Urticaria
What is urticaria?
Urticaria and angioedema occurs in up to 25 per cent of the population during life, usually as a self-limiting condition requiring no investigation, and short-term treatment with antihistamines. The emphasis of this article is on the evaluation and treatment of urticaria, and modern concepts regarding its pathogenesis. Other conditions may mimic urticaria and should be considered in the differential diagnosis (Table 1).
Pathogenesis
When discussing the aetiology and investigation
of patients with urticaria, it is useful conceptually to introduce
the concept of hyper-acute urticaria, defined as symptomatic urticaria
lasting less than 48 hours.
Most patients with urticaria of allergic origin will have severe
and dramatic symptoms within a few hours of exposure to the implicated
allergen, with disappearance within 24 hours. Whilst notable exceptions
do exist (antibiotic allergy, atypical serum sickness reactions,
insect sting reactions), investigation of patients presenting
with "acute" urticaria lasting more than 48 hours
for an allergic cause is generally non-rewarding.
Patients presenting with recurrent episodes of hyper-acute urticaria (particularly if following exercise) should be carefully evaluated for an allergic cause. Foods, herbal remedies and medications should all be considered as potential causes. Reactions to anti-inflammatory drugs (such as aspirin) and to food additives are independent of IgE. One of the commonest causes of acute urticaria is infection, particularly in young infants. Other causes as listed in Table 2.
An explanation for chronic urticaria is rarely
found once physical urticaria and allergic triggers are excluded.
An association with thyroid autoimmunity has been noted,
yet few patients respond to treatment of thyroid dysfunction when
detected.
Chronic infection is a similarly overrated cause of chronic
urticaria. Notwithstanding its role in the pathogenesis of mixed
cryoglobulinaemia with cutaneous vasculitis, there is conflicting
evidence regarding an increased Hepatitis C seroprevalence
in urticaria patients. An association with Helicobacter pylori
has also been reported, but both disorders are common anyway,
and the effectiveness of antibiotic eradication therapy on urticaria
is both anecdotal and conflicting. There is no evidence that Candida
albicans causes urticaria.
Malignancy is an exceedingly rare trigger of urticaria, although angioedema related to acquired C1 inhibitor deficiency may occur rarely in lymphoid malignancy.
Isolated angioedema in a patient taking ACE inhibitors should be attributed to the medication until proven otherwise. Atypical clinical features or the presence of systemic symptoms should prompt an early examination for underlying disease, notwithstanding the fact that most associated disorders are clinically obvious by the time urticaria appears.
Urticaria and Autoimmunity
Perhaps more interesting is increasing
evidence of an autoimmune pathogenesis in some patients
with chronic "idiopathic" urticaria.
Initial publications by Grattan (1986) noted the resemblance between the late allergic response and the histological appearance of the skin in chronic urticaria. Autologous skin test induced weals were noted in a high proportion of such patients, which also induced in vitro histamine release when incubated with human basophils.
Hide (1993) demonstrated that such patients
had autoantibodies directed against the Fc receptor of IgE, which
is present on mast cells, basophils, Langerhan cells and platelets.
Subsequent studies have confirmed the finding using immuno-blotting,
ELISA, and cells transfected with the FcEIR.
Overall, 10 studies have been published including some in the
last couple of months demonstrating positive autologous skin tests
in 40 - 80% of such patients, in vitro histamine release
from basophils in 27 - 56%, anti Fc receptor antibodies in 23
- 60%, and anti-IgE autoantibodies in 5 - 12%. In theory, these
antibodies could not only trigger mast cell degranulation, but
also induce cytokine release and the recruitment of inflammatory
cells that is the hallmark of chronic disease. Surprisingly, there
is no evidence of similar mechanisms operating in the physical
urticarias.
Patient Evaluation
Patients should be questioned about
the circumstances surrounding the onset of symptoms, the characteristics
of the lesions and the presence or absence of systemic symptoms
leading to a suspicion of underlying disease. In the absence of
unusual clinical features or historical evidence of underlying
disease, hyper acute episodes are best evaluated clinically
(with or without appropriate allergy testing), acute episodes
treated and observed, and chronic or atypical urticaria
subjected to further testing.
The yield from routine laboratory investigations is disappointingly
low. Appropriate routine investigations include urinalysis, FBC,
ESR, and tests of renal and liver function. Other investigations
are often performed routinely but have a similar low yield of
clinically relevant abnormalities including ANA, Rheumatoid Factor,
chest Xray and stool examination. Measurement of complement, serum
electrophoresis (EPG), cryoglobulins and Hepatitis B and C and
syphilis serology are indicated in patients with suspected urticarial
vasculitis or cold urticaria.
Patients with isolated angioedema should have measurements of
C4 complement, serum EPG and C1 inhibitor levels to exclude an
acquired or inherited C1 inhibitor deficiency. A useful investigation
is a punch biopsy of atypical lesions, which may confirm the presence
of urticarial vasculitis or suggest an alternative diagnosis.
Management
The majority of patients presenting
with urticaria have a self-limiting condition, which will respond
to a sympathetic explanation and symptomatic treatment with antihistamines
and clinical follow-up.
Antihistamines are the mainstays of therapy. Nevertheless,
mast cells release pre-formed and newly synthesized mediators,
so it is naive to assume that antihistamines will always be completely
effective. The clinical significance of the antiinflammatory effect
of antihistamines is uncertain at this time. Inflammatory cells
in chronic urticaria release non-immunoglobulin histamine releasing
factors, some of which appear to be chemokines.
Corticosteroids appear inhibit their synthesis and release, providing an explanation for the synergistic effect of antihistamines and corticosteroids in this condition. Corticosteroids are best avoided in patients with chronic disease where possible, should always be closely supervised, and must be given with an antihistamine.
Inhaled or injected adrenalin may be required in patients experiencing upper airway angioedema. ACE inhibitors should be ceased in patients presenting with isolated angioedema.
Evidence in favour of an autoimmune pathogenesis
in some patients provides a rationale for trying immunomodulatory
agents in occasional patients with refractory symptoms.
Elimination Diets are useful in selected patients but should
be temporary, closely supervised and followed by challenge procedures
if successful.
Table 1. Differential Diagnosis of Urticaria
Erythema multiforme
Bullous skin diseases (early stages)
Scabies
Urticarial vasculitis
Urticaria pigmentosa (cutaneous mastocytosis)
Papular urticaria
(due to insect bites)
Pruritis of other cause
(dry skin, cholestasis,
malignancy etc)
Pruritic Urticarial Papules & Plaques of
Pregnancy (PUPPP)
Table 2. Potential Causes of Urticaria
Acute
Allergy (food, medications, stings, aero allergen, contact
allergens)
Infection
Serum sickness
Food additives (MSG, tartrazine, benzoates, antioxidants, sulphites)
Radiographic contrast dyes
Chronic/Recurrent
Physical urticarias
Chronic infection
Systemic disease (autoimmune thyroid disease, connective tissue
disease, systemic or cutaneous vasculitis, malignancy)
Urticaria pigmentosa (cutaneous mastocytosis)
Table 3. Management Principles
TIME. 50 % of patients with chronic urticaria will settle
over 6 months and 80 % over 12 months, but recurrences are frequent.
AVOID IDENTIFIABLE AGGRAVANTS such as excessive heat, tight clothing,
aspirin or alcohol.
MEDICATION. Antihistamines are the mainstays of therapy. Judicious
use of H2 antagonists, corticosteroids or other immunomodulatory
agents may be indicated in some cases. Avoid corticosteroids in
patients with chronic symptoms where possible. Inhaled or injected
adrenalin may be required in patients experiencing upper airway
angioedema. Consider stopping ACE inhibitors in patients experiencing
angioedema.
ELIMINATION DIETS are useful in selected patients but should be
temporary, closely supervised and followed by challenge procedures
if successful.
