Diagnostic Approach and
Treatment of Urticaria and
Angiodema:
An Update
Jonathan A. Bernstein, M.D.
Professor of Clinical Medicine
Division of Immunology/Allergy Section
Conflict of Interest Disclosures:
Jonathan A. Bernstein, MD FACAAI, FAAAAI
Employment: University of Cincinnati and Bernstein Allergy
Group and Clinical Research
Financial: CSL Behring; Dyax; Shire; Teva, Viropharma
Research: CSL Behring; Dyax; Pharming; Shire; Viropharma,
Novartis
Legal: Nothing to disclose
Organizational: AAAAI; ACAAI; AFI
Gifts: Nothing to disclose
Other: Editor in Chief Journal of Asthma
Objectives:
Upon completion of this lecture the participant should be able
to:
• Identify the differential diagnosis of urticaria and angioedema
• Explain the appropriate laboratory evaluation of urticaria and
angioedema
• Describe the conventional treatment approach for urticaria
and angioedema
WORLD ALLERGY ORGANIZATION POSITION PAPER
DIAGNOSIS AND TREATMENT of URTICARIA AND
ANGIOEDEMA: A WORLDWIDE PERSPECTIVE
Mario Sánchez-Borges 1, Riccardo Asero 2, Ignacio Ansotegui 3, Ilaria Baiardini 4,
Jonathan A. Bernstein 5, G Walter Canonica 4, Richard Gower 6, David A Kahn 7, Allen
P Kaplan 8, Connie Katelaris 9, Marcus Maurer 10, Hae Sim Park 11, Paul Potter 12,
Sarbjit Saini 13, Paolo Tassinari 14, Alberto Tedeschi 15, Young Min Ye 11, Torsten
Zuberbier 10
The Diagnosis and Management of
Acute and Chronic Urticaria: 2012 Update
Chief Editors
Jonathan Bernstein, MD and David Lang, MD
Workgroup Contributors
Timothy Craig, DO; David Dreyfus, MD; Fred Hsieh, MD;
David Khan, MD; Javed Sheikh, MD;
David Weldon, MD; and Bruce Zuraw, MD
Task Force Reviewers
David I. Bernstein, MD; Joann Blessing-Moore, MD; Linda Cox, MD;
Richard A. Nicklas, MD; John Oppenheimer, MD;
Jay M. Portnoy, MD; Christopher R. Randolph, MD; Diane E. Schuller, MD;
Sheldon L. Spector, MD; Stephen A. Tilles, MD; and Dana Wallace, MD
Features of Urticaria
 Raised, pink/erythematous skin lesions that are
markedly pruritic; lesions range from a few
millimeters to several centimeters in size and may
coalesce
 Evanescent; old lesions go and new ones come over
24 hours leaving no scarring
 Generally worsened by scratching
 Any area of the body may be involved; most common
areas are the perioral and periorbital regions, tongue,
genitalia and extremities
Prevalence of Urticaria
 Estimated to occur in 15-23% of the U.S.
population
 Up to 40% of patients who have chronic
urticaria longer than six months will still have
urticaria 10 years later
 Approximately 40% of patients with chronic
urticaria have angioedema
Prevalence of Urticaria With and
Without Angioedema
Urticaria
 Acute urticaria refers to hives lasting less than
six weeks; in approximately 15-20% of cases an
inciting cause can be identified
 Chronic urticaria refers to hives lasting longer
than 6-8 weeks; identification of a cause is less
than 5%
Differential Diagnosis: Immunologic Causes
More Often Responsible for Acute Urticaria
Foods
Many drugs
Insect stings
Transfusion reactions
Contactants/Inhalants (rare)
Differential Diagnosis: Non-Immunologic Causes
More Often Responsible for Chronic Urticaria
 Physical hives (i.e., dermatographism, pressure, solar, cold…)
 Hereditary (i.e., cold, heat, vibratory, porphyria, C3b
inactivator deficiency…)
 Vasculitis
 Neoplasms
 Infections
 Endocrine
 Drugs (i.e., aspirin/NSAIDs-exacerbate hives in up to 30% of
cases)
 Psychologic? More a myth than fact
Most CU is Idiopathic
• SUMMARY STATEMENT 13: Evaluation of a
patient with CU should involve consideration of
various possible causes. Most cases do not
have an identifiable cause [C]
Features of Physical Urticaria
Type
Age (yrs)
Clinical Features
Angioedema
Diagnostic Test
Dermatographism
20-50
Linear lesions
No
Light stroking of skin; +
transfer factor
Cold (primary vs.
secondary)
10-40
Itchy, pale lesions
(5% with cryos)
Yes
5-10 minute ice-cube
test; + transfer factor
Cholinergic (heat
bumps)
10-50
Itchy, monomorphic pale
or pink lesions
Yes
Exercise or hot shower; +
transfer factor
Pressure
20-50
Large painful or itchy
lesions
No
Dermographometer;
application of pressure to
skin or Sand bag test 15 lb
weight for 15 minutes
Solar
20-50
Itchy pale or red swelling
Yes
Irradiation by a solar
simulator;+ transfer
factor
sitesearch: exact match:
© 2002 by DermIS - Dermatology Information System
O
X
X
X
X
O
O
sitesearch: exact match:
© 2002 by DermIS - Dermatology Information System
Familial Cold Urticaria (aka. Familial Cold
Autoinflammatory Syndrome)
 Autosomal dominant
 Characterized by episodic urticaria, arthralgias, fever and
conjunctivitis after exposure to cold
 Same genetic locus on chromosome 1q44 as Muckle-Wells
syndrome (an autosomal dominant periodic fever syndrome
associated with hives and sensorineural hearing loss)
 Cryopyrin gene preferentially expressed in families with this
disorder; significant homology to the Nod2 gene implicated in
Crohn’s disease
Hoffman HM, et.al. Nat Genet 2001; 29:301-5.
lesion
description
opaleness
owheal
opurpura
opale red
opolycyclic
additional description
Urticarial Vasculitis:
Features That Differentiate It From CIU
Feature
Chronic urticaria
Urticarial vasculitis
Wheal duration
<24 hr
>24 hr (not always true)
Purpura/pain/hyperpigmentation
No
Yes
Systemic signs
Usually none
Yes
Laboratory findings
Usually normal
Increased WSR, Acute
Phase Reactants;
Decreased C3/C4
Leukocytoclasia or
extravasation of RBCs
No
Yes
Response to antihistamines
Yes
Sometimes
Chronic Urticaria: The Evaluation
History and Physical Examination
1. Onset (e.g. timing of symptoms with any change in medication or other exposures).
2. Frequency, duration, severity, and localization of wheals and itching.
3. Dependence of symptoms on the time of day, day of the week, season, menstrual
cycle, or other pattern.
4. Known precipitating factors of urticaria (e.g. physical stimuli, exertion, stress, food,
medications).
5. Relation of Urticaria to Occupation and leisure activities.
6. Associated angioedema, systemic manifestations (headache, joint pain,
gastrointestinal symptoms, etc.)
7. Known allergies, intolerances, infections, systemic illnesses or other possible
causes.
8. Family history of urticaria and atopy.
9. Degree of impairment of quality of life.
10. Response to prior treatment.
11. General physical examination.
Laboratory Evaluation
• Routine evaluation: There is no consensus regarding the appropriate tests
which should routinely be performed for patients with CU without atypical
features by history or physical exam.
• Commonly performed tests are:
• CBC with differential
• Sedimentation rate and/or C-reactive protein.
• Some clinicians routinely perform:
• Chemistry panel
• Hepatic panel
• TSH
• Anti-microsomal antibodies, anti-thyroglobulin antibodies
Evaluation (Cont.)
Possible additional evaluation warranted by elements of history or physical
exam which would make these tests appropriate:
Functional autoantibody assay (for autoantibodies to FcεRIά) and/or autologous serum or
plasma skin testing
Complement system: e.g. C3, C4, and CH50
Stool analysis for ova and parasites
H. pylori workup (limited experimental evidence to recommend this)
Hepatitis B and C workup
Chest radiograph and/or other imaging studies
Antinuclear antibody (ANA)
Rheumatoid factor
Cryoglobulin levels
Serologic and/or skin testing for immediate hypersensitivity
Physical challenge tests
Skin biopsy
Urinalysis
Recommendations on Specific Tests
• Testing not indicated on routine basis
– Autoimmune serology (SS #15)
– Testing for H pylori or celiac disease (SS #19)
– Thyroid Autoantibodies (SS #30)
– CU Autoantibody Tests (SS #31)
– Skin Biopsy (SS #34)
– Hypersensitivity Testing (e.g. skin testing) (SS # 35)
• Retrospective study to investigate the
proportion of abnormal test results in patients
with CU leading to a change in management
and in outcomes of care
• 356 CU pts seen at Cleveland Clinic
Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.
17% of 1,872 ordered tests were
abnormal
Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.
1/356 (0.28%) benefitted from testing!
1 patient with hypothyroidism with normal
TSH and elevated microsomal AB
responded to higher dose thyroxine
Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.
Diagnostic Testing in CU
• SUMMARY STATEMENT 29: After a thorough history and physical
examination, no diagnostic testing may be appropriate for some
patients with CU; however, limited routine lab testing may be
performed to exclude underlying causes. Targeted lab testing based
on clinical suspicion is appropriate. Extensive routine testing for
exogenous and rare causes of CU, or immediate hypersensitivity
skin testing for inhalants or foods, is not warranted. Routine
laboratory testing in patients with CU, whose history and physical
examination lacks atypical features, rarely yields clinically significant
findings.[C]
Conventional Therapy of Chronic Urticaria
Antihistamines in Chronic Urticaria
• Nearly all symptoms of urticaria are primarily
mediated by H1-receptors located on nerves
and endothelial cells
• H1 antagonists mainstay of therapy for most all
chronic urticaria
International Consensus
Meeting on Urticaria
• “The recommended first line treatment is
new generation, nonsedating H1antihistamines.”
• level of evidence: high quality
• strength of recommendation: strong
Allergy 2009;64:1427-43.
High Dose Antihistamines in CU
• Cetirizine: conflicting studies
• Fexofenadine: no difference between 60 mg,
120 mg and 240 mg twice a day
• Desloratadine
– 20 mg > 5 mg in cold urticaria
• Levocetirizine and desloratadine
– Higher doses better
Kavosh ER, Khan DA. Am J Clin Dermatol 2011 Dec 1;12(6):361-76.
High Dose Antihistamines in CU
Staevska M, Popov T et al. J Allergy Clin Immunol 2010;125:676-82.
Response to Antihistamines in CU
• Study of 390 urticaria patients from general
dermatology or urticaria clinics, majority of which had
CU
• 297 had evaluable treatment outcomes with
antihistamines
– 58% had good response
– 20% had partial relief
– 22% had no benefit
• More likely to have physical urticaria or NSAID exacerbated CU
Humphreys F et al. Br J Derm 1998: 138: 635-638.
Antihistamine Resistance in CU
• Definition
– Fail despite high doses of
antihistamines
– Unable to tolerate higher doses of
antihistamines
Systemic Corticosteroids in CU
• Systemic corticosteroids are frequently used in
patients with CU refractory to antihistamine therapy
• No controlled trials have demonstrated the efficacy of
systemic corticosteroids in CU
• “systemic corticosteroids should be avoided for longterm treatment of CU, since dosages necessary to
suppress symptoms are usually high with significant
adverse effects” (International Consensus Meeting on
Urticaria)
Allergy 2009;64:1427-43.
Alternative Agents in Urticaria
• Alternative agents for CU are therapies used
for patients failing conventional (i.e.
antihistamine) therapy
• Alternative agents have a variety of
mechanisms
•
•
•
•
Antiinflammatory
Immunosuppressant
Immunomodulatory
other
Evidence for Alternative Therapies in CU
• Overall the evidence for most alternative
therapies is weak
• Few agents have well designed randomized
placebo-controlled studies
• Most studies have small number of participants
Khan DA. In: Maibach HI, Gorouhi F ed. Evidence Based
Dermatology 2nd ed. 2011
Natural Course/Prognosis of Chronic Urticaria
Kozel MM, et.al. J Am Acad Dermatol 2001;45:387-91
 220 adults with chronic urticaria were followed prospectively
for 1-3 years at the University of Amsterdam
 After one year, 35% were free of all symptoms and 30% had
decreased symptoms
 47% of patients with CIU had spontaneous remission over 3
years compared to only 16% who had a component of physical
urticaria
 Conclusion: Prognosis for spontaneous remission of chronic
urticaria is reasonable with the exception of the subgroup
with a physical component
Conclusions
•
•
•
•
Chronic Urticaria and/or Angioedema is common
A thorough history and physical exam is essential
Should consider a broad differential diagnosis
The initial laboratory evaluation of patients should
be limited unless history dictates otherwise
• Outcomes are variable but generally good if
appropriate evaluation and treatment algorithms are
followed