Drug Information

Management of rosacea

Management of rosacea
Management of rosacea
Management of rosacea
Lisa E Maier, MD
Section Editor
Mark V Dahl, MD
Deputy Editor
Abena O Ofori, MD

INTRODUCTION — Rosacea is a chronic and relapsing inflammatory skin disorder that primarily involves the central face. Common clinical features include facial erythema, telangiectasias, and inflammatory skin lesions. Many patients seek therapy due to concern over the effect of rosacea on physical appearance. As there is no cure for rosacea, treatment is focused on symptom suppression.

The management of rosacea will be discussed here. The pathogenesis and clinical features of rosacea are reviewed separately. (See "Rosacea: Pathogenesis, clinical features, and diagnosis".)

PATIENT ASSESSMENT — Rosacea is divided into four subtypes which are defined by the presence of specific clinical features [1] . Identification of the disease subtype and severity of involvement are essential for the selection of appropriate therapy. (See "Rosacea: Pathogenesis, clinical features, and diagnosis".)

The subtypes of rosacea include:

  • Erythematotelangiectatic rosacea: Features of erythematotelangiectatic rosacea include transient facial erythema (flushing), centrofacial nontransient erythema, telangiectasias, skin sensitivity, edema, and a dry or scaly skin texture (picture 1A-B). (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Erythematotelangiectatic rosacea'.)
  • Papulopustular rosacea: Patients with papulopustular rosacea present with inflammatory papules and pustules on the central face. In addition, persistent erythema, telangiectasias, flushing, and other features of erythematotelangiectatic rosacea may occur in patients with papulopustular disease (picture 2A-B). (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Papulopustular rosacea'.)
  • Phymatous rosacea: Phymatous rosacea is characterized by skin and sebaceous hypertrophy that results in distortion of facial contours. Severe disfigurement may occur (picture 3). (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Phymatous rosacea'.)
  • Ocular rosacea: A variety of ocular findings may occur in rosacea, including conjunctival hyperemia, anterior blepharitis, keratitis, lid margin telangiectasias, abnormal tearing, cicatricial conjunctivitis, and chalazion or hordeolum (stye) formation. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Ocular rosacea'.)

Features of more than one subtype of rosacea may occur simultaneously.

GENERAL MEASURES — Nonpharmacologic interventions may be useful for the management of the cutaneous manifestations of rosacea, regardless of clinical subtype. These include avoidance of triggers of flushing, gentle skin care, sun-protection, and the use of cosmetic products.

Avoidance of flushing — Easy flushing is a common feature of rosacea that may occur in all subtypes, particularly in the setting of erythematotelangiectatic or papulopustular disease. Flushing is a prominent and troubling symptom for some patients, and some authors have proposed that flushing may contribute to worsening of other features of rosacea, such as inflammatory papules, erythema, and skin sensitivity [2-4] .

Potential triggers for flushing include [3,5-7] :

  • Extremes of temperature
  • Sunlight
  • Spicy foods
  • Alcohol
  • Exercise
  • Acute psychological stressors
  • Medications
  • Menopausal hot flashes

Individual patients may also have unique triggers for flushing, and the degree of flushing in response to the above stimuli is variable. Thus, asking patients to keep a diary of flushing episodes and potential associated factors can be useful for identifying and avoiding pertinent triggers. In addition, practical measures to reduce flushing after encounters with stimuli, such as applying cool compresses and transferring to cool environments, may be helpful.

A variety of pharmacologic agents, including clonidine, beta-blockers, antidepressants, gabapentin, and topical oxymetazoline have been used in attempts to reduce flushing [8-14] . However, data are limited on their efficacy in rosacea and no single therapy appears to be consistently effective. Moreover, the potential for drug-related adverse effects must be considered. (See "Flushing", section on 'Treatment'.)

Laser, intense pulsed light, and photodynamic therapy also have been used for patients with rosacea-related flushing, but data are limited on treatment effects [15-18] .

Skin care — Patients with rosacea, particularly those with the erythematotelangiectatic subtype, can experience heightened sensitivity of facial skin characterized by difficulty tolerating topical cosmetics, skin care products, and topical medications [19] . In addition, rough, dry, or scaly facial skin is a common feature of erythematotelangiectatic rosacea.

It is unclear whether subjective skin sensitivity and dryness result from abnormalities in skin barrier function that precede the development of rosacea, or whether they occur as a consequence of the inflammatory process [20] . Regardless, gentle skin care practices may help to reduce symptoms. Appropriate measures include:

  • Frequent skin moisturization – Emollients help to repair and maintain cutaneous barrier function and may be useful in rosacea [21,22] . In a 15-day split-face study of 20 patients with erythematotelangiectatic rosacea treated with metronidazole 0.75% gel, concomitant application of a moisturizing cream twice daily was associated with a significant reduction in experimentally-induced symptoms of skin sensitivity [22] . Relatively greater reductions in scores of skin dryness, roughness, and discomfort were also detected.
  • Gentle skin cleansing – Patients should be instructed to cleanse their skin gently with lukewarm water, to wash with their fingers, and to avoid harsh mechanical scrubbing [19,23] . Non-soap cleansers with synthetic detergents (eg, beauty bars, mild cleansing bars, many liquid facial cleansers) are usually better tolerated than traditional soaps. The latter are alkaline which may raise the pH of the skin to abnormal levels and impair skin barrier function [24] . In contrast, synthetic detergent cleansers typically have a pH that more closely approximates the normal pH of the skin (skin pH = 4.0 to 6.5).
  • Avoidance of irritating topical products – Patients should avoid topical products that may irritate the skin, such as toners, astringents, and chemical exfoliating agents (eg, alpha hydroxy acids) [23,24] . Manual exfoliation with rough sponges or cloths also should be avoided. Skin care products in the form of powders or creams are generally better tolerated than gels and thin lotions [23] . In addition, cosmetics should be easy to remove to avoid the need for harsh cleansing [23] .

Sun protection — The role of sun exposure in the pathogenesis of rosacea is uncertain. Flares of facial redness and flushing may be stimulated by exposure to radiant heat from the sun, and ultraviolet radiation may induce cutaneous changes that promote rosacea. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Ultraviolet radiation'.)

We routinely recommend daily application of a broad-spectrum sunscreen with a sun protection factor (SPF) of at least 30, and educate patients on mid-day sun avoidance and the use of sun-protective clothing. Sunscreens in the form of creams, lotions, or preparations that contain barrier protective silicones (eg, dimethicone or cyclomethicone) are preferred over those in an alcohol-based vehicle, which may be more likely to cause irritation [25,26] .

Cosmetic camouflage — For female patients who are bothered by facial erythema or telangiectasias, green-tinted foundation can help to camouflage these features. A flesh-colored facial foundation should be applied on top of the green-tinted foundation to achieve a color that matches the patient’s complexion [27] . For men, light application of a green-tinted cosmetic facial powder can be useful for camouflaging facial redness.

ERYTHEMATOTELANGIECTATIC ROSACEA — Erythematotelangiectatic rosacea is characterized by persistent centrofacial erythema, telangiectasias, flushing, skin dryness, skin sensitivity, and/or facial edema [1] . (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Erythematotelangiectatic rosacea'.)

Approach to treatment — Nonpharmacologic measures may assist with reducing facial redness, flushing, skin sensitivity, and skin dryness, and are sufficient for the management of some patients with mild symptoms. When satisfactory improvement cannot be attained with these interventions, treatment with lasers, intense pulsed light, or pharmacologic agents is an option. The treatment of flushing is challenging; the management of this feature is discussed in greater detail elsewhere. (See 'Avoidance of flushing' above and "Flushing", section on 'Treatment'.)

First-line interventions — Behavioral changes can be beneficial in patients with erythematotelangiectatic rosacea. We educate all patients on the avoidance of triggers of flushing, proper use of sun protection, and gentle skin care [2,25] . (See 'General measures' above.)

Second-line interventions — Patients who fail to improve adequately with behavioral interventions and who desire additional treatment may benefit from medical intervention. Options include light-based modalities and multiple pharmacologic agents.

Laser and intense pulsed light — Laser and light-based therapies, which have been used extensively for the treatment of a variety of vascular lesions, have also been used for the vascular features of rosacea, especially telangiectasias. During treatment, light energy is absorbed by hemoglobin in cutaneous vessels, leading to vessel heating and coagulation. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Principles'.)

Vascular lesions are commonly treated with lasers that emit green or yellow light (eg, pulsed dye or potassium titanyl phosphate [KTP] lasers) due to the relatively high absorption of light in these ranges by hemoglobin (figure 1 and table 1). Intense pulsed light devices, which are also frequently used for this indication, are lower energy light sources that emit noncoherent light in a broad range of wavelengths. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Vascular lasers'.)

Improvement in both facial erythema and telangiectasias can occur after treatment with pulsed dye lasers, KTP lasers, or intense pulsed light [15,28-41] . Most data on the efficacy of these modalities are derived from uncontrolled studies. One split-face randomized trial compared treatment with a pulsed dye laser with nonpupuragenic settings to intense pulsed light and no treatment in 29 patients with erythematotelangiectatic rosacea. The two therapies were similarly beneficial for facial erythema and telangiectasias [41] . (See "Laser and light therapy for cutaneous vascular lesions", section on 'Telangiectasias and the red face'.)

Near infrared lasers can be used to treat large, deep telangiectasias, but are associated with increased risk for adverse effects (table 1). Improvement in other clinical features, such as flushing, skin sensitivity, and skin texture have also been reported in patients treated with laser or intense pulsed light therapy [15,17,42] .

Light-based modalities do not cure rosacea, and periodic treatments to maintain improvement are often required. Potential adverse effects of laser and intense pulsed light therapy include skin dyspigmentation, blistering, ulceration, and scarring.

Pharmacologic therapy — The cost of treatment with light-based modalities may be prohibitive for some patients. Data from studies in patients with papulopustular rosacea suggest that medications primarily used for papulopustular disease (eg, topical antimicrobials, azelaic acid, and oral antibiotics) may also have benefit for the reduction of rosacea-associated facial erythema [43-51] . However, no high quality randomized trials have evaluated efficacy in patients with exclusively erythematotelangiectatic disease. In our experience, satisfactory improvement in persistent facial erythema with these agents is uncommon. Telangiectasias are particularly unlikely to improve with medications, and are best managed with light-based treatments (see 'Laser and intense pulsed light' above).

Additional studies are necessary to determine the roles of topical retinoids [52,53] , licochalcone A (an ingredient derived from the licorice plant that is present in Eucerin® Redness Relief) [54] , oral isotretinoin [25] , and topical oxymetazoline [55]  (an alpha adrenergic receptor agonist primarily used for nasal congestion that reduced facial erythema and flushing in two patients) in the treatment of erythematotelangiectatic rosacea. The efficacy of topical brimonidine, another alpha adrenergic agonist, is under investigation [56] . The role of topical calcineurin inhibitors (tacrolimus and pimecrolimus) in erythematotelangiectatic rosacea is uncertain. Improvement with topical tacrolimus has been reported in small numbers of patients [57,58] .

Data on the reduction of facial erythema in patients with papulopustular rosacea are reviewed below (see 'Papulopustular rosacea' below).

PAPULOPUSTULAR ROSACEA — Papulopustular rosacea is characterized by inflammatory papules and/or pustules primarily distributed on the central face. Patients often also exhibit features of erythematotelangiectatic rosacea, such as persistent facial erythema, frequent flushing, and telangiectasias.

Approach to treatment — Most patients with mild to moderate disease (picture 4A-B) can be managed with topical therapies such as metronidazole, azelaic acid, or sulfacetamide-sulfur. Systemic agents are typically used in patients who fail to respond satisfactorily to topical agents or who present with numerous inflammatory lesions (picture 2B). Tetracycline-class antibiotics are first-line systemic agents for papulopustular rosacea; for patients who fail to respond to tetracyclines or who cannot tolerate these drugs, treatment with other oral antibiotics is an option. Laser therapy, intense pulsed light, and photodynamic therapy have also been used in papulopustular rosacea, but the efficacy of these therapies remains uncertain.

Mild to moderate disease — Topical metronidazole and azelaic acid are considered first-line therapies in mild to moderate disease (picture 4A-B) due to evidence from randomized trials in support of their efficacy and the relative safety of these medications. Other agents, such as sulfacetamide-sulfur, also may be beneficial.

Topical metronidazole — The mechanism through which metronidazole improves rosacea is unknown, but may involve antimicrobial, antiinflammatory, or antioxidant properties [59] . Topical metronidazole is most effective for the treatment of inflammatory papules and pustules, but may also contribute to improvement in facial erythema.

A systematic review of randomized trials performed primarily in patients with papulopustular rosacea supported the use of topical metronidazole [60] . Metronidazole was superior to placebo (relative risk [RR] 1.95; 95% CI 1.48-2.56).

Topical metronidazole is available as a 0.75% cream or gel, a 1% cream or gel, and a 0.75% lotion. Unlike 1% formulations, which are labeled for once-daily application, drug labels for 0.75% formulations recommend twice daily use. However, the product concentration, frequency of application, and vehicle (cream, gel, or lotion) may not significantly affect treatment efficacy:

  • In a 12-week single-blind randomized trial that compared once daily application of 0.75% cream to once daily application of 1% cream in 72 patients with papulopustular rosacea, no significant difference in the percent reduction in median inflammatory lesion counts (62 versus 60 percent) or erythema scores (26 versus 30 percent) was detected [61] .
  • Data from a meta-analysis of randomized placebo-controlled trials were insufficient to draw definitive conclusions on the relative efficacy of once versus twice daily dosing [62] .
  • Randomized trials comparing metronidazole 0.75% cream versus 0.75% gel and 0.75% gel versus 0.75% lotion have found similar treatment efficacy [60,62] .

The data above suggests that once daily application of 0.75% metronidazole may be sufficient, but additional studies are necessary. The drug vehicle should be selected based upon patient preference and tolerability. (See "Treatment of acne vulgaris", section on 'Choice of vehicles for topical treatments'.)

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Improvement in inflammatory lesions may occur after as few as two to four weeks of therapy, but full results are typically observed after eight to nine weeks of treatment [63-66] . Relapses often occur when metronidazole is discontinued; thus, long-term therapy is usually needed [67] .

Topical metronidazole is generally well-tolerated; the most common adverse effects are local irritation, dryness, and stinging sensations [65] .

Topical azelaic acid — Azelaic acid is a naturally occurring dicarboxylic acid with antiinflammatory and antioxidative properties. Similar to metronidazole, azelaic acid improves papular and pustular lesions, and may also reduce erythema.

Azelaic acid is available as a 20% cream or lotion, or as a 15% gel [68] . Only the cream and gel formulations are available in the United States.

The utility of azelaic acid for rosacea is supported by a systematic review of randomized trials performed primarily in patients with papulopustular rosacea. Azelaic acid was a more effective treatment than placebo (RR 1.52, 95% CI 1.32 to 1.76) [60] . Examples of trials demonstrating efficacy of this agent include:

  • Two 12-week vehicle-controlled randomized trials with a total of 664 patients with papulopustular rosacea found significantly greater mean reductions in inflammatory lesions in patients treated with twice daily applications of azelaic acid 15% gel than in the vehicle group (58 versus 40 percent and 51 versus 39 percent, respectively) [44] . Patients in the active treatment group were also more likely to exhibit improvement in erythema (44 versus 29 percent and 46 versus 28 percent, respectively). Facial telangiectasias did not respond to therapy.
  • A three-month vehicle-controlled randomized trial in 116 patients with papulopustular rosacea found that twice daily application of azelaic acid 20% cream led to superior mean percent reductions in inflammatory lesion counts (73 versus 50 percent) and erythema severity scores (48 versus 38 percent) [69] .

Initial improvement from azelaic acid may be noted within the first few weeks of use. Better results are typically observed after 12 to 15 weeks of therapy [66] .

Although package inserts for azelaic acid recommend twice daily application, a randomized trial in 72 patients treated with the 15% gel failed to identify a difference in efficacy between once daily and twice daily dosing, suggesting that once daily application may be sufficient for improvement [70] . Rates of adverse effects and treatment tolerability were similar in the two groups.

The most frequent side effect of azelaic acid is skin discomfort after application [69,71,72] . In two randomized trials in which a total of 333 patients were treated with azelaic acid 15% gel, 38 percent of patients reported burning, itching, or stinging sensations [44] . Symptoms were transient and mild to moderate in the majority of patients, and less than 1 percent of all patients had severe, persistent sensory symptoms.

Azelaic acid versus metronidazole — Azelaic acid appears to be at least equally as effective as metronidazole for the treatment of papulopustular rosacea and some trials have demonstrated superior efficacy:

  • The largest randomized trial (n = 251) comparing azelaic acid to metronidazole in patients with papulopustular rosacea found that twice daily application of azelaic acid 15% gel for up to 15 weeks was superior to twice daily application metronidazole 0.75% gel [66] . Azelaic acid was associated with significantly greater mean reductions in inflammatory lesion counts (73 versus 56 percent with metronidazole) and a higher rate of improvement in erythema (56 versus 42 percent of patients).
  • A 15-week investigator-blinded randomized trial in 160 patients that compared twice daily applications of azelaic acid 15% gel to once daily applications of metronidazole 1% gel found similar improvements in inflammatory lesion counts and erythema [73] .
  • A 15-week split-face randomized trial (n =40) in which twice daily application of azelaic acid 20% cream was compared with twice daily application of metronidazole 0.75% cream found similar improvements with the two preparations in inflammatory lesions, erythema, and skin dryness, and no difference in burning sensations related to rosacea [45] . Stinging sensations associated with drug application were more frequent in patients treated with azelaic acid.
  • A randomized trial (n =24) comparing azelaic acid 20% cream, metronidazole 0.75% cream, and permethrin 5% cream found that azelaic acid was superior to the other therapies for the treatment of inflammatory lesions [74] . The three agents had similar benefit for erythema.

Based upon these observations, both metronidazole and azelaic acid are reasonable choices for first-line topical therapy for papulopustular rosacea. The lower cost of metronidazole 0.75% gel (the least expensive formulation of metronidazole) compared with azelaic acid favors the initial use of metronidazole. We also favor metronidazole in patients who present with significant facial sensitivity, due to the fairly frequent occurrence of irritation early in the course of therapy with azelaic acid [69,71,72] . (See 'Topical azelaic acid' above.)

Alternative topical agents — Less well-studied topical agents used for the management of rosacea include topical sulfacetamide-sulfur, benzoyl peroxide, erythromycin, clindamycin, topical retinoids, and permethrin. We generally utilize these agents in patients who cannot tolerate or obtain metronidazole or azelaic acid, or who fail to respond to those therapies but prefer to avoid oral agents.

Sulfacetamide-sulfur — Sulfacetamide-sulfur is available in a variety of formulations, including topical suspensions, lotions, cleansers, creams, foams, and cleansing pads. The most common concentration is sulfacetamide 10% with sulfur 5%. Other drug concentrations and formulations with added sunscreen or cosmetically-beneficial green coloring are also available (see 'Cosmetic camouflage' above). The mechanism of action of sulfacetamide-sulfur in rosacea is unknown.

In comparison to metronidazole and azelaic acid, data on the efficacy of sulfacetamide-sulfur is limited. A vehicle-controlled randomized trial in 103 patients and an open-label study in 59 patients reported benefit of this agent for inflammatory lesions and erythema [75,76] . Additional studies are necessary to confirm the results of a 12-week randomized trial of 152 patients that found that a sulfacetamide 10%-sulfur 5% cream containing sunscreen was superior to metronidazole 0.75% cream for the reduction of pustular, but not papular, lesions [77] .

Side effects of sulfacetamide-sulfur include local irritation and allergic reactions [25,75] . Use of sulfacetamide-sulfur should be avoided in patients with sulfonamide (“sulfa”) allergies [25] . Of note, some patients find the odor of sulfacetamide-sulfur agents unfavorable.

Other therapies

  • Other topical antimicrobials – In a 12-week randomized trial of 53 patients with papulopustular rosacea, a gel containing a combination of benzoyl peroxide 5% and clindamycin 1% was superior to vehicle for the reduction of papulopustules (mean percent reduction 71 versus 19 percent), erythema, and flushing/blushing [47] . Monotherapy with clindamycin or erythromycin may also be beneficial; clindamycin lotion was as effective as tetracycline in one randomized trial of 43 patients with papulopustular disease [46] , and erythromycin solution was associated with improvement in papulopustules and erythema in an open-label study of 15 patients [78] .
  • Topical retinoids – Topical retinoids have antiinflammatory and extracellular matrix repair properties, and may be beneficial for patients with rosacea. In a randomized trial that compared adapalene 0.1% gel to metronidazole 0.75% gel in 55 patients with papulopustular rosacea, adapalene was associated with significantly greater reductions in inflammatory lesions [79] . Unlike metronidazole, adapalene did not induce significant improvement in erythema. Tretinoin 0.025% cream has also been used for the treatment of rosacea [52] . The potential for drug-induced skin irritation must be considered when prescribing topical retinoids.
  • Permethrin – Although a causal relationship between Demodex mites and rosacea is uncertain, topical permethrin, an antiparasitic agent, may have benefit for the treatment of rosacea. In a randomized trial of 63 patients with papulopustular rosacea that compared treatment with permethrin, metronidazole gel, and placebo, improvement with permethrin was equivalent to metronidazole and superior to placebo [80] . The validity of these results may be questionable due to the close clinical resemblance of Demodex folliculitis to rosacea. The safety of long-term permethrin use also is unknown. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Demodex' and "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Papulopustular rosacea'.).

Topical calcineurin inhibitors do not appear to be beneficial for papulopustular rosacea. Small placebo controlled randomized trials failed to find statistically superior efficacy for pimecrolimus 1% cream [81,82] , and tacrolimus 0.1% ointment was not effective for papulopustular lesions in a small uncontrolled study [58] . In addition, the development of rosacea-like cutaneous eruptions has been reported in patients treated with topical tacrolimus for other indications [83] .

Moderate to severe disease — Patients who present with numerous inflammatory papules or pustules (picture 2B), or those with milder disease that fails to respond to one or more topical therapies may benefit from oral antibiotic therapy. Tetracyclines are the best studied agents.

Oral tetracyclines — Tetracycline, doxycycline, and minocycline have been used for many years for the management of papulopustular rosacea. These agents are most useful for improving inflammatory papules and pustules, and may also reduce erythema [48,50] .

Since no definitive microbial cause of rosacea has been identified, the efficacy of oral antibiotics in rosacea is often attributed to their antiinflammatory properties [84] . Tetracyclines may decrease levels of proinflammatory cathelicidins (components of the innate immune system) through inhibition of serine proteases, may reduce levels of proinflammatory cytokines, and may have matrix-protecting capabilities [84,85] . (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Immune dysfunction'.)

Efficacy and administration — Traditional, antimicrobial doses for tetracycline are 250 mg to 1000 mg per day and 100 to 200 mg per day for doxycycline and minocycline [86,87] . Few placebo-controlled randomized trials have evaluated the efficacy of these doses in rosacea. In two early, small trials, tetracycline (250 mg twice daily for four to eight weeks or 750 mg per day for one week followed by 250 mg to 500 mg per day for five weeks) was associated with improvement in inflammatory lesions [48,88] . In addition, randomized trials comparing doxycycline to other oral antibiotics found that a 100 mg per day dose of doxycycline effectively improves papulopustular rosacea [51,89] . (See 'Alternative oral antibiotics' below.)

Due to concern for the development of antibiotic resistance, interest has grown in the use of subantimicrobial doses of antibiotics, which retain antiinflammatory properties but lack antibacterial effects. Support for the efficacy of subantimicrobial doses of doxycycline (20 mg taken twice daily or a combination pill containing 30 mg of immediate release doxycycline and 10 mg of delayed release doxycycline taken once daily) come from both randomized trials [90,91]  and an open label study of almost 1200 patients [50] . In two 16-week placebo-controlled randomized trials performed in 537 patients with 10 to 40 inflammatory lesions, doxycycline was associated with significantly greater reductions in inflammatory lesion counts [90] . In addition, one of the two trials and the open-label study found improvement in erythema [50] .

No randomized trials have compared subantimicrobial dose doxycycline to a 100 mg twice daily dose or to traditional doses of tetracycline and minocycline. One randomized trial with 91 patients compared subantimicrobial dose doxycycline (40 mg once daily) with doxycycline 100 mg per day [92] . Both doses were similarly effective for the treatment of inflammatory lesions, but the lower dose was associated with a reduced rate of gastrointestinal side effects (5 versus 26 percent).

We typically initiate treatment with doxycycline 50 to 100 mg twice daily, minocycline 50 to 100 mg twice daily, or tetracycline 250 to 500 mg twice daily and continue treatment for 4 to 12 weeks in an attempt to quickly decrease inflammation. Initiating treatment with subantimicrobial dose doxycycline is another reasonable option.

After satisfactory improvement is attained with the initial course of therapy, we transition patients to a topical agent, most often metronidazole or azelaic acid (see 'Topical metronidazole' above and 'Topical azelaic acid' above). Continuing oral therapy at the lowest effective dose is another option in patients who fail to maintain improvement or who are unable to tolerate topical therapy [2] . Subantimicrobial dose doxycycline is our preferred choice for long-term oral therapy.

Patients who respond well to topical maintenance therapy may have occasional “break-through” flares of papulopustular lesions spaced by several months or more. For such patients, we have found the administration of an abbreviated course of an oral antibiotic (eg, tetracycline 500 mg twice daily for 10 days) useful for quieting the acute flares, circumventing the need for long-term oral therapy. These patients are continued on topical maintenance therapy during and after oral treatment.

Adverse effects of oral tetracyclines include gastrointestinal distress and photosensitivity. Minocycline is the least photosensitizing of these agents, but it may cause vertigo, a lupus-like syndrome, and skin discoloration. Tetracyclines should not be given to children under the age of nine due to a risk for permanent tooth discoloration and reduced bone growth.

Combined with topical agents — Adding an oral antibiotic to topical therapy may improve treatment results. Two randomized trials that compared treatment with topical metronidazole alone to topical metronidazole plus subantimicrobial dose doxycycline found superior improvement in inflammatory lesions with combination therapy [91,93] . Additional trials are necessary to determine whether combination therapy has advantages over monotherapy with an oral antibiotic.

Alternative oral antibiotics — Other oral antibiotics are less frequently used for the treatment of rosacea, but may also be effective. These include macrolides (clarithromycin, azithromycin, and erythromycin) and oral metronidazole [25,49,51,89] .

An eight-week randomized trial comparing clarithromycin (250 mg twice daily for four weeks followed by 250 mg daily for four weeks) to doxycycline (100 mg twice daily for four weeks followed by 100 mg once daily for four weeks) found significantly greater improvement in objective measures of inflammatory lesions, erythema, and telangiectasias in patients treated with clarithromycin at early study time points, but differences among the two groups dissipated by week eight [51] . A separate 12-week trial that compared azithromycin (500 mg three times per week followed by a taper) to doxycycline 100 mg daily found that the drugs were similarly effective [89] .

Oral metronidazole is commonly used for the treatment of rosacea in Europe. In a randomized trial of 40 patients that compared treatment with metronidazole (200 mg twice daily) to oxytetracycline (250 mg twice daily), the agents appeared to be similarly effective [94] . Alcohol should be avoided during treatment with metronidazole due to the possibility of the induction of a disulfiram-like reaction.

Refractory disease

Oral isotretinoin — Patients who fail to respond to topical therapies and oral antibiotics may improve with oral isotretinoin [52,95-97] . Oral isotretinoin is not used as first-line therapy due to the drug’s many adverse effects, including teratogenicity. In the United States, oral isotretinoin can only be prescribed through the iPLEDGE program, an internet-based risk management program. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Isotretinoin safety' and "Oral isotretinoin therapy for acne vulgaris", section on 'Teratogenicity and the iPLEDGE program'.)

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Although improvement in inflammatory lesions and facial erythema has been reported in several studies [52,95-97] , high quality data on the efficacy of isotretinoin for rosacea are lacking, and the ideal regimen for treatment has not been established. Doses of 0.5 to 1 mg/kg per day have been utilized in some patients, but lower doses may be effective and better-tolerated. The authors of a 12-week dose-comparison trial reported a 90 percent reduction of inflammatory lesions in patients treated with 0.3 mg/kg per day [97] . Additionally, compared with patients who were treated with 0.5 mg/kg/day, these patients had a lower incidence of drug-related facial dermatitis.

We typically treat patients with around 0.2 mg/kg per day (usually a total of 10 to 20 mg per day) until the inflammatory component is consistently well-controlled for one to two months. In our experience, this usually occurs after five to six months of therapy.

The longevity of treatment effect varies; in a series of 20 patients with severe rosacea treated with doses of 0.5 to 1 mg/kg per day for three to six months, remissions lasting at least one year were reported in 17 patients [98] . Of note, five out of six patients initially treated with 1 mg/kg per day required dose reductions due to adverse effects.

Laser and intense pulsed light — Treatment with light-based therapies has yielded variable results in patients with papulopustular rosacea. Although the results of two uncontrolled studies utilizing intense pulsed light or pulsed dye laser suggest that some improvement in inflammatory papules is possible [99,100] , other studies have found conflicting results [33,101,102] , and there is insufficient evidence to conclude that improvement is long-lasting.

Photodynamic therapy, which involves the application of a photosensitizing agent (aminolevulinic acid or methyl aminolevulinic acid) to skin and exposure of the treatment site to a light source, has also yielded mixed results. Improvement in inflammatory lesions lasting three months or longer was reported in a small retrospective study and two out of four patients in a case series [103,104] ; however, in another case series, disease severity returned to baseline in three out of four patients within 12 weeks after treatment [101] .

Maintenance therapy — Because rosacea is a chronic disorder and treatments for papulopustular rosacea are not curative, continued therapy is typically necessary to maintain treatment response. Most commonly, long term topical therapy is administered. Subantimicrobial doses of doxycycline are also an option. (See 'Oral tetracyclines' above.)

OCULAR ROSACEA — Ocular rosacea may occur in the presence or absence of cutaneous manifestations. Examples of features of ocular rosacea include foreign body sensations, blepharitis, lid margin telangiectasia, tear abnormalities, meibomian gland inflammation, frequent chalazion, conjunctivitis, and rarely, corneal ulcers and vascularization [105] . Patients who present with signs or symptoms of ocular rosacea should be referred to an ophthalmologist for further evaluation.

Lid scrubs and warm compresses may help improve meibomian gland function [106] , and topical antibiotics such as topical erythromycin and metronidazole may quell mild lid inflammation [105,107,108] . For those with more moderate to severe ocular rosacea, short courses of oral tetracycline-class antibiotics, macrolide antibiotics, or metronidazole are often needed [107,109,110] . Topical cyclosporine may also minimize inflammation [111] .

PHYMATOUS ROSACEA — Tissue hypertrophy, dilated follicles, and irregular nodular overgrowths are characteristic features of the phymatous subtype of rosacea. These changes most commonly affect the nose (rhinophyma), but may also affect other areas such as the chin, cheeks, and ears (picture 3) [6,112] . Features of other subtypes of rosacea may also be present. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Phymatous rosacea'.)

Early disease — The best approach to the treatment of early phymatous rosacea is unknown. Improvements in phymatous changes have been reported in patients treated with 0.3 to 1 mg/kg per day of isotretinoin administered for periods of 12 to 28 weeks [97,113] . The duration of benefit is uncertain.

Advanced disease — Laser ablation and surgical techniques can be used to debulk and recontour tissue distorted by phymatous changes. Ablative carbon dioxide lasers [114]  and infrared diode lasers [115,116]  have been used for this purpose. Surgical debulking can be performed through dermabrasion, scalpel excision, electrosurgery, or cryosurgery [117,118] .

The potential side effects of laser and surgical interventions include hypopigmentation, scarring, and pain. The risk for pigmentary changes rises with increasing skin pigmentation.


Granulomatous rosacea — Granulomatous rosacea may be a variant of rosacea. It presents with uniform red-brown or yellow-brown papules on the face. Other manifestations of rosacea may or may not be present [1,119,120] . (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Granulomatous rosacea'.)

Efficacy data on treatment for granulomatous rosacea are limited to case reports. Treatments are similar to those used for papulopustular rosacea. However, lesions may be slower to respond or less-likely to respond to therapy [121,122] , and oral antibiotic therapy is often required [122,123] . Successful treatment with oral isotretinoin, oral dapsone, topical pimecrolimus, and intense pulsed light has also been documented [124-128] .

Pediatric rosacea — Infrequently, rosacea develops in children. All subtypes, except for phymatous rosacea may occur. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Pediatric rosacea'.)

As with adults, nonpharmacologic measures aimed at reducing symptoms are recommended. Mild to moderate papulopustular disease is usually managed with topical agents, such as metronidazole, azelaic acid, sulfacetamide-sulfur, and erythromycin (see 'Mild to moderate disease' above). Oral antibiotics may be necessary for patients with more severe papulopustular eruptions. Because tetracyclines are contraindicated in children under the age of nine, oral erythromycin (30 to 50 mg/kg/day), azithromycin, or clarithromycin may be substituted as a first line oral agent [121,129] . Oral metronidazole (20 to 30 mg/kg per day) has also been used in the treatment of children [130] . As in adults, after oral antibiotics produce a remission, treatment with a topical agent may be used to maintain clearance.

Ocular rosacea is managed similarly as in adults, with the exclusion of tetracycline antibiotic therapy in children under the age of nine. Granulomatous rosacea in the pediatric population may respond to topical or oral antibiotics [121,130] . Several months of treatment may be required for improvement.

Pyoderma faciale — Pyoderma faciale (also known as rosacea fulminans) is an unusual eruption that is not officially recognized as a rosacea variant. The disorder is characterized by an abrupt onset of papules and suppurative nodules on the face [131] . Young women are most commonly affected [132] . (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Pyoderma faciale (rosacea fulminans)'.)

Data on the treatment of pyoderma faciale is limited to reports of clinical experience. Patients can be managed with a combination of prednisone and oral isotretinoin. Prednisone is often started at 0.5 to 1 mg/kg per day and tapered over a period of weeks, and isotretinoin is initiated around two weeks after the start of prednisone therapy with low doses of 0.2 to 0.5 mg/kg per day [129,132,133] . During the steroid taper, the isotretinoin dose is slowly increased to 0.5 to 1 mg/kg per day as tolerated. Some authors advocate treating until a cumulative dose of 150 mg/kg has been attained [133] ; others believe that isotretinoin can be discontinued once inflammatory lesions have resolved [132] . We typically treat until a cumulative dose of 120 to 150 mg/kg has been attained, provided treatment is tolerated.

Alternatives to the above regimen include initiation of minocycline or tetracycline (1 g per day) along with a prednisone taper as above [132,134] . Successful treatment with dapsone has also been reported [135] .


  • Rosacea is a common disorder that presents with a variety of clinical findings. The four main subtypes of rosacea are erythematotelangiectatic rosacea, papulopustular rosacea, ocular rosacea, and phymatous rosacea. The subtype of rosacea determines the approach to treatment. (See 'Patient assessment' above.)
  • General measures to improve symptoms of flushing, erythema, and skin irritation can be beneficial for patients with rosacea. Patients should be educated on the avoidance of triggers of flushing, gentle skin care, and sun protection. Cosmetic camouflage is a useful adjunct for some patients. (See 'Erythematotelangiectatic rosacea' above.)
  • Patients with erythematotelangiectatic rosacea suffer from persistent facial erythema, telangiectasias, flushing, and sensitive skin. Behavioral modification may reduce symptoms. If persistent facial erythema does not improve sufficiently with behavioral changes, we suggest treatment with laser or intense pulse light (Grade 2C). Periodic retreatment is often necessary to maintain improvement. (See 'Erythematotelangiectatic rosacea' above.)
  • The cost of treatment of persistent facial erythema in erythematotelangiectatic rosacea with light-based modalities may be prohibitive for some patients; in patients who defer light-based treatment, a trial of pharmacologic therapy is reasonable. For these patients, treatment with topical metronidazole, topical azelaic acid, or subantimicrobial doxycycline may be attempted. In our experience, satisfactory improvement with these therapies is uncommon. Facial telangiectasias are best managed with laser or intense pulsed light therapy. (See 'Pharmacologic therapy' above.)
  • Inflammatory papules and pustules characterize the papulopustular subtype of rosacea. For patients with mild to moderate disease, we suggest treatment with topical metronidazole or azelaic acid (Grade 2A). (See 'Mild to moderate disease' above.)
  • For patients with papulopustular rosacea who present with numerous inflammatory lesions or who have milder disease that fails to improve with topical agents, we suggest treatment with oral tetracycline, doxycycline, or minocycline for 4 to 12 weeks (Grade 2B). Improvement may be maintained with topical agents or subantimicrobial doxycycline. (See 'Moderate to severe disease' above and 'Maintenance therapy' above.)
  • Patients with refractory papulopustular rosacea may benefit from treatment with oral isotretinoin. (See 'Refractory disease' above.)
  • Ocular rosacea can result in damage to the ocular tissues. Patients with signs or symptoms of ocular involvement should be referred to an ophthalmologist for further evaluation. (See 'Ocular rosacea' above.)
  • Childhood rosacea is managed similarly to rosacea in adults. However, the use of oral tetracyclines should be avoided in children under the age of nine. (See 'Pediatric rosacea' above.)


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