Drugs (2014) 74:14571465

DOI 10.1007/s40265-014-0281-x

LEADING ARTICLE

Rosacea: New and Emerging Treatments

Farah A. Moustafa Laura F. Sandoval
Steven R. Feldman

Published online: 26 August 2014

Springer International Publishing Switzerland 2014

Abstract Rosacea is a chronic inflammatory skin condition that negatively impacts patients quality of life. We
sought to review important aspects of the pathogenesis of
rosacea and the role of new treatment options in its management. New, emerging treatments show promise; however, quality randomized controlled trials for many of these
drugs are lacking. Brimonidine tartrate is an effective
newly approved treatment for erythematotelangiectatic
rosacea. Topical oxymetazoline has potential for the
treatment of erythematotelangiectatic rosacea, with efficacy described in case reports and randomized controlled
trials currently underway. Both oral and topical ivermectin
have been studied for the treatment of papulopustular
rosacea, both showing benefit; however, only topical
ivermectin 1 % cream has been studied in randomized
controlled trials. As our understanding of the etiology of
rosacea continues to evolve, so will our options for therapeutic interventions. Further studies need to be performed
to assess the long-term safety and efficacy of these
treatments.

F. A. Moustafa
L. F. Sandoval
S. R. Feldman (&)

Department of Dermatology, Center for Dermatology Research,
Wake Forest School of Medicine, Medical Center Boulevard,
Winston-Salem, NC 27157-1071, USA
e-mail: sfeldman@wfubmc.edu; sfeldman@wakehealth.edu
S. R. Feldman
Department of Pathology, Wake Forest School of Medicine,
Winston-Salem, NC, USA
S. R. Feldman
Department of Public Health Sciences, Wake Forest School
of Medicine, Winston-Salem, NC, USA

Key Points
Rosacea is a chronic inflammatory skin condition
that remains difficult to treat.
New, emerging treatments such as brimonidine
tartrate, oxymetazoline, and ivermectin have been
studied and show promise; however, evidence is
limited at this time.
Further studies are needed to assess the long-term
safety and efficacy of these treatments.

1 Introduction
Rosacea is a chronic inflammatory skin disease and is one
of the most common conditions that dermatologists treat.
The reported prevalence of rosacea is between 1 and 22 %
[1]. This wide discrepancy in data largely stems from
various methodologies used to capture prevalence and
therefore cannot be reliably compared. The National
Rosacea Society recently reported that rosacea now affects
16 million Americans [2]. There are four well-known
manifestations of disease: erythematotelangiectatic (ET),
papulopustular (PP), phymatous (PH), and ocular [3]. It is
more common in middle-age individuals, women, Caucasians, and those with Fitzpatrick skin type I and II. Because
it typically localizes on the central face, and can be disfiguring in some cases, many patients experience a
decreased quality of life [4]. The pathogenesis of this
disease is complex and poorly understood. Many theories
have been proposed and include dysregulation of innate
immunity, dysregulation of the neurovascular system, and
overgrowth of commensal organisms (e.g., Demodex).

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Treatment recommendations vary based on subtype of

rosacea or on the signs and symptom present; however,
effective treatment can prove difficult [5]. Therapies primarily focus on symptom suppression, in general targeting
inflammation. A better understanding of the pathogenesis
of rosacea is necessary to ensure better treatment outcomes.
In this paper, we review the recent developments in the
pathogenesis of rosacea and discuss the role of new treatments and their relationship to the pathophysiology of
rosacea.

2 Pathogenesis of Rosacea
The pathogenesis of rosacea is complex and thought to
involve dysregulation of the immune, vascular, and nervous systems. While not caused by microorganisms,
another evolving theory of the pathophysiology of rosacea
is the involvement of overgrowth of commensal mites on
the skin (Demodex folliculorum and Demodex brevis) in
some patients with rosacea. Evolving theories on the
pathophysiology of rosacea appreciate the complex interplay of dysregulation from these systems culminating in
the clinical picture of rosacea [6]. There is also a strong
suggestion of a genetic component, as transcriptome analysis has verified distinct gene profiles of rosacea subtypes
[7].

Fig. 1 The role of innate

immune system dysregulation in
rosacea pathogenesis.
CAP18 cathelicidin-related
antimicrobial peptide 18, KLK5
kallikrein-related peptidase 5,
TLR2 Toll-like receptor 2, UV
ultraviolet

F. A. Moustafa et al.

2.1 Dysregulation of the Innate Immune System

Dysregulation of the innate immune system may contribute
to chronic inflammation and vascular abnormalities in
patients with rosacea [8]. One pathway that may be relevant
involves Toll receptor activation. Initially, Toll-like receptor 2 (TLR2) (a component of the innate system) is triggered by inciting factors. Numerous environmental stimuli
can trigger TLR2, such as physical or chemical trauma, UV
light, and microorganisms. This results in release of a
processing enzyme, Kallikrein 5 (KLK5), from epidermal
keratinocytes. This enzyme is responsible for processing the
antimicrobial peptide cathelicidin into active its active
form, LL-37. In rosacea-prone skin, the proteolytically
processed forms of cathelicidin peptides are also different
from normal individuals and are more pro-inflammatory. It
is unclear how the abnormal form of cathelicidin is developed, but it is hypothesized to be the result of post-translational processing abnormalities associated with an
increase in KLK5, also known as stratum corneum tryptic
enzyme (SCTE), in the epidermis [8]. There is also higher
expression of TLR2 in keratinocytes of rosacea skin [9].
Increased levels of cathelicidin and KLK5 present in skin
from rosacea patients support the hypothesis of their role in
pathogenesis [8]. Downstream effects of these proteins
result in increased inflammatory cytokine release and
angiogenesis, contributing to the clinical picture of rosacea

Rosacea: New and Emerging Treatments

(Fig. 1). Mouse studies involving the injection of cathelicidin peptides from patients with rosacea led to inflammation
and vascular dilation, further supporting the role of cathelicidin in rosacea pathogenesis [8].
2.2 Dysregulation of the Vascular and Neurovascular
System
Facial erythema is a central component of rosacea and is
required for diagnosis. Worsening of disease is associated
with persistence and intensity of facial erythema. Skin
blood flow is increased in some patients, raising questions
regarding the role of vascular dysregulation in the pathogenesis of rosacea and a potential factor to facial erythema
in rosacea patients [1014]. Facial erythema in rosacea can
be divided into two major groups with different etiologies:
(1) central facial erythema; and (2) perilesional erythema
(surrounding papules and pustules in PP rosacea) [3, 15,
16]. Distinguishing between these types of erythema is
important for treatment selection.
Persistant facial erythema is a result of abnormal vasculature that results from chronic inflammation present in
rosacea-prone skin. This is a multifactorial process, but one
component involves LL-37 (the active form of cathelicidin)
promotion of inflammation and angiogenesis through its
downstream effects on endothelial growth factor receptors
(EGFRs) in keratinocytes [9]. Chronic inflammation also
leads to the associated telangiectasias found in rosacea
[15]. Increases in vascular endothelial growth factor
(VEGF) and endothelial nitric oxide (eNO) leading to
increased vascularization and vasodilation, respectively,
are also implicated in the chronic facial erythema present
in rosacea [8, 9].
Neurovascular dysregulation or increased vasoactivity
is also thought to play an important role [17]. The superficial cutaneous system is largely regulated by the sympathetic nervous system through action on adrenoreceptors.
While their role in rosacea pathophysiology is currently
poorly understood, they do seem to play an important role
as evidenced by the ability of new medications targeting
these adrenoreceptors to reduce erythema [14, 18].
2.3 Overgrowth of Commensal Organisms
D. brevis and D. folliculorum are two commensal mite
species that colonize the pilosebaceous follicle of human
skin. The role of the Demodex overgrowth in the pathogenesis of rosacea has been controversial. Because the
presence of these mites on human skin is ubiquitous,
developing a causal relationship is difficult. The presence
of Demodex does not indicate rosacea; however, Demodex
infestation (defined as C5 mites/cm2) is higher in some
patients with ETR and PPR rosacea [17, 19].

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Key components of Demodex overgrowth on the skin

and their interaction with an aberrant immune system
makes it an important consideration to better understand
the etiology of rosacea as well as therapeutic options.
Demodicosis (Demodex infestation) closely resembles
rosacea clinically; patients often experience erythema, telangiectasias, and itching [2022]. It is difficult to differentiate
patients as having Demodex infestation resembling rosacea or
rosacea with greater than average density of Demodex.
Perhaps it is not simply a Demodex infestation that
triggers rosacea, but the interaction of Demodex mite products interacting with the already aberrant and sensitive
innate immune system in rosacea-prone skin. As mentioned
above, TLR2 is over-expressed and more sensitive to activation in rosacea prone skin. Recently, Bacillus oleronius
bacterium has been cultured from Demodex mites and its
role in the pathogenesis of rosacea is under investigation
[23]. Antigens on the mite as well as the bacteria may could
potentially be recognized by TLR2 and result in its activation and downstream inflammatory effects in the skin.
In cases in which patients are found to have high Demodex
counts, it may be worth considering anti-parasitic agents
(ivermectin, permethrin) for the treatment of their rosacea.

3 Overview of Treatment
3.1 Current Treatment
In general, adjunct measures including high-factor sunscreens, cosmetic camouflage, cooling, and avoidance of
irritants and triggers (extremes of temperatures, sunlight,
diet, alcohol, exercise, acute psychological stressors,
medications, menopausal hot flashes) are recommended for
all patients with rosacea [5]. The use of photoprotection is
particularly important in that it may prevent a flare triggered by UV exposure, as well as help avert photodamage
skin changes such as erythema and telangiectasias that only
contribute to vascular changes of rosacea [24].
When conservative measures fail to control disease,
patients may benefit from medical interventions, including
pharmacologic and light-based therapies (Table 1). A
treatment algorithm based on signs and symptoms, with
consideration to severity, has been proposed by the Rosacea International Expert Group [5]. For episodic erythema
or flushing, only experimental treatments are suggested
such as oxymetazoline, nadolol, and clonidine. In patients
with persistent erythema, topical treatment with azelaic
acid or sulfacetamide should be considered. However,
since the publication of guidelines, brimonidine tartrate
(BT) has recently been approved in the USA specifically
for treatment of persistent facial erythema. Oxymetazoline,
which works by a similar mechanism as brimonidine,

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F. A. Moustafa et al.

stimulating a-adrenergic receptors resulting in vasoconstriction, could potentially also fall under the category for
treatment of persistent erythema. When topical therapies
fail to control disease or the rosacea is more severe, shortterm oral antibacterials including tetracyclines and macrolides can be added. Topical agents, including brimonidine, do not target telangiectasias; however, electrosurgery
can be used to treat these small vessels and laser can be
used to treat both telangiectasias and PH changes. Support
for the use of lasers is limited, but a Cochrane review by
van Zuuren et al. [25] did find some evidence for the use of
pulsed dye laser (PDL) and intense pulse light (IPL) therapy for reducing erythema and telangiectasias. The
American Acne and Rosacea Society current consensus
recommendations for the use of physical modalities for the
treatment of rosacea include the use of IPL, PDL, and
neodymium-doped yttrium aluminium garnet (Nd:YAG)
lasers to target telangiectasias [26]. The recommendations
encourage appropriate patient selection and setting of
patient expectations; while improvement of 5075 % in
telangiectasias over one to two sessions can be achieved,
improvement is of a much lesser extent in persistent erythema, and complete resolution should not be anticipated.
The treatment of acne rosacea with papules and pustules
involves the use of topical agents for mild disease and
combination topical and oral therapy for more severe disease. Topical treatments including the topical antibacterials
metronidazole, clindamycin, and sulfacetamide-sulfur as
well as topical azelaic acid and retinoids are recommended.
A Cochrane systematic review of rosacea therapies provided support for the use of topical metronidazole and
azelaic acid, which were both more effective than placebo
[25]. There was some evidence that azelaic acid was more
effective than metronidazole in the treatment of PP rosacea, but metronidazole may be better tolerated. When oral
therapy is warranted, low-dose doxycycline (40 mg/day) is
recommended for less severe disease, and for severe disease, high-dose antibacterials or low-dose oral isotretinoin

(10 mg/day) should be considered [5]. The anti-inflammatory properties of the tetracyclines, rather than their
antibacterial properties, are a primary rationale for their use
in rosacea [27, 28]. It is noteworthy that in a comparison
study doxycycline 40 and 100 mg/day were equally
effective, with the lower-dose regimen having few adverse
effects, specifically gastrointestinal symptoms [29]. In
addition, of all the systemic drugs used for rosacea, only
the modified-release doxycycline 40 mg/day formulation is
US Food and Drug Administration (FDA) approved. This
specific formulation was designed to exert anti-inflammatory properties, with no antibacterial effects [30]. In rosacea with nodules and plaques, systemic treatment with
high-dose tetracyclines and macrolides or isotretinoin
(0.51 mg/kg/day) is recommended, combined with topical
therapy. The use of isotretinoin is considered off-label for
the treatment for rosacea; however, studies support its use
in recalcitrant PP rosacea [31]. Unlike in the treatment of
acne, the use of isotretinoin is not likely to result in
remission of rosacea.
3.2 New and Emerging Treatments
3.2.1 Brimonidine Tartrate
Brimonidine 0.33 % gel (which contains 0.5 % BT salt)
was approved by the FDA in August 2013 for treatment of
persistent facial erythema. BT is an a2-adrenergic receptor
agonist, with vasoconstriction its primary mechanism of
action. To a lesser degree, it may also exert anti-inflammatory effects [32]. It has historically been used in the
treatment of open-angle glaucoma.
Phase II Clinical Trial (Table 2) The phase II clinical
trial consisted of two studies [33]. In Study A, BT gel was
effective in a dose-dependent fashion in reduction of erythema for up to 12 h after a single application. The percentage of subjects who achieved a one-grade
improvement in Clinicians Erythema Assessment (CEA)

Table 1 Current and emerging treatment options for rosacea

Rosacea presentation

Current and emerging drug treatment options

Episodic erythema or
flushing

Topicals (oxymetazoline)

Persistent erythema

Topical a-adrenoreceptor agonists (brimonidine tartrate and oxymetazoline)

Topical azelaic acid or sulfacetamide

Papulopustular

Mild: topical antimicrobials (metronidazole, clindamycin, and sulfacetamide-sulfur, and ivermectin),

azelaic acid, or retinoids

Oral (nadolol and clonidine)

Moderate: topicals plus oral antimicrobials [tetracyclines (low-dose doxycycline 40 mg/day), macrolides,
or ivermectin]
Severe: topicals plus high-dose tetracyclines or low-dose isotretinoin
Recommendations based on the Rosacea International Expert Group, the Consensus Recommendations from the American Acne and Rosacea
Society on the management of rosacea, and the current literature [5, 14, 18, 20, 21, 33, 34, 4143, 46, 47]

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269

254

283

Phase
II(a)

Phase
II(b)

Phase
III(a)

Phase
III(b)

Same as phase IIIa

Patients were randomized in a 1:1 fashion to apply BT gel

0.5 %:vehicle for 4 weeks. Six visits (screening visit, days 1,
15, 29 of treatment phase, and weeks 6 and 8 of the follow-up
phase). During the treatment phase (days 1, 15, 29), subjects
remained in the clinic for 12 h and were assessed prior to
study drug application, then again at 30 min, and 1, 3, 6, 9,
and 12 h after application

Patients were randomized in a 1:1:1:1:1 to receive BT 0.5 %

once daily:BT 0.18 % once daily:vehicle once daily:BT
0.18 % twice daily:vehicle twice daily for 4 weeks

Subjects were randomized in a 1:1:1:1 to receive BT 0.5 %:BT

0.18 %:BT 0.07 %:vehicle

Methods

One-grade improvement in CEA

and PSA (secondary)

Two-grade improvement in
CEA and PSA

One-grade improvement in CEA

and PSA (secondary)

Two-grade improvement in
CEA and PSA

One-grade improvement in CEA

and PSA (secondary)

Two-grade improvement in
CEA and PSA (primary)

One-grade improvement in CEA

and PSA scores

Outcome measures

BT brimonidine tartrate, CEA Clinicians Erythema Assessment, PSA Patients Self-Assessment

No. of
subjects

Study

Percentage of subjects using BT 0.5 % gel who had a one-grade

improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and
12 after application was 71.1, 64.8, 66.9, and 53.5 %, respectively
(vs. 40.1, 43.0, 29.4, and 40.1 % for vehicle) (p \ 0.001)

Percentage of subjects using BT 0.5 % gel who had a two-grade

improvement on CEA and PSA scores on day 29 at hours 3,6, 9, and
12 after application was 25.4, 25.4, 17.6, and 21.1 %, respectively
(vs. 9.2, 9.2, 10.6, and 9.9 % for vehicle once daily) (p \ 0.05)

Percentage of subjects using BT 0.5 % gel who had a one-grade

improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and
12 after application was 70.9, 69.3, 63.8, and 56.7 %, respectively
(vs. 32.8, 32.0, 29.7, and 30.5 % for vehicle) (p \ 0.001)

Percentage of subjects using BT 0.5 % gel who had a two-grade

improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and
12 after application was 31.5, 30.7, 26.0, and 22.8 %, respectively
(vs. 10.9, 9.4, 10.2, and 8.6 % for vehicle once daily) (p \ 0.05)

Percentage of subjects using BT 0.5 % gel who had a one-grade

improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and
12 after application ranged from 60 to 76 % (vs. 3142 % for
vehicle once daily) (p \ 0.001)

Percentage of subjects using BT 0.5 % gel who had a two-grade

improvement on CEA and PSA scores on day 29 at hours 3, 6, 9, and
12 after application was 30, 28, 32, and 19 %, respectively (vs. 4, 7,
4, and 4 % for vehicle once daily) (p \ 0.001)

Largest effect was observed in the BT 0.5 % group

Percentage of subjects with one-grade improvement in CEA and PSA

was 84, 81, 75, and 28 % (BT 0.5, 0.18, 0.07 %, vehicle,
respectively)

BT topical gel was effective in a dose-dependent fashion in reduction

of erythema for up to 12 h after one application

Results

Table 2 Summary of Fowler et al. [33, 34]: phase II and III clinical trials of brimonidine tartrate in rosacea erythema treatment

Rosacea: New and Emerging Treatments

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and the Patients Self-Assessment (PSA) was 84, 81, 75,

and 28 % (BT 0.5, 0.18, 0.07 %, and vehicle, respectively).
In Study B, the outcome measure was defined as a twograde improvement in the CEA and PSA scores over 12 h
[33]. The percentage of subjects using BT 0.5 % gel who
had a two-grade improvement on CEA and PSA scores on
day 29 at hours 3, 6, 9, and 12 after application was 30, 28,
32, and 19 %, respectively, compared with 4, 7, 4, and 4 %
for vehicle once daily (p \ 0.001).
Phase III Clinical Trial (Table 2) The phase III clinical
trial comprised of two identical studies, with a total of 537
subjects randomized in a 1:1 fashion to apply BT gel 0.5 %
or vehicle daily for 4 weeks, followed by a 4-week followup phase [34]. CEA and PSA were assessed during the
treatment phase before drug application as well as 30 min,
3, 6, 9, and 12 h after study drug application. The primary
outcome measure or defined treatment success was a twograde improvement on both CEA and PSA scores over
12 h. In Study A, the percentage of subjects using BT gel
0.5 % who had a two-grade improvement on CEA and PSA
scores on day 29 at hours 3, 6, 9, and 12 after application
was 31.5, 30.7, 26.0, and 22.8 %, respectively (vs. 10.9,
9.4, 10.2, and 8.6 % for vehicle once daily; p \ 0.05). In
Study B, the percentage of subjects using BT gel 0.5 %
who had a two-grade improvement on CEA and PSA
scores on day 29 at hours 3,6, 9, and 12 after application
was 25.4, 25.4, 17.6, and 21.1 %, respectively (vs. 9.2, 9.2,
10.6, and 9.9 % for vehicle once daily; p \ 0.05).
One-grade improvement was a secondary outcome
measure in phase II and III clinical trials. Although there
were modest two-grade improvements in CEA and PSA in
these studies, one-grade improvements were significant
(Table 2) and represented clinically relevant effects.
All doses of topical BT gel were safe and well-tolerated
during the studies. The majority of related adverse events
were dermatological (skin irritation, erythema, skin burning sensation, dry skin, and pruritus). Most of these cases
were transient and mild. In B10 % of cases, the following
adverse effects occur: flushing, skin burning sensation, and
contact dermatitis. No clinically significant rebound
(worsening of erythema compared with baseline after
stopping treatment) was observed. In practice, however,
rebound has been an issue for select patients. A case report
describes rebound erythema in three patients using an
FDA-approved dosage of brimonidine gel 0.33 % for
treatment of rosacea [35]. All three patients reported
reduced erythema from baseline 16 h after application,
followed by severe erythema and burning sensation lasting
for approximately 12 h. Signs of hypersensitivity such as
urticaria and edema were not present. In our clinical
practice, we have seen a handful of patients who cannot
tolerate the medication due to rebound erythema. It is also
important to remind patients to avoid trigger factors while

F. A. Moustafa et al.

using brimonidine, as the use of brimonidine does not

override flares as a result of exposure to a trigger.
An open-label study assessing the long-term safety and
efficacy of once-daily topical BT 0.5 % gel for 1 year
reported that efficacy of BT gel was maintained over the
time period with no observed tachyphylaxis (mean CEA
score prior to application of BT gel reduced gradually from
3.1 on day 1 to 2.4 at month 3 and remained stable until
month 12) [36]. PSA results were similarly maintained.
Drug-related adverse events were highest during the first
90 days of the study, and decreased after continued use.
The most frequently observed adverse events were flushing
(9.1 %), worsening of erythema (6.5 %), worsening of
rosacea (3.6 %), skin burning sensation (3.3 %), skin irritation (3.1 %), contact dermatitis (2.2 %), and pruritus
(2.0 %).
The efficacy of brimonidine on PP lesions of rosacea has
not been studied. It appears not to aggravate inflammatory
lesions of rosacea in randomized trials evaluating its efficacy for facial erythema, including when patients used
concomitant topical medications for PP rosacea [36].
However, due to the vasoconstrictive effects of the drug
and reduction of erythema, PP lesions may be more
noticeable. Brimonidine does not have effects on fixed
changes such as telangiectasia, and these lesions too may
become more visible when erythema is reduced. Patients
should be educated on expectations of treatment with
brimonidine prior to use.
3.2.2 Oxymetazoline
Oxymetazoline, a derivative of xylometazoline, is a
selective adrenoreceptor agonist (a1 and partial a2) and is
present in over-the-counter decongestants. It is also indicated for the treatment of epistaxis, allergic rhinitis, and
conjunctivitis [37]. Although there is a much more complex action than previously understood, topical application
reduces erythema through vasoconstrictive effects on the
a1-adrenoreceptors on smooth muscle surrounding blood
vessels that maintain vascular tone. Because of its action
on the a-receptors present on smooth muscle of larger
blood vessels, it has no effect on smaller blood vessels,
capillaries, and telangiectasias that are not surrounded by
smooth muscle (and are therefore not regulated by the
sympathetic nervous system). Activation of a-receptors has
also demonstrated anti-inflammatory effects [32, 38].
Oxymetazoline and xylometazoline have been shown to
inhibit neutrophilic phagocytosis and to decrease the generation of proinflammatory cytokines, which could contribute to the inflammation in rosacea [38]. Oxymetazoline
and xylometazoline work through a similar mechanism as
BT (a2-agonist), and therefore have potential indications
for the treatment of persistent facial erythema. Compared

Rosacea: New and Emerging Treatments

to brimonidine, oxymetazoline was a less potent vasoconstrictor of the small subcutaneous vessels (less than
200 lm in diameter) that are thought to be the most
important in rosacea [32]. Concerns regarding long-term
use of these medications include tachyphylaxis and
rebound phenomenon.
Several case reports have described the off-label topical
use of oxymetazoline and xylometazoline in rosacea. In
two patients with recalcitrant ETR, once-daily application
of OTC nasal decongestant containing oxymetazoline hydrocholoride 0.05 % resulted in significant improvement of
facial erythema after application [18]. At long-term followup (8 and 17 months), both patients reported continued
satisfaction with their treatment and had discontinued all
other medications for rosacea control except for the oxymetazoline nasal spray, with no reported tachyphylaxis or
rebound erythema. One patient with ETR treated topically
with xylometazoline 0.05 % solution experienced
improvement in erythema as well as in subjective symptoms (flushing, itching). Improvement in symptoms lasted
hours after application and long-term follow-up (8 months)
showed that daily topical application of the solution controlled facial erythema with no reported adverse effects
[14].
Erythema is universal in patients with rosacea, yet it
remains the most difficult feature to treat. Given the
reported efficacy and safety of oxymetazoline and xylometazoline in the treatment of persistent erythema, formal
randomized control trials are underway to assess its longterm safety and efficacy [39].
3.2.3 Ivermectin
Both oral and topical ivermectin have been used to treat
rosacea and rosacea-like dermatitides. Ivermectin is a
macrocyclic lactone disaccharide antiparasitic agent typically used to treat parasitic infestations such as onchocerciasis, strongyloidiasis, and filariasis, among others. In
dermatology, it is also used for the treatment of scabies, an
ectoparasitic infection. Ivermectin also targets the overgrowth of Demodex mites. As support for the role of
D. folliculorum and D. brevis in the pathophysiology
of rosacea grows, more interest is taken in investigation of
anti-parasitic agents that can control overpopulation of
these commensal mites on the skin. Ivermectin also has
anti-inflammatory properties that may contribute to mitigating rosacea symptoms. Ivermectin exerts its antiinflammatory effect by down-regulating the nuclear transcription factor jB activation pathway that leads to
downstream production of pro-inflammatory cytokines
such as tumor necrosis factor (TNF)-a [40].
Two case reports of immunocompetent patients
describe the use of single doses of oral ivermectin (200

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and 250 lg/kg) and topical permethrin resulting in complete resolution of rosacea-like demodicidosis [20, 21].
Both patients had many Demodex mites on biopsy.
Another patient with recalcitrant PP rosacea with many
Demodex organisms on histologic examination was treated
with oral ivermectin (3 mg daily for a total dose of
24 mg) with complete resolution [41]. Oral ivermectin
was also safe and effective in three cases of demodicidosis
in patients with HIV infection [42]. Although there are no
formal randomized control trials to date that assess oral
ivermectin for treatment of rosacea, these cases suggest
that it can be a valuable treatment consideration in
patients who have recalcitrant rosacea and are found to
have excess Demodex infestation.
The efficacy and safety of topical ivermectin 1 % cream
has recently been investigated in PP rosacea with promising results. Two phase III multicenter, randomized, double-blinded, parallel-group, vehicle-controlled trials of
identical design assessed use of ivermectin 1 % cream or
vehicle daily in patients to moderate to severe PP rosacea
[43]. At 12 weeks, significantly more patients in the ivermectin 1 % group achieved clear or almost clear on the
Investigators Global Assessment of Rosacea Severity in
both Study 1 (38.4 %) and Study 2 (40.1 %) compared
with vehicle (11.6 and 18.8 %, respectively). Inflammatory
lesion counts were also reduced with a mean difference of
-8.13 lesions (Study 1) and -8.22 (Study 2) between
ivermectin 1 % and vehicle (p \ 0.001 for both studies).
No serious related adverse effects were reported and the
ivermectin group reported less related adverse effects than
the vehicle group in both studies (4.2 and 2.6 % vs. 7.8 and
6.5 %, respectively). In a related extension study, patients
used vehicle used azaleic acid 15 % twice daily for
40 weeks instead of vehicle, with less treatment-related
adverse effects in the ivermectin group than in azaleic acid
group: 1.3 vs. 5.3 %, respectively [44]. A 16-week study
comparing the efficacy and safety of ivermectin 1 % cream
and metronidazole 0.75 % cream has also been completed
with results yet to be published.
3.2.4 Other Antiparasitics
Other scabicidal treatments such as permethrin and crotamatin cream have been used for treatment of Demodex
dermatitis [20, 41, 45]. A retrospective chart review of 63
patients with resistant rosacea-like dermatitis treated twice
daily with topical crotamatin showed that 90.6 % of
patients experienced C50 % reduction in erythema, dryness, scaling, roughness, and/or papules/pustules at the first
follow-up visit (range 1355 days) compared with baseline
[45]. Improvements in symptoms were sustained over the
second follow-up visit (1359 days after the first followup).

1464

4 Conclusion
As our understanding of the etiology of rosacea continues to
evolve, so will our options for therapeutic interventions. The
emergence of BT and oxymetazoline/xylometazoline for ET
rosacea, as well as ivermectin for PP rosacea show promise
for the future of rosacea treatment and more targeted therapy. These drugs need further investigations assessing longterm safety and efficacy in the treatment of rosacea. Rosacea
is a common skin condition that affects many people, and
can negatively impact quality of life. Interventions aimed at
controlling this chronic inflammatory condition and delaying disease progression can positively affect the quality of
life of the many people affected by rosacea.
Acknowledgments The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Dr. Feldman is a consultant and speaker for Galderma,
Connetics, Abbott Labs, Warner Chilcott, Centocor, Amgen, Photomedex, Genentech, BiogenIdec, and Bristol Myers Squibb. Dr.
Feldman has received grants from Galderma, Connetics, Astellas,
Abbott Labs, Warner Chilcott, Centocor, Amgen, Photomedex,
Genentech, BiogenIdec, Coria, Pharmaderm, Ortho Pharmaceuticals,
Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol Myers
Squibb, Stiefel, GlaxoSmithKline, and Novartis and has received
stock options from Photomedex. Farah Moustafa and Dr. Sandoval
have no conflicts to disclose.

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