current AARS recommendations emphasize selecting therapy
based on correlation with the clinical manifestations present in
the individual patient and, as best as possible, the pathophysiologic
mechanisms that are likely to be contributory.
Azaleic acid 15% gel was approved by the FDA on December 24
2002 for the treatment of papulopustular lesions of rosacea.22
The statement “the mechanism(s) by which azelaic acid interferes
with the pathogenic events in rosacea are unknown†was
written in the approved product labeling over a decade ago.40
Azaleic acid has been shown to exhibit multiple pharmacologic
properties.24,48 These include:
Comedolytic activity and reduction in follicular keratinization
support the development and FDA approval of AzA 20% cream
for the treatment of inflammatory acne vulgaris. However,
other than a possible contribution by antioxidant activity (if it
occurs in vivo in rosacea-affected skin), none of the aforementioned
pharmacologic effects of AzA are known to correlate
with pathophysiologic mechanisms thought to be operative in
rosacea. It is important to recognize that approved product labeling
does not necessarily reflect current evidence related to
how a given therapeutic agent may modulate the pathophysiology
of disease, and that product labeling is not automatically
updated by the FDA based on new evidence.
The augmented immune response and detection that is characteristic
of rosacea-prone skin refers primarily to studies
demonstrating upregulation of the cathelicidin (LL-37) production
pathway in the facial skin of patients with PPR.4,9-12
The increased expression of toll-like receptor-2 (TLR2) is also
consistent with the hyper-responsive nature of central facial skin
of rosacea when exposed to exogenous trigger factors.9 Interestingly,
over the past 5 years, a series of in vitro studies performed
with murine or human skin showed that AzA directly inhibited
the following: (1) kallikrein 5 (KLK5) in cultured keratinocytes, (2)
gene expression of KLK5, (3) TLR2 expression, and (4) cathelicidin
(LL-37) formation.12,49 An in vivo 16-week study performed in
patients with PPR demonstrated that cathelicidin and KLK5 activity
decrease with AZA 15% gel exposure; subjects with rosacea
showed reduction in cathelicidin and KLK5 messenger RNA after
treatment with AzA 15% gel twice daily.49 These data performed
in keratinocyte cell cultures, in murine skin, and in the facial
skin of adult subjects with PPR support that inhibition of the upregulated
cathelicidin pathway and possibly inhibition of TLR2
expression in rosacea-affected skin at least partially explain the
therapeutic effects of AzA 15% gel in patients with PPR.
The efficacy of AzA 15% gel is greatest in those subjects with
PPR who exhibit higher baseline levels of KLK5, further supporting
this mode of action.49
This information on possible modes of action of AzA in PPR
may also account to some extent for the observation of augmented
benefit when AzA 15% gel is used in combination with
doxycycline because this latter agent inhibits the upregulated
cathelicidin pathway at a different step in the cathelicidin cascade
of inflammation (inhibition of matrix metalloproteinases).12,50
