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Rosacea is a common, chronic skin disorder that frequently affects light-skinned Caucasian population. Overall prevalence of rosacea ranges from less than 1% to 10%. The nose, cheeks, chin, forehead, and glabella are the most frequently affected sites. The disease has a variety of clinical manifestations ranging from flushing, persistent erythema, telangiectasias, papules, pustules and sebaceous gland hyperplasia.
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Currently, only the following medications are FDA-approved for use in rosacea:
Other non-FDA approved treatments used off-label have also been beneficial and will be discussed below.
Extended information on rosacea
Rosacea is a common, chronic skin disorder that frequently affects light-skinned Caucasian population. Overall prevalence of rosacea ranges from less than 1% to 10%. The nose, cheeks, chin, forehead, and glabella are the most frequently affected sites. The disease has a variety of clinical manifestations ranging from flushing, persistent erythema, telangiectasias, papules, pustules and sebaceous gland hyperplasia. Significant psychological stress and diminished perceive quality of life often accompanies this condition. The pathogenesis is likely multifactorial and includes genetic and vascular elements, climatic exposures, pilosebaceous unit abnormalities, and possibly microbial organisms.
Diagnosis of rosacea is based primarily on clinically recognizable morphologic characteristics. An expert committee assembled by the National Rosacea Society on the Classification and Staging of Rosacea defined and classified rosacea in April 2002 into 4 clinical subtypes based primarily on morphologic characteristics. The subtypes include erythemato-telangiectatic rosacea (ETR), papulo-pustular rosacea (PR), phymatous rosacea, and ocular rosacea.
In order to design appropriate treatment regimen it is essential to correctly identify the subtype of rosacea. In addition, rosacea has to be distinguished from its clinical mimickers. ETR must be differentiated from chronic sun damage and photodermatitis.PR must be distinguished from acne vulgaris, seborrheic dermatitis, lupus miliaris disseminates faciei, collagen vascular diseases, perioral dermatitis, and Demodex folliculitis. Differential diagnosis of ocular rosacea includes allergic conjunctivitis and blepharitis.
Therapy of rosacea is centered on symptomatic improvement i.e. reduction of facial erythema and number of inflammatory lesions, decrease in the number, duration and intensity of flares, and reduction of concomitant symptoms of itching, burning, and facial tenderness.
In addition to medical therapy sun protection and appropriate skin care regiment need to chosen as rosacea patients often exhibit marked skin sensitivity and suffer from intolerance to skin products and cosmetics. Triggers for cutaneous flushing should be identified and eliminated. Commonly identifiable triggers include topical cosmetics and corticosteroids, alcohol, tobacco, exercise, hormonal changes, sun exposure, hot weather, exercise, ingestion of hot or spicy foods/ drink, caffeine, emotional stress and medications such as topical and systemic steroids, niacin and nitroglycerin. A flare of rosacea may be anticipated when steroids are discontinued and may be dramatic requiring therapy with systemic antibiotics and topical tacrolimus.
Currently, only the following medications are FDA-approved for use in rosacea:
Other non-FDA approved treatments used off-label have also been beneficial and will be discussed below.
Erythemato-telangiectatic rosacea (ETR)
ETR subtype is clinically characterized by diffuse erythema and telangiectasias on the cheeks, forehead, dorsal nose, or sometimes entire face. Patients frequently complain of intolerance or sensitivity to topical products and cosmetics.
This type of rosacea is best treated with avoidance of triggers leading to flushing, strict photoprotection, electrosurgery and phototherapy. In recent years phototherapy and laser therapies are gaining popularity as treatments of rosacea associated erythema and telangiectasias. Laser therapies include pulse-dye laser (PDL), potassium-titanyl-phosphate (KTP) laser, Nd-YAG laser, or intense-pulsed light (IPL). In a study of 34 patients with ETR, IPL treatment resulted in overall patient and physician reported over 50% improvement in 73% and 83% of patients, respectively. The results were sustained at 6 months. In a different study 83% of patients had less facial redness, 75% noted less flushing and better skin texture, and 64% noted fewer acneiform breakouts.
Topical selective alpha-agonist, oxymetazoline, represents a novel approach to management of ETR associated erythema and flushing. A small study showed significant benefit with the use of the alpha-agonist oxymetazoline in reducing the flares and the inflammatory symptoms in patients with traditional medication resistant ETR.
Facial edema may be a prominent clinical feature of rosacea. Recurrent vasodilation results in a feeling of fullness of the cheeks and visible subtle induration of the cheeks, so called solid facial edema. Solid facial edema of ETR responds to isotretinoin.
Papulo-pustular rosacea (PR)
PR subtype is characterized by papules and pustules often on erythematous base primarily affecting the nose, cheeks, and forehead. Predilection of the lesions on the central, convex aspect of the face, sometimes with corresponding central facial edema is frequently noted.
The major topical antibiotics used to treat PR are metronidazole, clindamycin and erythromycin. Other topical therapies include azelaic acid, pimecrolimus, antiparasitics, alpha-adrenergic agonists and topical sulfacetamide 10% with sulfur 5%.
Clinical efficacy of the topical metronidazole in the treatment of rosacea has shown in a number of clinical trials. The mechanism of action of metronidazole is not yet well established, but appears to be anti-inflammatory. Topical metronidazole is commercially available in a 0.75% gel, lotion and cream for twice daily use, and a 1% cream or gel for once daily use. Twice-daily 0.75% metronidazole was shown to be well-tolerated and effective in the treatment of 582 patients with mild to moderate severity PR. Mean erythema severity score was reduced by 50% by week 12 of treatment. In a 12-week, randomized control study, Jorizzo et al. showed that once daily dosing of 1% metronidazole cream is as effective as twice daily dosing. Metronidazole is generally well tolerated and has a low incidence of adverse side effects. Most commonly reported include mild pruritus, skin irritation and dryness.
In a recent Cochrane review, topical metronidazole was shown to be significantly more effective than a vehicle in 174 patients with marked reduction of number of inflammatory lesions and erythema scores with an odds ratio of 5.96. Metronidazole plays a role in maintenance therapy, either with or without prior concomitant systemic antibiotic therapy. Effect of metronidazole on rosacea associated telangiectasias is generally minimal.
Sodium sulphacetamide with sulphur
Despite the lack of randomized controlled studies, sodium sulphacetamide 10% with sulfur 5% has been used as a safe, well-tolerated and effective treatment option for rosacea for over 50 years. Eight week therapy with sodium sulphacetamide 10% with sulfur 5% resulted in a significant reduction in inflammatory lesions and facial erythema (78% vs. 36% and 83% vs. 31%, respectively) compared to a vehicle. Adverse effects of topical application were generally mild and included pruritus, contact dermatitis, irritation, erythema, scale and xerosis.
Newer, emollient foam formulation of 10% sodium sulphacetamide and 5% sulfur offer similar benefits with less lingering odor and reduced irritation potential. Preliminary anecdotal evidence suggests synergistic benefit of concurrent sodium sulphacetamide10% with sulfur 5% and metronidazole application.
Azelaic acid, commercially available as 15% gel or 20% cream, is a naturally occurring, saturated 9-carbon dicarboxylic acid derived from Pityrosporum ovale. Azelaic acid is FDA-approved for the treatment of mild to moderate rosacea. Its biologic effects encompass anti-inflammatory, anti-keratinizing and anti-bacterial properties. Recently, PPAR gamma activation was shown as a main modulator of the inflammatory response modulated by azelaic acid in normal human keratinocytes.
Clinical safety and efficacy of azelaic acid 15% gel applied twice daily for 12 weeks has been demonstrates in two phase III, vehicle-controlled, randomized trials of 664 patients with PR. On average improvement of erythema ranged from 44-46% in patients treated with azelaic acid, compared with 28-29% in the vehicle group. A mean reduction in inflammatory papules and pustules ranged from 51-58% in the azelaic acid group, compared with 39-40% in the vehicle group.
Data from three clinical trials analyzed by Cochrane review showed rates of improvement in azelaic acid group of 70-80% compared with 50-55% in the placebo group. In a randomized trial comparing topical metronidazole with azelaic acid the efficacy of 20% azelaic acid was greater than metronidazole in improving erythema and inflammation in physician rating of global improvement. Application of azelaic acid was associated with a greater irritation. Wolf et al. found the efficacy of once-daily application of metronidazole 1% gel and twice daily azelaic acid 15% gel to be similar. Both medications were well tolerated, with the number of adverse effects slightly higher in azelaic acid group. All reported adverse effects were mild to moderate.
Anecdotal evidence suggests beneficial effects of topical clindamycin, erythromycin, and combination benzoyl peroxide-clindamycin in the treatment of rosacea, but efficacy of these modalities have not yet been evaluated in well-designed clinical trials. In a double-blind, randomized controlled trial of once daily clindamycin 1% benzoyl peroxide 5% gel a significant reduction in inflammatory lesion count and erythema was noted. The treatment was generally well tolerated.
Tacrolimus and pimecrolimus
Topical tacrolimus (0.03% or 0.1%ointment) and pimecrolimus (1% cream) are macrolide non-steroidal immunomodulators. Their mechanism of action is by inhibition of T-cell activation and inhibition of subsequent cytokine release. In a pilot study, topical pimecrolimus showed clinical benefit with decreased erythema and number of inflammatory lesions in after 12-18 weeks of therapy. Another randomized trial, nonetheless, demonstrated that pimecrolimus was no more effective than the vehicle when used for 4 to 6 weeks.
A recent single-centre, randomized, open-label study of 48 patients comparing pimecrolimus with metrondazole both treatments were very effective in the treatment of PR. There were no significant differences between the treatments in inflammatory lesion counts, overall erythema severity scores and physician global assessment scores evaluated from baseline to week 12. Neither treatment produced any clinically relevant improvement in telangiectasia.
Rarely pimecrolimus may produce a syndrome similar to steroid-induced acne.
Anecdotal evidence suggests that topical tacrolimus may be an effective treatment of steroid induced rosacea especially when combined with systemic minocycline.
The role of topical retinoids in the management of rosacea remains controversial. The mechanism of action of the retinoids is by regulation of the retinoic acid receptor, an important regulator of keratinocyte proliferation, differentiation, and cutaneous inflammation. Use of retinoids carries a theoretical benefit of decreased angiogenesis and decrease in cutaneous vascularity and possible prevention of new telangiectasias. In a few small series, topical retinoid, tretinoin, have demonstrates benefit for rosacea with a lessening degree of erythema and a partial to complete disappearance of telangiectasias as well as decreased in the number of inflammatory lesions although the clinical response was delayed and not evident until 2 or more months of therapy.
A small study demonstrated the efficacy of topical free radical scavenger vitamin C for rosacea suggesting the possibility that free radical production may play a significant role in the pathological inflammatory response seen in rosacea.
Some antiparasitic drugs have been observed to be helpful as both oral and topical agents in the treatment of the inflammatory rosacea. Oral ivermectin and lindane have shown some efficacy in the eradication of Demodex folliculorum, one possible factor that may lead to the inflammation underlying rosacea. Permethrin and crotamiton topically have not shown great usefulness in eradicating Demodex folliculorum, but may still lead to the resolution of some of the underlying inflammation. In a small randomized double-blind placebo-controlled study permethrin 5% cream was found superior to the vehicle and similar in efficacy to 0.75% metronidazole gel.
Tetracyclines are broad-spectrum antibiotics that remain the mainstay of oral pharmacotherapy for rosacea. Tetracycline (250 to 500 mg twice daily) and more recently second generation tetracyclines, doxycycline (100 to 200 mg per day and extended release 20-40 mg per day) and minocycline (100-200 mg per day),are commonly used oral therapies. Second generation tetracyclines have an improved bioavailability, longer elimination half-life, once daily dosing and can be taken with food which minimizes gastrointestinal side effects. Azithromycin has also been shown to be beneficial for treating rosacea, is better tolerated than first generation tetracyclines and can be dosed 3 times a week.
The precise mechanism of action of tetracyclines remains unknown. Most likely anti-inflammatory and not anti-microbial actions of tetracyclines such as their actions on inhibition of angiogenesis, neutrophil chemotaxis, release of pro-inflammatory cytokines, cellular apoptosis, cell proliferation and inhibition of matrix metalloproteinases contribute to clinical benefit in management of rosacea. A significant benefit of second generation tetracyclines is their clinical effectiveness at sub anti-microbial, anti-inflammatory doses limiting undesired side effects (candidal vulvovaginitis, gastrointestinal distress) and possibly bacterial resistance. Systemic tetracycline antibiotics should not be used in children under the age of 8 because of potential permanent discoloration of teeth.
Anti-inflammatory dose of doxycycline, a 40 mg doxycycline monohydrate containing 30 mg immediate-release and 10 mg delayed release doxycycline, commercially available as Oracea, is the only tetracycline approved in the US for the long-term (12 months) use. Oracea has been shown effective in treatment of PR with favorable risk/benefit ratio. Used at sub anti-microbial doses, long-term use of anti-inflammatory doxycycline might not exert selective pressure on bacteria, and thus limit development of bacterial resistance.
Two phase III, controlled studies have demonstrated the safety and efficacy of a 16-week treatment with anti-inflammatory 40 mg doxycycline administered daily in the management of PR. Both studies included patients with inflammatory PR with 10-40 papules, moderate to severe erythema and telangiectasias. At the end of 16 weeks, the mean change in lesion count in doxycycline groups was -11.8 and -9.5 in compared with -5.9 and -4.3 in the placebo group? Doxycycline was well tolerated with low incidence of side effects. Most commonly reported side effects included nasopharyngitis, diarrhea and headaches. Efficacy beyond 16 weeks and safety beyond 9 months has not yet been established in randomized controlled studies.
Current research on small number of patients suggests that combination therapy of oral anti-inflammatory dose of doxycycline and topical metronidazole leads to quicker and more effective alleviation of inflammatory lesions.
Oral erythromycin at 250-1000 mg per day is considered an effective drug for the treatment of PR. The use of erythromycin is reserved for those patients that are intolerant, allergic or refractory to tetracyclines or in cases when tetracycline therapy is contraindicated (e.g. pregnancy).
Second generation macrolides, clarithromycin and azithromycin have both been found to be effective and tolerable drugs in short term therapy of rosacea. At the end of a 12-weektreamtent with azithromycin, a 75% decrease in total scores and an 89% decrease in inflammatory lesion scored was noted compared with baseline values.
A significant amount of circumstantial evidence links the eradication of Helicobacter pylori with the “triple therapy,” consisting of omeprazole and 2 of the following antibiotics: clarithromycin, amoxicillin, or metronidazole and the successful treatment of rosacea.
In a randomized study of oral metronidazole (200 mg twice daily) vs. oxytetracycline (250 mg twice daily) both drugs produced an improvement after 6 and 12 weeks of therapy with no significant differences between the two. In rare instances, treatment with oral metronidazole might be associated with epileptiform seizures, encephalopathy, and sensory neuropathy. Oral metronidazole also requires abstinence from alcohol.
In a small number of clinical trials, isotretinoin was found to be effective for both ETR and PR. Isotretinoin, although not working directly as an antibiotic, has strong antibacterial effects. Irvine et al. noted a reduced facial cutaneous blood flow in the isotretinoin group compared with oxytetracycline group.
A small study of 22 patients showed the effectiveness of a 4 month low-dose (10 mg) isotretinoin therapy in patients with therapy-resistant rosacea. The treatment led to a reduction of number of inflammatory lesions, erythema and telangiectasia. The overall effect of isotretinoin therapy was delayed in comparison to therapy with oral antibiotics.
Gollnick et al. compared efficacy of isotretinoin (0.1. mg/kg, 0.3 mg/kg or 0.5 mg/kg) with doxycycline (100 mg daily for 14 days, followed by 50 mg daily) in the treatment of grade II and III rosacea in a double-blinded randomized 12 week study. Isotretinoin 0.3 mg/kg proved to be the most effective dose compared with placebo. Isotretinoin 0.3 mg/kg treatment resulted in 90 % reduction of number of lesions compared with 83 % reduction with doxycycline. Isotretinoin 0.3 mg/kg was generally well-tolerated.
Other oral therapies
Other oral therapies that have shown benefit are medications that reduce flushing beta-blockers, clonidine, naloxone, ondansetron, and selective serotonin reuptake inhibitors.
Oral contraceptive therapy has been helpful in patients who provide historical information of worsening rosacea with their hormonal cycle.
Dapsone has been used in severe, refractory rosacea, and dapsone has been particularly beneficial for patients who cannot take isotretinoin.
Phymatous rosacea is characterized by marked by thickening of the skin, irregular skin texture, edema, hypertrophy and hyperplasia of sebaceous glands, connective tissue, and vascular bed. Phymatous rosacea commonly involves the nose (rhinophyma) but changes can also be seen on the chin (gnathophyma), ears (otophyma), forehead (metophyma), and eyelids (blepharophyma). This severe form of rosacea requires aggressive medical therapy with systemic antibiotics, and sometimes warrants use of isotretinoin. Once the medical regimen has been maximized, the patient is a candidate for surgical/ laser resurfacing of the affected area. Electrosurgical sculpturing of the phymatous skin gives excellent results, is fast, and is almost bloodless. A CO2 laser or erbium-YAG laser may also be used for the treatment of rhinophyma, although it is more costly and time-consuming than electrosurgical treatment. Electrosurgical treatment is more likely to scar compared to laser therapy.
Cold-steel surgery and dermabrasion are also effective, but they are more difficult owing to the vascularity of the nose.
Ocular rosacea can be seen in the presence or absence of skin manifestations of rosacea. Clinically, ocular rosacea is characterized by conjunctival erythema and injection, sometimes accompanied by eyelid edema), foreign body sensation, inflammation of the lids , blepharitis and meibomian glands, interpalpebral conjunctival hyperemia, conjunctival telangiectasias and/or glandular inflammation (chalazion) along the eyelid margin.43 Patients report subjective symptoms: foreign body sensations, dry eyes, stinging, itching and burning, photosensitivity. The vision is rarely affected. Ocular rosacea requires systemic antibiotics, and oral tetracyclines including low dose doxycycline are an excellent first-line therapy for this form of rosacea. Topical corticosteroid eyedrops may also be beneficial.
Granulomatous rosacea is a variant of rosacea clinically presenting with erythemaotus to brownish papules with peripheral erythema on the malar and perioral region. Treatment of granulomatous variant is difficult. In a case report, granulomatous rosacea refractory to traditional treatments was treated with IPL with satisfactory improvement.44 Authors postulated that IPL system with non-fixed wavelengths, ranging from visible to infrared might provide added benefit of treating telangiectasias at different depths leading to subsequent improvement.
Rosacea fulminans (sudden onset of coalescent papules, pustules, nodules) may occur during pregnancy, thyroid diseases, depression, emotional stress, induced by medications. This exacerbation may require use of systemic corticosteroids (prednisone 0.5 to 1 mg/kg/day) and/or isotretinoin.
The mainstay of rosacea therapy remains topical metronidazole or azelaic acid and oral tetracyclines. As this disease process causes increased skin sensitivity, many of the topical therapies may not be well tolerated, necessitating other therapies. It is therefore important to have as many treatment options as possible.