Urticaria, often caused "hives", is a very mixed group of diseases. All the types
(and subtypes) of this disease share the common distinctive skin reaction pattern
of urticarial skin lesions and or angioedema. The EAACI / GALEN / EDF / WAO (1)
guideline defines urticaria as characterized by the sudden appearance of wheals
and /or angioedema.
A wheal consists of 3 typical features:
- a central swelling of variable size, almost invariably surrounded by a reflex erythema
- associated itching or, sometimes, burning sensation
a fleeting nature, with the skin returning to its normal appearance, usually within
1 – 24 hours
Angioedema is characterized by:
- a sudden pronounced swelling of the lower dermis and subcutis
- sometimes pain rather than itching
- frequent involvement under mucous membranes
- resolution that is slower than for wheals and can take up to 72 hours.
Classification of urticaria on basis of its duration, frequency, and causes
Spontaneous urticaria, sometimes called ordinary urticaria is characterized by the
fact that the urticaria episodes occur seemingly "out of the blue", with no apparent
Spontaneous Urticaria is further subdivided by duration into:
i. Acute: spontaneous wheals and / or angioedema lasting less than
6 weeks and
ii. Chronic: spontaneous wheals and / or angioedema lasting longer
than 6 weeks
Physical Urticaria, is always triggered by a physical stimulus,
i. Cold contact urticaria, where the trigger is cold liquids, objects,
ii. Heat contact urticaria is triggered by localized heat
iii. Solar urticaria is triggered by UV and / or visible light
iv. Vibratory urticaria is triggered by vibratory force such as
a pneumatic drill
v. Delayed pressure urticaria is triggered by vertical pressure
e.g. the strap of a handbag, and there is 3 – 12 hour latency for the wheal to arise
after the pressure is applied.
vi. Demographic urticaria is triggered by mechanical shearing forces
e.g. stroking or scratching the skin. The wheals occur within 1 – 5 minutes.
Other types of urticaria
Exercise-induced urticaria (with or without anaphylaxis) is elicited
by physical exercise such as jogging, tennis or even brisk walking.
Contact urticaria is triggered by urticariogenic substances such
as latex, raw meat, fish and some plants and vegetables.
Aquagenic urticaria is triggered by water of any temperature.
Cholinergic urticaria is triggered by any increase of the core
body temperature, such as physical exercise and spicy foods. The wheals in cholinergic
urticaria are typically small (pinpoint) 2-3 mm and surrounded by patches of red
skin. They are sometimes called “heat rash”.
Prevalence of urticarias
Urticaria is a very common skin problem. It is one of the 10 most common skin disorders.
It is estimated that up to 25% of adults will experience at least one episode of
acute urticaria sometimes in their lifetime, while only about 3% will develop chronic
Angioedema occurs with wheals in one third of all cases. It mainly affects the face.
The eyes are affected in about 70% of cases, the lips in 60%, and the whole face
in 35%. Non steroidal anti-inflammatory drugs and antibiotics are the most common
drugs causing angioedema without urticaria.
Angioedema occurs without urticaria in about 6% of cases of chronic urticaria.
Physical urticaria account for about 35% of all cases of Urticaria.
In one study of urticaria in Japan, more than one-third of the subjects had more
than 1 type of urticaria or angioedema.
Acute spontaneous urticaria
Acute spontaneous urticaria is more common in children. It is usually a self-limiting
condition commonly related to infections, food or drugs. In more than 90% of cases
there is usually complete resolution within 3 weeks.
Infections, particularly upper respiratory viral infections, are the most commonly
identified causes of acute urticaria (40% of cases). In some cases it is the combination
of the viral infection - which increases mast cell activity - and drug intake (e.g.
nonsteroidal anti-inflammatory drugs) that triggers the urticaria.
Chronic spontaneous urticaria (CSU)
Chronic spontaneous urticaria, formerly known as chronic idiopathic urticaria or
chronic urticaria has a point prevalence of about 1% of the population at any time.
In accordance with the EAACI / GALEN guideline CSU is defined by at least 6 weeks
of continuous or recurrent urticaria (wheals) and / or angioedema. This definition
excludes non-histamine-mediated angioedema, which is usually drug-induced.
All ages are affected, but the peak is seen between 20 and 40 years of age (the
working population), it is rare in children.
The majority of studies show that women suffer from chronic spontaneous urticaria
nearly twice as often as men.
CSU is thought to have an autoimmune basis in about 45% of patients, where an IgG
autoantibody can be found in the serum.
10% to 50% of chronic spontaneous urticaria occurs in combination with physical
urticarias, especially symptomatic dermographism and delayed pressure urticaria.
The role of stress in CSU
Several neuroendocrinoimmunological studies show the clear bidirectional crosstalk
between the nervous system and the skin. Studies have shown that neurotrophin, a
nerve growth factor released during stress is a priming agent for mast cells activation
in the skin.
Stress might act as a (precipitating) trigger as well as an exacerbation factor
in CSU, but CSU itself is a major cause of stress.
Impact of CSU on Quality of Life (QOL)
The majority of patients with CSU suffer from sleep deprivation.
“The detrimental effect of CSU on QOL is greater than that of most other skin diseases,
and is similar to that of severe coronary artery disease”.
“Many patients with CSU exhibit psychiatric comorbidities, most commonly anxiety
and depression, which should be taken into account in patient management” (2).
The results of studies on the duration of the disease vary greatly, probably due
to differences in patient selection. However, in summary the data shows clearly
that many patients suffer for 1 – 5 years. One study showed that 50% of the patients
with non-acute urticaria were symptom-free after a period of 3 months and 80% were
symptom-free after 12 months. However, 11% still suffered after 5 years. Another
study in the Netherlands showed that 51% suffered for more than 10 years.
The prognosis is worse for patients who suffered from wheals and angioedema, compared
to patients who have wheals only. The prognosis is even worse for patients who developed
Prognosis is also related to severity of the symptoms; one study showed that while
all patients with mild disease were symptom free after 2 years, almost 60% of those
with moderate to severe disease still had symptoms.
Autoimmune CSU also has a worse prognosis.
The overall disease duration of physical urticarias is usually longer than that
of chronic spontaneous urticaria.
Masqueraders of Urticaria / Skin disease that can be confused with Urticaria
- Usually affects elderly patients ( Average age 60 yrs old)
Long lasting (>72 hours) patches of with some features of Urticaria (wheal-like)
and some features of eczema / dermatitis.
- Lesions are extremely itchy
- Usually affects the trunk bilaterally & symmetrically
- Drugs are often implicated as triggers
- Oral steroids are effective treatment
- Presents with an itchy eczematous reaction
- Triggered by allergens or irritants at the site of contact
- Diagnosed by careful history and patch testing
- Wheals occur within 45 minutes of contact with allergens like:
- Natural latex
- Foods – fruits, meats, seafood
- Topical medications
Insect bite reactions or popular Urticaria
- Usually appear as fixed, red itchy bumps
- More often on exposed areas
- Lesions often appear in summer and lasts days to months
Measles-like drug eruptions
- Red, fixed, flat or raised wheal-like lesions
- History of prior drug intake 4 – 14 days prior to onset
- May be accompanied by low grade fever
Commonly bilaterally symmetrical distribution on trunk & upper extremities.
Commonly starting in axillae or the groin
Cutaneous mastocytosis or Urticaria Pigmentosa
Brownish lesions which either occurs spontaneously or after rubbing the skin (Darier
sign), heat or sunlight exposure
- Residual brown pigmentation persists after healing
Diagnosis is made from a biopsy of the lesion or blood test for Mast Cell Tryptase
- In 65% of cases the disease starts in children under the age of 15 years.
Treatment of chronic spontaneous urticaria
It is important even in CSU (which was formerly called chronic idiopathic urticaria)
to attempt to identify and eliminate the underlying cause(s) and / or the trigger
– or eliciting factor. Therefore a thorough history is the most important diagnostic
procedure. In many patients, the causes and triggers of CSU are not found, and the
cornerstone of treatment is symptomatic relief using pharmacotherapy.
Asses the disease using the urticaria activity scores:
Sum of score: 0 - 6
Mild (<20 wheals="" / 24 hr)
Mild (present but not troublesome)
Moderate (troublesome but does not
Interfere with daily activities or sleep)
Intense (>50 wheals /24h
Or large, confluent wheals)
Intense (severe itching, interferes with
normal daily activity or sleep)
Treatment of chronic spontaneous urticaria
H1-antihistamines are considered first-line therapy for CSU.
Classification of Antihistamines:
The older 1st generation H1 antihistamines are efficacious in urticaria, but their
use is limited by their sedative side-effects. These drugs are associated with impairment
of driving ability and handling tasks requiring concentration and alertness. One
survey of fatal road traffic accidents spanning a year found the adjustment culpability
rate for antihistamines to be 72%.
Most second-generation H1 antihistamines have little or no sedative side effects.
They also have a faster onset of action and a longer duration of action than their
Some 2nd generation antihistamines also have anti-inflammatory properties independent
of their effects on H1- receptors, due to suppression of cytokines.
Dose of antihistamines in chronic spontaneous urticaria
At the standard recommended doses, second generation antihistamines such as fexofenadine
and desloratidine prevented positive skin prick test reactions in only 10 – 20%
of patients while more than 50% of patients treated with Hydroxyzine (a first generation
antihistamine) had negative reactions to histamine in a double-blind randomized
Patients with CSU often require a higher dose of second-generation antihistamines,
up to four times the standard dose, to control symptoms.
Beyond Antihistamines: Treating Chronic Urticaria (5)
H2 antihistamines like ranitidine and cimetidine are often used in conjunction with
H1 antihistamines in the treatment of CSU. However, there is very little evidence
that H2 antihistamines make a clinically relevant impact in CSU.
Leukotriene are potent inflammatory mediators, which along with histamine bring
about allergic reactions, including asthma, urticaria, and anaphylaxis. In one study,
Leukotriene D4 was shown to be more potent than histamine in inducing urticarial
wheals. In 5 randomized controlled trials the Leukotriene inhibitors montelukast
(Singulair) and zafirlukast (Accolate) were effective alone or in combination with
antihistamines in treating urticaria. (5)
Systemic (Cortico) Steroids
In the European guideline, oral steroids are not recommended for maintenance therapy
but can be used to treat relapses, while in the USA systemic steroids are regularly
used on a long-term basis, at a dose of 10mg daily or 20mg on alternate days. My
personal preference is to avoid treatment with steroids at all cost, because of
the false hope that it gives, and difficulty in weaning patients off it.
Cyclosporine is an attractive alternative to corticosteroids for short-term and
rapid control of flares in chronic urticaria, because it has comparable efficacy
to steroids, but with relatively fewer side effects and the potential for sustained
remission lasting several months after discontinuation. In one study (6) 70% of
patient treated with cyclosporine demonstrated improvement, with 40% achieving complete
remission. Side effects are dose dependent and amenable to dose reduction.
Omalizumab is a recombinant humanized monoclonal anti-IgE antibody that selectively
bind to IgE and may ultimately down regulate the expression of surface IgE receptors
on mast cells, basophils and serum IgE. Over the last few years a growing body of
evidence suggest a remarkable reduction in urticaria symptoms by omalizumab, with
many patients becoming free of symptoms. The following types of urticaria have been
shown to respond to Omalizumab:
- Autoimmune urticaria
- Physical urticarias
- Urticarial vasculitis
Antimalarials like hydroxychloroquine have been used successfully for their anti-inflammatory
effects in treating CSU. However, their long latency to onset of effect and modest
efficacy make them an infrequent treatment option in chronic urticaria.
Diet in Chronic spontaneous urticaria
In a large prospective study (3) of over 800 patients with CSU in Germany, 30% improved
on a food additive-free diet, including those with and without a history of food
intolerance. Only a small proportion had a positive challenge to food additives.
Urticaria is a very common disorder with many triggers. Unlike acute urticaria (lasting
less than 6 weeks), in chronic urticaria (lasting more than 6 weeks) a specific
trigger is usually not identified, but one should always be considered. The response
to antihistamines is usually much better in acute urticaria. Chronic urticaria is
often refractory to the recommended doses of antihistamines, and up to four times
the recommended doses are sometimes required. Because of this treatment-refractoriness
of chronic urticaria, newer treatment modalities with less side-effect than steroids
were desperately needed. Omalizumab (Xolair) might be just the drug that we have
been waiting for.
The EAACI / GALEN / EDF / WAO guideline: definition, classification and diagnosis
of urticaria. Allergy 64 Issue 10, 1417 – 1426 (Oct 2009).
Maurer M et al. Unmet clinical needs in Chronic Spontaneous Urticaria. A GALEN task
force report. Allergy 66 (2011) 317-330
Di Lorenzo G, Pacor ML, Mansueto P et al. Food-additive-induced urticaria: a survey
of 838 patients with recurrent chronic idiopathic urticaria. Int Arch Allergy Immunol
2005; 138: 235-42
Dos Santos RV, Magerl M, Mlynek A, Lima HC et al. Suppression of histamine and allergen-induced
skin reactions: Comparison of first- and second-generation antihistamines.
2009; 123(1): 174-178
Beyond Antihistamines: Treating Chronic Urticaria Journal of Drugs in Derm
2009; 8 (11) 1043 – 1048
Kessel A et al. Low dose cyclosporine is a good option for severe chronic urticaria.
J Allergy Clin Immunol. 2009; 123(4):970