Chronic Urticaria

Urticaria/Angioedema
Beth A. Miller, MD
University of Kentucky
Associate Professor
Chief, Allergy/Immunology
Urticaria
 Acute
 Last
<6 wks
 20% of population
 Often due to drug,
food, allergen,
infection
 Chronic
 Present
>6wks
 1% of population
 45% due to autoimmune cause
Urticaria & Angioedema

Urticaria

Superficial dermis
Pruritic
 Non-painful
 Occur anywhere


Angioedema
Deep dermis &
subcutaneous tissue
 No pruritus
 May be
painful/burning
 Often face, tongue,
extremeties, genitalia

Pathogenesis

Due to the release of a diverse array of
vasoactive mediators that arise from the
activation of cells or enzymatic pathways
Mast cells
 Complement system
 Hageman factor-dependent pathway
 Mononuclear cells

Mediators of Urticaria
Middleton’s Allergy Principle & Practice Seventh Edition, page 1064
Chronic Urticaria

Perivascular infiltrate similar to a late-phase
reaction but some variable
Eosinophils may be prominent or sparse
 Monocytes can comprise 20% of cells
 Lymphocytes prominent (not Th2)
 Mast cells increased in some, not all
 Basophils less than other late phase reactions

Chronic Urticaria
Major Causes of
Urticaria/Angioedemia

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Drug reactions
Foods or food additives
Inhalation, ingestions of, or contact with antigens
Transfusion reactions
Infections-bacterial, viral, fungal, helminthic
Insects (papular urticaria)
Collagen Vascular Disease-vasculitis, serum sickness
Malignancy- angioedema with acquired C1 and C1
inhibitor depletion
Urticaria Pigmentosa- Systemic Mastiocytosis
Urticaria Pigmentosa
Major Causes of Urticaria/Angioedemia
Classes of Drugs that Commonly
Cause Urticaria

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Antibiotics- Penicillin, cephalosporins
sulfonamides
Analgesics
Radiocontrast materials
Sedatives & tranquilizers
Diuretics
Penicillin hypersensitivity
reactions

Type I

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Type II

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Hemolytic anemia, thrombocytopenia, interstitial nephritis
Type III

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anaphylaxis, urticaria
Serum sickness, drug fever, some cutaneous
eruptions/vasculitis
Type IV

Contact dermatitis/ ?morbiliform eruptions
Non-immunological reactions to
NSAIDS/Aspirin


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Reactions are probably not immunologic
Inhibitors of COX-1
Can exacerbate skin eruptions in patients with
CIU


5-20%
Can induce skin eruptions (aspirin-induced
urticaria)
NSAIDS/Aspirin


In CIU, increase in urticaria can take place from
15 minutes to 24 hrs (ave 1-4 hrs)
May not persist life-long


In 22 patients with urticaria/angioedema to Aspirin
challenge, 4 years later when re-challenged only
14/22 +
Aspirin sensitive patients demonstrate elevated
urinary LTE4
NSAIDS/Aspirin


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10% of CIU patients when challenged with Aspirin will
develop airway manifestations
Treatment is to avoid all drugs that inhibit COX-1 &
CIU patients should be cautious
Salicylates tolerated include choline salicylate, sodium
salicylate, disalicylates
Tylenol also weak inhibitor usually tolerated
Highly selective COX-2 inhibitors are usually tolerated
(rofecoxib, celecoxib)
Allergic Reactions to a
Specific NSAID


Single-induced urticaria/angioedema
Single-NSAID-induced
anaphylaxis/anaphylactoid reactions
Diclofenac, naproxen, ibuprofen, ketorolac
 Prevelance of IgE mediated reactions 0.1-3.6%
 Can tolerated aspirin and structurally different
NSAIDS

Stevenson et al, Ann Allergy Asthma Immunol 2001; 87:1-4
ACE Inhibitors

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Most common cause of acute angioedema
presenting to the ER
Occurs 0.1-0.7%
More common in African-Americans
Usually delayed in onset, mean 1.8 yrs
Due to local increases in bradykinin levels
ARB’s can be used cautiously (<10% crossreactivity)
Chronic Urticaria


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Recurrent, transitory, pruritic, erythematous,
elevated wheals that blanch with pressure
present for > 6 weeks
1% of general population affected
Up to 40% associated angioedema
Many cases are idiopathic
45% autoimmune
Severe autoimmune urticaria consider
immunomodulatory agents
Chronic UrticariaAngioedema
Chronic Urticaria
40%
Chronic Urticaria
with Angioedema
40%
Angioedema
20%
Evaluation for Chronic Urticaria and
Angioedema
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History
Physical examination
CXR
Blood test
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CBC with diff, WSR, ANA, Antithyroglobulin and
antimicrosomal antibodies, Serum-induced basophil
histamine release
Stool for ova and parasites
Skin biopsy and immunofluorescence
Kaplan, Middleton’s Allergy
Associated Diseases/Symptoms

Fever, arthralgia, elevated WSR- think vasculitis and
Collagen Vascular disease

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Order CH 50, C3, C4
Biopsy
Thyroid disease

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Hyperthyroidism can have urticaria as the initial symptom
Hypothyroidism is associated with increase in chronic
urticaria
24% of patients with hives have auto-antibodies to thyroid**
*Pace JL, Garretts M. Urticaria and Hyperthryoidism. Br J Dermatol 1075;93(1)97-99
**Kaplan A., Finn A. Autoimmunity and the etiology of chronic urticaria. Can J Allergy
Clin Immunology 1999;4:286-292
Chronic Urticaria/Angioedema
Physical

Cold Urticaria
Rapid onset of pruritus, erythema, and swelling after
exposure to a cold stimulus
 Location confined to exposed area
 Symptoms maximal after re-warming
 Total body exposure, can result in hypotension (ie
swimming in cold water)
 Ice Cube test

Ice Cube Test
Cold-dependent syndromes
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Idiopathic cold urticaria
Cold urticaria associated with abnormal serum proteins
(cold agglutinins, cryoglobulin, cryofribrinogen,
Donath-Landsteiner antibody)
Systemic cold urticaria
Cold-induced cholinergic urticaria
Cold-dependent dermographism
Delayed cold urticaria
Localized cold urticaria
Cold reflex urticaria
Cold Urticaria


In most patients, an abnormal circulating protein
cannot be found, ie idiopathic
Theories for mechanisms leading to mediator release?

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Cryoaggregation of an abnormal protein
IgE antibody to cold-induced skin antigen
Treatment- cyproheptadine 8-16 mg divided daily, drug
of choice (non-sedating anti-histamines may be
effective in high doses)
Disease may last for a few months or many years,
appears variable
Cholinergic Urticaria /Local Heat
Urticaria

Local Heat Urticaria
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Skin with warm stimulus produces hive at site
Test tube test
Extremely rare
Therapy often ineffective; desensitization can be helpful
Cholinergic Urticaria (generalized)

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Lesions small, punctate wheals surrounded by erythematous
flare
Associated with exercise, hot showers, sweating, and anxiety
Cholinergic Urticaria
Cholinergic Urticaria

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Mediated via cholinergic nerve fibers
Lesions can be reproduced by ID injection of
0.01 mg of methacholine in 0.1 ml saline or
exercising for 15 min
May have other cholinergic symptomsLacrimation, salivation, diarrhea
 May wheeze

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Treatment drug of choice is hydroxyzine 100200mg/day
Pressure Urticaria/Angioedema

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Typically occurs 4-6 hrs after pressure is applied
Sometimes only involves swelling with normal appearing skin (ie
angioedema)
Skin biopsy similar to chronic urticaria with neutrophilic and
eosinophilic infiltrate
Symptoms occur with tight clothing, hands from hammering,
foot swelling with walking, buttocks swelling from sitting
Lesions often are painful and burning, less pruitic…..kinins
possible involved
Treatment often requires corticosteroids, anti-histamines
ineffective
Dermatographism
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Ability to write on the skin
Can be observed by stroking the skin with a tongue
blade
Classic wheal and flare reaction-pruritus, erythema,
swelling
2-5% population
50% of patients associated with IgE reaction (Ag not
identified)
Treatment of choice-diphenhydramine/hydroxazine
Dermatographism
Solar Urticaria
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1-3 minutes of light exposure causes hives
Pruritus occurs first, then erythema, edema
surrounded by erythematous zone
Rare disorder
Lesions typically disappear 1-3 hrs
6 types depending on wavelength of light that
induced reaction
Treatment can include antihistamines,
antimalarial, and corticosteroids
Aquagenic Urticaria


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13 reported patients
Small wheals develop after contact with water,
regardless of temperature
Test by direct contact with tap water compress
to skin, and all other forms of physical urticaria
negative
Hereditary Forms of Chronic
Urticaria
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Familial Cold Urticaria
Amyloidosis with deafness and urticaria
(Muckle-Wells syndrome)
Hereditary Angioedema
C3b inactivator deficiency
Hereditary Forms of Urticaria and
Angioedema
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Familial cold urticaria
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Renamed “Cold autoinflammatory syndrome” (FCAS)
Rare, 1 in a million, about 300 patients in US
a form of periodic fever, autosomal dominant
Develop burning papular skin eruptions (100%), limb pain,
fever (92%), chills, arthralgias (96%), myalgias, conjunctivitis
(84%), headache and leukocytosis with cold exposure
Typically delay of 2.5 hrs, episodes last 12 hrs
Biopsy reveals mast cell degranulation, edema, inflammatory
infiltrate with eosinophils
Inflammatory markers elevated-CRP
Hereditary Forms of Urticaria and
Angioedema -Familial cold urticaria
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Linkage to chromosome 1q44
Defective protein is termed CIAS which encodes the
protein cryopyrin
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Regulator protein of inflammation and apoptosis
Also responsible for Muckle-Wells (MWS), NOMID
Key component of inflammasome which activates IL-1 β
Treatment with canakinumab (monoclonal antibody to IL-1βFDA approved for FCAS and MWS); some have used
Anakinra (IL-1 RA), non-FDA approved
Hereditary Urticaria- Muckle Wells
Syndrome
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CIAS1 gene mutation
Familial urticaria (chol urticaria, angioedema, or
classic hives)
Renal amyloidosis
Deafness
Polyarthralgias
Treatment with Canakinumab
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Anti-IL1β human monoclonal antibody
FDA approved for treatment of FCAS and MWS in
patients 4 and older
Dose 150 mg if body weight >40 kg or 2 mg/kg for
body weight 15 kg to <40 kg
SC q 8weeks
97% treated patients achieved complete response in 8
weeks- symptoms/markers of inflammation
May be associated with increased risk of infectionsavoid live viral vaccines
Hereditary Angioedema
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Autosomal dominant, 1:10,000-1:50,000
Absence of C1 INH results in increased
bradykinin
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Regulates complement, kinin-kallikrein, coagulation,
fribinolytic system
Swelling without urticaria; abd pain/N/V
Spontaneous, or traumatic event (dental work)
Laryngeal edema is a major cause of mortality
Abdominal attacks can last 1-3 days
Herediatry Angioedema
Hereditary Angioedema
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C4 low, both when asymptomatic and
symptomatic
C2 low when symptomatic only
15-20% have normal C1 INH levels, but protein
dysfunctional
Acquired C1 INH Deficiency
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Initially described in lymphoma patients; also seen in
SLE, cryoglobulinemia, carcinoma
Not hereditary, later onset (4th decade or later)
C1q levels are low, and C4, C2, and C3 depleted
Low C1q distinguishes this from hereditary form
Depressed C1 INH secondary to immune complexes or
anti-idiotypic antibodies
Responds to androgens
Treatment Options
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Acute AE
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Short-term prophylaxis
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Airway management, hydration, pain relief
C1-INH concentrate
FFP
Androgens, 3-5 days prior
FFP
C1-INH concentrate
Long-term prophylaxis
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Attenuated androgens (danazol)
CI-INH concentrate
Issues with Therapies for HAE

Attenuated Androgens
Hepatotoxicity, weight gain, menstrual irregularities,
decreased libido, virilization, acne, myalgias, fatigue,
headache, hypertension, hyperlipidemia
 Contraindication- pregnancy, lactation, childhood,
prostate CA
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C1 Esterase Inhibitor (Human)
Berinert (CSL Behring)
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Human plasma derived, purified, lyopholized concentrate
IV use indicated for the treatment of acute abdominal or facial
attacks
Dose at 20 units/kg
Half-life of 22 hrs
Clinical trials have shown
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62.8% of txm arm vs 26.2% placebo had symptom relief within 60 min of
txm (mean 48 min in txm arm)
69.8% of txm arm vs 42.9% placebo had symptom relief within 4 hrs of
txm
4.6% of txm arm vs 14.3% placebo had new HAE symptom within 4 hrs
after txm
0 patients receiving txm reported worsening of symptoms at 4 hrs after
txm
Kallikrein Inhibitor (Human)
Kalbitor (Dyax Corp)
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Human plasma kallikrein inhibitor
SQ use indicated for the treatment of acute attacks in patients
>16 yrs
Dose at 30 mg ?
Phase 3 clinical studies
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Reduction in mean symptom complex severity at 4 hrs
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Improved Treatment outcome score at 4 hrs
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Txm arm 53 vs placebo arm 8, p=0.003
Potential serious hypersensitivity

Txm arm –0.8 vs placebo arm -0.4, p=0.010
3% anaphylaxis
Available 2010
C1 Esterase Inhibitor (Human)
Cinryze (ViroPharma)
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Human plasma derived, purified, lyopholized
concentrate
IV use indicated for the prophylaxis of acute
abdominal or facial attacks
Dose at 1000 units IV every 3-4 days
Half-life 56 hrs
Clinical trials demonstrated
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66% reduction in days of swelling (p<0.0001)
decreased in average severity of attacks (p=0.0006)
decreased average duration of attacks (p=0.0023)
Factor 1 Deficiency (C3b inactivator)
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Rare disorder (3 patients)
Autosomal recessive
May present with urticaria
Depressed C3 levels
Chronic Urticaria and Idiopathic
Angioedema
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
If eliminate acute urticaria and physical urticaria,
successful diagnosis of an etiological agent is
about 2%
Patients as a group are not atopic
Incidence of atopic dermatitis, allergic rhinitis, and
asthma is not increased
 Serum IgE levels are normal

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Some have dermatographism, usually mild, and
wax and wanes
Idiopathic Angioedema
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More common in men
Incidence of antithyroid antibodies is
uncommon
Antibody to IgE receptor is uncommon
Laryngeal edema is not seen; can affect lips,
tongue, pharynx, cheeks, eyes, extremities, penis
and scrotum
Some patients respond to antihistamines and
some do not- may need steroids
Idiopathic Angioedema
Chronic Urticaria
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Chronic Autoimmune
(CAU)

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40-45%
Have associated
Antibodies

Chronic Idiopathic (CIU)

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55-60%
No antibodies found
Chronic Urticaria
Autoimmune Urticaria
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Autologous serum skin test
Basophil Histamine Release
In vitro vs in vivo
 Patient sera mixed with donor basophils,
autoantibodies in patients sera bind and activate
basophils with subsequent histamine release
 Inherent variability of donor basophils

IgE Autoantibodies and Chronic
Urticaria

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5-10%, IgG anti-IgE
35-40%, IgG with specificity for α-chain of the
FcεRI
5-10%, FcεRII/CD23
Thyroid Autoantibodies and Chronic
Urticaria
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Present in >20% of CU patients
Anti-thyroid peroxidase antibodies > antithyroglobulin antibodies
Most patient euthyroid, some hyper- or hypo
Chronic Autoimmune Urticaria
Proposed Mechanism
Treatment of Chronic Urticaria
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Aimed at relieving symptoms rather than suppressing
the urticaria
Non-sedating antihistamines are first-line agents and
can decrease the number of lesions, the frequency of
eruptions, and diminish pruritus
Dose can be doubled or tripled in severe cases
Short-acting antihistamines can be added at 200
mg/day given TID or QID
Take medicines as prescribed not as needed
JACI 2009, Kaplan
Treatment


Steroids can be used for antihistamine failures but no more than
10 mg/d or 20 to 25 mg every other day
Cyclosporine is an alternative to corticosteroids or can be used
when steroids are unsatisfactory (nonresponse or excessive
requirement for control).

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adult dose is 200 to 300 mg/d. Monitoring blood pressure and blood urea
nitrogen and creatinine levels every 6 weeks is essential.
Methotrexate or intravenous gamma globulin can be
reserved for cyclosporine failures (occasionally work)
Agents such as hydroxychloroquine, dapsone, and colchicine
can be reserved for urticarial vasculitis (about 1%)
JACI 2009, Kaplan
Treatment
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Antihistamines
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Short acting
Long acting
H2 Blockers
Leukotriene modifiers- small trials
Dapsone- small trials, not placebo controlled
Steroids
Cyclosporine
Treatment of Autoimmune Urticaria
with Omalizumab


Recombinant humanized mAb binds to IgE
Rationale- Anti-IgE would decrease circulating
IgE and decrease FcER1 expression on mast
cells and basophils thereby decreasing mast cell
and basophil activation
JACI September 2008;122:569-73
XOLAIR Characteristics
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Humanized monoclonal
antibody against IgE
Binds circulating IgE
regardless of specificity
Forms small, biologically
inert XOLAIR:IgE complexes
Does not activate complement
CDR=complementarity-determining region.
Adapted from Boushey HA Jr. J Allergy Clin Immunol. 2001;108:S77-S83.
Please refer to the Full Prescribing Information.
Murine CDRs
(5% of molecule)
IgG1 kappa
human
framework
(95% of molecule)
Treatment of Autoimmune Urticaria
with Omalizumab
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12 patients CAU resistant to antihistamines were
enrolled; had to have 4 out of 9 UAS
4 week placebo, 16 weeks treatment omalizumab
q2-4 wks
Endpoints: Mean change in urticaria activity
symptoms, rescue medicine use, and QOL
Urticaria Activity Score
score
# hives
0
Pruitus
severity
None
0
Size of
largest hive
0 cm
1
Mild-easily
1-6
<1.25 cm
2
Moderate-
7-12
1.25-2.5 cm
tolerable
bothersome but
tolerable
3
Severe-difficult >12
to tolerate
>2.5 cm
Treatment of Autoimmune Urticaria
with Omalizumab
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Results- baseline vs. last 4 wks of treatment, UAS
decreased from 7.50 to 2.66, p=.0002
7 patients achieved complete remission
4 patients had decreased UAS, but hives persisted
1 non responder
This proof of concept study suggests Omalizumab is an
effective treatment for CAU resistant to antihistamines
Low-dose Dapsone in Chronic
Idiopathic Urticaria
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Open label study
11patients with CIU recalcitrant to treatment
with antihistamines were enrolled
Baseline G6PD level & CBC @ 2 wks,then q6
wks
Patients received 25 mg dapsone daily and 10
mg cetirizine daily
Journal of Drugs in Dermatology, Nov-Dec 2005
Low-dose Dapsone in Chronic
Idiopathic Urticaria
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Cetirizine was discontinued once control achieved
Dapsone discontinued no sooner than 4 weeks after
resolution of symptoms
Patient assessment was subjective, q 4 wks
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Complete= remission
Partial=improvement
Poor=no change

Dose of dapsone increased to 50 mg
Journal of Drugs in Dermatology, Nov-Dec 2005
Low-dose Dapsone in Chronic
Idiopathic Urticaria

Results
9/11 patients complete remission within 3 months
of txm with 25 mg daily
 Median time to start of response was 3-4 weeks
 Majority patients discontinued cetirizine after 4-6
weeks
 1 of the 2 non-responders had complete remission
with dapsone 50 mg daily
 No adverse events

Journal of Drugs in Dermatology, Nov-Dec 2005
Summary
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Causes of Acute Urticaria are different from
causes of Chronic Disease
Recognize symptoms of HAE- usually familial
and do not hive
Treatment options for Chronic urticaria
1st line therapy with high doses of long acting antihistamines
 Add hydroxyzine up to 200 mg/day
 Corticosteroids should be given as 3rd option

Chronic UrticariaAngioedema
Chronic Urticaria
40%
Physical
Hereditary
CAU
CIU
Chronic Urticaria
with Angioedema
40%
Angioedema
20%
HAE
Idiopathic
ACE inhibitor
induced
Possible Board Questions
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Causes of acute urticaria
Causes of chronic urticaria
Treatment of urticaria
ACE inhibitor induced angioedema
ASA sensitivity- non-IgE, increased LTE4
HAE- presentation, treatment
Urticaria pigmentosa-systemic mastiocytosis
Dermatographism
CAU and thyroid disease