Epidemiology, Pathogenesis, Clinical Presentation, and Treatment

MEDICINE REVIEW ARTICLE Rosacea Epidemiology, Pathogenesis, Clinical Presentation, and Treatment Percy Mario Lehmann SUMMARY Introduction: Rosacea ...
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MEDICINE

REVIEW ARTICLE

Rosacea Epidemiology, Pathogenesis, Clinical Presentation, and Treatment Percy Mario Lehmann

SUMMARY Introduction: Rosacea is a common and chronic dermatological disorder of the face. Its effect on facial appearance makes it potentially distressing for patients who can suffer psychosocial disturbances. Methods: Selective literature review. Results: Rosacea occurs in adults, peaking between 40 and 50 years of age. Three main stages are identifiable: Rosacea erythematosateleangiectatica, rosacea papulopustulosa, and hyperglandular-hypertrophic rosacea. Numerous specialized forms exist, which complicate differential diagnosis and require specific treatment strategies. These include rosacea conglobata, rosacea fulminans, granulomatous rosacea, persisting edema, ocular rosacea, and steroid rosacea. A recent increase has been noted in patients with rosacea induced by inhibitors of epidermal growth factors (cetuximab, geftinib, erlotinib) used for chemotherapy in patients with malignancy. These side effects have been described as acneiform eruptions but at least some of the described patients clearly have a rosacea like appearance. Discussion: A variety of physical and chemical agents can induce rosacea in predisposed individuals and trigger exacerbations of preexisting disease. Treatment of the various forms of rosacea should be adapted to the stage and phase of the disease. Rosacea is not curable but the symptoms can for the most part be effectively controlled, thus preventing permanent damage to the skin, such as scarring and permanent edema. Dtsch Arztebl 2007; 104(24): A 1741–6. Key words: rosacea, dermatosis, chronic disease, topical therapy

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osacea is one of the most common skin disorders in adults. Because it affects mainly the face, it is disfiguring for many patients and has serious psychosocial sequelae. Rosacea progresses over many years, in intermittent episodes that result in different manifestations of the disease, and clinically discrete stages are differentiated. This article provides the classification and stages of rosacea as agreed in recent consensus conferences. The course of the disease is different in every individual, but rosacea may occur at any stage. Acne and rosacea may have similarities but are fundamentally different disorders. Exact morphological knowledge is necessary for a definite diagnosis and treatment that is appropriate for the stage. No causative treatment leading to permanent cure exists. However, rosacea can be controlled adequately with therapy that is appropriate for the respective stage and phase (1, 3). Treatment concepts are explained below.

Epidemiology An estimated 2–5% of adults in Germany develop rosacea. Rosacea affects middle aged people; it usually starts in the third or fourth decade of life and peaks between age 40 and 50. Children are rarely affected. In the countries of northern Europe, where people are predominantly light skinned, red haired, and of the Celtic skin type, rosacea is notably more common than in the south. In the north, the reported prevalence is up to 10% and in the south, 2% (4). Women develop rosacea more often than men, but as a rule it takes a milder course.

Pathogenesis No scientifically based, comprehensive, pathogenetic principle for rosacea has thus far been developed. Well defined and known stimuli result in initial manifestations or exacerbate Klinik für Dermatologie, Allergologie und Umweltmedizin, HELIOS-Klinikum Wuppertal, Universität Witten-Herdecke: Prof. Dr. med. Lehmann

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Figure 1: Rosacea grade I – rosacea erythematosa teleangiectatica. Extensive centrofacial erythema and telangiectasia.

Figure 2: Rosacea grade II – rosacea papulopustulosa. Center face, in addition to erythema and telangiectasia, papules and pustules, also affecting chin, forehead, and capillitium.

existing rosacea. These include sun radiation, irritants (cosmetics, soaps, synthetic soaps, peelings, and others), changes in temperature, heat, and psychovegetative influences. Since flushing (strong persistent blushing) initially determines the disorder in all rosacea patients, and since the angular venous system of the face is connected to the cooling circulation mechanism for the brain, a dysregulation of the thermoreactive mechanism has been postulated. Brinnel et al. (5), however, demonstrated in an experimental study that this thermoreactive mechanism is disrupted in rosacea patients. Further studies (e1, 6) showed that rosacea patients react to certain stimuli with a stronger and prolonged erythematous facial reaction than control patients. On the basis of these data, the following hypothesis is formulated: patients with rosacea have a genetic predisposition for the disorder. Many well documented factors result in vascular dilatation and damage and subsequently to alterations to the connective tissues in a context of increased activity of reactive oxygen radicals. A chronic inflammatory reaction with flooding of inflammatory cells and inflammatory mediators then leads to the rosacea phenotype, with erythema, papules, and pustules. Involvement of the lymphatic system results in edema. Chronic inflammation and lymphedema induce a tissue hyperplasia that phenotypically manifests as a hyperplastic-glandular form of rosacea. In the sense of an amplification cycle, the chronic inflammation may damage the dermal vessels and surrounding connective tissues (1, 7, 8). Dtsch Arztebl 2007; 104(24): A 1741–6 ⏐ www.aerzteblatt.de

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Clinical presentation and subtypes Rosacea presents with different symptoms and in different phenotypes, which may occur together but also independently. The following centrofacial manifestations indicate rosacea: > Transient, intense erythema ("flushing and blushing") > Persistent facial erythema > Papules and pustules > Telangiectasia > Burning and stabbing sensations > Erythematous plaques > Dry skin, occasionally in association with seborrheic dermatitis > Extrafacial manifestations.

Clinical stages Building on detailed clinical descriptions and investigations, consensus conferences confirmed the valid classification of rosacea, which considers the different manifestations of the disorder and defines them clinically. Distinction is made between one preliminary stage, three main stages, and special manifestations (8, 9). Preliminary stage – the rosacea diathesis Most patients notice transient erythema as their first symptom of rosacea. This recurs increasingly often and has a flush-like character. Intermittently occurring erythematous blushing occurs in rosacea patients at all stages and is felt to be particularly disagreeable. The skin is easily irritable and reacts to minor stimuli. The initially transient erythema then develops into persistent erythema. Stage I – Rosacea erythematosa teleangiectatica Enduring erythema characterizes the first stage of rosacea (rosacea I), with telangiectasia of different severity (figure 1). The irritability of the skin increases notably throughout this stage. Stabbing, burning, and itching are among the subjective symptoms of this stage that particularly impair patients. Stage II – Rosacea papulopustulosa Inflamed erythematous papules and pustules occur centrofacially on erythematous skin at this stage (rosacea II). These persist usually for longer periods of time (weeks) (figure 2). This presentation is sometimes confused with Acne vulgaris, although in rosacea, the primary acne efflorescences – comedones – are absent. As a rule, the efflorescences occur symmetrically; after a lengthier amount of time, the chin and cheeks are affected and then the entire face. The rash does not usually spread beyond the facial area but it has been known to occur on occasion. In extrafacial rosacea, the entire integumentary system (skin) of the patient should be investigated. Stage III – glandular hyperplastic rosacea Large inflammatory nodules and plaques with infiltrations as well as tissue hyperplasia characterize this stage of rosacea (rosacea III). The nose and cheeks are the most commonly affected sites (figure 3). Extensive inflammatory infiltrates occur, as does an increase in connective tissue and massive hyperplasia of the sebaceous glands. The result of the tissue hyperplasias is the development of the different phymas (figure 4). Phymas (phyma, Greek: swelling, mass, tuberosity) develop in different facial sites; rhinophyma is most common, whereas gnatophyma, otophyma, blepharophyma, and metophyma are rarer.

Special forms Rosacea conglobata Similar to acne conglobata, patients with rosacea may develop confluent hemorrhagic nodular abscesses. Painfully indurated strands are further signs of rosacea conglobata. Women are more often affected than men; the course is chronic-progressive. This condition differs from acne conglobata only in that it is limited to the face, comedones do not occur, and chest, back, shoulders, and extremities are spared. Only in exceptional cases do conglobating nodules occur on the chest.

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Rosacea fulminans Large conglobating nodules develop acutely on the face, and abscessing fistulas may affect the entire facial area (10). Seborrhea, abscesses, numerous pustules, and carbuncular nodules characterize this condition (figure 5a). This, the most severe form of rosacea, always affects younger women. Most women report during their medical history for rosacea that the sudden start of the condition on the face was preceded by strong seborrhea. In 1940, O'Leary and Kierland described this dramatic pathology for the first time, using the term pyoderma faciale (11), a misleading term as microbiological investigations never found germs that were responsible for the condition. The patient's general condition is normally barely affected; the patients Figure 3: Rosacea grade III – glandular hyperplastic rosacea. Papules, pustules, inflammatory nodules, and fibrosing inflammation with tissue hyperplasia.

are primarily affected psychologically, owing to the disfiguring skin condition. Although this most severe form of rosacea is very disfiguring, early and intensive therapy usually yields good results (figure 5b). Equally positive and encouraging is the finding that recurrences have not been observed after successful treatment (12). Granulomatous rosacea This special form of rosacea is particularly difficult to treat. Reddish-brown nodules or papules develop on the basis of a diffusely reddened skin. Such lupoid epitheloid granulomas are disseminated over the face. Histology shows lymphohistiocytary infiltrates with giant cells and epitheloid cellular tuberculoid granulomas. This manifestation was previously referred to as lupus miliaris disseminatus faciei, but this term is not used anymore. Germs (mycobacteria) were excluded as causative agents. Persistent edema in rosacea (Morbihan's disease) Rough facial edema in rosacea develops owing to more involvement of the lymphatic system in addition to the blood vessels. Forehead, glabella, nose, and cheeks are most commonly affected. Histologically notable are increased mastocytes in all levels of the connective tissue (13). This led to the concept that the particular induration through chronic inflammation is caused concomitantly with fibrosis induced by mastocytes. The condition ("curse of the Celts") is said to be common in the Morbihan region (Brittany), where a large part of the population is of Celtic origin. A recent study (14) found immunological dysregulations in patients, in the form of contact urticaria with disrupted lymphatic flow, by using laser Doppler investigation. This mechanism is also under discussion as a pathogenetic contributing cause in rosacea. Steroid rosacea Steroid rosacea presents clinically as a mixture of rosacea papulopustulosa and the steroid side effects atrophy and telangiectasia (15, 16). Topical treatment with potent corticosteroids,

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Figure 4: Rhinophyma

as well as occasional systemic application of such preparations, will result in steroid rosacea over a longer period of time. If corticosteroid treatment is stopped, severe exacerbations will occur; strict abstinence from steroids is the only way to control this condition, which is difficult to treat (16). As a new therapeutic option, calcineurin inhibitors (pimecrolimus, tacrolimus) have been applied successfully (e2). Skin changes owing to inhibitors of epidermal growth factor receptor Different side affects on the skin have been described after use of inhibitors of epidermal growth factor receptor (EGFR), among others, these included "acneiform skin reactions" or "rosacea-like dermatitis." According to the author's observations (figures 6a, 6b) and studies of some case descriptions (17, 18), the skin changes in some of these cases were very similar to rosacea manifestations of different grades. These side effects may, however, affect the entire integumentary system (skin) and induce further, eczema-like changes in addition to the rosacea-like changes. EGFR inhibitor treatment should not be stopped because the skin side effects obviously correlate with the therapeutic response to the underlying condition. Two of the author's patients responded well to phase adapted rosacea therapy. Further studies should further evaluate this undesirable effect because the patients suffer severely from these disfiguring side effects, in addition to their serious underlying condition. Ocular rosacea Some 25% of rosacea patients have ocular manifestations, independent of the stage and severity of the underlying illness. The eye is affected by chronic inflammatory processes, sometimes accompanied by ulcerations and nodular infiltrates, which may result in blindness if left untreated (2, 3).

Therapy In contrast to the manifold phenotypes of rosacea, relatively few – compared with acne – controlled studies into the treatment of rosacea exist (19). Independent of stage and phase, it will have to be explained to the patient that skin affected by rosacea reacts unusually sensitively to chemical and physical irritants. All locally irritating agents have to be avoided, such as irritant soaps, alcoholic tinctures, astringents, and peelings. The doctor needs to emphasize especially the harmful effects of sun radiation. Topical therapy In stages I and II of rosacea, topical therapy is often sufficient. Many different creams, lotions, and gels are recommended for the treatment, but only for few substances is there scientific, evidence

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Figure 5: Rosacea fulminans a) suddenly occurring conglobating nodules and abscessing fistulas on strongly seborrheic skin; b) after treatment with systemic glucocorticosteroids (1 mg/kg body weight prednisolone equivalent) and subsequently with isotretinoin (0.5 mg/kg body weight)

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Figure 6: Rosacea-like dermatitis a) induced by drug treatment with cetuximab; b) after 3 weeks' combination therapy with topical metronidazole (0.75%), systemic minocycline twice daily (50 mg/day). Treatment was given for several weeks after the chemotherapy had ended, as the side effects induced by cetuximab had not subsided spontaneously.

based proof of reliable efficacy. The best and most comprehensive studies exist on the agents metronidazole and azelaic acid (19, 20), so that these substances are officially licensed for use in rosacea as topical drugs. The effects of azelaic acid versus metronidazole has been investigated in randomized, prospective, multicenter studies in papulopustulous rosacea (22, e3). Both were found to be efficacious; azelaic acid was better at reducing papulopustules than metronidazole. However, the substance with the largest amount of clinically documented experience is metronidazole (19, 20). For a long time, it could be prescribed in Germany only as a drug confected as a formula magistralis, but since 2001, it has been available as a 0.75% gel preparation and since 2003, as a cream. The efficacy of metronidazole is beyond doubt; numerous double blinded, placebo controlled studies have been conducted for this substance (23, 24). After some 3 weeks, a reduction in papules and pustules by 50% can be achieved, and the maximum effect will set in after 9 weeks (in more than 75% of patients). In 1%, irritation was noted as a side effect, but this was mostly transient. Antibiotics used in acne treatment are often effective, although the mechanism has not been explained. The assumption is that a generally anti-inflammatory ingredient in several antibiotics is effective in rosacea. Those antibiotics used include erythromycin, clindamycin, and the tetracyclines, in concentrations Dtsch Arztebl 2007; 104(24): A 1741–6 ⏐ www.aerzteblatt.de

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between 0.5% and 2%. The strongest effect is assumed for erythromycin, but topical tetracyclines seem relatively ineffective. Topical retinoids are a possible future therapeutic option, which is currently being investigated for the treatment of rosacea in studies. A recently published randomized controlled prospective study showed the efficacy of adapalene in papulopustulous rosacea (21). Topical antibiotics and retinoids are not officially licensed for rosacea, so that these substances are used exclusively off label. Systemic treatment Systemic therapy for rosacea is used only for the severe forms. Oral tetracyclines (tetracycline hydrochloride, oxytetracycline) have been the gold standard in oral therapy for severe rosacea for 40 years (3). Three to four week's therapy with 250 mg/day can bring skin and eye symptoms of rosacea under control. Minocycline and doxycycline, second generation tetracyclines, are similarly effective, although well controlled studies are lacking. Attention has to be paid to side effects. Doxycycline is phototoxic, and minocycline may result in discolorations of skin and mucosa and other tissues. Pregnancy is a contraindication for this class of substances. Macrolide antibiotics are an alternative to the tetracyclines. Isotretinoin: Isotretinoin is effective in medium to severe rosacea, even though it has not been officially licensed for this indication (25, e4). The initially applied doses were 0.5–1 mg/kg body weight, but more recently, an increasingly promoted and well documented low dosage (0.1–0.2 mg/kg body weight) has been proved to be effective. Glucocorticosteroids: In the most severe forms of rosacea – rosacea conglobata and rosacea fulminans – initially, to reduce the inflammatory component, systemic glucocorticosteroids (0.5–1 mg prednisolone equivalent dose/kg body weight) may be administered, which are normally contraindicated in the treatment of rosacea. After the inflammatory signs have subsided, a combination with isotretinoin and downstepping of the glucocorticosteroids has yielded the most favorable results (25). Other pharmacological therapeutic options: Reports exist on the successful use of dapsone, antimalarial drugs, antimycotics, cyproteronacetate, spironolactone, clonidine, and nadolol. For reasons of space, they cannot be dealt with in this article.

Surgical treatment for rosacea Mainly rhinophyma in rosacea can be treated effectively with surgery. By administering systemic isotretinoin, the rhinophyma can be shrunk, but the most effective therapy is surgical ablation. Different techniques have been described in the literature, and the surgeon's experience seems most important for the success of the respective methods. Excision and cryotherapeutic as well as electrosurgical ablation, vaporization with a CO2 laser, ablation with an erbium:YAG laser, derma shaving with a scalpel or dermabrasion are effective methods (3). Conflict of Interest Statement The author has received lecture honorariums from the companies Galderma and Novartis in the past two years. Manuscript received 17 August 2006, final version accepted on 7 February 2007. Translated from the original German by Dr Birte Twisselmann.

REFERENCES For e-references please refer to the additional references listed below.

1. Lehmann P: Rosazea. Klinik, Pathogenese, Therapie. Hautarzt 2005; 56: 871–87. 2. Plewig G, Kligman AM: Acne and Rosacea. Berlin, Heidelberg: Springer, 3rd edition, 2000; 365. 3. Schöfer H: Rosazea: Klinik und aktuelle Therapie. Stuttgart, New York: Georg Thieme Verlag, 2003. 4. Berg M, Liden S: An epidemiological study of rosacea. Acta Derm Venereol 1989; 69: 419–23. 5. Brinnel H, Friedel J, Caputa M, Cabanac M, Grosshans E: Rosacea: disturbed defense against brain overheating. Arch Dermatol 1989; Res 281: 66–72. 6. Nagasaki T, Brinnel H, Hales JR, Ogawa T: Selective brain cooling in hyperthermia: the mechanisms and medical implications. Med Hypotheses 1998; 50: 203–11. 7. Wilkin JK: Rosacea: pathophysiology and treatment. Arch Dermatol 1994; 130: 359–62. 8. Crawford GH, Pelle MT, James WD: Rosacea. I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol 2004; 51: 327–41.

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9. Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, Odom R 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; 445: 584–7. 10. Lehmann P, Arens A: Rosacea fulminans. In: Dermatologie an der Schwelle zum neuen Jahrtausend (Hrsg. A. Plettenberg, W.N. Meigel, I. Moll). Berlin, Heidelberg: Springer Verlag 2000; 257–9. 11. O'Leary PA, Kierland RR: Pyoderma faciale. Arch Dermatol 1940; 41: 451–62. 12. Plewig G, Jansen T, Kligman AM: Pyoderma faciale – a review and report of 20 additional acses: Is it rosaea? Arch Dermatol 1992; 128; 1611–7. 13. Hölzle E, Jansen T, Plewig G: Morbus Morbihan – Chronisch persistierendes Ödem des Gesichtes. Hautarzt 1995; 46: 796–8. 14. Wohlrab J, Lueftl M, Marsch WC: Persistent erythema and edema of the midthird and upper aspect of the face (morbus morbihan): evidence of hidden immunologic contact urticaria and impaired lymphatic drainage. J Am Acad Dermatol 2005; 52: 595–602. 15. Jansen T, Melnik B, Plewig G: Gramnegative Follikulitis als Begleitkomplikation bei Rosazea. Akt Dermatol 1994; 20: 381–4. 16. Leyden JJ, Thew M, Kligman AM: Steroid rosacea. Arch Dermatol 1974; 111: 619–22. 17. Segaert S, van Cutsem E: Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005; 16: 1425–33. 18. Gutzmer R, Werfel T, Kapp A, Elsner J: Kutane Nebenwirkungen einer EGF-Rezeptor-Blockade und deren Management. Hautarzt 2006; 57: 509–13. 19. Van Zuuren EJ, Graber MA, Hollis S, Chaudrdhry M, Gupta AK, Gover M: Interventions for rosacea. Cochrane database syst Rev 2004; (1): CD00326. 20. Lehmann P: Klinische Studien zur topischen Therapie mit Metronidazol bei Rosazea. In: Rosazea – Klinik und aktuelle Therapie. Schöfer) H (ed.), Stuttgart: Georg Thieme Verlag 2003; 41–50. 21. Altinyazar HC, Koca R, Tekin NS, Esturk E: Adapalene vs. Metronidazole gel for the treatment of rosacea. Int J Dermatol 2005; 44: 252–5. 22. Czernielewski J, Liu Y: Comparison of 15 % azelaic acid gel and 0,75 % metronidazole gel for the topical treatment of papulopustular rosacea. Arch Dermatol 2004; 140: 1282–3. 23. Bleicher PA, Charles JH, Sober AJ: Topical metronidazole therapy for rosacea. Arch Dermatol 1987; 123: 609–14. 24. Dahl MV, Katz I, Krueger GG et al.: Topical metronidazole maintains remissions of rosacea. Arch Dermatol 1998; 134: 679–83. 25. Erdoan FG, Yurtsever P, Aksoy D, Eskioglu F: Efficacy of low-dose isotretinoin in patients with treatment-resistant rosacea. Arch Dermatol 1998; 134: 884–5.

ADDITIONAL REFERENCES e1. Guerrera M, Parodi A, Cipriani C, Divano C, Rebora A: Flushing in rosacea: a possible mechanism. Arch Dermatol Res 1982; 272: 311–6. e2. Ljubojeviae S, Basta-Juzbasiae A, Lipozeneiae J: Steroid dermatitis resembling rosacea: aetiopathogenesis and treatment. J Eur Acad Dermatol Venereol 2002; 16: 121–6. e3. Elewski BE, Fleischer AB Jr, Pariser DM: A comparison of 15 % azelaic acid gel and 0,75 % metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol 2003; 139: 1444–500. e4. Vogt E, Friedrich HC: Orale 13-cis-Retinsäure-Therapie bei Adenoma sebaceum symmetricum und schwerster Akne- und Rosazeaform. Z Hautk 1982; 58: 646–67. Corresponding author Prof. Dr. med. Percy Mario Lehmann Klinik für Dermatologie, Allergologie und Umweltmedizin HELIOS-Klinikum Wuppertal Universität Witten-Herdecke Heusnerstr. 40 42283 Wuppertal, Germany [email protected]

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