Management of facial erythema of rosacea: What is the role of topical α-adrenergic receptor agonist therapy?

Management of facial erythema of rosacea: What is the role of topical a-adrenergic receptor agonist therapy? James Q. Del Rosso, DO, FAOCDa,b,c Las Vegas and Henderson, Nevada Several more recent advances have led to a better understanding of the pathophysiologic mechanisms involved in rosacea and therapeutic modalities used for treatment. Although the clinical features may vary among patients, there are some unifying mechanisms that appear to relate to the more common presentations of rosacea. Both neurovascular dysregulation and augmented immune detection and response appear to play central roles that lead to many of the signs and symptoms of rosacea. Diffuse central facial erythema is a very common finding that intensifies during flares and persists to varying degrees between flares. This background of facial redness occurs secondary to vasodilation and fixed vascular changes that develop over time. Physical modalities are commonly used to treat the erythema that persists as a result of fixed changes in superficial cutaneous vasculature that do not remit after treatment with agents whose mechanisms are active primarily against some of the inflammatory processes operative in rosacea (ie metronidazole, azelaic acid, tetracyclines). As enlarged superficial cutaneous vessels that contribute to the fixed background facial redness of rosacea remain vasoactive to sympathetic nervous system innervation, topical a-adrenergic receptor agonists, namely brimonidine and oxymetazoline, are currently under evaluation for the treatment of facial erythema of rosacea. This article focuses on the clinical differentiation of facial erythema of rosacea and its management. ( J Am Acad Dermatol 2013;69:S44-56.) Key words: a-adrenergic receptor agonist; brimonidine; facial erythema; papules; pustules; rosacea; topical therapy.

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acial erythema is an integral component of the predominant clinical presentations of rosacea and has been described as a mandatory clinical manifestation for the diagnosis of rosacea.1-3 The 2 most common clinical presentations include central facial diffuse erythema without inflammatory lesions (papules and/or pustules), classically referred to as ‘‘erythematotelangiectatic rosacea’’ (subtype 1), and central facial diffuse erythema with inflammatory lesions, classically referred to as ‘‘papulopustular rosacea’’ (subtype 2).1-3 Importantly, facial erythema of rosacea is not caused by one pathophysiologic source, but rather is related to multiple sources that are inherent to and operative in both rosacea-prone

skin and rosacea-affected skin.1,3-5 ‘‘Rosacea-prone skin’’ refers to underlying characteristics that are innate to the facial skin of individuals with rosacea (Table I). These inherent underlying characteristics are present during both flares and quiescent periods of rosacea. ‘‘Rosacea-affected skin’’ refers to the underlying cutaneous characteristics that are present

From the Dermatology Residency Program, Valley Hospital Medical Center Las Vegasa; Dermatology, Touro University College of Osteopathic Medicine, Hendersonb; and Dermatology and Cutaneous Surgery, Las Vegas Skin and Cancer Clinics, Las Vegas and Henderson.c Publication of this article was supported by a grant from Galderma International. Editorial support provided by Galderma International. Disclosure: Dr Del Rosso has served on advisory boards for Allergan, Galderma, Bayer, Medicis, Valeant, Promius, Obagi, and Ranbaxy; has served as a consultant for Allergan, Dermira, Galderma, Bayer, Medicis, Valeant, Promius, Primus, Eisai,

Unilever, Obagi, Ranbaxy, and Taro Pharma; is a speaker with Allergan, Bayer, Galderma, Medicis, Valeant, Promius, Unilever, Warner-Chilcott, Obagi, and Ranbaxy; has served as an investigator for Allergan, Galderma, and Medicis; and has received honoraria as compensation. Accepted for publication June 16, 2013. Reprint requests: James Q. Del Rosso, DO, FAOCD, James Q. Del Rosso DO, LLC, 9811 West Charleston Boulevard suite 2434, Las Vegas, NV 89117. E-mail: [email protected]. 0190-9622/$36.00 Ó 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.06.009

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Abbreviations used: EGFR: KLK: TLR: VEGT:

endothelial growth factor receptor kallikrein Toll-like receptor vascular endothelial growth factor

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during a visible flare of the disease, including immucontribute to the overall picture of facial redness nologic and inflammatory cascades that have been in the patient with rosacea.4-37 4,5 The clinician is encouraged to conceptualize the reported to be operative in facial skin of rosacea. The pathophysiologic components that are differences between facial erythema of rosacea preconsistently present in both major clinical presentasent during a flare, and the facial erythema that is tions of rosacea are ‘‘neurovascular dysregulation’’ persistent between flares of the disease. Despite and ‘‘augmented immune detection and response,’’ variations in the intensity of facial redness, diffuse including the less common central facial erythema is a subset of patients with rosacea very common clinical maniCAPSULE SUMMARY who also exhibit phymatous festation of a flare of rosacea, changes.4-19 Multiple studies and is a consistent finding In rosacea, diffuse central facial erythema using techniques such as gene among patients with rosacea, is a very common finding that intensifies array analyses, immunohisincluding those with presenduring flares and persists to varying tochemical techniques, and tations classically described degrees between flares. real-time polymerase chain as erythematotelangiectatic Topical a-adrenergic receptor agonists, reaction have identified inherrosacea (subtype 1), papulosuch as brimonidine and oxymetazoline, ent physiochemical changes pustular rosacea (subtype 2), may prove effective for the treatment of in patients affected by the and in many cases of phymfacial erythema of rosacea. major clinical presentations atous rosacea (subtype 1-5,38,39 In patients with inof rosacea, classically referred 3). Further research may help broaden flammatory lesions (ie, papto as ‘‘rosacea subtypes’’ understanding of pathophysiologic ules, pustules), perilesional (erythematotelangiectatic mechanisms and selection of effective erythema contributes to the [subtype 1]; papulopustular therapies. overall facial erythema of ro[subtype 2], and phymatous sacea and blends in with the [subtype 3]).4-16 The physiochemical changes associated with clinically apparent overall clinical picture of diffuse central facial eryrosacea are depicted in more detail in Table II. thema that is present. As the papules and pustules subside, the contribution of these inflammatory lesions to the overall picture of facial erythema regresses. DIFFERENTIATING ERYTHEMA OF Facial erythema of rosacea, either during a flare or ROSACEA IN THE CLINICAL SETTING between periods of flaring, is most often confluent The facial erythema of rosacea relates to a and diffuse, hence the common designation of combination of several factors, but principally com‘‘background erythema.’’4,5,39 In the majority of prises 2 predominant components.1-5 The first is cases, diffuse facial erythema of rosacea exhibits diffuse central facial erythema that tends to be more central accentuation involving the inner cheeks, confluent, is macular, and may exhibit a soft nose, chin, and/or mid forehead. However, involveedematous quality in some cases. The second is ment of the peripheral face may also be present. perilesional erythema, which refers to the flare of Diffuse central facial erythema present during rosaredness that focally surrounds individual papules cea flares and that which is persistent between and pustules in those cases of rosacea where rosacea flares (including after conventional medical inflammatory lesions are present. When multiple therapies) both manifest similarly, although the inflammatory lesions are observed, the perilesional intensity is amplified to varying degrees in the flared erythema that is focally present around individual state.1-5 This variable degree of intensity during a papules and pustules can easily blend in and flare of rosacea depends on the intensity of the flare become confluent with diffuse central facial eryand the underlying overall severity of rosacea in the thema, although the latter is not directly related to given patient. Several factors influence the presenthe inflammatory lesions. The inability to clinically tation of facial erythema in a given patient, however, differentiate the sources of the overall facial erysome common pathophysiologic factors appear to thema of rosacea can confound the ability to assess be operative in the vast majority of patients, and the response of erythema to treatment after use of have been reviewed in more detail elsewhere.4-19 specific therapeutic approaches.5 This is because Many of the pathophysiologic mechanisms shown to facial redness, referred to here as the ‘‘facial erybe operative in the facial skin of patients with thema of rosacea,’’ is related to several underlying rosacea and/or well supported by various benchtop pathophysiologic factors that have been reviewed research studies appear to correlate with many of the in more detail elsewhere, all of which can d

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Table I. What is rosacea-prone skin? Patients with rosacea have skin inherently programmed to exhibit the following characteristics1-6 Flare of rosacea requires rosacea-prone skin 1 inciting trigger factor(s) Programming of rosacea-prone skin believed to be result of genetic predisposition Cross-talk mechanisms between neurovascular dysregulation and augmented immune detection and response Two inherent characteristics of rosacea-prone skin (1) Neurovascular dysregulation1-3 All presentations of rosacea exhibit structural and chemical alterations as compared with normal-appearing skin Induces vasodilation and neurosensory symptoms (2) Augmented immune detection and responses1,2,4-6 Patients with rosacea exhibit increased immunologic response to multiple triggers (most are exogenous) via multiple cascades Triggers acute and chronic inflammatory mechanisms Changes in cellular infiltration, vascular alteration, activity of stratum corneum serine protease enzymes (ie, KLK-5) and substrates (ie, cathelicidin precursor), increased cathelicidin-derived peptides (ie, LL-37 long form) and downstream effects on vasculature (VEGF stimulation by LL-37) KLK, Kallikrein; VEGF, vascular endothelial growth factor.

clinical manifestations that are characteristic features of rosacea.4-6,10,11 Some clinical manifestations of cutaneous rosacea are intermittent and some are persistent (Table III).

Facial erythema during flares During flares of rosacea, the diffuse background erythema intensifies in magnitude of redness, may become edematous, and is often more symptomatic (ie burning, stinging) (Fig 1).1-5 Available medical therapies that decrease papulopustular lesions and reduce their surrounding erythema (perilesional erythema), such as topical metronidazole, topical azelaic acid, and oral tetracyclines, may potentially counteract some of the rosacea-associated vascular inflammation and associated dilation that is not fixed in an enlarged state. However, these agents produce negligible to no decrease in diffuse background facial redness that is caused by permanently altered superficial cutaneous vasculature.4,5,38-46 Permanently altered superficial facial vascular changes, referred to as ‘‘fixed vascular changes of

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Table II. Physiochemical changes innate in facial skin in rosacea1-19 Greater density and co-localization of specific neurosensory receptors and sensory nerve fibers Greater density of perivascular mast cells Increase in specific neuropeptides Increase in antimicrobial cathelicidin-precursor peptides that promote inflammatory and vascular response Up-regulation of stratum corneum serine protease enzyme (KLK-5) that convert cathelicidin-precursor peptide to multiple active peptides Increased production of LL-37 Other variant peptides produced in rosacea Recruit specific patterns of inflammatory cell infiltration Induce acute and chronic vascular changesevasodilation Downstream promotion of more chronic vascular changes Impaired stratum corneum permeability barrier function Increased central facial transepidermal water loss KLK, Kallikrein.

Table III. Clinical manifestations of cutaneous rosacea1-5 Intermittent (present during flares and absent between flares) Inflammatory lesions Papules Pustules Perilesional erythema Diffuse central facial erythema that is related to acute inflammation of rosacea and not related to chronically enlarged superficial blood vessels Persistent (present during and between flares) Diffuse central facial erythema* Telangiectasias Phymatous changes *Increases in magnitude during flare of rosacea.

rosacea,’’ occur secondary to inflammatory pathways reported to occur in rosacea-affected skin that contribute over time to vascular proliferation and enlargement.4-11,16-20 The visible manifestations of fixed vascular changes includes dilated and enlarged facial blood vessels, enlarged vascular nets, and telangiectasia formation.4,5,20 When the visible manifestations associated with a flare of rosacea are present, the pathogenic mechanisms that lead to vasodilation, increased blood flow, and augmentation of cutaneous inflammatory pathways are set into motion leading to visibly accentuated central facial erythema, with variable degrees of soft edema.4-6,8,10,11 Some patients exhibit cytokine

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Fig 1. Facial erythema during flare of rosacea with diffuse background erythema and perilesional erythema.

patterns of cutaneous inflammation that also promote chemoattraction of neutrophils that leads to emergence of inflammatory lesions (ie, papules, pustules).6,8-11,14,15 Regardless of whether inflammatory lesions are present, during an active flare of rosacea most patients exhibit some magnitude of central facial erythema that is generally diffuse (hence the designation of background erythema). In a patient with rosacea who presents with several inflammatory lesions during a flare, it is often difficult to distinguish the relative contributions of perilesional erythema and background erythema to the overall picture of facial erythema of rosacea at that point in time.1,3-5,39 Ultimately, several factors contribute to the facial erythema of rosacea at any given time point, either during a flare or between flares, with a major component of background erythema being the extent of fixed, enlarged, and dilated superficial cutaneous vasculature that is present.4,5,20 Facial erythema between flares Between flares, the extent and magnitude of facial erythema of rosacea is directly dependent on the density of fixed changes in superficial cutaneous blood vessels, the extent of confluence of these vessels, and the number and pattern of telangiectasias. As a result, the facial erythema that is persistent between flares of rosacea is typically diffuse,

macular, and accentuated on the central face, and is commonly referred to as ‘‘background erythema’’ (Fig 2).4,5,39 Fig 3 depicts facial erythema of rosacea after treatment of a flare with conventional medical therapies, such as topical metronidazole, topical azelaic acid, and oral tetracyclines. These agents are believed to act therapeutically by inhibiting inflammatory mechanisms involved in rosacea, but do not exhibit direct vasoactive properties that induce vasoconstriction (ie, metronidazole, azelaic acid, tetracyclines).4,5,38-52

PATHOPHYSIOLOGIC MECHANISMS ASSOCIATED WITH ACUTE AND CHRONIC EFFECTS IN ROSACEA Much more information is needed about the pathophysiologic mechanisms involved in rosacea, and how some mechanisms may correlate with specific manifestations seen in some patients and not others. However, there is some information gleaned from basic science and clinical research that appears to explain at least some of the manifestations and cutaneous changes that we observe clinically.4-17,22,24,25,29 Importantly, available evidence supports that rosacea is not caused by an underlying bacterium, and that the pathophysiology of rosacea is better explained as a complex inflammatory disorder involving cross

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Fig 2. Persistent background erythema (diffuse central facial erythema) between flares of rosacea.

Fig 3. Diffuse central facial erythema (background erythema) of rosacea persistent after treatment with conventional medical therapies.

talk among neurovascular dysregulation, augmented immune detection and response, and chronic alteration of superficial cutaneous vasculature.4-6,8-17,20-22,24,25,29,35-38 As noted above, rosacea-prone facial skin is ‘‘hard wired’’ to exhibit heightened detection of various triggers such as light, hot spicy foods, heat, or Demodex mite proliferation.3-8,10,22,26,29-31,35 An upregulation of the innate immune response system has been reported based on a variety of studies, mostly in patients with rosacea and inflammatory lesions, but also in those with diffuse facial erythema only.4-13,36 In addition, the pattern recognition receptor, Tolllike receptor-2 (TLR-2), has been shown to be

increased in affected facial skin in patients with papulopustular rosacea.13 Also, TLR-2 has been shown to increase the expression of the stratum corneum serine protease enzyme, kallikrein (KLK)-5, which induces intraepidermal conversion of the cathelicidin-precursor peptide into the principal cathelicidin, LL-37.8-10,13,53 In addition, the matrix metalloproteinase enzymes that induce activation of KLK-5 from its precursor state are increased, thus allowing for augmentation of this proinflammatory and angiogenic cascade by indirectly accelerating increased production of LL-37.6-10,36,53 In addition to its physiologic role as an antimicrobial peptide active against many microbial organisms including

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some bacteria, viruses, and fungi, LL-37 induces acute inflammatory responses and downstream stimulation of more chronic changes in blood vessels.8-10,13,16,25,36 LL-37 has been shown to possess angiogenic properties and can induce alterations in endothelial cells through a variety of signaling pathways including promotion of angiogenesis with increased vascularization mediated through interaction with endothelial cell receptors, receptor transactivation with downstream signaling in epithelium, and receptor-mediated induction of vascular endothelial growth factor in keratinoCollectively, the cytes.4,5,8-10,16,17,21,24,25,36,53-57 above pathophysiologic aberrations of this cathelicidin-related antimicrobial cascade promote both acute and chronic inflammatory sequelae that lead to visible manifestations in rosacea.4,5 Ultimately, as compared with normal-appearing facial skin, rosacea-prone skin exhibits hyperresponsiveness to a variety of triggers that are mostly exogenous in origin. With rosacea, the receptor that detects the trigger factor is up-regulated (TLR-2), the cathelicidin precursor peptide is increased, the stratum corneum protease enzyme that promotes conversion to LL-37 is increased (KLK-5), and the enzymes that promote activation of KLK-5 are increased.4-17,53,56 The net result is amplification of this inflammatory cascade related to increased production of LL-37 and some other variant peptides, the effects of which at least partially explain many of the clinical features of rosacea. The cathelicidin-derived peptides formed by this augmented and accelerated inflammatory cascade, especially LL-37, appear to serve as a common denominator for multiple pathophysiologic processes involving both inflammatory effects and vascular changes, both of which appear to correlate with some of the observed clinical features in rosacea.4-6,8-10 The role of augmented innate immunity and the altered cathelicidin pathway in rosacea is discussed in more detail elsewhere.8-15,36,53

CORRELATION OF VASCULAR CHANGES AND FACIAL ERYTHEMA OF ROSACEA Vasodilation and increased facial blood flow occur in areas affected by a flare of rosacea, which may correlate temporally with an identified exposure to a trigger such as ultraviolet light exposure, hot spicy food, or ingestion of a hot liquid, or may be inexplicable by history.1,3-5,19 Concurrent perilesional erythema also occurs if inflammatory lesions are present. As discussed above, over time, more permanent vascular changes occur with repeated exposure to the inflammation of rosacea, which leads to proliferation and enlargement of superficial

Table IV. Vascular changes in rosacea1-25,29,34,36,42,47,53-57 Response and blood blow Easier 1 more prolonged flushing response (to heat)1 Oral-thermal flushing2 Rosacea with facial erythema without inflammatory lesions Altered blood flow1,3-7 Greater lesional blood flow in rosacea vs controls refuted5,6 Decreased venous blood flow from periphery (facial skin) to core (brain) in response to heating7 Increased blood flow in affected skin [ nonaffected skin Greater difference with inflammatory lesions Physiochemical stimulation of angiogenesis Increase in VEGF in rosacea (nonphymatous)and via ultraviolet exposure8,9 Endothelial nitric oxide / vasodilation10,11 Cathelicidins / angiogenesis/neovascularization8,12 Potential role in increased vascularity in rosacea through cathelicidin-induced endothelial changes Via FPRL1 and EGFR-induced increased in VEGF Permanent (fixed) dilation of superficial vessels Telangiectasias are consistent clinical feature in rosacea (reflects underlying chronic stimulus)1,13 Facial cheek skin of rosacea without inflammatory lesions evaluated by videocapillaroscopy (n = 30)14 Compared facial cheek skin in seborrheic dermatitis (n = 30) and normal-appearing skin (n = 30) Vessel diameter, telangiectasia diameter, and vascular net (polygon) diameter in rosacea [ seborrheic dermatitis and normal-appearing skin (P \ .001 for all 3 parameters) EGFR, Epithelial growth factor receptor; FPRL1, formylpeptide receptor-like 1; VEGF, vascular endothelial growth factor.

vasculature (Table IV).4-18,21,24,25,29,36,47,53-57 These fixed vascular changes result in persistent diffuse central facial erythema coupled with visible telangiectasia.4,5 This progressive sequence of vascular changes and clinical manifestations is depicted in Fig 4.

SUPERFICIAL CUTANEOUS VASCULATURE IN NORMAL-APPEARING SKIN IN ROSACEA Despite some variability based on anatomic site, the microanatomy of the superficial cutaneous vasculature remains relatively constant.58 Within the dermis, a subpapillary horizontal network of vessels, the superficial vascular plexus, is located at the juncture of the papillary and reticular dermis. The subpapillary plexus contains a network of smaller vessels, including postcapillary venules, end arterioles, and capillaries that supply the dermal papillae.

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Fig 4. Progression of vascular changes in rosacea. VEGF, Vascular endothelial growth factor.

A second vascular network, the deep horizontal plexus, is located at the juncture of the deep reticular dermis and panniculus. This deeper vascular network contains larger caliber vessels than the superficial plexus, including distal resistance vessels that are modulated primarily by peripheral adrenergic innervation of the sympathetic nervous system.58,59 Vertically arranged connecting vessels allow for flow between both the superficial and deep plexuses, and both lymphatics and nerves are co-localized with cutaneous blood vessels.58 The superficial cutaneous vasculature serves major physiologic and homeostatic functions that are directly involved in maintenance of core body temperature. If a radiator effect is needed, the superficial vessels vasodilate and dissipate heat. If an insulation effect is needed to retain heat, the vessels vasoconstrict.59 Changes in magnitude and distribution of blood flow may be influenced by several reflexes and responses, however, the dominant influence on central body temperature is reflex thermoregulatory control both centrally and peripherally, with both the arterial and venous systems modulated by sympathetic adrenergic innervation.59-61 Also, local changes in temperature can induce maximal vasodilation or vasoconstriction via adrenergic, endothelial, and sensory mechanisms, which include nitric oxideeinduced vasodilation and a2-adrenoreceptor up-regulation.60 The sympathetic nervous system is the primary modulator of the cutaneous vasculature, with several adrenoreceptors identified (Table V).58-61 The

Table V. Adrenergic receptors and superficial cutaneous vasculature61-66 Regulation of cutaneous circulation is complex; mediated primarily by sympathetic nervous system Interaction of several reflex responses Thermoregulatory reflex is dominant physiologic response Complex family of structurally related receptors 6 a-Subtypes 1 1 conformational variant 3 b-Subtypes 1 1 conformational variant Contraction of peripheral vascular smooth-muscle primarily mediated by a-adrenergic receptor (adrenoreceptor) subtypes Receptor distribution varies in different anatomic areas Specific subtypes may differ in distribution and function Overlap of subtypes in different anatomic locations is common

current model recognizes 6 a-receptor subtypes and 3 b-receptor subtypes, and 2 conformational variants.61-66 Based on data primarily from animal studies, adrenoreceptor subtypes can differ in distribution, function, and affinities for specific stimuli or exogenous agonists, with vascular smoothmuscle contraction mediated by more than 1 a-adrenoreceptor subtype.61-66 In addition, receptor ligands exhibit the ability to interact with multiple receptor subtypes, with various studies showing that vasoconstriction of peripheral vasculature may be mediated by a1- and a2-adrenoreceptor subtypes and agonists.61-68

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Fig 5. Modulation of cutaneous vasculature by a-adrenergic receptor agonists.

It is currently not known whether or not selective stimulation or inhibition of individual adrenoreceptor subtypes in patients with rosacea will correlate with clinically relevant differences in therapeutic outcomes and/or adverse sequelae. However, it is known that the enlarged vessels associated with the fixed vascular changes of rosacea remain vasoactive and responsive to the modulating effects of sympathetic innervation, and that cutaneous application of an a-adrenoreceptor agonist reduces diffuse facial erythema of rosacea over several hours.3-5,61,67,68

EXPERIENCE WITH APPLICATION OF a-ADRENORECEPTOR AGONISTS FOR FACIAL ERYTHEMA OF ROSACEA Diffuse central facial erythema of rosacea is often persistent and as noted earlier is often poorly responsive to conventional topical and systemic medical options for the treatment of rosacea.3-5,38-46 Some physical modalities, such as specific laser and light systems, have been shown to effectively treat the refractory background erythema and individual linear blood vessels that are visible in many patients affected by rosacea, including telangiectasias.69-75 Currently, there are no Food and Drug Administration (FDA)-approved medical therapies for the facial erythema of rosacea. Topical application of 2 a-adrenoreceptor agonists (a-agonists), brimonidine and oxymetazoline, are under evaluation in the United States for treatment of facial erythema of rosacea.5,61,68,76 The therapeutic target of these agents are a-adrenoreceptors located in the smooth-muscle sheath that

encases the vessel wall of superficial cutaneous blood vessels of adequate caliber to modulate vascular tone, such as the horizontal vessels of the superficial and deep plexuses (Fig 5).5,61-64,67,68,76 As smaller papillary vessels (ie, capillaries) and telangiectasias do not contain a fully formed smoothmuscle layer, these vessels are not responsive to a-adrenoreceptor stimulation.5,61,67,68,76 Topical application of oxymetazoline 0.05% solution once daily (n = 2), and xylometazoline 0.05% solution once daily (n = 1), have both been shown in case reports to reduce facial erythema of rosacea over several hours in adult patients who presented with diffuse facial erythema and absence of inflammatory lesions (erythematotelangiectatic rosacea).61,67 Facial erythema decreased within 1 to 3 hours and lasted several hours during the day with efficacy continued with repeated daily use. No tachyphylaxis was observed in any of the 3 patients treated over a range of 8 to 17 months with daily application. In all 3 cases, several other topical therapies and oral antibiotics were reported to be ineffective.61,67 Both xylometazoline and oxymetazoline, a derivative of xylometazoline, are reported to be highly selective for the a1A-adrenoreceptor and partially selective for the a2A-adrenoreceptor.5,61,67 Neither agent is FDA approved for the treatment of rosacea, although both are available as nasal decongestant formulations that were applied to facial skin in the 3 published case reports. Dose-ranging studies and large-scale, randomized, controlled trails need to be completed with these agents in formulations designed for cutaneous application to optimize and better define their

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Fig 6. Reduction in facial erythema of rosacea at 3 hours as compared with baseline, brimonidine 0.5% gel once daily.

efficacy and safety for treatment of facial erythema of rosacea. Brimonidine tartrate is a highly selective a2-adrenoreceptor agonist that is FDA approved as a 0.1% and 0.15% ophthalmic solution for the treatment of open-angle glaucoma.5,68 As peripheral vasoconstriction, including cutaneous vasculature, is induced by topical application of brimonidine tartrate, the drug is under formal evaluation for FDA approval in the United States for erythema associated with rosacea. Phase II and III research trials have already been completed, including assessments of dosage ranging, response of facial erythema after single-dose application, and oncedaily application over 4 weeks.68,76 The optimal dose based on studies completed to date is oncedaily application of brimonidine tartrate 0.5% gel. In the clinical studies, patients with rosacea and diffuse facial erythema were enrolled with an exclusion of subjects with 3 or more inflammatory lesions to avoid the influence of perilesional erythema as a confounding variable.68,76 In a phase II dose-ranging trial, a single application of brimonidine tartrate gel at a variety of concentrations reduced diffuse facial erythema in a dose-dependent manner over 12 hours as compared with vehicle based on investigator assessments, subject assessments, and objective testing using a chromameter.68 The 0.5% gel formulation of brimonidine tartrate demonstrated the greatest decrease in erythema at all time points over the 12-hour duration of examination, with statistically

significant superiority versus vehicle noted in 2-grade improvement in erythema by both investigator and subject assessments, and in median change of chromameter values (P \.001). Brimonidine tartrate 0.5% gel induces its onset of erythema reduction within 30 minutes with the peak effect lasting over 4 to 6 hours, ultimately providing duration of peak erythema reduction lasting from 2 through 8 hours after a single application. Fig 6 depicts a characteristic peak response in erythema reduction showing both the baseline (pretreatment) time point and at 3 hours after application of brimonidine tartrate 0.5% gel, with this peak response range normally continuing for approximately 6 to 8 hours. With waning of the peak effect, the typical pattern of reappearance of erythema was a progressive return over the ensuing hours. However, at the final evaluation time point of the day (12 hours after application), the intensity of erythema did not return to the level noted at baseline.68 This time course of rapid facial erythema reduction, persistence of effect over several hours, and gradual return toward baseline by 12 hours after application of brimonidine tartrate 0.5% gel has been documented by investigator and patient assessment, clinical photography, and RBX photographic technology (Canfield Scientific, Fairfield, NJ), with the latter designed to better depict facial erythema through subsurface visualization with differentiation and separation of vascularity and pigmentation (Fig 7).77 In a second phase II study (N = 269), application of brimonidine tartrate 0.5% gel once daily for

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Fig 7. Facial erythema reduction over 12 hours by global redness analysis (RBX, Canfield Scientific, Fairfield, NJ) after single application of brimonidine 0.5% gel.

4 weeks followed by a 4-week posttreatment phase was evaluated in adult patients with rosacea who presented with moderate to severe facial erythema and 2 or fewer inflammatory lesions.68 The efficacy results were consistent with what was observed with single application. With regard to repeated daily use of brimonidine tartrate 0.5% gel, reduction in erythema after 28 days was the same or better than what was observed on the first day of the trial. These results were significantly superior to vehicle (P \ .001), tachyphylaxis was not observed over the 28 days of daily use, worsening of inflammatory lesion counts or telangiectasia severity was not noted, and clinically relevant aggravation of facial erythema (rebound) was not observed.68 Safety assessments completed during the clinical trials reported that brimonidine tartrate gel at all concentrations and application frequencies studied, including the 0.5% concentration once daily, was safe and well tolerated. Assessments of safety included skin tolerability, intraocular pressure, blood pressure, and heart rate. Two phase III double-blind, randomized, clinical studies evaluated application once daily of brimonidine tartrate 0.5% (n = 277) versus vehicle gel once daily (n = 276) after active treatment over 4 weeks followed by a 4-week posttreatment phase.76 The results mirrored what was reported in the phase II clinical trial, with daily application of brimonidine tartrate 0.5% gel in the phase III studies demonstrating superiority to vehicle at days 1, 15, and 29 (P \ .001 at all time points), an onset of visible facial

erythema noted within 30 minutes, maximum effect observed usually over a duration of 3 to 6 hours after application, and a gradually progressive return toward baseline by 12 hours after application. No major adverse reactions or safety signals emerged and facial tolerability was favorable in both study groups with only occasional reports of signs or symptoms of skin irritation in both study arms that were usually mild and transient. Tachyphylaxis was not observed with repeated once-daily use of brimonidine tartrate 0.5% gel and there was no clinically meaningful aggravation of facial erythema in the follow-up phase as compared with baseline. The investigators noted less than 5% of patients exhibiting some increase in facial erythema scores at followup as compared with baseline at certain time points; response to application of active treatment was sustained without further exacerbation or tachyphylaxis. The results of the 2 pivotal phase III studies further confirmed the observations from the phase II studies.76 Case reports and available studies of facial erythema of rosacea treated with a2-adrenoreceptor agonist agents are promising so far.61,67,68 Additional studies are forthcoming and are expected to provide important information about the efficacy, safety, and optimal use of these agents. It is also hoped that studies will be completed that will evaluate whether or not continued use of these agents, through more prolonged vasoconstriction, is associated with other mechanisms of action helpful in rosacea. As

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vasodilation associated with rosacea is countered by continued use of an a2-adrenoreceptor agonist, a reduction in chronic vascular and perivascular inflammation is theoretically a potential benefit of these agents that is worthy of evaluation.4-6,23,78

CONCLUSIONS Facial erythema of rosacea occurs secondary to a variety of factors, although neurovascular dysregulation and augmented immune detection and response are pivotal components. Although inflammatory lesions when present may contribute to the overall facial redness of rosacea by creating perilesional erythema, persistent diffuse central facial erythema of rosacea is caused primarily by fixed vascular changes. Importantly, specific clinical features of rosacea correlate with certain pathophysiologic mechanisms that appear to be operative in rosacea. The predominant contributors to the background facial redness that intensifies during flares and is persistent between flares of rosacea are the fixed vascular changes that develop over time, characterized by thick and enlarged superficial vessels, some of which are telangiectasias. Physical modalities shown to reduce these vascular changes, such as intense pulsed light and some laser systems (ie, pulse dye laser) are commonly used and are successful in reducing currently present areas when completed properly. There are published data on some topical a-adrenoreceptor agonists being used to treat the diffuse facial erythema of rosacea. Topical brimonidine tartrate gel has been shown in controlled, prospective, randomized clinical trials to reduce the facial erythema of rosacea after single and repeated applications once daily, with favorable cutaneous and systemic safety profiles. The optimal concentration is the 0.5% gel formulation of brimonidine tartrate and the optimal application frequency is once daily, based on dose ranging studies in human beings with rosacea that have been completed to date. In addition, both topical oxymetazoline and xylometazoline have been shown in 3 published case reports to reduce the diffuse facial erythema of rosacea with continued efficacy over several months of once-daily application using nasal solution formulations applied to facial skin. Topical oxymetazoline is in the early stages of clinical development in rosacea through more formal evaluation in prospective and randomized controlled studies using a formulation designed for topical application to skin. It is hoped that further research will lead to an even greater understanding of the pathophysiologic mechanisms involved in rosacea and to a broader selection of effective therapies to reduce the many

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