Indian J Dermatol 2006; 51(3) 171

CMYK 171
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Editorial
CHRONIC URTICARIA: AN OVERVIEW
Sudha Yadav, Amitabh Upadhyay, A K Bajaj
Abstract
Urticaria is a fairly common condition characterized by transient swellings of the skin. This could be an extremely
disabling and difficult-to-treat condition. Chronic urticaria has multifactorial aetiologies including intolerance to food or
drugs, infectious diseases, and autoimmune processes. With the demonstration of auto antibodies against IgE receptor or
IgE itself, a new subset of chronic urticaria has been identified as autoimmune urticaria. Further studies in this field in
the recent past have contributed considerably in understanding the pathomechanism of urticarias in a better way.
Controlled trials with immunomodulator drugs have further broadened our pharmacologic approach, especially in patients
with severe refractory urticaria. This article reviews the types of urticaria, its causes, pathophysiologic basis and current
approaches in its management.
Key Words: Chronic urticaria, autoimmune urticaria, antihistamines
Indian J Dermatol 2006:51(3):171-7
Introduction
Chronic urticaria is associated with diverse clinical
presentations and causes. Conventionally it is defined as
the repeated occurrence of daily or almost daily cutaneous
wheals accompanied by redness and itching for more than
6 weeks. Superficial swellings of the dermis are called
wheals, whereas, the deeper swellings of the dermis and
subcutaneous and/or sub mucosal tissues are called
angioedema. Most episodes of acute urticaria last for only
a short duration, but chronic urticaria can be quite distress-
ing and even disabling for many patients. Symptomatically
urticaria looks like an allergic reaction, yet often the
disease process is autoimmune or idiopathic in nature.
The term chronic urticaria makes no assumption about its
cause. In a number of patients it is associated with various
aggravating factors including drugs, food and food
additives, infections and infestations, systemic diseases
etc. Circulating antibodies against the high affinity IgE
receptors and anti FCRI antibodies have been detected
on mast cells in about 30 to 50% cases of chronic urticaria.
In spite of extensive laboratory investigations,50% cases of
chronic urticaria remain idiopathic.
Epidemiology
Prevalence
Approximately 15 to 20% of the general population will
have urticaria at least once during their lifetime. Although
persons of any age may experience urticaria and/or
angioedema, the urticaria occurs most frequently after
adolescence, with the highest incidence in young adults.
The exact incidence and prevalence of chronic urticaria are
not known, although it occurs in at least 0.1% and
possibly up to 3% of the population.
1
Chronic urticaria is
twice as common in women as in men. An Indian study
showed that out of 500 cases of urticaria, 37% were
suffering from physical urticaria.
2
Genetics
There are reports that HLA-DRB1*4,HLA-
DQB1*0302,HLA-DOB1*06 have been found with
increased frequency in patients with chronic idiopathic
urticaria as compared with a control population.
3
HLA-
DRB1*4, HLA-DQB1*0301/4, HLA-DQB1*0302 have been
found in increased frequency in patients with anti-FCRI
auto antibodies.
Histopathology
Both urticaria and angioedema, are associated with dilation
of the venules. Urticaria and/or angioedema are
characterized by shorts lived swellings of the skin and
mucous membranes due to transient leakage of plasma from
small blood vessels into the surrounding connective tissue.
Oedema involving the superficial portion of the dermis is
characteristic of urticaria, whereas, angioedema involves
the deeper dermis and subcutaneous tissue. Superficial
swelling of the dermis is known as wheal and the
surrounding flare is due to an axon reflex.
Histopathological findings of urticarial wheals are usually
nonspecific, comprising of vascular and lymphatic
dilatation, edema and a variable perivascular cellular dermal
From Bajaj Skin Clinic, Allahabad, India. Address
Correspondence to: Dr. A. K. Bajaj, 3/6, Pannalal Road,
Allahabad - 211002. E-mail: bajajak1945@yahoo.co.in
[Downloaded free from http://www.e-ijd.org on Saturday, November 28, 2009]
Indian J Dermatol 2006; 51(3) 172
172 CMYK
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infiltrate. The spectrum of cellular changes depends upon
the age of the wheals and their underlying cause. In acute
urticaria, there is interstitial dermal oedema, dilated venules
with endothelial swellings and a few inflammatory cells,
whereas in chronic urticaria besides the dermal edema, a
perivascular and interstitial cellular dermal infiltrate
consisting of lymphocytes, monocytes, neutrophils and
eosinophils is also seen. In the majority of wheals, there is
a sparse perivascular infiltrate, predominantly of helper-T
lymphocytes.
Pathophysiology
Urticaria was named after the stinging nettle plant (Latin,
urtica), which is now known to contain histamine. The
importance of histamine as a mediator of urticaria has been
recognized for many years. The mast cell is believed to be
the major effecter cell in most forms of urticaria, though
other cell types may be involved. Degranulation of mast
cells with release of histamine is central to the development
of wheals and angioedema. Urticaria is due to a local
increase in permeability of capillaries and venules. These
changes are dependent on activation of the cutaneous
mast cells, which contain a range of mediators
predominantly histamine. Vascular permeability in skin is
produced by the interaction of both H
1
and H
2
histamine
receptors. Activation of H
1
receptors in the skin induces
itching, flare, erythema, whealing and contraction of
smooth muscle in respiratory and gastro-intestinal tract.
Activation of H
2
receptors contributes to erythema and
whealing in the skin and increased gastric acid secretion.
Histopathologically chronic urticaria is characterized by an
inflammatory infiltrate comprising of CD4 + and CD8 + T
lymphocytes, eosinophils, basophils and neutrophils.
4
With
the discovery of IgG anti-IgE antibodies
5
and the more
common IgG anti-FCRI antibodies
6
in the sera of some
patients with chronic urticaria, the term autoimmune
urticaria is commonly used for these patients.
Classification
Traditionally urticaria is classified in to acute and chronic,
with a time division arbitrarily chosen at 6 weeks to 3
months. When the tendency to wheals format is present
for less than 6 weeks, urticaria is termed acute, whereas if
wheals continue on most days for longer than 6 weeks, it
is categorized as chronic. If the episodes are of shorter
duration than the symptom free period, the urticaria is
considered recurrent. A working classification (Table 1) dis-
tinguishes urticaria provoked by physical stimuli, skin
contact, or small vessel vasculitis from other presentations,
which are grouped under the term ordinary urticaria.
Clinical Features
Urticaria clinically presents as circumscribed, raised
(edematous), usually pruritic evanescent skin lesions. The
lesions may be pink or red, although classically they are
pale wheals surrounded by an erythematous flare. The
individual lesions of urticaria arise suddenly, rarely persist
for more than 24 hours, and may continue to recur for an
indefinite period. These lesions usually are discrete, round
or oval in shape; less commonly they may be irregular,
serpiginous, or gyrate. Urticarial wheals are variable in size
ranging from a few millimeters to lesions involving whole
extremity. Lesions may appear anywhere on the body in-
cluding scalp, palms and soles. In 50% of cases urticaria is
associated with angioedema.
7
Wheals usually resolve
within 24 hours passing through a macular erythematous
phase, but nearly always leaving the skin with a normal
appearance. Urticarial wheals are very itchy and patients
tend to rub rather than scratch, hence excoriation marks are
not seen. Headache, dizziness, hoarseness, wheezing,
sensation of a lump in the throat, shortness of breath,
nausea, vomiting and an abdominal pain, diarrhea and
arthralgias may occur as concomitant systemic
manifestations of severe episodes of urticaria.
Depending upon the various aggravating factors and the
presence of circulating auto antibodies, chronic urticaria
can be further divided in three subgroups:
1. Chronic urticaria with potential provoking factors
2. Autoimmune urticaria
3. Chronic idiopathic urticaria (CIU)
Chronic urticaria with potential provoking
factors
These include drugs, food, food additives, infections
(bacterial, viral, fungal), parasitic infestations, collagen and
endocrine disorders, dermatological disorders etc.
1. Drugs: Drugs frequently cause acute urticaria, but
these are also associated with chronic urticaria. Aspi-
rin may exacerbate chronic urticaria in 6.7 to 67% of
patients.
7-9
The causal relationship between penicillin
and chronic urticaria is a complex one.
10
Though
ACEIs (angiotensin converting enzyme inhibitors) are
commonly associated with angioedema they rarely
cause chronic urticaria also. Other drugs implicated
are alcohol, narcotics (codeine, morphine) and oral
contraceptives.
8
2. Food and food additives: The reported incidence of
chronic urticaria exacerbated by specific food varies
from 2 to 30% or more, but an allergic cause for all
Table 1. Classification of urticaria
Yadav S, et al.: Chronic urticaria
Physical urticaria
Idiopathic Allergic Non Allergic
Auto immune
urticaria
Chronic idiopathic
urticaria
Chronic urticaria
associated with
potential
provoking factors
Acute urticaria Chronic urticaria
Urticarial vasculitis Ordinary urticaria Angio-edema Contact urticaria
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ordinary urticarias has been found in fewer than
3.5%.
11
More frequently implicated food additives are
tartrazine, other azo dyes including amaranth and
sunset yellow, benzoic acid compounds etc.
3. Infections/infestations: Chronic urticaria is frequently
flared by intercurrent viral infections. The incidence of
bacterial infections such as dental sepsis, sinusitis,
gall bladder, and urinary tract infection varies in
different series.
12-14
A possible role of Helicobacter
pylori has also been suggested in chronic urticaria.
15
Fungal infections such as onychomycosis, tinea pedis
and candida have been considered as possible
associations.
16
Chronic urticaria has been associated
with parasitic infestations such as strogyloidiasis,
giardiasis and amoebiasis, particularly in developing
and underdeveloped countries.
17
4. Systemic diseases: Among the systemic causes the
most significant conditions belong to the categories
of rheumatic, other autoimmune disorders including
thyroiditis, and neoplasm. Though collagen vascular
diseases usually cause urticarial vasculitis rarely do
they cause chronic urticaria also. Chronic urticaria can
be seen as a manifestation of hypothyroidism
(Hashimotos thyroiditis) or hyperthyroidism (Graves
disease), but patients most commonly are clinically
and biochemically euthyroid.
18,19
5. Miscellaneous: Grass pollens, mould, spores, animal
dander, house dust and even tobacco smoke may
provoke chronic urticaria.
20
Urticaria may worsen
during pregnancy and also premenstrually.
21
Urticaria
has been associated with a metal pin in femur, metal
dental prostheses, and with dental amalgams.
22-24
Depression may also cause or aggravate chronic
urticaria.
25
Many dermatological conditions such as
urticaria pigmentosa, dermatitis herpetiformis,
pemphigoid etc may also produce urticaria-like lesions.
Autoimmune Urticaria
In 1983, Leznoff et al
26
suggested an autoimmune basis for
the urticaria. This was after the observation that there was
an association between thyroid disease and chronic
idiopathic urticaria. After that in 1988 Gruber et al
27
detected functional anti IgE antibodies and proposed that
these could be the cause of urticarial wheals. In 1991
Grattan et al
28
showed evidence of histamine releasing auto
antibodies with anti-IgE properties in sera from chronic
idiopathic urticaria patients. Since 1993 it is well
established that about 30 to 50% patients with chronic
urticaria have circulating functional auto antibodies against
the high affinity IgE receptor (FCRI) or against IgE.
These auto antibodies appear to be specific to the patients
with chronic urticaria.
Mast cells and basophils express FCRI. This receptor
consists of 4 transmembrane polypeptide chains, i.e., 1,
1, and 2 chains. The second domain of the extra cellular
part of the -chain binds with the central domain C3 of
the Fc region of IgE. Mast cells and basophils are
activated by cross linkage of FCRI receptors, usually via
surface bound antigen specific IgE. This cross linkage of
FCRI receptor is only one of the several triggers for
degranulation. The anti FCRI auto antibodies, which are
of isotypes IgG1 or IgG3, release histamine from mast cells
and basophils and are therefore functional. Nonfunctional
anti-FCRI auto antibodies have been detected in the sera
of patients with autoimmune disease such as
dermatomyositis and pemphigus vulgaris and some healthy
subjects. These auto antibodies do not release histamine
from basophils and are predominantly of subtypes IgG2
and IgG4.
29
Points in favour of the autoimmune hypothesis of the
chronic urticaria include reproducibility of the autologous
serum skin test through passive transfer of serum of
affected patients into the skin of healthy subjects;
correlation of functional auto antibody plasma levels with
disease severity; and disease remission following removal
or suppression of the antibody. An increased incidence of
a particular major histocompatibility complex class II allele
(HLADR4) in patients with chronic urticaria is in agreement
with the proposed autoimmune origin.
30
Evidence for
autoimmune thyroid disease and abnormal thyroid function
was largely found among the autologous serum skin test
(ASST) positive patients, supporting an autoimmune
etiology in this subgroup of patients.
31
The diagnosis of autoimmune urticaria depends primarily
on clinical suspicion that is supported by tests when
available. Although patients with autoimmune antibodies
have no distinctive diagnostic clinical features, the
diagnosis of chronic urticaria often can be suspected from
a history of highly symptomatic and severe continuous
whealing associated with systemic features of malaise,
indigestion, and feeling hot or cold. A past or family
history of autoimmune diseases, especially thyroiditis, can
give a clue. Histological examination in these cases shows
pronounced eosinophil degranulation in older lesions
compared with non-autoimmune cases. The in vivo test for
autoimmune urticaria is autologous serum skin test,
whereby the patients own serum is centrifuged and used
for skin prick testing.
32
The gold standard in vitro methods
are basophil histamine release assays, or western blot
analysis, but these are not available to the majority.
33
Peripheral blood basophil count is almost unmeasurable in
autoimmune urticaria patients compared with non
autoimmune, and this could be developed as a method of
detection.
Chronic Idiopathic Urticaria
Even after evaluation for evidence of autoimmunity and
other provoking factors, approximately 50% cases of
chronic urticaria remain unexplained and are categorized as
Yadav S, et al.: Chronic urticaria
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CIU. In most series, this subgroup represents a substantial
number of patients, but must remain a diagnosis of
exclusion.
Investigations
Establishing the cause of chronic urticaria is difficult and at
times almost impossible. The most important part in the
investigation of urticaria is detailed and comprehensive
history and thorough physical examination. The history
itself can be regarded as the most valuable diagnostic tool
in identifying causes of chronic urticaria.
34
History should
include information regarding time of onset, duration and
distribution of individual lesions, food and food additives,
home and/or work environment, enquiry about potential
source of infection, accompanying systemic features e.g.,
fever, joint pains etc, family history of thyroid or other
autoimmune diseases, history of atopy, drug intake and
dental diseases.
Routine laboratory screening does not contribute
substantially to the diagnosis of chronic urticaria or to the
detection of underlying disorders. In chronic urticaria, only
a total and differential full blood count and erythrocyte
sedimentation rate (ESR) should be performed routinely. An
elevated ESR suggests the possibility of an underlying
systemic disease and eosinophilia would prompt a search
for parasitic diseases. Screening test for thyroid function
and antithyroid peroxidase and antithyroglobulin
antibodies may be worth while.
Autologous serum skin test (ASST)
32
should be performed
in all the patients with chronic urticaria because a positive
test suggests that an autoimmune mechanism underlies the
disease. ASST requires minimal technical equipment and
can be performed routinely in all allergy or dermatology
outpatient clinics. The test is performed by injecting 0.05 to
0.1 ml of the patients own serum intradermally into the
flexor aspect of the forearm, 2 inches below the antecubital
crease and saline control into the right forearm. A reading
of wheal should be taken after 30 minutes. A wheal and
flare of more than 1.5 mm diameter than that of the control
is considered positive. The patient is advised to stop
antihistamines for at least 3-4 days and doxepin and
steroids for 4-6 weeks, before the test.
The ASST has a sensitivity of 70% and a specificity of
80%. A positive test is suggestive but not diagnostic of an
autoimmune basis for the patients chronic urticaria.
Confirmation is needed by in vitro testing of the patients
serum for the anti-FCRI or the anti-IgE auto antibodies.
In vitro the basophil histamine release assay
33
is currently
the gold standard for detecting functional auto antibodies.
However, it is available only at a few research centres and
can not be performed as a routine.
Management
A step by step approach to the management of chronic
urticaria should be taken. There are a number of potential
causes of urticaria, and the severity and clinical
presentation can differ substantially from patient to patient.
Many pharmacological and nonpharmacological
interventions are available but none is universally
acceptable. For these reasons, the treatment regimen
should be tailored to the individual patient. The routine
management of autoimmune and non autoimmune chronic
urticaria is the same.
General measures
General measures include removal of any identifiable cause,
explanation, information and reassurance. Advice regarding
avoidance of alcohol overuse, excessive tiredness, stress,
prolonged pressure on the skin, and overheated
surroundings are important. Frequent tepid showers and
application of 1% menthol or calamine in aqueous cream/
lotion can be prescribed as cooling agents. Some cases of
urticaria may be caused exclusively by the non allergic trig-
gers e.g., aspirin, other NSAIDs
35
and opiates. Even if
analgesics are not the main cause for chronic urticaria, they
can be an aggravating factor. Avoidance of aspirin and
other NSAIDs should usually be recommended because
these drugs aggravate chronic urticaria in about 30% of
patients.
36
Patients taking low dose aspirin for its
antithrombotic properties can usually continue regular
treatment. ACE inhibitors should usually be avoided in
chronic urticaria because angioedema and, rarely, urticaria
are recognized adverse effects.
37
The value of an elimination diet or oral food challenge is
controversial. Avoidance of dietary pseudo allergens,
including food colors, preservatives, and natural salicylates
have been not found beneficial in treating chronic
urticaria.
38
There is a general agreement that dietary
measures have no role in most forms of chronic urticaria
unless proven by double-blind, placebo-controlled
challenge.
Treatment of underlying diseases
Urticaria may be a manifestation of an underlying disease,
and in these cases, treatment of the underlying condition
may be warranted. The best example of a systemic
condition that commonly is associated with chronic
urticaria is autoimmune thyroid disease i.e., Hashimotos
thyroiditis.
39
Treatment with thyroxin has been reported to
alleviate the urticaria.
40
Examples of other conditions are
cryoglobulinemia and endocrine tumors.
41
A few reports
have suggested that Helicobacter pylori might be
associated with chronic urticaria in some patients.
42,43
According to one report, five patients with chronic urticaria
went into complete remission with oral acyclovir therapy.
44
Use of nasal filters in treating chronic urticaria has
occasionally been found beneficial.
45
Pharmacotherapy: Depending upon the severity of the
disease and response to various medicines, the drug
therapy can be considered at various levels.
Yadav S, et al.: Chronic urticaria
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CMYK 175
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(A) First line therapy
Histamine is the main mediator of urticaria and H1
antihistamines represent the initial and mainstay treatment
of all urticarias.
46
These agents are reasonably effective for
many patients. Different studies on role of antihistamines
in chronic urticaria showed 44 to 91% response rate.
47,48
The newer generation H1 antihistamines with less sedating
and less cholinergic effects are preferred over the older
generation H1 antihistamines as the initial choice of
therapy.
49
Antihistamines should be taken on regular basis,
not as and when required to get consistent results.
Antihistamines should be given with due regard to age,
pregnancy, state of health, and individual response. The
consensus is that in pregnancy chlorpheniramine is the
safest antihistamine without any mutagenic effect. Certain
antihistamines have been proposed as preferred for
particular subtypes of chronic urticaria, such as hydroxizine
for cholinergic urticaria or cyproheptadine for cold induced
urticaria.
50
The treatment can be started with a second generation non
sedating (or less sedating) antihistamines like cetirizine,
loratidine, fexofenadine, astemizole, mizolastine, ebastine
etc. Different types or combination should be tried for best
response. If little response, then:
1 Add sedating antihistamine at night: such as
hydroxyzine, diphenhydramine or the tricyclic
antidepressant doxepin
51
2. Add an H2 antihistamine
52
3. Add mast cell stabilizer e.g., ketotifen
3
4. -agonist terbutaline
53
and the calcium channel
antagonist nifedipine
54
also have been combined with
H1 antihistamine in small number of patients
(B) Second line therapy:
The use of systemic corticosteroids in the treatment of
urticaria is a controversial issue. Short courses of systemic
steroids (20-30 mg of prednisolone) can be given in
resistant cases of chronic urticaria that have not responded
to H1 antihistamine.
55
The efficacy of corticosteroid
therapy is high, but long term therapy can not be proposed
because of known adverse effects, such as diabetes
mellitus, hypertension, osteoporosis and gastrointestinal
bleeding. Prolonged treatment of chronic urticaria with oral
corticosteroids should usually be avoided except in
disabling delayed or pressure urticaria and urticarial
vasculitis, which are usually nonresponsive to
antihistamines.
Leucotriene receptor antagonists, zafirlukast (20 mg
twice daily) and montelukast (10 mg once daily) have
been shown to have beneficial effect in treatment of
chronic urticaria especially in cases which were
aggravated by the NSAIDs and food additives.
56
Zileuton, a 5-lipooxygenase inhibitor, which inhibits
Leucotriene generation has been found to be effective
in improving chronic urticaria.
Rofecoxib,
57
newer COX-2 inhibitor, has shown
promising role in treating patients with refractory
chronic idiopathic urticaria.
(C) Third line therapy
Immunotherapy could be tried in patients with severe
refractory autoimmune urticaria. Cyclosporine
58
has
been shown to be effective in severe unremitting
urticaria that had a poor response to conventional
treatment with antihistamines. Long term treatment
with cyclosporine over the short term therapy has not
been found to be associated with more benefit in the
clinical improvement.
59
High dose of intravenous immunoglobulin
60
has been
found to be associated with some apparent benefits in
the treatment of chronic urticaria. Plasmapheresis
61
has
been used to treat some patients with autoantibody
positive severe chronic urticaria.
According to some reports oral tacrolimus, low dose
methotrexate, hydroxychloroquine, sulfasalazine, and
dapsone, which have immunomodulatory properties,
are effective in the treatment of chronic urticaria.
62-65.
Cyclophosphamide has also shown beneficial effect in
treating severe autoimmune chronic urticaria.
66
Warfarin therapy may be considered in a subgroup of
patients with ASST negative chronic urticaria and
angioedema unresponsive to antihistamine.
67
In a recent placebo controlled study
autohaemotherapy has shown a beneficial role in
ASST positive chronic urticaria patients.
68
Autologous
serum therapy, a modified form of autohaemotherapy,
has been found to be fairly effective in cases of
autoimmune urticaria (personal observation, AKB).
(D) Future directions
More selective immunotherapies are possibilities. The
extracellular part of the subunit of FCRI or shorter
peptide sequences containing the autoantibody epitopes
could be used to bind to circulating FCRI auto
antibodies, thereby inhibiting their attachment to receptors
on mast cells or basophils. Also development of new
therapeutic agents that inhibit other known mast cell
activators or products, should be investigated for effect on
treatment of urticaria.
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Source of Support: Nil, Conflict of Interest: None declared.
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