REVIEW Pathogenesis of Rosacea Anetta E. Reszko, MD, PhD; Richard D. Granstein, MD Rosacea is a chronic, common skin disorder whose pathogenesis is incompletely understood. An inter- play of multiple factors, including genetic predisposition and environmental, neurogenic, and microbial factors, may be involved in the disease process. Rosacea subtypes, identified in the recently published standard classification system by the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea, may in fact represent different disease processes, and identifying subtypes may allow investigators to pursue more precisely focused studies. New developments in molecular biology and genetics hold promise for elucidating the interplay of the multiple factors involved in the pathogen- esis of rosacea, as well as providing the bases for potential new therapies. osacea is a common, chronic skin disorder and secondary features needed for the clinical diagnosis primarily affecting the central and con- of rosacea. Primary features include flushing (transient vex areas of COSthe face. The nose, cheeks, DERM erythema), persistent erythema, papules and pustules, chin, forehead, and glabella are the most and telangiectasias. Secondary features include burn- frequently affected sites. Less commonly ing and stinging, skin dryness, plaque formation, dry affectedR sites include the infraorbital, submental, and ret- appearance, edema, ocular symptoms, extrafacial mani- roauricular areas, the V-shaped area of the chest, and the festations, and phymatous changes. One or more of the neck, the back, and theDo scalp. Notprimary Copy features is needed for diagnosis.1 The disease has a variety of clinical manifestations, Several authors have theorized that rosacea progresses including flushing, persistent erythema, telangiecta- from one stage to another.2-4 However, recent data, sias, papules, pustules, and tissue and sebaceous gland including data on therapeutic modalities of various sub- hyperplasia. Diagnosis of rosacea is based on clini- types, do not support this notion.5 A possible exception cally recognizable morphologic characteristics. However, is PPR, which may progress to the phymatous form. establishing precise, comprehensive diagnostic criteria is The National Rosacea Society Expert Committee on the difficult given the variety of clinical manifestations and Classification and Staging of Rosacea does not qualify the the lack of laboratory testing. rosacea subtypes as a spectrum from ETR to phymatous. The National Rosacea Society Expert Committee on the Rosacea subtype designation is of pivotal importance Classification and Staging of Rosacea defines and clas- because the therapeutic implications are different for sifies rosacea into the following clinical subtypes based various subtypes, and individual subtypes may in fact primarily on morphologic characteristics: erythematotel- represent pathologically distinct disease processes. angiectatic rosacea (ETR), papulopustular rosacea (PPR), To confirm diagnosis of rosacea, several diseases with phymatous rosacea, and ocular rosacea. similar cutaneous manifestations must be excluded. The National Rosacea Society Expert Committee on the These include polycythemia vera, connective tissue Classification and Staging of Rosacea identifies primary diseases (lupus erythematosus, dermatomyositis, and mixed connective tissue disease), carcinoid syndrome, Dr. Reszko is Resident in Dermatology, and Dr. Granstein is mastocytosis, photosensitivity, and allergic or irritant Professor of Dermatology, both at Department of Dermatology, contact dermatitis.6 Weill Cornell Medical College and New York-Presbyterian The pathogenesis of rosacea is complex and a subject of Hospital, New York. literature controversy. One hindering factor is that much The authors report no conflicts on interest in relation to of the data on rosacea were acquired before the National this article. Rosacea Society Expert Committee on the Classification 224 Cosmetic Dermatology® • april 2008 • VOL. 21 NO. 4 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Figure Not Available Online Figure Not Available Online Figure 1. Patient with erythematotelangiectatic rosacea displaying Figure 2. Patient with papulopustular rosacea displaying persis- persistent erythema and telangiectasias. Photograph courtesy of the tent central erythema with inflammatory papules and pustules in National Rosacea Society. a centrofacial distribution. Photograph courtesy of the National Rosacea Society. and Staging of Rosacea established strict diagnostic cri- teria. Moreover, various clinicalCOS subtypes of rosacea thatDERM be reported. Telangiectasias may be present but difficult may or may not represent the same clinicopathologic to distinguish from the erythematous background. irrita- process were studied simultaneously, possibly masking tion from external stimuli is not a constant feature; thus, true insights into rosacea. scaling and roughness are often absent. ROSACEA SUBTYDoPES NotPhymatous Copy Rosacea Erythematotelangiectatic Rosacea Phymatous rosacea is characterized by marked skin thick- The predominant sign of ETR is centrofacial flushing last- ening and edema with irregular surface nodularities of the ing more than 10 minutes, accompanied by a burning or nose, chin, forehead, ears, or eyelids (Figure 3). The skin stinging sensation with or without persistent erythema surface is often pitted with prominent sebaceous glands (Figure 1). The erythema usually spares the periocular and enlarged follicular openings. The clinical changes and submental skin but may involve the ears, neck, or result from extensive chronic inflammatory infiltration, upper part of the chest. Typically, patients with ETR will connective tissue hypertrophy with fibrosis, and marked possess skin with a fine texture without oiliness or the sebaceous gland hyperplasia.7 prominence of sebaceous glands. The erythematous areas Four distinct histologic variants may occur with rhi- of the face may appear rough with scales likely from nophyma (nasal phymatous rosacea): glandular, fibrous, chronic, low-grade inflammation. Telangiectasias are fibroangiomatous, and actinic. in addition to the nose, common but not essential for diagnosis.6 other commonly affected areas include the chin (gnatho- phyma), forehead (metophyma), ears (otophyma), and Papulopustular Rosacea eyelids (blepharophyma). PPR is characterized by persistent central erythema with inflammatory papules or pustules in a centrofacial dis- Ocular Rosacea tribution (Figure 2). This subtype may involve perioral The prevalence of ocular rosacea is the subject of debate, and perinasal areas. Prolonged periods of facial erythema with incidence rates of 3% to 58% reported in the litera- or flushing may lead to soft tissue edema lasting up to ture.8 Ocular manifestations may precede the cutaneous several days. Reports of patients developing solid, hard, signs of rosacea in approximately 20% of patients or they nonpitting edema of the forehead, glabella, upper eye- may develop concurrently with skin manifestations.9 lids, nose, and cheeks (Morbihan disease) have been Ocular manifestations include blepharitis, conjunctivi- described in the literature. A history of flushing may also tis, inflammation of the eyelids and meibomian glands, VOL. 21 NO. 4 • april 2008 • Cosmetic Dermatology® 225 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. PATHOGENESIS OF ROSACEA Figure Not Available Online Figure Not Available Online Figure 3. Patient with phymatous rosacea displaying marked skin Figure 4. Patient with ocular rosacea displaying eyelid and thickening and edema with irregular surface nodularities of the nose conjunctival involvement. Photograph courtesy of the National (rhinophyma). Photograph courtesy of the National Rosacea Society. Rosacea Society. interpalpebral conjunctival hyperemia, corneal infiltrates, sebaceous gland hyperplasia and rhinophyma more often ulcers, and vascularizationCOS (Figure 4).9,10 in one series, DERM than women.12,15 conjunctival telangiectasias and irregularity of eyelid mar- Recent data from a large epidemiologic study of the gins were noted in 81% of patients with ocular rosacea.11 irish population, conducted with strict diagnostic cri- Meibomian gland dysfunction occurs in 78% of patients teria and using precise clinical definitions, showed no with ocular rosacea, leading first to decreased lipid significant difference in the prevalence of PPR between secretion and then to Doinflammation and Not foreign body males Copy and females and no significant association between sensation.11 Patients with rosacea frequently describe rosacea and UVR exposure and cutaneous solar damage.16 eye stinging or burning, dryness, irritation from light, or The study also revealed no correlation between family foreign body sensation. A potentially vision-threatening history of PPR and later development of PPR. complication of ocular rosacea is Staphylococcus aureus keratitis that may lead to corneal opacity, scarring, and PATHOGENESIS OF ROSACEA vision loss.12 Despite decades of study, the etiology of rosacea remains Ocular rosacea frequently occurs in association with unknown. The pathogenesis of rosacea is likely to be other rosacea subtypes, although there is no direct corre- multifactorial,