Updates on the Pathophysiology and Management of Acne Rosacea

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1 c l i n i c a l f e at u r e s Updates on the Pathophysiology and Management of Acne Rosacea Mohamed L. Elsaie, MD, MBA 1 Sonal Choudhary, MD 1 1 Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, FL Abstract: There are many options for the treatment of acne rosacea, including topical and systemic therapies, laser and light-based therapies, and surgical procedures. A classification system for rosacea identifies 4 subtypes (ie, erythematotelangiectatic, papulopustular, phymatous, and ocular), which may help guide therapeutic decision making. Until recently, the pathophysiology of acne rosacea has been poorly understood and limited to descriptions of factors that exacerbate or improve this disorder. Recent molecular studies suggest that an altered innate immune response is involved in the pathogenesis of the vascular and inflammatory disease seen in patients with rosacea. These findings may help explain the benefits of current treatments and suggest new therapeutic strategies helpful for alleviating this disease. The goals of therapy include reduction of papules, pustules, erythema, physical discomfort, and an improvement in quality of life. Standard topical treatment agents include metronidazole, azelaic acid, and sodium sulfacetamide-sulfur. Second-line therapies include benzoyl peroxide, clindamycin, calcineurin inhibitors, and permethrin. There are also various systemic therapy options. Keywords: acne rosacea; erythema; pustules; sulfur Correspondence: Mohamed L. Elsaie, MD, Department of Dermatology and Cutaneous Surgery, 1475 NW 12th Ave., #2175, University of Miami, Miami, FL Tel: Fax: egydoc77@yahoo.com Introduction Acne rosacea is a chronic relapsing skin disorder characterized by facial flushing, persistent erythema, telangiectasia, and inflammatory papules and pustules affecting the central face. The National Rosacea Society has described a classification system based on 4 main subtypes: erythematotelangiectatic, papulopustular, phymatous, ocular. 1 Rosacea can contribute to lower self-esteem and have significant psychosocial implications, such as stress at work and social isolation. 2 This can have a significant impact on quality of life and should be taken into consideration when treating these patients. Most individuals affected by rosacea are of northern European origin and up to one-third have a family history of the disorder. The disease affects mostly facial skin and is characterized by flushing, nontransient erythema, papules, pustules, inflammatory nodules, and telangiectasia. Secondary features that often occur include burning and stinging of the face, occasional dermatitis or scaling of the face, and edema. In many patients, rosacea can be worsened or triggered by factors that initiate flushing, such as exercise, emotion, menopause and alcohol. 3 Molecular Pathology of Rosacea Since the phenotypes of rosacea are clinically heterogeneous, rosacea studies were widely conducted based on the findings in clinical manifestations, histology, and factors exacerbating the skin disorder. From the diverse findings, the pathology of rosacea was thought to be unknown and was expected to be from multiple factors (Table 1). Postgraduate Medicine, Volume 121, Issue 5, September 2009, ISSN , e-issn

2 Mohamed L. Elsaie and Sonal Choudhary Table 1. Mechanisms of Rosacea Development Mechanism Role in Rosacea Development Innate immunity sun exposure (UV-induced apoptosis), dermal matrix changes, and microbes 45,46 act as triggers for susceptible innate immune system in rosacea patients. Altered toll-like receptors (TLR2) and nucleotide-binding domain and leucine-rich repeat containing (NLR) expression in rosacea skin 47 is the cause of this susceptibility and leads to increased cathelicidin (an anti-microbial molecule with vasoactive and proinflammatory properties), 48 cytokines, and kallikrein production. 49 Those forms of cathelicidin, which are involved in rosacea, promote and regulate leukocyte chemotaxis, 50 angiogenesis, 51 and expression of extracellular matrix components. 52 Vascular changes Hypervascularity in rosacea is triggered by emotional stress, spicy foods, hot beverages, high environmental temperatures, and menopause, 53 and is relieved by α-1 adrenergic receptor agonist. 54 Reactive oxygen species (ROS) Ultraviolet radiation Proteases Microbes Increased expression of vascular endothelial growth factor (VEGF), CD31 and D2-40 are seen in rosacea skin. 55 VEGF increases permeability of vessels and is induced by UV-irradiation in human keratinocytes and skin. 56 CD31 is a platelet/endothelial cell adhesion molecule (PECAM1). D2-40 is a lymphatic endothelium marker. cathelicidin (LL-37) produced by rosacea skin mediates angiogenesis through formyl peptide receptor-like 1 (FPRL1), a G-protein coupled receptor on endothelial cells. 57 LL-37 transactivates epidermal growth factor receptor (EGFR) 58 which in turn induces VEGF in keratinocytes. 59 rosacea skin has increased ROS production than normal skin. 60,61 UV radiation generates ROS, which activates cellular signaling, mediates cytokine production by tumor necrosis factor alpha (TNF-α) in keratinocytes, 62 induces chemokine production by TLR2 stimuli in monocytes, 63,64 stimulates fibroblasts and alters matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) expression. Increased fibroblast activity, increases MMP-1 and MMP-2 mrna expression and depressed proalpha1(i) and proalpha1 (III). All of these effects of ROS together result in enhanced inflammatory reactions and dengeneration of collagens and matrix in dermis, seen in rosacea. Medicines that inhibit ROS generation in neutrophils, such as tetracyclines, 65 metronidazole, 66 and retinoids, 67 are used for rosacea treatment. UV and sun exposure cause flushing response and worsen the clinical symptoms of rosacea. uv irradiation increases the expression of angiogenic factors (VEGF and fibroblast growth factor [FGF2]) 56,68,69 in keratinocytes and degeneration of extracellular matrix (by production of ROS that increases MMPs and causes vascular and dermal matrix damage). 70,71 uv mediates cytokine and MMPs expression in keratinocytes. Overexpression of dominant positive form of myeloid differentiation factor 88 (MyD88) (an adaptor molecule for TLR signaling), increases (IL-6) and MMP-1 expression; indicating TLRs/MyD88 signaling would be part of link between UV irradiation and skin inflammation. serine protease kallikrein 5 (KLK5), which is the processing enzyme of cathelicidin, digests corneodesmosome proteins desmocollin 1 and desmoglein 1 of epidermal keratinocytes 72,73 and extracellular matrix components, collagens type I, II, III and IV, fibronectin and laminin. 74 KLK5 is elevated in rosacea skin, 48 causing inflammatory reactions by affecting dermal matrix and vascular remodeling. MMPs (proved to be inducible by UV irradiation and ROS stimulation of keratinocytes), 75,76 MMP-8 (collagenase 2) and MMP-9 (gelatinase B) (which are found to have higher activity in the fluid of ocular rosacea patients) 77,78 digest dermal matrixes such as collagens, fibronectin, elastin, etc. Balanced levels of MMPs and their inhibitors TIMPs are seen in normal skin, unlike rosacea skin where the effect of MMPs appears to be higher. Bacillus oleronius isolated from mite Demodex folliculorum, found in sebaceous follicles 79 (more in density in rosacea patients than normal subjects), 80 stimulates mononuclear cells and induces inflammation likely by way of their heat shock proteins (HSP) and a lipoprotein molecule in their antigen. Such HSP and similar components in other microbes are known to stimulate TLRs and thus the innate immune system. 81,82 seropositivity to Helicobacter pylori has been seen in rosacea patients. 83 H pylori induces ROS 83,84 and cytokine release through TLR2 and TLR4 in gastric epithelial cells. 85,86 These may be the mediators that worsen rosacea symptoms. Treatment is initiated only after a proper diagnosis is made, including identification of subtype. Afterward, conservative measures, such as trigger avoidance, proper skin care, camouflaging cosmetics, and photoprotection should be discussed in detail. Topical pharmacotherapeutic options include: azelaic acid (Finacea gel; Intendis/Bayer, Pine Brook, NJ), clindamycin, clindamycin 1%-benzoyl peroxide 5% gel (BenzaClin ; sanofi-aventis, Bridgewater, NJ; Duac, Stiefel Laboratories, Inc., Coral Gables, FL), erythromycin, metronidazole (MetroCream, MetroLotion, MetroGel, Rozex gel; Galderma Laboratories, Ft. Worth, TX; Noritate ; Dermik/sanofi-aventis, 2 Postgraduate Medicine, Volume 121, Issue 5, September 2009, ISSN , e-issn

3 Acne Rosacea Bridgewater, NJ), or sodium sulfacetamide 10% + sulfur 5% (Plexion ; Medicis Pharmaceutical Corp., Scottsdale, AZ; Rosac Cream; Stiefel Laboratories, Inc.; Rosula Lotion; Doak Dermatologics, Fairfield, NJ; Sulfacet-R, Novacet Lotion; Perrigo Co., Allegan, MI). For patients with moderate-to-severe papulopustular rosacea or those with ocular involvement, systemic therapy is often prescribed and options include doxycycline, erythromycin, metronidazole, minocycline, tetracycline, or in severe cases, low-dose isotretinoin. The telangiectatic component does not respond to either oral or topical therapy, and is best treated with laser and light-based therapies. Surgical intervention may be required for the phymatous subtype. Therapeutic choices will depend on patient expectations, tolerance, previous therapies used, rosacea subtype, and severity. Topical Therapies Azelaic Acid Azelaic acid (ACA) is a newer therapeutic option for the treatment of rosacea. It was approved by the US Food and Drug Administration in 2002, the European Union in 2003, and in Canada in 2004, although it has only recently become commercially available in Canada. Azelaic acid is a naturally occurring dicarboxylic acid that can be found in dietary sources, such as whole grains. 4 It lacks toxicity, is nonteratogenic, and nonmutagenic. It has multiple biologic effects including anti-inflammatory, antikeratinizing, and antibacterial activities. The likely mechanism of action is via inhibition of reactive oxygen species produced by neutrophils. 5 A novel 15% gel formulation (Finacea ) is available for the treatment of rosacea, in addition to a 20% cream formulation approved for use in acne vulgaris. The 15% gel, although formulated to a lower concentration than the cream, is significantly more bioavailable than the cream because of an optimized aqueous gel vehicle. Multiple reviews have been published examining the use of AZA in rosacea. 6,7 Two pivotal phase 3 trials have shown that AZA 15% gel, applied twice daily for 12 weeks, was superior when compared with the vehicle for patients with papulopustular rosacea. 8 A mean reduction in inflammatory lesion counts ranged from 51% to 58% in the AZA group, compared with 39% to 40% in the vehicle group. Improvement in erythema scores ranged from 44% to 46% in patients treated with AZA, compared with 28% to 29% in the vehicle group. 7 In a 15-week study, AZA 15% gel applied twice daily also showed significant benefit over metronidazole 0.75% gel. 8 In these studies, the use of AZA 15% gel led to a mean reduction in inflammatory lesion counts ranging from 51% to 73% and a reduction of erythema severity ranging from 44% to 56%. The number of patients achieving success, as defined by the investigator global assessment, ranged from 61% to 69%. 9,10 A split-face study by Maddin 11 comparing AZA 20% cream with metronidazole 0.75% cream showed a reduction in inflammatory lesions of 78.5% and 69.4%, respectively. There was also a reduction in erythema of 25.5% and 18.7% for AZA and metronidazole, respectively. Both treatments led to a significant reduction in inflammatory lesions over 15 weeks, but the difference between treatments was not significant. 10 Of note, the physician rating of global improvement was significantly higher on the side treated with AZA at both weeks 9 and In the comparative studies, AZA had a greater potential to cause irritation than the metronidazole, which included facial skin signs and symptoms. However, these events were reported as mild to moderate and transient in nature. 8 There was no improvement reported in telangiectasia severity in any study of AZA for rosacea. The dosing recommendation for AZA 15% gel is a twice-daily application. However, Thiboutot et al 12 found once-daily dosing to be as effective as twice daily. Research has shown that AZA, when used as a treatment for papulopustular rosacea, is safe and effective and exhibits a favorable tolerability profile. Metronidazole Metronidazole has been the mainstay of topical rosacea treatment. It is a nitroimidazole antibiotic whose mechanism of action in rosacea is not well established, but appears to work through an anti inflammatory mechanism. 13,14 It is the most widely used topical agent for rosacea and is available in a 0.75% gel, lotion, and cream format for twice-daily use, and a 1% cream or gel for once-daily use. Jorizzo et al 15 found that once-daily dosing of 1% metronidazole cream was as effective as twice-daily dosing. It is generally well tolerated and has a low incidence of adverse effects. 12,13 A review by van Zuuren et al 16 and a condensed version of this work 6 summarizes 9 high- and intermediate-quality trials, which show clear evidence that topical metronidazole is significantly more effective than vehicle alone. Most of these studies used 0.75% metronidazole and ranged from 8 to 9 weeks in duration, with 1 trial lasting 6 months. A reduction in inflammatory lesions and erythema scores were noted, as was an improvement in physicians global evaluation, and patient-assessed measures when these were available. 5,15 No benefits were noted for the telangiectasia Postgraduate Medicine, Volume 121, Issue 5, September 2009, ISSN , e-issn

4 Mohamed L. Elsaie and Sonal Choudhary in these studies, however, a study by Tan et al 17 showed improvement in telangiectasiae scores, as well as erythema and inflammatory lesion counts, using a 1% metronidazole cream with SPF. Although data are limited, 2 studies have shown that topical metronidazole may be as effective as oral tetracycline in reducing the inflammatory component of rosacea. 18,19 Efficacy of metronidazole is constant regardless of the formulation, strength, and frequency of application. This drug also plays a role in maintenance therapy, either with or without prior concomitant systemic antibiotic therapy. 12 Given its high efficacy and tolerability, it will continue to play an important role in the management of rosacea. Sodium Sulfacetamide 10% + Sulfur 5% Sodium sulfacetamide 10% + sulfur 5% is an older treatment that has gained new popularity. It is used to treat acne, rosacea, and seborrheic dermatitis, 13 and is available in multiple formulations as a lotion, cream, gel, or cleanser. 9,13 The mechanism of action is not well understood, but the sulfacetamide has antibacterial properties, and the sulfur component confers antifungal, antidemodectic, and keratolytic effects. 20 Two studies, one comparing the sodium sulfacetamide sulfur combination with the vehicle and another comparing it with metronidazole 0.75% gel showed a significant reduction in both inflammatory lesion counts and erythema scores in papulopustular rosacea. 19,21 This combination has antifungal, antibacterial, keratolytic, and anti-inflammatory benefits and has been recognized as an effective treatment for rosacea due to its combination of active ingredients. Until recently, use of this combination was somewhat limited by the unpleasant odor associated with the sulfur. 22 Newer wash-on-wash-off sodium sulfacetamide formulations have additional benefits such as less lingering odor, a lower irritation potential and fewer interactions with other topical regimens or cosmetics. 23 Anecdotal evidence and preliminary studies suggest at least some additional benefit when sodium sulphacetamide 10%/sulphur 5% is applied in combination with topical metronidazole. 24 Other Therapies Many other topical treatments for rosacea have been reported. Some are effective, but are not yet approved. Further investigation is needed to determine their potential role in the topical armamentarium of rosacea therapy (Table 2). Systemic Therapy Oral Antibiotics Systemic antibiotic therapy tends to be effective for treatment of papules, pustules, erythema, and ocular inflammation, but not for telangiectasia, rhinophyma, or the flushing that nearly always accompanies rosacea. Effective treatment often requires a prolonged course (months or sometimes years) of Table 2. Other Topical Therapies Treatment Modality Moisturizers MimyX (Stiefel Laboratories, Inc., Coral Gables, FL), Atopiclair (Graceway Pharmaceuticals LLC, Bristol, TN), Eletone (Ferndale Laboratories Inc., Ferndale, MI) and EpiCream (Promius TM Pharma, LLC, Bridgewater, NJ) Topical antibiotics Clindamycin 1%-benzoyl peroxide 5% gel calcineurin inhibitors, tacrolimus (Protopic ; Astellas Pharma US, Inc., Deerfield, IL) and pimecrolimus (Elidel, Novartis, Basel, Switzerland) Use in Rosacea Management Restore the lipids back into the skin and repair the barrier to reduce transepidermal water loss to a physiologic level. 87 Inhibits bacterial growth, possibly by blocking dissociation of peptidyl trna from ribosomes, causing RNA-dependent protein synthesis to arrest. It has shown benefits in rosacea treatment and is well-tolerated. 88 Investigated for use in papulopustular rosacea because of their anti-inflammatory effects. 89 Permethrin 5% cream Anti-parasitic effects; may target Demodex mites, a potential cause of rosacea. 90,91 Metronidazole Effective in inflammatory rosacea. 92 Oxymetazoline (awaiting FDA approval) Tried in patients with erythematotelangiectatic rosacea; gave impressive results by decreasing erythema. 93,94 Cyclosporine It has been shown to be useful in treating ocular rosacea. 95 Artificial tears help with the dry eyes. 4 Postgraduate Medicine, Volume 121, Issue 5, September 2009, ISSN , e-issn

5 Acne Rosacea an oral antibiotic, such as doxycycline. The antibiotic dose can often be reduced when papules and pustules improve. Low-dose (40 mg), once-daily doxycycline (Oracea ; Galderma Laboratories, Ft. Worth, TX) has been shown to be effective and safe in the treatment of rosacea, but it is expensive. 25 Immediate-release doxycycline (Vibramycin ; Pfizer, Inc., New York, NY) and 40-mg delayed-release doxycycline (which is an anti-inflammatory agent with no antibiotic properties) were compared in a multicenter, randomized, double-blind study in adult subjects with inflammatory rosacea. 26 The study lasted for 16 weeks, and the results showed that both formulations of doxycycline had the same onset of effect and the same degree of efficacy at all study time points. The only difference was that all side effects were noted with 100 mg per day doxycycline and mainly consisted of gastrointestinal disturbances such as nausea, vomiting, and abdominal discomfort. Another study described the use of azelaic acid 15% gel (Finacea gel; Intendis/Bayer, Pine Brook, NJ) and doxycycline 100 mg twice daily for up to 3 months in patients requiring maintenance and remission of inflammatory rosacea. 27 Oral metronidazole (Flagyl ; Pfizer, Inc.) is also effective for rosacea, but has some unpleasant side effects such as metallic taste. Six-week therapy with twice-daily 200-mg oral metronidazole significantly reduced papules and pustules in 29 patients. 28 A randomized study investigated the effectiveness of oral metronidazole (200 mg twice daily) or oxytetracycline (250 mg twice daily). Both drugs produced an improvement after 6 weeks and especially after 12 weeks of therapy, but there was no significant difference between them. 29 In rare cases, treatment with oral metronidazole might be associated with epileptiform seizures, encephalopathy, and sensory neuropathy. Although rarely used in the United States, oral metronidazole is prescribed frequently in Europe for long-term therapy of rosacea at doses of 200 mg twice daily. In a double-blind study of patients with papulopustular rosacea, it was shown to be as effective as oral oxytetracycline 250 mg twice daily. 30 Oral erythromycin at a dose of 250 to 1000 mg per day is considered an effective drug for the treatment of papulopustular rosacea. 31 The usual practice is to use erythromycin for patients intolerant, allergic, or refractory to tetracyclines or in cases in which tetracyclines are contraindicated such as pregnancy. 23 Erythromycin use is also restricted due to its gastrointestinal side effects. Second-generation macrolides, azithromycin, and clarithromycin are better tolerated. These have been shown to be effective and tolerable in short-term therapy of rosacea. After a 12-week treatment with azithromycin in decreasing doses, there was a 75% decrease in total scores and an 89% decrease in inflammatory lesion scores compared with basal values. 32 According to a trial with a 3-year follow-up, rosacea patients that were treated with clarithromycin required a significantly shorter treatment period (10.2 weeks) than patients who received an antibiotic effective dose (200 mg per day) of doxycycline. 33 Controlled clinical trials are necessary to further elucidate the role of second-generation macrolides in both short-term and, in particular, long-term therapy for rosacea. Isotretinoin Patients with severely inflamed rosacea, or those whose disease has a marked nodulocystic component and phymatous rosacea, can be treated with low doses of isotretinoin ( mg/kg/day) for 6 to 8 months. As with acne treatment, careful monitoring is necessary in women of childbearing age. Significant reductions in erythema, papules, and telangiectasia occur after about 2 months of treatment; no other pharmacologic treatment has been reported to reduce telangiectasia. A combination of topical and systemic therapies have also given great results in rosacea treatment. The use of combined therapy of anti-inflammatory dose doxycycline and topical metronidazole gel 1% probably has synergistic effects. 34 The combination has been studied and used for mild-to-moderate rosacea and is found to be effective and well tolerated. 35 Light-based Therapy In small clinical trials, light and laser therapies were effective in decreasing the severity of telangiectasias and erythema in patients with rosacea. 36 Adverse effects included purpura and hyperpigmentation. In 1 randomized, controlled, split-face trial in 20 patients, treatment with long-pulsed dye laser or intense pulsed light (IPL) was similarly effective in reducing telangiectasia and irregular pigmentation; subjects reported less pain with laser therapy. 37 Long-pulsed dye lasers and IPL devices can offer patients effective treatment without the purpura of short-pulsed dye lasers. 38 Long-term studies are lacking; maintenance treatment with topical drugs or with additional light-based therapy every 4 to 6 months would contribute to decrease the magnitude of the problem. Vascular lasers remain the gold standard in the treatment of erythematotelangiectatic forms of rosacea as their wavelengths (585 nm or 595 nm) correspond closely to the absorption peak of oxyhemoglobin Postgraduate Medicine, Volume 121, Issue 5, September 2009, ISSN , e-issn

6 Mohamed L. Elsaie and Sonal Choudhary (577 nm) and are thus useful in targeting superficial blood vessels. This phenomenon is also referred to as selective photothermolysis. 39 Multiplexed/dual wavelength lasers incorporate both long pulsed dye and Nd:YAG lasers, which have shown promise in the treatment of erythematotelangiectatic rosacea. 40 Intense pulsed light performs by destroying both small superficial and deeper vessels of the dermis by heating them to about 70 C. Additionally, a study in 2002 indicated that coagulation of Demodex by IPL may be one of the mechanisms of action of IPL in rosacea treatment. In 2008, a study was conducted to assess the efficacy of IPL for treatment of stage I rosacea (flushing, erythema and telangiectasia) in which 34 patients were treated with IPL ( nm). 41 After 4 treatments the mean reduction of the erythema values was 39% on the cheeks (P 0.001) and 22% on the chin (P 0.001). The results were sustained at 6 months. Side effects were minimal and self-limiting. In a randomized, controlled, single-blind, split-face trial, a comparison between nonpurpuragenic pulsed dye laser and IPL treatment in the ability to reduce erythema, telangiectasia, and symptoms in patients with moderate facial erythematotelangiectatic rosacea was studied. 42 The PDL and IPL resulted in significant reduction in cutaneous erythema, telangiectasia, and patient-reported associated symptoms. No significant difference was noted between PDL and IPL treatment. In a study in 2005 by Nybaek and Jemec, 43 the outcome of photodynamic therapy (PDT) in 4 patients with rosacea was reported. These patients had received prior treatment with tetracycline and metronidazole and either resulted in no success or patient dissatisfaction. Photodynamic therapy was used for treatment and the skin cleared in 3 of the 4 patients. In 1 of the patients there has been no relapse during a 9-month follow-up. In 2 patients, remissions lasted 3 months, during which time no additional or supplementary treatment was used. This led to assessment of the possible benefit of PDT for treatment of rosacea in Copenhagen through an exploratory review of case notes from rosacea patients treated with PDT. 44 Routine MAL-PDT with methylaminolevulate and red light was administered to patients 1 to 4 times and results were evaluated 1 to 2 months after initial PDT treatment. Good results were seen in 10 of 17 patients, and fair results in another 4 patients. The majority of patients treated could stop or significantly reduce other rosacea therapy for a period lasting ~3 months to 2 years. Photopneumatic technology (Isolaz and PPx; Aesthera Corp., Pleasanton, CA) uses heat and vacuum suction and is thought to reduce follicular plugging and the sebaceous load, as well as sebaceous gland activity and inflammation. It delivers broadband pulsed light ( nm) to dermal targets and, unlike other devices, uses gentle pneumatic energy (vacuum) to draw target tissue into the treatment tip. This elevates the sebaceous glands, opens the pore and evacuates the trapped sebum and necrotic cells, thus removing a breeding ground for Propionibacterium acnes. In addition, the light and heat can induce activation of endogenous porphyrins, leading to a decrease in colonization by Propionibacterium acnes. Suction-induced stretching of the skin may also reduce the concentration of competing chromophores that is thought to be a factor limiting the effectiveness of traditional intense pulsed light treatment. This modality holds promise in treatment of rosacea but still remains unproven, generating the need for long-term clinical studies. Conclusion Because of its chronic, inflammatory nature, rosacea requires continuous long-term management. Treatment can be tailored to the subtype and may involve a combination of therapies. Patients should first be counseled on the triggers of rosacea, proper skin care, photoprotection, and camouflaging cosmetic options. Topical therapy is usually first line, but in moderate-to-severe cases, or those with ocular involvement, systemic therapy may be required. Laser or light-based treatments and surgical procedures can offer added benefit. Many topical agents are available for the treatment of rosacea, and the erythematotelangiectatic and papulopustular variants usually respond most favorably. There is good evidence that topical AZA and metronidazole are both safe and effective treatments. Other treatment options also include sodium sulfacetamide 10%-sulfur 5%, benzoyl peroxide 5%-clindamycin 1%, or clindamycin alone, which may prove effective depending on the presentation and course of rosacea. Much about rosacea remains to be learned; more studies that provide strong evidence of the effectiveness of various rosacea management therapies and their combinations are necessary for better defining which cases benefit most from which drug options. Conflict of Interest Statement Mohamed L. Elsaie, MD, MBA and Sonal Choudhary, MD disclose no conflicts of interest. 6 Postgraduate Medicine, Volume 121, Issue 5, September 2009, ISSN , e-issn

7 Acne Rosacea References 1. Wilkin J, Dahl M, Detmar M, et al; National Rosacea Society Expert Committee. Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2004;50(6): National Rosacea Society. What is rosacea? Accessed January 20, Del Rosso JQ. Update on rosacea pathogenesis and correlation with medical therapeutic agents. Cutis. 2006;78(2): Gupta AK, Gover MD. Azelaic acid (15% gel) in the treatment of acne rosacea. Int J Dermatol. 2007;46(5): Breathnach AS. Azelaic acid: potential as a general antitumoural agent. Med Hypothesis. 1999;52(3): van Zuuren EJ, Gupta AK, Gover MD, Graber M, Hollis S. Systematic review of rosacea treatments. J Am Acad Dermatol. 2007;56(1): Liu RH, Smith MK, Basta SA, Farmer ER. Azelaic acid in the treatment of papulopustular rosacea: a systematic review of randomized controlled trials. 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