Rosacea L71.9

Author: Prof. Dr. med. Peter Altmeyer

Co-Autor: Bahareh Ebrahimi

Our authors

Last updated on: 29.10.2020

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Synonym(s)

acne rosacea; Copper fin; Couperose; Red fin; Rosacea

History
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Presumable first descriptors were the Persian doctors Rhazes (865-932) and Avicenna (989-1037); later important descriptors: de Chauliac 14th century, Bateman 1812, Piffard 1891, Kaposi 1893.

Definition
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Frequent, chronic, initially recurrent, later persistent, inflammatory disease with centrofacial telangiectasias, persistent or flush-like onset of temperature, food or psychologically triggered erythema, as well as longer lasting inflammatory episodes with follicular, also parafollicular papules and plaques, follicular papulopustules and pustules. In severe cases, the clinical picture is complicated by connective tissue and sebaceous gland hyperplasia (phymogenesis) and eye involvement. A relapsing course is characteristic.

Classification
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A distinction is made between different stages of development:

  • Stage 0: Functional (transient) erythema: Volatile, often seizure-like livid facial erythema (flushing).
  • Stage I(rosacea erythematosa): Persistent erythema for hours and days. There is a risk of increasing formation of telangiectasias (rosacea teleangiectatica), which are mainly located nasolabially and in the cheek area.
  • Stage II(rosacea papulopustulosa): Individual or grouped, inflammatory, reddened, possibly finely lamellar scaly papules that persist for days to weeks. Papulopustules and pustules containing sterile or normal follicular flora. Scarless healing of the individual episodes, in the course of which the episodes accumulate.
  • Stage III(phymatous or glandular hyperplastic rosacea ): Large, inflammatory nodules and infiltrates, diffuse hyperplasia of the sebaceous glands (phymogenesis), especially on the nose (see rhinophyma below), cheeks, chin, forehead and ears. This stage of phymogenesis occurs almost exclusively in men.
  • Complication: Ocular rosacea - called ophthalmorosacea - is to be expected in 30% of the rosacea collectives. Eye involvement: Blepharitis, conjunctivitis, iritis, iridocyclitis, hypopyoniritis, keratitis with photophobia, pain, risk of blindness.
  • Special forms:
  • Localized phymogenesis (in glandular hyperplastic rosacea)
  • Solid facial edema in rosacea (see below M. Morbihan).

Occurrence/Epidemiology
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The prevalence figures are different.

In a population of working people > 30 years, a prevalence of 22% was reported in an Estonian study. Rosacea would thus be the most common skin disease.

In a German population of 90,880 workers, a prevalence of 2.3% was found, while a Swedish study of 809 workers found a prevalence of 10%.

Compared to the Mediterranean population, rosacea occurs more frequently in the Celtic constitution type (Reinholz 2016).

Etiopathogenesis
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The aetiopathogenesis has not yet been fully clarified:

  • Congenital immunity: Genetic dispositions with abnormalities in congenital immunity (these concern the antimicrobial peptide cathelicidin and its activator kallikrein 5), concomitant vascular dysfunction are considered the most likely cause. Human cathelicidin LL-37, as the active cleavage product of cathelicidin, plays a central role in the pathogenesis of rosacea (BW Park et al. 2018). This peptide has both antimicrobial and immunomodulatory properties. The increased activities of cathelicidin peptides and the increased protease activities lead to pro-inflammatory cathelicidin fragments, some of which are not found in healthy skin. They release the pro-inflammatory interleukin-8. It has also been found that cathelicidin fragments stimulate vascular growth by releasing VEGF (vascular endothelial growth factor) from keratinocytes.
  • Adaptive immune system: The activation of B and T cells is a key factor in the development of various diseases. forms of rosacea. Already in an early form of rosacea the immigration of proinflammatory T-cell lymphocytes (Th1/Th17) is observed. This leads to an upregulation of proinflammatory cytokines such as TNF-alpha, interleukin -17 and interferons. Furthermore, macrophages and mast cells are involved in the inflammatory tissue reaction. In rosacea papulopustulosa, IL-8 are overexpressed and the chemokines CXCL1, CXCL2 and CXCL6 are overexpressed, leading to recruitment of neutrophilic leukocytes and angiogenesis .
  • Role of microorganisms: Follicular demodex mites are possible co-triggers of the inflammatory tissue reaction. In the skin of rosacea patients the density of demodex mites is increased. Specific antibodies against mite components can be detected. The success of systemic and local therapy approaches with antiskabiosa points to the pathogenetic significance of mite colonization. The pathogenicity of an increased colonization with Helicobacter pylori or a general bacterial miscolonization of the small intestine is rather doubtful (Gravina A et al. 2015).
  • Neuroinflammation and vascular hyperresponsiveness: Flushing and persistent erythema are the leading clinical features of rosacea. Dysregulation of the neuroimmunological unit is blamed for this (Steinhoff 2015). Trigger factors of flushing include UV rays, X-rays, heat, cold, agitation, coffee, alcohol, tea, pungent spices (pepper, curry), temperature fluctuations, external (too fatty) cosmetics and hormonal fluctuations (menstruation, pregnancy, menopause). The influence of Helicobacter pylori is controversially discussed.
  • Biologics: Rosacea-like skin changes are detected in 30-40% (!) of oncological patients treated with EGFR receptor inhibitors, e.g. cetuximab, erlotinib, panitunumab and gefitinib. Tyrosine kinase inhibitors such as imatinib and nilotinib can also cause rosacea-like changes.

Manifestation
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Mainly occurring in the 4th and 5th decade of life. About 80% of the patients are > 30 years old.

Women are affected more frequently (?) than men. This statement is used in various publications. This statement is disputed in various studies (apparently there are worldwide regional differences in the prevalence pattern). Women typically develop rosacea from the age of 35 with a peak of frequency around the 61st-65th year of life.

Rosacea is more severe in men than in women. In particular, stage III rosacea (phymic rosacea) is rarely seen in women. Men have the highest prevalence around the age of 76 to 80.

The complicative pyoderma faciale is almost exclusively observed in younger women.

Localization
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Initially centrofacially occurring, later extending to the neck, retroauricular region and pre-sternal area.

Histology
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Ectatic blood and lymph vessels, perivascular and perifollicular lymphohistiocytic infiltrates; especially in sebaceous gland follicle regions, follicular papules and pustules.

Differential diagnosis
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Stage I (rosacea erythematosa):

  • Constitutional redness of the face(erythema perstans faciei): persistent redness, not variable, no flushing symptoms.
  • Chronic frost damage: extensive erythema, actinic damage, no flushing history.
  • Scarlet fever: Acute course; severe disease symptoms; such symptoms are completely absent in the r.
  • Erysipelas: Acute course; fever, painfulness, painful lymphadenopathy
  • Circulation disturbances versch. (hypertension, mitralvitium); known internal medicine problems; blue-red facial colour; no flushing symptoms.
  • Flush phenomena(carcinoid syndrome, medication erythema e pudore): Seizure-like erythema, no triggers as in rosacea (here e.g. alcohol)
  • Lupus erythematosus, systemic: butterfly erythema, sometimes comparable; severe symptoms (patient appears sick!).
  • Dermatomyositis: extensive heliotropic erythema; purple; severe symptoms (patient appears sick!); conspicuous muscle weakness.
  • Long-term pre-treatment with glucocorticoid ointments(see also steroid skin): Usually flat, blurred erythema, often pustules, considerable feeling of tension (patient suffers!). Polycythaemia(Polycythaemia vera): No changeable but persistent redness; colour rather blue-red.
  • Seborrheic eczema: Centrofacial scaly redness, usually also discrete fine-lamellar scaling of the head. Often infestation of other seb. zones (e.g. sternal area):
  • photodermatoses(actinic reticuloid; chronic actinic dermatitis).

Stage II (rosacea papulosa/pustulosa):

Stage III (skin lesions are diagnostic):

Complication(s)
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A connection between rosacea and migraine has been proven. In a larger Danish study 12.1% of rosacea patients (16% of women, 4% of men) suffered from migraine (in the total population it was only 7.3% (Egeberg A et al. 2017).

Other neurological diseases are also more common in rosacea: Parkinson's disease, multiple sclerosis, Alzheimer's disease.

General therapy
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  • Skin care: The skin of rosacea patients is particularly sensitive to chemical and physical stimuli. Irritating applications such as overly irritating soaps, syndets, alcoholic tinctures. Astringents and peeling agents should be avoided.
  • Sunlight: Sunlight often aggravates diseases. Sunscreens are recommended. In contrast to the widely used chemical sunscreens, physical light protection filters are recommended, which contain strongly crushed, 20-50 nm particles of zinc oxide and/or titanium oxide and do not burn the skin or eyes (e.g. Micro sun 20, Eucerin Sun). Alternatively, broadly effective sun protection creams with SPF > 15 should be used if possible with protective effects against UVB and UVA as well as infrared (e.g. Anthelios).
  • Facial massage: Nowadays, massage treatments according to Sobye are only rarely carried out. In the morning and evening, massage is applied with circular movements over the nose, cheeks and forehead.

External therapy
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See table

Brimonidine: Brimonidine tartrate (preparation: Mirvaso®) is approved for the treatment of erythematous rosacea. In clinical trials, 0.3% of the gel of brimonidine had achieved significantly greater improvements in facial flushing in rosacea than placebo. The most common side effects (incidence ≥ 1%) during short-term treatment were flushing, erythema, burning of the skin and contact dermatitis. The good clinical and persistent effect has been confirmed by an open-label long-term study over 12 months (Moore A et al 2014). The preparation can be combined with anti-inflammatory rosacea therapeutics.

Alternative: Ivermectin (1% ivermectin cream) is an alternative to permethrin and metronidazole formulations. Approved is a 1% ivermectin cream (Soolantra®). The good tolerability and efficacy has been proven in a long-term study over 52 weeks (Taieb A et al. 2016).

Alternative: Metronidazole has been a cornerstone of rosacea therapy (papulo-pustular rosacea) for >30 years. It is available both as a magistral formulation and in numerous ready-to-use preparations (gel, cream, lotion, e.g. Metrogel®). An antioxidative and anti-inflammatory effect is assumed.

Supplementary: To cover reddened skin areas (with simultaneous sun protection), a tinted masking paste is recommended as indicated in the NRF in several tinting levels (NRF 11.59.).

Topical off-label therapy:

  • Permethrin: If rosacea superimposed by Demodex folliculorum is suspected, therapy with antiscabiosa such as low-dose permethrin (1-2% in ungu. emulsific. aquos) is recommended (over several months).
  • Alternative: Benzyl benzoate: If rosacea superimposed by Demodex folliculorum is suspected, benzyl benzoate (10-20% in commercial preparations) may be a well tolerated alternative.
  • Alternative: Topical retinoids (especially adapalene 0.1%) are considered as an alternative to metronidazole in chronic use. The efficiency is considered better than a 0.75% metronidazole gel (e.g. Metrogel®) in inflammatory rosacea
  • Alternative: The clinical results of the calcineurin inhibitors Tacrolimus and Pimecrolimus are evaluated with different results in inflammatory rosacea. They cannot be considered as first choice remedies.
  • Alternatively to the treatment of erythema: lesional botulinum toxin injections (off-label use). This has positive effects in smaller groups (Park KY et al. 2015).

Internal therapy
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Antibiotics: Excellent response to oral antibiotics, especially in papulopustular forms. Functional erythema is also reduced. Since patients are often very good at assessing disease activity themselves, patients' suggestions should be taken into account in the dosage.

  • Tetracyclines: Antibiosis is usually carried out over several weeks with tetracyclines p.o. (e.g. Tetracycline-Wolff Kps.) 500-1000 mg/day distributed over 1-2 ED, with improvement of the clinical findings reduction to 500-250 mg/day.
  • Alternatively: Minocycline (e.g. Klinomycin, Mino-Wolff) 100 mg/day p.o., reduction to 50 mg/day according to the clinic or Doxycycline in a dosage of initially 100mg/day after 14 days of 50mg/day are equally effective.
  • Alternative: Doxycycline in non-antibiotic concentration: In papulo-pustular rosacea oral doxycycline in "subantimicrobial" low dosage (40mg/day p.o.) is as effective as conventional therapy with 100 mg/day (preparation Oraycea®).
  • Remember! Minocycline has less phototoxic effect than other tetracyclines!

  • Alternative: Macrolide antibiotics: In case of intolerance or unsuccessful treatment, Erythromycin (e.g. Erythro Hefa 500) can be used 2-3 times/day 500 mg and other macrolide antibiotics like Roxithromycin (e.g. Rulide) 2 times/day 150 mg: Clarithromycin (e.g. Klacid) initially 2 times/day 250 mg, later 250mg once/day or Azithromycin.
  • Alternatively, rifaximin, a broad-spectrum oral bactericidal antibiotic, is a semi-synthetic derivative of rifamycin. Rifaximin is practically not absorbed (< 1%) and is therefore only effective in the intestinal lumen. Dosage: 3x400mg/day for 10 days (Weinstock LB et al. 2013).

Alternatively(off-label): Isotretinoin (e.g. acne normin): In severe and refractory forms of rosacea which do not respond or do not respond adequately to antibiotic therapy, such as lupoid rosacea, stage III rosacea, conglobate rosacea, Gram-negative rosacea and rosacea fulminans, monotherapy with isotretinoin is indicated. The standard dose is 0.3 mg/kg bw/day; for milder forms of rosacea, 0.1-0.2 mg/kg bw/day is sufficient. These doses are also used in ophthalmorosacea. In mild to moderate forms of rosacea, good results can be achieved with daily doses as low as 2.0-2.5 mg (!). Duration of therapy: several months/years. The therapy is. Cave! Isotretinoin systemic therapy is not approved for women of childbearing age. Civil law and possibly also criminal law responsibility is therefore explicitly the responsibility of the treating physician! Contraceptive measures are therefore absolutely necessary for women of childbearing age! Pregnancy test before the start of therapy, safe contraception one month before the start of therapy, during the entire course of therapy and one month after the end of therapy.

Remember! No combination with tetracyclines, as there is a risk of cerebral pressure increase and pseudotumour cerebri!

Alternative for complicated forms: glucocorticoid/isotretinoin combinations: In selected severe forms such as rosacea fulminans it may be necessary to combine isotretinoin (dosage see above) briefly with glucocorticoids. Dosage: 20-40 mg prednisolone equivalent/day for 1-2 weeks, followed by rapid balancing to shorten the course of the disease. Treatment with isotretinoin is continued until all inflammatory changes have healed.

Alternative antiandrogen/isotretinoin combinations: In women, isotretinoin therapy can be combined with antiandrogenic substances. In addition to isotretinoin, cyproterone acetate and ethinyl estradiol can be given in combination, e.g. Diane 35 (2 mg cyproterone acetate and 35 μg ethinyl estradiol) 1 drag/day on the 1st to 21st day of the cycle, then 7 days rest, then again 21 days 1 drag/day, then again 7 days rest, etc.

Notice! In the case of therapy-resistant rosacea-like skin changes, demodicosis should be considered, see below. Demodicosis (see also: external therapy with 1% ivermectin cream).

Alternatively Carvedilol: Patients with restrictive flushing symptoms: Carvedilol (a non-selective beta-blocker leads to an improvement of the erythema tendency in a dosage of 2x 6.25mg/day p.o. The therapy is designed as a long-term therapy (1-3x 6.25mg/day p.o.), possibly in combination with doxycycline. Control of blood pressure and pulse rate is necessary (preparations: Dilatrend®, Dimetil®)

Naturopathy
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The active ingredient complex of rutoside (rutin), nicotiflorin and epicatechin acts as a phytoextract in rosacea anti-inflammatory (IL-1 inhibition) and inhibits the angiogenesis factor VEGF.

Tables
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Stage-dependent external and internal therapy of rosacea

Ammonium bituminosulfonate pastes

Azelaic acid

Metronidazole

Other antibiotics

Isotretinoin

Laser

External

External

External

External

Internal

External

Internal

Stage I (rosacea erythematosa)

Persistent erythema

++

+++

+++

-

+

-

-

-

Teleangiectasia

-

-

-

-

-

-

-

+++

Stage II (rosacea papulosa/pustulosa)

Persistent erythema

++

+++

+++

+

++

-

-

-

Teleangiectasia

-

-

-

-

-

-

-

+++

Papules, pustules

+++

+++

+++

+

+++

(+)

+

-

Edema

++

+++

++

-

+

-

+

-

Stage III

Persistent erythema

++

+++

+++

-

++

-

+

+

Teleangiectasia

-

-

-

-

-

-

-

+++

papules, pustules, knots

+++

+++

+++

+

+++

(+)

+++

-

Edema

++

++

++

-

+

-

++

-

hyperplasia of sebaceous glands and connective tissue

++

-

-

+

++

++

+++

-

Diet/life habits
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A specific rosacea diet does not exist. However, erythema-inducing factors such as hot drinks, strongly spiced food and alcohol should be avoided. Each patient should find out for himself which foods are tolerated and which are not.

Note(s)
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In an epidemiological study it was shown that women with rosacea have a significantly increased risk of thyroid cancer (60%), bronchial cancer and basal cell carcinoma (50%). (Li WQ et al. 2015; Egeberg A et al. 2017)

Literature
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  1. Abram K et al (2010) Prevalence of rosacea in an Estonian working population using a standard classification. Acta Derm Venereol 90:269-273
  2. BW Park et al (2018) A Study on Vitamin D and Cathelicidin Status in Patients with Rosacea: SerumLevel
    and Tissue Expression. Ann Dermatol 30:136-142.
  3. Chu CY (2005) The use of 1% pimecrolimus cream for the treatment of steroid-induced rosacea. Br J Dermatol 152: 396-399
  4. de Bersaques J (1995) Historical Notes on Rosacea. European Journal of Dermatology 5: 16-22
  5. Egeberg A et al (2017) Prevalence and risk of migraine in patients with rosacea: A population-basedcohort
    study.J Am Acad Dermatol 76:454-458.
  6. Egeberg A et al (2017) Rosacea and risk of cancer in Denmark.
    Cancer epidemiol 47:76-80.
  7. Elewski BE et al (2003) A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papular rosacea. Arch Dermatol 139: 1444-14450
  8. Gonsoer LI et al (2016) Pathogenesis, kiknik and current therapy of rosacea. Dermatologist 67: 69-84
  9. Gravina A et al (2015) Helicobacter pylori infection but not small intestinal bacterial overgrowth mayplay
    a pathogenic role in rosacea. United European Gastroenterol J 3:17-24.

  10. Gregory A et al (1994) A Comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea. Arch Dermatol 130: 319-324

  11. Hsu CC et al (2012) Pronounced facial flushing and persistent erythema of rosacea effectively treated by carvedilol, a nonselective β-adrenergic blocker. J Am Acad Dermatol 67:491-493.
  12. Jappe U, Schnuch A, Uter W (2005) Rosacea and contact allergy to cosmetics and topical medicaments - retrospective analysis of multicentre surveillance data 1995-2002. contact dermatitis 52: 96-101
  13. Li WQ et al (2015) Personal history of rosacea and risk of incident cancer among women in the US.
    Br J Cancer 113:520-523.
  14. Moore A et al (2014) Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5%for the treatment of moderate to severe facial erythema of rosacea: results of a 1-year open-label study. J Drugs Dermatol 13:56-61.
  15. Park KY et al (2015) Botulinum toxin for the treatment of refractory erythema and fl ushing of rosacea.
    Dermatology 230:299-301.
  16. Powell FC (2005) Clinical practice. rosacea. N Engl J Med 352: 793-803
  17. Rebora A (2002) The management of rosacea. At J Clin Dermatol 3: 489-496
  18. Reinholz M et al (2016) Pathogenesis and Clinic of Rosacea as a Key to Symptom-Oriented Therapy
    . J Dtsch Dermatol Ges 14 Suppl 6:4-16.
  19. Schaller M et al (2016) Rosacea Management: Update on general measures and topical therapy options
    .J Dtsch Dermatol Ges 14 Suppl 6:17-28.
  20. Schöfer H (2013) Topical therapy of rosacea. Dermatologist 64: 494-499
  21. Steinhoff M et al(2016) Facial Erythema of Rosacea - Aetiology, Different Pathophysiologies and Treatment Options. Acta Derm Venereol 96:579-586.
  22. Taieb A et al (2016) Maintenance of remission following successful treatment of papulopustular rosaceawith
    ivermectin 1% cream vs. metronidazole 0.75% cream: 36-week extension of theATTRACT
    randomized study.J Eur Acad Dermatol Venereol 30:829-36.
  23. Taub AF (2003) Treatment of rosacea with intense pulsed light. J Drugs Dermatol 2: 254-259
  24. Veien NK (1985) Topical metronidazole in the treatment of rosacea. Cutis 38: 209-210
  25. Vine LB (2013) Rosacea in Crohn's Disease: Effect of Rifaximin. J Clin Gastroenterol 45:295-296.
  26. Wilkin JK (1994) Rosacea. Pathophysiology and treatment. Arch Dermatol 130: 359-362

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