Rosacea: A Multifaceted Skin Disorder

Payer Perspectives in Dermatology
Caroline Helwick

Rosacea is a chronic inflammatory skin disorder with multiple signs and symptoms. Although one symptom or subtype of rosacea may be predominant in a given individual, another person with the same condition may have different manifestations.1 The treatment of rosacea is optimized when it is individualized.1

The true incidence of rosacea is unknown, but the generally accepted prevalence rate is 10%.2 Although rosacea is reported to predominantly affect people with fair skin, it can be seen in persons of any race or skin tone.3 A genetic link has also been proposed.4

Inflammation: The Underlying Defect
The pathophysiology of rosacea has become an active area of research in the past decade, especially now that inflammation has become appreciated for its role in many diseases. Rosacea is now considered to be an inflammatory condition that occurs in the context of an altered innate immune response involving several different regulatory systems.5,6 More precisely, it is the dysregulation and interplay of various components of the immune, vascular, and nervous systems that seem important to the pathogenesis of rosacea.5,6

The results are vasodilation, neurosensory symptomatology, and a hyperreactive immune response to triggers (eg, extreme temperatures) that activate a cascade of inflammatory factors: toll-like receptors; the stratum corneum enzyme kallikrein-5; antimicrobial peptides, such as cathelicidin; cathelicidin-derived peptides, such as LL-37; reactive oxygen species; and matrix metalloproteinase enzymes.6-8 These factors unite to form a scenario of inflammation and vascular reactivity that includes an augmented innate immune response, an altered vasculature, neurovascular dysregulation, dermal matrix degradation, vasodilation, and dermatitis—all resulting in the appearance of inflammatory papules and pustules and/or facial erythema.6

Evidence Builds for Demodex Role
For years, microorganisms have been implicated in the pathogenesis of rosacea, but recent evidence has solidified this concept, especially colonization with Demodex folliculorum, a skin mite that harbors a certain type of bacteria.6 The theory is that the presence of these microorganisms triggers a complex cascade of events that produce the symptoms of rosacea.6

Some studies suggest that a microbial source is not mandatory for rosacea to occur6; however, the proliferation of Demodex may incite a flare by triggering an immune response that is dysregulated and augmented in patients with rosacea.6 The most recent studies suggest that what is important is not the mere presence of Demodex—because the organism is also found in skin that is not affected by rosacea—but the density of colonization.9-13

This hypothesis was supported by a recent study from Mexico, which found significantly more numbers and greater density of Demodex in the skin of patients with rosacea than in individuals without rosacea.13 Demodex was present in 80% of skin biopsies of patients with rosacea versus in 30% of the control patients, and the mean infestation density was nearly 3 times greater in the patients with rosacea (P <.005). Interestingly, patients with rosacea and a mite infestation reported 9 times greater “suffering” than patients with rosacea without the presence of mites (P = .001).13

A new drug in development for the treatment of rosacea (ivermectin 1% cream) has been shown to clear skin lesions in clinical trials, possibly through a direct action to reduce mite count and but it is not yet available on the market.14-16

The 4 Subtypes of Rosacea
The diagnosis of rosacea is based on its clinical manifestations. At least 1 of the following primary features must be present for a diagnosis of rosacea17:

  • Erythema for at least 3 months (nontransient)
  • Transient erythema (ie, flushing and blushing)
  • Papules and pustules (ie, pimples)
  • Telangiectasia (ie, small dilated blood vessels near the skin’s surface).
  • Secondary features that may occur but that are not necessary for diagnosis include burning or stinging, plaques, dry appearance, edema, ocular manifestations, peripheral location, and phymatous changes. Based on its clinical features, rosacea is classified into 4 subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. These subtypes should be properly diagnosed, because the symptoms of each subtype usually respond to different treatments.17

    1. Erythematotelangiectatic rosacea. This is considered the most common subtype of rosacea. Patients with this type of rosacea experience flushing and persistent central facial erythema, with or without the presence of telangiectasia. Patients with this subtype experience prolonged (≥10 minutes) flushing, which can result from environmental triggers such as stress, hot or spicy foods, alcohol, hot showers, sun exposure, or hot or cold weather.17
    2. Papulopustular rosacea. This subtype of rosacea is marked by the presence of persistent central facial erythema with transient, central facial inflammatory papules or pustules, or both. Persistent erythema of the central face, subtle telangiectasias, facial edema, and ocular inflammation may also be present.17
    3. Phymatous rosacea. Patients with phymatous rosacea have thickening skin and irregular surface nodularities and enlargement. This may occur on the nose, chin, forehead, cheeks, eyelids, or ears, and is disfiguring. This condition is uncommon and develops over years.17
    4. Ocular rosacea. This type of rosacea can be indicated by blurred vision; telangiectasia of the sclera or other parts of the eye; periorbital edema; dry, burning, stinging, or itchy eyes; ocular photosensitivity; or a foreign body–like sensation in the eyes, which can be the first indication of rosacea in some patients.17

    Because of the underlying role of inflammation, most current therapies aim to modulate various points of the inflammatory cascade (eg, low-dose doxycycline, which is antiinflammatory, is effective in the papulopustular rosacea subtype when topical treatments are insufficient). For patients with erythematotelangiectatic rosacea, the newly approved agent brimonidine, the only US Food and Drug Administration–approved therapy for this condition, is a vasoconstrictive agent that addresses the vascular abnormality that produces redness.18 Ivermectin 1% cream is a late-stage development aimed at arresting the inflammatory cycle by reducing the number of Demodex. In all subtypes of rosacea, the first line of attack is the avoidance of triggers and proper skin care. Future articles will more fully describe the effective treatment of rosacea.

    References

    1. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol. 2004;51:499-512.
    2. Berg M, Liden S. An epidemiological study of rosacea. Acta Dermatovenereol. 1989;69:419-423.
    3. Woolery-Lloyd H, Good E. Acne and rosacea in skin of color. Cosmet Dermatol. 2011;24:159-162.
    4. National Rosacea Society. Widespread facial disorder may be linked to genetics. June 2, 2008. www.rosacea.org/press/archive/20080602.php. Accessed April 11, 2014.
    5. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6 suppl 1):S15-S26.
    6. Del Rosso JQ, Gallo RL, Kircik L, et al. Why is rosacea considered to be an inflammatory disorder? The primary role, clinical relevance, and therapeutic correlations of abnormal innate immune response in rosacea-prone skin. J Drugs Dermatol. 2012;11:694-700.
    7. Yamasaki K, Kanada K, Macleod DT, et al. TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes. J Invest Dermatol. 2011;131:688-697.
    8. Two AM, Del Rosso JQ. Kallikrein 5-mediated inflammation in rosacea: clinically relevant correlations with acute and chronic manifestations in rosacea and how individual treatments may provide therapeutic benefit. J Clin Aesthet Dermatol. 2014;7:20-25.
    9. Sattler EC, Maier T, Hoffmann VS, et al. Noninvasive in vivo detection and quantification of Demodex mites by confocal laser scanning microscopy. Br J Dermatol. 2012;167:1042-1047.
    10. Zhao YE, Wu LP, Peng Y, Chang H. Retrospective analysis of the association between Demodex infestation and rosacea. Arch Dermatol. 2010;146:896-902.
    11. Forton FM. Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. J Eur Academ Dermatol Venereol. 2012;26:19-28.
    12. Jarmuda S, McMahon F, Zaba R, et al. Correlation between serum reactivity to Demodex-associated Bacillus oleronius proteins, and altered sebum levels and Demodex populations in erythematotelangiectatic rosacea patients. J Med Microbiol. 2014;63(Pt 2):258-262.
    13. Rios-Yuil JM, Mercadillo-Perez P. Evaluation of Demodex folliculorum as a risk factor for the diagnosis of rosacea in skin biopsies. Mexico’s General Hospital (1975-2010). Indian J Dermatol. 2013;58:157.
    14. Brown M, Hernández-Martín A, Clement A, et al. Severe demodexfolliculorum-associated oculocutaneous rosacea in a girl successfully treated with ivermectin. JAMA Dermatol. 2014;150:61-63.
    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;13:316-323.
    16. Salem DA, El-Shazly A, Nabih N, et al. Evaluation of the efficacy of oral ivermectin in comparison with ivermectin-metronidazole combined therapy in the treatment of ocular and skin lesions of Demodex folliculorum. Int J Infect Dis. 2013;17:e343-e347.
    17. 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;46:584-587.
    18. Galderma. Galderma Receives FDA Approval of Mirvaso. Press release. August 26, 2013. www.galderma.com/Media/Press-releases/articleType/ArticleView/articleId/41/Galderma-Receives-FDA-Approval-of-Mirvaso. Accessed April 15, 2014.
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Last modified: May 2, 2014
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