinoids (16). Figure 3 shows a patient with inflammatory acne at day 23 after the initiation of adapalene monotherapy. Retinoids have been shown to enhance the penetration of other topical agents that are used in acne (17). They may affect skin permeability by loosening the attachments among skin surface corneocytes and reducing the number of cell layers (18). In addition, retinoids increase turnover of the follicular epithelium which permits the enhanced delivery of antibiotics to their intended site of action (19). Because of their ability to prevent the formation of microcomedones, retinoids are highly effective monotherapy in the essential maintenance phase of acne treatment. As during the active treatment phase, the retinoid should be applied to the entire affected area rather than just to lesions. Combination Therapy is the Standard of Care for Mild-to-Moderate Acne While retinoid monotherapy is capable of treating both noninflammatory and inflammatory lesions, the Acne Consensus Recommendations state that topical retinoids should be combined with antibiotics from the start of therapy when inflammatory lesions are present. This recommendation is in keeping with the consensus view that acne therapy should be targeted to as many of its pathophysiologic mechanisms as possible. This combination targets ductal hypercornification, P. acnes proliferation and inflammation. These mechanisms are independent, but also to some extent additive, processes. By addressing all of these mechanisms, combination retinoid and antibiotic therapy offers additive and synergistic effects that can potentially increase efficacy and accelerate response (20). Numerous studies over the past 30 years have shown that the combination of topical retinoids and topical or oral antibacterials reduce both noninflammatory and inflammatory acne lesions more rapidly and to a greater degree than can be effected with antibacterial therapy alone (1,20). Through their comedolytic action, retinoids enhance the penetration of topical antibiotics, thus facilitating delivery to their intended site of action in the follicle where P. acnes resides. It has been suggested that topical retinoids can potentiate the antibiotic effect by increasing tissue concentrations (21). Retinoids also offer indirect antibacterial activity because of their ability to normalize the follicular microclimate which discourages the growth of P. acnes (17). Antibiotics are Adjunctive Therapy in Inflammatory Acne Both topical and systemic antibiotics are suitable and efficacious in a combination regimen with topical retinoids for inflammatory acne. The choice should be based on the extent and severity of inflammatory lesions. Severe acne that is refractory to topical therapy or acne which covers a large area of the body may respond better to systemic antibiotic administration in combination with a topical regimen Systemic antibiotics eradicate or decrease P. acnes and S. epidermis. P. acnes is believed the trigger the inflammatory response in acne that leads to later scarring. Antibiotics offer indirect anti-inflammatory activity by inhibiting the growth of the bacteria and reducing their production of inflammatory mediators. Erythromycin and tetracyclines directly suppress inflammation by their action on neutrophil chemotaxis and the production of chemotactic factors (1,22). The microcomedo contains significant lipid concentrations and is thus poorly penetrated by hydrophilic antibiotics (22). The preferred antibiotics are tetracyclines and erythromycin. Topical antibiotics are not used as monotherapy due to their slow onset of action and because of the potential for the development of bacterial resistance if they are used for a prolonged course. A topical antibiotic may be used in combination with a systemic antibiotic. Topical antibiotics that are useful in acne include erythromycin, clindamycin, benzoyl peroxide (BP) and combinations of BP and erythromycin and clindamycin (1). They are available in many different types of formulations and in combination with BP. The increasing problem of bacterial resistance to antibiotics by many pathogens is a serious one and is an important concern in acne therapy. In 2003, the Food and Drug Administration finalized a mandatory warning to be placed in the package inserts for all systemic antibiotics warning about antibiotic overuse and the emergence of resistant bacterial strains. The Consensus Guidelines state that, in addition to always combining antibiotics with topical retinoids, antibiotics should only be used for as long as necessary to control inflammatory lesions. Combined therapy using a topical retinoid and a topical antibiotic has been shown to yield more rapid results while also targeting several pathogenetic factors and reducing antibiotic use (22). If antibiotic therapy is to be used for longer than three months, it is recommended that BP be added to the regimen so to reduce the emergence of resistant P. acnes populations (1,22). BP may be initiated earlier in the course of therapy, exercising caution to reduce the risk of irritation when combined with a topical retinoid. The complementary, nonspecific antibacterial action of BP is believed to help reduce the selection of drug resistant P. acnes variants. BP has not been associated with bacterial resistance. However, if used as monotherapy, BP does not target microcomedones, therefore should be used in combination with a topical retinoid. One study showed that the combination of adapalene and BP was less irritating than either of its components alone (16). A synergism between BP and erythromycin has also been demonstrated (23). A randomized, double-blind comparison of BP/clindamycin versus clindamycin monotherapy showed significantly greater reductions in total and inflammatory lesion counts after 16 weeks of therapy. Importantly, there were significant reductions from baseline in the numbers of clindamycin-resistant isolates in the combination therapy group versus a 1600% increase in resistant isolates in the monotherapy group (24). Once control of inflammatory lesions has been achieved, and antibiotic therapy is discontinued, topical retinoid therapy, with or without BP, should continue so as to maintain remission by preventing the formation of new microcomedones. It is important to note that some patients may require intermittent course of antibiotics to control flares. The Guidelines state that if re-treatment is necessary, the same antibiotic should be used if it was effective. The use of BP for a minimum of 5-7 days between antibiotic courses may enhance antibiotic efficacy by removing resistant bacteria from the skin (1). Hormonal Therapy is Useful in Androgen-Driven Acne Hormonal therapy is used in acne to oppose androgenic effects on the sebaceous gland. It is aimed at reducing sebum production. While, excessive sebum production is the most proximal event in the acne pathogenetic cascade, hormones are rarely used as monotherapy. Hormonal therapy should be combined with topical retinoids and when necessary, antibiotics and BP. The mainstays of hormonal therapy include oral contraceptives (OCs), and the androgen antagonist, spironolactone. Hormonal therapy can be used early in the treatment of women with clinical signs of hyperandrogenism and in those with normal serum androgens who have been non-responsive to more conventional therapies. Hormonal therapy is a particularly good choice for women who desire oral contraception and/or those who require medical therapy to control their menstrual periods. Triphasic norgestimate/ethinyl estradiol is approved for the treatment of acne in women not controlled by topical therapy (1). The Consensus Guidelines state that hormonal therapy seems to work best in adult females and sexually active teens who have persistent papules and nodules, particularly of the lower face. These women frequently report acne flare-ups in conjunction with menstruation. Such patients often note little improvement with multiple courses of antibiotics and sometimes with isotretinoin (1). Oral Isotretinoin is the Standard of Care for Severe Acne Isotretinoin is an oral retinoid which targets all acne pathophysiologic factors. It decreases the size and activity of sebaceous glands, normalizes follicular keratinization, prevents the formation of new comedones, has some anti-inflammatory effect as well as an indirect antibacterial effect by virtue of its normalization of the follicular environment (1). Oral isotretinoin is indicated as first-line treatment in severe nodular acne or moderate to severe acne that is unresponsive to conventional therapy. It is also indicated in the treatment of patients with moderate to severe acne with scarring and in patients whose acne is causing them significant psychosocial distress. Patient counseling is imperative when treating with oral isotretinoin. Its use is associated with side effects such as dry skin and eyes and chapped lips. Rare side effects include skeletal changes and osteoporosis. There is also a potential for mood swings and depression during therapy. Oral isotretinoin is teratogenic, and patients must be using highly effective contraception. Because of these possible adverse events, patient counseling and frequent followup, as well as specific monitoring of serum lipids and liver function, is essential. While oral isotretinoin can provide rapid and dramatic improvement, relapse may occur. Most cases of severe acne respond to a 4-6-month course. Some patients can be treated successfully with conventional therapy while others will require another course of oral isotretinoin. After completion of oral isotretinoin, topical retinoid therapy is important for maintenance and may reduce the risk of relapse by preventing the formation of new microcomedos. General Acne Management Strategies Are A Useful Part of Therapy Daily skin care, patient counseling and office procedures are all essential adjuncts to pharmacologic treatment of acne. Compliance is aided by patients having an accurate understanding of acne and the rationale for each of the agents that are prescribed for them. Take-home materials instructing them in the correct use of their medications (e.g., applying topical medications to the entire affected area), the possibility of flare-ups, proper cleansing and moisturizing and the need for sun protection, are all important in ensuring the success of acne treatment. Skin care in acne should be gentle, first and foremost. Patients should be taught that acne is not a hygiene problem and that vigorous cleansing with harsh soaps, hot water and physical exfoliants, are detrimental. Take-home materials should contain suggestions for cleansers and non-comedogenic moisturizers and sun protection at several price levels. In-office procedures, such as comedo extraction, chemical peels and intra-lesional corticosteroid injections can be helpful adjuncts in selected patients. Comedo extraction, if skillfully performed so that extraction is complete and tissue damage does not occur can show an immediate, visible improvement. Chemical peels can help correct scarring and hyperipigmentation once the acne is controlled. Intralesional corticosteroid injections can be helpful for large inflammatory lesions that are of recent origin. Photodynamic therapy (PDT) using blue (peak 415 nm) or mixed red and blue lights (peaks at 415 and 660nm) with or without aminolevulinic acid as a photosensitizer, and several types of lasers including the pulsed-dye laser have shown excellent results in the treatment of inflammatory acne (25-28). Light therapies have been shown to produce results that are comparable to those obtained with traditional antibiotics, although lesional clearance is significantly faster (4 vs 8-12 weeks), and adverse events are much fewer (26). In one study, 30 patients with mild to moderate acne were treated with a high-intensity, narrow-band blue light source twice weekly for up to 5 weeks. There was a 64% reduction in acne lesions and a reduction in the numbers of P. acnes, but not S. epidermis with this regimen (27). Light therapy can be considered as a strategy for reducing the dose of oral isotretinoin. Most clinical experience suggests a reduction in the size and number of inflammatory lesions as well as reduced skin oiliness after the second week of light-based treatment. Improvement may not be evident until after the eighth treatment (26). Topical Therapies in Combination With Light Based Therapies The excellent results that have been obtained with light-based therapies have led to the newest acne treatment paradigm--the combined use of light therapy and medical management with systemic and topical agents. Topical therapy including BP, topical retinoids or chemical peels is used as pre-treatment and maintenance. This new way of combining modalities is advantageous as a strategy for reducing the use of antibiotics and isotretinoin, as well as improving cosmetic results in a shorter time frame. The selection of a pre-treatment topical regimen is an important challenge when treating patients with light-based modalities. At present, the pre-treatment protocol is based on the guidelines recommended by the Global Alliance to Improve Outcomes in Acne. Retinoids in combination with a topical or systemic antibiotic to gain control over the formation of new microcomedones and inflammation should be the first-line therapy. While all topical retinoids have proven efficacy, adapalene has been shown to be the least irritating of the topical retinoids (16,29). Oral or topical antimicrobial therapy should also be instituted if inflammatory lesions are present. Topical maintenance therapy, preferably with retinoid monotherapy is an essential follow-up to light-based therapies. It has been suggested that that the destruction of P. acnes continues for a few weeks following the termination of light treatments and that the effects of light therapy will be maintained until bacterial populations rebuild to their initial concentration. Some patients may require a maintenance retreatment with light 6 months following the initial round of treatment (26). If retinoid monotherapy does not offer sufficient reductions in inflammatory lesions, then combination BP and retinoid or antibiotic and retinoid therapy should be instituted. Chemical peels applied between light treatments may be beneficial. Rosacea is a chronic, progressive erythematous skin condition that is associated with flushing, blushing, papules, pustules and telangiectasia. Its stigmata typically appear on the central face. According to a report by the National Rosacea Society the disease afflicts at least 14 million people in the United States, typically between 20 and 50 years of age (2). While it is most common in fair-skinned individuals, it can also affect darker-complected individuals (9). Rosacea is more common in women, but it is generally more severe in men, with men more apt to present with phymatous changes. Risk factors for its development include photodamage, Northern or Eastern European origin, the use of topical corticosteroids, genetics and a tendency to flushing (30). Rosacea is a cutaneous vascular disorder. Rather than a disease, it may actually be a phenotype that is expressed in rosaceaprone individuals (31). It has no specific etiology although a variety of causes have been suggested, including gastrointestinal infection with Helicobacter pylori (H. pylori), psychogenic factors, immunologic response to colonization with Demodex mites or disturbances of the microvasculature. Underlying the contribution to the clinical picture of many of the above factors is inflammation. Rosacea, with its inflammatory papules and pustules can potentially be considered an inflammatory disorder. The first stage of rosacea is vascular and consists of erythema. Flushing reactions are due to trigger factors such as temperature extremes, wind, alcohol, and leads to increased blood flow through the dermis. Extracellular fluid accumulates faster than the lymphatics can drain it (31). In the setting of this lymphatic failure, plasma protein exudates accumulate and produce a self-sustaining inflammation. These plasma proteins may also play a role in the fibroplasia which is characteristic of later stages of the disease (32,33). As the rosacea progresses, continued inflammation leads to the release of cytokines and other inflammatory mediators as well as enzymes, such as neutrophil elastase, which can degrade elastin and collagen. This leads to reduced capillary wall integrity and the sustained accumulation of extravascular fluids. Elastin degradation is also the result of photodamage which is commonly encountered in the typical rosacea-prone phenotype. The telangiectatic phase of rosacea may be due to actinic damage and angiogenesis as well as the disruption of the mechanical integrity of the superficial dermal connective tissue, allowing the passive dilation of blood vessels (31,34). The issue of whether or not Demodex folliculorum overgrowth is present and whether an immunologic response to the mites or their products contribute to the inflammation of rosacea is an ongoing controversy. Likewise, the role of H. pylori infection is controversial (30). New Standard Classification of Rosacea: Subtypes of Rosacea In 2002, an expert committee within the National Rosacea Society developed a new classification system for rosacea, aimed at simplifying diagnosis and facilitating the sharing of information among physicians, patients, researchers and insurers. Guidelines for Diagnosis: The committee developed guidelines for the diagnosis of rosacea that require the presence of one or more primary features. One or more secondary features must also be present (Table 3) (35). The primary rosacea features include flushing (transient erythema), nontransient erythema or persistent redness of the central face, which is the most common sign of rosacea. Papules and pustules, which often appear in clusters, and telangiectasia are also considered primary features. The secondary features, which are not required for diagnosis, frequently appear in combination with one or more of the primary features or may appear on their own. They are: burning or stinging, plaques, dryness resembling xerosis, edema often in concert with prolonged flushing, ocular manifestations, peripheral location and phymatous changes, typically rhinophyma. The new classification system also identifies subtypes of rosacea. These are clusters of primary and secondary rosacea features that often occur together. Subtype 1 is erythematote-langiectatic rosacea. Subtype 2 is papulopustular rosacea. Subtype 3 is phymatous rosacea and Subtype 4 is ocular rosacea (Table 4) (35). There are no laboratory tests or clinical markers to verify a diagnosis of rosacea. Observation and history-taking are the two most important diagnostic tools in rosacea (Table 5). The patient should be questioned regarding what triggers and what palliates symptoms. Triggers have great inter-patient variability. A recent survey of 1066 patients was conducted by the National Rosacea Society identified the most frequent rosacea triggers (Table 6) (36). The physician should assess the presence and type of lesions and their associated secondary features. The differential diagnosis of rosacea most commonly includes acne, seborrheic dermatitis, perioral dermatitis, carcinoid syndrome, and lupus erythematosus (Table 7). Table 8 lists some of the neurologic and systemic factors and diseases that might cause the symptoms of rosacea. Rosacea is not a disease with a cure. There is not currently for rosacea a panoply of rational therapies developed from a thorough understanding of its etiology and targeting known pathogenetic factors. However, it is manageable with a combination of lifestyle measures to reduce exposure to known triggers, topical and systemic medications tailored to the disease manifestations and light therapies. In addition to avoiding known triggers, rosacea patients should practice assiduous sun avoidance and use a high SPF broad-spectrum sunscreen. Physical sunblocks, such as titanium dioxide and zinc oxide, are particularly useful for erythemic rosacea patients. Rather than converting light energy to heat energy in the skin which could exacerbate the erythemic response, they scatter light before it penetrates the skin. Topical and systemic therapies are chosen based on the type and severity of the rosacea. For all but the most mild manifestations, initial rosacea treatment often includes an oral antibiotic to help alleviate erythema and gain control of inflammatory lesions. Table 9 lists the first- and second-line oral antibiotics used in rosacea management. Typically, papules, pustules and sometimes nodules and plaques respond rapidly and completely to systemic tetracyclines. If not, agents from the second tier may be tried. Telangiectasia and phymatous changes are unaffected by systemic antibiotics. Topical metronidazole, an imidazole with anti-inflammatory and antimicrobial effects is considered the workhorse of topical rosacea therapies and is the most widely studied therapy. Its mechanism of action in rosacea is unclear. It has been suggested that its effects in rosacea may be related to inhibition of neutrophil-generated inflammatory mediators and free radicals (37,38). Metronidazole is effective against papules and pustules and may, in some patients, reduce erythema. Similar to other topical therapies and oral antibiotics, it is rarely effective for telangiectasias. Since rosacea is a recurring and potentially progressive disease. maintenance therapy is essential following initial systemic antibiotic use or light- or laser-based therapy. Topical metronidazole has been shown to be effective in maintaining remission. In a 2-phase study, patients who were initially treated with systemic tetracycline in combination with topical metronidazole, were later included in a blinded 6-month study comparing metronidazole gel 0.75% [Metro[R] Gel] to placebo vehicle. Topical metronidazole was significantly superior to vehicle in maintaining remission (43% relapsed vs 23% relapsed) and in reducing lesion counts. Relapse of erythema was also less frequent in patients treated with metronidazole (74% vs 55%) (39). Metronidazole is available as a cream [Metro[R] Cream 0.75%, Noritate[R] 1%], gel [Metro[R] Gel 0.75%] and lotion [Metro[R] Lotion 0.75%]. It is generally well tolerated at both dosages and in all three formulations. Sodium sulfacetamide 10%/sulfur 5% combinations have been recommended for more than 40 years. This combination is approved for treatment of acne, seborrheic dermatitis and rosacea. Sulfonamides act as competitive antagonists to para-aminobenzoic acid (PABA) which is essential for bacterial growth (40). It is therefore useful as an antibiotic-sparing strategy, and there is no limitation on its duration of therapy. Sodium sulfacetamide 10%/sulfur 5% combinations also have comedolytic and keratolytic activity which makes it an appropriate adjunct for rosacea with an overlap of acne and/or seborrheic dermatitis. Sodium sulfacetamide 10%/sulfur 5% combinations are not generally regarded as effective monotherapy except in mild cases of rosacea, although studies have shown 78% and 81% reductions in inflammatory lesions and an 83% decrease in facial erythema at 8 weeks of treatment (41,42). In an 8-week study comparing sodium sulfacetamide 10%/sulfur 5% to metronidazole 0.75% gel, papule/pustule scores, erythema ratings and overall severity were lower in the sodium sulfacetamide 10%/sulfur 5% group. Patient global evaluations of improvement were similar and tolerability was favorable and similar for both agents (43). A sodium sulfacetamide 10%/sulfur 5% cleanser is available and has been shown to be useful in rosacea management. When the cleanser was used alone or in combination with metronidazole 0.75% twice daily in an 8-week, investigator-blinded trial, the cleanser alone was found to be efficacious as monotherapy for reducing papule counts and erythema. However, when used in combination with metronidazole, better results were obtained in reducing papule counts and overall rosacea severity (44). The use of the sodium sulfacetamide 10%/sulfur 5% cleanser is advantageous for the treatment of rosacea, acne and seborrheic dermatitis or combinations thereof. The product is applied to moistened skin and massaged for 10-20 seconds and rinsed twice daily. It may be used in both the active treatment phase and in maintenance. The only contraindication is for patients with a known hypersensitivity to sulfonamides, sulfur or other components. In a recent trial comparing 5 topical products for the treatment of rosacea (sodium sulfacetamide 10%/sulfur 5% cream with sunscreens, sodium sulfacetamide 10%/sulfur 5% suspension without sunscreens, metronidazole 0.75% cream and gel and metronidazole 1% cream) all products were found to produce little irritation following a 21-day cumulative irritation patch test. However, the sodium sulfacetamide 10%/sulfur 5% product with sunscreen produced significantly less irritation than a comparative product without sunscreens (p<0.001) (45). Azelaic acid is a naturally-occurring dicarboxylic acid that has been used in the treatment of acne and melasma. Its anti-inflammatory activity has led to investigation of its use in roseacea. An 8-week multicenter, double-blind, randomized, parallel group study comparing 15% azelaic acid gel to 0.75% metronidazole gel found the azelaic acid to be superior in reducing mean nominal lesion count and mean inflammatory lesion percent. Erythema severity was improved in 56% of azelaic acid-treated patients versus 42% of metronidazole-treated patients. Neither treatment produced notable improvements in telangiectasias (46). Azelaic acid is available as a 15% gel [Finacea[TM]] or 20% azelaic acid creams [Finevin[R], Azelex[R]]. Telangiectasia and phymatous changes, most notably rhinophyma, are not manageable with topical or systemic therapy. Their treatment has traditionally been surgical. Telangiectasia have been treated by electrodestructive methods or with lasers targeted to vascular lesions such as the KTP, 1064 nm Nd:YAG, visible light lasers and intense pulsed light (IPL). Phymatous changes can be treated using a variety of ablative lasers. A new approach has been the use of photodynamic therapy with ALA-PDT as is being used to treat actinic keratoses (47). As in the case of acne, appropriate daily skincare is an essential aspect of management. In addition to avoiding known triggers, patients should receive a regimen and a list of recommended products for cleansing, moisturizing and sun protection in addition to their medications. They, like acne patients, should be instructed to treat their skin very gently. Rather than rubbing, they should blot the skin dry, since rubbing can create a rosacea flare. They should use tepid rather than hot water which can strip oils from the skin and cause vasodilation of the blood vessels near the surface. The importance of sun protection and avoidance should be stressed. Acne and rosacea are two very common skin disorders with several characteristics in common which make it useful to discuss them together and for which similar treatment paradigms can be applied. Both are essentially inflammatory in nature. Both present with papules and pustules, and both can cause severe psychosocial disability. For both diseases, combination therapy employing combinations of topical and systemic therapies are the treatment of choice. For acne, current best practice mandates the early use of a topical retinoid for all patients so as to normalize the follicle, treat existing comedones and prevent the formation of new ones, as well as to modulate inflammation and enhance the penetration into the follicle of other topically applied agents. In cases where inflammatory lesions are present, a topical or systemic antibiotic is also required for the shortest interval possible so as to minimize the risk of acquiring resistant bacterial variants. Topical therapy with metronidazole is the standard and most widely used topical agent for rosacea, but an oral antibiotic may be required to more rapidly clear papules and pustules in all but the most mild cases. As in acne treatment, the use of systemic antibiotics should be discontinued as early as possible after the presenting lesions have resolved. Azelaic acid 15% gel and sodium sulfacetamide 10%/sulfur 5% either as a topical lotion or a cleanser have also been shown to confer benefits similar to those obtained with topical metronidazole in rosacea. The new paradigm that is emerging, however, is the use of laser or light-based modalities in combination with the topical/systemic regimens to improve and hasten the cosmetic results obtained with conventional therapy. As this combination of prescription and procedural therapy becomes more common-place, there will be continued evolution in the ways in which light-based therapies can be optimally combined with topical and systemic regimens. The use of conventional topical therapies is essential to maintain the remission obtained with the combined conventional and procedural treatment regimens. Table 1. Primary Pathophysiologic Factors in Acne (1) Excessive sebum production Abnormal desquamation of follicular epithelium P. acnes proliferation Inflammation Table 2. Recommendations for Initial Acne Therapy by Stage (1) Mild Comedonal Mild to Moderate Moderate to Severe Acne Inflammatory Acne Severe Acne Nodulocystic Acne Topical Retinoid Topical Retinoid Topical Retinoid Oral Isotretinoin BP [+ or -] Topical Oral Antibiotics Antibiotic For Up to 3 Months [+ or -] BP OCs for females Table 3. Rosacea Features: New Standard Classification (35) Primary Features (presence of one or more) Flushing (transient erythema) Nontransient erythema Papules and pustules Telangiectasia Secondary Features (one or more may also be present) Burning or stinging Plaque Dry appearance Edema Ocular manifestations Peripheral location Phymatous changes Table 4. Subtypes of Rosacea (35) Subtype Characteristics Erythematotelangiectatic Flushing, central facial edema [+ or -] telangiectasia Papulopustular Central facial edema [+ or -] papules/pustules Phymatous Thick skin, nodularities, enlargement Ocular Foreign body sensation, burning/stinging, dryness, itching, blurred vision, telangiectasia of sclera or other parts of eye. Periorbital edema Table 5. Diagnosis: Patient History History * Provocative and palliative factors * Morphology * Associated features * Temporal characteristics * Frequency of flushing * Duration of flushing * Association of flushing with workplace, exercise, food, drugs Table 6. Most Common Rosacea Triggers(36) Percent of Patients Affected Most Common Factors 81% Sun 79% Stress 75% Hot Weather 57% Wind 56% Exercise 52% Alcohol 51% Hot Baths 46% Cold Weather 45% Spicy Foods 44% Humidity 41% Indoor Heat 41% Skin-Care Products 36% Heated Beverages Table 7. Rosacea vs Acne Characteristics Rosacea Acne Papules and pustules Yes Yes Nose and cheeks primarily involved Yes No Erythema Yes No Telangiectasia Yes No Comedones No Yes Table 8. Underlying Conditions Leading to Rosacea-Like Erythema Neurologic Causes Systemic Diseases Anxiety Carcinoid Syndrome Simple Blushing Mastocytosis Brain Tumors Basophilic Chronic Granulocytic Leukemia Spinal Cord Lesions Pheochromocytoma Migraine Headaches Medullary Carcinoma of Thyroid Parkinson's Disease Pancreatic Tumors Menopausal Flushing Renal Cell Carcinoma Cholinergic Erythema Horseshoe Kidneys Table 9. Systemic Antibiotics in Rosacea First-Line Antibiotics Tetracycline Minocycline Doxycycline Erythromycin Second-Line Antibiotics Trimethoprim-Sulfamethoxazole 1. Gollnick H, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol 2003;49(1 Suppl):S1-37. 2. National Rosacea Society. 14 Million Americans Have Rosacea. And Most of Them Don't Know it. http::// Accessed September 23, 2002. 3. Swinyer LJ, Swinyer TA, Britt MR. Topical agents alone in acne. A blind assessment study. JAMA 1980;243:1640-1643. 4. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999;41:577-580. 5. Norris JF, Cunliffe WJ. A histological and immunocytochemical study of early acne lesions. Br J Dermatol 1988;118:651-659. 6. Guy R, Kealey T. Modelling the infundibulum in acne. Dermatology 1988;196:32-37. 7. Puhvel SM, Sakamoto M. The chemoattractant properties of comedonal components. J Invest Dermatol 1978;71:324-329. 8. Cunliffe WJ. The sebaceous gland and acne-40 years on. Dermatology 1998;196:9-15. 9. Wolf JE. Potential anti-inflammatory effects of topical retinoids and retinoid analogues. Advance Ther 2002;19:109-118. 10. Shalita A, Weiss JS, Chalker DK. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: A multicenter trial. J Am Acad Dermatol 1996;34:482-485. 11. Plewig G, Kligman AM. Acne and Rosacea 3rd Ed. New York: Springer-Verlag. 2000. 12. Thielitz AS, et al. Lipid analysis of follicular casts from cyanoacrylate strips as a new method for studying therapeutic effects of antiacne agents. Br J Dermatol 2001;145:19-27. 13. Wolf JE. The use of topical retinoids as maintenance therapy for acne. Poster presented at the Summer Academy 2003, Chicago, IL. 14. DelRosso JQ. The use of topical retinoids in the initial management of inflammatory acne vulgaris. Poster presented at Annual American Academy of Dermatology, February 2003, New Orleans, LA. 15. Nagpal S, Athanikar J, Chandraratna RAS. Separation of transactivation and AP1 antagonism functions of retinoic acid receptor alpha. J Bio Chem 1995;270:923-927. 16. Wolf JE. An update of recent clinical trials examining adapalene and acne. Eur Acad Dermatol and Venereol 2001;15 (suppl 3):23-29. 17. Shalita A R. Clinical Efficacy of topical retinoids in acne. In: Update of Topical Retinoid Therapy in Acne. Highlights from a symposium. The 25th Hawaiian Dermatology Seminar. February 7, 2001. Maui, Hawaii. 18. Kaidby K, Kligman AM, Yoshida H. Effects of intensive application of retinoic acid on human skin. Br J Dermatol 1975;92:693-701. 19. Kligman AM, et al. Acne therapy with tretinoin in combination with antibiotics. Acta Dermatovener (Stockholm). 1975:74 (suppl):111-115. 20. Weiss JS, Shavin JS. Retinoid and antibiotic combination therapy for acne management. Poster Presented at American Academy of Dermatology Meeting. Summer 2003. Chicago, IL. 21. Mills OH, Kligman AM. Treatment of acne vulgaris with topically applied erythromycin and tretinoin. Acta Dermatovener (Stockholm) 1978;58:555-557. 22. Leyden JJ. Current issues in anti-microbial therapy for the treatment of acne. J European Academy of Dermatology and Venereology 2001;15: (Suppl 3); 51-55. 23. Burkhart CN, Specht K, Neckers D. Synergistic activity of benzoyl peroxide and erythromycin. Skin Pharmacol Appl Skin Physiol 2000;13:292-296. 24. Cunliffe WJ, et al. A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther 2002;24:1117-1133. 25. Papageorgiou P, Katsambas A, Chu A. Phototherapy with blue (415 nm) and red (660nm) light in the treatment of acne vulgaris. Br J Dermatol 2000;142:973-978. 26. Elman M, Lebzelter J. Light therapy in the treatment of acne vulgaris. Dermatol Surg 2004;30:139-146. 27. Kawada A, et al. Acne phototherapy with a high-intensity, enhanced, narrow band, blue light source: an open study and in vitro investigation. J Dermatol Sci 2002;30:129-135. 28. Barclay L. Pulsed-dye laser therapy effective for treatment of inflammatory acne. Medscape Medical News. Accessed 6/15/04 29. Grosshans E, et al. Evaluation of clinical efficacy and safety of adapalene 0.1% gel versus tretinoin 0.025% gel in the treatment of acne vulgaris with particular reference to the onset of action and impact on quality of life. Br J Dermatol 1998;139(suppl 52):26-33. 30. Wolf JE Acne and rosacea: differential diagnosis and treatment in the primary care setting. http::// Accessed 10/23/02. 31. Wilkin JK. Rosacea, Pathophysiology and treatment. Arch Dermatol 1994;130:359-362. 32. Penneys NS. Factor Xiii expression in the skin: observations and a hypothesis. J Am Acad Dermatol 1990;22:484-488. 33. Ryan TJ. Structure and function of lymphatics. J Invest Dermatol 1989;21:115-130. 34. Motley RJ, Barton S, Marks R. The significance of telangiectasia in rosacea. In: Acne and Related Disorders: An International Symposium. Cardiff, Wales. Martin Duntz; 1989:339-344. 35. Wilkin J, et al. Standard grading system for rosacea: Report of the national rosacea society expert committee on the classification and staging of rosacea. J Am Acad Dermatol 2004;50:907-912. 36. National Rosacea Society, Rosacea Review, Summer 2002. New Survey pinpoints leading factors that trigger symptoms. Available at 3.html. Accessed September 23, 2002. 37. Akamatsu H, et al. The inhibition of free radical generation by human neutrophils through the synergistic effects of metronidazole with palmitoleic acid: a possible mechanism of action of metronidazole in rosacea and acne. Arch Dermatol Res 1990;282:449-454. 38. Gnarpe H, Belsheim J, Persson S. Influence of nitroimdiazole derivatives on leukocyte migration. Scand J Infect Dis Suppl.1981;26:68-71. 39. Dahl MV, et al. Topical metronidazole maintains remission of rosacea. Arch Dermatol 1998;134:679-683. 40. Shalita A, Leyden J. Mechanism-based selection of pharmacologic agents for rosacea. Cutis 2004;73 (suppl 1): 15-18. 41. David GF, Glazer SD, Medansky RS. Successful treatment of rosacea with a novel formulation of sodium sulfacetamide 10%/sulfur 5% lotion and metronidazole 0.75% gel in the treatment of rosacea. J Dermatol Treat 1995;3:183-185. 42. Sander D, et al. The treatment of rosacea: the safety and efficacy of sodium sulfacetamide 10% and sulfur 5% lotion is demonstrated in a double-blind study. J Dermatol Treat 1997;8:79-85. 43. Lebwohl MG, et al. The comparative efficacy of sodium sulfacetamide 10%/sulfur 5% lotion and metronidazole 0.75% in the treatment of rosacea. J Dermatol Treat 1995;3:183-185. 44. Swinyer L. Evaluation of a novel sodium sulfacetamide 10% and sulfur 5% prescription cleanser for treatment of rosacea. Poster P-147 presented at: American Academy of Dermatology 59th Annual Meeting; March 2-7, 2001, Washington, DC. 45. Fraser JM, Muscatiello MJ, Katz HI. Comparison of the irritation potential of five topical rosacea products. Poster Presented at the American Academy of Dermatology 62nd Annual Meeting. Washington, DC. February 6-11, 2004. 46. Elewski B E, Fleischer AB, Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea. Results of a randomized trial. Arch Dermatol 20031444-1450. 47. Bissonette R, Bergeron A, Liu Y. Large surface photodynamic therapy with aminolevulinic acid: treatment of actinic keratoses and beyond. J Drugs Dermatol.2004;3:S26-31. AUTHOR DISCLOSURES/CONFLICT OF INTEREST: With respect to the information contained within this article, Dr. Roger Ceilley has received research support, consultant fees, and/or honoraria from the following companies: Allergan, Inc., Bioglan Pharma, Inc., Connetics Corporation, DUSA Pharmaceuticals, Inc., Galderma Laboratories, L.P., Valeant Pharmaceuticals International, and 3M Pharmaceuticals. Dr. Roger Ceilley has no stock ownership in these companies.


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