Cutaneous rosacea: a thorough overview of pathogenesis, clinical presentations, and current recommendations on management

Rosacea is a common inflammatory disorder that af­ fects both genders and most commonly presents on the central face [1]. The prevalence of rosacea has been esti­ mated in epidemiologic studies from selected populations; suffice it is to say that it is a very common disorder that presents regularly in dermatology and primary care clinics [1]. Although reported to most commonly affect individuals with facial skin rated as fitzpatrick Skin Type I­II, rosacea can affect people of any race, skin color, and creed. The published frequency of rosacea derived from patient visit data collected over a fifteen year period at a large practice in the united Kingdom reported an incidence of 1.65 per 1000 person­years, with patients >30 years of age repre­ senting over 80% of the rosacea cases that were encoun­ tered [3].

Rosacea is a common inflammatory disorder that af fects both genders and most commonly presents on the central face [1]. The prevalence of rosacea has been esti mated in epidemiologic studies from selected populations; suffice it is to say that it is a very common disorder that presents regularly in dermatology and primary care clinics [1]. Although reported to most commonly affect individuals with facial skin rated as fitzpatrick Skin Type III, rosacea can affect people of any race, skin color, and creed. The published frequency of rosacea derived from patient visit data collected over a fifteen year period at a large practice in the united Kingdom reported an incidence of 1.65 per 1000 personyears, with patients >30 years of age repre senting over 80% of the rosacea cases that were encoun tered [3].

Clinical Manifestations of Rosacea
Rosacea usually manifests clinically in the third to fourth decade of life. The earliest feature is often char acterized to be a transient "flushing" which reflects an acutesubacute vasodilation of central facial vasculature that subsides without any other visible features of rosa cea, thus confounding the ability to diagnose the disorder at this early time point. The usual clinical course of rosa cea is typified by periods of exacerbation of visible signs and symptoms followed by variable durations of remission. Over time, there are clinical manifestations of rosacea that are present during flares and some that persist between flares, thus making it easier to make a correct diagnosis of rosacea. The clinical presentations of rosacea and its clini cal course vary from patient to patient and may change over time [2,47].
It is important for the clinician to appreciate and dif ferentiate that some clinical facial manifestations of ro sacea are intermittent (transient), occurring during a ro sacea flare, and others are permanent (nontransient), present both during and between flares (figure 1). The visible features of rosacea that are present intermittently (i.e. during a flare) are increased central facial erythema due to vascular dilatation (flushing of rosacea) that oc curs in the vast majority of patients, and papulopustular lesions, that occur on the inner cheeks, central forehead and/or chin in a defined subset of patients [1,2,49]. Papules and pustules are often described as the inflam matory lesions of rosacea, and when present as visible findings, they are intermittent, as they emerge during a rosacea flare and resolve as the rosacea flare dissipates [1,2,46]. The predominant permanent visible manifes tation that persist between flares is nontransient central facial erythema, referred to as background erythema, that is diffuse, macular, usually confluent, and some times associated with soft edema, and associated facial telangiectasias, that are linear, and often very fine in ap pearance, or some can individually be thicker and more defined (figure 2) [2,49]. Phymatous proliferations, which represent confluent sebaceous hyperplasia some times with mucinous and fibrous changes, occur most often on the nose (rhinophyma), are permanent findings [2,4,7].
The visible patterns of rosacea have been defined as subtypes to differentiate clinically with correlations of sub set presentations to approaches to management [2,46,10]. The frequency of rosacea patients with central facial erythema only, which is designated as erythematotelan giectatic rosacea (subtype 1), is reported to be fourfold higher compared to patients presenting with papulopustu lar rosacea (subtype 2) [1,2,4]. Phymas have been esti mated to affect from 14% of individuals with rosacea, and are seen more often in men [1,2,47].

Clinical Course of Rosacea and Current Rosacea Assessment
At its initial onset, rosacea commonly presents as tran sient bouts of central facial flushing caused by vasodilation and increased blood flow which is most dominant on the central face [2,4,79]. As described above, after the va sodilation that causes the flushing resolves, the facial skin visibly appears normal [48]. As bouts of central facial flush ing repeatedly exacerbate and remit over time, the facial vasculature progressively becomes dilated and enlarged and also proliferates, leading to the emergence of nontran sient background erythema and telangiectasias; both back ground erythema and telangiectasias are present between flares and persist between the flares [2,5,610].
ultimately, the optimal management of rosacea war rants the static evaluation of the visible manifestations that are present in the individual patient at a given point in time [1,5,6,10]. At the time of presentation, the cur rent assessment of rosacea depends on (1) if the condi tion is flared or in remission; (2) if papulopustular lesions are present during a flare; (3) if phymatous changes are present; (4) the visible intensity of background erythema; (5) the magnitude, size, and pattern of telangiectasias; (6) if rosacea dermatitis is clinically apparent; and (7) if as sociated symptomatology is present (discussed below). As increased central facial transepidermal water loss (TEwL) and decreased stratum corneum water content (hydra tion) have been shown to be present in rosacea, especially during a flare, visible pink erythema and diffuse fine facial Вестник дерматологии и венерологии scaling may be noted, and has been described as rosacea dermatitis [5,6,10,11].
As referred to earlier, rosacea has been classified us ing subtype designations that were published in 2002 [4]. A series of more recent publications from the American Acne & Rosacea Society have stressed the clinical rel evance of defining the visible manifestations in the indi vidual patient at the time of presentation. This allows for selection of a therapeutic approach that is targeted to treat the manifestations that are present in that patient, and not based solely on a irrespective of a subtype category [6,10,13]. The two most commonly encountered presenta tions of rosacea are diffuse central facial erythema without papulopustular lesions and diffuse central facial erythema with papulopustular lesions (figure 3) [1,2,5,6,13]. Phy matous changes and/or ocular manifestations of rosacea can occur concurrently in patients with any presentation of rosacea [1,2,4,5,6,7,10,13].

Symptomatology Associated With Rosacea
Episodic flushing during a rosacea flare is often associ ated with symptomatology. This includes a sensation of fa cial warmth. Symptoms of increased facial skin sensitivity, such as stinging, burning, tingling and pruritus are common, including when facial skin is contacted by several products commonly used for skin care and personal hygiene [1,2,412]. Symptoms of skin sensitivity are more common and more severe during a rosacea flare, but may also be pres ent between flares in rosaceaprone skin [2,5,6,10].

Rosacea Flares and Possible Triggers
The natural disease course of rosacea has not been well studied, yet it is known that rosaceaaffected individu als experience episodic exacerbations that are character ized by specific clinical features. These are the following: (1) flushing of rosacea with increased facial erythema due to dilation of central facial vasculature; (2) augmented in flammation which translates visibly to increased facial ery thema; (3) soft central facial edema of variable magnitude; and (4) papulopustular lesions in some patients. Some of the triggers that have been noted to induce rosacea flares are ambient heat, hot liquids which cause oralthermal flushing, spicy foods, and vasodilatory ingestants such as alcohol (e.g. red wine) and niacin [1,2,58,10,1418].
Although not a mandatory pathogenic component of rosa cea, proliferation of Demodex mites can serve as a trig ger in some rosaceaprone patients through stimulation of specific inflammatory pathways [5,19,20]. Neurogenic, immunologic, and inflammatory pathways have been iden tified that appear to be operative in rosacea pathophysiol ogy; physiochemical and structural difference in rosacea affected skin as compared to normal skin have been re ported [5,6,1518,2125].

Pathophysiologic Mechanisms in Rosacea and Clinical Relevance
Publications devoted primarily to pathophysiology of rosacea appear elsewhere in the medical literature; nev ertheless, explanations of rosaceaprone skin and the basic pathophysiologic mechanisms that seem to be op erative in rosacea are necessary in order to better un derstand the direct correlations with specific signs and symptoms of rosacea and allow for more rational selec tion of individual therapies in each case that address spe cific clinical manifestations of rosacea [5, 6, 13, 22, 26 32]. Rosaceaprone skin is characterized by three major (2) augmented immune detection and response; and (3) several physiochemical alterations that identified in the facial skin of rosaceaaffected individuals as compared to normal facial skin of individuals without rosacea [5, 6, 15 17, 33]. Essentially, rosaceaprone facial skin is "wired" to react to inciting factors that do not usually trigger an immunologic and/or inflammatory response in those without rosacea. Trigger that are recognized to induce rosacea flares (e.g. heat, uV light, spices) induce sev eral reactions in rosaceaprone skin. These include neu rogenic responses that cause vasodilation (flushing) and sensitive skin symptoms (stinging, burning, tingling) and cascade upregulation that increases antimicrobial pep tide production (especially cathelicidin (LL37) and other variant proinflammatory peptides) that induce cutaneous inflammation and vasodilation during the flare; repeated episodes of cathelicidin production are also believed to increase the density and diameter of superficial vascu lature of central facial skin which progressively leads to nontransient facial erythema that is persistent between rosacea flares [2,56,810,1518,2128,33]. current information related to the potential modes of action of specific therapies used to treat specific clinical features of rosacea appear to at least partially explain why certain therapeutic agents improve some visible signs of rosacea and not others [2,5,6,10,13,26,29,3135].

Conventional Medical Management of Rosacea
The majority of studies of medical therapies for ro sacea evaluate subjects with papulopustular lesions as a primary parameter, and also assess the associated lesional and perilesional erythema secondarily. To add, other than studies and reports with topical alphaadren ergic agonists (e.g. bromonidine, oxymetazoline), none of the commonly used topical or oral therapies have dem onstrated efficacy for the background nontransient facial erythema that persists between flares [5, 6, 9, 13, 26, 31 33, 3638].

Proper Skin Care for Rosacea
Although skin care products and methodology are not controlled in many rosacea studies, proper skin care is an integral part of the rosacea management plan for sev eral reasons [1013,3538]. To summarize, using a prop erly selected gentle cleanser and moisturizer counteracts permeability barrier impairment when lessens signs and symptoms of facial skin irritation inherent to the disease or related to topical products applied to the skin. Photo protection is also very important in the management of ro sacea, as ambient heat and ultraviolet light are rosacea triggers, and chronic photodamage independently induces persistent erythema and telangiectasia in chronically ex posed skin [1,2,5,1013,16,1835].
The mechanism of action of topical metronidazole in rosacea is unknown. Mechanisms which can reduce in flammation in rosacea have been suggested but data are limited [31,32,37,38]. Research data, including studies completed in subjects with papulopustular rosacea dem onstrate that AzA reduces serine protease activity in rosa ceaaffected central facial skin which leads to decreased cathelicidin (LL37) production and reduction in inflamma tion [34,41].
Although reported to be of benefit in some small studies and case reports, less clinical and basic science research data are available with other topical agents that have been used for rosacea, such as sulfacetamide 10%sulfur 5% formulations, calcineurin inhibitors, and permethrin [5,13,29,31,32,3638].

Overview of Oral Agents for Rosacea
The predominant oral therapeutic class that has been used for rosacea has been the tetracyclines, primarily oxy tetracycline, tetracycline, and doxycycline utilized for treat ment of papulopustular rosacea [31,32,3638,42]. Other oral antibiotics that have demonstrated efficacy for papulo pustular rosacea include metronidazole and azithromycin [31,32,36,38,4244]. Interestingly, oral antibiotics have been used to treat rosacea for over five decades despite the lack of definitive evidence that a bacterium is a caus ative or mandatory component of the pathogenesis of ro sacea [2,6,16,18,21,22,30,39].
It is believed that the biologic antiinflammatory proper ties of tetracyclines that are unrelated to antibiotic activity are the major reason why these agents are of therapeu tic benefit for rosacea [30,34,4547]. This concept is fur ther supported by several studies which demonstrate the effectiveness of subantimicrobial dose doxycycline (e.g. doxycycline hyclate 40 mg modifiedrelease [MR] capsule once daily) in the treatment of papulopustular rosacea [30,42,4851]. Subantimicrobial dose doxycycline exhibits a pharmacokinetic profile that is devoid of antibiotic selection pressure, but retains antiinflammatory activity including downregulation of the cathelicidin pathway, thus circum venting alteration of the host microbiome and the antibiotic resistance that are inevitable with oral antibiotic therapy [42,4852]. In the phase III pivotal trials completed with doxycycline MR 40 mg capsule once daily versus placebo, no cases of vaginal candidiasis or photosensitivity were observed in the active treatment group [50]. Doxycycline MR 40 mg capsule once daily has demonstrated efficacy equivalent to doxycycline 100 mg daily for papulopustular rosacea, with a significantly lower incidence of gastrointes tinal side effects [48]. Doxycycline 20 mg twice daily is also subantimicrobial, however, data are limited for treatment of rosacea, and antiinflammatory activity is likely to be in adequate if there is incomplete adherence with twice daily use [42,49,52].
Oral isotretinoin may be effective in selected cases of recalcitrant papulopustular rosacea or in early phyma for mation that has not progressed to a mucinous or fibrotic phase [39,42,53]. unlike acne vulgaris, prolonged remis sions of rosacea do not occur after isotretinoin is discon tinued.

More Recent Additions to the Medical Therapy Armamentarium for Rosacea
Two topical therapies for rosacea that incorporate new active ingredients have emerged over the past three years. The first, brimoninide tartrate 0.5% (brimonidine 0.33%) gel is the first fDAapproved for treatment of persistent nontransient facial erythema of rosacea (background ery thema). The second, ivermectin 1% cream, is indicated for treatment of papulopustular rosacea.
Topically applied αadrenergic receptor agonists (αagonist) are the first class of topical agents shown to decrease the background facial erythema of rosacea. Bri monidine tartrate has been evaluated most extensively, with oxymetazoline and xylometazoline also discussed in case reports [33,37,5658]. The therapeutic target of an αagonist are the αadrenoreceptors present in the smooth muscle layer encasing the wall of superficial dermal blood vessels. These vessels function physiologically to modu late vascular tone and relative blood flow within the su perficial and deep plexuses of skin [26,33]. The vasocon striction that occurs after facial application of an αagonist leads to reduction in erythema which persists over the duration of adequate binding with the αadrenoreceptors in the vessel walls. Smaller papillary vessels such capillar ies and telangiectasias do not vasoconstrict as they do not contain a fully formed smooth muscle sheath and hence, are not modulated by αadrenergic control [26,33,5658].

Topical Brimonidine for Non-Transient Erythema of Rosacea
Brimonidine tartrate (BT) is an αagonist with selectiv ity for α 2 adrenergic receptors [57]. A single application dose ranging study (n = 122) demonstrated that BT 0.5% gel (equivalent to brimonidine 0.33%) applied once daily exhibited the greatest effect on erythema reduction [57]. Pharmacokinetic analysis after application of BT gel to fa cial skin over 29 days compared to ocular application of BT 0.2% ophthalmic solution (used for openangle glauco ma) showed a superior safety profile for BT 0.5% gel with low systemic exposure and no systemic drug accumula tion observed over the course of the study [59]. The phase III pivotal trials evaluated adults (n = 553) with background erythema of rosacea and a maximum of two papulopus tular lesions, with results consistent with those reported from a similarly designed phase II study (n = 269). Study outcomes demonstrated efficacy, favorable tolerability, a lack of systemic safety signals, absence of tachyphylaxis, and minimal potential for rebound with patients assessed at two weeks posttherapy [57,60]. A 52week open la bel, multicenter, evaluated BT 0.5% gel applied once daily in subjects with facial erythema of rosacea (n = 449) both with and without papulopustular lesions, with 29.2% of patients using concomitant topical (i.e. metronidazole, az elaic acid) or oral (i.e. tetracyclines) medications [61]. The long term data demonstrated that the efficacy of BT 0.5 gel sustained over the duration of the study and that toler ability and safety was consistent with data from the phase II and phase III trials.
Data from available studies demonstrate overall that BT 0.5% gel induces its onset of erythema reduction as early as 30 minutes, a peak effect at approximately 3 hours, and a duration of peak erythema reduction of ap proximately 6 hours after a single application. As the peak effect wanes, the usual pattern of reappearance of ery thema was a progressive return of facial erythema over 2 to 3 hours to a level that was slightly less than baseline, however, in some cases the intensity of erythema can ex ceed what was noted at baseline before application or a paradoxical increase in erythema may be observed occa sionally in some patients [57,60]. Neither tachyphylaxis or worsening of papulopustular rosacea were observed in the long term study which included 335 subjects and 279 sub jects treated with BT 0.5% gel once daily for 6 months and 12 months, respectively [61].
Safety assessments completed during the pivotal and long term studies with facial application of various concen trations of BT gel support an overall favorable safety profile with no systemic safety signals. BT 0.5% gel applied once daily for up to 52 weeks was associated with a cutaneous adverse event noted at some time in 105 subjects (23.4%), with worsening of erythema or rosacea, skin burning sen sation, skin irritation, pruritus, flushing, and allergic derma titis reported in 10.1%, 3.3%, 3.1%, 2.0%, 8.9%, and 1.6% of subjects, respectively.61 BT 0.5% gel was discontinued in 12.7% of subjects (n = 57) due to a cutaneous adverse event, which is not unexpected given the inherent vascular reactivity and skin sensitivity of rosacea and the potential for contact dermatitis in some patients. Sporadic cases of rebound erythema or paradoxical erythema with use of BT 0.5% gel have been published, most likely due to interpa tient variability in vascular reactivity or confounding effects of exogenous rosacea triggers [62,63]. It is recommended that clinicians and their staff inform patients that an in crease in facial redness may sometimes occur, and to use BT 0.5% gel only how it is recommended.
Oxymetazoline, another αagonist, is currently under research development in the uS.

Topical Ivermectin for Papulopustular Rosacea
Ivermectin (IVM) is a semisynthetic endectocide that is from the avermectin family of compounds. for over two decades, IVM has been utilized orally to treat a variety of endoparasitic infestations, and both orally and topically to treat exoparasitic infestations [64]. The antiparasitic activ ity of IVM is through blockade of specific channels involved in neural synapse transmission found in invertebrates (e.g. worms, mites, lice) that can infest mammals, including hu mans [62]. Oral administration of IVM has been reported to be effective for demodecidosis, and in patients with cu taneous and ocular findings related to Demodex folliculo rum proliferation [65,66]. An increased density of facial D folliculorum has been demonstrated in some patients with both erythematotelangiectatic or papulopustular rosacea compared to facial skin of healthy controls, leading to stud ies of IVM cream in subjects with papulopustular rosacea [19,20,67]. As antiinflammatory properties have been reported with IVM, the therapeutic activity of IVM may be related at least partially to these effects as Demodex prolif eration is not present in all cases of rosacea [67].
Вестник дерматологии и венерологии IVM 1% cream applied once daily was shown to be su perior to vehicle cream once daily in subjects with moder ate to severe papulopustular rosacea in two randomized, controlled, pivotal trials (n = 1371). The mean inflamma tory lesion count at baseline in the two studies were 30.9 (+/ 14.33) and 32.9 (+/ 13.70), which are markedly higher than baseline mean inflammatory lesion counts in studies of other fDAapproved drugs used to treat papulopustular rosacea. 67 In both studies, a greater percentage of sub jects in the IVM 1% group achieved "treatment success", defined as "clear" or "almost clear", based on investigator global assessment, with outcomes of 38.4% and 40.1% , and 11.6% and 18.8%, in the IVM study arms and the vehi cle study arms, respectively (both p < 0.01). Inflammatory lesion count reductions compared to baseline was 76.0% and 75.0% in both IVM groups vs 50.0% for both vehicle groups, respectively, which was also significant [67]. The efficacy, safety, and tolerability assessments in pivotal and long term trials demonstrated the effectiveness of IVM 1% cream, with a low incidence of cutaneous application site reactions (e.g. burning, pruritus; no serious adverse events, no significant systemic side effects, and absence of clinically significant laboratory abnormalities [67,68]. A randomized controlled study of IVM 1% cream once daily (n = 478) versus Metro 0.75% cream twice daily (n = 484) for papulopustular rosacea demonstrated the superior ef ficacy of IVM 1% in reducing inflammatory lesions as early as week 3 and by investigator global assessments evalu ating treatment success (p < 0.001 for both) [69]. Addition ally, remission of rosacea after discontinuation of therapy lasted approximately 4 weeks longer with IVM 1% as com pared to Metro 0.75% cream [69].

Rosacea Management Recommendations: From the Benchtop to the Treatment Room
The following points summarize management recom mendations based on the above review and supporting references, designed to optimize medical treatment of the more common clinical presentations of rosacea: central fa cial erythema with papulopustular lesions (papulopustular presentation) and central facial erythema without papulo pustular lesions (erythematotelangiectatic presentation).
The first step in optimal management of rosacea after obtaining pertinent details of the patient's history, is to assess the current visible and symptomatic manifestations that are present. control of the selection of skin care products and how they are integrated into the treatment regimen by the clinician is very important in all cases of rosacea. This supports use by the patient of a gentle cleanser and moisturizer which serves to reduce TEwL and symptoms of skin sensitivity, and decreases the potential for skin tolerability reactions related to medications and other products applied to rosacea affected facial skin [2,6,1013,21,31,32,39]. As best as is possible from a practical perspective, avoidance of known rosacea triggers is strongly recommended in the management of rosacea [1,2,4,5,6,31,32,39]. Photoprotection, including avoidance of direct sunlight exposure as much as possible (especially during peak hours), and use of broadspectrum sunscreen is strongly recommended. Avoidance of direct sunlight exposure and sunscreen use lessen the potential triggering effect of ultraviolet light on rosaceaprone facial skin. Avoidance of direct sunlight exposure, especially during peak hours, decreases the intensity of ambient heat which could otherwise serve as trigger for rosacea [1,2,6,1013,31,32].
In patients with papulopustular rosacea, topical therapy, oral therapy, or a combination of both may be used, depending on severity.
-If the papulopustular rosacea is mild to moderate in severity, topical therapy (e.g. Metro, IVM, AzA) alone is usually very effective in reducing inflam matory lesions and their associated erythema.
Oral therapy with a tetracycline agent can also be used, with subantimicrobial dose doxycycline offering the major advantage of efficacy without emergence of antibiotic resistant bacteria [13,31,36,37,39,42,4851]. -for papulopustular rosacea rated in severity as moderate to severe, a combination of topical and oral therapy is commonly used to achieve con trol, usually followed within a few months (e.g. 23 months) by transition to topical therapy alone to continue the suppression of rosacea and re duce the frequency and severity of rosacea flares. Alternatively, the pivotal trials and other studies of subantimicrobial dose doxycycline were completed as monotherapy, supporting its use over a longer duration when transcending off of initial combination therapy. If it is elected to uti lize topical therapy alone for papulopustular ro sacea that is within the higher range of moderate severity or is graded as severe, IVM 1% cream was studied in subjects with a higher baseline mean inflammatory lesion count (approximately 30 lesions) than other agents for papulopustular rosacea (approximately 18 to 21 lesions) [31,36,37,42,4851,67,70]. -Once a flare of papulopustular rosacea is con trolled, background erythema which is nontran sient and persistent often becomes more evi dent. Background erythema may be treated by the addition of an αagonist such as BT 0.5% gel once daily. It is important that gentle skin care and photoprotection be continued and that trig gers be avoided. Telangiectasias that are both ersome to the patient may be treated with the appropriate laser and/or light modalities [13,26,33,35,37,42,5761].
-If topical αagonist therapy is initiated for papu lopustular rosacea before therapy is given to reduce inflammatory lesions, background ery thema will dissipate, but lesionalperilesional ery thema will initially persist as small red dots until the inflammatory lesions resolve [33,37]. -Oral isotretinoin is reserved for selected cases of recalcitrant papulopustular rosacea. Once con trolled, low dose and intermittent dose regimens may be effective for long term management. Teratogenicity and potential side effects of oral isotretinoin therapy must be taken into consider ation both before and during use [42,53]. central facial erythema without papulopustular lesions may be managed medically by proper skin care, photoprotection, and application of an αagonist, such as BT 0.5% gel. Physical modalities such as lasers (e.g. pulse dye laser [PDL]) and intense pulse light (IPL) can also be used for treatment of vascular erythema and telangiectasias. Oral agents have not been shown to be effective for persistent background erythema of rosacea [13,26,33,35,37,42,5763]. fully developed phymas require surgical intervention. Early phymatous changes may respond to oral isotretinoin therapy [31,35,39]. Although the focus of this article is cutaneous rosacea, ocular rosacea is responsive to therapy with an oral tetracycline, especially oral doxycycline. Ophthalmologic consultation is clearly warranted if vision is impaired, if associated symptomatology is severe, or if refractory to oral tetracycline therapeutic or other therapeutic measures [31,32,39,42].