Rosacea

Part II. Topical and systemic therapies in the treatment of rosacea

Aimee M. Two, MD, Wiggin Wu, MD, Richard L. Gallo, MD, PhD, and Tissa R. Hata, MD
San Diego, California

Learning objectives
After completing this learning activity, participants should be able to develop a treatment plan for rosacea using a symptom-based approach; describe the efficacy, safety, and
mechanism of action of current rosacea therapies; and identify emerging rosacea treatments.

Disclosures
Editors
The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with
commercial interest(s).
Authors
The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Planners
The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved
with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Although rosaceas impact on physical health is limited, it has profound effects on a persons psychological
well-being. Therefore, treating rosacea can greatly affect a persons quality of life. Patient education regarding
trigger avoidance and skin care techniques such as moisturizing and sun protection are important non-
pharmacologic first steps in treating rosacea. Pharmacologic interventions range from topical to systemic
medications, with the ideal medication choice dependent on the symptoms and severity of each individual
patient. Despite this variety of therapeutic options, none of these therapies are completely curative, and
therefore further research into the pathophysiology of rosacea is required in order to create more targeted and
efficacious treatment options. ( J Am Acad Dermatol 2015;72:761-70.)

Key words: alpha-adrenergic receptor agonists; azelaic acid; isotretinoin; metronidazole; rosacea;
tetracyclines.

TREATMENT OF ROSACEA
Key point Abbreviations used:
d Rosacea treatments focus on 3 main cate- ETR: erythematotelangiectatic rosacea
gories: patient education, skin care, and FDA: US Food and Drug Administration
KLK5: kallikrein 5
pharmacologic/procedural interventions MMP: matrix metalloproteinase
PPR: papulopustular rosacea
Rosacea is a chronic inflammatory skin condition ROS: reactive oxygen species
that affects the central portion of the face. Although TLR2: Toll-like receptor 2
rosacea itself is a relatively benign condition, there UV: ultraviolet
are significant morbidities associated with rosacea in

From the Division of Dermatology, University of California Correspondence to: Tissa R. Hata, MD, Division of Dermatology,
San Diego. University of California San Diego, 8899 University Center Ln,
Funding sources: None. Ste 350, San Diego, CA 92122. E-mail: [email protected].
Dr Two has served as an unpaid consultant for Bayer Pharmaceu- 0190-9622/$36.00
ticals, Dr Gallo has served as an investigator for Bayer 2014 by the American Academy of Dermatology, Inc.
Pharmaceuticals and Galderma, and Dr Hata has served as an http://dx.doi.org/10.1016/j.jaad.2014.08.027
investigator for Bayer Pharmaceuticals. Dr Wu has no conflicts Date of release: May 2015
of interest to declare. Expiration date: May 2018
Accepted for publication August 18, 2014.

761
762 Two et al J AM ACAD DERMATOL
MAY 2015

terms of its impact on patients quality of life 0.75% gel plus a gentle nonirritating moisturizing
and psychological well-being.1 For example, one cream (Cetaphil; Galderma, Uppsala, Sweden) to
study found that 75% of affected individuals metronidazole alone found that patients applying
experience low self-esteem, and that the odds for metronidazole 0.75% gel plus the moisturizer
being diagnosed with depressive disorder in the reported improved skin dryness, roughness,
rosacea patient population is 4.81 compared to that desquamation, and skin sensitivity compared to
of the general population.2 These findings highlight patients applying metronidazole alone.7 Therefore,
the necessity of controlling the symptoms of rosacea. diligent skin care, including mild cleansing,
A variety of both topical and systemic treatment moisturizing, and sun protection has been shown
options are available for these patients, however, to significantly improve skin hydration, objective
patient education and routine skin care are also and subjective skin sensitivity, and overall skin
important aspects of treating rosacea. All of these health.8
aspects of rosacea management will be discussed Acute ultraviolet (UV) light exposure is known to
below. trigger rosacea symptoms because it stimulates LL-37
production and has been suggested to deplete
PATIENT EDUCATION antioxidant reserves in the skin9-12 and increase the
Taking a thorough history and spending quality production of reactive oxygen species (ROS).13-15
time reassuring patients of the benign nature of their Therefore, daily sun protection is an essential part of
skin condition are beneficial to the psychological skin care and maintenance in patients with
well-being of patients. If specific triggers or rosacea.16-18 Many topical sun blocks can be
exacerbating factors can be identified, avoiding irritating to rosacea patients, so choosing a
these triggers, if possible, can be beneficial in well-tolerated regimen can be difficult.3 While no
controlling an individuals symptoms. Common specific sunscreen products have been shown to be
triggers include wind, hot and cold temperatures, consistently most beneficial in patients with rosacea,
exercise, spicy foods, alcohol, hot drinks, and a product with a sun protectant factor of at least 30
physical or psychological stress.3 Medication should be recommended to rosacea patients.18
reconciliation also plays an important role in the Finding the most convenient and tolerable skin
treatment of rosacea, because common medications, care regimen for these patients is crucial to
such as niacin or the application of topical steroids improving symptoms and preventing relapse.
to the face, can exacerbate flushing.4,5 Finally,
personally addressing the most bothersome aspects PHARMACOLOGIC TREATMENTS
of each individuals disease process and discussing Topical medications
realistic goals of therapy can improve patiente Key points
physician communication and patients quality of d Topical treatments approved by the US Food

life. and Drug Administration for rosacea include

topical sodium sulfacetamide, azelaic acid,
SKIN CARE/NONPHARMACOLOGIC metronidazole, and the alpha-adrenergic
TREATMENTS agonist brimonidine
d The off-label use of topical retinoids, topical
Key points
d Moisturizers are an important aspect of calcineurin inhibitors, topical macrolides,
treating rosacea because rosacea skin has benzoyl peroxide, topical permethrin
increased transepidermal water loss cream, and ivermectin cream have also
d By blocking ultraviolet light, sunscreens shown to be somewhat beneficial in treating
decrease LL-37 production and the subse- rosacea in smaller case series
quent production of reactive oxygen species
Topical sodium sulfacetamide
that can trigger rosacea
d Topical sodium sulfacetamide is useful in
Proper skin care plays a pivotal role in maintain- treating patients with rosacea, especially
ing remission and alleviating the symptoms of those who have concomitant seborrheic
rosacea. Rosacea skin has been shown to have dermatitis.
increased transepidermal water loss indicative of
defective barrier functions, and therefore moistur- Topical sodium sulfacetamide/sulfur formulations
izers are important to help restore this barrier and are now available in several vehicles that have been
facilitate remission of rosacea exacerbations.6 A approved by the US Food and Drug Administration
study comparing the effects of using metronidazole (FDA), including lotions, creams, and cleansers. The
J AM ACAD DERMATOL Two et al 763
VOLUME 72, NUMBER 5

most common formulation consists of 10% sodium FDA. These formulations have been shown to
sulfacetamide with 5% sulfur lotion, applied twice improve rosacea symptoms.31,32 According to a 2011
daily. Efficacy of the lotion has been reported Cochrane review, pooled participant-assessed data
in papulopustular rosacea (PPR) in multiple from 6 studies showed that 70% to 80% of patients
studies.19,20 One controlled, double-blind study of using azelaic acid reported complete remission or
103 patients noted a 65% decrease in inflammatory marked improvement in their rosacea symptoms,
lesions and a 66% decrease in facial erythema compared to only a 50% to 55% response rate
compared to 44% and 33% reductions, respectively, reported by the placebo group.22 Although previous
in the control group.21 Sulfacetamide cleansers have studies have suggested that the mechanism of action
also shown repeated efficacy when used in of azelaic acid in treating rosacea is via its anti-
combination with other products, such as topical inflammatory properties and ability to decrease
metronidazole.20 Although the exact mechanism of ROS,33 a recent study on 55 adults with papulopust-
sodium sulfacetamide is unknown, it is thought to ular rosacea found that twice daily application of 15%
have antiinflammatory effects based on clinical azelaic acid gel decreases expression of both
studies and clinical experience.19,20 The most kallikrein 5 (KLK5) and cathelicidin, suggesting that
common adverse reactions include dryness, this medication directly targets the increased KLK5
erythema, or irritation at the application site, which and cathelicidin levels thought to contribute to
decrease in frequency over time.21 Topical rosaceas pathogenesis (Fig 1).34 Azelaic acid is
sulfacetamide is also particularly useful in treating generally well tolerated and serves as a viable
patients with rosacea with concomitant seborrheic treatment option for rosacea patients.
dermatitis, which can be fairly common.20 Topical alpha-adrenergic receptor agonists
Topical metronidazole d Topical alpha-adrenergic receptor agonists

d Topical metroniadazole is thought to be have been shown to reduce persistent facial

beneficial in rosacea because of its ability to erythema in rosacea by vasoconstricting
decrease reactive oxygen species generation dermal blood vessels.
and inactivate existing reactive oxygen d Brimonidine tartrate 0.5% is approved by the

species production. US Food and Drug Administration for the

treatment of rosacea-associated erythema.
Topical metronidazole has been used as a topical d Oxymetazoline has also been shown to
treatment for rosacea since the 1950s. The clinical significantly reduce baseline erythema in
efficacy of metronidazole has been attributed to its patients with rosacea and is currently
ability to decrease ROS generation and inactivate undergoing phase III clinical trials.
existing ROS production (Fig 1).14 Compared to
placebo, metronidazole has been shown to be Topical alpha-adrenergic receptor agonists have
more efficacious in reducing erythema, papules, recently been recognized as a treatment for the
and pustules in multiple trials of patients with mod- persistent facial erythema seen in rosacea. These
erate to severe rosacea.22-26 Metronidazole cream is agents work specifically on the smooth muscles
available in 2 concentrations: 0.75% and 1%. Both surrounding the vessels of the superficial and deep
creams have proven equally efficacious at reducing dermal plexuses. Upon binding to receptors on these
erythema, papules, and pustules when applied muscles, these medications cause vasoconstriction
once daily.27 Metronidazole has also been (Fig 1),35 diverting blood flow away from the central
shown to maintain remission after discontinuation face and reducing the persistent centrofacial
of treatment. Compared to 42% of subjects in the erythema seen in rosacea. These agents do not
tetracycline group, only 23% of subjects in the impact telangiectasias, though, because these vessels
metronidazole group had a relapse of their lack vasomotor tone; nor do they affect inflammatory
symptoms 6 months after discontinuation of their lesions, making them uniquely suited for the
assigned therapy.28-30 treatment of persistent erythema alone.
Topical azelaic acid The alpha-2 agonist brimonidine tartrate gel 0.5%
d Azelaic acid has been shown to decrease (brimonidine gel 0.33%) was recently approved by
expression of kallikrein 5 and cathelicidin. the FDA for once-daily application for treating
rosacea-associated erythema. Clinical trials have
Azelaic acid, a naturally occurring saturated shown a reduction in baseline facial erythema in as
dicarboxylic acid, is available as a 15% azelaic acid few as 30 minutes after application of the gel, with
gel and 20% azelaic acid cream for the treatment of maximal erythema reduction lasting between 6 and 7
rosacea, and both have been approved for use by the hours after a single application.36,37 After this time,
764 Two et al J AM ACAD DERMATOL
MAY 2015

Fig 1. Mechanism of action of rosacea treatments. Metronidazole and macrolides inhibit

reactive oxygen species production. Ivermectin and permethrin are antiparasitic agents used to
treat cutaneous demodecidosis. Isotretinoin inhibits Toll-like receptor 2 signaling. Azelaic
acid decreases kallikrein 5 and cathelicidin expression. Tetracyclines inhibit matrix
metalloproteinases.

the patients erythema scores returned to baseline, can be used in combination with antiinflammatory
with \5% of subjects noting an adverse response of agents, such as metronidazole, azelaic acid, and
rebound or a sudden return of erythema. In a oral antibiotics, to better target specific disease
separate study of the posttreatment effects of manifestations in individual patients.
brimonidine tartrate gel 0.5%, erythema scores
28 days after discontinuation of the drug were either Topical medications for rosacea that have not
the same or reduced compared to baseline scores, been approved by the US Food and Drug
and these scores differed significantly compared to Administration
placebo. In addition, rebound facial erythema was The off-label use of topical retinoids, topical
not noted at this time point.36 Overall, bromonidine calcineurin inhibitors (TCIs), benzoyl peroxide,
appears to be well tolerated and have a favorable topical permethrin cream, and ivermectin cream
safety profile, despite scattered reports of rebound have also proven to be somewhat beneficial in
erythema have been reported in the literature. In all treating rosacea in smaller case series (Table I). Of
cases thus far, the rebound erythema has been these, topical retinoids, TCIs, topical permethrin
reversible, but patients should be advised of cream, and topical ivermectin cream will be
this possibility before beginning to take this discussed in additional detail below.
medication.38,39 Topical retinoids
Oxymetazoline, a selective alpha-1 adrenergic d Topical retinoids promote connective tissue

receptor agonist, has also been used to treat rosacea. remodeling and downregulate Toll-like
In 2 adult subjects with erythematotelangiectatic receptor 2 expression.
rosacea (ETR), once daily application of oxymetazo-
line 0.05% led to a decrease in rosacea-associated Topical retinoids have been shown to repair
redness when applied to the affected skin.40 These photodamaged skin by promoting connective tissue
effects were observed within 1 to 3 hours of remodeling.41,42 Therefore, it has been theorized
application and lasted for several hours in that topical retinoids may be effective in decreasing
both patients. Oxymetazoline 0.05% is currently rosacea symptoms by reversing the contribution of
undergoing phase III trials to evaluate its efficacy in UV radiation to rosaceas manifestations.43 In
rosacea. addition, tretinoin, an all trans retinoic acid, has
In subjects presenting with persistent facial erythema been shown to down-regulate Toll-like receptor 2
and inflammatory lesions, alpha-adrenergic agonists (TLR2) expression in human monocytes in vitro.44
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Table I. Topical medications shown to be beneficial in the treatment of rosacea*

Medication name Level of evidence Mechanism of action
Treatments approved by the FDA
Sodium sulfacetamide IA Unknown, but likely antiinflammatory19,20
Metronidazole IA Decreased ROS generation and inactivates existing ROS production14
Azelaic acid IA Decreased expression of KLK5 and cathelicidin34
Alfa-adrenergic agonists IB Vasoconstriction of smooth muscles surrounding vessels of the
superficial and deep dermal plexuses35
Treatments not approved
by the FDA
Retinoids IIB Connective tissue remodeling39,40 and TLR2 downregulation44
Calcineurin inhibitors IIB Antiinflammatory51,52
Benzoyl peroxide IB Unknown
Permethrin IB Antiparasitic properties treat cutaneous demodicidosis53,54
Ivermectiny IB Antiparasitic properties treat cutaneous demodicidosis53

Level of evidence: IA evidence includes evidence from metaanalysis of randomized controlled trials; IB evidence includes evidence from at
least 1 randomized controlled trial; IIA evidence includes evidence from at least 1 controlled study without randomization; IIB evidence
includes evidence from at least 1 other type of experimental study; III evidence includes evidence from nonexperimental descriptive studies,
such as comparative studies, correlation studies, and case control studies; IV evidence includes evidence from expert committee reports or
opinions or clinical experience of respected authorities, or both.
FDA, US Food and Drug Administration; KLK5, kallikrein 5; ROS, reactive oxygen species; TLR2, Toll-like receptor 2.
*This table lists topical medications shown to improve rosacea that have been approved by the FDA, those that have not been approved by
the FDA, the level of evidence supporting the use of each treatment, and the mechanism of action of each treatment.
y
Ivermectin has now received FDA approval.

Therapy with tretinoin may therefore be beneficial pimecrolimus cream 1% to vehicle found no sig-
because of its downregulation of TLR2 expression. nificant difference in erythema between the 2
Topical tretinoin as a monotherapy or in combina- groups at week 4.49,50 TCIs are antiinflammatory
tion with other topical agents has been reported in nature, and their role in rosacea likely relates to
in multiple studies to clinically reduce erythema, their ability to inhibit T cell activation, thereby
papules and pustules, and telangiectasias.45,46 One preventing the release of inflammatory cytokines
study compared treatments of either oral or topical from both T cells and mast cells.51,52 Additional
retinoid or both among 20 rosacea subjects. studies of these medications in the rosacea popu-
The results found that while oral isotretinoin lation may help better define the role of these
produced more rapid improvement, all subjects agents in this condition.
had significant reductions in papules, pustules, Topical permethrin cream. Permethrin cream
and erythema.45 However, the study was not 5% has been tested in the rosacea population based
well controlled, because placebo cream was on its ability to treat cutaneous demodicosis
only used in the final 16 weeks while retinoid (Fig 1).53,54 In a randomized, double blind study
treatments were withheld. More data are therefore comparing permethrin to metronidazole gel 0.75%,
needed to show the clinical efficacy of topical these 2 medications had equal efficacy in terms
retinoids.22 of reducing erythema and papules.55 Subjects
Topical calcineurin inhibitors randomized to the permethrin group did not have
d Topical calcineurin inhibitors are hypothe- changes with respect to telangiectasias, rhinophyma,
sized to be beneficial in reducing rosacea or pustule counts. This therapy can therefore be
symptoms because of their ability to inhibit considered in subjects with specific complaints of
T-cell activation, thereby preventing the erythema or papules.
release of proinflammatory cytokines. Ivermectin cream. Ivermectin cream is
currently undergoing investigation as a possible
The TCIs pimecrolimus and tacrolimus have rosacea treatment. Oral ivermectin has been recog-
both been used to treat ETR and PPR. Studies nized as a treatment for cutaneous demodicidosis,53
measuring their efficacy in improving rosacea which has been postulated to play a role in the
symptoms have had mixed results. Both medica- pathophysiology of rosacea (Fig 1). Whether a cream
tions have led to significant improvement in formulation of ivermectin can produce the same
erythema in separate open-label studies47,48; how- result is currently being studied. Several phase III
ever, 2 randomized controlled trials comparing clinical trials are currently underway on this topic
766 Two et al J AM ACAD DERMATOL
MAY 2015

Table II. Systemic medications shown to be beneficial in the treatment of rosacea*

Medication name Level of evidence Mechanism of action
Treatments approved by the FDA
Tetracyclines IA Antiinflammatory; decrease KLK5 activity by inhibiting
MMPs61
Treatments not approved by the FDA
Beta-adrenergic receptor antagonists III Vasoconstriction of smooth muscles surrounding blood
vessels65
Isotretinoin IB Downregulation of TLR273

Level of evidence: IA evidence includes evidence from metaanalysis of randomized controlled trials; IB evidence includes evidence from at
least 1 randomized controlled trial; IIA evidence includes evidence from at least 1 controlled study without randomization; IIB evidence
includes evidence from at least 1 other type of experimental study; III evidence includes evidence from nonexperimental descriptive studies,
such as comparative studies, correlation studies, and case control studies; IV evidence includes evidence from expert committee reports or
opinions or clinical experience of respected authorities, or both.
FDA, US Food and Drug Administration; KLK5, kallikrein 5; MMP, matrix metalloproteinase; TLR2, Toll-like receptor 2.
*This table lists systemic medications shown to improve rosacea that have been approved by the FDA, those that have not been approved
by the FDA, the level of evidence supporting the use of each treatment, and the mechanism of action of each treatment.

(clinicaltrial.gov identifiers NCT01493687, NCT014 multiple studies have shown the clinical efficacy of
94467, and NCT01493947).* antiinflammatory dose doxycycline in improving
the symptoms of PPR.58-60 Antiinflammatory dosing
SYSTEMIC MEDICATIONS of doxycycline has been shown to decrease
Key points expression of matrix metalloproteinases (MMPs)
d Tetracyclines have been the foundation of that proteolytically cleave the serine protease KLK5
systemic rosacea therapy for [50 years into its active form61 (Table II and Fig 1). In addition,
d Beta-blockers and isotretinoin have also low-dose doxycycline in rosacea has been
been shown to have therapeutic benefits in shown to downregulate inflammatory cytokines
rosacea; however, these medications are not that contribute to neutrophil infiltration, reduce
approved by the US Food and Drug Admin- levels of ROS that destroy connective tissue, and
istration for use in patients with rosacea inhibit nitric oxide to reduce vasodilation.62 It has
been proposed that the antiinflammatory effects of
Tetracyclines tetracyclines are the main mechanism of action in
Key point reducing rosacea symptoms,63,64 suggesting that the
d Antiinflammatory dosing of doxycycline antibacterial properties of doxycycline have a limited
improves the manifestations of rosacea by role in rosacea at best.
decreasing matrix metalloproteinase expres-
sion, downregulating inflammatory cytokines, Beta-blockers
reducing reactive oxygen species levels, and Key point
d By vasoconstricting dermal blood vessels,
inhibiting nitric oxideemediated vasodilation
beta-blockers have been shown to decrease
Although tetracyclines have been used to treat erythema and flushing in some rosacea
rosacea for [50 years, FDA approval for the first patients
systemic medication for treating PPR came in
2006 with the approval of doxycycline at anti- Several case reports have suggested a role for
inflammatory doses. Before its approval, doxy- beta-blockers in the treatment of rosacea. In 2005, a
cycline at both antimicrobial (50-200 mg daily) and case series of 9 patients with rosacea reported that 8
antiinflammatory (\50 mg daily) doses, and less patients had fewer instances of and less severe
commonly tetracycline, were the most frequently flushing with propranolol.65 Later reports on
prescribed agents for PPR. While antimicrobial carvedilol have shown dramatic decreases in facial
dosing of doxycycline has been shown to reduce redness 2 to 3 weeks after treatment initiation in
inflammatory lesion counts in PPR, its necessity was ETR patients with facial redness refractory to
questioned because no definite bacterial pathogen multiple other agents.66,67 Although the patients in
has been identified in rosacea.56,57 Since then, these reports tolerated these medications well,
hypotension and bradycardia are always a
*Author addendum: Since the acceptance of this article, ivermectin concern when administering these medications to
cream has received FDA approval. normotensive subjects.67
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Nonselective beta-blockers are thought to decrease rosacea is divided into 2 major common types:
erythema and flushing in rosacea by inhibiting (1) centrofacial erythema with papulopustular
beta-adrenergic receptors on the smooth muscles lesions and (2) centrofacial erythema without
surrounding blood vessels, leading to vasoconstric- papulopustular lesions. Centrofacial erythema with
tion of these vessels.65 These medications may also papulopustular lesions is then further classified as
reduce anxiety and tachycardia, both of which can mild (\10 papules/pustules, mild erythema, with or
exacerbate flushing episodes.67 Carvedilol has also without symptoms), moderate (10-19 papules/
been shown to have antioxidant and antiinflammatory pustules, moderate erythema, with or without
actions, which may further contribute to its efficacy in symptoms), or severe ([20 papules/pustules, severe
rosacea.66 erythema, with or without symptoms). Although the
authors state the recommendations are not inclusive
Isotretinoin of all clinical practice situations, their recommenda-
Key point tions are based on thorough literature review and
d Isotretinoin may be useful in treating consensus among the authors (Fig 2). Taken together
patients with severe, recalcitrant papulo- with the above review, the information in the
pustular rosacea by downregulating Toll- consensus guidelines should provide the clinician
like receptor 2 expression with not only a treatment algorithm but also insight
into the mechanism of action behind established and
emerging therapies.
Although it has not been approved by the FDA for
the treatment of rosacea, several studies have shown Emerging therapies
that oral isotretinoin is an effective treatment for Key points
severe, recalcitrant PPR.3,68,69 The reported dose for d Novel serine protease inhibitors may be

recalcitrant rosacea ranges from 0.5 to 1.0 mg/kg useful in treating papulopustular rosacea
daily; however, studies have also shown that because they inhibit the cleavage of the
low-dose isotretinoin (10 mg daily) is effective in cathelicidin precursor into LL-37, the
treating refractory rosacea with evidence of less molecules active form
adverse effects.69,70 In another study, the efficacy of d Although larger scale studies are needed, an

lower doses of isotretinoin (0.1, 0.3, or 0.5 mg/kg per initial pilot study suggests that topical appli-
day) was compared to doxycycline and placebo cation of the mast cell stabilizer cromolyn
among 573 patients.71 After 12 weeks, isotretinoin sodium may be beneficial in treating rosacea
0.3 mg/kg proved to be the most effective daily dose. because mast cells release known rosacea
When compared to doxycycline, this dose of triggers such as LL-37, matrix metalloprotei-
isotretinoin had superior efficacy, with subjects nases, and inflammatory cytokines
having a 90% reduction in inflammatory lesions
compared to the 83% reduction seen with Topical serine protease inhibitors. As dis-
doxycycline. The safety profile of isotretinoin in cussed in part I of this continuing medical education
these subjects was similar to that seen in the article, individuals with rosacea have high levels of
treatment of acne, and therefore routine safety and the serine protease KLK5.75 KLK5 cleaves the
laboratory monitoring is required.71 cathelicidin precursor into LL-37, its active form.
Although in vitro 13-cis retinoic acid (isotretinoin) Abnormally high levels of KLK5 are thought to
has been shown to induce KLK5 and KLK7 contribute to the increased levels of cathelicidin
expression in cultured keratinocytes,72 in vivo that play a role in the pathogenesis of rosacea.76
isotretinoin has been shown to significantly decrease Inhibiting KLK5 would therefore serve as a
monocyte TLR-2 expression.73 The effectiveness of therapeutic option in rosacea, and these findings
isotretinoin in the treatment of rosacea is therefore have been confirmed in studies showing that 15%
thought to be secondary to the downregulation of azelaic acid gel decreases expression of KLK5 and
TLR2 (Fig 1).73 LL-37 in lesional rosacea skin (Fig 1). To further
investigate the role of serine protease inhibitors in
CONSENSUS RECOMMENDATIONS FROM rosacea, 1 study looked at the efficacy of topical
THE AMERICAN ACNE AND ROSACEA epsilon-aminocaproic acid (ACA), a serine protease
SOCIETY inhibitor currently approved by the FDA for
In 2014, the American Acne and Rosacea Society promoting hemostasis, in patients with PPR.77 As
published consensus recommendations on the man- early as 6 weeks after treatment initiation, subjects
agement of rosacea.74 In these recommendations, assigned to the ACA group had a statistically
768 Two et al J AM ACAD DERMATOL
MAY 2015

Centrofacial erythema with papulopustular lesions

Gentle skin care and photoprotec on,

May add topical -adrenergic receptor agonist
for persistent non-transient facial erythema

Mild Rosacea Moderate and Severe Rosacea

Topical therapy with Topical therapy with

Subanmicrobial
metronidazole or Subanmicrobial
metronidazole or And dose doxycycline
azelaic acid for And/or dose doxycycline
azelaic acid for
minimum 6-8 weeks minimum 6-8 weeks

Mild to Severe Rosacea FOLLOW UP 6-8 WEEKS

Marked Improvement

Connue therapy
for a full 12 weeks
Response not adequate

Increase doxycycline dose, and/or

switch to alternave oral anbioc and topical*

Maintenance therapy
for 6-9 months. Doxycycline
taper as tolerated
Consider oral isotrenoin
*Clinician may ini ate mul ple alterna ve treatment combina ons for refractorory cases

Fig 2. Recommended treatment plan for rosacea patients. This diagram presents an algorithm
for treating rosacea adapted from a recent consensus statement from the Del Rosso et al.74

significant reduction in serine protease activity management of rosacea. With recent advances in the
compared to the control group. This difference understanding of the pathogenesis of rosacea, more
persisted throughout the 12-week duration of the opportunities for therapeutic interventions are being
study. At week 12, subjects in the treatment group discovered. In addition to the antiinflammatory and
also had reduced erythema scores compared to those antioxidant effects of current topical and systemic
in the control group, further suggesting a therapeutic medications, new therapies, such as serine protease
role for serine protease inhibitors in treating rosacea. inhibitors and mast cell stabilizers, may also improve
Mast cell stabilizers. Mast cells have been rosacea symptoms. Approaching treatment through
suggested to play a role in mediating the both standard and novel pathways while focusing on
cathelicidin-induced inflammation found in rosacea patient education and skin care can allow for better
by releasing LL-37, MMPs, and inflammatory symptom control and improved quality of life for
cytokines.78,79 Blocking mast cell degranulation individuals with rosacea.
was therefore hypothesized to be a potential
therapeutic target in rosacea, and this hypothesis REFERENCES
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demographic and clinical characteristics and various
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cromolyn sodium 4% solution or a vehicle solution 2. Gupta MA, Gupta AK, Chen SJ, Johnson AM. Comorbidity
alone to their face twice daily.80 After 8 weeks, facial of rosacea and depression: an analysis of the National
erythema and MMP, cathelicidin, and KLK5 levels Ambulatory Medical Care Survey and National
had decreased in the treatment group, with MMP Hospital Ambulatory Care Surveyoutpatient department
data collected by the U.S. National Center for Health
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