Updates from the New
Urticaria Practice Parameter
David A. Khan, MD
Professor of Medicine
Allergy & Immunology Program Director
Division of Allergy & Immunology
University of Texas Southwestern
Medical Center - Dallas
1
Disclosures

Research Grants


Speaker Honoraria


NIH, Vanberg Family Fund
Merck, Genentech, Viropharma, Baxter
Organizations:

Joint Task Force on Practice Parameters
All medications other than antihistamines are
considered “off-label” for treatment of chronic
urticaria
2
Objectives



To be able to discuss limitations and
recommendations on testing in chronic
urticaria
To develop a step-wised approach to
chronic urticaria
To gain an understanding of the use of
alternative agents in refractory chronic
urticaria
3
The Diagnosis and Management of
Acute and Chronic Urticaria: 2014 Update
Chief Editors
Jonathan Bernstein, MD; David Lang, MD; David Khan, MD
Workgroup Contributors
Timothy Craig, DO; David Dreyfus, MD; Fred Hsieh, 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
4
Urticaria Parameter Update

Manuscript in submission


Summary statements and other
recommendations presented may change
Publication in 2014?
5
Urticaria Practice Parameter

Sections
I. Executive Summary
II. Acute Urticaria
III. Diagnosis and Management of Chronic Urticaria
IV. Physical Urticaria/Angioedema
V. Differential Diagnosis
VI. Treatment for Acute and Chronic Urticaria
6
Diagnostic Evaluation in Urticaria
How Many and What Tests Are
Required?
7
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]
8
Chronic Urticaria Etiologies




Idiopathic
Physical
Autoantibody Associated
Urticarial Vasculitis
Systemic diseases (other than perhaps thyroid disease) are very rarely
associated with CU
9
Tests For Physical Urticaria
Cold
Ice cube test
Localized Heat
Test tube water 44ºC
Cholinergic
Exercise for 15-20 min.
Leg immersion in 44ºC bath
Sand bag test: 15 lb weight
for 15 minutes
Stroking skin
Delayed
Pressure
Dermographism
Solar
Aquagenic
Specific wavelength light
exposure
Water compress
Vibratory
Vortex for 5 minutes
10
Tests for Autoantibodies in CU

Skin tests



Autologous serum skin test
Autologous plasma skin test
Commercially Available Tests


CU Index (IBT Labs)
 Measures histamine release from donor
basophils activated by patient sera
IGERAB (National Jewish Labs)
 Measures CD203c by flow cytometry on
donor basophils activated by patient sera
11
Autoantibodies in CU

SUMMARY STATEMENT 22: The
utility of the autologous serum skin test
(ASST) and the autologous plasma skin
test (APST) is unclear, as evidence has
not clearly demonstrated this testing
identifies a distinct subgroup of patients
with CU. Current evidence does not
support routine performance of ASST or
APST in patients with CU. (C)
12
Autoantibody Testing

SUMMARY STATEMENT 30: While
commercial assays are now available, the
utility of testing for auto-antibodies to the
high-affinity IgE receptor or autoantibodies
to IgE has not been determined.(C)
13
Autoimmune Tests Usually Not Warranted


SUMMARY STATEMENT 15: Serology to
diagnose underlying autoimmune diseases
(e.g., connective tissue disease) is not
warranted in the initial evaluation of CU.
(B)
No need to get ANA routinely in patients
with CU
14
Routine Testing for H Pylori and Celiac
Not Required

SUMMARY STATEMENT 19: The co-
occurrence of CU with a number of conditions,
including Helicobacter pylori infection and celiac
disease, has been reported. However, evidence
does not support testing for these conditions in a
CU patient with an otherwise unremarkable history
and physical examination. Moreover, there are no
convincing data which demonstrate that treatment
based on abnormal test results consistent with
these conditions being present leads to
improvement or change in the course of CU. (C)
15
Role of H. pylori in CU ?
Conclusion:
The evidence that H. pylori eradication leads to improvement of chronic
urticaria outcomes is weak and conflicting; this leads to a weak
recommendation for routine H. pylori eradication for patients with chronic
urticaria.
Shakouri A. et al. Curr Opin Allergy Immunol 2010;10:362-9.
16
Urticarial Vasculitis May Look Like CIU

SUMMARY STATEMENT 18: Urticarial
vasculitic lesions may sometimes be
evanescent lasting less than 24 hours,
similar to CU; for this reason, urticarial
vasculitis cannot be completely excluded
based on the history of lesions spanning
less than 24 hours. (B)
17
Cutaneous Features of UV

Urticaria description


Duration of lesions


Painful, tender, burning or
pruritic
24-72 hrs (may be only present
in ~40%)
Lesions may resolve with
purpura or hyperpigmentation
Tosoni C. et al. Clin Exp Derm 2008;34:166-70.
18
Laboratories in UV

All forms of UV



 ESR
50% ANA +
 dsDNA –
HUV/HUVS (hypocomplomentemic UV/
syndrome)



 C3 ,C4, CH50
  C1q
Anti C1q antibodies present in 100% of HUV

Also seen in Felty’s syndrome, SLE, Sjogren’s
syndrome, and MPGN

Kallenberg CG. Autoimmun Rev 2008;7:612-5.
19
Thyroid Labs

SUMMARY STATEMENT 29: Screening
for thyroid disease is of low yield in patients
without specific thyroid-related symptoms
or history of thyroid disease. Elevated levels
of anti-thyroglobulin or anti-thyroid
antibodies in euthyroid (i.e. normal TSH)
individuals are commonly detected,
although the clinical implications of this
finding are unclear. [C]
20
Skin Biopsy

SUMMARY STATEMENT 32: Skin biopsy
may be performed when vasculitis is
suspected, such as in refractory CU, or
when other non-urticarial immunological
skin diseases are a consideration. Routine
skin biopsies are not required in most cases
of CU. [D]
21
Skin Testing

SUMMARY STATEMENT 33: Immediate
hypersensitivity skin or serologic testing
for food or other allergens is rarely useful,
and is not recommended on a routine
basis. [D]
22
Diagnostic Labs in CU


Systematic review of 29 studies involving
6462 urticaria patients
Large variability in determining an etiology:
1-84% (median 38%)


Most studies excluding physical urticarias had
lowest identifiable diagnoses (1-20%)
Only 1.6% patients thought to have an
internal disease responsible

Majority were cutaneous vasculitis
Kozel MM, et al.. J Am Acad Dermatol 2003; 48 (3): 409-16
23
Diagnostic Labs in CU



Most authors concluded that history is important
Most authors concluded that routine laboratory
tests are not required
Laboratories should be guided by the history,
which is the most important instrument in finding
an etiology
Kozel MM, et al. J Am Acad Dermatol 2003; 48 (3): 409-16
24


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.
25
17% of 1,872 ordered tests
were abnormal
Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.
26
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.
27
Diagnostic Testing in CU

SUMMARY STATEMENT 28: After a
thorough history and physical examination, no
diagnostic testing may be appropriate for
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.
28
Routine Labs

Summary Statement 28 (cont’d):
Routine laboratory testing in patients
with CU, whose history and physical
examination lack atypical features,
rarely yields clinically significant
findings.[C]
29
30
Task Force Labs in CU Consensus
31
Differential Diagnosis and
Evaluation of Urticaria
32
Drug Exanthem vs. Urticaria
Drug Exanthem
Urticaria
33
Contact Dermatitis
34
urticaria
subacute
cutaneous lupus
urticaria
pigmentosa
fixed drug eruption
Brodell LA, Beck LA. Ann Allergy Asthma Immunol 2008;100:181-8.
angioedema
Multiformelooking lupus
(Rowell
syndrome)
Sweet syndrome
Urticarial phase
of bullous
pemphigoid
35
Common and Less / Uncommon
Urticaria
Angioedema or Urticaria-like
Dermatoses
Anaphylaxis
Atopic dermatitis
Autoantibody to IgE receptor
Autoimmune thyroid disease
Bullous pemphigoid
C-1 inhibitor deficiencies
Contact dermatitis
Angiolymphoid hyperplasia with eosinophilia
Autoimmune progesterone-associated dermatoses
Blepharochalasis
Chelitis glandularis
Chelitis granulomatosa
Cryoglobulinemia
Cryopyrinopathies
MuckleWells, NOMID
Familial Cold-Autoinflammatory Syndrome
Drug related eosinophilia with systemic symptoms
Episodic angioedema with eosinophilia
Estrogen-induced angioedema
Factor I (C3b) deficiency
Hypereosinophilia syndrome
Periodic Fever Syndromes
Hyper IgD, TRAPS, PFAPA, PAPA
Familial Mediterranean Fever
Schnitzler’s syndrome / Malignancies
Systemic mastocytosis
Common
Contact urticaria
Cutaneous and systemic lupus erythematosus
Cutaneous mastocytosis
Dermatitis herpetiformis
Erythema multiforme
(infection, drug)
Exacerbation of physical urticaria
Food/Insect Allergies
Medication allergies
Angioedema with ACE inhibitors
Fixed drug eruptions
Parasite / Bacterial infections
Polymorphous light eruption
Recall Urticaria
Scabies
Urticarial Vasculitis (e.g. hepatitis)
Viral infections
Less or Uncommon
Urticaria-like dermatoses of pregnancy
Gestational pemphigoid
PUPPS, Prurigo of pregnancy
Well’s syndrome
36
Management of Chronic Urticaria
37
Principles of Step Therapy



Begin treatment at step appropriate for
patient’s level of severity and previous
treatment history
At each level of the step-approach,
medication(s) should be assessed for patient
tolerance and efficacy or discontinuation to
avoid unnecessary polypharmacy.
NOTE: “Step-down” in treatment is
appropriate at any step described, once
consistent control of
38
urticaria/angioedema is achieved
Step 1
39
H1 Antihistamines in CU


SUMMARY STATEMENT 76: H1
antagonists are effective in the majority
of patients with CU but may not achieve
complete control in all patients. (C)
SUMMARY STATEMENT 77: Secondgeneration antihistamines are safe and
effective therapies in CU and are
considered first-line agents. (A)
40
Step 2
41
Higher Dose H1 Antihistamines

SUMMARY STATEMENT 78: Higher
doses of second-generation antihistamines
may provide more efficacy but data are
limited and conflicting for certain agents.
(B)
42
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
43
High Dose Antihistamines in CU
Staevska M et al. J Allergy Clin Immunol 2010;125:676-82.
44
H2 Antihistamines

SUMMARY STATEMENT 80: H-2
antihistamines, taken in combination with first and
second-generation H-1 antihistamines, have been
reported to be more efficacious compared to H-1
antihistamines alone for the treatment of CU. (A)
However, this added efficacy may be related to
pharmacologic interactions and increased blood
levels of first-generation antihistamines. (B) As
these agents are well tolerated, the addition of H2antagonists may be considered when CU is not
optimally controlled with second-generation
antihistamine monotherapy.(D)
45
Leukotriene receptor antagonists

SUMMARY STATEMENT 81: Leukotriene
receptor antagonists have been shown in
several but not all randomized controlled
studies to be efficacious in patients with
CU.(A) Leukotriene receptor antagonists
are generally well tolerated (A).
Leukotriene receptor antagonists may be
considered for CU patients with
unsatisfactory responses to 2nd generation
antihistamine monotherapy.
46
Step 3
47
1st Generation Antihistamines

SUMMARY STATEMENT 79: First-
generation antihistamines have proven efficacy in
the treatment of CU. Efficacy of first-generation
antihistamines is similar to second-generation
antihistamines but sedation and impairment are
greater with first-generation antihistamines,
especially with short-term use. (A) Firstgeneration antihistamines may be considered in
patients who do not achieve control of their
condition with higher dose second-generation
antihistamines.(D)
48
Hydroxyzine and Doxepin

SUMMARY STATEMENT 82:
Treatment with hydroxyzine or doxepin
may be considered in patients who
remain poorly controlled with dose
advancement of second-generation
antihistamines, and the addition of H2antihistamines, first-generation H-1
antihistamine at bedtime, and/or antileukotrienes.(D)
49
Corticosteroids

SUMMARY STATEMENT 83: Systemic
corticosteroids are frequently used for refractory
CU patients, but no controlled studies have
demonstrated efficacy. In some patients, shortterm use (e.g. 1-3 weeks duration) may be
required to gain control of their disease until other
therapies can achieve control. Because of the risk
of adverse effects with systemic corticosteroids,
long-term use for treatment of CU patients should
be avoided as much as possible. (D)
50
Step 4
51
Refractory Chronic Urticaria

SUMMARY STATEMENT 84: CU
patients who are not adequately
controlled on maximally tolerated
antihistamine therapy (e.g., doxepin at
a dose of 100-125mg/day) may be
considered to have refractory CU. (E)
52
Alternative Agents

SUMMARY STATEMENT 85: A
number of alternative therapies have
been studied for the treatment of CU;
these therapies merit consideration for
patients with refractory CU. (D)
53
Rationale for Alternative Agents in
Chronic Urticaria



While most urticaria is antihistamine responsive,
not all patients have adequate control with
antihistamine therapy at any dose
Glucocorticoids while typically effective, have
predictable and nearly universal toxicity for
treatment of chronic urticaria
Alternative Agents



Immunomodulatory
Immunosuppressant
Other
54
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
55
J Allergy Clin Immunol: In Practice 2013
56
57
Anti-inflammatory Agents

SUMMARY STATEMENT 86: Antiinflammatory agents including dapsone,
sulfasalazine, hydroxychloroquine, and
colchicine have limited evidence for efficacy
in CU and some require laboratory
monitoring for adverse effects.(C) These
agents are generally well tolerated, may be
efficacious in properly selected patients,
and may be considered for treatment of
antihistamine refractory CU patients.(D)
58
Immunosuppressants

SUMMARY STATEMENT 87: Several
immunosuppressant agents have been
used in patients with refractory CU.
Cyclosporine has been studied in several
randomized controlled trials. (A) For this
reason, cyclosporine was selected for
closer examination as to the quality of
evidence supporting its administration in
patients with refractory chronic
urticaria/angioedema.
59
Khan DA. In: Maibach HI, Gorouhi F ed. Evidence Based Dermatology 2nd ed. 201160
Trojan T, Khan DA. Curr Opin Allergy Immunol 2012;12:412-20.
61
Trojan T, Khan DA. Curr Opin Allergy Immunol 2012;12:412-20.
62
Omalizumab

SUMMARY STATEMENT 88: In contrast to other
alternative agents for refractory CU, the therapeutic
utility of omalizumab has been supported by findings
from large double-blind randomized controlled trials
and is associated with a relatively low rate of
clinically significant adverse effects. On the basis of
this evidence, omalizumab should be considered for
refractory CU if from an individualized standpoint a
therapeutic trial of omalizumab is favorable from the
standpoint of balancing the potential for benefit with
the potential for harm/burden, and the decision to
proceed is consistent with patient values and
63
preferences. (A)
N Engl J Med. 2013 Mar 7;368(10):924-35.
64
Treatment period
N Engl J Med. 2013 Mar 7;368(10):924-35.
65
J Allergy Clin Immunol 2013;132:101-9.
66
Omalizumab in CU refractory to H1 plus
H2 and/or LTRA therapies
67
Selecting an Alternative Agent

SUMMARY STATEMENT 93: Multiple factors are
involved in selecting an alternative agent in
refractory CU patients including but not limited to
the presence of comorbid factors, frequency of
treatment-related visits, cost, rapidity of response,
adverse effects and patient values and preferences.
The potential for harm and burden association with
a given alternative agent is extremely important
and needs to be weighed against the patient’s
potential for benefit, current quality of life, and any
adverse effects from current therapy for their CU.
(D)
68
Personal Preferences in Alternative
Therapies

I typically start with dapsone


In patients demonstrating steroid
toxicity, I start with tacrolimus


Hydroxychloroquine, sulfasalazine other
similar alternatives
better tolerated than cyclosporine in my
experience
Omalizumab or mycophenolate used
after these agents
69
How Long to Treat?

Once successful alternative agent found




Taper off steroids
Taper off other medications
I treat with alternative agent until urticaria
free for at least 3 months then taper over
~3 months
Some patients require long term (years)
usage

Find lowest dose to control CU
70
Why Aren’t Alternative Agents Used
More?
Fear
 Lack of Training
 Outside of comfort zone

71
72
Conclusions




In the absence of history, diagnostic tests
have a low yield in evaluation of CU
The presence of autoantibodies may not
aid in management of CU patients
Upcoming urticaria guidelines will provide
a very comprehensive resource to aid in
management of urticaria patients
Step-wised approach to chronic urticaria
should aid allergists in managing patients
73