There are very few drugs approved for the systemic use of rosacea and in fact, many drugs are used off-label. Both first and second generation tetracyclines are often the first choice to treat systemic rosacea specifically for papules and pustules, and ocular rosacea (inflamed phyma).^1,2 A sub-antimicrobial dose doxycycline (40-mg controlled-release capsule) is available from some years and approved for papulopustular rosacea.¹

A randomized, multi-center, double-blind, active-control, 16-week trial evaluated the efficacy of anti-inflammatory dose doxycycline (40 mg) and topical metronidazole gel 1% once daily versus conventional dose doxycycline (100 mg) and metronidazole gel 1% once daily in adults with moderate-to-severe rosacea.² This study demonstrated that although both doxycycline dosage are effective once-daily treatments, a higher incidence of adverse events, especially in the gastrointestinal (GI) tract, was associated with the use of the 100 mg dose.

Oral macrolides including erythromycin, clarithromycin, and azithromycin are narrow-spectrum antibiotics and have all been used for systemic treatment of rosacea. These are especially useful in patients who are intolerant, allergic or refractory to tetracyclines or in cases where tetracyclines are contraindicated, such as in pregnancy. Macrolides offer an alternative systemic treatment option for patients with papulopustular rosacea.³

Clarithromycin and azithromycin exhibit a faster onset of action, a prolonged efficacy, and a reduced risk of GI side effects compared to erythromycin.^3,4

Suggested doses for macrolides include:

• Erythromycin 250 mg-1000 mg daily
• Clarithromycin 250 mg every other day for four weeks followed by once daily administration of 250 mg for four weeks
• Azithromycin 250 mg-500 mg 2-3 times a week.

Isotretinoin has been used for the treatment of papulopustular and phymatous rosacea. It was first used in the 1980s,^5,6 but the dose and duration remain difficult to quantify.

Rademaker M⁷ treated 52 resistant to treatment patients with mild-to-moderate papulopustular rosacea with isotretinoin over a 5-year period. Patients were started on a 20 mg dose of isotretinoin per day. After 3 months, the dose was reduced to 10-20 mg once to five times a week (equivalent to 5 mg/day) in 67%, increased in 15% (who all had additional acne) to 30-40 mg/day, and maintained the dose in 18%. In terms of dose/kg/day, 29% received ≤0.1 mg/kg/day, 46% received 0.11-0.25 mg/kg/day, and 10% received >0.5 mg/kg/day. Very low-dose isotretinoin (eg, 10-20 mg once to five times a week, equivalent to 5 mg/day) resulted an effective treatment for mild-to-moderate papulopustular rosacea and was well tolerated. Six patients (12%) did not attend follow-up, while in 91% (42/46) the rosacea had cleared or was excellent. However, 31% of patients relapsed.

In a study by Gollnick et al.,⁸ 573 patients with rosacea subtype II and III received one of three different dosages of isotretinoin (0.1, 0.3 or 0.5 mg/kg/day), doxycycline (100 mg daily for 14 days, then 50 mg daily) or placebo in a double-blinded, randomized study for 12 weeks. The 0.3 mg/kg/day dose was the most effective, was non-inferior, and had a better rating by patients when compared to doxycycline. Isotretinoin did have higher adverse events at 33% compared to 25% for doxycycline.

In a French study by Sbidian et al.,⁹ patents with difficult-to-treat or frequently relapsing papulopustular rosacea were treated with 0.25 mg/kg/day for 16 weeks. There was at least a 90% reduction in papules and pustules compared to placebo. Patients experienced an improved quality-of-life with isotretinoin. Treatment discontinuation due to adverse events was comparable to placebo. Unfortunately, approximately 50% of patients did relapse within 15 weeks. Relapse is an ongoing concern when using isotretinoin.

Other systemic drugs that have been used with various efficacy are included in the Table 1.

The Cochrane review noted an increase in randomized control trials for rosacea with a prevalence in papulopustular rosacea >erythema of rosacea >ocular rosacea and no studies for phymatous.¹⁷ Over 13,000 patients have been included in studies.

The levels of evidence, based on the Cochrane review, are shown in the Table 2.

The current recommendations are based on the American Acne and Rosacea Society as well as the Global ROSacea COnsensus (ROSCO) panel.¹⁸ These organizations provided a phenotypic approach to treatment to allow for easy visibility and access (Table 3).

The systemic treatment of choice for ocular rosacea is doxycycline (50-100 mg doxycycline BID + topical therapy + eyelid hygiene).¹⁹ Schaller et al.¹⁸ reviewed retrospective cases and found that 40 mg of doxycycline is the best oral therapy for moderate-to-severe blepharitis and/or symptoms of ocular rosacea that persist despite topical treatment.

Oral macrolides such as erythromycin (30-50 mg/kg/day - children) or azithromycin (500 mg on 3 consecutive days/week for 4 weeks) demonstrated significant improvement in ocular symptoms, eyelid findings, and conjunctival hyperemia.²⁰ There was no effect on punctate epithelial keratopathy.

There are no randomized controlled trials for phymatous rosacea specifically. However, tetracycline and doxycycline have shown improvement in the inflamed forms as has isotretinoin.