Swiss S1 Guideline For The Treatment of Rosacea: Jeadv

DOI: 10.1111/jdv.
14349 JEADV
GUIDELINES
Swiss S1 guideline for the treatment of rosacea

F. Anzengruber,1 J. Czernielewski,2 C. Conrad,2 L. Feldmeyer,3 N. Yawalkar,3 P. Ha €usermann,4 A. Cozzio,5
€uchli,1 L. Imhof,1 C. Brand,8 E. Laffitte,9 A.A. Navarini1,*
C. Mainetti,6 D. Goldblum,7 S. La
1
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
2
Department of Dermatology, University Hospital Lausanne, Lausanne, Switzerland
3
Department of Dermatology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland
4
Department of Dermatology, University Hospital Basel, Basel, Switzerland
5
Department of Dermatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
6
Department of Dermatology, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland
7
Department of Ophthalmology, University Hospital Basel, Basel, Switzerland
8
Department of Dermatology, Lucerne Cantonal Hospital, Lucerne, Switzerland
9
Department of Dermatology, University Hospital Geneva, Geneva, Switzerland
*Correspondence: A.A. Navarini. E-mail: [email protected]
Abstract
Rosacea (in German sometimes called ‘Kupferfinne’, in French ‘Couperose’ and in Italian ‘Copparosa’) is a chronic and
frequently relapsing inflammatory skin disease primarily affecting the central areas of the face. Its geographic prevalence
varies from 1% to 22%. The differential diagnosis is wide, and the treatment is sometimes difficult and varies by stage of
rosacea. For erythematous lesions and telangiectasia, intense pulsed light (IPL) therapy and lasers are popular treatment
option. In addition, a vasoconstrictor agent, brimonidine, has recently been developed. For papulopustular rosacea, topi-
cal antibiotics, topical and systemic retinoids, as well as systemic antibiotics are used. A topical acaricidal agent, iver-
mectin, has undergone clinical development and is now on the market. In the later stages, hyperplasia of the sebaceous
glands develops, resulting in phymatous growths such as the frequently observed bulbous nose or rhinophyma. Ablative
laser treatments have largely replaced classical abrasive tools. Here, we reviewed the current evidence on the treatment
of rosacea, provide a guideline (S1 level) and discuss the differential diagnosis of rosacea.
Received: 20 December 2016; Accepted: 8 May 2017
Conflicts of interest
F.A. has received honoraria from Abbvie, Celgene, Leo Pharma and Novartis. He is funded by HSM2
(Hochspezialisierte Medizin) from the canton of Zurich and CTI-grant (18556.1).
A.A.N. is funded by the Promedica and Bruno-Bloch Foundation. He is also on the advisory board of Galderma.
D.G. has no conflict of interests regarding rosacea.
N.Y. has served as an advisor for Galderma and does not hold any shares or other financial interest in any related
pharmaceutical company.
All other authors have stated that no conflict of interest exists.
Funding sources
None declared.
Key message
This article provides an extensive review on the treatment of rosacea and is a practical guideline for the clinician.
Introduction and Epidemiology pustules and disfiguring growth of hyperplastic sebaceous glands
Rosacea is a common centrofacial skin disease most often of the on the nose and other facial regions occurs.
middle-aged and elderly.1,2 It can start with flush-like temporary The incidence is 165/100 000 per year,1 and the prevalence
dilation of capillaries and fleeting erythema, subsequently telang- varies greatly between countries from 1% to 22%.3,4–7 Persons
iectasias develop and persisting erythematous macules, especially with fair skin type have an increased risk of rosacea.8,9–11 Vari-
on cheeks and nose. In more severe cases, development of ous studies revealed conflicting data on rosacea’s gender
JEADV 2017, 31, 1775–1791 © 2017 European Academy of Dermatology and Venereology
1776 Anzengruber et al.
preference, which might vary between distinct populations. Adaptive immune cells
1–2,4,7,12
The usual age of onset is between 30 and 50 years; how- T cells (especially Th1/Th17-polarized immune cells), macro-
ever, in rare cases, rosacea can already occur in children.13 phages, mast cells and neutrophils are present in rosacea of all
While recently, an expert panel of dermatologists and oph- subtypes I-III. Neutrophils are assumed to play an essential part
thalmologists has agreed on a phenotype-based classification in the pathogenesis of rosacea.35–38 Reactive oxygen species
(transient and persistent erythema, telangiectasias, inflammatory (ROS) and other proteases are produced by neutrophils and
papules or pustules, and phyma),14 the most commonly used damage blood vessels. This causes inflammation as well as angio-
and the best known classification refers to subtype I or erythe- genesis, subsequently leading to telangiectasias.8 Recently, an
matotelangiectatic rosacea (ETR), subtype II, or papulopustular involvement of B cells in the pathomechanism of rosacea was
rosacea (PPR), subtype III (phymatous rosacea) and subtype IV shown as well.37
(ocular rosacea).
Mites
Pathomechanism Demodex mites, even though they are present in normal adult
skin as well, can be found in increased numbers in numerous
Genetics rosacea patients.39–43 A decrease in demodex mites in human
Rosacea has genetic risk factors15 including a genomewide associ- skin correlates with improvement of rosacea symptoms.44
ation signal in polymorphisms nearby the BPTK316 as well as sig-
nals in the MHC class II molecules. Twin studies17 revealed that Blood vessels
about half of the risk of apparent rosacea is due to genetics, the Vascular dilatation results in erythema, in its fleeting form often
other half to environment factors. It is considered a complex dis- perceived as facial flushing. In rosacea, the papillary dermal vas-
order and does not show Mendelian inheritance in pedigrees. An culature is dilated and perfusion of the skin is increased.40,45
autosomal-dominant genodermatosis called Haber’s syndrome is
the only example whereby rosacea – as part of a syndrome with Nerves
multiple other clinical features – can be inherited directly.18 Sensory nerve endings are activated to release vasoactive neu-
ropeptides by transient receptor potential (TRPs) channels.46–48
Environment Two calcium channel blockers and members of the TRP family,
Environmental trigger factors include exposure to extremes of transient receptor potential vanilloid 1 (TRPV 1) and Ankyrin 1
temperature (hot and cold air), temperature changes, caffeine, (TRPA 1) are of special interest in rosacea as they mediate
alcohol, hot and spicy foods, sunlight, exercise, acute psycholog- inflammatory response(s). They are triggered by spices, alcohol
ical stresses, menstruation, demodex mites and certain medica- consumption and temperature changes. When depolarized,
tions.8,19 There is controversy whether H. pylori should be TRPV 1 and TRPA 1 induce neuropeptides such as pituitary
considered a trigger factor or rosacea as well.20–23 adenylate cyclase-activating polypeptide (PACAP), substance P
(SP) as well as calcitonin gene-related peptide (CGRP) that
Cytokines overall cause flushing and erythema through vasodilatation.
Due to an impaired permeability barrier in the stratum PACAP, SP and CGRP also lead to an inflammatory response
corneum,24–30 the release of various cytokines such as tumour through activation of mast cells, macrophages, neutrophils and
necrosis factor a (TNF-a), IL-1 and IL-6 is triggered, leading to T cells.49
cutaneous inflammation, perhaps in an attempt of the epidermis Due to the multifactorial pathogenesis that cannot be
to initiate self-repair.27–30 These pathomechanisms can lead to easily addressed therapeutically, treatment strategy currently
neurological symptoms such as stinging and burning sensa- focuses on symptomatic suppression of inflammation and
tions.27,29,30 reduction of disfiguring features. Clinically, four types of
rosacea are differentiated according to apparent features and
Antimicrobial peptides severity.
Recently, overproduction of antimicrobial peptides (AMPs) has
been identified as a cause of rosacea lesions.31 AMPs include Clinical manifestations and subtypes of rosacea
defensins and cathelicidins, such as LL-37. Patients with subtype I have centrofacially located erythematous
macules due to dilated capillaries in the face, especially on the
Toll-like receptors nose and cheeks. Episodes of transient erythema (flushing) or
Keratinocytes express Toll-like receptors in order to sense patho- non-transient (persistent) erythema can occur.40,45 ETR flares
gen-associated patterns (PAMPs).32,33 Toll-like receptor 2 are due to acute vasodilatation and innate inflammation. Once
(TLR2)33 and Toll-like receptor 4 (TLR4)34 have been shown to the vasculature becomes chronically dilated, persistent facial ery-
be overexpressed in rosacea skin. thema develops. Additionally, chronic oedema due to
S1-rosacea guideline 1777
extravascular fluid leakage and perivascular inflammation can acne conglobate, Gram-negative folliculitis and lupus erythe-
occur.24–26,50–53 Differential diagnosis in subtype I includes matosus. A Gram-negative variant of rosacea has also been
menopausal flushes, insufficiently controlled arterial hyperten- described.62
sion, emotional distress, lupus erythematosus, seborrhoeic der- Steroid-triggered (or induced) rosacea is important to recog-
matitis, (photo-)allergic or phototoxic reactions, erythema facial nize but often missed. It can arise due to prolonged systemic or
perstans, heliotropic rash in dermatomyositis, familial facial ery- topical use of glucocorticosteroids.62 It first produces macular
thema due to atopic eczema, nitrite/sulphite ingestion, alcohol erythema with telangiectasia and later results in follicular
ingestion, caffeine withdrawal, autonomic hyperreflexia, papules and pustules. Steroids need to be stopped, even though
pheochromocytoma, VIPoma, carcinoid syndrome, brain this leads to an initial flare of skin lesions. Reddish-brown
tumours, renal cell carcinoma, Frey syndrome, mastocytosis, papules or nodules presenting concomitantly with diffuse facial
polycythemia vera, Parkinson’s disease, as well as multiple scle- erythema are the hallmark sign for granulomatous rosacea also
rosis. In subtype II, inflammatory papules and pustules are seen known as lupoid rosacea.8 Atypical presentations of rosacea
in the central region of the face. In addition, signs of subtype I include persistent erythema in locations such as the scalp or the
rosacea can be present as well. Erythema in subtype II patients scrotum (Table 1).
can be due to either acute or chronic vasodilation secondary to
inflammation.24–26,53–56 Important differential diagnoses in sub- Process for differential diagnosis
type II include papulopustular acne, perioral dermatitis, allergic Clinical diagnosis of rosacea should include history, symp-
or toxic contact dermatitis, granulomatous rosacea, lupus mil- toms, skin lesions age and gender as initial stratification
iaris disseminatus faciei, cutaneous sarcoidosis, gramnegative fol- tools. Clinicians particulary look for centrofacial erythema,
liculitis and demodicosis but also perifolliculitis capitis and telangiectasia, papules and pustules, and phymatous growths
eosinophil folliculitis. on nose, chin, glabella and front. In addition, clinical signs
Disfiguring growth of hyperplastic sebaceous glands on the that are less well compatible with a diagnosis of rosacea are
nose and other facial regions is seen in subtype III rosacea. sought, such as extended scaling (seborrhoeic dermatitis,
Most often encountered is rhinophyma. Laymen wrongly tinea), sharp demarcation of erythema (sometimes in erysipe-
attributed it to excessive alcohol consumption, even though so las), extended scarring, unilateral inflammation (i.e. demodi-
far it has not statistically been associated with abuse of cosis), exclusively perioral or periorbital inflammation with a
ethanol.57 Important differential diagnoses of subtype III millimetre-wide non-inflamed zone around the orifices (peri-
include eosinophilic granuloma, Chilblain lupus, angiosarcoma oral dermatitis), exquisite sensitivity to sunlight (lupus, poly-
and facies leontina. morphic light dermatosis) and many more (see Table 2). In
Ocular rosacea can include symptoms such as conjunctivitis, the vast majority of cases, the diagnosis of rosacea remains a
blepharitis, irritation, dryness or keratitis.58,59 The prevalence purely clinical one and distinctive investigations such as skin
rates reported range from 3% to 72%; however, most sources biopsies are usually not needed. However, it can be life-sav-
assume a prevalence of more than 50% of all rosacea ing not to miss an angiosarcoma that in the early stage is an
patients.1,8,53,60–66 Ocular manifestations occur in around 20% important imitator of rosacea. A biopsy should always be
before, 27% during and in 53% after skin symptoms of subtype analysed additionally with direct immunofluorescence for
I-III have evolved.63 An ophthalmologist should be involved to lupus erythematosus in cases of high clinical suspicion of
confirm the diagnosis as it can also result in complications such lupus erythematosus, and the results should be compared
as alterations of the lids, cornea, sclera and anterior chamber with a biopsy taken from non-sun-exposed skin to avoid
(uveitis). It is often accompanied by oedema of the lid or the false-positive interpretation. Clinical evaluation should define
periorbital regions.58,59 As differential diagnoses, bacterial and potential differential diagnosis such as lupus erythematosus,
viral conjunctivitis as well as allergic conjunctivitis and infec- polymorphic light eruption, perioral dermatitis, acne, for
tious keratitis needs to be considered. example, and finally the relatively new entity of mixed facial
Rare conditions imitating rosacea include Morbihan’s dis- dermatosis which is an important and possibly quite com-
ease,67–69 which produces persistent lymphoedema and ery- mon disorder that shows overlapping features of both sebor-
thema of the mid-third and upper aspects of the face. It is rhoeic dermatitis and rosacea.73
sometimes imitated by a Melkersson–Rosenthal syndrome with
additional solid persistent facial oedema.70 Rosacea fulminans, Dermatopathology (skin biopsy)
previously called pyoderma facial or rosacea conglobata, occurs All subtypes of rosacea show dilated blood and lymph vessels in
almost exclusively in young women, predominantly in their 20s the upper and mid-dermis. A superficial perivascular and peri-
or 30s with a sudden appearance of an eruption including ery- follicular mononuclear lympho-histiocytic infiltrate is routinely
thema, papules, sterile pustules, coalescing cystic nodules and observed. Oedema and thickened elastic fibres may be seen. In
draining sinuses.71,72 Important differential diagnoses include subtype I, histologic changes are sparse. In subtype II, epithelia
Table 1 Differential diagnosis of rosacea

Do not miss Differential Diagnosis Distinguishing Features
! Acne vulgaris Scarring, comedones, no telangiectasia
! Acute cutaneous lupus erythematosus Sharp demarcation, sensitivity to sunlight
AIDS Acute outbreak of seborrhoeic dermatitis, coccidioidomycosis,
! Angiosarcoma Doughy oedema, erysipelas-like inflammation
Arterial hypertension Flushing associated with high blood pressure
Carcinoid syndrome Systemic symptoms during flush
Chronic actinic dermatitis Photodistribution
Cutaneous sinus histiocytosis Mostly young, dark-skinned persons
(Rosai–Dorfman disease)
! Demodicosis Unilateral follicular inflammation
Dermatomyositis Periocular oedema, Gottron papules
Eosinophilic granuloma Swelling and pain around osteolytic lesions
Folliculitis Pustules are located at the follicle opening
Glucagonoma Crusts, blisters
Granuloma faciale Few, larger plaques. Can have telangiectasia.
No epidermal involvement.
Granulomatous periorificial dermatitis Granulomatous histology
! Haber’s syndrome Seborrheic keratosis in axillary and inguinal regions
Halogenoderma Often epilepsy, history of bromide or iodine
! Lupus miliaris disseminatus faciei Brownish papules in diascopy
Lupus vulgaris Solitary lesion at beginning, quantiferon positive
Lymphoedema Scarce inflammation
Mastocytosis Mostly flushing, more monomorphic papules
! Facies ethylica Anamnestic C2 abusus, liver enzymes
Facies mitralis Mitral stenotic systolic heart sound
Mixed connective tissue disorder Hyperkeratotic nail fold, U1-RNP antibodies
! Mixed facial dermatosis Features of seborrhoeic dermatitis and rosacea
Pellagra Photodistribution of lesion
Perifolliculitis capitis Pustules are located mainly on the scalp
Perioral dermatitis Exclusively periorificial inflammation with demarcation zone
Pheochromocytoma Systemic symptoms, flush only
Photosensitive drug reaction History of drug intake.
Polycythaemia vera Pruritus after contact with warm water, blood tests.
! Polymorphous light eruption Monomorphic, densely set papules to plaques.
Less frequent on face. Mostly younger persons.
Recurrent erysipelas Confluent erythematous lesions
Rubeosis diabeticorum Hyperglycaemia, polyuria
Sarcoidosis No epidermal involvement, few signs of rosacea
! Seborrhoeic dermatitis Scaling and erythema, retroauricular and scalp involvement
Syringomas Brownish / translucent 1-5 mm papules, little inflammation
Tinea faciei Sharply demarcated, accentuated at the edge, scaling
Trichoepitheliomas Whitish-yellow papules, when disseminated check Brooke syndrome
Zinc deficiency Periorificial eczematous lesions
of follicular infundibula can show spongiotic changes and Methods

intrafollicular neutrophils as well as lymphohistiocytic infiltrates. This guideline was created under the auspices of the Swiss Society
In subtype III, sebaceous glands are hyperplastic and granuloma of Dermatology and Venereology. On 1 November 2016, a litera-
formation and cysts develop. In the granulomatous subtype of ture search in PubMed and Google Scholar using the reference
rosacea, non-caseating epithelioid cell granulomas arise.74–76 words ‘rosacea’, ‘erythematotelangiectatic rosacea’, ‘papulopustular
Demodex mites are found in around 10% of routine biopsies rosacea’, ‘phymatous rosacea’ and ‘ocular rosacea’ was performed
and cause follicular dilation, folliculitis and perifollicular inflam- to collect all relevant publications between 1990 and 2016. A total
mation.77,78 number of more than 300 publications were incorporated in the
Table 2 Level of evidence according to Lebwohl. Two randomized, vehicle-controlled, phase II trials (n = 122,
A: n = 269) using BT 0.07%, 0.18% and 0.5% showed dose-depen-
• ≥1 prospective randomized, double-blind, controlled trial. dent effects in the treatment of moderate-to-severe facial ery-
• No major design flaws. thema.83 Two phase III, randomized, multicentre, controlled
B: studies (n = 260, n = 293) of moderate facial erythema using BT
• Prospective clinical trials (≥20 participants). observed 1 and 2 grade improvements. Another similar study
• No adequate controls or lacking of another key facet of came to almost identical results.84 In its ability to reduce ery-
design.
C:
thema, BT is superior to azelaic acid 15% gel.85 There is no signif-
icant effect on telangiectasias. First responses can be seen within
• Small trials (<20 participants).
• Clinical trials with significant design limitations. 30 min.19,86 Adverse effects include burning sensation, contact
• Case reports (overall ≥20 cases reported). dermatitis, flushing as well as rebound erythema.87,88 One study
• Retrospective analyses of data. reported the occurrence of a persistent erythema located adjacent
D: to an area being treated with brimonidine for 7 months.89
• Case series (≥5 participants) There are no long-term data on brimonidine in the treatment
E:
of facial erythema. Two randomized, double-blind and
• Case reports. vehicle-controlled trials of BT yielded a good safety profile.19
• Case series (<5 participants).
A pharmacokinetic study compared the bioavailability and phar-
Level of evidence A (green), B (yellow), C (light orange), D (dark orange), E (red).
macokinetics of BT gel (0.07%, 0.18% and 0.5%) to the oph-
thalmic solution. Additionally, the safety profile was evaluated
final analysis leading to this work. The data were discussed with 13 showing that the cutaneous application was safer.90 In the experi-
national experts on rosacea, who came to an informal (S1) consen- ence of the authors, many patients are unable to achieve homoge-
sus towards the recommendations as given in this guideline. neous reduction of erythema and tend to stop the treatment
The level of evidence (A-E) was measured according to Leb- again. Also, it may not be useful to treat erythema with BT when
wohl 79 and refers to the strength of evidence published (Table 2). papulopustules are present, as these become more exposed in the
Table 3 encompasses the level of evidence for all therapeutic process.
options. To demonstrate the utility of compounds in daily practice, The official limitation for this drug is moderate-to-severe
we have summarized the Swiss Recommendations in Table 4. rosacea, which means that it can only be prescribed in a fraction
of cases of subtype I.19,83,86,91 Even though it seems to be effec-
Treatment tive also in erythema due to other causes than rosacea,92–104 this
is considered off-label and may not be covered by the insurance.
General recommendations Conclusion: Brimonidine is recommended for moderate-to-
In our opinion, the trigger factors as mentioned above severe subtype I rosacea (level of evidence: A).
should be strictly avoided. Non-occlusive sunscreen is rec-
ommended, but the ambient heat from infrared light can Laser Laser therapy can reduce erythema and telangiec-
still act as a trigger factor itself.25,26,54,56,80,81 Irritation of tasias.95 A variety of laser and light-based devices have been
facial skin either due to soap or to occlusive cosmetics has demonstrated to be useful in the treatment of the vascular
to be strictly prevented using mild facial cleansers and light manifestations of rosacea. Usually, one to four sessions are
cosmetics.28 To restore the barrier of the stratum corneum, needed to achieve good results.96–112 Neodymium-doped,
remoisturizing products can be applied, even though scien- yttrium–aluminium–garnet (Nd:YAG), pulsed dye laser (PDL)
tific evidence for their effectiveness is slim.82 or intense pulsed light (IPL) are physical options for facial
erythema and telangiectasias.
Treatment of erythematotelangiectatic rosacea The Nd:YAG laser can cause haemoglobin destruc-
Erythema of the face, flushing and telangiectasias are the main tion.99,113,114 A double-blind, randomized, controlled trial com-
symptoms of ETR. Only few studies have been performed on paring the effectiveness of a 595-nm pulsed dye laser and a
patients with rosacea subtype I. microsecond 1064-nm Nd:YAG laser including 16 patients
showed slightly more efficient data for the PDL for fair skinned
Brimonidine tartrate (BT) Brimonidine 0.33–1% gel 3 mg/g, a patients, while Nd:YAG induced less pain. Nd:YAG lasers are
vasoconstrictive alpha-2 adrenergic receptor agonist, once daily, efficient and safe.115 The combination of topical retinaldehyde
is registered for subtype I rosacea. BT has traditionally been used and a 532 nm Nd:YAG laser led to a greater degree of improve-
to treat open angle glaucoma, but recently emerged as a therapy ment than using laser alone, as a prospective randomized
for rosacea-induced facial erythema. blinded clinical trial with 14 patients showed.96
Table 3 Level of evidence of topical and systemical treatments in rosacea.

I II III
Topical steroids Contraindicated Contraindicated Contraindicated
Topical brimonidine A ND ND
Intense Pulsed Light (IPL) A ND ND
Pulsed Dye Laser (PDL) B ND ND
Neodymium-doped, yttrium– B B ND
aluminium–garnet (Nd:YAG)
Propranolol C ND ND
Nadolol D ND ND
Carvedilol D ND ND
Topical metronidazole ND A ND
Topical azelaic acid ND A ND
Botulinum toxin D ND ND
Topical ivermectin ND A ND
Pimecrolimus ND A ND
Tacrolimus D D ND
Topical retinoids ND A ND
Topical permethrin ND A ND
Topical benzoyl peroxide/clindamycin ND A ND
Topical erythromycin ND A ND
Topical dapsone ND A ND
Oral doxycycline/ tetracycline ND A A
Doxycycline (low-dose) ND A ND
Oral minocycline ND A ND
Oral metronidazole ND B ND
Oral ampicillin ND A ND
Oral azithromycin ND B ND
Oral clarithromycin ND B ND
Oral isotretinoin ND A A
Oral zinc sulphate ND A ND
Oral ivermectin ND D ND
Surgery/Blepharoplasty Not appl. Not appl. C
Ablative laser treatment Not appl. Not appl. C
Level of evidence A (green), B (yellow), C (light orange), D (dark orange), E (red), ND (no data).
Pulsed dye lasers (PDL) use a wavelength of 595 nm and tar- significant benefits of intense pulsed light therapy.102 Similar
get haemoglobin, leading to an obstruction of blood ves- studies with 60,98 34,106 32119 and 4108 patients led to almost
sels.95,99,113,116 Several studies have confirmed the safety and identical conclusions. Combining IPL and radiofrequency in 21
efficacy of pulsed dye lasers in rosacea. The largest trial consisted patients with moderate-to-severe rosacea over the period of
of 40 patients,100 but multiple smaller ones with 32,109 25,103 5 months improved erythema, flushing and telangiectasias. The
16,104 16,111 12,110 12,107 11101 and 997 patients have also been same efficacy was achieved after 3 and 5 treatments. No signifi-
performed. All came to the same conclusion that PDL represents cant adverse effects were reported.111
a safe and effective treatment option for facial erythema and/or At present, pulsed dye laser (PDL) and IPL are typically used.
telangiectasias. These trials were prospective, and some of them IPL has with a larger spot size and fewer side-effects some advan-
were randomized,101,103 controlled, but none of them was tages over PDL. Despite the published efficacy of devices for
blinded. The additional application of topical niacin showed a rosacea treatment, they are usually not reimbursed by health
beneficial treatment effect in dark-skinned Asians, a randomized, insurances.78
prospective, split-face trial with 15 patients concluded.80 Conclusion: IPL (level of evidence: A) Nd:YAG (B), and PDL
The improvement lasts a number of years. Intense pulsed light (B) treatment are recommended for rosacea subtype I.
has a wavelength between 550 and 670 nm, which is absorbed by
melanin and oxyhaemoglobin.113,117,118 A randomized, con- b-Blockers Non-selective b-blockers can reduce flushing by
trolled, single-blind, split-face trial with 29 patients showed blocking b-receptors on cutaneous blood vessels.119
Table 4 Swiss treatment recommendations for rosacea

Rosacea grade (classical) I II III IV
Rosacea grade (new) Erythema Telangiectasias Papules/Pustules Phyma Ocular Rosacea
Azelaic acid + No data +++ No data (+)
Botulinum toxin No effect No data No data No data
BPO/Clindamycin No data No data ++ No data No data
Brimonidine +++ No effect No data No data No data
Topical drugs
Dapsone No data No data Not available in CH No data No data

Erythromycin No data No data ++ No data No data
Ivermectin No data No data +++ No data +
Metronidazole + No data +++ No data ++
Permethrin No data No data + No data No data
Pimecrolimus + No data ++ No data No data
Retinoids No data No data ++ No data No data
Steroids +
Tacrolimus + No data No data +
Ampicillin No data No data + No data No data
Azithromycin No data No data + No data ++
Carvedilol + No data No data No data No data
Clarithromycin No data No data + No data No data
Oral drugs
Doxycycline (low dose) No data No data +++ +++ +++

Doxycycline/ tetracycline No data No data +++ ++ +++
Isotretinoin No data No data ++ ++ No data
Ivermectin No data No data + No data No data
Metronidazole No data No data + No data No data
Minocycline No data No data No data No data
Zinc sulphate No data No data + No data No data
phototherapy
IPL, PDL, Nd:YAG +++ +++ + No data No data

Physical /
Surgery/Blepharoplasty No data Not appl. Not appl. +++ +

Ablative laser treatment No data Not appl. Not appl. +++ Not appl.
Physical therapy No data Not appl. Not appl. Not appl. +++
Tear replacements No data Not appl. Not appl. Not appl. +++
Eyedrops
Ocular cyclosporin No data Not appl. Not appl. Not appl. +++
Ocular azithromycin No data Not appl. Not appl. Not appl. ++
Ocular tetracyclines No data Not appl. Not appl. Not appl. ++
Green, recommended; Red, not recommended.
Propranolol has shown clinical benefits in a case series of Topical metronidazole Topical metronidazole has shown to
nine patients120 and a non-randomized, non-blinded, non- reduced erythema of rosacea in six double-blind studies,126–131
placebo-controlled cohort study including 78 patients.121 including two multicentre trials128,131 with up to 113 patients.130
However, it is hardly ever used for the treatment of rosacea- However, those studies were performed on patients suffering
induced facial flushing due to its adverse effects as hypoten- from subtype II. There is no trial exclusively on patients with
sion an bradycardia.122 In one case series with 15 patients erythematotelangiectatic rosacea.
using the non-selective b-blocker, nadolol, no clear benefit on Conclusion: A treatment with topical metronidazole 0,75-1%
the flushing reactions was detected.123 cream or gel may be attempted in patients with subtype I. As
Carvedilol, an a1-, b1- and b2- antagonist, is effective in some there are no studies available exclusively on subtype I patients,
patients. One case report124 and one case series with 11 partici- no level of evidence statement can be given.
pants 125 showed some efficacy.
Conclusion: Propranolol (evidence level: C) and nadolol (evi- Topical azelaic acid A randomized, double-blind, multicentre
dence level: E) is not recommended for flushing in rosacea. As study (n = 116) showed efficacy of azelaic acid in the treatment
an off-label therapy, carvedilol, for example at a dosage of of erythema.132 Two vehicle-controlled, randomized phase III
6.25 mg twice a day, can be considered (D). studies (n = 664) showed improvement of erythema using
azelaic acid 15% gel.133 Nonetheless, those studies included only Topical treatment of papulopustular rosacea
patients with papulopustular rosacea.
Conclusion: The application of topical azelaic acid 15% cream Metronidazole Metronidazole (MTZ) is a nitroimidazole
or gel can be attempted in patients with subtype I. As there are antibiotic. For subtype II rosacea, 0.75–1% cream or
no studies available exclusively on subtype I patients, no level of gel129,130,146,147 are most commonly used and should be applied
evidence statement can be given. twice daily. In Europe, multiple formulation with metronidazole
are on the market. However, one study found no difference in
Botulinum toxin Botulinum toxin is a neurotoxic protein. efficacy between 0.75% and 1% metronidazole.146 It remains
Intradermal injection of botulinum toxin was evaluated in a unclear whether the higher dose is associated with improved effi-
clinical, non-randomized, non-placebo-controlled, non-blinded cacy. The efficacy of MTZ has been confirmed in multiple dou-
trial with 25 patients suffering from facial erythema of erythema- ble-blind studies.126–131 Compared to azelaic acid (AZA), similar
totelangiectatic rosacea. Only 15 patients completed the study, or even superior results of azelaic acid in reducing facial ery-
and the others were excluded in the statistical analysis, which thema have been observed.147–149 However, MTZ is considered
may greatly bias the results. The reported data claimed a signifi- to have a more tolerable profile than AZA.150 In a head-to-head
cant improvement of facial erythema.134 trial with pimecrolimus 1%, both agents reduced erythema
Conclusion: Not recommended at this point, the evidence is in equally. No improvement of telangiectasias was seen.151 The
our opinion insufficient/potentially biased (level of evidence: D). strongest reduction in lesion count is clinically observed around
6 weeks.152 MTZ has a similar efficacy as oral (oxy)tetracycline,
Tacrolimus A small study with 10 patients evaluated the effi- a randomized double-blind trial (n = 51) reported. Noteworthy,
cacy of tacrolimus in eight patients with subtype I rosacea and an improvement was observed in 90% of both groups.153
two with steroid-induced rosacea. Tacrolimus showed good Conclusion: Metronidazole is recommended (A) for subtype
effects causing complete remission in 6 of 10 patients after II rosacea patients.
6 weeks.135 Similar positive effects were described in a case
report using the combination of azithromycin and tacrolimus Tacrolimus One study with 24 patients suffering from subtype
0.1% ointment in a subtype III patient.136 Adverse effects I and II rosacea showed no effect on the number of papules, but
include burning sensations upon treatment initiation.135 Also, reduced erythema.154
consumption of ethanol can induce paradoxical erythema of the Conclusion: Tacrolimus is not recommended (D) for subtype
treated skin. II rosacea patients.
Conclusion: Tacrolimus can be considered for subtype I rosa-
cea (level of evidence: D). Azelaic acid Azelaic acid is a saturated dicarboxylic acid. Aze-
laic acid inhibits the production of ROS and upregulation of
Pimecrolimus Pimecrolimus 1% cream was effective in reduc- pro-inflammatory cytokines as IL-1, IL-6 and TNF-a. Also,
ing erythema of rosacea in two prospective, open-label studies phosphorylation of ERK1/2 and p38 as well as UV-induced NF-
(n = 26, n = 40).137,138 Patients suffered, however, from subtype jB activation is downregulated. PPARc inhibits inflammatory
II. Notably, other data have suggested that calcineurin inhibitors responses and is induced by azelaic acid.8,155 Multiple, mostly
can induce a rosacea-like dermatitis,139,144 and in one case, a randomized, double-blind, multicentre studies have provided
rosacea-like demodicidosis was caused.145 good data on the beneficial effects of azelaic acid on subtype II
Conclusion: The use of pimecrolimus may be considered in rosacea. Erythema as well as inflammatory lesions responded
subtype I rosacea patients. As there are no studies available very well.133,147,156–162
exclusively on subtype I patients, no level of evidence statement Conclusion: Azelaic acid is recommended (A) for subtype II
can be made. In therapy-resistant cases, the use can be considered. rosacea patients.
Ondansetron, praziquantel, TDT068, oxymetazoline, 4-ethox-
ybenzaldehyde 1%, laropiprant and calcium channel blockers Ivermectin Ivermectin is a broad-spectrum antiparasitic agent.
are all not recommended, please see the in Data S1. In one phase 3, investigator-blinded, randomized, parallel-group,
head-to-head trial (n = 962) ivermectin 1% cream showed supe-
Treatment of papulopustular rosacea riority over metronidazole 0.75% cream.152 It is newly registered
Inflammatory lesions such as papules and pustules as well as ery- in Switzerland, many other European countries and the
thema occur in subtype II. In mild manifestations of papulopus- USA.152,160,163
tular rosacea, topical treatments alone can be successful. For Conclusion: We recommend the use of topical ivermectin (A).
more severe cases, systemical treatment or combinations thereof
are recommended.8,55 A combination of local and systemic ther- Pimecrolimus The calcineurin inhibitor, pimecrolimus 1%, has
apies is recommended. successfully been used in the treatment of subtype II rosacea. It
has shown efficacy in a placebo-controlled, randomized trial as well as erythromycin 2% gel lead to cutaneous improvements
(n = 40).164 Compared to metronidazole 1% cream, no superi- in papulopustular rosacea.178 It was comparable in efficacy to
ority of pimecrolimus cream was observed.151 Topical pime- topical azithromycin in a phase II, randomized, double-blind,
crolimus 1% also showed some efficacy in two case reports of a single-centre study (n = 20).177 In combination with benzoyl
patient with granulomatous rosacea.165,166 Flares and facial ery- peroxide, it was superior compared to metronidazole.176 Con-
thema after alcohol intake have been described in patients using clusion: We recommend (A) the use of topical erythromycin 2%
calcineurin inhibitors.167 As mentioned above, induction of gel for subtype II rosacea patients.
rosacea by pimecrolimus has been reported.139–144
Conclusion: Pimecrolimus can be considered (A) for subtype Dapsone In a double-blind randomized clinical trial (n = 56),
II rosacea patients. 5% dapsone gel was as effective as 0.75% metronidazole gel.179
Conclusion: Based on the evidence, topical dapsone could be
Retinoids Regarding the study mentioned above, tretinoin recommended (A), but it is not available in many European
0.025% gel in combination with clindamycin phosphate 1.2% countries as Switzerland.
has not shown beneficial results.168 In contrast, a randomized,
double-blind trial (n = 20) described significant improvement Neodymium-doped yttrium–aluminium–garnet laser In an
and identical results of oral low-dose isotretinoin and tretinoin open clinical trial (n = 66), the Nd:YAG laser was shown to be
0.025% cream after 16 weeks.169 In a randomized open trial with safe and effective against papulopustular lesions.180
55 patients, adapalene was efficacious in the treatment of sub- Conclusion: In therapy-resistant cases, we recommend (B) the
type II rosacea patients.170 Topical retinoids can be irritative and treatment with Nd:YAG lasers.
should be only used if well tolerated.
Conclusion: Retinoids, tretinoin 0.025% and adapalene gel Systemic treatments for papulopustular rosacea
can be used (A, but conflicting data) in subtype II rosacea
patients. However, in each patient, the individual tolerance of Doxycycline Doxycycline is an antibiotic drug of the tetracy-
topical retinoids must be considered. cline family. While doxycycline is administered at 100 mg (or
200 mg) daily in other diseases, low-dose doxycycline (40 mg:
Permethrin One pilot study (n = 6)171 and one randomized 30 mg immediate-release and 10-mg delayed-release) has shown
double-blind placebo-controlled study (n = 63)129 with subtype to provide similar results with less adverse effects in rosacea.181
II patients have been successfully performed. The data of both At a dosage of 40 mg, no antibiotic selection pressure is pro-
studies showed that the rosacea-induced erythema and papules duced leading to the avoidance of antibiotic resistance, even when
were reduced with topical permethrin 5% cream, but there was administered over a prolonged duration of several months.181–184
no effect on pustules nor telangiectasias. Several multicentre, randomized, double-blind, active control
Conclusion: Even though solid evidence (A) is available on study with (n = 40, n = 91, n = 134, n = 269, n = 268), one
some outcomes, but not all relevant end points. Topical perme- retrospective study (n = 826), and a community-based assess-
thrin may be considered, but is rarely used in Switzerland. ment (ORCA), open-label study (n = 1197) yielded very good
results in terms of reduction of erythema and inflammatory
Benzoyl peroxide formulations Two double-blind, random- lesions.162,181,183,185–188
ized, vehicle-controlled clinical trials (n = 53, n = 50) of a In a randomized, open clinical trial focusing on erythema and
combination of benzoyl peroxide/clindamycin gel observed sig- telangiectasia, no difference between clarithromycin 250 mg
nificant superiority of BP/C.172,173 Another placebo-controlled twice daily for 4 weeks, then 250 mg once daily for 4 weeks
trial (n = 64) provided similar results.174 To find the best dosage (n = 23) or doxycycline 100 mg twice daily for 4 weeks, then
a randomized, phase 2, dose-ranging study (n = 92) with encap- 100 mg once daily for 4 weeks (n = 17) was seen. The decrease
sulated benzoyl peroxide gel was performed and yielded results in rosacea lesions was more rapidly seen in the group treated
that showed superiority of the 5% vs. the 1% gel.175 Benzoyl with clarithromycin.189
peroxide-erythromycin gel is efficient in decreasing demodex A randomized, open, clinical trial compared azithromycin
folliculorum when compared to metronidazole gel.176 Benzoyl (first month: 500 mg three times a week; second month: 250 mg
peroxide can be irritative and should be only used if well three times a week; third month: 250 mg twice weekly) to doxy-
tolerated. cycline 100 mg daily. Doxycycline was not inferior to azithromy-
Conclusion: BP/C 5% gel can be used (A) for subtype II rosa- cin (n = 67).190
cea patients. In a 16-week, double-blind, randomized, placebo-controlled
study comparing doxycycline 40 mg and topical metronidazole
Erythromycin Topical erythromycin was efficacious in several gel 1% vs. solely metronidazole topical gel 1%, the combination
studies.176–178 In a head-to-head trial, metronidazole 0.75% gel therapy proved to be effective and well tolerated.191
In severe cases, multiple centres in Switzerland have had good 8 weeks) to doxycycline 100 mg daily demonstrated an equal
experience in using 200 mg daily for 4 weeks, reducing to efficacy of both treatments.190 Four case reports have described
100 mg daily for another 4 weeks. Afterwards 40 mg once daily an efficacy of oral azithromycin 500 mg once daily.116,136,199,200
for prolonged periods of time can be applied.192 Three open-label studies (n = 34, n = 18, n = 10) also
Conclusion: We recommend (A) oral tetracycline for subtype showed significant treatment benefits. The dosage slightly varied
II rosacea patients. amongst those studies.201–203
Conclusion: Oral azithromycin may be used (B) for subtype II
Tetracycline In a randomized, double-blind, clinical trial rosacea patients; however, the available evidence is stronger for
(n = 56) tetracycline and ampicillin showed comparative tetracyclines.
effects.193
One randomized, double-blind study of 40 patients with sub- Clarithromycin Compared to doxycycline 100 mg twice daily in
type II rosacea showed no significant difference between oral a randomized, open clinical trial (=40), clarithromycin was not
oxytetracycline and metronidazole.194 inferior.189
Conclusion: We recommend (A) oral tetracyclines for subtype Conclusion: Oral clarithromycin may be used (B) for subtype
II rosacea patients. II rosacea patients; however, the available evidence is stronger
for tetracyclines.
Isotretinoin Retinoids can have anti-inflammatory proper-
ties.168,195,196 One randomized, double-blind trial with 20 patients Zinc sulphate Zinc sulphate 100 mg daily showed significant
compared oral low-dose isotretinoin with the topical retinoid, tre- superiority over placebo in a randomized, controlled, double-
tinoin 0.025% cream. The group treated with oral isotretinoin blind trial (n = 25).204
showed a more rapid onset of improvement. However, after Conclusion: Oral zinc may be used (A) for subtype II rosacea.
16 weeks, both groups showed equally beneficial results.169
A multicentre study with 92 patients described oral isotreti- Minocycline No difference in efficacy was found in a random-
noin to be highly effective.197 A placebo-controlled, randomized ized double-blind trial compared with topical metronidazole
clinical study with 573 patients of subtype II and III showed (n = 51).153 Because rarely, autoimmune hepatitis occurs due to
complete remissions in 24% and an improvement in 57% of minocycline, it is not recommended any longer.195
patients treated with isotretinoin, using 0.3 mg/kg.168 Conclusion: Because of rare but severe side-effects, we do not
An open-label study (n = 25) published data indicating a sig- recommend oral minocycline for subtype II rosacea patients
nificant improvement of patients receiving isotretinoin 20 mg (level of evidence: A).
daily. When treatment was halted, within 11 months 45% of the
patients relapsed.206 Ivermectin There are several case reports206–210 and one case
Conclusion: Low-dose isotretinoin treatment (0.3 mg/kg) can series211 where oral ivermectin (200 microg/kg) mostly in com-
be recommended (A) for subtype II rosacea patients. From per- bination with topical permethrin 5% cream207,208,211 lead to
sonal experience, we find that also a dose of 0.15 mg/kg can be treatment success in some cases, even in immunocompromised
effective. patients.207,208,211
Conclusion: Oral ivermectin can be used (D) for rosacea sub-
Ampicillin In a randomized, double-blind clinical trial type II.
(n = 56), randomized effects were shown between ampicillin
and tetracycline.200 Treatment of phymatous rosacea
Conclusion: Oral ampicillin can be used (A) for subtype II For phymatous rosacea, ablative laser treatments as well as classi-
rosacea patients; however, the available evidence is stronger for cal surgery are available (level of evidence: C). In subtype III,
doxycycline. To our knowledge, it is not used any European systemic treatment with isotretinoin 0.3 mg per kg bodyweight
countries. once daily off-label (level of evidence: A) or with low-dose doxy-
cycline (level of evidence: A) together with surgical interventions
Metronidazole A double-blind trial (n = 29) showed superior- are typically used.168 We are not aware of any clinical studies of
ity of oral metronidazole compared to placebo.198 oral drugs for the treatment of phymatous rosacea; thus, no
Conclusion: Oral metronidazole may be used for subtype II statement on the level of evidence can be made
rosacea (B).
Treatment of ocular rosacea
Azithromycin A randomized, open clinical trial (n = 67) com- For ocular rosacea, we recommend lid hygiene and lid massages,
paring oral azithromycin (500 mg 3 times weekly for 4 weeks, the application of warm wet tissues to unblock the meibomian
afterwards reducing the dosage to 250 mg 3 times a week for glands, lipid containing tear replacements212–217 as well as
topical cyclosporine,218,219 azithromycin,220–224 tetracyclines225 In one case, minocycline alone showed a decline in skin
or grade I steroids.226 Long-term use of topical corticosteroids changes, but no complete remission. The combination of
should be prevented due to side-effects as glaucoma or catar- minocycline and dapsone led to a full response. Also another
act.32 In moderate-to-severe ocular rosacea, oral antibiotics such case report described a remission under dapsone.254
as tetracycline as doxycycline 100 mg once or twice daily for A possible association with Crohn’s disease,253 ulcerative coli-
6–12 weeks can be used.32,66,227–229 Oral azithromycin is also a tis and erythema nodosum255 has been reported. Infliximab,
251
viable treatment option.237 In extreme cases, blepharoplasty also in combination with azathioprine, followed by methotrexate
might become necessary.68,231,232 All therapies mentioned in resulted in no significant improvement. Subsequently, oral doxy-
this article have been tried to some extend as off-label treatments cycline, topical antibiotic and corticosteroid preparations, and
for ocular rosacea. The current lack of high-quality studies serial intralesional triamcinolone acetonide injections, slowly
specifically addressing ocular rosacea precludes systematic lead to some improvement.256
recommendations.
Morbihan’s disease
Granulomatous rosacea (GR) There are a few publications on Morbihan’s disease.
There are limited data on patients treated for granulomatous Intralesional injection of triamcinolone as well as surgery showed
rosacea. Only case reports and case series have been published. good results in two case series.16,68 Surgery followed by lymphatic
Minocycline,233 dapsone,234,235 isotretinoin236 and intense drainage also showed beneficial results in a case report.69 In one
pulsed light (IPL)237 have been published as successful treatments. patient, surgery did not improve any symptoms.16
Additionally, in one patient, all symptoms of GR disappeared Overall, in at least seven cases, isotretinoin leads to an
after an eradication of Helicobacter pylori with clarithromycin, improvement of symptoms.257–259 In one case, no changes were
metronidazole and pantoprazole had been performed.238 Topical seen.260
treatments with pimecrolimus cream166 and azelaic acid gel239 A mixed response to minocycline was reported.259,261,262 Oral
were successful. doxycycline as well as oral prednisone showed no improve-
One patient was treated with PDT using d-aminolevulinic ments.16
acid (ALA), which led to a remission of symptoms. However, six The use of ketotifen (1–2 mg/day) in combination with iso-
treatments were needed.240 tretinoin has shown efficacy in two case reports.263,264
Besides the known trigger factors for rosacea, also an infec-
tion with herpes simplex virus 2241 or treatment with tacroli- Combination treatment
mus242 has been discussed to be a possible trigger factor. A Often, systemic and topical treatments can be combined.
possible association with ulcerative colitis has been men- Nonetheless, due to increase antibiotic resistance, combination
tioned.243 of topical and systemic antibiotics is not recommended.265,266
GR appeared during the use of etanercept, and no relapse of
symptoms was found after the administration of infliximab.244
Discussion and conclusion
In practice, treatment that has qualified for papulopustular
Patient information and avoidance of trigger factors in rosacea
rosacea can be used for GR.
patients are not always possible, and therefore, effective treat-
ment options are routinely introduced. The treatment of rosacea
Rosacea fulminans (RF)
continuously improves and new options become available. With
Also in rosacea fulminans, there is a lack of sufficient data.
lasers such as PDL and IPL, topical brimonidine and ivermectin,
Multiple therapies have been used, according to publications
as well as the off-label use of systemic drugs such as isotretinoin,
dating back to 1940.245 Therapies included high-caloric foods,
we can nowadays achieve long-standing treatment successes. It
vitamins A, B and C, topical treatment with Vleminckx’s solu-
has to be considered that the use of most drugs is off-label. In
tion, Nomland’s lotion, Ayers’ ointment, benzoyl peroxide facial
some cases, treatments that are not reimbursed by insurances
massage, hot compresses, sulphur, UV or X-ray radiation,
have to be included for optimal results. In the future, we will
typhoid vaccine, oral contraceptives as well as surgical modali-
most likely have even more efficient drugs to control rosacea
ties.245
and potentially even approach disease resolution at some point.
Topical (clindamycin 1% lotion) and oral antibiotics (cotri-
moxazole, minocycline, oxytetracycline, flucloxacillin, metron-
References
idazole, diaminophenylsulfone) as well as oral corticoids,
1 Spoendlin J, Voegel JJ, Jick SS, Meier CR. A study on the epidemiology
sometimes in combination, have been used with mixed of rosacea in the U.K. Br J Dermatol 2012; 167: 598–605.
success.72,245–247 2 Kyriakis KP, Palamaras I, Terzoudi S, Emmanuelides S, Michailides C,
Isotretinoin, in various dosages from 0.2 to 1 mg/kg, showed Pagana G. Epidemiologic aspects of rosacea. J Am Acad Dermatol 2005;
53: 918–919.
good overall good results.246,248–253
3 Weinkle AP, Doktor V, Emer J. Update on the management of rosacea. 26 Del Rosso JQ. Advances in understanding and managing rosacea:
Plast Surg Nurs 2015; 35: 184–202. part 2: the central role, evaluation, and medical management of dif-
4 Augustin M, Herberger K, Hintzen S, Heigel H, Franzke N, Schafer I. fuse and persistent facial erythema of rosacea. J Clin Aesthet Derma-
Prevalence of skin lesions and need for treatment in a cohort of 90 880 tol 2012; 5: 26–36.
workers. Br J Dermatol 2011; 165: 865–873. 27 Dirschka T, Tronnier H, Folster-Holst R. Epithelial barrier function and
5 Tan J, Berg M. Rosacea: Current state of epidemiology. J Am Acad Der- atopic diathesis in rosacea and perioral dermatitis. Br J Dermatol 2004;
matol 2013; 69: S27–S35. 150: 1136–1141.
6 Lomholt G. Prevalence of skin diseases in a population; a census study 28 Del Rosso JQ, Thiboutot D, Gallo R et al. Consensus recommendations
from the Faroe Islands. Dan Med Bull 1964; 11: 1–7. from the American Acne & Rosacea Society on the management of rosa-
7 Abram K, Silm H, Oona M. Prevalence of rosacea in an Estonian work- cea, part 1: a status report on the disease state, general measures, and
ing population using a standard classification. Acta Derm Venereol 2010; adjunctive skin care. Cutis 2013; 92: 234–240.
90: 269–273. 29 Elias PM. The skin barrier as an innate immune element. Semin Immu-
8 Elewski BE, Draelos Z, Dreno B, Jansen T, Layton A, Picardo M. Rosa- nopathol 2007; 29: 3–14.
cea - global diversity and optimized outcome: proposed international 30 Del Rosso JQ, Levin J. The clinical relevance of maintaining the func-
consensus from the Rosacea International Expert Group. J Eur Acad tional integrity of the stratum corneum in both healthy and disease-
Dermatol Venereol 2011; 25: 188–200. affected skin. J Clin Aesthet Dermatol 2011; 4: 22–42.
9 Khaled A, Hammami H, Zeglaoui F et al. Rosacea: 244 Tunisian cases. 31 Coda AB, Hata T, Miller J et al. Cathelicidin, kallikrein 5, and serine
Tunis Med 2010; 88: 597–601. protease activity is inhibited during treatment of rosacea with azelaic
10 Alexis AF. Rosacea in patients with skin of color: uncommon but not acid 15% gel. J Am Acad Dermatol 2013; 69: 570–577.
rare. Cutis 2010; 86: 60–62. 32 Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea patho-
11 van Zuuren EJ, Kramer S, Carter B, Graber MA, Fedorowicz Z. Interven- physiology: A review of recent findings. J Am Acad Dermatol 2013; 69:
tions for rosacea. Cochrane Database Syst Rev, 2011; 16: CD003262. S15–S26.
12 Berg M. Facial skin complaints and work at visual display units. Epi- 33 Yamasaki K, Kanada K, Macleod DT et al. TLR2 expression is increased
demiological, clinical and histopathological studies. Acta Derm Venereol in rosacea and stimulates enhanced serine protease production by ker-
Suppl (Stockh) 1989; 150: 1–40. atinocytes. J Investigat Dermatol 2011; 131: 688–697.
13 Kellen R, Silverberg NB. Pediatric rosacea. Cutis 2016; 98: 49–53. 34 Wladis EJ, Carlson JA, Wang MS, Bhoiwala DP, Adam AP. Toll-like
14 Schaller M, Almeida L, Bewley A et al. Rosacea treatment update: Rec- receptors and vascular markers in ocular rosacea. Ophthalmic Plast
ommendations from the global ROSacea COnsensus (ROSCO) panel. Br Reconstr Surg 2013; 29: 290–293.
J Dermatol 2017; 176: 465–471. 35 Millikan L. The proposed inflammatory pathophysiology of rosacea:
15 Abram K, Silm H, Maaroos HI, Oona M. Risk factors associated with implications for treatment. SKINmed 2003; 2: 43–47.
rosacea. J Eur Acad Dermatol Venereol 2010; 24: 565–571. 36 Parodi A, Guarrera M, Rebora A. Flushing in rosacea: An experimental
16 Carruth BP, Meyer DR, Wladis EJ et al. Extreme eyelid lymphedema approach. Arch Dermatol Res 1980; 269: 269–273.
associated with rosacea (Morbihan Disease): case series, literature 37 Buhl T, Sulk M, Nowak P et al. Molecular and morphological character-
review, and therapeutic considerations. Ophthal Plast Reconstr Surg ization of inflammatory infiltrate in rosacea reveals activation of Th1/
2017; 33 (3 Suppl 1): S34–S38. Th17 pathways. J Investigat Dermatol 2015; 135: 2198–2208.
17 Aldrich N, Gerstenblith M, Fu P et al. Genetic vs environmental factors 38 Wilkin JK. Why is flushing limited to a mostly facial cutaneous distribu-
that correlate with rosacea: a cohort-based survey of twins. JAMA Der- tion? J Am Acad Dermatol 1988; 19: 309–313.
matol 2015; 151: 1213–1219. 39 Sattler EC, Maier T, Hoffmann VS, Hegyi J, Ruzicka T, Berking C. Non-
18 Binet O, Audefray D, Beltzer-Garelly E, Gauchy O, Cesarini JP. Haber’s invasive in vivo detection and quantification of Demodexmites by con-
syndrome. First French family (2 cases). Ann Dermatol Venereol 1986; focal laser scanning microscopy. Br J Dermatol 2012; 167: 1042–1047.
113: 43–50. 40 Sibenge S, Gawkrodger DJ. Rosacea: A study of clinical patterns, blood
19 Fowler J Jr, Jackson M, Moore A et al. Efficacy and safety of once-daily flow, and the role of Demodex folliculorum. J Am Acad Dermatol 1992;
topical brimonidine tartrate gel 0.5% for the treatment of moderate to 26: 590–593.
severe facial erythema of rosacea: results of two randomized, double- 41 Bonnar E, Eustace P, Powell FC. The Demodex mite population in rosa-
blind, and vehicle-controlled pivotal studies. J Drugs Dermatol 2013; 12: cea. J Am Acad Dermatol 1993; 28: 443–448.
650–656. 42 Roihu T, Kariniemi A-L. Demodex mites in acne rosacea. J Cutan Pathol
20 Roby KD, Di Nardo A. Innate immunity and the role of the antimicro- 1998; 25: 550–552.
bial peptide cathelicidin in inflammatory skin disease. Drug Discovery 43 Forton F, Seys B. Density of Demodex folliculorum in rosacea: a case-
Today: Disease Mechan 2013; 10: e79–e82. control study using standardized skin-surface biopsy. Br J Dermatol
21 Kim BJ, Kwon HH, Park SY et al. Double-blind, randomized non-infer- 1993; 128: 650–659.
iority trial of a novel botulinum toxin A processed from the strain 44 Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial anti-
CBFC26, compared with onabotulinumtoxin A in the treatment of gens stimulate inflammatory cells in rosacea. Br J Dermatol 2007; 157:
glabellar lines. J Eur Acad Dermatol Venereol 2014; 28: 1761–1767. 474–481.
22 Kutlubay Z, Zara T, Engin B et al. Helicobacter pylori infection and skin 45 Guzman-Sanchez DA, Ishiuji Y, Patel T, Fountain J, Chan YH,
disorders. Hong Kong Med J 2014; 20: 317–324. Yosipovitch G. Enhanced skin blood flow and sensitivity to noxious heat
23 Vemuri RC, Gundamaraju R, Sekaran SD, Manikam R. Major patho- stimuli in papulopustular rosacea. J Am Acad Dermatol 2007; 57: 800–
physiological correlations of rosacea: a complete clinical appraisal. Int J 805.
Med Sci 2015; 12: 387–396. 46 Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M.
24 Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, Neuronal control of skin function: the skin as a neuroimmunoendocrine
and subtype classification. J Am Acad Dermatol 2004; 51: 327–341; quiz organ. Physiol Rev 2006; 86: 1309–1379.
342-324. 47 Aubdool AA, Brain SD. Neurovascular aspects of skin neurogenic
25 Del Rosso JQ. Advances in understanding and managing rosacea: part 1: inflammation. J Investigat Dermatol Symposium Proc 2011; 15: 33–39.
connecting the dots between pathophysiological mechanisms and com- 48 Julius D, Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine
mon clinical features of rosacea with emphasis on vascular changes and JD. The capsaicin receptor: a heat-activated ion channel in the pain
facial erythema. J Clin Aesthet Dermatol 2012; 5: 16–25. pathway. Nature 1997; 389: 816–824.
49 Steinhoff M, Schmelz M, Schauber J. Facial erythema of rosacea – aetiol- 74 Two AM, Wu W, Gallo RL, Hata TR. Rosacea: Part I. Introduction, cate-
ogy, different pathophysiologies and treatment options. Acta Derm gorization, histology, pathogenesis, and risk factors. J Am Acad Dermatol
Venereol 2016; 96: 579–586. 2015; 72: 749–758; quiz 759-760.
50 Del Rosso JQ. Management of facial erythema of rosacea: What is the 75 Marks R. Histopathology of rosacea. Arch Dermatol 1969; 100: 683.
role of topical a-adrenergic receptor agonist therapy? J Am Acad Derma- 76 Powell FC. The histopathology of rosacea: ‘Where’s the Beef?’. Dermatol-
tol 2013; 69: S44–S56. ogy 2004; 209: 173–174.
51 McAleer MA, Lacey N, Powell FC. The pathophysiology of rosacea. G 77 Aylesworth R, Vance JC. Demodex folliculorum and Demodex brevis in
Ital Dermatol Venereol 2009; 144: 663–671. cutaneous biopsies. J Am Acad Dermatol 1982; 7: 583–589.
52 Steinhoff M, Buddenkotte J, Aubert J et al. Clinical, cellular, and molec- 78 Basta-Juzbasic A, Subic JS, Ljubojevic S. Demodex folliculorum in devel-
ular aspects in the pathophysiology of rosacea. J Investigat Dermatol opment of dermatitis rosaceiformis steroidica and rosacea-related dis-
Symposium Proc 2011; 15: 2–11. eases. Clin Dermatol 2002; 20: 135–140.
53 Wilkin J, Dahl M, Detmar M et al. Standard classification of rosacea: 79 Mark G, Lebwohl M, Warren R, Heymann MD, John Berth-Jones FRCP,
report of the national rosacea society expert committee on the classifica- Ian Coulson FRCP. Treatment of Skin Disease. 4 ed. Expert Consult. 2014.
tion and staging of rosacea. J Am Acad Dermatol 2002; 46: 584–587. 80 Kim TG, Roh HJ, Cho SB, Lee JH, Lee SJ, Oh SH. Enhancing effect of
54 Del Rosso JQ, Baldwin H, Webster G, American A, Rosacea S. American pretreatment with topical niacin in the treatment of rosacea-associated
Acne & Rosacea Society rosacea medical management guidelines. J Drugs erythema by 585-nm pulsed dye laser in Koreans: a randomized,
Dermatol 2008; 7: 531–533. prospective, split-face trial. Br J Dermatol 2011; 164: 573–579.
55 Del Rosso JQ, Thiboutot D, Gallo R et al. Consensus recommendations 81 Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad
from the American Acne & Rosacea Society on the management of rosa- Dermatol 2004; 51: 499–512; quiz 513-494.
cea, part 2: a status report on topical agents. Cutis 2013; 92: 277–284. 82 Asai Y, Tan J, Baibergenova A et al. Canadian clinical practice guidelines
56 Odom R, Dahl M, Dover J et al. Standard management options for rosa- for rosacea. J Cutan Med Surg 2016; 20: 432–445.
cea, part 1: overview and broad spectrum of care. Cutis 2009; 84: 43–47. 83 Fowler J, Jarratt M, Moore A et al. Once-daily topical brimonidine tar-
57 Li S, Cho E, Drucker AM, Qureshi AA, Li W-Q. Alcohol Intake and Risk trate gel 0.5% is a novel treatment for moderate to severe facial erythema
of Rosacea in US Women. 2017; 76: 1061–1067.e2. of rosacea: results of two multicentre, randomized and vehicle-con-
58 De Marchi SU, Cecchin E, De Marchi S. Ocular rosacea: an underdiag- trolled studies. Br J Dermatol 2012; 166: 633–641.
nosed cause of relapsing conjunctivitis-blepharitis in the elderly. Case 84 Layton AM, Schaller M, Homey B et al. Brimonidine gel 0.33% rapidly
Reports. DOI: 10.1136/bcr-2014-205146. improves patient-reported outcomes by controlling facial erythema of
59 Vieira AC, Mannis MJ. Ocular rosacea: Common and commonly rosacea: a randomized, double-blind, vehicle-controlled study. J Eur
missed. J Am Acad Dermatol 2013; 69: S36–S41. Acad Dermatol Venereol 2015; 29: 2405–2410.
60 Ghanem VC, Mehra N, Wong S, Mannis MJ. The prevalence of ocular 85 Kendall JWW. A comparison of 3 assessments in the treatment of rosa-
signs in acne rosacea. Cornea 2003; 22: 230–233. cea in the context of a comparative effectiveness study. Value Health
61 Karamursel Akpek E, Merchant A, Pinar V, Foster CS. Ocular rosacea. 2014; 17: 181–182.
Ophthalmology 1997; 104: 1863–1867. 86 Jackson JM, Fowler J, Moore A et al. Improvement in facial erythema
62 Reinholz M, Tietze JK, Kilian K et al. Rosacea - S1 guideline. JDDG. J within 30 minutes of initial application of brimonidine tartrate in
der Deutschen Dermatologischen Gesellschaft 2013; 11: 768–780. patients with rosacea. J Drugs Dermatol 2014; 13: 699–704.
63 Borrie P. Rosacea with special reference to its ocular manifestations. Br J 87 Ilkovitch D, Pomerantz RG. Brimonidine effective but may lead to sig-
Dermatol 1953; 65: 458–463. nificant rebound erythema. J Am Acad Dermatol 2014; 70: e109–e110.
64 Starr PA, Macdonald A. Oculocutaneous aspects of rosacea. Proc R Soc 88 Routt ET, Levitt JO. Rebound erythema and burning sensation from a
Med 1969; 62: 9–11. new topical brimonidine tartrate gel 0.33%. J Am Acad Dermatol 2014;
65 Michel JL, Cabibel F. Frequency, severity and treatment of ocular rosacea 70: e37–e38.
during cutaneous rosacea. Ann Dermatol Venereol 2003; 130: 20–24. 89 Gillihan R, Nguyen T, Fischer R, Rajpara A, Aires D. Erythema in skin
66 Quarterman MJ, Johnson DW, Abele DC, Lesher JL Jr, Hull DS, Davis adjacent to area of long-term brimonidine treatment for rosacea: a novel
LS. Ocular rosacea. Signs, symptoms, and tear studies before and after adverse reaction. JAMA Dermatol 2015; 151: 1136–1137.
treatment with doxycycline. Arch Dermatol 1997; 133: 49–54. 90 Benkali K, Leoni M, Rony F et al. Comparative pharmacokinetics and
67 Wohlrab J, Lueftl M, Marsch WC. Persistent erythema and edema of the bioavailability of brimonidine following ocular and dermal administra-
midthird and upper aspect of the face (morbus morbihan): Evidence of tion of brimonidine tartrate ophthalmic solution and gel in patients with
hidden immunologic contact urticaria and impaired lymphatic drainage. moderate-to-severe facial erythema associated with rosacea. Br J Derma-
J Am Acad Dermatol 2005; 52: 595–602. tol 2014; 171: 162–169.
68 Renieri G, Brochhausen C, Pfeiffer N, Pitz S. Chronic eyelid oedema and 91 Johnson AW, Johnson SM. The role of topical brimonidine tartrate gel
rosacea (Morbus Morbihan): diagnostic and therapeutic challenges. Klin as a novel therapeutic option for persistent facial erythema associated
Monbl Augenheilkd 2011; 228: 19–24. with rosacea. Dermatol Ther (Heidelb) 2015; 5: 171–181.
69 Lamparter J, Kottler U, Cursiefen C, Pfeiffer N, Pitz S. Morbus Morbi- 92 Del Barrio-Dıaz P, Moll-Manzur C, Vera-Kellet C. Brimonidine gel for
han: A rare cause of edematous swelling of the eyelids. Ophthalmologe the treatment of recalcitrant facial erythema in diseases other than rosa-
2010; 107: 553–557. cea: a novel tool for clinicians. J Eur Acad Dermatol Venereol 2017; 31:
70 Mainetti C, Masouye I, Harms M, Saurat JH. Solid persistent facial e32–e33.
edema of the young adult. Melkersson-Rosenthal syndrome. Ann Der- 93 Navarrete-Dechent C, Manriquez JJ, del Puerto C, Vera-Kellet C. Bri-
matol Venereol 1994; 121: 165–170. monidine gel for the treatment of persistent heliotrope rash in a patient
71 Koh H, Ng S, Tan W. Rosacea fulminans. Indian J Dermatol Venereol with amyopathic dermatomyositis: a case report. J Eur Acad Dermatol
Leprol 2014; 80: 272. Venereol 2016; 30: 476–477.
72 Smith LA, Meehan SA, Cohen DE. Rosacea fulminans with extrafacial 94 Reinholz M, Heppt M, Tietze JK, Ruzicka T, Gauglitz GG, Schauber J.
lesions in an elderly man: successful treatment with subantimicrobial- Topical 0.5% brimonidine gel to camouflage redness of immature scars.
dose doxycycline. J Drugs Dermatol 2014; 13: 763–765. J Dermatol Case Reports 2015; 9: 87–88.
73 Springinsfeld G, Cribier B, Lipsker D. Dermatose mixte de la face, une 95 Shim TN, Abdullah A. The effect of pulsed dye laser on the dermatology
entite frequente meritant d’être individualisee: etude de 25 cas. Annales life quality index in erythematotelangiectatic rosacea patients: an assess-
de Dermatologie et de Venereologie 2009; 136: 543–545. ment. J Clin Aesthet Dermatol 2013; 6: 30–32.
96 Maxwell EL, Ellis DA, Manis H. Acne rosacea: effectiveness of 532 nm 118 Nymann P, Hedelund L, Haedersdal M. Long-pulsed dye laser vs.
laser on the cosmetic appearance of the skin. J Otolaryngol Head Neck intense pulsed light for the treatment of facial telangiectasias: a
Surg 2010; 39: 292–296. randomized controlled trial. J Eur Acad Dermatol Venereol 2010; 24:
97 Iyer S, Fitzpatrick RE. Long-pulsed dye laser treatment for facial telang- 143–146.
iectasias and erythema: evaluation of a single purpuric pass versus multi- 119 Liu J, Liu J, Ren Y, Li B, Lu S. Comparative efficacy of intense pulsed
ple subpurpuric passes. Dermatol Surg 2005; 31: 898–903. light for different erythema associated with rosacea. J Cosmet Laser Ther
98 Schroeter CA, Haaf-von Below S, Neumann HA. Effective treatment of 2014; 16: 324–327.
rosacea using intense pulsed light systems. Dermatol Surg 2005; 31: 120 Craige H, Cohen JB. Symptomatic treatment of idiopathic and rosacea-
1285–1289. associated cutaneous flushing with propranolol. J Am Acad Dermatol
99 Bernstein EF, Kligman A. Rosacea treatment using the new-generation, 2005; 53: 881–884.
high-energy, 595 nm, long pulse-duration pulsed-dye laser. Lasers Surg 121 Park JM, Mun JH, Song M et al. Propranolol, doxycycline and combina-
Med 2008; 40: 233–239. tion therapy for the treatment of rosacea. J Dermatol 2015; 42: 64–69.
100 Tan ST, Bialostocki A, Armstrong JR. Pulsed dye laser therapy for rosa- 122 Layton A, Thiboutot D. Emerging therapies in rosacea. J Am Acad Der-
cea. Br J Plast Surg 2004; 57: 303–310. matol 2013; 69: S57–S65.
101 Alam M, Dover JS, Arndt KA. Treatment of facial telangiectasia with 123 Wilkin JK. Effect of nadolol on flushing reactions in rosacea. J Am Acad
variable-pulse high-fluence pulsed-dye laser: comparison of efficacy with Dermatol 1989; 20: 202–205.
fluences immediately above and below the purpura threshold. Dermatol 124 Hsu CC, Lee JY. Carvedilol for the treatment of refractory facial flushing
Surg 2003; 29: 681–684; discussion 685. and persistent erythema of rosacea. Arch Dermatol 2011; 147: 1258–
102 Neuhaus IM, Zane LT, Tope WD. Comparative efficacy of nonpurpura- 1260.
genic pulsed dye laser and intense pulsed light for erythematotelang- 125 Hsu CC, Lee JY. Pronounced facial flushing and persistent erythema of
iectatic rosacea. Dermatol Surg 2009; 35: 920–928. rosacea effectively treated by carvedilol, a nonselective beta-adrenergic
103 Rohrer TE, Chatrath V, Iyengar V. Does pulse stacking improve the blocker. J Am Acad Dermatol 2012; 67: 491–493.
results of treatment with variable-pulse pulsed-dye lasers? Dermatol Surg 126 Bleicher PA, Charles JH, Sober AJ. Topical metronidazole therapy for
2004; 30: 163–167; discussion 167. rosacea. Arch Dermatol 1987; 123: 609–614.
104 Tanghetti E, Sherr EA, Sierra R, Mirkov M. The effects of pulse dye laser 127 Nielsen PG. Treatment of rosacea with 1% metronidazole cream. A dou-
double-pass treatment intervals on depth of vessel coagulation. Lasers ble-blind study. Br J Dermatol 1983; 108: 327–332.
Surg Med 2006; 38: 16–21. 128 Breneman DL, Stewart D, Hevia O, Hino PD, Drake LA. A double-blind,
105 Kassir R, Kolluru A, Kassir M. Intense pulsed light for the treatment of multicenter clinical trial comparing efficacy of once-daily metronidazole 1
rosacea and telangiectasias. J Cosmetic Laser Therapy 2011; 13: 216–222. percent cream to vehicle in patients with rosacea. Cutis 1998; 61: 44–47.
106 Papageorgiou P, Clayton W, Norwood S, Chopra S, Rustin M. Treat- 129 Kocak M, Yagli S, Vahapoglu G, Eksioglu M. Permethrin 5% cream ver-
ment of rosacea with intense pulsed light: significant improvement and sus metronidazole 0.75% gel for the treatment of papulopustular rosa-
long-lasting results. Br J Dermatol 2008; 159: 628–632. cea. A randomized double-blind placebo-controlled study. Dermatology
107 Jasim ZF, Woo WK, Handley JM. Long-pulsed (6-ms) pulsed dye laser 2002; 205: 265–270.
treatment of rosacea-associated telangiectasia using subpurpuric clinical 130 Dahl MV, Katz HI, Krueger GG et al. Topical metronidazole maintains
threshold. Dermatol Surg 2004; 30: 37–40. remissions of rosacea. Arch Dermatol 1998; 134: 679–683.
108 Mark KA, Sparacio RM, Voigt A, Marenus K, Sarnoff DS. Objective and 131 Bitar A. A double-blind randomised study of metronidazole (Flagylâ)
quantitative improvement of rosacea-associated erythema after intense 1% cream in the treatment of acne rosacea. Drug Invest 1990; 2:
pulsed light treatment. Dermatol Surg 2003; 29: 600–604. 242–248.
109 Lonne-Rahm S, Nordlind K, Edstrom DW, Ros AM, Berg M. Laser treat- 132 Bjerke R, Fyrand O, Graupe K. Double-blind comparison of azelaic acid
ment of rosacea: a pathoetiological study. Arch Dermatol 2004; 140: 20% cream and its vehicle in treatment of papulo-pustular rosacea. Acta
1345–1349. Derm Venereol 1999; 79: 456–459.
110 Clark SM, Lanigan SW, Marks R. Laser treatment of erythema and 133 Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic
telangiectasia associated with rosacea. Lasers Med Sci 2002; 17: 26–33. acid (15%) gel as a new treatment for papulopustular rosacea: results
111 Tan SR, Tope WD. Pulsed dye laser treatment of rosacea improves ery- from two vehicle-controlled, randomized phase III studies. J Am Acad
thema, symptomatology, and quality of life. J Am Acad Dermatol 2004; Dermatol 2003; 48: 836–845.
51: 592–599. 134 Bloom BS, Payongayong L, Mourin A, Goldberg DJ. Impact of intrader-
112 Taub AF, Devita EC. Successful treatment of erythematotelangiectatic mal abobotulinumtoxinA on facial erythema of rosacea. Dermatol Surg
rosacea with pulsed light and radiofrequency. J Clin Aesthet Dermatol 2015; 41(Suppl 1): S9–S16.
2008; 1: 37–40. 135 Garg G, Thami GP. Clinical efficacy of tacrolimus in rosacea. J Eur Acad
113 Butterwick KJ, Butterwick LS, Han A. Laser and light therapies for acne Dermatol Venereol 2009; 23: 239–240.
rosacea. J Drugs Dermatol 2006; 5: 35–39. 136 Sehgal VN, Sharma S, Sardana K. Rosacea/acne rosacea: efficacy of com-
114 Karsai S, Roos S, Raulin C. Treatment of facial telangiectasia using a bination therapy of azithromycin and topical 0.1% tacrolimus ointment.
dual-wavelength laser system (595 and 1064 nm): a randomized con- J Eur Acad Dermatol Venereol 2008; 22: 1366–1368.
trolled trial with blinded response evaluation. Dermatol Surg 2008; 34: 137 Kim MB, Kim GW, Park HJ et al. Pimecrolimus 1% cream for the treat-
702–708. ment of rosacea. J Dermatol 2011; 38: 1135–1139.
115 Alam M, Voravutinon N, Warycha M et al. Comparative effectiveness of 138 Chu CY. An open-label pilot study to evaluate the safety and efficacy of
nonpurpuragenic 595-nm pulsed dye laser and microsecond 1064-nm topically applied pimecrolimus cream for the treatment of steroid-
neodymium: yttrium-aluminum-garnet laser for treatment of diffuse induced rosacea-like eruption. J Eur Acad Dermatol Venereol 2007; 21:
facial erythema: A double-blind randomized controlled trial. J Am Acad 484–490.
Dermatol 2013; 69: 438–443. 139 Teraki Y, Hitomi K, Sato Y, Izaki S. Tacrolimus-induced rosacea-like
116 Kim J-H, Oh YS, Choi EH. Oral azithromycin for treatment of intract- dermatitis: a clinical analysis of 16 cases associated with tacrolimus oint-
able rosacea. J Korean Med Sci 2011; 26: 694. ment application. Dermatology 2012; 224: 309–314.
117 Kawana S, Ochiai H, Tachihara R. Objective evaluation of the effect of 140 Lubbe J, Stucky L, Saurat JH. Rosaceiform dermatitis with follicular
intense pulsed light on rosacea and solar lentigines by spectrophotomet- Demodex after treatment of facial atopic dermatitis with 1% pime-
ric analysis of skin color. Dermatol Surg 2007; 33: 449–454. crolimus cream. Dermatology 2003; 207: 204–205.
141 Bernard LA, Cunningham BB, Al-Suwaidan S, Friedlander SF, 161 Thiboutot DM, Fleischer AB Jr, Del Rosso JQ, Graupe K. Azelaic acid
Eichenfield LF. A rosacea-like granulomatous eruption in a patient using 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs
tacrolimus ointment for atopic dermatitis. Arch Dermatol 2003; 139: Dermatol 2008; 7: 541–546.
229–231. 162 Thiboutot DM, Fleischer AB, Del Rosso JQ, Rich P. A multicenter study
142 Antille C, Saurat JH, Lubbe J. Induction of rosaceiform dermatitis dur- of topical azelaic acid 15% gel in combination with oral doxycycline as
ing treatment of facial inflammatory dermatoses with tacrolimus oint- initial therapy and azelaic acid 15% gel as maintenance monotherapy. J
ment. Arch Dermatol 2004; 140: 457–460. Drugs Dermatol 2009; 8: 639–648.
143 El Sayed F, Ammoury A, Dhaybi R, Bazex J. Rosaceiform eruption to 163 Ali ST, Alinia H, Feldman SR. The treatment of rosacea with topical
pimecrolimus. J Am Acad Dermatol 2006; 54: 548–550. ivermectin. Drugs of Today 2015; 51: 243.
144 Fujiwara S, Okubo Y, Irisawa R, Tsuboi R. Rosaceiform dermatitis asso- 164 Weissenbacher S, Merkl J, Hildebrandt B et al. Pimecrolimus cream 1%
ciated with topical tacrolimus treatment. J Am Acad Dermatol 2010; 62: for papulopustular rosacea: a randomized vehicle-controlled double-
1050–1052. blind trial. Br J Dermatol 2007; 156: 728–732.
145 Yoon TY, Kim HJ, Kim MK. Pimecrolimus-induced rosacea-like 165 Cunha PR, Rossi AB. Pimecrolimus cream 1% is effective in a case of
demodicidosis. Int J Dermatol 2007; 46: 1103–1105. granulomatous rosacea. Acta Derm Venereol 2006; 86: 71–72.
146 Dahl MV, Jarratt M, Kaplan D, Tuley MR, Baker MD. Once-daily topical 166 Gul U, Gonul M, Kilic A et al. A case of granulomatous rosacea success-
metronidazole cream formulations in the treatment of the papules and fully treated with pimecrolimus cream. J Dermatolog Treat 2008; 19:
pustules of rosacea. J Am Acad Dermatol 2001; 45: 723–730. 313–315.
147 Elewski BE, Fleischer AB Jr, Pariser DM. A comparison of 15% azelaic 167 Stinco G, Piccirillo F, Sallustio M, Patrone P. Facial flush reaction after
acid gel and 0.75% metronidazole gel in the topical treatment of papulo- alcohol ingestion during topical pimecrolimus and tacrolimus treat-
pustular rosacea: results of a randomized trial. Arch Dermatol 2003; 139: ment. Dermatology 2009; 218: 71–72.
1444–1450. 168 Gollnick H, Blume-Peytavi U, Szabo EL et al. Systemic isotretinoin in
148 Maddin S. A comparison of topical azelaic acid 20% cream and topical the treatment of rosacea - doxycycline- and placebo-controlled, random-
metronidazole 0.75% cream in the treatment of patients with papulo- ized clinical study. J Dtsch Dermatol Ges 2010; 8: 505–515.
pustular rosacea. J Am Acad Dermatol 1999; 40: 961–965. 169 Ertl GA, Levine N, Kligman AM. A comparison of the efficacy of topical
149 Wolf JE Jr, Kerrouche N, Arsonnaud S. Efficacy and safety of once-daily tretinoin and low-dose oral isotretinoin in rosacea. Arch Dermatol 1994;
metronidazole 1% gel compared with twice-daily azelaic acid 15% gel in 130: 319–324.
the treatment of rosacea. Cutis 2006; 77: 3–11. 170 Altinyazar HC, Koca R, Tekin NS, Esturk E. Adapalene vs. metron-
150 Kaufmann H, Oribe E, Miller M, Knott P, Wiltshire-Clement M, Yahr idazole gel for the treatment of rosacea. Int J Dermatol 2005; 44:
MD. Hypotension-induced vasopressin release distinguishes between 252–255.
pure autonomic failure and multiple system atrophy with autonomic 171 Signore RJ. A pilot study of 5 percent permethrin cream versus 0.75 per-
failure. Neurology 1992; 42: 590–593. cent metronidazole gel in acne rosacea. Cutis 1995; 56: 177–179.
151 Koca R, Altinyazar HC, Ankarali H, Muhtar S, Tekin NS, Cinar S. A 172 Breneman D, Savin R, VandePol C, Vamvakias G, Levy S, Leyden J.
comparison of metronidazole 1% cream and pimecrolimus 1% cream in Double-blind, randomized, vehicle-controlled clinical trial of once-daily
the treatment of patients with papulopustular rosacea: a randomized benzoyl peroxide/clindamycin topical gel in the treatment of patients
open-label clinical trial. Clin Exp Dermatol 2010; 35: 251–256. with moderate to severe rosacea. Int J Dermatol 2004; 43: 381–387.
152 Taieb A, Ortonne JP, Ruzicka T et al. Superiority of ivermectin 1% 173 Leyden JJ, Thiboutot D, Shalita A. Photographic review of results
cream over metronidazole 0.75% cream in treating inflammatory lesions from a clinical study comparing benzoyl peroxide 5%/clindamycin
of rosacea: a randomized, investigator-blinded trial. Br J Dermatol 2015; 1% topical gel with vehicle in the treatment of rosacea. Cutis 2004;
172: 1103–1110. 73: 11–17.
153 Nielsen PG. A double-blind study of 1% metronidazole cream versus sys- 174 Montes LF, Cordero AA, Kriner J, Loder J, Flanagan AD. Topical treat-
temic oxytetracycline therapy for rosacea. Br J Dermatol 1983; 109: 63–65. ment of acne rosacea with benzoyl peroxide acetone gel. Cutis 1983; 32:
154 Bamford JT, Elliott BA, Haller IV. Tacrolimus effect on rosacea. J Am 185–190.
Acad Dermatol 2004; 50: 107–108. 175 Leyden JJ. Randomized, phase 2, dose-ranging study in the treatment of
155 Mastrofrancesco A, Ottaviani M, Aspite N et al. Azelaic acid modulates rosacea with encapsulated benzoyl peroxide gel. J Drugs Dermatol 2014;
the inflammatory response in normal human keratinocytes through 13: 685–688.
PPARc activation. Exp Dermatol 2010; 19: 813–820. 176 Ozturkcan S, Ermertcan AT, Sahin MT, Afsar FS. Efficiency of benzoyl
156 Del Rosso JQ, Bruce S, Jarratt M, Menter A, Staedtler G. Efficacy peroxide-erythromycin gel in comparison with metronidazole gel in the
of topical azelaic acid (AzA) gel 15% plus oral doxycycline 40 mg treatment of acne rosacea. J Dermatol 2004; 31: 610–617.
versus metronidazole gel 1% plus oral doxycycline 40 mg in mild- 177 McHugh RC, Rice A, Sangha ND et al. A topical azithromycin prepara-
to-moderate papulopustular rosacea. J Drugs Dermatol 2010; 9: tion for the treatment of acne vulgaris and rosacea. J Dermatolog Treat
607–613. 2004; 15: 295–302.
157 Draelos ZD, Elewski B, Staedtler G, Havlickova B. Azelaic acid foam 178 Verea Hernando MMFL, Seco Vilari~ no C, Feal Cortizas B, Cu~ na Estevez
15% in the treatment of papulopustular rosacea: a randomized, double- B. Comparative study of topical erythromycin and topical metronidazole
blind, vehicle-controlled study. Cutis 2013; 92: 306–317. in the treatment of rosacea. Farmacia Clinica 1992; 9: 472–479.
158 Draelos ZD, Elewski BE, Harper JC et al. A phase 3 randomized, dou- 179 Faghihi G, Khosravani P, Nilforoushzadeh MA et al. Dapsone gel in the
ble-blind, vehicle-controlled trial of azelaic acid foam 15% in the treat- treatment of papulopustular rosacea: a double-blind randomized clinical
ment of papulopustular rosacea. Cutis 2015; 96: 54–61. trial. J Drugs Dermatol 2015; 14: 602–606.
159 Jackson JM, Kircik LH, Lorenz DJ. Efficacy of extended-release 45 mg 180 Say EM, Okan G, Gokdemir G. Treatment outcomes of long-pulsed nd:
oral minocycline and extended-release 45 mg oral minocycline plus 15% YAG laser for two different subtypes of rosacea. J Clin Aesthet Dermatol
azelaic acid in the treatment of acne rosacea. J Drugs Dermatol 2013; 12: 2015; 8: 16–20.
292–298. 181 Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflam-
160 Stein Gold L, Kircik L, Fowler J et al. Long-term safety of ivermectin 1% matory dose doxycycline versus doxycycline 100 mg in the treatment of
cream vs azelaic acid 15% gel in treating inflammatory lesions of rosa- rosacea. J Drugs Dermatol 2008; 7: 573–576.
cea: results of two 40-week controlled, investigator-blinded trials. J Drugs 182 Del Rosso JQ. Anti-inflammatory dose doxycycline in the treatment of
Dermatol 2014; 13: 1380–1386. rosacea. J Drugs Dermatol 2009; 8: 664–668.
183 Del Rosso JQ, Webster GF, Jackson M et al. Two randomized phase III 206 Forstinger C, Kittler H, Binder M. Treatment of rosacea-like demodici-
clinical trials evaluating anti-inflammatory dose doxycycline (40-mg dosis with oral ivermectin and topical permethrin cream. J Am Acad
doxycycline, USP capsules) administered once daily for treatment of Dermatol 1999; 41: 775–777.
rosacea. J Am Acad Dermatol 2007; 56: 791–802. 207 Aquilina C, Viraben R, Sire S. Ivermectin-responsive Demodex infesta-
184 Preshaw PM, Novak MJ, Mellonig J et al. Modified-release subantimi- tion during human immunodeficiency virus infection. A case report and
crobial dose doxycycline enhances scaling and root planing in subjects literature review. Dermatology 2002; 205: 394–397.
with periodontal disease. J Periodontol 2008; 79: 440–452. 208 Clyti E, Sayavong K, Chanthavisouk K. Demodecidosis in a patient
185 Sanchez J, Somolinos AL, Almodovar PI, Webster G, Bradshaw M, infected by HIV: successful treatment with ivermectin. Ann Dermatol
Powala C. A randomized, double-blind, placebo-controlled trial of the Venereol 2005; 132: 459–461.
combined effect of doxycycline hyclate 20-mg tablets and metronidazole 209 Brown M, Hernandez-Martin A, Clement A, Colmenero I, Torrelo A.
0.75% topical lotion in the treatment of rosacea. J Am Acad Dermatol Severe demodexfolliculorum-associated oculocutaneous rosacea in a girl
2005; 53: 791–797. successfully treated with ivermectin. JAMA Dermatol 2014; 150: 61–63.
186 Alexis AF, Webster G, Preston NJ, Caveney SW, Gottschalk RW. Effec- 210 Allen KJ, Davis CL, Billings SD, Mousdicas N. Recalcitrant papulopustu-
tiveness and safety of once-daily doxycycline capsules as monotherapy in lar rosacea in an immunocompetent patient responding to combination
patients with rosacea: an analysis by Fitzpatrick skin type. J Drugs Der- therapy with oral ivermectin and topical permethrin. Cutis 2007; 80:
matol 2012; 11: 1219–1222. 149–151.
187 Del Rosso JQ, Preston NJ, Caveney SW, Gottschalk RW. Effectiveness 211 Clyti E, Nacher M, Sainte-Marie D, Pradinaud R, Couppie P. Ivermectin
and safety of modified-release doxycycline capsules once daily for papu- treatment of three cases of demodecidosis during human immunodefi-
lopustular rosacea monotherapy results from a large community-based ciency virus infection. Int J Dermatol 2006; 45: 1066–1068.
trial in subgroups based on gender. J Drugs Dermatol 2012; 11: 703–707. 212 Coroneo M. Management of chronic blepharitis. Arch Ophthalmol 1989;
188 Webster GF. An open-label, community-based, 12-week assessment of 107: 951.
the effectiveness and safety of monotherapy with doxycycline 40 mg 213 Mori A. Disposable eyelid-warming device for the treatment of meibo-
(30-mg immediate-release and 10-mg delayed-release beads). Cutis mian gland dysfunction. Jpn J Ophthalmol 2003; 47: 578–586.
2010; 86: 7–15. 214 Olson MC, Korb DR, Greiner JV. Increase in tear film lipid layer thickness
189 Torresani C, Pavesi A, Manara GC. Clarithromycin versus doxycycline following treatment with warm compresses in patients with meibomian
in the treatment of rosacea. Int J Dermatol 1997; 36: 942–946. gland dysfunction. Eye Contact Lens: Sci Clinical Pract 2003; 29: 96–99.
190 Akhyani M, Ehsani AH, Ghiasi M, Jafari AK. Comparison of efficacy of 215 Blackie CA, Solomon JD, Greiner JV, Holmes M, Korb DR. Inner eyelid
azithromycin vs. doxycycline in the treatment of rosacea: a randomized surface temperature as a function of warm compress methodology.
open clinical trial. Int J Dermatol 2008; 47: 284–288. Optom Vis Sci 2008; 85: 675–683.
191 Fowler JF Jr. Combined effect of anti-inflammatory dose doxycycline 216 Matsumoto Y, Dogru M, Goto E et al. Efficacy of a new warm moist air
(40-mg doxycycline, usp monohydrate controlled-release capsules) and device on tear functions of patients with simple meibomian gland dys-
metronidazole topical gel 1% in the treatment of rosacea. J Drugs Der- function. Cornea 2006; 25: 644–650.
matol 2007; 6: 641–645. 217 Haque RM, Torkildsen GL, Brubaker K et al. Multicenter open-label study
192 Laffitte E. Hôpitaux Universitaires de Genève (HUG) - internal guideline evaluating the efficacy of azithromycin ophthalmic solution 1% on the signs
for rosacea. 2015. and symptoms of subjects with blepharitis. Cornea 2010; 29: 871–877.
193 Marks R, Ellis J. Comparative effectiveness of tetracycline and ampicillin 218 Schechter BA, Katz RS, Friedman LS. Efficacy of topical cyclosporine for
in rosacea. A controlled trial. Lancet 1971; 2: 1049–1052. the treatment of ocular rosacea. Adv Ther 2009; 26: 651–659.
194 Saihan EM, Burton JL. A double-blind trial of metronidazole versus 219 Arman A, Demirseren DD, Takmaz T. Treatment of ocular rosacea:
oxytetracycline therapy for rosacea. Br J Dermatol 1980; 102: 443–445. comparative study of topical cyclosporine and oral doxycycline. Int J
195 Baldwin HE. Oral therapy for rosacea. J Drugs Dermatol 2006; 5: 16–21. Ophthalmol 2015; 8: 544–549.
196 Uslu M, Savk E, Karaman G, Sendur N. Rosacea treatment with interme- 220 Sadrai Z, Hajrasouliha AR, Chauhan S, Saban DR, Dastjerdi MH, Dana
diate-dose isotretinoin: follow-up with erythema and sebum measure- R. Effect of topical azithromycin on corneal innate immune responses.
ments. Acta Derm Venereol 2012; 92: 73–77. Invest Opthalmol Visual Sci 2011; 52: 2525.
197 Hoting E, Paul E, Plewig G. Treatment of rosacea with isotretinoin. Int J 221 Mantelli F, Di Zazzo A, Sacchetti M, Dianzani C, Lambiase A, Bonini S.
Dermatol 1986; 25: 660–663. Topical azithromycin as a novel treatment for ocular rosacea. Ocular
198 Pye RJ, Burton JL. Treatment of rosacea by metronidazole. Lancet 1976; Immunol Inflammat 2013; 21: 371–377.
1: 1211–1212. 222 John T, Shah AA. Use of azithromycin ophthalmic solution in the treat-
199 Pereira TM, Vieira AP, Basto AS. Rosacea with extensive extrafacial ment of chronic mixed anterior blepharitis. Ann Ophthalmol (Skokie)
lesions. Int J Dermatol 2008; 47: 52–55. 2008; 40: 68–74.
200 Fuentelsaz V, Ara M, Corredera C, Lezcano V, Juberias P, Carapeto FJ. 223 Luchs J. Efficacy of topical azithromycin ophthalmic solution 1% in the
Rosacea fulminans in pregnancy: successful treatment with azithromy- treatment of posterior blepharitis. Adv Therapy 2008; 25: 858–870.
cin. Clin Exp Dermatol 2011; 36: 674–676. 224 Opitz DL, Tyler KF. Efficacy of azithromycin 1% ophthalmic solution
201 Dereli T, Inanir I, Kilinc I, Gencoglan G. Azithromycin in the treatment for treatment of ocular surface disease from posterior blepharitis. Clin
of papulopustular rosacea. J Dermatol 2005; 32: 926–928. Exp Optom 2011; 94: 200–206.
202 Bakar O, Demircay Z, Gurbuz O. Therapeutic potential of azithromycin 225 Seal DV, Wright P, Ficker L, Hagan K, Troski M, Menday P. Placebo
in rosacea. Int J Dermatol 2004; 43: 151–154. controlled trial of fusidic acid gel and oxytetracycline for recurrent ble-
203 Elewski BE. A novel treatment for acne vulgaris and rosacea. J Eur Acad pharitis and rosacea. Br J Ophthalmol 1995; 79: 42–45.
Dermatol Venereol 2000; 14: 423–424. 226 Oltz M, Check J. Rosacea and its ocular manifestations. Optometry - J
204 Sharquie KE, Najim RA, Al-Salman HN. Oral zinc sulfate in the treat- Am Optometric Assoc 2011; 82: 92–103.
ment of rosacea: a double-blind, placebo-controlled study. Int J Derma- 227 Gupta AK, Chaudhry MM. Rosacea and its management: an overview. J
tol 2006; 45: 857–861. Eur Acad Dermatol Venereol 2005; 19: 273–285.
205 Lawrenson RA, Seaman HE, Sundstrom A, Williams TJ, Farmer RD. 228 Stone DU, Chodosh J. Oral tetracyclines for ocular rosacea: an evidence-
Liver damage associated with minocycline use in acne: a systematic based review of the literature. Cornea 2004; 23: 106–109.
review of the published literature and pharmacovigilance data. Drug Saf 229 Frucht-Pery J, Sagi E, Hemo I, Ever-Hadani P. Efficacy of doxycycline
2000; 23: 333–349. and tetracycline in ocular rosacea. Am J Ophthalmol 1993; 116: 88–92.
230 Bakar Demircay Z, Toker E, C ß akır S. Ocular signs, symptoms and tear 251 Rosen T, Unkefer RP. Treatment of pyoderma faciale with isotretinoin
function tests of papulopustular rosacea patients receiving azithromycin. in a patient with ulcerative colitis. Cutis 1999; 64: 107–109.
J Eur Acad Dermatol Venereol 2009; 23: 544–549. 252 Firooz A, Firoozabadi MR, Dowlati Y. Rosacea fulminans (pyoderma
231 Bechara FG, Jansen T, Losch R, Altmeyer P, Hoffmann K. Morbihan’s faciale): successful treatment of a 3-year-old girl with oral isotretinoin.
disease: treatment with CO2 laser blepharoplasty. J Dermatol 2004; 31: Int J Dermatol 2001; 40: 203–205.
113–115. 253 McHenry PM, Hudson M, Smart LM, Rennie JA, Mowat NA, White MI.
232 Marzano AV, Vezzoli P, Alessi E. Elephantoid oedema of the eyelids. J Pyoderma faciale in a patient with Crohn’s disease. Clin Exp Dermatol
Eur Acad Dermatol Venereol 2004; 18: 459–462. 1992; 17: 460–462.
233 Khokhar O, Khachemoune A. A case of granulomatous rosacea: sorting 254 Bormann G, Gaber G, Fischer M, Marsch WC. Dapsone in rosacea ful-
granulomatous rosacea from other granulomatous diseases that affect minans. J Eur Acad Dermatol Venereol 2001; 15: 465–467.
the face. Dermatol Online J 2004; 10: 6. 255 Akhyani M, Daneshpazhooh M, Ghandi N. The association of pyo-
234 Krause MH, Torricelli R, Kundig T, Trueb RM, Hafner J. Dapsone in derma faciale and erythema nodosum. Clin Exp Dermatol 2007; 32:
granulomatous rosacea. Hautarzt 1997; 48: 246–248. 275–277.
235 Ehmann LM, Meller S, Homey B. Successful treatment of granulomatous 256 Razeghi S, Halvorson CR, Gaspari AA, Cross RK. Successful treatment
rosacea with dapsone. Hautarzt 2013; 64: 226–228. of localized pyoderma faciale in a patient with Crohn’s disease. Gastroen-
236 Rallis E, Korfitis C. Isotretinoin for the treatment of granulomatous terol Hepatol (N Y) 2013; 9: 541–543.
rosacea: case report and review of the literature. J Cutan Med Surg 2012; 257 Balakirski G, Baron JM, Megahed M. Morbihan disease as a special form
16: 438–441. of rosacea: review of pathogenesis and new therapeutic options. Hau-
237 Lane JE, Khachemoune A. Use of intense pulsed light to treat refractory tarzt 2013; 64: 884–886.
granulomatous rosacea. Dermatol Surg 2010; 36: 571–573. 258 Smith LA, Cohen DE. Successful long-term use of oral isotretinoin for
238 Tomita-Yamaguchi M, Santoro TJ. Constitutive turnover of inositol- the management of morbihan disease: a case series report and review of
containing phospholipids in B220+ T cells from autoimmune-prone the literature. Arch Dermatol 2012; 148: 1395–1398.
MRL-lpr/lpr mice. J Immunol 1990; 144: 3946–3952. 259 Hu SW, Robinson M, Meehan SA, Cohen DE. Morbihan disease. Der-
239 Mitoma C, Takahara M, Furue M. Severe granulomatous rosacea in a matol Online J 2012; 18: 27.
boy successfully treated with topical azelaic acid. Indian J Dermatol 2015; 260 Veraldi S, Persico MC, Francia C. Morbihan syndrome. Indian Dermatol
60: 323. Online J 2013; 4: 122–124.
240 Baglieri F, Scuderi G. Treatment of recalcitrant granulomatous rosacea 261 Kabuto M, Fujimoto N, Honda S, Tanaka T. Successful treatment
with ALA-PDT: report of a case. Indian J Dermatol Venereol Leprol 2011; with long-term use of minocycline for Morbihan disease showing
77: 536. mast cell infiltration: A second case report. J Dermatol 2015; 42:
241 Mula KN, Cassler NM, Lackey JN. Granulomatous rosacea manifesting 827–828.
after herpes simplex 2 infection: a case of Wolf’s isotopic response. J Am 262 Fujimoto N, Mitsuru M, Tanaka T. Successful treatment of Morbihan
Acad Dermatol 2015; 72: e36–e37. disease with long-term minocycline and its association with mast cell
242 Hu L, Alexander C, Velez NF et al. Severe tacrolimus-induced granulo- infiltration. Acta Derm Venereol 2015; 95: 368–369.
matous rosacea recalcitrant to oral tetracyclines. J Drugs Dermatol 2015; 263 Mazzatenta C, Giorgino G, Rubegni P, de Aloe G, Fimiani M. Solid per-
14: 628–630. sistent facial oedema (Morbihan’s disease) following rosacea, success-
243 Sigl I, Bauerdorf R. Granulomatous rosacea associated with ulcerative fully treated with isotretinoin and ketotifen. Br J Dermatol 1997; 137:
colitis: 2 case reports. Z Hautkr 1989; 64: 499–502. 1020–1021.
244 Winter UM, Treudler R, Paasch U, Sticherling M, Simon JC. A case of 264 Jungfer BJT, Przybilla B, Plewig G. Solid persistent facial edema of acne:
granulomatous rosacea coinciding with the use of etanercept: no relapse successful treatment with isotretinoin and ketotifen. Dermatology 1993;
with infliximab. Hautarzt 2008; 59: 724–727. 187: 34–37.
245 Plewig G, Jansen T, Kligman AM. Pyoderma faciale. A review and report 265 Walsh TR, Efthimiou J, Dreno B. Systematic review of antibiotic resis-
of 20 additional cases: is it rosacea? Arch Dermatol 1992; 128: 1611– tance in acne: an increasing topical and oral threat. Lancet Infect Dis
1617. 2016; 16: e23–e33.
246 Fender AB, Ignatovich Y, Mercurio MG. Pyoderma faciale. Cutis 2008; 266 Nast A, Bayerl C, Borelli C et al. S2k-guideline for therapy of acne. J
81:488–490. Dtsch Dermatol Ges 2010; 8(Suppl 2): s1–s59.
247 Costello MJ. Pyoderma faciale; unimproved by local and parenteral
penicillin therapy. Arch Derm Syphilol 1946; 54: 249.
Supporting information
248 Marks VJ, Briggaman RA. Pyoderma faciale: successful treatment with
isotretinoin. J Am Acad Dermatol 1987; 17: 1062–1063. Additional Supporting Information may be found in the online
249 Green DT, Champion RH, Allenby CF. Pyoderma faciale. Br J Dermatol version of this article:
1989; 119: 96–97.
250 Waibel M. Pyoderma faciale: Therapieerfolg mit 13-cisRetins€aure. In: Data S1. Recommendations for drugs rarely used for rosacea.
Wolff HH, Schmeller W, eds. Infektionen an Haut and Schleimhaut.
Grosse, Berlin, Germany, 1989:198–200.

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DOI: 10.1111/jdv.

Swiss S1 guideline for the treatment of rosacea

Table 1 Differential diagnosis of rosacea

of follicular infundibula can show spongiotic changes and Methods

Table 3 Level of evidence of topical and systemical treatments in rosacea.

Table 4 Swiss treatment recommendations for rosacea

Dapsone No data No data Not available in CH No data No data

Doxycycline (low dose) No data No data +++ +++ +++

IPL, PDL, Nd:YAG +++ +++ + No data No data

Surgery/Blepharoplasty No data Not appl. Not appl. +++ +

Green, recommended; Red, not recommended.

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