Urticaria/Angioedema - Management
David M. Lang, MD
Head, Allergy/Immunology Section
Respiratory Institute
Cleveland Clinic
Disclaimer
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I have received honoraria from, have carried
out clinical research with, and/or have
served as a consultant for:,
Genentech/Novartis, GlaxoSmithKline,
Hycor, Merck, Sanofi-Aventis,
Schering/Key.
My presentation will include discussion of
off-label uses of a number of FDA approved
products, but not agents that are not FDAapproved.
Disclaimer
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Updated Urticaria/Angioedema parameter in preparation.
Workgroup
o Chair: Jonathan Bernstein, MD
o Liaison: David Lang, MD
o Members:
 Timothy Craig, DO
 David Dreyfus, MD
 David Khan, MD
 Javed Sheikh, MD
 David Weldon, MD
 Bruce Zuraw, MD
Learning Objective
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Describe evidence-based
management of patients with
chronic urticaria/angioedema
H-1 Antihistamines
High Quality Evidence
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Preferred 1st line therapy for patients with
chronic urticaria/angioedema.
H1-antihistamines efficacious in numerous
published RCTs since 1950s.
1st generation agents associated with risk
for sedation and anti-cholinergic effects
2nd generation agents also efficacious and
in many patients are better tolerated
Strong Recommendation
Efficacy of Doxepin Compared
with Diphenhydramine
Doxepin 10 mg TID
* Total or partial
Diphenhydramine 25 mg TID
10%
control of
pruritus and
urticaria
74%
* Total clearing of
5%
pruritus and
urticarial lesions
43%
0%
* p < .001
10%
20%
30%
40%
50%
60%
70%
80%
Green SL, et al. J Am Acad Dermatol 1985 12: 669-75
Dose Advancement of 2nd Generation Antihistamines
Number of patients symptom free
• 80 patients with refractory urticaria, 72% previously treated with steroids
• Randomized to antihistamine, with dose advancement to 4x standard dose
• Goal = symptom free (13 at 5 mg vs. 28 at higher dose, p = 0.02, X2)
Antihistamine Dose
Staevska M, et al. J Allergy Clin Immunol 2010; 125: 676-82
Refractory Urticaria/Angioedema
Refractory = Obstinately resistant to authority or control, unruly
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H2 anti-histamines
Anti-leukotrienes
Colchicine
Sulfasalazine
Hydroxychloroquine
Methotrexate
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Stanozolol
IVIG
Methotrexate
Omalizumab
Cyclosporine
Others…
Antihistamines: H1 Combined with H2
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Evidence difficult to interpret
o Small numbers of patients studies
o Different H1 antihistamines used
o Dose of H2 antihistamine variable
 Cimetidine 800-1200 mg/day
 One study: cimetidine 400 mg QID
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Superior efficacy
o Clin Allergy 8:429, 1978
o Br J Dermatol 117: 81; 1987
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No advantage
o Br J Dermatol 99: 675; 1978
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Drug-Drug interaction: Hydroxyzine & Cimetidine
o Simons EF, et al. J Allergy Clin Immunol 1995; 95: 685-93
Anti-Leukotrienes
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Montelukast/Zafirlukast/Zileuton
Substantial safety advantage compared with
other “alternative” or “steroid sparing” agents
RCTs
o 5: favorable
o 1: no advantage
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Data suggest salutary effect more likely
o ASA-exacerbated urticaria/angioedema
o Physical Urticaria/Angioedema
o Positive Autologous Serum Skin Test
Morgan M, Khan D. Ann Allergy Asthma Immunol 2008; 100: 403-11
Methotrexate for Refractory
Chronic Urticaria/Angioedema
• Retrospective report, total = 88 patients, period = 2005-2009
• 8 patients receiving high dose anti-HA & oral steroids.
• Response: 3 groups based on symptom severity, tx = 4.5 +/- 3 months
• Complete: no symptoms, tx = MTX with/without anti-HA, no steroid
• Partial:: decrease in U/A severity and/or frequency with reduction in
steroid dose
• No response
• No serious AE’s; 1 case of mild increase in LFT, 2 cases of GI
discomfort, managed with switch to IM route.
Sagi L. Acta Derm Venereol 2001; 91: 303-306
RCT: Hydroxychloroquine
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21 patients with chronic urticaria/angioedema, randomized to
Hydroxychloroquine (?dose) or Placebo for 12 weeks, in addition to other
medications for urticaria (H1 & H2 antihistamines, doxepin, corticosteroids).
Med taper q 2 weeks if well controlled; 18 completed trial, ITT analysis.
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* p < 0.05
* p = 0.05 – 0.10
Reeves GEM, et al. Intern Med J 2004; 34: 182-6.
Cyclosporine
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Most extensively studied agent for treatment
of refractory chronic urticaria/angioedema
May exert salutary effect via down-regulation
of Th1 responses and T cell dependent
antibody generation of B lymphocytes, along
with inhibition of release of histamine and
other mediators from mast cells and
basophils
Madan V, Griffiths CE. Dermatol Ther 2007; 20: 239-50.
Therapeutic Utility of Cyclosporine for
Refractory Chronic Urticaria/Angioedema
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Case Series and Case Reports
o Fradin MS, et al. J Am Acad Dermatol 1991; 25:
1065-7.
o Toubi E, et al. Allergy 1997; 52: 312-16.
o Serhat Inaloz H, et al. J Dermatol 2008; 35: 27682.
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Subject to bias, and do not provide high
quality evidence.
Therapeutic Utility of Cyclosporine for
Refractory Chronic Urticaria/Angioedema
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PubMed Search:
o “urticaria”, “cyclosporine”
o Limit = RCT
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4 RCT’s
o Grattan CE, et al. Br J Dermatol 2000; 143: 352-72.
o Di Gioacchino M, et al. Allergy Asthma Proc 2003; 24: 285-90.
o Baskan EB, et al. J Dermatolog Treat 2004; 15: 164-8.
o Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9.
Therapeutic Utility of Cyclosporine for
Chronic Urticaria/Angioedema
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Vena GA, et al. J Am Acad Dermatol 2006;
55: 705-9.
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DBRPC study with three arms, N=99:
o 16 weeks cyclosporine: 5 mg/kg tapering to
4 mg/kg, then 3 mg/kg.
o 8 weeks cyclosporine
o placebo
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Primary outcome
o Improvement in severity score
Therapeutic Utility of Cyclosporine for
Chronic Urticaria/Angioedema
Mean Improvement in Severity Score
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* p< .05
* p< .01
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Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9.
Evidence of Autoimmunity in Patients with Chronic Urticaria
Kaplan A., N Engl J Med 2002; 346: 175-9.
Autologous Serum Skin Test (ASST)
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3 of 4 studies enrolled only patients with positive ASST.
ASST not performed in the remaining study
o Vena GA, et al. J Am Acad Dermatol 2006; 55: 705-9.
In other published studies, results of ASST has not
consistently correlated with in vitro assays and positive
ASST has been observed in patients without urticaria.
o Taskapan, et al. Clin Exp Dermatol 2008; 33: 754-8.
o Asero, et al. Clin Exp Allergy 2004; 34: 1111-14.
The role of positive ASST in predicting salutary effect of
cyclosporine is unclear.
Cyclosporine
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4 RCTs in patients with chronic urticaria/angioedema
Methodologic shortcomings recognized in each study.
In the context of study limitations, potential harms and
costs, the quality of evidence supporting cyclosporine
administration is LOW -- leading to a WEAK
RECOMMENDATION, based on current evidence.
o Implies that patients in different clinical contexts, with
different values or preferences, are candidates for different
choices.
o Encourages clinicians to be more deliberate and judicious in
incorporating evidence regarding risks/benefits in the context
of patient circumstances, values, and preferences to make
the best management decision.
Step Wise Approach
Chronic Urticaria/Angioedema
Step-wise = Marked by a gradual progression
2nd Generation
Antihistamine
Advance dose of
Anti-histamine
(1st +/or 2nd
Generation)
Add
H2-Antihistamine
Add
Anti-Leukotriene
Step Care Approach
Refractory Chronic Urticaria/Angioedema
Step-wise = Marked by a gradual progression
Therapeutic Role For Anti-IgE
• Open trial of omalizumab in patients “with hives present
most days of the week despite antihistamines”.
• 7/12 achieved complete symptom resolution.
Kaplan A., et al. J Allergy Clin Immunol 2008; 122: 569-73