Optimal Management of Papulopustular Rosacea:Rationale for Combination Therapy

July 2012 | Volume 11 | Issue 7 | Original Article | 838 | Copyright © July 2012

Neal D. Bhatia MDa and James Q. Del Rosso DO FAOCDb

aPrivate Practice, Long Beach, CA bValley Hospital Medical Center, Las Vegas, NV


The pathophysiology of papulopustular rosacea (PPR) is primarily characterized by inflammation associated with several factors such as abnormal innate immune response, neurovascular dysregulation, stratum corneum barrier dysfunction, and depletion of antioxidant reserve, with no definitive evidence supporting an underlying microbial etiology. Several molecular inflammatory pathways have now been identified that enable the development of therapeutic agents that target the signs and symptoms of disease by modifying specific pathophysiological mechanisms. Available evidence demonstrates that topical and oral agents commonly used to treat PPR appear to modify some of these pathophysiological mechanisms and may prove to be complimentary when used in combination potentially leading to better therapeutic outcomes.

During the past two decades, six clinical studies have been published on the benefits of combining oral and topical therapies for PPR. Four studies suggest that doxycycline, including anti-inflammatory dose doxycycline (doxycycline 40 mg modified-release capsule once daily) can be combined with topical metronidazole or azelaic acid in patients with PPR to achieve more rapid control of a flare. At present, subantimicrobial dosing of a tetracycline agent that also maintains anti-inflammatory activity has only been established with doxycycline. Although antibiotic doses of tetracycline agents (such as doxycycline, minocycline, and tetracycline) are known to be effective for PPR, the use of subantimicrobial dosing of doxycycline avoids the risk of antibiotic resistance.

J Drugs Dermatol. 2012;11(7):838-844.


Rosacea can be classified into four different subtypes, of which papulopustular rosacea (PPR) has been the most extensively studied with regard to pathophysiology and treatment.1-3 Papulopustular rosacea is characterized by both fluctuating and persistent central facial erythema, along with the intermittent emergence of inflammatory papules and pustules, or both.2,4 Similar to the diffuse macular erythema of erythemato-telangiectatic rosacea, the papules and pustules of PPR tend to concentrate primarily on the central face, including the inner cheeks, nose, central forehead, and chin. Some patients with PPR also experience symptoms that reflect facial skin sensitivity, such as burning and/or stinging, especially during flares.1
Histopathologic study demonstrates that rosacea has a significant inflammatory component; however, the etiologic agent is still debated.5 Current basic science and clinical data support the contention that bacteria are not definitively involved in the pathogenesis of rosacea, which is primarily driven by inflammatory mechanisms.6-9 Because it is anti-inflammatory effects and not antibiotic activity that is required to modify the process caused by the inflammation of rosacea, subantimicrobial dosing of oral doxycycline has emerged as a commonly used approach by many clinicians. Anti-inflammatory dose doxycycline, specifically defined as once daily administration of doxycycline 40 mg formulated as a modified-release capsule (30 mg immediate-release and 10 mg delayed-release beads), has been shown to be subantimicrobial, has demonstrated efficacy and safety for treatment of PPR in multiple studies, and is approved by the Food and Drug Administration for PPR.10-15 As a result, some clinicians avoid prescribing oral antibiotics (such as tetracyclines) in dosages that produce antibiotic selection pressure, which would include doxycycline given in doses of 50 mg or more daily.10
Anti-inflammatory therapy devoid of antibiotic activity is recommended for initial treatment of PPR in accordance with guidelines for management of rosacea published by the American Acne and Rosacea Society.16 The combination of topical therapy with either metronidazole or azelaic acid and oral anti-inflammatory dose doxycycline with topical therapy (eg, metronidazole, azelaic acid) is often used for faster control of a moderate or severe flare of PPR, as reported by several investigators.13-15
In this review, we discuss the latest data on the pathogenesis of PPR, how current therapies address the underlying pathophysiology of PPR, and why combination therapy may represent the optimal approach for the treatment of flares of PPR that are moderate to severe in magnitude.15