Management of rosacea

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 papules or pustules. 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 can manifest with a wide variety of cutaneous features. Examples include persistent centrofacial redness, phymatous skin changes (eg, rhinophyma), papules, pustules, flushing, telangiectases, burning or stinging sensations, edema, and skin dryness (picture 1A-E). Ocular involvement may also occur, manifesting with lid margin telangiectases, conjunctival injection, ocular irritation, or other signs and symptoms. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.)

The classification of rosacea has evolved from a division into distinct subtypes (erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea) to a phenotype-based approach that views the various features of rosacea as manifestations of a continuous multivariate disease process. The approach to treatment is guided by the clinical features present in an individual patient. Given the common presence of multiple features, combination therapy may be necessary to achieve satisfactory control of disease [1,2]. (See 'Facial redness, flushing, skin sensitivity, and skin dryness' below and 'Papules and pustules' below and 'Ocular manifestations' below and 'Phymatous skin changes' below and "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Classification'.)

GENERAL MEASURES — Nonpharmacologic interventions may be useful for the management of the cutaneous manifestations of rosacea. 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. 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 [3-5].

Potential triggers for flushing include [4,6-8]:

●Extremes of temperature

●Sunlight

●Spicy foods

●Alcohol

●Exercise

●Acute psychologic 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 [9-16]. 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 "Approach to flushing in adults", 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 [17-20].

Skin care — Patients with rosacea, particularly those with centrofacial erythema and telangiectases, can experience heightened sensitivity of facial skin characterized by difficulty tolerating topical cosmetics, skin care products, and topical medications [21]. In addition, rough, dry, or scaly facial skin is a common feature.

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 [22]. 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 [23,24]. In a 15-day, split-face study of 20 patients with rosacea (manifesting as erythema, flushing, sensitive and dry skin, stinging, burning, and/or skin discomfort) 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 [24]. Relatively greater reductions in scores of skin dryness, roughness, and discomfort were also detected.

●Gentle skin cleansing – Despite their sensitive skin, patients should cleanse their faces at least once daily. Patients should be instructed to cleanse their skin gently with lukewarm water, to wash with their fingers, and to avoid harsh mechanical scrubbing [21,25]. 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 [26]. 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) [25,26]. Manual exfoliation with rough sponges or cloths also should be avoided. Skin care products in the form of foams, powders, or creams are generally better tolerated than alcohol-based gels and thin lotions [25]. In addition, cosmetics should be easy to remove to avoid the need for harsh cleansing [25].

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.

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 [27,28].

Cosmetic camouflage — For 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 [29]. Light application of a green-tinted cosmetic facial powder can also be useful for camouflaging facial redness.

FACIAL REDNESS, FLUSHING, SKIN SENSITIVITY, AND SKIN DRYNESS

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 "Approach to flushing in adults", section on 'Treatment'.)

First-line interventions — Behavioral changes can be beneficial. We educate all patients on the avoidance of triggers of flushing, proper use of sun protection, and gentle skin care [3,27]. (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 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 of laser therapy'.)

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 'Types of vascular lasers'.)

Improvement in both facial erythema and telangiectasias can occur after treatment with pulsed dye lasers, KTP lasers, or intense pulsed light [17,30-43]. Most data on the efficacy of these modalities are derived from small, randomized controlled trials and uncontrolled studies. One split-face, randomized trial compared treatment with a pulsed dye laser with nonpurpuragenic settings to intense pulsed light and no treatment in 29 patients with rosacea. The two therapies were similarly beneficial for facial erythema and telangiectasias [43]. (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 [17,19,44].

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 pharmacologic agent with the strongest evidence for efficacy for persistent facial erythema in rosacea is topical brimonidine [45]. 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 [46-54]. However, no high-quality randomized trials have evaluated the efficacy of these therapies in patients without papules and pustules. In our experience, satisfactory improvement in persistent facial erythema with medications used for papulopustular disease 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.)

Topical brimonidine — Brimonidine tartrate, a vasoconstrictive alpha-2 adrenergic receptor agonist used in the treatment of open angle glaucoma, has emerged as a treatment for rosacea-associated facial erythema [45]. The efficacy of this agent when applied topically is supported by the results of phase II and phase III randomized trials [55,56]. In 2013, the US Food and Drug Administration (FDA) approved brimonidine 0.33% gel for the treatment of persistent (nontransient) facial erythema of rosacea based upon the findings of two 29-day placebo-controlled randomized trials conducted in a total of 553 adults with moderate to severe persistent facial erythema of rosacea [57]. At the end of the study, at least two-grade reductions in both clinician and patient assessment scales were achieved three hours after application by 31 and 25 percent of patients treated with brimonidine 0.33% gel versus only 11 and 9 percent of patients treated with vehicle. The efficacy of topical brimonidine has not been directly compared with laser or intense pulsed light therapy.

Topical brimonidine 0.33% gel appears to be well tolerated [57,58]. An open-label study in which women applied a 0.5% formulation of brimonidine tartrate gel supports the potential for continued safety and efficacy of topical brimonidine over one year of treatment [59]. The most common adverse effects are erythema, flushing, skin burning sensation, and contact dermatitis. The occurrence of severe, transient rebound erythema several hours after application has been reported [60,61]. An occurrence of persistent erythema in skin adjacent to the site of long-term brimonidine application also has been reported [62]. The true incidence of worsening erythema is not known but has been estimated to be up to 20 percent [63]. Patients should be counseled about these side effects prior to therapy.

The effect of brimonidine on papulopustular lesions of rosacea has not been specifically studied. Topical brimonidine has not appeared to aggravate papulopustular lesions of rosacea in randomized trials evaluating its efficacy for facial erythema [55,56]. Our experience suggests that brimonidine is not effective for the treatment of papulopustular lesions. Use in conjunction with other therapies may be beneficial for patients with both erythema and papulopustular lesions [64]. (See 'Papules and pustules' below.)

Topical oxymetazoline — Oxymetazoline, an alpha-adrenergic receptor agonist used for the treatment of nasal congestion, may have modest efficacy for facial erythema in rosacea [45].

The 2017 FDA approval of oxymetazoline 1% cream for reducing persistent facial erythema associated with rosacea in adults was based upon two randomized trials in which a total of 885 adults with rosacea applied either oxymetazoline or vehicle once daily for 29 days [65,66]. More patients in the oxymetazoline groups achieved the primary efficacy endpoint (at least a two-grade reduction in erythema from baseline on both a five-point clinician erythema assessment scale and a five-point patient self-assessment scale at 3, 6, 9, and 12 hours after application) than in the vehicle groups. On day 29 in the first trial, 12 and 6 percent of patients receiving oxymetazoline and vehicle, respectively, achieved this endpoint three hours after application. In the second trial, this was achieved at the same time point by 14 and 7 percent of patients in the oxymetazoline and vehicle groups, respectively. Potential side effects of oxymetazoline include application site dermatitis, worsening of inflammatory rosacea lesions, pain, pruritus, and erythema.

A 52-week, open-label study (REVEAL study) of 440 patients treated with oxymetazoline for moderate to severe facial erythema of rosacea supports long-term efficacy and tolerability [67]. In this study, less than 1 percent of patients experienced post-treatment rebound erythema; however, data from postmarketing surveillance is pending. The REVEAL study also demonstrated increased chance of meaningful treatment response with prolonged use, thus suggesting that best clinical results may come from daily, long-term, continued use of oxymetazoline [68].

Additional safety considerations — Because of concern for risk for potentiation of vascular insufficiency and hypotension during treatment with alpha-2 adrenergic agonists, cautious use is recommended in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension, thromboangiitis obliterans, scleroderma, Sjögren's disease, and severe cardiovascular disease. Caution is also recommended for patients who are receiving treatment with antihypertensives, cardiac glycosides, central nervous system depressants, and monoamine oxidase inhibitors. Ingestion of brimonidine may result in serious adverse effects and should be avoided.

Other interventions — Additional studies are required to determine the value of topical retinoids [69,70], licochalcone A (an ingredient derived from the licorice plant) [71], oral isotretinoin [27], oral apremilast [72], topical tranexamic acid [73], dual-frequency ultrasound [74], microfocused ultrasound [75], and botulinum toxin injections in the treatment of facial redness and skin sensitivity in rosacea. The role of topical calcineurin inhibitors (tacrolimus and pimecrolimus) in this presentation of rosacea is uncertain. Improvement with topical tacrolimus has been reported in small numbers of patients [76,77].

PAPULES AND PUSTULES — Rosacea can present with inflammatory papules and/or pustules primarily distributed on the central face. Patients often also exhibit persistent facial erythema, frequent flushing, and telangiectasias.

Approach to treatment — Most patients with mild to moderate disease (picture 1C, 1F) can be managed with topical therapies such as metronidazole, azelaic acid, topical ivermectin, 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 1D). Tetracycline-class antibiotics are first-line systemic agents for papules and pustules of 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, but the efficacy of these therapies remains uncertain.

Mild to moderate disease — Topical metronidazole, azelaic acid, and topical ivermectin are considered first-line therapies in mild to moderate disease (picture 1F-G) due to evidence from randomized trials in support of their efficacy and the relative safety of these medications. A systematic review found high-quality evidence to support the efficacy of these drugs [78]. 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, anti-inflammatory, or antioxidant properties [79]. 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 features of rosacea found moderate certainty evidence in support of the use of topical metronidazole [45]. Metronidazole was superior to placebo (relative risk [RR] 1.98; 95% CI 1.29-3.02).

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 with once-daily application of 1% cream in 72 patients with papulopustular presentations, 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 [80].

●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 [81].

●Randomized trials comparing metronidazole 0.75% cream versus 0.75% gel and 0.75% gel versus 0.75% lotion have found similar treatment efficacy [78,81].

The data above suggest 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.

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 [82-85]. Relapses often occur when metronidazole is discontinued; thus, long-term therapy is usually needed [86].

Topical metronidazole is generally well tolerated; the most common adverse effects are local irritation, dryness, and stinging sensations [84].

Topical azelaic acid — Azelaic acid is a naturally occurring dicarboxylic acid with anti-inflammatory and antioxidative properties. Similar to metronidazole, azelaic acid improves papular and pustular lesions, and may also reduce erythema. The mechanism of action for azelaic acid in rosacea is not well understood. Reductions in messenger RNA for cathelicidin and kallikrein 5, potential contributors to the development of rosacea, have been detected following treatment with topical azelaic acid in patients with rosacea [87]. Azelaic acid-induced modulation of the inflammatory response via activation of peroxisome proliferator-activated receptor-gamma is an additional potential mechanism of action [88]. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Immune dysfunction'.)

Azelaic acid is available as a 20% cream or lotion, or as a 15% foam or gel [89]. The cream, foam 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 that found high certainty evidence to support this therapy. Azelaic acid was a more effective treatment than placebo (RR 1.40, 95% CI 1.28-1.53) [45]. Examples of trials demonstrating efficacy of this agent include:

●Two 12-week vehicle-controlled randomized trials with a total of 664 patients with papules, pustules, persistent erythema, and telangiectasia 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) [47]. 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 papules, pustules, persistent erythema, and telangiectasia 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) [90].

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 [85].

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 [91]. 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 [90,92,93]. 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 [47]. 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 papules and pustules in rosacea, and some trials have demonstrated superior efficacy [45]:

●The largest randomized trial (n = 251) comparing azelaic acid with metronidazole in patients with papules, pustules, persistent erythema, and telangiectasia 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 [85]. 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 with once-daily applications of metronidazole 1% gel found similar improvements in inflammatory lesion counts and erythema [94].

●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 [48]. 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 [95]. The three agents had similar benefit for erythema.

Topical ivermectin — Ivermectin is an agent with both anti-inflammatory and antiparasitic properties. The drug is commercially available for the treatment of inflammatory lesions of rosacea as a 1% cream. Ivermectin 1% cream is applied once daily. A pea-sized amount is applied to each affected area of the face (eg, forehead, chin, nose, each cheek) and spread into a thin layer [96].

Use of topical ivermectin 1% cream for papular and pustular lesions of rosacea is supported by two high-quality, vehicle-controlled, randomized trials that demonstrated efficacy in adults with moderate to severe rosacea (defined in the study as 15 to 70 inflammatory papules or pustules) [45,97]. In the first trial, 173 of 451 patients (38 percent) treated with ivermectin were clear or almost clear of inflammatory lesions after 12 weeks. In contrast, this endpoint was achieved by only 27 of 232 patients (12 percent) in the vehicle group. The results of the second trial were similar; after 12 weeks, 184 of 459 patients (40 percent) treated with ivermectin versus 43 of 229 patients (19 percent) given vehicle were clear or almost clear of inflammatory lesions.

Treatment with ivermectin cream is well tolerated. A long-term safety study found use of topical ivermectin 1% cream safe and effective for up to 52 weeks [98].

The efficacy of topical ivermectin may be related to anti-Demodex and anti-inflammatory activity. Of note, patients in the randomized trials were not evaluated for Demodex infestation prior to therapy. A retrospective study of 50 patients with rosacea papules and pustules treated with topical ivermectin once daily found both a reduction in Demodex mites and clinical improvement after 16 weeks of treatment [99].

Ivermectin versus metronidazole — A 16-week randomized trial that compared once-daily use of ivermectin 1% cream with twice-daily use of metronidazole 0.75% cream in 962 adults with moderate to severe rosacea presenting with papules, pustules, and erythema found that topical ivermectin was more effective for reducing inflammatory lesions [100]. Moreover, a 36-week extension phase of this study revealed longer remissions after treatment with topical ivermectin than after treatment with topical metronidazole (115 versus 85 days) [101].

Choice of treatment — Based upon these observations, topical ivermectin, metronidazole, and azelaic acid are reasonable choices for first-line topical therapy for papules and pustules in rosacea. The lower cost of metronidazole 0.75% gel (the least expensive formulation of metronidazole) compared with azelaic acid and ivermectin favors the initial use of metronidazole. We also favor metronidazole or ivermectin 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 [90,92,93,98]. (See 'Topical azelaic acid' above.)

Alternative topical agents — Topical minocycline has emerged as an additional treatment option for papulopustular manifestations of rosacea based upon data from randomized trials. 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, ivermectin, or azelaic acid or who fail to respond to those therapies but prefer to avoid oral agents.

Topical minocycline — Topical minocycline 1.5% foam is applied once daily to affected areas.

Two identical, 12-week, phase 3, randomized trials (n = 751 and n = 771) support the efficacy of topical minocycline for papulopustular manifestations of rosacea [102]. In the trials, adults with moderate to severe papulopustular rosacea were randomly assigned in a 2:1 ratio to once-daily application of either minocycline 1.5% foam or vehicle foam to the entire face. Greater reductions in inflammatory lesion counts at week 12 occurred in the minocycline groups in both trials. Similarly, more patients in the minocycline groups achieved treatment success (defined as at least a two-grade improvement on the five-point Investigator's Global Assessment scale).

Treatment with topical minocycline was generally well tolerated. No serious adverse events occurred. Minocycline-induced skin dyspigmentation, a potential adverse effect of oral minocycline, was not reported. An open-label, extension study of the aforementioned trials of minocycline foam did not demonstrate any dyspigmentation in subjects using minocycline foam up to 52 weeks [103].

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 are 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 [104,105]. 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 [106].

Side effects of sulfacetamide-sulfur include local irritation and allergic reactions [27,104]. Use of sulfacetamide-sulfur should be avoided in patients with sulfonamide ("sulfa") allergies [27]. 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 rosacea with persistent erythema, telangiectases, papules, and pustules, 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 [50]. Monotherapy with clindamycin or erythromycin may also be beneficial; clindamycin lotion was as effective as tetracycline in one randomized trial of 43 patients in whom papules and pustules were a major manifestation of their disease [49], and erythromycin solution was associated with improvement in papulopustules and erythema in an open-label study of 15 patients [107].

●Topical retinoids – Topical retinoids, which are known to have anti-inflammatory and extracellular matrix repair properties, have been studied for the treatment of papules and pustules in rosacea with variable results. In a 12-week randomized trial that compared adapalene 0.1% gel with metronidazole 0.75% gel in 55 patients with papulopustular rosacea, adapalene was associated with significantly greater reductions in inflammatory lesions [108]. Unlike metronidazole, adapalene did not induce significant improvement in erythema. Although improvement in papulopustular lesions was observed after topical tretinoin therapy in a small randomized trial (n = 22) that compared treatment with tretinoin 0.025% cream to oral isotretinoin [69], a subsequent randomized trial (n = 79) that compared once-daily application of a gel containing tretinoin 0.025% and clindamycin 1.2% to placebo failed to find a statistically significant difference in effect on papulopustular lesions between the two groups [109]. Additional studies are necessary to confirm the effects of topical retinoids on papulopustular lesions of rosacea. Skin irritation is a potential adverse effect of 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 5% cream, metronidazole 0.75% gel, and placebo, improvement with permethrin was equivalent to metronidazole and superior to placebo [110]. 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 'Microorganisms'.)

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 [111,112], and tacrolimus 0.1% ointment was not effective for papulopustular lesions in a small uncontrolled study [77]. In addition, the development of rosacea-like cutaneous eruptions has been reported in patients treated with topical tacrolimus for other indications [113].

Moderate to severe disease — Patients who present with numerous inflammatory papules or pustules (picture 1D), or those with milder disease that fails to respond to one or more topical therapies may benefit from oral antibiotic therapy. Of the oral antibiotics, tetracyclines are the best-studied agents.

Oral tetracyclines — Tetracycline, doxycycline, and minocycline have been used for many years for the management of rosacea. These agents are most useful for improving inflammatory papules and pustules, and may also reduce erythema [51,53].

Since no definitive microbial cause of rosacea has been identified, the efficacy of oral antibiotics in rosacea is often attributed to their anti-inflammatory properties [114]. 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 [114,115]. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Immune dysfunction'.)

Efficacy and administration — Traditional, antimicrobial doses for tetracycline are 250 to 1000 mg per day and 100 to 200 mg per day for doxycycline and minocycline [116,117]. 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 [51,118]. In addition, randomized trials comparing doxycycline with other oral antibiotics found that a 100 mg per day dose of doxycycline effectively improves papulopustular rosacea [54,119]. (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 anti-inflammatory 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 [120,121] and an open label study of almost 1200 patients [53]. 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 [120]. In addition, one of the two trials and the open-label study found improvement in erythema [53].

Few randomized trials have compared subantimicrobial dose doxycycline with higher doses of oral tetracyclines. One randomized trial with 91 patients compared subantimicrobial dose doxycycline (40 mg once daily) with doxycycline 100 mg per day [122]. 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). In addition, a 16-week trial that compared doxycycline (40 mg once daily) with minocycline (100 mg once daily) found similar reductions in lesion counts in both groups [123].

We typically initiate treatment with doxycycline 100 mg twice daily, minocycline 100 mg twice daily, or tetracycline 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. We generally favor doxycycline over minocycline for initial treatment because of minocycline's broader side effect profile.

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 [3]. 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, doxycycline 100 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 [121,124]. In an investigator-blinded, 12-week, randomized trial (n = 273), the combination of 40 mg per day of doxycycline and daily application of ivermectin 1% cream was associated with greater efficacy and faster improvement in papulopustular manifestations of severe rosacea compared with monotherapy with ivermectin 1% cream [125].

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 [27,52,54,119].

An eight-week randomized trial comparing clarithromycin (250 mg twice daily for four weeks followed by 250 mg daily for four weeks) with 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 [54]. A separate 12-week trial that compared azithromycin (500 mg three times per week followed by a taper) with doxycycline 100 mg daily found that the drugs were similarly effective [119].

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 [126]. 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 [69,127-129]. 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 'Teratogenicity' and "Oral isotretinoin therapy for acne vulgaris", section on 'Adverse effects'.)

Although improvement in inflammatory lesions and facial erythema has been reported in several randomized trials and observational studies [69,127-129], high-quality data on the efficacy of isotretinoin for rosacea are scarce, 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 randomized trial reported a 90 percent reduction of inflammatory lesions in patients treated with 0.3 mg/kg per day [129]. Additionally, compared with patients who were treated with 0.5 mg/kg/day, these patients had a lower incidence of drug-related facial dermatitis.

In another randomized trial, 156 patients with papulopustular rosacea that had failed to respond to three or more previous treatments were treated with low-dose isotretinoin (0.25 mg/kg) or placebo daily for four months [130]. The primary endpoint was a reduction in the lesion number of at least 90 percent. At the end of the study, more patients in the isotretinoin group than those in the placebo group reached the primary endpoint (57 versus 10 percent, absolute difference 47 percent, 95% CI 34 to 60 percent; number needed to treat 2). Adverse effects, including cheilitis, dry skin, and abdominal pain, were more common in the isotretinoin group than in the placebo group (69 versus 44 percent). Patients were followed for 4 months after isotretinoin completion. Rosacea relapsed in 53 percent of patients who responded to isotretinoin after a median time of 15 weeks.

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 isotretinoin 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 [131]. Of note, five out of six patients initially treated with 1 mg/kg per day required dose reductions due to adverse effects. The remission period may be shorter in patients treated with low-doses [130].

After completion of a successful course of isotretinoin, we routinely initiate maintenance therapy with topical metronidazole, azelaic acid, or other standard therapies for pustular rosacea in an attempt to increase the likelihood of sustained remission. However, the efficacy of this approach has not been studied.

Laser and intense pulsed light — Treatment with light-based therapies has yielded variable results in patients with papules and pustules. Although the results of two uncontrolled studies utilizing intense pulsed light or pulsed dye laser suggest that some improvement in inflammatory papules is possible [132,133], other studies have found conflicting results [35,134,135], 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 [136,137]; however, in another case series, disease severity returned to baseline in three out of four patients within 12 weeks after treatment [134].

Maintenance therapy — Because rosacea is a chronic disorder and treatments 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 MANIFESTATIONS — Ocular involvement 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 [138]. Patients who present with signs or symptoms of ocular involvement should be referred to an ophthalmologist for further evaluation. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.)

Lid scrubs and warm compresses may help improve meibomian gland function [139], and topical antibiotics such as topical erythromycin and metronidazole may quell mild lid inflammation [138,140,141]. For those with moderate to severe ocular rosacea, short courses of oral tetracycline-class antibiotics, macrolide antibiotics, or metronidazole are often needed [140,142,143]. Topical cyclosporine may also minimize inflammation [144].

PHYMATOUS SKIN CHANGES — Tissue hypertrophy, dilated follicles, and irregular nodular overgrowths are characteristic features of the phymatous skin changes of rosacea. These changes most commonly affect the nose (rhinophyma), but may also affect other areas such as the chin, cheeks, and ears (picture 1E) [7,145]. Features of other subtypes of rosacea may also be present. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.)

Early disease — The best approach to the treatment of early phymatous skin changes 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 [129,146]. 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 [147] and infrared diode lasers [148,149] have been used for this purpose. Surgical debulking can be performed through dermabrasion, scalpel excision, electrosurgery, or cryosurgery [150,151].

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

SPECIAL CASES

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 [152-154]. (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 [155,156], and oral antibiotic therapy is often required [156,157]. Successful treatment with oral isotretinoin, oral dapsone, topical pimecrolimus, and intense pulsed light has also been documented [158-162].

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

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 [155,163]. Oral metronidazole (20 to 30 mg/kg per day) has also been used in the treatment of children [164]. As in adults, after oral antibiotics produce a remission, treatment with a topical agent may be used to maintain clearance.

Ocular manifestations of rosacea are managed similarly as in adults, with the exclusion of tetracycline antibiotic therapy in children under the age of nine. Systemic antibiotics may be required for several months to achieve complete remission [165]. Granulomatous rosacea in the pediatric population may respond to topical or oral antibiotics [155,164]. 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 [166]. Young women are most commonly affected [167]. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Pyoderma faciale (rosacea fulminans)'.)

Data on the treatment of pyoderma faciale are 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 [163,167,168]. 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 [168]; others believe that isotretinoin can be discontinued once inflammatory lesions have resolved [167]. 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 doxycycline, minocycline, or tetracycline along with a prednisone taper as above [167,169]. Successful treatment with dapsone has also been reported [170].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rosacea".)

SUMMARY AND RECOMMENDATIONS

●Overview – Rosacea is a common disorder that presents with a variety of clinical findings. The phenotype of rosacea determines the approach to treatment. (See 'Patient assessment' above.)

●General measures – 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 'Facial redness, flushing, skin sensitivity, and skin dryness' above.)

●Persistent facial erythema and telangiectasias – Behavioral modifications may improve persistent facial erythema, telangiectasias, flushing, and sensitive skin. If persistent facial erythema does not improve sufficiently with behavioral changes, therapeutic interventions can be useful. For patients who desire a topical therapy for facial erythema that can be self-administered, we suggest treatment with topical brimonidine (Grade 2A). Laser or intense pulsed light are additional effective treatment options for facial erythema. Periodic retreatment with laser or intense pulsed light is often necessary to maintain improvement. Facial telangiectasias are best managed with laser or intense pulsed light therapy. (See 'Facial redness, flushing, skin sensitivity, and skin dryness' above.)

●Papules and pustules – There are few data to support benefit of treatments effective for papules and pustules of rosacea (eg, topical metronidazole, topical azelaic acid, or subantimicrobial doxycycline) for the treatment of persistent facial erythema. In our experience, satisfactory improvement of persistent facial erythema with these therapies is uncommon (see 'Pharmacologic therapy' above):

•Mild to moderate disease – For patients with mild to moderate rosacea manifesting with papules and pustules, we suggest treatment with topical metronidazole, azelaic acid, or topical ivermectin (Grade 2A) (see 'Mild to moderate disease' above). The lower cost of metronidazole 0.75% gel (the least expensive formulation of metronidazole) compared with azelaic acid and ivermectin favors the initial use of metronidazole. We also favor metronidazole or ivermectin 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. Topical minocycline and topical sodium sulfacetamide are alternative topical therapies.

•Moderate to severe disease and milder disease that fails to respond to topical therapy – For patients who present with numerous papules or pustules 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.)

•Refractory disease – Patients with refractory papules or pustules may benefit from treatment with oral isotretinoin. (See 'Refractory disease' above.)

●Ocular involvement – Ocular involvement in 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 manifestations' above.)

●Children – 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.)