1. health and fitness
2. disease
3. allergies

REVIEW
URRENT
C
OPINION
Omalizumab in chronic urticaria
Martin Metz and Marcus Maurer
Purpose of review
The current EAACI/GA2LEN/EDF/WAO treatment guidelines for the management of urticaria recommend
omalizumab as fourth-line therapy. Within the last year, many reports of omalizumab treatment in chronic
urticaria have been published.
Recent findings
Two multicenter, randomized, placebo-controlled trials in chronic spontaneous urticaria have shown
excellent efficacy of omalizumab. Furthermore, in various case series and case reports, omalizumab has
been shown to be effective also in inducible urticarias; however, no randomized placebo-controlled trial
has been performed yet to thoroughly investigate the efficacy of omalizumab in inducible urticarias.
Summary
In this review, all published information on the use of omalizumab in urticaria will be summarized and
discussed with special emphasis on reports published within the last year. The available data indicate that
omalizumab is an effective and well tolerated drug in antihistamine-resistant chronic urticaria.
Keywords
anti-immunoglobulin (Ig) E, mast cell, physical urticaria, spontaneous urticaria, Xolair
INTRODUCTION
Urticaria is a frequent skin condition, which is
characterized by transient pruritic wheal and flare
type skin reactions and, in some patients, the occurrence of angioedema. In Europe alone, more than 5
million patients are thought to suffer from persisting urticaria symptoms [1 ], which either occur
spontaneously, that is in chronic spontaneous urticaria, or can be induced, for example as a result of
environmental physical stimuli such as pressure,
ultraviolet irradiation, heat or cold (physical urticaria), or by other means (Fig. 1). Patients with chronic
urticaria are often severely impaired in their quality
of life [2], with negative effects on sleep, daily
activities, school/work life and social interactions.
Therefore, the current guidelines of the European
Academy of Allergy and Clinical Immunology
(EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum
(EDF)/World Allergy Organization (WAO) state that
the aim of treatment for all types of urticaria is to
achieve complete symptom relief [3]. To accomplish
complete symptom control, specific underlying
causes can be identified and eradicated in some
patients with chronic spontaneous urticaria [4].
However, most patients with chronic spontaneous
urticaria and all patients with inducible urticaria
require symptomatic treatment for effective symptom control.
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www.co-allergy.com
The current EAACI/GA2LEN/EDF/WAO treatment guidelines for the management of urticaria
recommend the use of second-generation nonsedating oral H1-antihistamines as first-line therapy. In
more than 50% of the patients, symptoms persist
with standard dosing of antihistamines [1 ]. In these
patients, it is recommended to increase the dose of
the nonsedating H1-antihistamines up to four-fold
[3]. Thereafter, among several other third-line and
fourth-line options including ciclosporin A, the
guidelines suggest the possibility of using omalizumab.
Omalizumab (Xolair, Novartis, Switzerland and
Genentech, USA) is a recombinant humanized
monoclonal antibody that binds to immunoglobulin (Ig) E. It is specific for circulating free IgE and
cannot bind to cell-bound IgE or IgG, as it is engineered to bind to the CH3 domain of the e chain,
which is close to the binding site of IgE for FceRI and
CD23. Omalizumab has been approved in the
&
Allergie-Centrum-Charite´, Department of Dermatology and Allergy,
Charite´ – Universita¨tsmedizin Berlin, Berlin, Germany
Correspondence to Professor Dr med. Marcus Maurer, MD, Department
of Dermatology and Allergy, Charite´ – Universita¨tsmedizin Berlin,
Charite´platz 1, D-10117 Berlin, Germany. Tel: +49 30 450 518043;
fax: +49 30 450 518972; e-mail: marcus.maurer@charite.de
Curr Opin Allergy Clin Immunol 2012, 12:406–411
DOI:10.1097/ACI.0b013e328355365a
Volume 12 Number 4 August 2012
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Omalizumab in chronic urticaria Metz and Maurer
KEY POINTS
Omalizumab has been shown in two multicenter,
randomized, placebo-controlled trials to be highly
effective and well tolerated in patients with chronic
spontaneous urticaria.
urticaria patients exhibit on average higher total IgE
levels as compared with healthy controls [5]. A
transferable serum factor has been demonstrated
in some forms of inducible urticaria [6–8] and
autoallergic mechanisms can be identified as a
potential underlying cause in up to 50% of chronic
spontaneous urticaria patients [9 ].
&&
In various case series and case reports, omalizumab
has been reported to be effective in patients with
inducible urticaria including cholinergic urticaria,
urticaria factitia, solar, cold, heat and delayed
pressure urticaria.
Removal of autoreactive immunoglobulin (Ig) E is
hypothesized to be one potential mechanism of action
in chronic spontaneous urticaria.
In other diseases such as bullous pemphigoid, similar
mechanisms and similar efficacy of omalizumab may
be observed.
United States in 2003 for the treatment of moderate
to severe asthma in patients 12 years and older and
in Europe in 2005 for the treatment of severe allergic
asthma in patients 6 years and older. The postulated
mechanism of action accounting for the reduction
of exacerbations and symptoms of allergic asthma is
the fall in free IgE levels and the associated downregulation in the expression of FceRI receptors on
basophils and mast cells.
In chronic urticaria, there is general consent
that the underlying cause is never an allergy. Nevertheless, various lines of evidence indicated that antiIgE might still be beneficial in the treatment of
chronic urticaria: for example, chronic spontaneous
Spontaneous
Inducible
OMALIZUMAB IN CHRONIC
SPONTANEOUS URTICARIA
On the basis of the above-mentioned findings of a
potential role of IgE in urticaria and some initial case
reports, we therefore performed a first proof-ofconcept randomized, placebo-controlled doubleblind multicenter trial with omalizumab in chronic
spontaneous urticaria (Table 1 [10 ,11 ,12,13,14 ,
15–20,21 ,22 ,23–26]). In this study, a total of 49
patients with chronic spontaneous urticaria who
exhibit IgE against thyroperoxidase have been
treated. Omalizumab treatment resulted in rapid
and significant reductions in weekly urticaria
activity scores (UASs), and, most strikingly, in complete protection against the appearance of wheals
in 70.4% of the omalizumab versus 4.5% of the
placebo-treated patients [11 ].
The dose of omalizumab given to the patients in
this trial has been determined according to the
dosing scheme used in asthma patients, that is based
on total IgE levels and body weight. However,
we and others have observed within this trial as
well as in a number of case series and case reports
(Table 1 [10 ,11 ,12,13,14 ,15–20,21 ,22 ,23–26])
that treatment response to omalizumab appears to
&&
&
&&
&
&
&&
&&
&&
Spontaneous
urticaria
Acute spontaneous urticaria
Physical
urticaria
Cold urticaria
&
&
&
Chronic spontaneous urticaria
Heat urticaria
Pressure urticaria
Solar urticaria
Urticaria factitia/dermographic
urticaria
Other forms
of urticaria
Aquagenic urticaria
Cholinergic urticaria
Contact urticaria
Exercise-induced urticaria
FIGURE 1. Classification of urticaria.
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407
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Pharmacotherapy and evidence based medicine
Table 1. Trials and reports of omalizumab treatment in patients with chronic spontaneous urticaria
Reference
No. of patients
Comment
Saini et al. [10 ]
90 (21 placebo, 69 omalizumab)
Dose finding: 75, 300, 600 mg; significant
improvement with 300 and 600 mg
Maurer et al. [11 ]
49 (22 placebo, 27 omalizumab)
Complete protection from wheal development
in 70.4% of omalizumab vs. 4.5% placebotreated patients
14
Significant improvement in urticaria activity and
quality of life in all patients
Randomized controlled multicenter trials
&&
&&
Small trials/case series
Bu¨yu¨ko
¨ ztu¨rk et al. [12]
Godse [13]
Ferrer et al. [14 ]
&
5
Significant improvement in all patients
9
All patients responded, seven of nine showed
complete response
Groffik et al. [15]
9
All patients responded
Al-Ahmad [16]
3
All patients responded
Magerl et al. [17]
8
All patients responded, six of eight showed
complete response
Kaplan et al. [18]
12
Placebo controlled, seven complete response,
four significant improvement, one nonresponder
Spector and Tan [19]
3
All with complete response
Case reports
Rodriguez-Trabado et al. [20]
Response correlates with reduction in basophil
activation
Sa´nchez-Machin et al. [21 ]
Increased activity of CD4þ T cells associated
with effective treatment
Saavedra and Sur [22 ]
Successful treatment associated with FceRI down
regulation
Korkmaz et al. [23]
Complete response
Iemoli et al. [24]
Complete response associated with normalization
of B-cell activation and homing
Vestergaard and Deleuran [25]
Two patients with complete response
Romano et al. [26]
Two patients with complete response
&
&
be largely independent of total IgE. Therefore, a
larger dose-finding multicenter trial with a total of
90 chronic spontaneous urticaria patients from the
United States or Germany has been performed with
75, 300 and 600 mg omalizumab or placebo [10 ].
In this study, patients received a single dose of
omalizumab and efficacy was assessed by comparing
urticaria activity at baseline to week 4. Here, the
overall excellent and rapid response to omalizumab
has been confirmed and 300 mg omalizumab has
been identified as the optimal dose for the treatment
of urticaria symptoms. In currently ongoing clinical
trials, the additional dose of 150 mg of omalizumab,
which has been shown to be effective in a number of
patients reported in case series and case reports, will
also be evaluated. In both multicenter trials, treatment with omalizumab was found to be safe and
well tolerated and the incidence of adverse events
was found to be similar across all treatment groups.
&&
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Furthermore, a total of 63 patients with chronic
spontaneous urticaria treated with omalizumab
have been reported in the literature to date
(Table 1 [10 ,11 ,12,13,14 ,15–20,21 ,22 ,23–26]).
Overall, a significant clinical response has been
described in 62 out of the 63 patients, with no report
of relevant adverse events. Most of the patients
reported in these case series and reports have
been treated according to the escalating treatment
scheme recommended in the EAACI/GA2LEN/EDF/
WAO treatment guidelines, that is with high-dose
H1-antihistamines, H2-antihistamines, leukotriene
antagonists, dapsone and/or ciclosporin A. The
patients then received omalizumab because of failure
of the previous treatment or because of intolerable
side effects, such as kidney failure after cyclosporine
treatment.
Taken together, based on the results from two
multicenter placebo-controlled trials and numerous
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&&
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Omalizumab in chronic urticaria Metz and Maurer
patients treated individually, omalizumab appears
to be a highly effective and well tolerated treatment option in severe and antihistamine-resistant
chronic spontaneous urticaria.
OMALIZUMAB IN INDUCIBLE URTICARIA
Similar to chronic spontaneous urticaria, a classical
allergy is never the underlying cause of an inducible
urticaria disease. Nonetheless, IgE has often been
speculated to play a role in the pathomechanisms
underlying inducible urticarias. For example, early
work by Houser et al. [27] and Kaplan et al. [28] have
shown that in some patients with cold urticaria, a
transferable serum factor consistent with IgE may
exist [27,28]. Similarly, passive transfer experiments
have indicated the existence of a mast cell-activating IgE serum factor in some patients with urticaria
factitia [29], and in solar urticaria, the production of
a photoallergen in the skin and the subsequent
IgE-mediated activation of mast cells is often
hypothesized to be the relevant underlying mechanism [30]. A critical mast cell-activating factor
such as a photoallergen in solar urticaria or a
cold-induced allergen in cold urticaria has, however,
not yet been identified.
The first report of a successful treatment of
urticaria with omalizumab by Boyce in 2006
described a complete symptom control in a girl with
persistent asthma and severe cold urticaria [31].
Based on this case report and the considerations
of a potential role of IgE in inducible urticarias we
and others have described successful treatment of
patients with urticaria factitia, cholinergic, solar,
cold, heat, and delayed pressure urticaria (Table 2
&&
[32 ,33–40]). Overall, a total of 16 patients have
been reported with 11 patients showing a complete
response. Interestingly, not all patients responded;
some patients did not show any effect at all,
indicating different pathomechanisms in some
patients.
As of now, no randomized placebo-controlled
trial has been performed to thoroughly investigate
the efficacy of omalizumab in inducible urticarias.
OUTLOOK AND OPEN QUESTIONS THAT
NEED TO BE ADDRESSED
In moderate to severe asthma, omalizumab has been
shown to effectively improve symptoms and to
reduce the rate of exacerbations and emergency
visits [41]. The response to treatment in these
patients differs, however, considerably from the
one in patients with urticaria. For example, in asthmatic patients, low levels of total IgE are associated
with a smaller treatment benefit, and the response
to omalizumab is described as a progressive onset,
with 38% of patients responding within 4 weeks of
initiating treatment, and 64% after 16 weeks [42,43].
In contrast, treatment benefit in urticaria patients
appears to be independent of total IgE levels and
significant clinical improvement was observed
already after a few days of initiating treatment
[11 ]. These differences raise the question whether
the omalizumab-induced symptom improvement in
both asthma and urticaria follow similar underlying
mechanisms.
The main mechanism of omalizumab is the
reduction of free IgE to less than 10% of baseline
levels. Associated with the rapid reduction in free
&&
Table 2. Reports of omalizumab treatment in patients with inducible urticaria
Reference
No. of patients
Comment
7
Complete response in solar (2), cold (1),
delayed pressure urticaria (1) and
urticaria facitita (1), no response in
heat urticaria (1)
Case series
Metz et al. [32 ]
&&
Case reports
Duchini et al. [33]
Treatment failure in solar urticaria
Krause et al. [34]
Successful treatment in urticaria factitia
Waibel et al. [35]
Partial improvement in solar urticaria
Bullerkotte et al. [36]
Complete response in heat urticaria
Sabroe [37]
Treatment failure in cholinergic urticaria
Bindslev-Jensen and Skov [38]
Complete response in delayed pressure urticaria
Gu¨zelbey et al. [39]
Complete response in solar urticaria
Metz et al. [40]
Complete response in cholinergic urticaria
Boyce [31]
Complete response in cold urticaria
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409
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Pharmacotherapy and evidence based medicine
IgE levels, a subsequent down regulation of the IgE
receptor FceRI on mast cells and basophils occur,
which is also thought to contribute to the clinical
response [43]. In chronic spontaneous urticaria,
additional mechanisms may be relevant. For
example, we have recently identified a possible
novel pathogenic pathway in chronic spontaneous
urticaria. In more than 50% of chronic spontaneous
urticaria patients elevated levels of IgE autoantibodies against thyroperoxidase (TPO) can be
detected [9 ]. These IgE-anti-TPO autoantibodies,
when bound and activated on the surface of mast
cells, could cause an autoallergic mast cell degranulation. It can be speculated that in addition to IgEanti-TPO other IgE autoantibodies exist in chronic
spontaneous urticaria patients. Anti-IgE treatment
could result in the rapid reduction of these IgE and
thus to the suppression of urticaria symptoms.
Chronic spontaneous urticaria is not the only
disease in which IgE autoantibodies have been
shown to exist. For example, autoreactive IgE have
been detected in a large number of patients with
atopic dermatitis, especially in those with severe
disease [44,45 ]. Similarly, pathogenic autoreactive
IgE can be found in patients with bullous pemphigoid [46 ]. Interestingly, omalizumab treatment has
been reported to be effective in some patients with
atopic dermatitis [47] as well as in patients with
bullous pemphigoid [48]. These findings suggest
that IgE autoantibodies might be a relevant pathogenic pathway in several diseases and anti-IgE treatment could be beneficial in those diseases. Further
research has to confirm the existence and to identify
the relevance of other IgE auto antibodies.
Another open question that needs to be
addressed in the future is the required dosing and
treatment scheme of omalizumab in urticaria. In the
initial trials, case series and case reports in urticaria
the dosing scheme for omalizumab treatment in
asthma patients has been used, that is based on total
IgE levels and body weight. Currently available data
however indicate that efficacy of omalizumab in
urticaria is independent of these parameters and
that 150–300 mg every 4 weeks is sufficient in most
patients [10 ,17,32 ]. Future investigations will
have to confirm this and detailed treatment
schemes need to be developed. For example,
optimal treatment intervals, and modes of up dosing and tapering of dosing should be defined.
Furthermore, it is has not been studied in detail
yet whether omalizumab treatment can have a disease-modifying effect and may lead to a remission of
urticaria in some patients. The currently published
studies as well as our personal experience argue
against this possibility as the large majority of
patients return to similarly severe urticaria
&&
symptoms usually 4–8 weeks after the last omalizumab injection.
CONCLUSION
More than 50% of patients with chronic spontaneous urticaria and a large proportion of patients
with inducible urticarias such as solar or cold
urticaria are resistant to standard antihistamine
treatment. In these patients, treatment with the
monoclonal anti-IgE antibody omalizumab has
been found to be a highly effective and well tolerated therapy. Further investigations have to be
carried out to identify the exact mechanisms underlying the excellent efficacy, to provide the optimal
dosing scheme in urticaria and to identify other
diseases in which anti-IgE treatment might be
beneficial.
Acknowledgements
The development of this paper was supported in part by
Novartis; we thank Jodie Urcioli for medical writing
services including proofreading.
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www.co-allergy.com
Conflicts of interest
There are no conflicts of interest. The authors disclose
the following activities as speaker and/or advisor for
pharmaceutical companies: Abdi Ibrahim, Almirall
Hermal, Bayer Healthcare, Biofrontera, Dr R. Pfleger,
Essex Pharma, Genentech, JADO Technologies, Jerini,
Merckle Recordati, Novartis, Sanofi Aventis, ScheringPlough, Leo Pharma, MSD, Merck, Shire, Symbiopharm,
UCB, Uriach.
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&
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