Section 5: Disorders of Skin Components
Chapter 27: Disorders of Blood vessels: Flushing
Disorders
Rosacea
Introduction
Rosacea is a chronic disorder affecting
the facial convexities, characterized by
frequent flushing, persistent erythema and
telangiectasia, interspersed by episodes of
inflammation during which swelling, papules
and pustules are evident. Not all features are
always present. The presence of one or more
of the following signs with a central face
distribution is indicative of rosacea: flushing,
persistent erythema, papules and pustules,
telangiectasia. Rosacea is a common disease
representing
1%
of
dermatological
consultations and occurs mainly in young to
middle-aged adults. Women are more
commonly and less severely affected than men
who have the most incidence of rhinophyma.
Pathogenesis
The cause of rosacea remains uncertain
and there are 2 main theories: a possible role
of Helicobacter pylori infection of the gastric
mucosa and a possible role for Demodex
folliculorum infestation of the face skin and
Demodex brevis present in the eyelid hair
follicles and eyelash follicles. There is a high
prevalence of H. pylori in patients with
rosacea and its eradication with antibiotics
causes clearing of rosacea in 2-4 weeks.
However, antibiotics used in treatment of
rosacea are all potentially effective in
treatment of H. pylori.
The follicle mites, which are harmless
commensals, may have a pathogenic role in
rosacea. Histopathological sections of rosacea
show presence of the mites in 50% of patients.
Topical permethrin is as effective as topical
metronidazole in treatment of rosacea. The
mites may be associated with bacteria, in their
gut and on their skin, providing a potential
microbial target for antibiotics. Flushing in
rosacea may be mediated through a neural
reflex mechanism or through mediators (e.g.
serotonin, opioid peptides, prostaglandins,
substance P).
Several new theories have been
suggested to explain the aetiology of rosacea.
Vascular endothelial growth factor (VEGF)
receptor expression is increased in the
vascular epithelium of the skin in rosacea,
suggesting a possible role for VEGF in
mediating the vascular and inflammatory
changes. A role for oxidative stress is
suggested by reduced levels of superoxide
dismutase in the skin of rosacea, leading to
reduced antioxidant potential. The therapeutic
effect of antibiotics may be explained by their
antioxidant properties. A role for cathelicidin
is suggested by the presence of abnormally
high levels in the skin of rosacea. In addition
to its function as an antimicrobial skin peptide
capable
of
killing
microorganisms,
cathelicidin
triggers
inflammation
by
promoting
leukocyte
chemotaxis
and
angiogenesis.
Clinical features
Rosacea is a polymorphic disease with
several variants. It characteristically affects
the central convex areas of the face (nose,
forehead, cheeks and chin). The early stage
shows episodic flushing (unaccompanied by
sweating), mild telangiectasia and transient
oedema. The progressive stage shows
persistent erythema, papules (follicular and
non-follicular), pustules, sustained oedema
and extensive telangiectasia. The late stage
consists of induration (caused by oedema,
fibrosis and glandular hyperplasia, leading to a
peau d’orange appearance) and rhinophyma.
Factors which trigger flushing include emotion
and stress, hot drinks, alcohol and spicy foods.
Aggravating factors include the use of topical
steroids. Sun exposure may worsen or improve
rosacea. The classical progressive rosacea is
not always present. Some patients show
predominantly
the
vascular
features
(erythemato-telangiectatic rosacea), others
develop
mainly
inflammatory
lesions
(papulopustular rosacea), others develop
mainly chronic thickening and induration and
still others develop only rhinophyma.
Complications
Chronic lymphoedema of the face is a
rare complication that leads to coarsening of
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the features known as leonine facies.
Rhinophyma is also a complication of cases of
rosacea which persist for years. Eye
complications occur in 50% of the patients
and include blepharitis, conjunctivitis and
keratitis. These complications may be
secondary to reduced tear secretion.
Histopathology
Telangiectasia is indicated by the
presence of dilated superficial capillaries.
Solar elastosis is commonly present. The
perivascular lymphohistiocytic infiltrate is
mild in erythemato-telangiectatic cases and is
dense in papular rosacea. Pustules are
evidenced by polymorph accumulation in the
upper parts of hair follicles. Some lesions
show a granulomatous appearance containing
foreign-body
giant
cells.
Demodex
folliculorum is present in 50% of patients
densely populating the hair follicles.
Differential diagnosis
This includes acne vulgaris (no seborrhea
or comedones in rosacea), SLE (butterfly
erythema), perioral dermatitis, seborrhoeic
dermatitis, nasal sarcoidosis (lupus pernio,
also telangiectasia, but no peau d’orange
surface characteristic of rhinophyma), and
other causes of flushing e.g. carcinoid
syndrome.
Prognosis
This is highly variable. Relapse
commonly occurs after stop of treatment and
in persistent cases the course is usually
fluctuating for few or many years. Eye
involvement is usually mild and reversible but
flushing is difficult to suppress.
Treatment
Papulopustular rosacea responds well to
treatment but relapse is often prompt when
treatment is discontinued. Both systemic and
topical antibiotics are highly effective.
Systemic drugs include tetracyclines (250 mg
twice daily), erythromycin (250 mg twice
daily), doxycycline (100 mg once daily) and
oral metronidazole (400 mg daily). The latter
can cause peripheral neuropathy if used for
more than 3 months. Gram-negative
folliculitis is a rare complication of antibiotic
treatment of rosacea. Oral isotretinoin (10-60
mg/day) is an alternative in resistant rosacea
and can even improve rhinophyma. Topical
treatment with metronidazole 1% cream is
effective as is topical clindamycin gel 0.75%.
Antibiotic lotions used for treatment of acne
vulgaris are irritant in rosacea. Other effective
topical therapies in rosacea include azelaic
acid 20% cream and 15% gel, 0.025% retinoic
acid, and 10% sulfur cream. A novel therapy
is the use of photodynamic therapy which
produced a good response in 60% of resistant
cases. Combinations of topical and systemic
treatment are often used and for a period of 36 months, which may extend to several years
in many cases.
Flushing is difficult to treat. A mild
benefit may be obtained with -blockers such
as propranolol 40 mg twice daily or clonidine
50 g twice daily, probably through a nonspecific
vasoconstriction
effect.
Telangiectases are removed with vascular
lasers or intense pulsed light. Treatment of
lymphoedema of rosacea (leonine facies) is
far from satisfactory.
Isotretinoin 0.1-0.2 mg/kg/day and
regular facial massage may give some benefit.
The use of isotretinoin should be avoided in
patients with ocular rosacea. This is best
treated with oral tetracyclines 1 g/day or
doxycycline 100 mg/day together with topical
ophthalmic fusidic acid. Systemic isotretinoin
can significantly reduce the bulk of
rhinophyma although it does not restore
normal skin contour. Treatment
of
rhinophyma usually involves surgical removal
of excess tissue and remodelling. Excision and
vaporization with argon, carbon dioxide or
Nd: YAG lasers is effective.
Disorders related to rosacea
Corticosteroid-induced rosacea
The use of potent topical steroid on the
face often results in a papulopustular reaction
accompanied by erythema, closely resembling
rosacea. It is usually necessary to apply the
potent corticosteroid for 8 weeks or more
before steroid rosacea develops. If application
of the steroid continues, fixed erythema and
telangiectasia develop, further increasing the
similarity to idiopathic rosacea. The patient
complains of itching, burning and intense
redness. Whenever the corticosteroid is
discontinued, the eruption flares, leading to a
state of dependency.
Patients often fail to recognize the causal
link between the corticosteroid treatment and
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the rash. On the contrary, the application of
the corticosteroid produces prompt, but
transient improvement. Withdrawal of the
corticosteroid is essential. Patients are advised
to anticipate flare of the rosacea at this stage.
To reduce the severity of this flare, it is often
necessary initially to introduce a less potent
steroid. Topical or systemic antibiotics as used
for rosacea are effective. Steroid rosacea may
take several weeks or months to subside but
eventually complete resolution can be
anticipated.
Perioral dermatitis
This disorder occurs in young adult
females and consists of tiny papules and
pustules against a background of erythema and
variable scaling. It affects the area around the
mouth (‘muzzle’ area of the face) sparing the
lip margins. Pruritus, burning and soreness are
prominent symptoms. It is caused by topical
corticosteroid therapy. Periocular dermatitis
may be caused by corticosteroid eye ointment.
The histopathology shows mild eczematous
changes with spongiosis, oedema of the
papillary dermis and a perivascular and
perifollicular mononuclear cell infiltrate. The
differential diagnosis includes rosacea,
seborrhoeic dermatitis and contact allergic
dermatitis. Permanent remission usually
occurs after stop of the corticosteroid and a
short course (4 weeks) of systemic and/or
topical antibiotics used for treatment of
rosacea. Topical pimecrolimus 1% cream can
be effective.
Acne agminata
This disorder (acnitis, lupus miliaris
disseminatus
faciei,
facial
idiopathic
granulomas with regressive evolution
[FIGURE]) occurs in young adults and is not
related to acne vulgaris or tuberculosis but is
considered to be a self-limiting variant of the
granulomatous form of rosacea. It presents as
multiple monomorphic, symmetrical, reddishbrown papules on the chin, forehead, cheeks
and eyelids. Diascopy reveals an apple-jelly
nodule-like appearance indicating their
granulomatous histology, which also shows
central caseation. The eruption tends to be
self-limiting resolving completely over a few
months or up to 2 years. In some cases there is
scarring. The response to tetracyclines and
isotretinoin is variable. Dapsone and low-dose
prednisolone may be effective.
Pyoderma faciale
This disorder (rosacea fulminans)
affects mainly adult females. There is sudden
severe eruption of pustules and cystic
swellings, which may be interconnected by
sinuses, with marked erythema and oedema,
occurring on the central face (cheeks, chin,
nose and forehead). Comedones are absent.
Culture of purulent discharge is sterile or
contains commensals. Severe scarring may
occur. Treatment is with systemic steroids (1
mg/kg/day) for 3 weeks followed by
isotretinoin (0.2 – 0.5 mg/kg/day) for 3
months. Dapsone and systemic antibiotics may
be helpful.
Flushing
Flushing is intermittent redness often
accompanied by a sensation of warmth or
burning due to cutaneous vasodilatation. It is
usually most evident on the face and neck but
less conspicuous changes may occur over the
entire body. Flushing may be caused by the
action of circulatory vasodilator substances
(e.g. histamine) or by changes in the
neurological control of the cutaneous
vasculature in the affected areas. Since
autonomic nerve fibres also supply sweat
glands, neurally activated flushing is
frequently associated with sweating (wet
flushing) whereas flushing due to circulating
vasodilator mediators usually does not cause
sweating (‘dry flushing’).
The causes of flushing: Include those due to an
autonomic
mechanism,
including
physiological flushing, menopausal flushing
and flushing due to foods, and those caused by
vasodilator mediators, including drugs,
alcohol (acetaldehyde), scombroid fish
poisoning (histamine), carcinoid syndrome
(serotonin,
prostaglandins,
bradykinin),
mastocytosis
(histamine),
thyrotoxicosis
(thyroxine), medullary carcinoma of the
thyroid (prostaglandins, calcitonin), and
pancreatic tumors (vasoactive intestinal
peptide).
Physiological flushing: Occurs as a part of the
normal thermoregulatory response in a hot
environment or following exercise or hot
drinks. Emotionally-induced flushing is due
to embarrassment or anger and may be a
problem in some patients. The -blocker
propranolol may alleviate the symptoms in
severe cases, sympathectomy can be effective.
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Menopausal flushing: Occurs in 80% of
women and is associated with sweating.
Attacks are often preceded by a feeling of heat
and may be provoked by emotion, exertion
and hot food or drink. It is likely to be caused
by the endocrinal changes of menopause. It is
improved by oral oestrogen replacement
therapy or oral contraceptives. Non-hormonal
effective drugs include clonidine 0.05 mg
twice daily and selective serotonin reuptake
inhibitors (SSRIs).
Drug-induced flushing: Occurs with several
drugs including sildenafil (12% of patients),
vardenafil, fumaric acid esters (used in
treatment of psoriasis), gold therapy (for
rheumatoid arthritis), vasodilators (ACE
inhibitors, captopril, calcium channel blockers,
nifedipine, verapamil, hydralazine, nicotinic
acid, glyceryl trinitrate, phentolamine,
prostacycline, alcohol and prostaglandin E).
Alcohol-induced flushing: This is caused by its
metabolite acetaldehyde which causes
histamine release from mast cells. Symptoms
can be alleviated by aspirin or a combination
of H1 and H2 antihistamines. Chlorpropamidealcohol induced flushing occurring in diabetics
can also be controlled with aspirin.
Gustatory flushing: Occurs with eating spicy
foods and is due to a nerve reflex involving
autonomic neurones carried by the branches of
the trigeminal nerve, and is associated with
sweating. Scombroid fish poisoning (tuna and
mackerel) causes flushing, heat, sweating,
vomiting and diarrhoea. It is treated with a
combination of H1 and H2 antihistamines.
Carcinoid syndrome
Aetiology
This syndrome results from secretion of
endocrinologically
active
substances
(histamine,
serotonin,
kallikrein,
prostaglandins,
substance
P,
gastrin,
pancreatic polypeptide) by a malignant
carcinoid
tumour
anywhere
in
the
gastrointestinal tract, including the appendix.
The tumours are variable in their degree of
malignancy and the hormones they secrete.
Histamine is mainly responsible for the
flushing
(together
with
kallikrein,
prostaglandins and substance P) and serotonin
is responsible for the diarrhoea. Most tumours
are asymptomatic and only a minority
metastasize. The common site is the small
bowel and rarely carcinoid tumours may be
extra-intestinal (lung, ovary, testis). The
cardinal features of carcinoid syndrome is the
occurrence of episodic attacks of flushing,
diarrhoea and asthma. Flushing and diarrhoea
(watery diarrhoea) occur in 80% of cases
while asthma (episodic wheezing) occurs in
25% of cases. There is also cardiac
involvement (endocardial fibrosis leading to
right-sided heart failure). A photosensitive
eruption resembling pellagra occurs due to
diversion of tryptophan metabolism away
from synthesis of niacin.
Clinical features
Flushing is episodic and may be
spontaneous or precipitated by exercise,
alcohol, stress or foods. Foods containing
catecholamines (red wine, chocolate, blue
cheese) or serotonin (avocados, bananas,
plums, pineapples, tomatoes, walnuts) are
especially likely to induce flushing. The color
of flushing may be red (mid-gut tumours) or
violaceous (foregut and bronchial carcinoids).
The duration of the attack may be short (2 –
10 min in midgut tumors) or prolonged up to 2
weeks (bronchial carcinoids). Other skin
features include areas of pallor in midgut
carcinoids, cyanotic hue and facial
telangiectases in foregut carcinoid, and patchy
geographic flushing in bronchial carcinoids.
Watery eyes, profuse salivation and sweating,
nasal congestion, tachycardia and hypotension
occur with bronchial carcinoids. Carcinoid
syndrome is diagnosed clinically by flushing,
diarrhoea, wheezing, loss of weight and a
large liver (from metastases).
Laboratory diagnosis
This is by determination of 24 h urinary
excretion of 5-hydroxy indole acetic acid
which should be over 40 mg. Further
confirmation of the diagnosis may be obtained
by induction of flushing which can be
provoked by alcohol ingestion (4 ml of 45%
ethanol). The mean survival rate for carcinoid
syndrome is 8 years.
Treatment
Alcohol and foods which may exacerbate
symptoms should be avoided, as should
exercise and stress. Nicotinamide is provided
to reduce the risk of pellagra. Serotonin
antagonists
(e.g.
cyproheptadine
and
methylsergide) can control diarrhoea.
Clonidine (0.05 mg twice daily) can suppress
flushing. Antihistamines, both H1 and H2 can
suppress flushing due to gastric carcinoids.
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Corticosteroids are highly effective in
controlling prolonged flushing associated with
bronchial carcinoids. Phentolamine and
phenoxybenzamine are helpful in improving
flushing, diarrhoea and wheezing in some
cases. Depot injection of octreotide 20 mg i.m.
every 28 days relieves both flushing and
diarrhoea. Surgical excision of carcinoid
tumors is performed when possible. In
metastatic disease, reduction of tumour mass
can be useful in reducing symptoms.
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