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Rosacea: Time for a New Approach

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Forum for Nord Derm Ven 2017, Vol. 22, No. 1 3
Review
Rosacea: Time for a New Approach
CARSTEN SAUER MIKKELSEN1, PETER BJERRING2, MARGARETA LIRVALL3, MARGARETA SVENSSON4, HELENE RINGE
HOLMGREN5, ALEXANDER SALAVA6 AND THEIS HULDT-NYSTRØM7
1Private Practice in Dermato-Venereology, Brønderslev, 2Dermato-Venereology, Mølholm Private Hospital, Mølholm, Denmark,
3Dermato-Venereology and Pathology, Lund, 4Dermato-Venereology, Private Practice, Stockholm, Sweden, 5Dermato-Venereol-
ogy, Private Practice, Frederikshavn, Denmark, 6Dermatology and Allergology, Helsinki University Hospital, Helsinki, Finland
and, 7Dermato-Venereology, Private Practice, Namsos, Norway. Carsten Sauer Mikkelsen, Private Practice in Dermato-Venereology,
Brønderslev, Denmark. E-mail: c.s.mikkelsen@hotmail
Rosacea, also known as “the curse of the Celts”, probably
because of the predominance of Fitzpatrick skin type I + II
in Celtic people, is a skin disorder with multiple signs and
symptoms. In individuals, these symptoms may be multiple,
or a single symptom may predominate (1), and the symptoms
may vary over time. For clinicians the definition of rosacea is
not very stringent and depends on both clinical morphological
findings and specific reactions to stimuli.
Rosacea is a chronic skin condition with facial redness, small
and superficial dilated blood vessels on the facial skin, papules,
pustules, and swelling (2). It typically begins as redness on
the central face, across the cheeks, nose or forehead, but can
also less commonly affect the neck, chest, ears and scalp (3).
The eyes are often involved, and thickening of the skin, with
enlargement (phymas), especially of the nose, can occur (4,
5). Because rosacea is so visible, it can interfere substantially
with a person’s quality of life.
Rosacea is typically seen in the Scandinavian skin type, who
have fair skin, blue eyes and blond hair. Epidemiological stud-
ies show that the prevalence is as high as 10% in the Swedish
population (6), approximately 5% in the USA and 2–3% among
the French and Germans (7, 8). A familial background is pres-
ent in 15–40% of cases. In ancestors of rosacea patients the
condition is found in approximately 45% of cases, compared
with 13% of controls. Women are affected 2–3 times more
frequently than men (9).
Approximately 80% of cases of rosacea are diagnosed after the
age of 30 years. Women typically debut earlier (35 years of
age) than men, with the highest prevalence in the age range
61–65 years. Males debut at approximately 50 years of age,
with the highest prevalence in the age range 76–80 years.
There are no epidemiological studies of rosacea in childhood.
Clinically, rosacea is not often seen in children, although it
may be underdiagnosed.
Rosacea is not a disease specific to people of northern Europe;
it may have a wider distribution, consistent with the migra-
tion of people and mixture of genes between races. Rosacea
in persons with Fitzpatrick skin type IV–V is less common,
but is probably underdiagnosed, as shown in a study from
India (10). Unfortunately, rosacea is often misdiagnosed (11).
Pre-rosacea (early-onset rosacea)
The pre-rosacea stage is characterized by frequent occurrences
of facial flushing or blushing, which may come and go, with-
out inflammation or facial swelling. For many people who
identify the problem and take corrective measures, this is as
far as their rosacea progresses. The facial flushing of pre-rosa-
cea is often triggered by the same complex set of triggers that
influence the later stages of rosacea. Effective treatment at this
early stage can help control and manage the severity of this
progressive condition (12).
Rosacea subtypes
The 4 classical subtypes of rosacea are: erythematotelangiec-
tatic rosacea (ETR), papulopustular rosacea (PPR), phymatous
rosacea, and ocular rosacea, as described below.
Erythematotelangiectatic rosacea (ETR)
The most common subtype of rosacea.
Flushing, persistent redness of the central face.
Often occurs
before or at the
same time as the
bumps and pim-
ples of papulopus-
tular rosacea.
Telangiectasias
with small visible
blood vessels may
be present.
Patients tend to
have sensitive
skin with stings
or burns at times.
Fig. 1. Erythematotelangiectatic rosacea
(ETR). (Photo: Carsten Sauer Mikkelsen).
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C. Sauer Mikkelsen et al – Rosacea – time for a new approach
Papulopustular rosacea (PPR)
Papules/pustules come and go, combined with transient
or persistent facial redness, primarily on the central face.
Small visible blood vessels (telangiectasias).
Raised, scaly red patches known as plaques.
Burning and stinging.
Phymatous rosacea
Nose (rhinophyma)
Chin (gnatophyma)
Forehead (metophyma)
Ears (otophyma)
Eyelids (blepharophyma)
Upper lip region (philtrophyma)
Rhinophyma is the most frequent location and shows
marked skin thickenings and irregular surface nodules,
especially of the nose. Telangiectasia can also be present.
Fibrosis is present and increased volume of sebaceous
glands is observed. The 4 different histopathological types
of rhinophyma (13) are:
Fibrous
Glandular
Fibroangiomatous
Actinic
Ocular rosacea
Minor irritation, foreign body sensation, dryness, and
blurry vision due to severe ocular surface disruption and
inflammatory keratitis.
Patients frequently describe a gritty feeling, and they com-
monly experience blepharitis and conjunctivitis. Clinicians
should ask about problems related to air conditioning and
the sensation of “hairs” stuck in the eyes.
Other ocular findings include lid margin and conjunctival
telangiectasias, eyelid thickening, eyelid crusts and scales,
chalazion and hordeolum, punctate epithelial erosions,
corneal infiltrates, corneal ulcers, corneal scars, and corneal
vascularization.
More than 50% of patients with ocular rosacea show a
reduction in Schirmer’s test (14).
The definition of ocular rosacea is even less stringent
than that of cutaneous rosacea. The diagnosis depends on
inflammatory findings due to disturbance of the function
of the Meibomian glands and telangiectasias. There is
no reliable diagnostic test for ocular rosacea. Since many
ophthalmic and dermatological diseases can present with
similar inflammatory reactions to that of ocular rosacea the
diagnosis relies on careful investigation and follow-up, and
the collaboration of ophthalmologists and dermatologists.
The lack of stringent diagnostic criteria for ocular rosacea
probably also reflects the varying prevalence of this con-
dition, with 6–72% of rosacea patients affected (15, 16).
Time for a new approach?
The classification and subtyping of rosacea has, until now,
been based on a subset of symptoms and clinical findings.
More than 50% of rosacea patients have a combination of dif-
ferent subtypes, which shows that subtyping is inadequate and
has limitations both for research and selection of treatment.
The use of a phenotype approach will allow a more accurate
and stringent classification of rosacea. New diagnostic tools
emerge, and transcriptome analysis has revealed a possible
distinct gene profile for each subtype of rosacea. A change in
paradigm towards a phenotype classification, which can also
easily be combined with newer diagnostic methods, such as
transcriptome analysis, is an interesting possibility. The use of
more objective criteria will allow those aspects that are most
troubling to patients to be better targeted and allow the best
treatment to be selected (17, 18).
Fig. 4. Ocular rosacea (Photo: Galderma®).
Fig. 2. Papulopustular rosacea (Photo: Galderma®).
Fig. 3. Phymatous rosacea (rhinophyma) (Photo:
Carsten Sauer Mikkelsen).
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C. Sauer Mikkelsen et al – Rosacea – time for a new approach
Pathology
Cribier (19) recently performed a large clinicopathological
study and, the data from this study, together with other pub-
lished data, was used to identify the main histological features
of rosacea. Histological markers were shown to be useful in
the diagnosis of rosacea.
Extensive telangiectasias are seen in the superficial and middle
dermis, with enlarged lumens and unusual shapes (tortuous
or geometric contours) and a larger number and size of the
telangiectatic vessels. There is a relatively low number of en-
dothelial cells, with a perivascular infiltrate that surrounds the
dilated vessels. The infiltrate is composed of mononuclear cells
(lymphocytes, histiocytes, and plasma cells). Oedema, visible
as a lucent band in superficial papillary and reticular dermis,
occurs. An increased number of dermal mast cells is seen.
Potential pathways of pathogenesis (20)
Innate immunity
Adaptive immunity
Neurocutaneous mechanisms
Vasculopathy
Innate and adaptive immunity (inflammation). Both the
innate and adaptive immune system are involved in the
development of rosacea at a very early stage (21). Initially,
T cells and macrophages infiltrate the skin, releasing factors
leading to prolonged vasodilation, as seen as erythema.
These cells are also responsible for the recruitment of
neutrophils and other cells, resulting in the formation of
pustules. The critical cells involved in the inflammatory
response in rosacea are Th1 and Th17 cells, mast cells,
macrophages, antibody-presenting B-cells, and neutrophils.
Increased serine protease activity and cathelicidin promotes
skin inflammation in rosacea. This knowledge of inflam-
mation is, in our opinion, important in order to prescribe a
correct stepwise treatment-algorithm with initial treatment
with anti-inflammatory drugs (22).
Neurocutaneous mechanism. Increased skin sensitivity to
noxious heat stimuli is observed in rosacea-affected skin,
more prominently in patients with PPR than in those with
ETR. A lower heat pain threshold is found in affected vs
non-affected areas (based on heating the skin with a probe
from 32°C to 50°C); enhanced perception of noxious
heat stimulus; subjective burning perception is increased
(based on Visual Analague Scale) in patients with rosacea
vs control subjects; elevated skin blood flow occurs in
PPR-affected skin vs non-affected skin (based on Laser
Doppler imaging). This component is not significant for
ETR-affected skin (23).
Vasculopathy. Facial hypersensitivity is based on vascular
changes due to: stasis, increased blood flow, inflammation,
lower pain threshold (as described above), higher skin tem-
perature and hypersensitivity (non-allergic) (24).
Neurogenic rosacea is a distinct clinical subtype requiring
a modified approach to treatment with drugs such as gab-
apentin, pregabalin and duloxetine (25).
Demodex and rosacea
Two types of Demodex mites are present in rosacea: Demodex
folliculorum and Demodex brevis. Demodex brevis is located
deepest. The mites are 0.1–0.4 mm long and have a life-cycle
of 14–18 days. Demodex are found in the hair follicles, seba-
ceous glands and eyelid glands. Corneal manifestations of
ocular Demodex infestation, causing severe corneal changes
with vascularization, infiltration and scarring, has also been
found (26). Demodex specifically causes papulopustular rosa-
cea. In immunocompromised patients Demodex may be located
elsewhere. A higher prevalence of Demodex folliculorum and a
higher mean mite density was found in rosacea patients, with
the greatest density in the involved areas (27). These findings
are confirmed by reflectance confocal microscopy (28) and
biopsies. The cut-off value of the Demodex density associated
with rosacea is 15 mites/cm2.
Demodex has been shown to induce neutrophilic and gran-
ulomatous inflammation. It causes upregulation of toll-like
receptor 2 (TLR2) proKLK5-proll-37; alarmin activity;
macrophage recruitment; activation of interleukin 8 (IL-8)
(neutrophil recruitment), cyclooxygenase-2 (COX-2) (pain);
and tumour necrosis factor alpha (TNF-a) (inflammation) (27).
Bacillus oleronius is a Gram-negative bacteria isolated from
Demodex. The mite-related bacterial antigen is, as expected,
present more frequently in patients with rosacea, and the
bacterial proteins induce neutrophil activation (29, 30). A
correlation has been shown between ocular Demodex infesta-
tion and serum immunoreactivity to Bacillus oleronius proteins
(31). The microbiota of Demodex mites from rosacea is different
from that of controls (32). Some bacterial species are found
only in Demodex from patients with rosacea (Proteobacteria,
Synergistetes, Firmicutes, Cyanobacteria, Bacteroidetes, Actini-
bacteria) but their role in the pathogenesis of this condition
remains unknown.
Psychosocial impact on patients with rosacea
In surveys performed by the National Rosacea Society, more
than 90% of patients with rosacea reported that their condi-
tion had reduced their self-confidence and self-esteem, 41%
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C. Sauer Mikkelsen et al – Rosacea – time for a new approach
reported that it had caused them to avoid public contact or
cancel social engagements. Among rosacea patients with se-
vere symptoms 88% reported that the disorder had adversely
affected their professional interactions, and 51% reported that
they had missed work because of their condition. Rosacea can
affect quality of life, and several controlled studies of patients
with rosacea show that using the Dermatology Life Quality
Index (DLQI) and Rosacea Quality of Life Index (RosaQoL)
the condition has a small-to-moderate negative effect on
health-related quality of life (33, 34).
There is evidence that treatment of rosacea with metronida-
zole, ivermectin, isotretinoin, low-dose doxycycline and laser
improves quality of life (35–39).
Co-morbidity and rosacea
No recommendations have yet been made in national, Nor-
dic or European Guidelines on screening for these possible
correlations (Table I).
In patients with concomitant rosacea and gastrointestinal dis-
orders, we suggest that the new data is taken into consideration
and follow-up is performed for inflammatory bowel diseases.
The following 3 HLA alleles (major histocompatibility com-
plex (MHC) class II) are significantly associated with rosacea:
HLA-DRB1
HLA-DQB1
HLA0DQA1 (20)
These 3 alleles are also associated with type I diabetes, reti-
nopathy (vascular proliferation), and coeliac disease.
Prophylaxis/trigger avoidance (50)
Ultraviolet (UV) light (see below).
Certain foods and beverages, such as hot drinks (e.g. soup,
hot chocolate), citrus fruits, and caffeinated beverages
(tea or coffee).
Spicy seasonings (e.g. white or black pepper, paprika, red
pepper and cayenne).
Alcohol, especially red wine.
Stress: emotional upset is one of the most common
triggers associated with rosacea flare-ups. Such patients
should seek ways to manage stress.
Strenuous exercise: high-intensity workouts overheat the
body and trigger flushing. Avoiding vigorous exercise or
dividing it into shorter sessions may help. It is recom-
mended to find ways to keep cool, such as exercising
outdoors during cooler weather, and indoors in an
air-conditioned space during hot weather.
Extreme temperatures: extremely hot or cold weather
conditions, very dry or humid, wind, and indoor heat
exposure can act as triggers. Patients should stay cool in
hot weather, cover up the skin and moisturize when it
is cold outdoors, and avoid hot baths, saunas or other
environmental factors that raise their body temperature
Medication: certain medications can cause flushing and
flare-ups. Drugs causing vasodilation (e.g. angioten-
sin-converting enzyme inhibitors (ACE inhibitors) and
some cholesterol-lowering drugs (e.g. niacin)) may play
a role. Approximately 90% of people treated for colorec-
tal, bronchial or breast cancer with chemotherapy with
epidermal growth factor (EGF))-receptor antagonist
(erlotinib, cetuximab, gefitinib, afatinib) develop skin
side-effects, including papulopustular rosacea-like ex-
anthema (51).
Treatments for rosacea
The Cochrane database produces high-quality, relevant sys-
tematic reviews that enable professionals and patients to make
evidence-based health decisions. The Grading of Recommen-
dations, Assessment, Development and Evaluation (GRADE)
scale enables judgements to be made about the quality of
evidence and strength of recommendations (50).
In the current paper we have used the GRADE scale as much
as possible regarding the following aspects of rosacea and
treatment:
Redness
Anti-parasitic
Anti-inflammatory
Ocular rosacea
Phyma
Table I. Co-morbidity and rosacea
Possible co-morbidities of rosacea
Depression (40)
Migraine (41, 42)
Brain tumour (glioma) (43)
Parkinson’s disease (44)
Dementia (45)
Autoimmunity (46)
Gastro-intestinal disorders (47)
Cardiovascular diseases (48)
Hypertension (49)
Diabetes mellitus type 1 (48)
Metabolic diseases (49)
Coeliac disease (48)
Multiple sclerosis (48)
Rheumatoid arthritis (46)
Schizophrenia (46)
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C. Sauer Mikkelsen et al – Rosacea – time for a new approach
Treatment for redness
Differential approach to redness
Redness is frequent and has been universally confirmed as the
most bothersome feature of rosacea (52). It is important to
classify and treat the underlying erythema correctly to ensure
the best possible control of redness.
Current definition-based symptoms and signs (5, 53–55)
1. Primary features associated with facial redness:
Transient flushing: of variable intensity and frequency
Inflammatory lesions: lesional or perilesional redness
Persistent (non-transient) macular background erythema:
independent of lesions. Inflammation from papules and
pustules or dry, inflamed skin may obscure the level of
non-transient erythema.
Teleangiectasia(s)
2. Secondary features associated with facial redness:
Burning, stinging, oedema. In rosacea the central fa-
cial erythema is seen on the: inner cheeks, nose, chin,
mid-forehead, and is confluent or diffuse.
Background erythema is caused by dilated deep located
vessels.
Telangiectasia is caused by dilated superficial vessels.
3. Neurovascular dysregulation can modulate vasodilation in
rosacea:
Adrenergic receptors are G-protein coupled receptors.
Alpha 1-adrenergic receptor: larger arteries (diameter
> 200 µm).
Alpha 2-adrenergic receptor: smaller arteries (diameter
< 200 µm). Brimonidine is a highly selective 2-adrenergic
receptor agonist and causes vasoconstriction of facial
blood vessels, which are abnormal in rosacea. It is a
symptomatic treatment and erythema returns as the
effect of the drug wears off after approximately 12 h.
There is high-quality GRADE evidence for all outcomes,
supporting that brimonidine is twice as effective as
vehicle for erythema. In rosacea it is the first and only
proven efficacious treatment for persistent erythema
(51). Brimonidine adverse events are seen in approxi-
mately 11% of cases. Most common are worsening of
erythema, flushing and worsening of rosacea (56).
Treatment of telangiectasia (57–62):
Telangiectatic rosacea is amenable to laser and intense pulsed
light (IPL) management. Nine randomized controlled trials
(RCT) have shown that pulsed dye laser and/or light-based
therapies appear to be effective, but limited data are provided
and only small sample sizes are enrolled. IPL is probably best
for centrofacial erythema.
Very early laser treatment on inflamed skin may lead to sting-
ing and burning. If the inflammation is under control with
a systemic drug in combination with a topical treatment,
subsequent laser or IPL therapy, these side-effects occur more
rarely. After visible telangiectasia are treated with laser or IPL
only the background erythema due to inflammation remains.
Treatment suggestions for erythema
Marked background erythema and minimal telangiectasia:
brimonidine
Marked background and marked telangiectasia: brimoni-
dine and laser/IPL
Minimal background erythema and severe telangiectasia:
laser/IPL only
Other treatment options for redness
Antihistamines. Mast cells are key mediators of cathelicidin-in-
itiated skin inflammation in rosacea (22). LL-37 is also mast
cell-associated, especially in patients with rosacea (22). Despite
poor GRADE evidence, we regard antihistamine treatment as
useful in the treatment of flushing.
b-blockers. Traditional b-blockers (propanolol, nadolol) have
been shown to be effective against erythema in rosacea pa-
tients in small case series. A small case series of normotensive
rosacea patients treated with carvedilol up to 25 mg/day was
shown to be effective in the treatment of facial erythema,
cheek temperature, as well as patient assessment of symptom
severity (63). Despite effective suppression of flushing, lim-
itations in the use of this drug are due to potential adverse
effects, such as hypotension and bradycardia.
Botulinum toxin. A Chinese group (64) showed that botulinum
toxin could decrease the intensity and duration of erythema
and rosacea flushing.
Anti-parasitic treatment
There is clinical and theoretical evidence for a dual mode
of action of ivermectin by anti-parasitic (65–67) and an-
ti-inflammatory activity (68–70). The anti-parasitic effect
occurs through reducing the numbers of Demodex. However,
3–4 weeks after treatment with ivermectin the Demodex will
spontaneously return. Topical ivermectin should be continued
as a maintenance treatment 2 times/week after clearance.
Neither doxycycline nor topical metronidazole 7.5–10 mg/g
have a significant anti-parasitic effect. The degree of Demodex
infestation does not decrease in parallel with improvement
under tetracycline treatment.
Anti-inflammatory effects occur through reducing the cellular
and humoral immune response by neutrophil phagocytosis,
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oxidant production by phagocytes, chemotaxis and pro-in-
flammatory cytokines (TNF-a, IL-1, IL-10).
Anti-inflammatory treatment
Topicals for papulopustular rosacea
High-quality evidence supports that ivermectin is effective and
safe for papulopustular rosacea in 2 trials with 1,371 partici-
pants (39). There is high-quality evidence that azelaic acid is
effective and safe for papulopustular rosacea in 5 trials. There
is moderate-quality evidence that metronidazole is effective
and safe for papulopustular rosacea in 9 trials.
Systemic treatment for papulopustular rosacea
High-quality evidence supports that ivermectin was more
effective than metronidazole in papulopustular rosacea in 962
participants (71). Modified-release doxycycline 40 mg might
be as effective as doxycycline 100 mg (quality of GRADE evi-
dence: low), with a quarter of the side effects.
Azithromycin might be as effective as doxycycline 100 mg
(quality of GRADE-evidence: very low). Isotretinoin 0.3 mg/
kg vs. doxycycline 100 mg (after 2 weeks, tapered to 50 mg/
day). High-quality GRADE- evidence for all outcomes support-
ing that isotretinoin was more effective than doxycycline in
papulopustular rosacea in one trial with 262 participants (72).
Ocular rosacea treatment
Mild (mild blepharitis with lid margin telangiectasia)
Topical: Lid hygiene. Topical antibiotic. Artificial tears re-
commended.
Moderate (blepharoconjunctivitis/blepharokeratoconjunctivitis)
Topical: Lid hygiene + topical cyclosporine
Systemic: Doxycycline 40 mg × 1 (or lymecycline 300 mg × 2
or tetracycline 500 mg × 2 tapering off to lowest effective dose
on effect). Artificial tears recommended.
Severe (sclerokeratitis)
Topical: Lid hygiene + topical corticosteroids or topical cyc-
losporine.
Systemic: Doxycycline 40 mg × 1 (or use lymecycline 300 mg
× 2 or tetracycline 500 mg × 2 tapering off to lowest effective
dose on effect. Artificial tears recommended.
In several small studies topical cyclosporine 0.05% has shown
a better effect than systemic doxycycline on ocular rosacea
symptom scores, Schirmer’s test and tear production (73,
74). In several studies topical cyclosporine has shown fewer
side-effects than oral doxycycline. Low-dose doxycycline has
a slower mode of action than the full dose in ocular rosacea
(75). Eyelid hygiene (removal of crusts, warm compresses) is
important in treatment of chronic blepharitis and meibomian
gland dysfunction (76).
In patients with dry eyes due to inflammatory diseases an
increased dietary intake of omega-3 fatty acids with lower
dietary ratio of omega-6 to omega-3 fatty acids, as well as
use of supplements containing linoleic and gamma-linoleic
acid, decreases the risk of complications associated with dry
eye symptoms (77, 78). Whether this data can be referred to
ocular rosacea is not known.
More RCTs are needed for recommendation on treatment of
ocular rosacea, since the GRADE evidence is low.
Phyma treatment (79)
Treatment options from Canadian guidelines:
C1. Topical retinoids
C2. Oral tetracycline or doxycycline
C3. Ablative laser surgery, using CO2 or Er:YAG modalities,
or surgery, including electrosurgery and cryosurgery
C4. Oral isotretinoin
C1. Topical retinoids
(Weak recommendation: very low confidence in effect
estimate)
Topical retinoids may help minimizing progression of rosa-
cea-associated phyma. Confidence in the effect is estimated
as very low because efficacy has not been evaluated by
RCTs. However, given the lack of non-invasive treatment
options for phymatous features of rosacea, topical retinoids
represent a safe option for those with mild-to-moderate
involvement that is less costly than procedural treatments.
C2. Oral tetracycline or doxycycline
(Weak recommendation: very low confidence in effect
estimate)
Oral tetracycline and doxycycline may be useful for mild
phymatous rosacea, particularly if there is an inflamma-
tory component. However, there have been no RCTs for
this indication.
C3. Ablative laser surgery, using CO2 or Er:YAG modalities, or
surgery, including electrosurgery and cryosurgery
(Weak recommendation: very low confidence in effect
estimate and variability in patient values and preferences)
Ablative laser resurfacing, using CO2 or Er:YAG modalities,
and surgery, including electrosurgery, may significantly
improve phymatous features of rosacea. The effect is esti-
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C. Sauer Mikkelsen et al – Rosacea – time for a new approach
mated as very low because the efficacy of these procedural
treatments for phymatous features has not been evaluated
by RCTs; however, their use was supported by strong rec-
ommendations based on clinical experience.
The efficacy of these interventions depends on the training
and expertise of the treating physician. Treatment may be
costly if not covered by provincial health plans, and access
may be limited. Swelling and redness may persist for sev-
eral weeks or longer. These risks are balanced against the
potential for excellent outcomes. This option, if available,
should be offered to all patients, acknowledging that the
patients’ preferences, values and treatment cost will influ-
ence their decision.
C4. Oral isotretinoin
(Weak recommendation: very low confidence in effect
estimate, but variability in patient values and preferences
regarding potential adverse events)
Oral isotretinoin may be effective at reducing early phy-
matous features of rosacea. For phymatous features, we
rated our confidence in the effect estimated as very low
because the outcome has not been validated; however, we
felt that it may have some benefit in patients with early
phymatous changes.
Treatment for bothersome symptoms
Acetylsalicylic acid (ASA) 500 mg 1–3 times a day
Non-steroidal anti-inflammatory drugs (NSAIDs) for tin-
gling and burning. Ibuprofen 400–600 mg 1–3 times a day
Topical corticosteroid. Only short courses (5–7 days) of mild
topical corticosteroids (group I) in emollient or lotion form
Cooling devices, such as cold-packs and ventilators
Only low GRADE evidence based information on the above
treatments
Photoprotection
UV light is a trigger for rosacea through stimulation of the
innate immune system. Factors that decrease ozone levels in
the atmosphere will increase UV exposure levels and thereby
increase the incidence of rosacea. Researchers from Boston
University found that exposure to UV radiation led to the
production of vascular endothelial growth factor (VEGF),
which is linked to the development of visible telangiectasia.
The activity of VEGF might be induced by TNF-a.
Melanin in the skin of Fitzpatrick skin types IV + IV makes
it difficult for UV radiation to reach the lower layers of the
skin. As a result, in darker-skinned individuals, VEGF would
tend to be induced only in the upper skin layers, and hence
not affect the blood vessels. We suggest at least sun-protec-
tion factor (SPF)30+ and minimizing the highest UV index
sun exposure from 11.00 h to 14.00 h. Rosacea patients may
be susceptible to irritation caused by sunscreen ingredients.
Appropriate protective ingredients (dimethicone, cyclome-
thicone) in the vehicle can often minimize irritation. Physical,
inorganic sun-blocks (titanium oxide, zinc oxide) are usually
well tolerated. Newer products utilizing micro-fine particles
are under evaluation (55).
Cosmetics
In a survey conducted by the US National Rosacea Society
including 1,066 patients, many cited the following ingre-
dients as triggers for irritation: alcohol (66%), witch hazel
(30%), fragrance (30%), menthol (21%), peppermint (14%)
and eucalyptus oil (13%). Most respondents said they avoided
astringents, exfoliating agents and other types of products that
may be too harsh for sensitive skin. Waterproof and opaque
make-up is usually preferred. Make-up containing ingredients
that provide sun protection and decrease inflammation is re-
commended. Make-up with lower allergenic potential should
be used. Mineral make-up is well tolerated. Formulations
containing silica and talc may be used with the aim of giving
a matte finish to the complexion.
Rosacea patients should consider reducing the number of
products they use on their skin by choosing fewer products
with multiple functions.
Application of a moisturizer immediately before topical treat-
ments has been shown to reduce stinging, burning, tingling,
and itching associated with rosacea symptoms. Whether this
procedure dilutes the active ingredients in topical medications
is unknown.
Patient education and empowerment
Rosacea patients need education to understand the complexity
of their skin disease and to ensure that they follow treatment
correctly. Patient empowerment is a process to help gain con-
trol, which includes taking the initiative, solving problems and
making decisions (80). With this new information about the
pathogenesis of rosacea and treatment options we will see a
shift from the biomedical model to a more patient-oriented
consultation and counselling.
Dermatologists and their staff should follow a holistic ap-
proach to ensure that their patients are empowered with
sufficient knowledge, understanding, skills and confidence
to use the new information on rosacea and to take an active
Forum for Nord Derm Ven 2017, Vol. 22, No. 110 REVIEW
C. Sauer Mikkelsen et al – Rosacea – time for a new approach
role in their own wellbeing. Health literacy is a significant
concern in the treatment of rosacea as well as in many other
skin conditions.
Suggested new treatment algorithm inspired by
Canadian Guidelines (81):
Conflicts of interest. All the writers received grants from Gal-
derma. Galderma has not been involved in the design of this
study or influenced the presentation.
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Article
Background: Rosacea features increased neurovascular reactivity; migraine is a complex neurologic disorder characterized by recurrent episodes of headache associated with nausea and increased sensitivity to light and sound. Objective: We evaluated the prevalence and risk of new-onset migraine in patients with rosacea. Methods: All Danish individuals 18 years of age or older were linked in nationwide registers. Adjusted hazard ratios (HRs) were estimated by Cox regression. Results: In the total cohort (n = 4,361,688), there were 49,475 patients with rosacea. Baseline prevalence of migraine was 7.3% and 12.1% in the reference population and in patients with rosacea, respectively. The fully adjusted HR of migraine was 1.31 (95% confidence interval 1.23-1.39) for patients with rosacea. Patients with phymatous rosacea (n = 594) had no increased risk of migraine (adjusted HR 0.45; 95% confidence interval 0.11-1.80), whereas patients with ocular rosacea (n = 6977) had a 69% increased risk (adjusted HR 1.69; 95% confidence interval 1.43-1.99). Notably, the risk was higher among patients age 50 years or older than in younger individuals, and the risk was only significant among women. Limitations: We were unable to distinguish between migraine subtypes. Conclusion: We found a significantly higher prevalence and risk of incident migraine especially in female patients with rosacea. These data add to the accumulating evidence for a link between rosacea and the central nervous system.
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In Reply In their commentary, He et al correctly state that rosacea should be regarded as an umbrella term, as several pathogenic and clinical subtypes exist. However, they also note that we examined the risk in patients with ocular rosacea, but not in other rosacea subtypes. We kindly direct their attention to the sensitivity analyses section of our article,1 in which we also described the risk for Parkinson disease (PD) in 751 patients with phymatous rosacea. This rosacea subtype had a fully adjusted incidence rate ratio of 1.43 (95% CI, 0.54-3.83; P = .50) associated with PD, and the incidence rate ratio for treatment with anti-Parkinson dopaminergic agents was 2.05 (95% CI, 1.21-3.45; P = .007). We encourage other groups with large data sets to replicate the association between rosacea and PD and, if possible, to further examine whether the association is restricted to certain subtypes.
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Rosacea is a chronic facial inflammatory dermatosis characterized by background facial erythema and flushing and may be accompanied by inflammatory papules and pustules, cutaneous fibrosis and hyperplasia known as phyma, and ocular involvement. These features can have adverse impact on quality of life, and ocular involvement can lead to visual dysfunction. The past decade has witnessed increased research into pathogenic pathways involved in rosacea and the introduction of novel treatment innovations. The objective of these guidelines is to offer evidence-based recommendations to assist Canadian health care providers in the diagnosis and management of rosacea. These guidelines were developed by an expert panel of Canadian dermatologists taking into consideration the balance of desirable and undesirable outcomes, the quality of supporting evidence, the values and preferences of patients, and the costs of treatment. The 2015 Cochrane review “Interventions in Rosacea” was used as a source of clinical trial evidence on which to base the recommendations.
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Objective: Rosacea is a common chronic inflammatory skin disorder where upregulation of matrix metalloproteinases (MMPs) and antimicrobial peptides (AMPs) is observed. Notably, inflammation, MMPs, and AMPs are also involved in the etiopathogenesis of neurodegenerative disorders including certain forms of dementia such as Alzheimer disease (AD). Based on several clinical observations, we investigated the association between rosacea and dementia, including AD in Danish registers. Methods: All Danish citizens aged ≥18 years between January 1, 1997 and December 31, 2012 were linked at the individual level through administrative registers. Cox regression was used to calculate unadjusted and adjusted hazard ratios (HRs). Results: The study comprised a total of 5,591,718 individuals, including 82,439 patients with rosacea. A total of 99,040 individuals developed dementia (any form) in the study period, of whom 29,193 were diagnosed with AD. The adjusted HRs of dementia and AD were 1.07 (95% confidence interval [CI] = 1.01-1.14), and 1.25 (95% CI = 1.14-1.37), respectively, in patients with rosacea. Stratified by sex, the HRs of AD were 1.28 (95% CI = 1.15-1.45) and 1.16 (95% CI = 1.00-1.35) in women and men, respectively. When results were stratified by age at study entry, the risk of AD was only significantly increased in individuals ≥60 years old (adjusted HR = 1.20, 95% CI = 1.08-1.32). When analyses were limited to patients with a hospital dermatologist diagnosis of rosacea only, the adjusted HRs of dementia and AD were 1.42 (95% CI = 1.17-1.72) and 1.92 (95% CI = 1.44-2.58), respectively. Interpretation: Rosacea is significantly associated with dementia, particularly AD. Increased focus on symptoms of cognitive dysfunction in older patients with rosacea may be relevant. Ann Neurol 2016.
Article
Background: Rosacea is a chronic skin condition that affects self-esteem and quality of life. However, data on depression and anxiety in patients with rosacea are scarce. Objective: The aim of this study was to investigate the relationship between rosacea and new-onset depression and anxiety disorders. Methods: Data on all Danish citizens aged ≥18 years between January 1, 1997, and December 31, 2011, were linked at individual level in nationwide registers. Incidence rates per 1,000 person-years were calculated, and crude and adjusted incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs) were estimated by Poisson regression models. Results: The study comprised a total of 4,632,341 individuals, including 30,725 and 24,712 patients with mild and moderate-to-severe rosacea, respectively. Mild and moderate-to-severe rosacea increased the risk of both depression [IRR 1.89 (95% CI 1.82-1.96) and IRR 2.04 (95% CI 1.96-2.12)] and anxiety disorders [IRR 1.80 (95% CI 1.75-1.86) and IRR 1.98 (95% CI 1.91-2.05)]. Conclusions: Rosacea was associated with a disease severity-dependent, increased risk of depression and anxiety disorders. The findings may call for increased awareness of psychiatric morbidity in patients with rosacea.
Article
Background: Rosacea is a common inflammatory skin condition that shares genetic risk loci with autoimmune diseases such as type 1 diabetes mellitus (T1DM) and celiac disease. A recent genomewide association study identified 90 genetic regions associated with T1DM, celiac disease, multiple sclerosis, and/or rheumatoid arthritis, respectively. However, a possible association with rosacea was not investigated. Objective: We evaluated the association between rosacea and T1DM, celiac disease, multiple sclerosis, and rheumatoid arthritis, respectively. Methods: We performed a population-based case-control study. A total of 6759 patients with rosacea were identified and matched with 33,795 control subjects on age, sex, and calendar time. We used conditional logistic regression to calculate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Results: After adjustment for smoking and socioeconomic status, patients with rosacea had significantly increased ORs for T1DM (OR 2.59, 95% CI 1.41-4.73), celiac disease (OR 2.03, 95% CI 1.35-3.07), multiple sclerosis (OR 1.65, 95% CI 1.20-2.28), and rheumatoid arthritis (OR 2.14, 95% CI 1.82-2.52). The association was mainly observed in women. Limitations: We were unable to distinguish between the different subtypes and severities of rosacea. Conclusions: Rosacea is associated with T1DM, celiac disease, multiple sclerosis, and rheumatoid arthritis, respectively, in women, whereas the association in men only reached statistical significance for rheumatoid arthritis.
Article
Facial erythema is a primary feature of rosacea. Currently, no validated scales exist that can accurately capture a patient's self-assessment of their own facial erythema. During phase 2 studies for brimonidine tartrate gel, a 5-point numeric rating scale was developed as a tool to allow subjects to provide an independent assessment of visible changes to the facial erythema associated with their rosacea. The objective of this study was to validate the revised patient's self-assessment (PSA) scale and evaluate it for statistical reliability and validity in quantification of facial erythema of rosacea. The validity of the PSA scale was evaluated by assessing the test-retest reliability, construct validity, and known-groups validity based on the data collected during a Phase 2b study on brimonidine gel for the treatment of persistent facial erythema of rosacea. Based on the results of this evaluation, this PSA scale demonstrated test-retest reliability, construct validity, and known-groups validity. Study results are most generalizable to those with moderate to severe erythema. The PSA is an appropriate scale to assess facial erythema associated with rosacea. J Drugs Dermatol. 2015;14(8):841-844.