INTRODUCTION
Since the publication of the landmark article by the National
Rosacea Society in 2002, which introduced a standard
classification system for rosacea, there has been a plethora
of basic science and clinical research publications addressing
the clinical presentations of rosacea and the underlying pathophysiologic
mechanisms that appear to correlate with specific
visible manifestations.1-6 The magnitude of the individual contribution
of each of these mechanisms can vary among different
patients, thus accounting for the range of differences in the
clinical presentations of rosacea.3,4,7-9
The 2 main pathophysiologic mechanisms fundamental to rosacea
that have been reported based on several studies are
neurovascular dysregulation and abnormal immune detection
and response, with both signaled by a variety of exogenous
triggers.3-13 A greater understanding of these underlying pathophysiologic
pathways has led to improved correlations between
the clinical features of rosacea and the integration of specific
therapies, although much more research needs to be completed
to achieve further understanding because the pathophysiology
of rosacea and the natural history of its progression are complex.
3-5,14,15 The current belief is that rosacea, especially in its
most common clinical presentations, is an inflammatory facial
skin disorder most commonly affecting adults who are affected
by rosacea-prone skin.3-6,10,11,16,17 Essentially, rosacea-prone skin
is “wired differently,†with the facial skin of those with rosacea
exhibiting physiochemical, neurovascular, and microanatomic
and ultrastructural differences compared with normal skin.3-13,15-17
Various triggers that have been noted to incite flares of rosacea
(such as ambient heat, ultraviolet light exposure, spicy foods, and
Demodex mite proliferation) induce the onset of central facial
vasodilation and cutaneous inflammation due to the heightened
responsiveness of both neurovascular and innate immunologic
pathways associated with rosacea-prone skin.3-12,16,17
Most of the development of medical therapies for rosacea occurred
while the pathophysiology was not well understood.1,5,13
As a result, researchers were limited by the absence of specific
targets against which to direct therapies, which hampered the
development of therapeutic agents for rosacea.5 Prior to 2013,
only 3 medical therapies have been submitted to the United
States (US) Food and Drug Administration (FDA) for approval
for rosacea, with all 3 receiving an approved indication for the
inflammatory lesions (papules and pustules) of rosacea, commonly
referred to as papulopustular rosacea (PPR). These 3
agents are topical metronidazole (first formulation 0.75% gel,
approved in 1988; 0.75% and 1% available subsequently in
multiple formulations); azelaic acid (AzA) 15% gel (approved in
2002); and doxycycline 40 mg modified-release capsule once
daily (doxy-MR 40 mg QD, approved in 2006).15,18 Most recently,
alpha-adrenergic agonists (brimonidine 0.33% gel, approved
in August 2013; oxymetazoline in Phase 3 studies) have been
