Rosacea L71.9

Author: Prof. Dr. med. Peter Altmeyer

Co-Autor: Bahareh Ebrahimi

All authors of this article

Last updated on: 06.02.2024

Dieser Artikel auf Deutsch

Synonym(s)

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

History
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Probable first descriptors were the Persian physicians 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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Common, chronic, initially recurrent, later persistent, inflammatory disease with centrofacial telangiectasias, persistent or flushing onset temperature-, sun exposure-, food-, or psychologically (emotional stress) triggered erythema, and prolonged inflammatory episodes with follicular or parafollicular papules and plaques, follicular papulopustules, and pustules. In severe cases, the clinical picture is complicated by connective tissue and sebaceous gland hyperplasia (phyma) and ocular involvement. A relapsing course of the disease is characteristic.

Classification
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The classical classification according to 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), localized mainly nasolabially and in the cheek area.
  • Stage II(Rosacea papulopustulosa): Single or grouped, inflamed, reddened papules that persist for days to weeks, possibly with fine lamellar scaling. Sterile or normal follicular flora containing papulopustules and pustules. Scarless healing of the individual episodes, accumulation of episodes in the course of the disease.
  • Stage III(phymatous or glandular-hyperplastic rosacea ): Large inflammatory nodules and infiltrates, diffuse sebaceous gland hyperplasia (phyma formation), especially on the nose (see rhinophyma), cheeks, chin, forehead and ears. This stage of phyma formation occurs almost exclusively in males.
  • Complication: Ocular rosacea ( called ophthalmorosazea ) is expected in 30% of rosacea collectives. Eye involvement: Blepharitis, conjunctivitis, iritis, iridocyclitis, hypopyoniritis, keratitis with photophobia, pain, risk of blindness.
  • Special forms:
  • Localized phyma formation (in glandular hyperplastic rosacea).
  • Solid facial edema in rosacea (see Morbihan's disease below).

Current classification according to phenotypes: ROSCO (Global ROSacea COnsensus) with individualized treatment algorithms.

Occurrence/Epidemiology
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Prevalence data vary from region to region.

In a population of working people > 30 years, a prevalence of 22% was reported in an Estonian study. This would make rosacea the most common skin disease of all.

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

Rosacea occurs more frequently in the Celtic constitutional type, compared to the Mediterranean population (Reinholz 2016).

Etiopathogenesis
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The etiopathogenesis is not yet fully understood:

  • Innate immunity: Genetic dispositions with abnormalities in innate immunity (these concern the antimicrobial peptide cathelicidin and its activator kallikrein 5) and accompanying vascular dysfunction are regarded as the most likely cause. The human cathelicidin LL-37, as the actual active cleavage product of cathelicidin, plays a central role in rosacea pathogenesis (BW Park et al. 2018). This peptide has both antimicrobial and immunomodulatory properties. The increased activities of the cathelicidin peptides and the increased protease activities lead to proinflammatory cathelicidin fragments, some of which are not found in healthy skin. They release the proinflammatory interleukin-8. Furthermore, cathelicidin fragments have been found to stimulate vascular growth by releasing VEGF (vascular endothelial growth factor) from keratinocytes.
  • Adaptive immune system: An activation of B and T cells can be assumed in the various forms of rosacea. Forms of rosacea can be assumed. The migration of pro-inflammatory T-cell lymphocytes (Th1/Th17) is already observed in an early form of rosacea. This leads to an upregulation of proinflammatory cytokines such as TNF-alpha, interleukin-17 and interferons. Macrophages and mast cells are also involved in the inflammatory tissue reaction. In rosacea papulopustulosa, IL-8 is overexpressed as well as the chemokines CXCL1, CXCL2 and CXCL6, which leads to the recruitment of neutrophilic leukocytes and angiogenesis .
  • Role of microorganisms: Follicular Demodex mites are possible co-triggers of the inflammatory tissue reaction. The density of Demodex mites is increased in the skin of rosacea patients. Specific antibodies against mite components can be detected. The success of systemic and local therapy approaches with antiscabiosa indicates the pathogenetic significance of mite colonization. The pathogenicity of increased colonization with Helicobacter pylori or general bacterial colonization of the small intestine is rather doubtful (Gravina A et al. 2015).
  • Neuroinflammation and vascular hyperreactivity: Intrusive and persistent erythema (flushing) are seminal clinical features of rosacea. A dysregulation of the neuroimmunological unit is held responsible for this (Steinhoff 2015). Trigger factors for flushing include UV rays, X-rays, heat, cold, excitement, coffee, alcohol, tea, hot spices (pepper, curry), temperature fluctuations, external (too oily) cosmetics and hormonal fluctuations (menstruation, pregnancy, menopause). The influence of Helicobacter pylori is controversially discussed. In summary, rosacea can contribute to the development of cardiovascular diseases, as its inflammatory properties cause endothelial dysfunction, which is the first step towards atherosclerosis.
  • Biologics: Rosacea-like skin changes are detected in 30-40% (!) of oncology 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.
  • Gluten sensitivity/diabetes mellitus and rosacea: A case-control study (Egeberg A et al. 2016/2017) with 6759 rosacea patients showed significantly increased rates of type 1 diabetes mellitus and gluten intolerance/coeliac disease, especially in women. These results indicate a link between gluten intolerance and rosacea and suggest that implementing a GFD (gluten-free diet) could provide relief for rosacea patients.

Manifestation
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Occurring mainly in the 4th and 5th decade of life. Approximately 80% of those with the disease are >30 years of age. The average age was 35.9 years in larger collectives (Yang F et al. 2023).

Women are affected more often (?) than men. This statement is disputed in versch. Studies dispute (apparently there are worldwide regional differences in the prevalence pattern). Women typically develop rosacea from 35 years of age with a peak incidence around 61-65 years of age.

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

Complicating pyoderma faciale is observed almost exclusively 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 irritants. Irritating applications such as overly irritating soaps, syndets, alcoholic tinctures. Astringents and peeling agents should be avoided.

Sunlight: Sunlight often exacerbates disease. Light protectants are recommended. In contrast to the widely used chemical sunscreens, physical sunscreens are recommended, which contain highly 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, use broad-spectrum sunscreens with SPF > 15, if possible with protection against UVB and UVA as well as infrared (e.g. Anthelios).

Facial massage: Today, massage treatments according to Sobye are rarely performed, with circular movements over the nose, cheeks and forehead in the morning and evening.

External therapy
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S. Table

Brimonidine: Brimonidine tatrate (preparation: Mirvaso®) is approved for the treatment of erythematous rosacea. In clinical trials, 0.3% brimonidine gel had 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 could be confirmed via 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. A 1% ivermectin cream (Soolantra®) is approved. Good tolerability and efficacy has been demonstrated 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 antioxidant and anti-inflammatory effect is assumed.

Supplementary: To cover reddened skin areas (with simultaneous light protection), a tinted concealer paste is recommended, as it is listed in the NRF in several tint levels (NRF 11.59.).

Topical off-label therapy:

  • Permethrin: If rosacea superimposed by Demodex folliculorum is suspected, therapy (for several months) with antiscabiosa such as low-dose permethrin (1-2% in Ung. emulsific. aquos) is recommended.
  • 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 (mainly Adapalene 0 .1%) are considered an alternative to metronidazole when used chronically. Efficacy 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 in inflammatory rosacea with different results. They cannot be considered as 1st choice agents.
  • Alternative treatment of erythema: lesional botulinum toxin injections (off-label use). Positive effects exist in smaller groups (Park KY et al. 2015).

Internal therapy
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Antibiotics: Excellent response to oral antibiotics, especially in papulopustular forms. In addition, functional erythema is reduced. Since patients are often very good at assessing disease activity themselves, patient suggestions should be taken into account in dosing.

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

  • Alternative: Macrolide antibiotics: In case of intolerance or lack of success, erythromycin (e.g. Erythro Hefa 500) 2-3 times/day 500 mg as well as other macrolide antibiotics like roxithromycin (e.g. Rulid) 2 times/day 150 mg: clarithromycin (e.g. Klacid) initially 2 times/day 250 mg, later 250mg 1 time/day or azithromycin can be used.
  • Alternative: Rifaximin, a broad-spectrum bactericidal oral antibiotic, is a semisynthetic derivative of rifamycin. Rifaximin is virtually unabsorbed (< 1%) and thus is effective exclusively in the intestinal lumen. Dosage: 3x400mg/day for 10 days (Weinstock LB et al 2013).
  • Alternative(off-label): Isotretinoin (e.g. acnenormin): Monotherapy with isotretinoin is indicated for severe and refractory forms of rosacea that do not respond or respond inadequately to antibiotic therapy, such as lupoid rosacea, stage III rosacea, rosacea conglobata, gram-negative rosacea, and rosacea fulminans. The standard dose is 0.3 mg/kg bw/day; in milder forms of rosacea, 0.1-0.2 mg/kg bw/day is sufficient. These doses are also used in ophthalmorosazea. 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 in women of childbearing age. Civil law and, if necessary, also criminal law responsibility therefore lie expressly with the treating physician! For women of childbearing age, contraceptive measures are therefore absolutely necessary! Pregnancy test before beginning therapy, safe contraception one month before beginning therapy, during the entire course of therapy and one month after the end of therapy.

Note: No combination with tetracyclines, as there is a risk of increased intracranial pressure and pseudotumor 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) with glucocorticoids for a short time. Dosage: 20-40 mg prednisolone equivalent/day for 1-2 weeks, then taper rapidly 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 antiandrogen agents. 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 drg./day on the 1st to 21st day of the cycle, then 7 days off, then 1 drg./day again for 21 days, then 7 days off again, etc.

Notice. In 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 limiting flushing symptoms: Carvedilol ( a non-selective- beta blocker leads in a dosage of 2x 6,25mg/day p.o. to an improvement of the erythema tendency. The therapy is designed as a continuous 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®).

Reminder. In refractory rosacea erythema, paroxetine has been successfully used (Wang B et al. 2023/Paroxetine is a selective serotonin reuptake inhibitor (SSRI) and approved in Germany for the following indications: depressive disorders, generalized anxiety disorder, panic disorder with or without agoraphobia, social phobia, posttraumatic stress disorder as well as obsessive-compulsive disorder) (dosage 25mg/day p.os.). Caution: the wide spectrum of side effects is to be considered with this substance!

Prophylaxis
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The following measures are recommended for prophylaxis:

- cleanse skin gently, e.g. with lukewarm water and dry dabbing

- use light/hydrophilic skin care products

Not recommended are:

- do not use strong rubbing, peelings and blood circulation-enhancing or astringent substances

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 themselves which foods are tolerated and which are not.

Mouth, nose and eye protection can lead to a worsening of rosacea - early therapy is indicated depending on the clinical picture, as well as regular changing of the masks.

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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  2. BW Park et al. (2018) A Study on Vitamin D and Cathelicidin Status in Patients with Rosacea: Serum
  3. Level and Tissue Expression. Ann Dermatol 30:136-142.
  4. Caf N et al. (2023) Evaluation of subclinical atherosclerosis in rosacea patients by flow-mediated dilatation method. J Cosmet Dermatol 22:1001-1010.
  5. Chu CY (2005) The use of 1% pimecrolimus cream for the treatment of steroid-induced rosacea. Br J Dermatol 152: 396-399
  6. de Bersaques J (1995) Historical Notes on Rosacea. European Journal of Dermatology 5: 16-22
  7. Egeberg A et al. (2016) Clustering of autoimmune diseases in patients with rosacea. J Am Acad Dermatol 74:667-72.
  8. 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.
  9. Egeberg A et al.(2017) Rosacea and risk of cancer in Denmark. Cancer Epidemiol 47:76-80.
  10. Egeberg A et al. (2017) Rosacea and gastrointestinal disorders: a population-based cohort study. Br J Dermatol 176:100-106.
  11. 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
  12. Gonsoer LI et al. (2016) Pathogenesis, clinical features and current therapy of rosacea. Dermatologist 67: 69-84
  13. Gravina A et al. (2015) Helicobacter pylori infection but not small intestinal bacterial overgrowth may
  14. play a pathogenic role in rosacea. United European Gastroenterol J 3:17-24.
  15. 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
  16. 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.
  17. 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
  18. Li WQ et al. (2015) Personal history of rosacea and risk of incident cancer among women in the US.
  19. Br J Cancer 113:520-523.
  20. 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.
  21. Park KY et al. (2015) Botulinum toxin for the treatment of refractory erythema and fl ushing of rosacea.
  22. Dermatology 230:299-301.
  23. Powell FC (2005) Clinical practice. Rosacea. N Engl J Med 352: 793-803
  24. Rebora A (2002) The management of rosacea. Am J Clin Dermatol 3: 489-496
  25. Reinholz M et al. (2016) Pathogenesis and clinic of rosacea as the key to symptom-oriented therapy. J Dtsch Dermatol Ges 14 Suppl 6:4-16.
  26. Schaller M et al. (2016) Rosacea management: update on general measures and topical therapy options.J Dtsch Dermatol Ges 14 Suppl 6:17-28.
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  28. Steinhoff M et al.(2016) Facial Erythema of Rosacea - Aetiology, Different Pathophysiologies and Treatment Options. Acta Derm Venereol 96:579-586.
  29. Taieb A et al. (2016) Maintenance of remission following successful treatment of papulopustular rosacea with ivermectin 1% cream vs. metronidazole 0.75% cream: 36-week extension of the
  30. ATTRACT randomized study.J Eur Acad Dermatol Venereol 30:829-36.
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  32. Veien NK (1985) Topical metronidazole in the treatment of rosacea. Cutis 38: 209-210
  33. Wang B et al. (2023) Paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the Prospective Rosacea Refractory Erythema Randomized Clinical Trial. J Am Acad Dermatol 88:1300-1307.
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