Treating Rosacea

US Pharm. 2007;32(9):45-53.

 
Rosacea is a common, chronic skin disorder characterized by transient or persistent central facial erythema, telangiectasia (visible blood vessels), inflammatory episodes with papules and pustules,  and, in severe cases, rhinophyma. ^1,2 It is estimated that approximately 14 million people in the United States are diagnosed with some form of this dermatosis. Rosacea most frequently occurs in people between the ages of 30 and 50 years, with women at two to three times greater risk than men. Northern European descendants are at greatest risk for developing this condition.²

The National Rosacea Society Expert Committee developed a standard classification system based on the morphologic characteristics of the condition. The system identifies the primary and secondary signs and symptoms of rosacea.³ Primary signs and symptoms include transient erythema, nontransient erythema, papules, pustules, and telangiectases.³ If one or more of the primary signs concomitantly occur with central face distribution, rosacea is suspected. Patients who are diagnosed with rosacea and exhibit one or more of the primary features often present with the secondary signs and symptoms. These include burning or stinging, plaques, dry appearance, edema, ocular manifestations, and phymatous changes. Secondary features usually appear in the presence of the primary symptoms but can also occur in the absence of primary signs and symptoms.³ Due to the various and numerous manifestations of the disease, the National Rosacea Society Expert Committee has created subtypes of the condition.

Classification
There are four major subtypes and several other nonclassic subtypes that describe the most common patterns associated with the signs and symptoms of rosacea. The subtypes include erythematotelangiectatic rosacea (ETR), papulopustular rosacea (PPR), phymatous rosacea, and ocular rosacea (TABLE 1).¹ ETR is the most common subtype and is characterized by flushing, which usually lasts longer than 10 minutes, accompanied by persistent central facial erythema. Telangiectasia is usually prominent on the cheeks and nose in patients with the ETR subtype and may contribute to erythema. This subtype of rosacea responds poorly to treatment.¹ PPR typically presents as small, dome-shaped erythematous papules with tiny surmounting pustules on the central portion of the face. This subtype, which is fairly uncommon, is also associated with erythema and telangiectatic vessels.¹ The most frequent manifestation of this subtype is rhinophyma. Rhinophyma can be a disfiguring condition of the nose that results from hyperplasia of both the sebaceous glands and the connective tissue. Although rosacea is more frequent among women, rhinophyma is predominant among men, with the ratio being approximately 20:1.¹ The last subtype, ocular rosacea, is common but often misdiagnosed. This type of rosacea can manifest as blepharitis and conjunctivitis with inflamed eyelids and meibomian glands; however, most patients present with mild symptoms, such as burning or stinging in the eye. This may precede, follow, or occur simultaneously with other classic rosacea symptoms.¹

Other nonclassic subtypes of rosacea include glandular rosacea and granulomatous rosacea. Glandular rosacea is characterized by thick, sebaceous skin; papules and pustules; and nodulocystic lesions. Granulomatous rosacea is described as the presence of yellow, brown, or red papules or lesions on the cheeks or around the mouth and eyes. Granulomatous rosacea may be classified as granulomatous facial dermatitis rather than a type of rosacea, because these patients do not have persistent erythema and usually present with lesions outside the central face or with disease in a unilateral distribution. Such patients are less likely to have the flushing, burning, and stinging characteristic of other subtypes. ¹

The development of rosacea occurs in four stages (TABLE 2). Stage I is described as prerosacea. In this stage, rosacea-induced blushing is the main symptom and can develop as early as childhood. Stage II is mainly vascular; the disease progresses into transitory erythema of the midfacial area, and mild telangiectasia begins to develop. During stage III, facial redness worsens, becoming deeper and permanent. Also during this stage, telangiectasia increases, ocular changes begin to develop, and papule and pustule formation occurs. In stage IV, there is continued and increased skin and ocular inflammation. The ocular inflammation can ultimately result in visual loss. It is also in this stage that fibroplasia and sebaceous hyperplasia of the skin lead to rhinophyma. ⁴

Etiology
The exact etiology of rosacea remains unknown; however, several factors have been implicated in its pathogenesis.^1-2,4 The erythema is caused by dilation of the superfacial vasculature of the face. This increased blood flow to the superfacial vasculature results in edema. It has been proposed that Helicobacter pylori may be a cause of this disease.⁴ Recent studies have also linked H pylori with urticaria, Schonlein-Henoch purpura, and Sjogren's syndrome. It remains controversial whether there is benefit from the eradication of H pylori on the symptoms associated with rosacea.⁴ Other possible etiologies include climatic exposure, ingested chemical agents, abnormalities in cutaneous vascular homeostasis, endothelial damage and matrix degeneration of the skin, and microbial organisms (e.g., Demodex folliculorum).^1,4

Prior to initiating treatment, factors that trigger signs and symptoms should be identified and, if possible, avoided. Triggers are patient-specific; however,  the most common known triggers include hot or cold temperatures, wind, hot drinks, exercise, spicy food, alcohol, emotional stress, topical products, menopausal flushing, and medications that may induce flushing (i.e., niacin, disulfiram, nitroglycerin). ^5,6 Some important preventive measures that patients with rosacea can take include the daily use of a gentle sunscreen, avoidance of midday sun, and the use of protective clothing.^5,6 Alcohol consumption is not known to be a direct cause of the disease, but it can aggravate the condition through peripheral vasodilation.⁵ Only hypoallergenic and nonirritating facial cleansers, lotions, and cosmetics should be used in these patients.^4,5  

Cure Still Elusive
The cure for rosacea remains elusive, and all of the medications currently used will only help in resolving symptoms but will not completely eradicate the disease. Therefore, the goal in managing rosacea is to control the symptoms as opposed to eradicating the disease. Rosacea should be treated within the early stages to prevent progression to edema and irreversible fibrosis. Treatment typically depends on the subtype and stage of rosacea.^1,4 Both topical and oral medications are used in the treatment of rosacea, and those agents most commonly prescribed include topical metronidazole, sodium sulfacetamide–sulfur cleanser, azelaic acid, and oral tetracycline and macrolide antibiotics. When treating rosacea, therapy should be initiated with a combination of both oral and topical products, as this regimen has been shown to reduce the initial prominent symptoms, prevent relapse when oral therapy is discontinued, and maintain long-term control. Oral therapy is usually continued until inflammation dissipates or for a maximum of 12 weeks--whichever comes first. Antibiotics have traditionally been considered first-line therapy, primarily due to their anti-inflammatory effects as opposed to their antimicrobial action alone.⁴ The tetracyclines and macrolides are the most commonly prescribed antibiotics for the treatment of rosacea.

Topical Treatments
To date, there are only three FDA-approved topical medications for the treatment of rosacea, particularly for the management of papules, pustules, and erythema. The three approved topical medications include 0.75% and 1% metronidazole, 10% sodium sulfacetamide with 5% sulfur, and 15% azelaic acid gel. Other medications that are not FDA approved for the treatment of rosacea but have shown some beneficial effects include benzoyl peroxide, clindamycin, retinoids, and topical steroids.^5,6

Several randomized, double-blind, placebo-controlled trials involving the use of topical metronidazole have indicated that it is safe and effective in the treatment of rosacea.^7-12 The pharmacologic mechanism responsible for the effectiveness of metronidazole in the treatment of rosacea remains unclear; however,  in vitro studies have shown that metronidazole interferes with the release of reactive oxygen species from neutrophils that cause tissue injury at the site of inflammation.¹³ Clinical trials suggest that topical metronidazole is most effective at reducing inflammatory lesions and erythema associated with rosacea.¹⁴ In addition, one of the other benefits to using topical metronidazole is the lack of systemic toxicity that is noted with the oral formulation.¹³ Although it is generally used as first-line treatment and continues to be one of the most widely prescribed medications in the treatment of rosacea, the optimal dose of metronidazole for this condition has yet to be determined. Daily dosing and twice-daily dosing of the 1% and 0.75% formulations, respectively, have proven to be effective for this condition. Currently, topical metronidazole is available as a twice-daily application of 0.75% cream or gel and as a once-daily 1% cream. The 0.75% formulation was originally approved as a twice-daily application based on its half-life of six hours. However, recent data suggest that metronidazole is metabolized into active metabolites that may prolong its efficacy, and once-daily dosing of the 0.75% cream is now regarded as an acceptable form of treatment.^5,13 The effectiveness of the once-daily 0.75% formulation was found to be equivalent to the once-daily 1% formulation in a 12-week, randomized trial that included 72 patients. No significant difference existed between the treatment groups with regard to reduction of erythema, papules, and pustules; treatment failure; dryness; safety; and global assessment of severity.¹²

Topical metronidazole has shown to reach significant reduction of erythema as early as week 2 and as late as week 10 depending on the formulation.^10,11 In a double-blind, randomized clinical trial, the 1% formulation significantly reduced inflammatory lesions by week 4.¹⁰ Maintenance therapy is a critical aspect of rosacea therapy. Typically, after discontinuing treatment, relapse occurs in one fourth of patients after one month and in two thirds of patients after six months.¹⁴ In a randomized, double-blind, placebo-controlled clinical trial, topical metronidazole effectively maintained remission over six months in those patients who were previously treated with combination therapy including tetracycline and topical metronidazole.¹⁵ After discontinuing oral medication in a multicenter, randomized, double-blind trial, topical metronidazole maintained remission longer than placebo, and 23% of patients relapsed with metronidazole gel compared to 42% with the placebo cream.^15,16 Topical metronidazole is poorly absorbed with either undetectable or trace serum concentrations reported after its use.¹³ Topical metronidazole is generally well tolerated, with adverse events reported in less than 5% of patients. The most common reactions reported were local reactions including dryness, redness, pruritis, burning, and stinging.¹³

The combination of sodium sulfacetamide 10% and sulfur 5% provides a safe, well-tolerated, and effective option for the treatment of rosacea that may be less irritating than metronidazole.^4,5 Traditionally, this combination's use was limited because of its unpleasant odor; however, it is now formulated as a cleanser with a masked odor. This new formulation has led to the reemergence of this product.⁶ The proposed mechanism of action of these agents in the treatment of rosacea is attributed to the antibacterial properties of sulfacetamide and its ability to compete with para-aminobenzoic acid along with the keratolytic properties of sulfur, which is believed to have an anti-inflammatory effect.¹⁷ In an eight-week, double-blind, placebo-controlled trial, the combination of sulfacetamide and sulfur decreased inflammatory lesions by 78%, compared to a 36% decrease in the placebo arm. The sodium sulfacetamide–sulfur combination also decreased erythema by 83%, compared to a 31% decrease in the placebo group.¹⁸ This twice-a-day cleanser is effective as monotherapy and has been shown to significantly reduce papule count and erythema.¹⁹ However, the use of sodium sulfacetamide-sulfur cleanser followed by metronidazole cream has proven to be superior to the cleanser alone in reducing papule counts and overall rosacea severity.¹⁹ The newer wash on/wash off sodium sulfacetamide–sulfur formulation has lower irritation potential, improved absorption through hydrated skin, less lingering odor, and fewer drug–drug interactions with other topical regimens or cosmetics.⁵ Most of the adverse reactions associated with sodium sulfacetamide-sulfur use are mild and include pruritis, contact dermatitis, irritation, and xerosis. The combination of sodium sulfacetamide and sulfur is contraindicated in patients with a sulfonamide hypersensitivity.²⁰

Azelaic acid 15% gel is the most recently FDA-approved topical agent for the treatment of rosacea. It is a naturally occurring saturated dicarboxylic acid similar to metronidazole and is thought to inhibit the reactive oxygen species produced by neutrophils. ⁵ The efficacy and safety of azelaic acid gel in PPR was investigated in two vehicle-controlled, randomized, phase III trials involving 664 subjects. ²¹ Improvement of erythema occurred in 44% and 46% of patients in the azelaic acid groups compared to 29% and 28% improvement in the placebo-treated patients. From baseline, the mean reductions of inflammatory lesions were 58% and 51% in the azelaic acid–treated groups compared to 40% and 39% in the control groups. Burning, stinging, or itching was experienced by 38% of the patients treated with azelaic acid. Scaling, dry skin, and rash occurred in approximately 12% of the azelaic acid–treated patients. The majority of these side effects were transient in those affected.²¹ In a smaller randomized, double-blind, parallel trial, azelaic acid 15% was compared to metronidazole gel 0.75% in patients with PPR. Patients received either azelaic acid or metronidazole twice daily for 15 weeks. Azelaic acid gel was significantly more effective at reducing inflammatory lesions and the mean lesion count.²² There was a 72.7% decrease in the inflammatory lesions in the azelaic acid group compared to a 55.8% decrease in the metronidazole group. Azelaic acid also significantly improved erythema severity, as 56% of the patients treated with azelaic acid improved versus 42% of metronidazole-treated patients.²² There were no serious or systemic adverse effects reported in either treatment group. However, 26% of the azelaic acid treatment group experienced facial skin reactions and symptoms compared to 7% in the metronidazole-treated patients.²²

Benzoyl peroxide, erythromycin, and clindamycin have all been used as topical agents for the treatment of rosacea; however, none of them has been FDA approved because there is limited data available to support the use of these topical products for this disorder; they are only to be used as alternative therapies.⁵ Benzoyl peroxide is typically used in patients with phymatous and glandular rosacea. The use of erythromycin for rosacea was prompted by its successful treatment of acne vulgaris. This twice-daily topical preparation has been shown to reduce erythema and suppress papules and pustules after four weeks of treatment.²³ Topical clindamycin is primarily used in the treatment of acne, but it can be an effective alternative to tetracycline and topical metronidazole in patients with rosacea who are pregnant.^5,24,25

Oral Antibiotics
Oral antibiotics have been a mainstay of rosacea therapy for more than 40 years. They have proven to be effective in reducing the signs and symptoms associated with this condition. Historically, rosacea was thought to be a result of a bacterial infection, and since the 1950s oral antibiotics have been used as off-label therapy.²⁶ Currently, there is only one FDA-approved antibiotic for the treatment of rosacea, the tetracycline doxycycline (Oracea). The number of FDA-approved antibiotics for the treatment of rosacea is limited, primarily because compelling evidence that the disorder is secondary to a bacterial infection is lacking. Tetracycline and its derivatives minocycline and doxycycline are the principal oral antibiotics of choice for the treatment of rosacea.²⁶ The tetracyclines have the ability to down-regulate production of proinflammatory cytokines such as interleukin-1 and tumor necrosis factor alpha. They also inhibit proteolytic enzymes produced by inflammatory cells that degrade collagen, thereby decreasing inflammation that is seen during the inflammatory response in rosacea.²⁶ Tetracyclines are most effective against PPR; however, relapse rates are high if they are used as monotherapy without a topical agent.^24,26 Traditionally, tetracycline 250 to 1,000 mg daily and doxycycline or minocycline 100 to 200 mg daily for three to four weeks have been the most common dosages used to achieve substantial improvement in the signs and symptoms.²⁶

In May 2006, the FDA approved doxycycline (Oracea) 40 mg once daily, the first oral medication approved for the treatment of rosacea. It is only indicated for the treatment of inflammatory lesions (papules and pustules) in adult patients.²⁸ To date, there have been two phase III clinical trials involving doxycycline. Both of these studies were double-blind, placebo-controlled trials and were conducted simultaneously. A total of 537 patients received either placebo or doxycycline 40 mg once daily for 16 weeks. In both studies, doxycycline significantly reduced inflammatory lesions compared to placebo. In the two studies, the doxycycline-treated patients had a mean reduction in inflammatory lesion count of 61% and 46% compared with 29% and 20% in those who received placebo.²⁹ There are also data supporting the use of doxycycline 20 mg twice daily in those patients with inflammatory lesions and erythema. ^5,27 The twice-a-day regimen is believed to have fewer adverse reactions and is less likely to cause bacterial resistance because it results in subantimicrobial blood levels.²⁶ Minocycline and doxycycline have longer elimination half-lives and improved bioavailability compared to the parent compound, which can prolong their duration of action and minimize gastrointestinal (GI) side effects.⁵ Possible adverse reactions that may occur with the use of tetracycline include GI irritation, rash, renal toxicity, hepatic cholestasis, anemia, thrombocytopenia, and hypersensitivity reactions. The tetracyclines are contraindicated in pregnancy and in children younger than 8 years.³⁰

The oral macrolides erythromycin, clarithromycin, and azithromycin have been used for the treatment of PPR.²⁶ The macrolides prevent bacterial growth by interfering with protein synthesis. They inhibit the translocation of peptides by binding to 50S of the bacterial ribosome. These antibiotics are most commonly used when intolerance, pregnancy, resistance, or allergies prevent the use of tetracyclines.⁵ One advantage of the use of the second-generation macrolides clarithromycin and azithromycin over erythromycin is that they have a faster onset of action and less GI irritation than erythromycin.^31,32 Clarithromycin 250 to 500 mg twice daily for six weeks has been found to be as effective as doxycycline with a more tolerable side-effect profile.³¹ In a trial that compared clarithromycin 250 mg twice daily for four weeks followed by clarithromycin 250 mg once daily for four weeks to doxycycline 100 mg twice daily for four weeks followed by doxycycline 100 mg daily for four weeks, clarithromycin reduced erythema and papules at a faster rate. The authors concluded that six weeks of clarithromycin treatment was as efficacious as eight weeks of doxycline treatment.³¹ Azithromycin 250 mg for 12 weeks proved to decrease inflammatory lesions by 89% from baseline.³² Clarithromycin and azithromycin are preferred over erythromycin because of better tolerance and improved bioavailability; however, these second-generation macrolides may be more expensive.²⁶ Larger, controlled clinical trials are necessary to determine the exact role of the second-generation macrolides in both initial and maintenance therapy for rosacea.

Oral metronidazole may serve as another alternative for those who cannot tolerate tetracyclines or for those who have been treated unsuccessfully with tetracycline. A double-blind, randomized trial evaluated the efficacy of oral metronidazole in rosacea treatment. Patients received oral metronidazole 200 mg twice daily or oxytetracyline 250 mg twice daily. Both therapies showed sustained improvement at 12 weeks.⁵ 

In some patients, isotretinoin can be used for refractory rosacea, as it reduces the size of sebaceous glands and alters keratinization. Small clinical trials have demonstrated that isotretinoin may reduce the number of papules and pustules, erythema, and nasal volume in rhinophyma in patients with refractory rosacea.⁵ More recently, Erdogan et al. evaluated low-dose isotretinoin 10 mg daily for four months in patients with treatment-resistant rosacea.³³ Isotretinoin significantly reduced inflammatory lesions, erythema, and telangiectasia. Use of isotretinoin is often limited due to its serious and abundant side-effect profile. The most common adverse effects include bone or joint pain, burning, redness, itching, eye inflammation, nosebleeds,  scaling, skin infection, and rash. Isotretinoin is contraindicated in pregnancy, as it is teratogenic; for this reason, it has to be prescribed under a special restricted distribution program.³⁴ Information regarding isotretinoin's optimal dosage and duration of therapy for the treatment of rosacea is limited. In addition, the majority of the clinical trials evaluating its safety and efficacy involve small sample sizes. Therefore, more studies involving larger patient populations are needed to determine the optimal dosage and duration of therapy.

Laser and Light Therapies

Vascular laser therapy and light therapy serve as additional options for the treatment of telangiectasia in patients who do not respond to conventional therapy. Laser and light therapy have the capability to reorganize and remodel dystrophic dermal connective tissue and strengthen the epidermal barrier by thermally inducing fibroblasts and endothelial proliferation or by causing endothelial disruption, leading to cytokine, growth factor, and heat shock protein activation.³⁵ The vascular laser therapies currently used for telangiectasia and erythema are the standard pulse-dye laser (585 or 595 nm), long pulsed-dye lasers (595 nm), the potassium titanyl phosphate laser (532 nm), and the diode-pumped frequency-doubled laser (532 nm). The short-wavelength lasers (541 and 577 nm) induce vessel destruction without causing collateral tissue damage.³⁵ Therefore, the short-wavelength vascular lasers are preferred for superficial red vessels and persistent erythema. Intense pulsed-light therapy penetrates the skin deeper than vascular laser therapy and is best suited for vascular lesions and pigmented lesions. Its main benefits are the ability to treat larger and deeper vessels and promote collagen remodeling. Laser and light therapies may require one to three treatments four to eight weeks apart to achieve the best results; however, their use is limited due to cost.^35,36

Summary and Conclusion
Currently, rosacea treatment is aimed at reducing symptoms and improving facial appearance. Many questions still remain regarding the pathogenesis and etiology of the disease. Even though a definitive cause has not been determined, therapy should begin with avoiding possible triggers. If a patient is still experiencing rosacea symptoms once triggers have been identified and, if possible, removed, topical metronidazole remains the first-line therapy for the treatment of rosacea. Other topical agents such as sodium sulfacetamide–sulfur combination, azelaic acid, benzoyl peroxide, erythromycin, and clindamycin can be used as an alternative to metronidazole. Oral antibiotics, which can prevent relapse and maintain remission, are often used in combination with the topical agents. Recently, the first oral antibiotic, doxycycline, was FDA approved for the treatment of inflammatory lesions associated with rosacea. If topical and oral treatments are unsuccessful, vascular laser and light therapies are options for refractory cases.

Even though there are a variety of therapeutic options for the treatment of rosacea, investigation of genetic factors and the histologic and pathologic basis of papules and pustules still need to be carried out; this will lead to new and improved treatment options and may help decrease psychosocial distress of affected individuals. Despite the lack of understanding, therapy has improved since the diagnostic criteria have become more uniform.

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