EPIDEMIOLOGY (A ARMSTRONG, SECTION EDITOR)

Updates in Rosacea: Epidemiology, Risk Factors,and Management Strategies

Jean-Phillip Okhovat & April W. Armstrong

Published online: 7 February 2014# Springer Science+Business Media New York 2014

Abstract Rosacea is a chronic, inflammatory skin diseasethat affects more than 15 million people in the United States.It is associated with significant psychosocial, physical, andeconomic burden. The pathogenesis of rosacea is poorly un-derstood. Initial events include dysregulation in cutaneousneurovascular control and neuroimmune communication. Ex-acerbating factors may include UV light and infectious agents.Recent therapeutic advances have increased treatment op-tions. Such therapies include avoidance of potential triggers,topical therapies, and systemic therapies. Treatment is targetedat reducing facial erythema and eliminating inciting agentsthat may contribute to the disease process. The tetracyclineclass of antibiotics has been most extensively studied forsystemic therapy. Novel agents such as α-2 agonists haveincreased therapeutic options in rosacea.

Keywords Rosacea . Epidemiology .Management .

Rhinophyma . Azelaic acid .Demodex . Papulopustular .

Ocular . Phymatous . Erythematotelangiectatic

Introduction

Rosacea is a chronic cutaneous inflammatory disease thataffects more than 15 million adults in the United States andinflicts a significant health burden [1]. Rosacea mainly affectsthe central face, including the cheek, nose, chin, and centralforehead and is characterized by episodes of exacerbation and

remission of facial erythema, telangiectasia, inflammatorypapules, and pustules [2].

According to the National Rosacea Society, rosacea is 2–3times more prevalent in women and most patients presentbetween 30–50 years of age [3]. In 2004, it was estimated thatthe prevalence of rosacea in the United States was 14.7 mil-lion, and the direct cost was $385 million. Furthermore, theindirect costs because of loss of productivity from rosaceaalone was estimated to be $80 million, with an estimatedintangible cost due to quality of life impact of $1.6 billion[1]. In this article, we discuss updates in the epidemiology, riskfactors, and management strategies for rosacea.

Epidemiology

Rosacea remains a chronic skin condition that has been ex-tensively studied across the world. Epidemiological studiesboth in the United States and abroad have investigated theprevalence of this disease through population-based studies.Romanowicz et al., found the prevalence of rosacea among9,151,174 persons from the United States to be 1.34 %,whereas Bamford et al., found the prevalence of rosacea inadults in the United States to be 2.1 % [4, 5]. A study ofGerman workers found that the prevalence of rosacea was2.3 % [6]. Khaled et al., found the prevalence of rosacea to be0.2 % among 244 persons in Tunisia [7]. Kyriakis et al., foundthe prevalence of rosacea to be 1.2 % in Greece among 50,237persons examined by a dermatologist [8].

Studies have reported rosacea to be more prevalent inmiddle-aged adults and females [9]. In a study involving60,042 patients and 60,042 controls, Spoendlin et al., aimedto identify rates of diagnosed rosacea in the United Kingdomand demonstrated that 80 % of the cases diagnosed withrosacea were over 30 years of age, with 61.5 % of the casesbeing female [9]. However, not all studies have replicated asimilar association between gender and rosacea. Augustin

J.<P. OkhovatUniversity of California, Los Angeles (UCLA),Los Angeles, CA, USA

A. W. Armstrong (*)Department of Dermatology, University of Colorado Denver,Aurora, CO, USAe-mail: aprilarmstrong@post.harvard.edu

Curr Derm Rep (2014) 3:23–28DOI 10.1007/s13671-014-0070-5

et al., revealed that among 91,000 subjects in Germany rosa-cea was found in 2.4 % of males and 2.1 % of females [6].

Although rosacea is also found in people with darker skin,it is less frequently diagnosed in such populations [10]. Theexact figures regarding prevalence in this population have notbeen extensively studied; this may be due to masking of facialredness by darker skin pigment or perhaps a protective mech-anism of melanin against UV radiation, which is a knowntrigger for rosacea exacerbations.

Pathogenesis and Risk Factors

The exact pathophysiology of rosacea is unknown, althoughproposed risk factors may include UV light exposure, immunedysregulation, and infectious agents.

UV radiation exposure has been recognized as a potentialidentifying risk factor for the development of rosacea [11].The pathogenesis underlying this risk factor is that UV mayinduce innate immune responses that can lead to this skindisorder in persons with a lighter skin phenotype [11]. Forinstance, in one study conducted by Bae et al., the authorssought to analyze the relationship between sun exposure andthe development of each subtype of rosacea [11]. The medicalrecords and photos of 168 patients diagnosed with rosaceafrom 2002 to 2007 were obtained. Results showed that sunexposure and hot baths/exercise were the two most commonprecipitating factors.

Newer basic molecular biology approaches to studying thepathophysiology of rosacea have also been carried out [12••].Antimicrobial peptides (AMPs) are molecules secreted byskin keratinocytes and which play an important role in theinnate immune system. Well-studied AMPs in the human skinare molecules known as defensins and cathelicidins. Onemolecule in particular, called cathelicidin AMP (CAMP),encodes for a peptide with antimicrobial activity. LL-37 is aparticular cathelicidin that also plays a role in chemotaxis oflocal cells and leukocytes and the enhancement of the prolif-eration of endothelial cells [12••]. In rosacea, increased levelsof LL-37 and similar peptide fragments are believed to play arole in vascular dysregulation, erythema, chemotaxis, andinflammation when exposed to triggers such as heat, cold,UV light, and even vitamin D [12••].

A variety of infectious agents have also been theorized tocontribute to rosacea pathogenesis [13•]. One infectious agent istheDemodexmite. Jarmuda et al., found the density ofDemodexmites to be higher in rosacea patients compared to controls[13•]. More specifically, the mean density of Demodex miteson the skin of rosacea patients was reported as 10.8 mites percm2 in comparison to 0.7 mites per cm2 in healthy people [13•].

It is possible that theDemodexmite carries a gram-negativeBacillus oleronius, which may induce mediators that contrib-ute to an inflammatory skin reaction.

Aside from the aforementioned risk factors, some epidemi-ologic studies found that family history and smoking statusmay be associated with rosacea development [14]. Abramet al., examined 145 skin healthy controls and 172 subjectswith flushing episodes or clinically diagnosed rosacea [14].Risk factors associated with the development of rosacea in-cluded photosensitive skin types (odds ratio 1.75, 95 % CI1.01–3.04, p<0.05), a positive family history of rosacea (oddsratio 4.31, 95 % CI 2.34–7.92, p<0.0001), and previoussmoking status (odds ratio 2.01, 95 % CI 1.07–3.80,p<0.05). Factors that were found not to be associated as riskfactors for rosacea in this particular study included gender,Helicobacter pylori serostatus, caffeine intake, occupation, oreducation level [14].

Clinical Phenotypes

There are currently four common clinically recognized phe-notypes of rosacea: erythematotelangiectatic, papulopustular,phymatous, and ocular rosacea [15].

Erythematotelangiectatic rosacea is characterized by facialerythema and episodes of facial flushing. Other characteristicsassociated with this subtype of rosacea include telangiectasia,roughness, scaling, and facial fullness. Facial flushing associ-ated with this subtype of rosacea may be triggered by emo-tional stress, hot drinks, alcohol, spicy foods, exercise, cold orhot weather, and hot baths [15–17].

Papulopustular rosacea is characterized by the presence ofpapules and pustules on the central part of the face, oftentimessimilar in appearance to acne vulgaris. Notably, however,there is almost always sparing of periocular skin. Furthermore,unlike acne vulgaris, papulopustular rosacea typically affectsan older age group, with absence of comedones [15].

Phymatous rosacea is characterized by thickened skin withirregular contours, whichmay occur on the nose (rhinophyma),chin (gnathophyma), forehead (glabellophyma), and cheeks.Patients with this subtype of rosacea, which most commonlyoccurs in adult men, have sebaceous hyperplasia and oily skin[15].

Ocular rosacea is most commonly characterized byblepharitis and conjunctivitis [18, 19]. Furthermore, this sub-type of rosacea can often present with recurrent chalazion andinflammation of the meibomian glands. Other characteristicsthat may be found include conjunctival telangiectases, wateryor dry eyes, and irritated eyes. Less frequent manifestations ofocular rosacea include keratitis, scleritis, and iritis [15].

Management Strategies

The treatment options currently known for rosacea includelifestyle modification and medication strategies, which

24 Curr Derm Rep (2014) 3:23–28

include the use of topical and systemic creams and medica-tions (Tables 1 and 2). The most effective lifestyle modifica-tion to avoid the symptoms of blushing and flushing that areassociated with rosacea includes the avoidance of triggeringfactors. Such triggering factors might include foods (meat,dairy products, vegetables, fruits), alcohol and hot beverages,stress and anxiety, certain medications, and exercise [20].

Topical Therapy

Topical therapies that have been extensively studied for thetreatment of rosacea include topical antibiotics (clindamycin,metronidazole), sodium sulfacetamide/sulfur, azelaic acid,permethrin cream, and newer agents such as brimonidinetartrate and oxymetazoline (Table 1).

Topical antibiotics have been used for the treatment ofrosacea. Breneman et al., evaluated the efficacy and tolerabil-ity of 5 % benzoyl peroxide and 1 % clindamycin in a topicalgel formula for the treatment of rosacea in a 12-week, double-blind, randomized, vehicle-controlled trial with 53 patientswith moderate to severe rosacea [21]. From baseline to theend of treatment, the mean percentage in the reduction inpapules and pustules was 71.3 % in the benzoyl peroxide/clindamycin group (n=26) compared to 19.3 % in the vehiclegroup (n=26, p=0.0056). There were also improvements withrespect to overall rosacea severity (p=0.0101), PhysicianGlobal Assessment (p=0.0026), and Patient’s Global Assess-ment (p=0.0002) compared to vehicle. The main adversereactions were application site reactions that were reportedin 14.8 % (n=4) patients in the treatment group. Once dailytopical 5 % benzoyl peroxide with 1 % clindamycin is a

therapeutic option for patients with moderate to severe rosacea[21].

Topical metronidazole has also been studied as a therapeu-tic option for rosacea patients. In a randomized parallel grouptrial, 72 rosacea patients with at least eight to 50 inflammatoryfacial lesions and moderately severe facial erythema wererandomly assigned to receive either 0.75 % metronidazolecream of 1.0 % metronidazole cream to apply once daily for12 weeks [22]. There were no significant differencesbetween both treatment groups; both experienced a de-crease in lesion count, erythema scores, and physicianassessment of global severity. Both 0.75 % metronida-zole cream and 1.0 % metronidazole cream used oncedaily are well-tolerated medications for moderate to severerosacea [22].

Azelaic acid is a saturated dicarboxylic acid found inwheat, rye, and barley. Bjerke et al., conducted a 3-monthrandomized, double-blind, multicenter study to determine theefficacy and safety of azelaic acid 20 % cream with its vehiclein the treatment of papulo-pustular rosacea [23]. A total of 116patients were enrolled in the study. The study showed that,compared to vehicle, azelaic acid cream produced greatermean reductions in total inflammatory lesions (73 % vs.50.6 %, p=0.011), and a greater decrease in erythema severityscore (47.9 % vs. 37.9 %, p=0.031). Physician and patientratings were also more favorable with azelaic acid treatmentcompared to vehicle. Azelaic acid 20 % cream is anothereffective and well-tolerated treatment for papulo-pustular ro-sacea [23].

Sulfacetamide with sulfur is a topical agent that is availablein many preparations, such as lotions, cleansers, and creams.

Table 1 Topical therapies for the treatment of rosacea

Study Treatment Dosage

Sauder 1997 [24] Topical sodium sulfacetamide/sulfur Sodium Sulfacetamide (10 %)/Sulfur (5 %) twice daily for 8 weeks

Fowler 2012 [26••] Topical brimonidine tartrate 0.5 % gel once daily for 4 weeks

Shanler 2007 [27] Topical oxymetazoline 0.05 % solution once daily

Breneman 2004 [21] Topical benzoyl peroxide/clindamycin 5 % benzoyl peroxide/1 % clindamycin once daily for 12 weeks

Dahl 2001 [22] Topical metronidazole 0.75 % metronidazole or 1.0 % metronidazole once daily for 12 weeks

Bjerke 1999 [23] Topical azelaic acid 20 % cream twice daily for 3 months

Kocak 2002 [25] Topical permethrin 5 % cream twice daily for 2 months

Table 2 Systemic therapies forthe treatment of rosacea Study Treatment Dosage

Del Rosso 2007 [28] Oral doxycycline 40 mg once daily for 16 weeks

Frucht-Pery 1993 [29] Oral doxycycline or oraltetracycline hydrochloride

Tetracycline hydrochloride 1 g/day or doxycycline100 mg/day for 6 weeks

Gollnick 2010 [30] Oral isotretinoin 0.3 mg/kg daily for 12 weeks

Curr Derm Rep (2014) 3:23–28 25

Sauder et al., conducted a vehicle-controlled double-blindstudy to determine the safety and efficacy of the combinationof sulfacetamide and sulfur for the treatment of rosacea [24].A total of 103 patients with moderate to severe facial erythemaand at least five papules and/or pustules were enrolled in thestudy, of which 94 patients completed the study. By week 4,inflammatory lesions decreased by 65 +/− 5.3 % in the treat-ment group compared to 44 +/− 5.0 % in the vehicle treatmentgroup (p=0.002). By week 4, there was also a significantdecrease in facial erythema by 66 % in the treatment groupcompared to a 33 % decrease in the vehicle group (p=0.005).The most common adverse events reported were applicationsite reactions. The study demonstrated the efficacy of topicalsodium sulfacetamide (10 %) and sulfur (5 %) lotion inreducing erythema and inflammatory lesions in patients withrosacea [24].

As mentioned previously, Demodex infection has beenproposed as another potentially contributing risk factor inthe development of rosacea. Studies demonstrate a link be-tween the use of permethrin 5 % cream, which is used againsthuman ectoparasites, in the treatment of papulopustular rosa-cea. Kocak et al., carried out a study of 63 patients withpapulopustular rosacea and randomly assigned them into per-methrin 5 % cream (n=23), metronidazole 0.75% gel (n=20),and placebo (n=20) groups [25]. The endpoints measuredincluded scores of erythema, telangiectasia, edema andrhinophyma, and the numbers of papules, pustules, inflamma-tory nodules, and Demodex folliculorum. The study showedthat permethrin 5 % cream was more effective on erythemaand papules compared to placebo; it was also more effectiveon reducing the number of Demodex folliculorum comparedto metronidazole 0.75 % gel and placebo. No effect was seenon telangiectasia, rhinophyma, and pustules with the use ofpermethrin 5 % cream [25].

Brimonidine tartrate (BT) is a selective α-2 adrenergicagonist with vasoconstrictive activity that has been found tobe effective against the erythema of rosacea, which is thoughtto be due to abnormal cutaneous vasomotor activity. Fowleret al., studied 122 subjects randomized to receive a singleapplication of either 0.07 % BT, 0.18 % BT, 0.5 % BT, orvehicle [26••]. In another study, 269 subjects were randomizedto receive BT 0.5 % once daily, BT 0.18 % once daily, vehicleonce daily, BT 0.18 % twice daily, or vehicle twice daily. Inthe latter study, BT 0.5 % once daily was shown to be moreeffective in terms of Clinician’s Erythema Assessment (CEA)and Patient’s Self-Assessment (PSA) compared to vehicle.The study demonstrated that once-daily BT gel 0.5 % is welltolerated and provides greater efficacy than vehicle gel for thetreatment of moderate to severe erythema of rosacea [26••].

Oxymetazoline is another synthetic sympathomimetic ag-onist, currently in phase III studies in the United States, withselectivity for the α-adrenergic receptors. It, thus, acts as avasoconstrictor. Shanler et al., described the use of

oxymetazoline in two patients with treatment-resistanterythematotelangiectatic rosacea [27]. In both patients, theuse of a commercially available preparation of oxymetazolinehydrochloride 0.05 % solution was applied once daily to theaffected area of the face. Both patients experienced improve-ment in erythema, marked decrease of erythematous flare,relief of symptoms involving stinging and burning, withoutany adverse side effects [27]. The use of 0.05 %oxymetazoline hydrochloride is another avenue that may befurther explored for the symptoms of erythematotelangiectaticrosacea [27].

Systemic Therapy

Systemic therapies for the treatment of rosacea include the useof the tetracycline class of antibiotics and oral isotretinoin(Table 2). Randomized clinical trials have been conducted todetermine the efficacy and safety of once-daily anti-inflammatory dose doxycycline for the treatment of rosacea[28]. In two randomized, double-blind, placebo-controlledstudies, patients were assigned to receive either 40-mg ofcontrolled-release doxycycline (n=269) or placebo (n=268)for 16 weeks [28]. At week 16, there was a significant de-crease from baseline in lesion count in the active treatmentgroups compared with the placebo groups (p<0.001). Themost common adverse events were nasopharyngitis (4.8 %),diarrhea (4.4 %), and headache (4.4 %). The study demon-strated that once-daily anti-inflammatory dose doxycycline iseffective and safe for the treatment of rosacea [28].

Similar studies show the efficacy of doxycycline and tetra-cycline hydrochloride for the treatment of ocular rosacea [29].Twenty-four patients with ocular rosacea were assigned toeither doxycycline 100 mg/day or tetracycline 1 g/day. Aftersix weeks of treatment, there was greater symptomatic relief inthe tetracycline hydrochloride-treated patients (p=0.041). No-tably, however, there was no significant difference in symp-toms (gastrointestinal tract complaints) between two groupsafter three months of treatment. Both tetracycline hydrochlo-ride 1 g/day and doxycycline 100 mg/day can be used safelyand effectively for the treatment of ocular rosacea [29].

Investigators have also studied the role of retinoids in thetreatment of rosacea. Gollnick et al., studied the efficacy oforal isotretinoin for the treatment of rosacea [30]. Five hun-dred and seventy-three patients with either papulopustular orphymatous rosacea received one of three dosages of isotreti-noin (0.1 mg, 0.3 mg, or 0.5 mg/kg), doxycycline (100 mgdaily for 14 days, then 50 mg daily), or placebo in a double-blind, randomized trial for 12 weeks. Isotretinoin 0.3 mg/kgwas most effective in reducing the number of lesions (90 %)compared to doxycycline (83 %) and placebo. There was alsocomplete remission in 24 % of patients and marked improve-ment in 57 % of patients with isotretinoin. Isotretinoin0.3 mg/kg proved to be an effective and well-tolerated

26 Curr Derm Rep (2014) 3:23–28

therapeutic option for papulopustular and phymatous subtypesof rosacea [30].

Conclusion

Rosacea remains a common chronic inflammatory skin condi-tion that is associated with morbidity and significant healthcarecosts [31••]. Ongoing research attempts to understand the path-ogenesis and risk factors of rosacea. Exposure to UV radiation,immune neurohumoral dysregulation, and infectious agentssuch asDemodex have been implicated in rosacea pathogenesisand exacerbation. Treatments including topical and systemicantibiotics, azelaic acid, and newer α-2 agonists have providedpatients with increasing therapeutic options. More research isnecessary to elucidate the specific mechanisms underlying thiscommon yet poorly understood skin disease.

Compliance with Ethics Guidelines

Conflict of Interest JP Okhovat declares no conflicts of interest.AWArmstrong declares no conflicts of interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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