Review

Management of cutaneous rosacea: emphasis on new medical therapies 1.

Introduction

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Pathophysiologic mechanisms operative in rosacea and clinical relevance

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Conventional medical therapies for rosacea

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Recently developed medical therapies

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Conclusion

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Expert opinion

James Q Del Rosso Touro University College of Osteopathic Medicine, Henderson, NV, USA

Introduction: Over the past decade, both basic science and clinical research have provided new information on pathophysiology and therapy that has led to advances in the management of rosacea. As rosacea is a very common facial skin disorder in adults of both genders and essentially all races and ethnicities, these advances can provide therapeutic benefit to many affected individuals around the world. Areas covered: This article provides a collective review of more recent information on the pathophysiology and clinical manifestations of rosacea, and discusses individual medical therapies based on PubMed literature searches on ‘rosacea’, ‘rosacea therapies’ and each therapy that are included in this article. The perspectives of the author on management of rosacea are also included. Newer therapies and treatment concepts received greater emphasis. Expert opinion: Management of cutaneous rosacea involves patient education, integration of proper skin care, differentiation of visible manifestations and symptoms, selecting therapies that correlate with the manifestations that are to be treated, setting realistic patient expectations on anticipated degree and time course of response and designing an overall management plan that addresses needs of the individual patient. In many cases, a combination approach is needed, and due to the chronicity of the disease long-term management is often warranted. Keywords: brimonidine gel, centrofacial erythema, ivermectin, rosacea, topical a-agonists Expert Opin. Pharmacother. (2014) 15(14):2029-2038

1.

Introduction

Rosacea is a common inflammatory disorder that predominantly affects the centrofacial skin of both adult women and men [1]. The prevalence of rosacea is difficult to determine as geographic differences have been noted and many epidemiologic studies are based on the selected population of patients presenting to dermatology clinics, which is not necessarily reflective of the general population [1]. Although observed most frequently in individuals with fair skin (Fitzpatrick Skin Type III), people of any ethnicity and/or skin color can be affected by rosacea [1,2]. In the United Kingdom, the incidence of rosacea based on a large general practice database of patients encountered from 1995 through 2009 calculated an incidence rate of 1.65 per 1000 person-years, with 80% of rosacea cases affecting individuals > 30 years of age [3]. Clinical presentations of rosacea The onset of rosacea is usually in the third to fourth decade of life, with a clinical course that is characterized by periods of exacerbation of visible signs and symptoms followed by variable durations of remission. The clinical presentation of rosacea and its course over time is variable among affected individuals and a given person can change over time [2,4-7]. Visible manifestations that are present in the 1.1

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The two major pathophysiologic mechanisms that are believed to be operative in rosacea-prone skin are neurovascular dysregulation and augmented immune detection and response. Many of the clinical manifestations associated with rosacea appear to correlate with specific pathophysiologic pathways and respond at least partially to therapies that modulate and/ or inhibit those pathways. The facial erythema of rosacea is induced by a variety of causative factors, including impairment of the permeability barrier, acute--subacute vasodilation of centrofacial skin vasculature (flushing of rosacea), increased inflammation due to upregulation of the cathilicidin pathway, and fixed dilation and increased density of superficial facial cutaneous vasculature. The majority of studies on therapy of rosacea evaluated treatment of papulopustular rosacea. Agents approved in the US for treatment of papules and pustules (inflammatory lesions) of rosacea are topical metronidazole, topical azelaic acid (AzA) (15% gel) and doxycycline 40 mg modified release capsule taken once daily (sub-antimicrobial dose doxycycline). As papulopustular lesions resolve, the associated lesional and perilesional erythema regresses also, which contributes to a partial reduction in overall facial erythema. Ivermectin 1% cream applied once daily is the newest agent that is under evaluation for treatment of papulopustular rosacea with pivotal trials already completed in the United States. Efficacy, safety and tolerability have been demonstrated in the pivotal studies, including two Phase III trials. Topically applied a-agonists (i.e., brimonidine, oxymetazoline) have been shown to reduce the persistent non-transient facial erythema of rosacea (background erythema). This form of erythema in rosacea is due to fixed enlargement and increased density of superficial facial vasculature that is accentuated by vasodilation (flushing) during flares, is persistent between flares and is distinct from the lesional and perilesional erythema associated with papulopustular lesions. Brimonidine tartrate 0.5% (brimonidine 0.33%) gel is approved in the US for the treatment of persistent non-transient facial erythema of rosacea based on pivotal studies and a 52-week trial. The latter included some patients with papulopustular lesions and concomitant treatment with other therapies for rosacea (i.e., metronidazole, AzA, tetracyclines). Efficacy, tolerability and safety were demonstrated. Overall, the onset of erythema reduction is generally within 30 -- 60 min, peak effect within 3 -- 6 h, duration of maximal effect over 6 -- 8 h, with return to near baseline by 12 h after application; tachyphylaxis has not been noted in the clinical studies. Some patients have been reported to experience rebound erythema or contact dermatitis. Management of rosacea warrants evaluation of the clinical manifestations present in a given patient and the formulation of a management plan that addresses the manifestations that bother them. Integration of therapies that treat the individual manifestations may involve combination therapy that often needs to be staggered and adjusted over time as rosacea is a chronic skin disorder.

This box summarizes key points contained in the article.

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vast majority of people affected by rosacea are intermittent episodes of increased centrofacial redness that occurs during a flare (referred to as the flushing of rosacea), non-transient centrofacial erythema that persists between flares (referred to as background erythema) and facial telangiectasias [2,4-7]. Inflammatory lesions (i.e., papules, pustules) occur in many patients and when present are intermittent clinical findings as they emerge during a flare of rosacea and remit as the flare resolves [1,2,4-6]. Overall, the prevalence of rosacea-affected individuals with centrofacial erythema only, classified as erythematotelangiectatic rosacea (subtype 1), is estimated to be fourfold higher as compared to those who also exhibit inflammatory lesions, classified as papulopustular rosacea (subtype 2) [1,2]. Phymatous proliferations (i.e., rhinophyma) that comprise confluent sebaceous hyperplasia often with fibrotic and/or mucinous changes have been reported to affect from 1 to 4% of rosacea subjects, usually men who also commonly develop papulopustular lesions and centrofacial erythema during flares [1,2,4-6]. Unlike papules and pustules, once phymas develop they do not resolve spontaneously and remain persistent between flares [2,5-7]. Rosacea typically manifests first as intermittent bouts of flushing caused by vasodilation and increased blood flow, which is most dominant on the central face [2,4,7]. After this flushing resolves, the facial skin appears normal [4-8]. Over time, as repeated episodes of flushing wax and wane, the central facial skin develops diffuse non-transient erythema and telangiectasias, both of which persist between the flares and result from fixed enlargement and dilation of superficial cutaneous vasculature [2,5,6,9,10]. Thus, the cutaneous manifestations of an individual with rosacea at a given point in time are dependent on if the condition is flared or quiescent, presence or absence of papulopustular lesions during flares, presence or absence of phymatous changes, the intensity of background erythema, the magnitude of telangiectasias, and the size and pattern of telangiectasia formation. In addition, as rosacea is associated with increased centrofacial transepidermal water loss and decreased stratum corneum (SC) hydration, especially during a flare, visible signs of rosacea dermatitis may be present characterized by diffuse fine scaling [5,6,10,11]. Although rosacea is commonly classified using the subtype designations as described in 2002, recent publications from the American Acne and Rosacea Society have emphasized the importance of defining the presentation in the individual patient at the time of presentation as this allows for therapy to be directed to the manifestations that are present in that patient, irrespective of a general subtype category [6,10,12]. The two most common clinical presentations that are encountered in dermatology practices globally are diffuse centrofacial erythema without papulopustular lesions and diffuse centrofacial erythema with papulopustular lesions [1,2,5,6,12]. Selected patients with either presentation may also present with phymatous changes and/or ocular manifestations of rosacea [1,2,4-6,10,12].

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Management of cutaneous rosacea

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1.2

Symptomatology of rosacea

During flares of rosacea, episodic flushing may be associated with a feeling of warmth in some cases, especially when the vasodilation of facial vasculature is acute and rapid. It is not uncommon for patients with rosacea to report symptoms of augmented skin sensitivity such as stinging, burning, tingling and pruritus [1,2,4-8,10]. A large survey completed by the National Rosacea Society in the United States reported that many rosacea patients experience symptoms of skin sensitivity when their facial skin is contacted by a variety of products commonly used for skin care and personal hygiene [13]. Symptoms of skin sensitivity tend to be more common and more severe during a flare of rosacea, but can occur during quiescent periods in rosacea-prone skin [2,5,6,10]. Rosacea flares The natural course of rosacea has not been well studied. However, it is known that rosacea patients experience intermittent exacerbations that are associated with centrofacial vasodilation and inflammation, which translate clinically as increased facial erythema, variable degrees of soft edema and, in some patients, papulopustular lesions. Several triggers have been reported to commonly induce rosacea flares, including ambient heat, hot liquids (oral-thermal flushing), certain foods (i.e., spicy), and alcohol ingestion (i.e., red wine) [1,2,5-8,14-18]. Increased density of Demodex mites, which is reported to be present in some patients with rosacea, although not mandatory for the development of rosacea in all patients, may be a trigger in some rosaceaaffected patients through stimulation of inflammatory pathways that are augmented in rosacea-prone skin [5,19,20]. Advances in basic science research techniques have led to the identification of neurogenic, immunologic and inflammatory pathways that appear to be involved in rosacea pathophysiology and physiochemical and structural difference in rosacea-affected skin as compared to normal skin of individuals without rosacea [5,6,15-18,21-25]. Many of these research findings on specific pathophysiologic mechanisms and differences noted in rosacea-prone and rosacea-affected skin seem to correlate with how certain triggers can precipitate rosacea flares in affected individuals [5,6,10,16-18,22]. 1.3

Pathophysiologic mechanisms operative in rosacea and clinical relevance

2.

neurovascular dysregulation, augmented immune detection and response, and a variety of physiochemical alterations that have been shown to affect facial skin of rosacea-affected individuals as compared to normal facial skin of those without rosacea [5,6,15-17,33]. A summary of rosacea-prone skin is depicted in Table 1. In a nutshell, rosacea-prone skin is wired to react to inciting triggers that do not induce a response in facial skin of an individual without rosacea. With a rosacea flare, certain triggers (i.e., heat, ultraviolet light spices) induce neurogenic responses that lead to vasodilation (flushing) and sensitive skin symptoms; these triggers also stimulate an upregulated immunologic cascade that increases the production of the antimicrobial peptide cathelicidin (LL-37) and variant pro-inflammatory peptides that immediately produce cutaneous inflammation and vasodilation during the flare and also contribute to increased size and density of superficial facial skin vasculature, which over time leads to non-transient facial erythema that is persistent between flares of rosacea [2,5,6,8-10,15-18,21-28,33]. Recent data on the mechanisms of action of specific therapies used to treat different manifestations of rosacea provide explanations that more clearly describe why certain therapies address some clinical features and not others [2,5,6,10,12,26,29,31-34]. Hence, is it very important for the clinician to differentiate in each patient which clinical findings of rosacea are present and which are most bothersome to them as combination approaches may be needed to address individual visible manifestations of rosacea [2,5,6,10,12,26,29,31-33,35]. 3.

Conventional medical therapies for rosacea

Conventional topical and oral therapy for rosacea has been studied almost exclusively in subjects with papulopustular rosacea. Proper skin care is also an integral component of the management of rosacea. Importantly, none of the conventional topical or oral therapies have been shown to be effective for the nontransient facial erythema of rosacea that persists between flares and is associated with an increase in density and size of superficial cutaneous vasculature [5,6,9,12,26,31-33,36-38]. As there is no specific microbial organism or bacterium that has been shown to be integral to the pathogenesis of rosacea, therapies which inhibit inflammatory pathways that have been correlated with rosacea have been a main focus of the therapeutic armamentarium [2,5,6,15-18,21,22,27,28,39]. Skin care in rosacea management Proper skin care using a gentle cleanser and moisturizer/ barrier repair formulation is important to integrate into the management plan for rosacea along with rational selection of other therapies, including topical agents, oral agents and/ or physical modalities [10,11,13,12,35-38]. Recently, a low-molecular-weight hyaluronic acid sodium salt 2% barrier repair formulation applied twice daily was shown to reduce signs (i.e., erythema, papular lesions) and symptoms (i.e., burning, stinging) of rosacea [40]. 3.1

Detailed discussion of more recent information on the pathophysiology of rosacea is beyond the scope of this article and is published elsewhere [5,6,8,15-18,21-24,26]. However, an overview of rosacea-prone skin and pathophysiologic mechanisms that appear to be operative in producing the clinical manifestations of rosacea based on basic science research completed over the past decade are important to discuss as many correlate directly with rational selection of specific therapies [5,6,12,22,26-32]. The designation of rosacea-prone skin describes the presence of

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Table 1. Physiochemical characteristics of rosacea-prone skin. Findings that correlate with neurovascular dysregulation and neurogenic inflammation in rosacea Increased tendency for vasodilation (flushing) in response to thermal stimuli such as oral-thermal flushing in erythematotelangiectatic rosacea [75] Increased density and co-localization of specific neurosensory receptors and sensory nerve fibers [15,17] Altered density of heterogenous transient receptor potential vanilloid receptors (TRPV 1 -- 4) on neuronal and or non-neuronal cells involved in nociception [15,17,25] Individual TRPVs can be activated by a variety of stimuli reported to be trigger factors in rosacea such as heat (thermosenation) and capsaicin [15,17,25] Increase in TRPV2 and TRPV4 (dermal immunolabeling) and TRPV1 (gene expression) in patients with erythematotelangiectatic rosacea [15,17,25] Increase in epidermal and dermal TRPV1+ nerve fibers in erythematotelangiectatic rosacea compared to healthy skin [17] Increase in TRPV2 and TRPV4 (immunoreactivity) and TRPV2 (gene expression) in patients with papulopustular rosacea [15,17,25] Increased density of perivascular mast cells in all rosacea subtypes [17,76] Increase in specific neuropeptides (some variations between studies noted) [17,15,77] Substance P and calcitonin gene-related peptide (CGRP) upregulated in one study and not increased in another study (differences may relate to disease activity and/or site selection of skin biopsy) [15,77] Upregulation of several vasoactive peptides [15,17] Increased cathilicidin antimicrobial peptide (LL-37) in all subtypes [15] Upregulation of pituitary adenyl cyclase activating peptide [15] Shown to induce vasodilation and flare in human forearm skin and an increased number of blood vessels (CD31+ lumina) in human whole-skin tissue culture [78] Findings that correlate with augmented immune detection and response in rosacea Upregulation of pattern recognition receptor (toll-like receptor-2), which detects triggers (i.e., ultra violet light) and signals the activation of the cathelicidin inflammatory cascade Increased production of LL-37 (cathilicidin) in stratum corneum (SC), which induces vasodilation, inflammation and angiogenic effects (downstream signaling of VEGF) [5,16,17,23,27,28] Repeated rosacea flares over time induce angiogenic effects that ultimately produce fixed changes in superficial cutaneous vasculature (enlargement, increased vessel density), which results in diffuse centrofacial erythema that persists between flares (persistent non-transient erythema) [5,16,17,23,27,28] Increase in antimicrobial cathelicidin-precursor peptides that when converted by trigger signaling promote inflammatory and vascular responses due to conversion to LL-37 [5,16,17,23,27,28] Upregulation of SC serine protease enzymes (i.e., kallikrein-5, startum corneum tryptic enzyme), which converts cathelicidinprecursor peptide to increased amounts of LL-37 and multiple other variant peptides in rosacea [5,16,17,23,27,28] Patterns of inflammatory cell infiltration reflective of clinical manifestations Th1 pattern early in erythematotelangiectatic rosacea (CD4+ lymphocytes, macrophages) [5,17] Th1 pattern + neutrophilic infiltration indicates greater acquired immune response in papulopustular rosacea [5,17] Impaired SC permeability barrier function Increased central facial transepidermal water loss [11]

3.2

Topical therapies

Prior to latter half of 2013, medical therapy for rosacea was limited to agents that were evaluated and used for the treatment of papulopustular rosacea [5,12,31,32,37]. The two most commonly used topical agents used over the past several years, both of which are approved in the US by the FDA for the treatment of inflammatory lesions of rosacea, are metronidazole (Metr; 0.75% gel, cream, lotion; 1%; gel, cream) and azelaic acid (AzA) 15% gel [31,32,36-38]. In papulopustular rosacea (i.e., subtype 2), both of these agents have been shown to markedly reduce inflammatory lesions (papules, pustules); perilesional erythema also decreases as the papulopustular lesions regress. The mode of action of topical metronidazole in rosacea is not known, although mechanisms that reduce inflammation in rosacea are believed to be involved [31,32,37,38]. In vitro research and clinical studies in patients with papulopustular rosacea have shown that AzA 15% gel reduces kallikrein-5 (serine protease) activity in affected facial skin, which inhibits the increase in cathelicidin production that 2032

has been documented in rosacea-affected skin [34,41]. This latter finding with AzA appears to explain, at least partially, the mode of action of this agent in rosacea [34]. Although reported to be of benefit in small studies and case reports, less data are available with other topical agents that have been used for rosacea such as sulfacetamide 10%-sulfur 5% (i.e., leave-on formulations, cleansers), calcineurin inhibitors and permethrin [5,12,29,31,32,36-38]. Oral therapies The major class of oral agents that have been utilized for the treatment of rosacea are the tetracyclines. Published data is reported primarily with oxytetracycline, tetracycline and doxycycline used to treat papulopustular rosacea [31,32,36-38,42]. Other oral antibiotics that have been reported to be effective for the treatment of papulopustular rosacea include metronidazole and azithromycin [31,32,36,38,42-44]. Although oral antibiotics have been used to treat rosacea for several decades, there is no evidence that a bacterium is a causative factor 3.3

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Management of cutaneous rosacea

or a mandatory component of the pathogenesis of rosacea [2,6,16,18,21,22,30,39]. Tetracyclines have been shown to exhibit multiple biologic and anti-inflammatory properties unrelated to antibiotic effects, some of which appear to be operative in rosacea [30,34,45-47]. Importantly, sub-antimicrobial dose doxycycline using 40 mg modified release capsule once daily has been shown to be effective in the treatment of papulopustular rosacea in several studies, likely through specific anti-inflammatory properties [30,42,48-51]. This approach exhibits a pharmacokinetic profile that has anti-inflammatory activity but is devoid of antibiotic selection pressure, thus avoiding antibiotic resistance associated with oral antibiotic therapy [42,48-52]. Doxycycline 20 mg twice daily is also sub-antimicrobial; however, data are limited for treatment of rosacea [42,49,52]. Oral isotretinoin has been used in selected cases of refractory papulopustular rosacea with favorable efficacy reported; however, prolonged remissions do not occur after discontinuation of therapy [39,42,53]. This agent is also effective in the treatment of early rhinophyma, which is primarily associated with hyperplastic sebaceous proliferation and has not yet progressed to a fibrous or mucinous stage. 4.

Recently developed medical therapies

The two most recently developed medical therapies for rosacea include two topical formulations, both with new active ingredients. The first is brimonidine tartrate (BT) 0.5% (brimonidine 0.33%) gel, which is the first agent approved by the US FDA for the treatment of persistent non-transient facial erythema (background erythema). The second is ivermectin (IVM)1% cream, which has completed pivotal trials and has been submitted for approval in the US. IVM 1% cream has been recently used for the treatment of papulopustular rosacea. A third topical agent, oxymetazoline is in an earlier phase of development for the treatment of background erythema of rosacea. Topical a-adrenergic receptor agonists Facial erythema is a primary diagnostic feature of rosacea. The background erythema of rosacea is predominantly centrofacial and diffuse, increasing in intensity during flares and persisting as non-transient erythema (background erythema) between flares [1-5,7,14,21,26]. Facial erythema occurring during a rosacea flare results from vasodilation (flushing of rosacea), neurogenic inflammation, augmented innate and acquired immunologic inflammation, lesional and perilesional erythema when papulopustular lesions are present, and SC barrier impairment [2,5,6,8,11,14-18,21-28,33]. Persistent non-transient facial erythema of rosacea appears to correlate primarily with increased density and size of superficial dermal facial vasculature and telangiectasia [2,5,6,9,14,16,18,21,26]. The enlarged dermal vasculature of rosacea that is enveloped by a layer of smooth muscle remains physiologically vasoactive with a-adrenergic innervation causing vasoconstriction [2,26,33,54,55]. 4.1

Topically applied a-agonists are the first class of agents shown to be effective in reducing the persistent non-transient facial erythema; BT has been the most extensively studied in clinical trials, with oxymetazoline and xylometazoline published in case reports [33,37,56-58]. The therapeutic target of a-agonists are a-receptors present in the smooth muscle layer of the vessel wall of superficial cutaneous blood vessels that physiologically modulate vascular tone such as the vasculature of superficial and deep plexuses [26,33]. The vasoconstrictive effect after facial application leads to reduction in facial erythema, which lasts over the duration of adequate binding of the a-agonist to its receptor. Smaller papillary vessels (i.e., capillaries) and telangiectasias do not contain a fully formed smooth muscle sheath and are not under a-adrenergic control; therefore, these smaller vessels do not vasoconstrict after application of an a-agonist [26,33,56-58]. Brimonidine BT is an a-agonist with high selectivity for a-2-adrenergic receptors [57]. Approved initially as a 0.1 and 0.15% ophthalmic solution for the treatment of open angle glaucoma, topical application of BT gel induces vasoconstriction of superficial facial skin vasculature, which led to approval in the US for treatment of persistent non-transient facial erythema of rosacea on August 23, 2013. A one-day application dose-ranging study (n = 122) demonstrated the optimal dose of BT gel to be 0.5% (equivalent to brimonidine 0.33%), applied once daily [57]. An analysis of the pharmacokinetic profile of BT gel after application to skin for 29 days compared to ocular application of BT 0.2% ophthalmic solution demonstrated a superior safety profile related to systemic exposure for BT 0.5% gel applied to facial skin with no systemic drug accumulation observed over the duration of the study [59]. Double-blind, randomized, vehicle-controlled Phase III pivotal trials evaluated once-daily application of BT 0.5% gel over 4 weeks for persistent nontransient facial erythema of rosacea in adult patients (n = 553) with £ 2 papulopustular lesions, corroborated outcomes from a similarly performed Phase II dose-ranging study (n = 269), with demonstration of efficacy, favorable tolerability, a lack of systemic safety signals, absence of tachyphylaxis, and a minimal potential for rebound [57,60]. A multicenter, open-label, long-term (52 week) study of BT 0.5% gel applied once daily included patients with facial erythema of rosacea (n = 449) both with and without papulopustular lesions, with 29.2% of patients using concomitant topical (i.e., metronidazole, AzA) or oral (i.e., tetracyclines) medications for papulopustular lesions. Data from available studies demonstrate overall that BT 0.5% gel induces its onset of erythema reduction as early as 30 min, a peak effect at approximately 3 h, and a duration of peak erythema reduction of approximately 6 h after a single application. As the peak effect wanes, the usual pattern of reappearance of erythema was a progressive return of facial erythema over 2 -- 3 h to a level that was slightly less than baseline; however, in some cases, the intensity of erythema 4.2

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can exceed what was noted at baseline before application [57,60]. It is prudent to inform patients of the possibility that facial erythema may worsen after the vasoconstrictive effect remits. In the Phase II and III pivotal studies, all of the enrolled subjects were affected by erythematotelangiectatic rosacea (facial erythema with £ 2 papulopustular lesions and no nodules). Repeated once-daily applications over 28 days of BT 0.5% gel in these pivotal studies reduced facial erythema on day 28, the same or better than what was noted after the first application at start of the trial [57,60]. These results were significantly superior to vehicle (p < 0.001), and loss of therapeutic effect (tachyphylaxis), worsening of papulopustular lesion counts, worsening of telangiectasia severity and clinically relevant aggravation of facial erythema (rebound) were not observed [57,60]. Tachyphylaxis was also not observed in the long-term study that included 335 subjects and 279 subjects treated with BT 0.5% gel once daily for 6 and 12 months, respectively [61]. Safety assessments completed during the pivotal studies and long-term study with facial application of BT gel at all concentrations and application frequencies demonstrated no systemic safety signals and an overall safety profile that was favorable [57,60,61]. With repeated applications of BT 0.5% gel once daily for up to 52 weeks, cutaneous adverse events were reported in 105 subjects (23.4%), with worsening of erythema or rosacea, skin burning sensation, skin irritation, pruritus, flushing and allergic contact dermatitis noted at some point during the study in 10.1, 3.3, 3.1, 2.0, 8.9 and 1.6% of subjects, respectively [61]. Fifty-seven subjects (12.7%) using BT 0.5% gel once daily were discontinued from the long-term study due to a cutaneous adverse event. It is not surprising that some patients with rosacea experienced cutaneous adverse events given the inherent skin sensitivity and vascular reactivity of rosacea and the potential for contact dermatitis induced by brimonidine itself or the gel vehicle, augmented potentially by the underlying inflammation and epidermal barrier impairment present in rosaceaaffected skin. In the 52-week study, contact dermatitis was reported in 2.2% of subjects treated with BT 0.5% gel; allergic contact dermatitis was identified in a small subset of patients due to either brimonidine or a vehicle excipient in clinical trials that preceded FDA approval of the drug in the US [57,60,61]. Reports of rebound erythema with use of BT 0.5% gel have been published suggesting that some patients may exhibit greater variability in vascular reactivity, either inherently and/or related to a major trigger exposure [62,63]. The clinician is encouraged to inform patients that this may occur and to not use BT 0.5% gel other than how it is recommended. In patients with papulopustular rosacea who were treated with BT 0.5% gel once daily for persistent non-transient facial erythema in the 52-week study, it is important to note that while facial erythema decreased, the papulopustular lesions and telangiectasias persisted as these clinical manifestations are not treated by application of BT [61]. Importantly, BT 0.5% gel was not associated with 2034

inducing the emergence of papulopustular lesions in subjects treated daily for 29 days and in subjects treated once daily up to 52 weeks [57,60,61]. Patients need to be informed about the different types of rosacea lesions, what treatments they are likely to favorably respond to, the anticipated time course of response and the potential adverse reactions they may experience. Oxymetazoline and xylometazoline Oxymetazoline and xylometazoline are topically applied a-agonists with high selectivity for a1A-adrenergic receptors and partial selectivity of a2A-adrenergic receptors; both are available in nasal formulations used to treat rhinitis with nasal congestion [33,56,58]. In a limited number of case reports, both oxymetazoline 0.5% nasal solution and xylometazoline 0.5% nasal solution were shown to be effective in reducing facial erythema in patients with erythematotelangiectatic rosacea [56,58]. Oxymetazoline is currently under research development in the US for use in rosacea. 4.3

Topical Ivermectin IVM is a semisynthetic derivative of the avermectin family, which has been used for treatment of endoparasitic and exoparasitic infections for over two decades both orally and topically [64]. The antiparasitic activity of IVM is through blockade of specific channels involved in neural synapse transmission that are found in invertebrates that can infect humans and animals (i.e., certain worms, mites, lice) [62]. Due to activity against Demodex mites, IVM has been shown to be effective orally in cases of demodecidosis and in patients with cutaneous and ocular manifestations associated with proliferation of Demodex folliculorum [65,66]. As an increased density of facial D. folliculorum has been shown in some patients with erythematotelangiectatic or papulopustular rosacea compared to facial skin of healthy controls, topical IVM has been evaluated for the treatment of papulopustular rosacea [19,20,67]. Additionally, as IVM has been shown to exhibit certain antiinflammatory properties, the possibility that some of these effects may provide therapeutic benefit is considered as Demodex mite proliferation is not present in all cases of rosacea [67]. IVM 1% cream has been submitted to the US FDA for approval for the treatment of papulopustular rosacea. In two randomized, double-blind, vehicle-controlled 12-week pivotal studies, IVM 1% cream applied once daily was compared to vehicle cream once daily in subjects with moderate-to-severe papulopustular rosacea (n = 1369). The mean inflammatory lesion count at baseline in the studies was 30.9 (+/- 14.33) and 32.9 (+/- 13.70), which is markedly higher than in studies with other FDA-approved therapies for papulopustular rosacea (mean range usually between 18 and 20 lesions) [48,50,67-70]. In both studies, a greater percentage of subjects in the IVM 1% cream group achieved treatment success defined as an Investigator Global Assessment of ‘clear’ or ‘almost clear’, specifically 38.4 and 40.1% in the IVM groups and 11.6 and 18.8% in the vehicle groups, respectively (both p < 0.001). 4.4

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Management of cutaneous rosacea

In addition, IVM 1% cream was superior to vehicle in inflammatory lesion count reduction compared to baseline with 76.0 and 75.0% in both IVM groups versus 50% for both vehicle groups, respectively. Safety and tolerability assessments showed a low incidence of skin tolerability reactions with skin burning, pruritus and dryness most commonly reported. No serious adverse events, significant systemic side effects or clinically significant laboratory abnormalities were noted [67]. The results of these pivotal studies suggest that IVM 1% cream is likely to be a very effective addition to the therapeutic armamentarium for papulopustular rosacea, including subjects with high numbers of papulopustular lesions. This agent may also be an important therapeutic tool in those patients with rosacea or a rosacea-like facial eruption where a proliferation of Demodex mites is present (demodecidosis). 5.

Conclusion

Cutaneous rosacea is a common inflammatory facial dermatosis seen most often in adults, which is characterized predominantly by centrofacial erythema. Periods of exacerbation present as increased facial erythema due to vasodilation (flushing) and in some patients papulopustular lesions occur. The two major pathophysiologic processes that contribute to the development of rosacea-prone skin are neurovascular dysregulation and augmented immune detection and response. A variety of triggers elicit inflammatory responses in rosacea-prone skin leading to different signs and symptoms of rosacea. Most patients present with flares of centrofacial erythema due to acute--subacute vasodilation (flushing of rosacea) and some magnitude of augmentation of cathelicidin-induced inflammation. Some may develop papulopustular lesions. A subset of patients present during flares with predominance of papulopustular lesions with minimal centrofacial erythema. In patients who have had rosacea over a period of years, persistent non-transient facial erythema is noted due to fixed enlargement and proliferation of superficial cutaneous vasculature that remains vasoactive. Phymas occur in a small subset of patients, usually males, often but not always associated with visible inflammation and papulopustular lesions during rosacea flares. Treatment of phymas is not addressed in this article and usually necessitates use of a surgical approach or physical modality. Individual medical therapies and also physical modalities (i.e., lasers, intense pulse light) address specific components of the clinical presentation, and in many cases are used in combination to achieve desired results [12,33,35,37,42,71-73]. For example, topical AzA (including the 15% gel formulation applied twice daily) and oral doxycycline (including subantimicrobial dosing with 40 mg modified release capsule once daily) have been shown both in laboratory models and in rosacea patients to inhibit the cathelicidin pathway, which is upregulated in rosacea and at least partially responsible for cutaneous inflammation especially during a flare [34,41,45]. There is no published data evaluating the effect of topical metronidazole on the

cathelicidin pathway, although like AzA 15% gel there is a large body of clinical data on efficacy in papulopustular lesions to reduce these lesions, both as monotherapy and in combination with oral doxycycline [68-71,73]. Additionally, one study has demonstrated that AzA 15% gel applied once daily or twice daily achieves comparable efficacy in patients with papulopustular rosacea [74]. The availability of an a-agonist such as BT 0.5% gel allows for topical treatment of persistent non-transient erythema, which is not effectively treated by other medical therapies used for rosacea to date [33]. IVM 1% cream based on published studies to date appears to offer another effective alternative for the treatment of papulopustular rosacea, especially considering the range of rosacea severity that was included in the studies [67]. The clinician is encouraged to assess the clinical manifestations that are present in a given patient and direct therapies to reduce these manifestations, especially those that are of most concern to the patient. This may require a combination therapy approach utilizing both medical management and physical modalities and may necessitate adjustment in therapy over time depending on therapeutic response and changes in the clinical manifestations of rosacea as it progresses over time [12,35,71-73]. 6.

Expert opinion

Management of cutaneous rosacea involves the incorporation of thorough patient education about the disease, integration of proper skin care, clinical differentiation of visible manifestations and symptoms at the time of presentation, determining what bothers the patient, setting patient expectations to be realistic on what therapies can do, explaining the time course of response of individual manifestations and designing a management plan that addresses the manifestations that are present in the given patient. It is also important to emphasize that rosacea is a chronic disorder so that the need for adherence with long-term management is understood at the outset, and that therapy may need to be adjusted over time. In many cases, a combination approach is warranted, with some therapies being used concurrently and at other times may be staggered. With papulopustular rosacea that is moderate or severe at the time of presentation, a combination therapy approach using a topical and an oral agent is helpful in expediting and optimizing improvement. As AzA and doxycycline have both been shown to mitigate the upregulated cathelicidin pathway present in rosacea-prone skin and at different steps in the cascade, the combination of AzA 15% gel applied twice daily and doxycycline-modified release 40 mg once daily is a rational choice based on known modes of action and clinical data, and appears to demonstrate the fastest onset based on global assessment as compared to topical metronidazole, although topical metronidazole has been utilized in this combination with overall efficacy demonstrated. The sub-antimicrobial dosing of doxycycline offers the advantage of clinical efficacy and avoidance of antibiotic selection pressure, especially as a higher antibiotic dose is not needed to treat most cases

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J. Q. Del Rosso

of papulopustular rosacea. To optimize the gastrointestinal absorption of doxycycline, instruct patients to ingest doxycycline with a large glass of water with a non-dairy meal (that also excludes calcium-fortified cereals) and to avoid concurrent ingestion within 2 -- 3 h of vitamin--mineral supplements (i.e., calcium, iron) and antacids that contain aluminum, magnesium and/or calcium. BT 0.5% gel once daily can be integrated with the above therapies when treating the persistent non-transient facial erythema in patients with papulopustular rosacea that is not addressed by the aforementioned medical therapies (which were included with some patients in the 52-week study), or it can be used for the same presentation in patients that present with no or few (£ 2) papulopustular lesions, as was shown in the Phase II and III pivotal studies. It is important to inform patients that use of some therapies may unmask manifestations that were present but not identifiable visibly due to the magnitude of diffuse facial erythema present during a flare. For example, application of a topical a-agonist such as BT 0.5% gel in a patient with papulopustular rosacea and diffuse facial erythema will reduce the diffuse background erythema; however, the persistent lesional and perilesional erythema associated with papules and pustules and the telangiectasias that do not vasoconstrict are more visibly apparent as they are no longer masked by the diffuse redness. If treatment has been concurrently started for the papulopustular Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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lesions, it will take at least a few weeks for these lesions and their associated erythema to remit, which also needs to be explained to the patient. If the linear telangiectasias and telangiectatic mats remain as bothersome to the patient, a physical modality such as pulse dye laser or intense pulse light is needed to eradicate these lesions, although periodic treatments may be required as new telangiectatic lesions emerge over time. It appears based on data to date that IVM 1% cream will be a welcome addition for the management of papulopustular rosacea. Potentially, this agent may be used as monotherapy or in combination with an oral agent or other topical agents depending on the severity of disease, other patient-related factors and results that emerge from additional studies.

Declaration of interest JQ Del Rosso is a consultant, speaker and/or researcher for Allergan, Bayer, Aqua, Dermira, Ferndale, Galderma, Innocutis, Promius, PuraCap, Ranbaxy, Unilever, Valeant. He also serves as chair of the Education Committee for the American Acne and Rosacea Society. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. papulopustular rosacea. J Am Acad Dermatol 2007;57:800-5

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Affiliation James Q Del Rosso DO Clinical Professor (Dermatology Adjunct Faculty), Touro University College of Osteopathic Medicine, Henderson, NV, USA E-mail: [email protected]