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
James Q. Del Rosso DO FAOCD,a Richard L. Gallo MD PhD,b Leon Kircik MD,c Diane Thiboutot MD,d Hilary E. Baldwin MD,e and David Cohen MDf
aValley Hospital Medical Center, Las Vegas, NV; Touro University College of Osteopathic Medicine, Henderson, NV; and Las Vegas Skin and Cancer Clinics, Las Vegas, NV and Henderson, NV bUniversity of California San Diego, San Diego, CA cPhysicians Skin Care, PLLC, Louisville, KY; Mount Sinai Medical Center, New York, NY and Indiana University School of Medicine, Indianapolis, IN dPennsylvania State University College of Medicine, Hershey, PA eDepartment of Dermatology, SUNY Downstate, Brooklyn, NY fNew York University School of Medicine, Department of Dermatology, New York, NY
Keyword: Rosacea
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).
Metronidazole
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.