Why Is Rosacea Considered to Be an Inflammatory Disorder?
The Primary Role, Clinical Relevance, and Therapeutic Correlations of Abnormal Innate Immune Response in Rosacea-Prone Skin

June 2012 | Volume 11 | Issue 6 | Original Article | 694 | Copyright © June 2012

with rosacea (ETR > PPR) reflecting impairment of the SC permeability barrier, a factor that appears to correlate with sensitive skin in many rosacea patients.1,3,40-42 As such, an important connection between the SC permeability barrier and innate immunity is the increased expression and secretion of AMPs (ie, cathelicidin) in response to impairment of the SC permeability barrier, the role of cathelicidin-derived LL-37 in SC permeability barrier homeostasis, and the direct correlation of activity of some serine proteases (including kallikreins) with impairment of SC permeability barrier function even when visible signs of skin irritation are not present.43,44 In the presence of SC permeability barrier impairment and increased TEWL, AMPs are packaged within lamellar bodies that deposit precursor lipids into the SC at the juncture of the granular layer as a homeostatic response to replenish and repair the SC intercellular lipid bilayer.45 Also, elevation of serine proteases can influence SC permeability barrier dysfunction and neurogenic inflammation through signaling of protease-activated receptors.44 Hence, the SC permeability barrier and the innate immune response system are intertwined both structurally and functionally.43-45

Medical Therapies Used in the Management of Rosacea

A variety of medical therapies have been used for the treatment of cutaneous rosacea, predominantly for PPR.4,12-14,46,47 Topical agents approved by the United States Food and Drug Administration (FDA) for use in patients with PPR are metronidazole (0.75% gel, cream, and lotion twice daily; 1% gel and cream once daily) and azelaic acid (15% gel twice daily). Both of these topical agents are backed by large-scale studies designed and submitted for FDA approval (in PPR) as well as several other studies demonstrating efficacy and safety for treatment of PPR.4,12-14,46-51 Topical sulfacetamide 10% sulfur 5%, available in several "leave on" and wash formulations, has an FDA approved monograph that includes rosacea as an indication, however, none of the formulations were submitted through the formal FDA drug approval process that would include phase II and phase III controlled studies.46,57,50 Other topical agents have been reported for the "off label" treatment of rosacea, primarily PPR, including antimicrobials (ie, benzoyl peroxide, erythromycin, clindamycin), calcineurin inhibitors (pimecrolimus, tacrolimus), and retinoids (adapalene, tretinoin), however, overall data is relatively limited with these topical agents.4,46,47,51
Among the oral agents used to treat rosacea, only anti-inflammatory dose doxycycline (doxycycline 40 mg modified-release capsule once daily) is FDA-approved.4,46,47,50 As with topical metronidazole (0.75%, 1%) and topical azelaic acid (15%), anti-inflammatory dose doxycycline is FDA approved for use in patients with PPR, and has been shown to be effective and safe in this study population with absence of antibiotic activity and antibiotic selection pressure (subantimicrobial dosing of doxycycline).4,30,46,50-54 Although not FDA approved for rosacea, antibiotic doses of tetracycline agents (tetracycline, doxycycline, minocycline) are effective in PPR, as are other oral agents used "off-label" to treat PPR, such as metronidaziole, azithromycin, and isotretinoin.46,50,51,55,56

Modulation of Inflammation by Medical Therapy in Rosacea

As discussed above related to treatment of rosacea, FDA approved medical therapies and the majority of data on other medical therapies used "off label" evaluated therapeutic outcomes in patients with PPR. Although a review of the potentially relevant modes of action of all the topical and oral agents used for the treatment of rosacea is beyond the scope of this article, an evaluation of the FDA approved agents suggests certain modes of action that may relate to the efficacy of these agents in rosacea.30,39,46,47,51 Importantly, the FDA approved agents and the majority of off-label medical therapies primarily exhibit therapeutic benefit for reduction of inflammatory lesions (ie, papules, pustules) and associated perilesional erythema. These agents exhibit lesser or negligible ability to decrease diffuse central facial erythema that is not directly related to the presence of inflammatory lesions and tends to persist to some degree after they resolve.4,12-14,30,46-54 The clinical manifestation of persistent diffuse central facial erythema is believed to correlate with fixed vascular changes of rosacea that are poorly responsive to most currently used medical therapies for rosacea.4,12-14,25,46-54,57,58 In order to address this recognized "unmet need" in medical therapy for rosacea, topical alpha-adrenergic receptor agonists (brimonidine, oxymetazoline) are being researched for the treatment of diffuse facial erythema of rosacea, with preliminary results from phase II studies (brominidine tartrate) and a few case reports (oxymetazoline) showing favorable outcomes thus far.50,59,60 Further studies are in progress with these alpha-adrenergic receptor agonists. At present, there is no medical therapy that is FDA approved for use solely for the facial erythema of rosacea.46,50,57-60
The following reviews the FDA approved agents used to treat rosacea with focus on modes of action that may be operative in modulating inflammatory processes that appear to be involved in the pathogenesis of rosacea (Table 1).
Topical metronidazole is FDA approved for treatment of PPR in several formulations. Metronidazole has been shown in vitro to inhibit neutrophil functions and the effects of ROS, findings that may correlate with efficacy in treating PPR and associated perilesional erythema.60-63 As ROS stimulate the upregulation of some MMPs that have also been shown to be increased in rosacea-affected facial skin (ie, MMP-1, MMP-3, MMP-9), and KLK-5 activation and dermal matrix degradation have been correlated with the presence of some MMPs, inhibition of ROS and neutrophil function by metronidazole may possibly explain at least some of its mode of action in patients with PPR.8,39.57,58,64 Further research is warranted, including human facial skin studies, to more fully understand the modes of action of topical metronidazole in rosacea.