CURRENT MANAGEMENT OF

URTICARIA AND ANGIOEDEMA

Hardyanto Soebono
Department of Dermatovenereology
Faculty of Medicine Universitas Gadjah Mada
Yogyakarta
 Urticaria & Angioedema
• Not a disease itself, but a reactive skin condition may
be a symptom of various clinical diseases
• Affects 15 – 25 % population at some point in their
lifetime
• Clinically can be mild, recurrent, and frustating for
patients and doctors, and some may end to life
threatening
• Many patients result in impairment of QoL

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Urticaria
• is characterized by pruritic,
evanescent, erythematous wheals
with central swelling of various sizes
(with or without surrounding
erythema) and well-defined borders.
• The skin returns to normal
appearance usually within 1–24
hours.
• Individual lesions can range in size
from <1 cm in diameter to affecting
an entire anatomical region without
leaving residual hypo- or
hyperpigmentation, or residual
ecchymosis.
 Angioedema
• is defined as an abrupt swelling
of the lower dermis and
subcutaneous tissue, with
occasional pain rather than
pruritus, commonly involving
the mucous membranes, with
skin returning to normal
appearance, usually within 72
hours.

• Approx. 50 % patients both urticaria and angioedema, only

10 % purely isolated angioedema
Severe angioedema
 Classification and Clinical Profiles
• Acute:
– Less than 6 weeks
– Common in young
– Most likely due to viral infections, food allergens,
medications
• Chronic :
– 6 weeks or more
– Most common in middle aged women
– Causative agent is found in less than 25 %
– Associated with: fungal infection (esp. candida), parasitic
or bacterial infection, hepatitis B, connective tissue
diseases, malignancy,physical stimuli, certain medication
or food additive

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 Classification of Urticaria/ Angioedema
Urticaria Angioedema
• Spontaneous urticaria • Allergic(IgE-mediated mast
– Acute urticaria cell/basophil degranulation)
– Chronic urticaria • Nonallergic (mast
• Physical urticaria cell/basophil degranulation)
• Other urticaria types • Bradykinin mediated
– Aquagenic • Leukotriene mediated
– Cholinergic • Unclear (idiopathic, etc.)
– Contact urticaria
• Urticarial vasculitis
 Causes of Urticaria/ Angioedema (1)

• Immunologic
• Non-immunologic
– Direct mast cell releasing agents
– Arachidonic metabolism altering agents
– Physical stimuli
– Idiopathic
– Others

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Causes of Urticaria/ Angioedema (2)
Immunologic
 IgE mediated
 Ingested of injected allergens (food, drugs, venom,
transfusion reactions)
 IgG-mediated
 IgG anti-IgE antibodies
 IgG anti-Fc() RI antibodies
 CIC-mediated
 C3b-inactivator deficiency
 Urticarial vasculitis
 T cell-mediated

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 Causes of Urticaria/ Angioedema (3)
• Direct mast cell-releasing agents
– Opiates
– Radiocontrast media
– Curare, tubocurarine

• Agent that alter arachidonic metabolism

– Aspirin
– NSAID
– Cyclooxygenase2 inhibitors

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 Causes of Urticaria/ Angioedema (4)

• Idiopathic
• Others
– Food additives ( dyes, benzoates)
– ACE inhibitors
– ARBs

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 Physical Urticaria
• Cold contact urticaria
• Delayed pressure urticaria
• Heat contact urticaria
• Cholinergic urticaria
• Solar urticaria
• Dermographism
• Vibratory urticaria/angioedema
 ACE-Inhibitor Angioedema
(ACEIn-AE)
• Incidence of ACEIn-AE ranges 0.1 – 1.0 %; the risk is
4.5 times higher in African-Americans compared to
Caucasians
• Clinically ACEIn-AE presents without urticaria
• 40 % patients with ACEIn-AE present months to years
after initial dose
• Class dependent, but not dose-dependent
• Due to the decreased degradation of bradykinin
 ARBs-induced Angioedema (ARBi-AE)

• The incidence of ARBi-AE is less than ACEIn-AE

• 32 % patients with ARBi-AE had prior episode
of ACEIn-AE
• Hypothesized that ARBs activate angiotensin
type II receptors, producing vasodilatation and
increased vascular permeability through nitric
oxic pathway.
 Hereditary Angioedema (HAE)
• A rare, autosomal dominant disorder, the incidence
1: 50,000 individuals
• Result of an inherited or acquired abnormality of C1-
INH.
• Two types:
– Type I : decreased production of C1-INH (80-85 %)
– Type II : functionally impaired C1-INH (15-20%)
• Patient with HAE sometime has an autoimmune
disorder (SLE, thyroiditis, IBD etc.)
 Pathophysiology
• Most types of urticaria are due to activation of
dermal mast cells, although basophils may also be
involved

• Release of histamine and other mediators (including

eicosanoids, proteases, cytokines) causes local
vasodilation, vasopermeability, fibrin deposition,
perivascular infiltration by lymphocytes, neutrophils,
and eosinophils, and pruritus
 Idiopathic

Direct Mast cell

Immune Mechanism degranulation
Autoimmune

Arachidonic
Physical stimuli
metab altering
agents

Mediator
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 Degranulation

• Degranulation of mast cells induces

immediate release of mediators (histamine,
TNF-α, serotonin, proteases, proteoglycanes)
which results in development of hives
 Cytokine and chemokine synthesis

• A range of cytokines and chemokines are produced

by activated mast cells between 6 – 24 hrs:
– Il-1 & TNF-α  activate endothelium
– IL-3, -4, - 6, -8, -9, -13, TGF-β, GMCSF etc. -
recruitment of leucocytes (eosinophils)
 Leukotrienes and PG synthesis

• Two enzymes, Cyclooxygenase (COX) and

lipooxygenase (LOX) participate in synthesis of
LTs and PGs
• LTB4 is important in the chronicity of wheals
• Prolonged remission can result from the use
of LT inhibitors and/ or NSAIDs
Management
 MANAGEMENT
• Aims:
– Reduction : pruritus, weal size, number and
frequency
– Loss of wakening
– Overall improvement (patient/ doctor)
– Total symptom score
– Permanent remission

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 MANAGEMENT
 Patient education
 Avoidance of triggers:
 Food additives, alcohol, hot environment,
stress etc.
 Aspirin, ACE inhibitors, NSAID, codein,
morphine
 Topical treatment
 Antipruritic lotion
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 Levels of Evidence
I. Evidence obtained from at least one properly designed, randomized
controlled trial
II-i. Evidence obtained from well designed controlled trials without
randomization
II-ii. Evidence obtained from well designed cohort or case-control analytic
studies, preferably more than one center or research group
II-iii. Evidence obtained from multiple time series with or without
intervention. Dramatic results in uncontrolled experiments could also be
regarded as this type of evidence
III. Opinions of respected authorities based on clinical experience,
descriptive studies, or reports of expert committees
IV. Evidence inadequate owing to problems of methodology (e.g. sample
size, or length or comprehensiveness of follow up or conflicts of
evidence)
 Levels of Recommendations
A. Good evidence to support the use of procedure
B. Fair evidence to support the use of procedure
C. Poor evidence to support the use of procedure
D. Fair evidence to support the rejection of procedure
E. Good evidence to support the rejection of
procedure
 General Recommendations
• Review medications, food, exposure to insect venom,
contact allergens, radiocontrast media
• Consider medications (i.e. ACE inhibitors), HAE,
abnormality in C1-INH
• Consider DD in patient with presumed urticaria last
longer than 24 hrs
• Routine laboratory examinations are NOT indicated
for acute urticaria and angioedema
 Acute Urticaria/ Angioedema
1. Epinephrine i.m./ s.c. 0.3 mg every
10 minutes (0.3 ml of 1:1000 • Strength of Evidence : I
dilution)
2. Antihistamines: • Recommendation Grade : A
1. 2nd generation of AH1
(loratadine, cetirizine,
desloratadine, levocetirizine,
fexofenadine)
2. Sometime 1st generation of
AH1 needed
3. If not controlled by AH1, anti
H2 can be added
3. Corticosteroids indicated for :
1. Anaphylaxis,
2. laryngeal edema
3. Severe symptoms
unresponsive to AH
 Isolated Angioedema
• Discontinue ACE • Strength of evidence : II-3
Inhibitors • Recommendation Grade : B
• Intubate patients with
respiratory distress,
stridor, drooling, tongue
edema, edema of the
floor of mouth
• AH and CS can be given
 HAE
• Obtain a C4 levels • Strength of Evidence : III
• Consider fresh frozen • Recommendation Grade : B
plasma (FFP) for acute,
severe episode
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