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
Azelaic Acid
Topical azelaic acid 15% gel is FDA approved for the treatment
of PPR. As with metronidazole, azelaic acid also inhibits neutrophil
function and generation of ROS.65 As described above, ROS
inhibition appears to be beneficial in the treatment of rosacea,
possibly due to reduction in ROS-induced MMP upregulation,
a decrease in MMP-induced activation of KLK-5, and/or reduction
in MMP-related dermal matrix degradation.39,57,58 In addition,
azelaic acid in vitro in a murine skin model has been shown to
decrease several components of innate immune response including
expression of TLR-2, cathelicidin, and KLK-5, although
the magnitude of these effects relevant to rosacea-affected human
skin warrants additional study.66
Doxycycline
Tetracyclines have been shown to exhibit a wide variety of biologic
and anti-inflammatory effects unrelated to their antibiotic
activity, which has led to their use in a variety of non-infectious
disorders, such as bullous diseases, sarcoidosis, and some
rheumatologic diseases.30,67-70 Inhibition of MMP activity by tetracyclines,
has been shown in research models, including inhibition
of MMP-1 (collagenase 1), MMP-2 (gelatinase A), MMP-8 (collagenase
2, neutrophil collagenase), MMP-9 (gelatinase B), MMP-12
(macrophage elastase), and MMP-13 (collagenase 3).8,30,68-70 To
date, a dose-response separation between anti-inflammatory
and antibiotic activities has been demonstrated only with doxycycline
based on both the pharmacokinetic profile after repeated
dosing (steady-state) and placebo-controlled microbiologic assays
obtained from gingiva, the gastrointestinal tract, skin, and
the vaginal tract, completed over 6 to 18 months.18,30,52,53,69,70 A
recent study completed with doxycycline using human skin keratinocytes
demonstrated that doxycycline does not directly inhibit
KLK-5 activity.39 Rather, activation of KLK-5 from its precursor
protein is dependent on MMPs. Therefore, MMP inhibition by
doxycycline resulted in downstream inhibition of KLK-5 activity
and subsequently reduced activation of cathelicidin . The end
result of this cascade is decreased production of cathelicidin-derived
proinflammatory and vasoactive peptides (ie, LL-37).39
Multiple in vitro, ex vivo, and in vivo studies have demonstrated
a variety of other biologic and anti-inflammatory mechanisms related
to one or more of the tetracyclines that may correlate with
therapeutic activity in rosacea (ie, PPR). These include inhibition
of neutrophil chemotaxis, downregulation of several proinflammatory
cytokines (ie, TNF-alpha, IL-1beta, IL-8, IL-10, TGF-beta1),
inhibition of granuloma formation, inhibition of ROS, and decreased
expression of nitric oxide (NO) synthases and activity
of NO, the latter serving as an endogenous chemical inducer
of vasodilation.30,67-70 Although it is difficult to determine which
of these effects are clinically relevant, and if so, to establish
their relative therapeutic contribution in the treatment of rosacea,
each of these biologic and/or anti-inflammatory properties
shown with tetracycline agents using various research models
may potentially contribute to improvement based on our current
understanding of the pathogenesis of rosacea.30,57,58,67-70 As noted
above, improvement of patients with PPR has been demonstrated
with use of oral doxycycline using either anti-inflammatory
dose therapy that is devoid of antibiotic activity or with daily doses
that produce antibiotic activity (> 50 mg daily).4,46,50-54,57,58,68-70 In
addition, anti-inflammatory dose doxycycline has been shown
to demonstrate speed of onset and extent of efficacy equivalent
to doxycycline 100 mg daily based on inflammatory lesion
reductions and investigator global assessments (IGA) in a comparative,
blinded, randomized study of patients who were also
treated with topical metronidazole for PPR. Ultimately, the collective
data evaluating the potential modes of action and clinical
use of tetracyclines, including the FDA approved approach of anti-
inflammatory dose doxycycline, further supports that it is the
anti-inflammatory and other biologic properties of doxycycline
and other tetracyclines that correlate with therapeutic benefit in
rosacea, and not antibiotic activity.4,30,46,50,58,68
CONCLUSION
The pathophysiology of rosacea has undergone renewed interest
over the past decade and has been the focus of several
advances in basic science and clinical research. There is a large
body of evidence supporting the role of an abnormal innate immune
response in rosacea as well as other mechanisms that
interact with the innate immune system. As a result, a variety
of potential triggers stimulate this immune detection system