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Rosacea: pathogenesis and therapy.

Abstract

Recent studies have illuminated the pathophysiology of rosacea. Evidence supports the hypothesis that rosacea is caused by dysregulation of the innate immune system, resulting in vasoactive and neuroinflammatory consequences. New treatments have been approved by the US Food and Drug Administration (FDA) in recent years, and studies have further documented the benefit of other therapies.

Keywords

Rosacea, inflammation, innate immunity, cathelicidins, brimonidine, ivermectin

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Rosacea is diagnosed based on the presence of one or more primary features: transient erythema (flushing), nontransient erythema (most common sign of rosacea), papules and pustules, and/or telangiectasia (small blood vessel lines). Patients may also display one or more secondary features: burning or stinging, plaque, dry appearance, edema, ocular manifestations, phymatous changes, and peripheral (ie, nonfacial) location of manifestations. (1) Rosacea is divided into three cutaneous and one ocular subtype, plus one variant (granulomatous: characterized by hard, brown, yellow, or red cutaneous papules or nodules of uniform size, generally less inflammatory than papules and pustules). Some evidence suggests that rosacea may evolve from one subtype to another; patients may also progress from mild to severe disease. (1)

Reported figures for incidence and prevalence vary, with the highest prevalence rates in people of northern European or Celtic ancestry (2.7%-10%).: Rosacea is more common among women than men, and in individuals with fair skin. Incidence peaks between the ages of 30 and 50 years old. (3) An estimated 16 million Americans have rosacea, according to the National Rosacea Society. (4)

Pathogenesis

A growing body of evidence has accumulated in recent years supporting the hypothesis that rosacea develops because of a disordered innate immune system. (5) Individuals with rosacea express abnormally high levels of cathelicidin in facial skin, compared with matched control. (6) A form of cathelicidin found in rosacea (LL-37) is typically present in neutrophils that are recruited to infected or injured skin. In patients with rosacea, this cathelicidin appears to result from abnormal activity of serine protease kallikrein 5 (KLK5; also known as stratum corneum tryptic enzyme). Injecting cathelicidin-producing peptides into murine skin produced skin inflammation resembling rosacea-like changes. (5-6) Cathelicidins can cause both vasoactive and inflammatory changes, consistent with those observed in rosacea. (5)

Mast cells, found in increased numbers in the dermis of individuals with rosacea, are among the primary sources of the cathelicidin peptide (LL-37) demonstrated to induce rosacea in murine skin. Mast cells have also been shown to mediate skin inflammation induced by cathelicidin. (7)

The skin of people with rosacea also expresses toll-like receptor 2 (TLR2) highly compared with healthy individuals. Increased TLR2 leads to increased production of cathelicidin. Recent experimental findings suggest that high levels of TLR2 in skin increases susceptibility to microbial and environmental stimuli, increasing cathelicidin and KLK5 expression. (5)

Reverse transcriptase polymerase chain reaction and gene array analysis support the concept of rosacea as an inflammatory disease. Proinflammatory genes involved in vasoregulation and neurogenic inflammation are upregulated in early rosacea, before clinical signs such as papules, nodules, or pustules have emerged. Different genes are upregulated in each subtype. (3)

A wide range of stimuli can trigger symptom exacerbations, including emotional stress, spicy food, hot beverages, alcohol consumption, high environmental temperatures, sun exposure, menopause, and microbes (Figure). (5) Many of these same triggers activate the transient receptor potential vanilloid receptor 1 (TRPV1), a cell surface receptor nerve fiber. The density of TRPV1+ nerve fibers is increased in erythematotelangiectatic rosacea compared with healthy skin. In individuals with healthy skin, TRPV1 activation produces brief periods of flushing and burning pain. It has been suggested that patients with rosacea experience hyperactive or dysregulated TRPV1, with sustained flushing and neurogenic inflammation. (3)

Treatment

It is important to set patients' expectations appropriately regarding the benefits of therapy. Rosacea cannot be cured but treatment can control the disease's signs and symptoms. Avoiding triggers, the use of gentle skin cleansers, and frequent moisturizing can help heal and minimize further skin damage. In the last few years, new treatments have been FDA-approved for some rosacea subtypes, and studies have documented the benefit of other treatments (Table).

Erythematotelangiectatic Rosacea

Intense pulsed light has been used to treat rosacea for many years and is clinically accepted despite the absence of high-quality evidence supporting its value. (8) A small (n=34) study reported significant improvements in erythema (46%) and telangiectasia by 55% from baseline after four treatments administered at 3-week intervals. Benefits were sustained at 6 months, with minimal and self-limiting side effects. (5)

Brimonidine gel 0.33%, a selective [alpha.sub.2]-adrenergic receptor agonist with vasoconstrictive activity, received FDA approval for persistent facial erythema of rosacea in August 2013. (10-11) When studied at a concentration of 0.5%, it significantly reduced erythema severity compared with vehicle when applied once daily for 4 weeks in phase III studies. Benefit was observed within as little as 30 minutes of application. No tachyphylaxis or rebound was reported after treatment cessation. (10) Efficacy was maintained over 1 year (n=345). Some patients experience exacerbation of rosacea signs and symptoms (flushing 10%, erythema 8%, rosacea 5%, and skin burning sensation 4%). (12)

Papulopustular Rosacea

Isotretinoin has been used for decades to treat rosacea despite the lack of evidence-based support. A double-blind, randomized, 12-week study conducted in 35 centers in Germany (n=573 with papulopustular or phymatous rosacea) compared oral isotretinoin (0.1. 0.3, or 0.5 mg per kg body weight) to doxycycline (100 mg daily for 14 days, then 50 mg daily) and placebo. The 0.3 mg/kg dose proved to be the most effective, demonstrating significant superiority to placebo and noninferiority compared with doxycycline. Lesions were reduced by 90% with isotretinoin 0.3 mg/kg and by 83% with doxycycline. Investigators determined that isotretinoin led to complete remission in 24% of patients and marked improvement in another 57% of patients. Comparable figures for doxycycline were 14% and 55%, respectively. The safety profile of isotretinoin 0.3 mg/kg was similar to that observed when it is used in the treatment of acne. (13)

Ivermectin 1% cream received FDA approval for inflammatory rosacea lesions as of December 2014. (14) Roughly 40% of patients with papulopustular rosacea randomized to ivermectin were rated "clear" or "almost clear" on the Investigator's Global Assessment (IGA) in two 12-week phase III trials (38.4% and 40.1%, respectively; P <0.001 vs vehicle). Ivermectin reduced lesion count by 76% and 75% in the 2 trials. Fewer subjects reported dermatologic adverse events with ivermectin than with vehicle, and more subjects experienced no skin drying or itching as compared with vehicle. (15)

Once-daily ivermectin 1% also demonstrated superiority compared with an active control (twice-daily metronidazole cream 0.75%) for 16 weeks (n=962). Inflammatory lesions were reduced from baseline by 83% with ivermectin and by 73.7% with metronidazole (P<0.001). The proportion of subjects attaining "clear" or "almost clear" (IGA rating) was also superior with ivermectin (84.9% and 75.4%, respectively; P<0.001). Ivermectin demonstrated better local tolerability than the comparator. (16)

A low-dose formulation of oral minocycline (45 mg extended release, once daily) demonstrated efficacy in papulopustular rosacea, alone or when used with once-daily 15% azelaic acid. Participants in a double-blind study (n=60) were randomized to receive one of these regimens for 12 weeks. Both treatments significantly reduced lesion count and improved IGA and Clinical Erythema Assessment compared with baseline, with no significant difference in efficacy or safety between the two regimens. Benefits were maintained 4 weeks after therapy discontinuation. (17)

Ocular Rosacea

The diagnosis of ocular rosacea is often missed, as symptoms are nonspecific and there is no specific test to confirm diagnosis. (18) Most but not all patients also have cutaneous signs and symptoms of rosacea. Manifestations include watery or bloodshot eyes, sensation of a foreign body, burning or stinging, dryness, itching, light sensitivity, and blurred vision. Ocular rosacea should be considered in patients with corneal damage, a history of blepharitis, recurrent conjunctivitis, iritis, keratitis or styes (chalazion, hordeolum), and meibomian gland dysfunction. Periocular erythema, or telangiectases at the eyelid margins or lid, may be present. Ocular rosacea can lead to vision loss; treating cutaneous rosacea without addressing the ocular component may be insufficient to prevent this consequence. (1)

Treatment with cyclosporine ophthalmic emulsion 0.05% was associated with an increase in Schirmer test scores (a measure of tear production), compared with a decrease (worsening) with artificial tears. Patients with rosacea-associated eyelid and corneal changes (ie, lid margin telangiectasia, meibomian gland inspissation, and/or fullness of the lid margin; n=37) were randomized to receive topical cyclosporine or artificial tears for 3 months. Quality-of-life scores also improved with therapy. (19)

Summary

An increasing body of pathophysiologic evidence supports the hypothesis that rosacea results from disordered innate immunity, which leads to neuroinflammation and vasoactive changes. (3-5-7) The introduction of brimonidine gel 0.33% for erythematotelangiectatic rosacea and ivermectin 1% cream for papulopustular rosacea offers new options for managing this common condition. A large (n=573), double-blind randomized trial has documented efficacy of oral isotretinoin (0.3 mg/kg) in papulopustular rosacea. (13) Low-dose (45-mg), extended-release oral minocycline has demonstrated efficacy in papulopustular rosacea, alone or when used in conjunction with once-daily 15% azelaic acid. (17) Topical cyclosporine 0.05% has demonstrated efficacy in ocular rosacea. (19)

References

(1.) Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46(4):584-587.

(2.) Abram K, Silm H, Oona M. Prevalence of rosacea in an Estonian working population using a standard classification. Acta Derm Venereal. 2010;90(3):269-273.

(3.) Steinhoflf M, Buddenkotte J, Aubert J, et al. Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011; 15(1):2-l 1.

(4.) Society NR. If you have rosacea, you're not alone, http://www.rosacea.org/patients/index.php. Accessed May 11.2015.

(5.) Yamasaki K, Gallo RL. Rosacea as a disease of cathclicidins and skin innate immunity. J Investig Dermatol Symp Proc. 2011; 15(1): 12-15.

(6.) Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007; 13(8):975-980.

(7.) Muto Y, Wang Z, Vanderberghe M, Two A, Gallo RL, Di Nardo A. Mast cells are key mediators of cathelicidin-initiated skin inflammation in rosacea. J Invest Dermatol. 2014; 134(11):2728-2736.

(8.) van Zuuren EJ, Fedorowicz Z. Carter B, van der Linden MM, Charland L. Interventions for rosacea. Cochrane Database Syst Rev.. 2015;(4):CD003262.

(9.) Papageorgiou P, Clayton W, Norwood S, Chopra S, Rustin M. Treatment of rosacea with intense pulsed light: Significant improvement and long-lasting results. Br J Dermatol. 2008; 159(3):628-632.

(10.) Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: Results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013; 12(6):650-656.

(11.) Galderma. Galderma receives FDA approval of Mirvaso[R] [press release]. 2013. http://www.galderma.com/Media/Press-releases/articleType/ArticleView/articleId/41/Galderma-Receives-FDA-Approval- of-Mirvaso. Accessed May 7, 2015.

(12.) Mirvaso [package insert]. Fort Worth, TX: Galderma Laboratories; revised August 2013.

(13.) Gollnick H. Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treatment of rosacea - doxycycline- and placebo-controlled, randomized clinical study. J Dtsc/i Dermatol Ges. 2010;8(7):505-515.

(14.) Galderma receives FDA approval of novel treatment option for rosacea patients [press release]. December 24, 2014. http://www.galderma.com/News/articleType/Article View/articleId/75/Galderma-Receives-FDA-Approval-of-Novel-TreatmentOption-for-Rosacea-Patients. Accessed July 21, 2015.

(15.) Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: Results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014; 13(3):316-323.

(16.) Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: A randomized, investigator-blinded trial. Br J Dermatol. 2015; 172(4): 1103-1110.

(17.) Jackson JM, Kircik LH, Lorenz DJ. Efficacy of extended-release 45 mg oral minocycline and extended-release 45 mg oral minocycline plus 15% azelaic acid in the treatment of acne rosacea. J Drugs Dermatol. 2013; 12(3):292-298.

(18.) Vieira AC, Mannis MJ. Ocular rosacea: Common and commonly missed. J Am Acad Dermatol. 2013;69(6):S36-S41.

(19.) Schechter BA, Katz RS, Friedman LS. Efficacy of topical cyclosporine for the treatment of ocular rosacea. Adv Ther. 2009;26(6):651-659.

Jerry K. L. Tan, MD, FRCPC *

* Adjunct Professor. Department of Medicine, University of Western Ontario, London, Ontario, Canada.

Publication of this CME/CE article was jointly provided by Rutgers. The State University of New Jersey, and Global Academy for Medical Education, LLC with Skin Disease Education Foundation (SDEF) and is supported by educational grants from AbbVie Inc., Amgen Inc., Bayer Healthcare, and Valeant Pharmaceuticals North America LLC.

Dr Tan has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Eileen McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Jerry K.L. Tan, MD, FRCPC, Grant/Research: Allergan, Inc., Bayer. Cipher Pharmaceuticals Inc, Dermira, Galderma Laboratories, L.P., and Valeant Pharmaceuticals North America LLC; Consultant: Cipher Pharmaceuticals, Galderma, GlaxoSmithKline Pharmaceutical Company, Hoffmann-La Roche, Stiefel Laboratories, Inc., and Valeant; Speakers Bureau: Cipher Pharmaceuticals, Galderma, Pierre-Fabre, and Valeant.

Address reprint requests to: Jerry K. L. Tan, MD, FRCPC, 2224 Walker Road, Suite 300, Windsor, Ontario, NBW 5L7 Canada; jerrytan@bellnet.ca.

Caption: FIGURE Multiple and Diverse Triggers

TABLE Rosacea Treatments and Mechanisms of Action

                                       Metronidazole   Azelaic Acid
Mechanism of Action        Retinoids      Topical        Topical

Demodex
TLR2 activation                +
Serine protease activity                                    +
Thl adaptive profile
Vasodilation
Reactive [O.sub.2] & NO                      +              +
Sebaceous hyperplasia       + (PO)

                           Ivermectin   Brimonidine
Mechanism of Action         Topical       Topical

Demodex                        +
TLR2 activation
Serine protease activity
Thl adaptive profile
Vasodilation                                 +
Reactive [O.sub.2] & NO        +
Sebaceous hyperplasia

                           Cyclosporine   Doxycycline
Mechanism of Action          Topical          po

Demodex
TLR2 activation
Serine protease activity                       +
Thl adaptive profile            +
Vasodilation
Reactive [O.sub.2] & NO                        +
Sebaceous hyperplasia

Source: Courtesy of Jerry K. L. Tan, MD, FRCPC.


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Title Annotation:HIGHLIGHTS OF SKIN DISEASE EDUCATION FOUNDATION'S 39th Annual Hawaii Dermatology Seminar[TM]: A CONTINUING MEDICAL EDUCATION CONFERENCE
Author:Tan, Jerry K.L.
Publication:Dermatology News
Article Type:Report
Date:Sep 1, 2015
Words:2375
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