Download The potential pharmacologic mechanisms of omalizumab in patients

The potential pharmacologic mechanisms of omalizumab in
patients with chronic spontaneous urticaria
Tse Wen Chang, PhD,a Christina Chen, BS,a Chien-Jen Lin, PhD,a Martin Metz, MD,b Martin K. Church, PhD, DSc,b and
Marcus Maurer, MDb
Taipei, Taiwan, and Berlin, Germany
In patients given a diagnosis of chronic spontaneous urticaria
(CSU), there are no obvious external triggers, and the factors
that initiate the clinical symptoms of wheal, flare, and itch arise
from within the patient. Most patients with CSU have an
autoimmune cause: some patients produce IgE autoantibodies
against autoantigens, such as thyroperoxidase or doublestranded DNA, whereas other patients make IgG autoantibodies
against FcεRI, IgE, or both, which might chronically activate
mast cells and basophils. In the remainder of patients with CSU,
the nature of the abnormalities has not yet been identified.
Accumulating evidence has shown that IgE, by binding to FcεRI
on mast cells without FcεRI cross-linking, can promote the
proliferation and survival of mast cells and thus maintain and
expand the pool of mast cells. IgE and FcεRI engagement can
also decrease the release threshold of mast cells and increase
their sensitivity to various stimuli through either FcεRI or other
receptors for the degranulation process. Furthermore, IgEFcεRI engagement potentiates the ability of mast cells to store
and synthesize de novo inflammatory mediators and cytokines.
Administration of omalizumab, by virtue of its ability to deplete
IgE, attenuates the multiple effects of IgE to maintain and
enhance mast cell activities and hence reduces the ability of
mast cells to manifest inflammatory mechanisms in patients
with CSU. (J Allergy Clin Immunol 2015;135:337-42.)
Key words: Chronic urticaria, omalizumab, IgE, FcεRI, autoantibodies, mast cells, activation/release threshold, IgE–FcεRI–mast
cell axis
Chronic spontaneous (idiopathic) urticaria (CSU) is characterized by the presentation of itchy wheal-and-flare skin reactions,
angioedema, or both for a period of greater than 6 weeks.1 For
most patients with severe CSU, damage to their appearance and
the unbearable itching extend beyond a physical ailment to psychological disorders, including anxiety and depression, and
severely impair the patient’s quality of life.2 Although the
From athe Genomics Research Center, Academia Sinica, Taipei, and bthe Department of
Dermatology and Allergy, Charite-Universit€atsmedizin Berlin.
Disclosure of potential conflict of interest: T. W. Chang has received research support
grant no. NSC-2320-B-001-005 from Nation Science Council Taiwan. M. Metz has
consultant arrangements with and has received research support and honoraria for
lectures from Novartis, Switzerland. M. K. Church has received payment for lectures
from Novartis, Switzerland. M. Maurer has received honoraria for lectures and
consulting, and funding for research from Novartis, Switzerland and Genentech. The
rest of the authors declare that they have no relevant conflicts of interest.
Received for publication February 24, 2014; revised April 26, 2014; accepted for publication April 30, 2014.
Available online June 17, 2014.
Corresponding author: Martin K. Church, PhD, DSc, Allergie-Centrum-Charite, Department of Dermatology and Allergy, Charite-Universit€atsmedizin Berlin, Chariteplatz 1,
D-10117 Berlin, Germany. E-mail: [email protected].
0091-6749/$36.00
Ó 2014 American Academy of Allergy, Asthma & Immunology
http://dx.doi.org/10.1016/j.jaci.2014.04.036
Abbreviations used
ASST: Autologous serum skin test
CSU: Chronic spontaneous urticaria
CU: Chronic urticaria
dsDNA: Double-stranded DNA
HC: Highly cytokinergic
ssDNA: Single-stranded DNA
TPO: Thyroperoxidase
symptoms of the majority of patients can be adequately treated
with antihistamines, in many cases they cannot. In these cases it
is necessary to consider second-line treatments.3
Between 2006 and 2008, a number of physician-initiated case
reports and pilot studies on CSU,4 chronic autoimmune urticaria,5
idiopathic angioedema,6 cold-induced urticaria,7 cholinergic urticaria,8 and solar urticaria9 showed that the humanized anti-IgE
antibody omalizumab was efficacious against urticarial diseases
not adequately treated with other medications. These reports
spurred subsequent broader investigation of the effects of
omalizumab in patients with chronic urticaria (CU).
To date, 2 phase II10,11 and 4 phase III multicenter, randomized,
placebo-controlled clinical trials12,13 have convincingly established that omalizumab is efficacious and safe for treating recalcitrant CSU that cannot be adequately treated with current standard
care. Furthermore, a retrospective clinical analysis of 51 patients
in Germany has shown omalizumab to be a rapidly acting, highly
effective, and safe drug in both patients with CSU and those with
chronic inducible urticaria.14 A summary of the clinical studies of
omalizumab in patients with urticaria is shown in Table E1 in this
article’s Online Repository at www.jacionline.org.
Omalizumab, which has been conceptualized for treating IgEmediated allergic diseases15 and approved for treating patients
with severe persistent allergic asthma in many countries, can
neutralize IgE, impede the IgE allergic pathway, and render
mast cells and basophils insensitive to activation through IgE/
FcεRI.16,17 Although reports showing the therapeutic effects of
omalizumab on CSU have suggested a mechanism by which it attenuates the pathology of CSU with an autoimmune cause, such
analyses are largely simplistic and incomplete. Furthermore,
there is a nearly complete void of explanation in the literature
on how omalizumab might achieve its therapeutic effects in patients with CSU and chronic inducible urticaria. This review
will focus on CSU and the possible mechanism or mechanisms
by which omalizumab might be effective in its treatment.
HISTAMINE, MAST CELLS, AND CSU
The activation of mast cells and their release of inflammatory
mediators are regarded as the ‘‘final common pathway’’ for a
myriad of proinflammatory factors, including those involved in
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338 CHANG ET AL
J ALLERGY CLIN IMMUNOL
FEBRUARY 2015
FIG 1. The inflammatory manifestation of mast cells in affected skin is the final common pathway in various
types of urticaria. For the inducible subtypes, there are identifiable external triggers. For physical urticaria,
the internal pathologic factors that transduce external triggers to mast cell activation have not been
identified. For the spontaneous type, the primary causative factors that cause the urticarial manifestation
arise internally. In one large subtype the patients have an autoimmune cause. For the remaining cases of the
spontaneous type, the internal abnormalities have not been identified.
the various types of urticaria,18,19 as shown in Fig 1. The clinical
response of CSU to H1-antihistamines and the finding of
increased concentrations of histamine in skin tissue fluid underscore the role of histamine derived from dermal mast cells as a
major mediator of urticaria.20 But what stimulates mast cells to
degranulate, and why does this happen in the skin?
Although highly unlikely, it cannot be excluded that in some
cases of CSU, the primary abnormality lies in the mast cells
themselves (eg, because of intrinsic or genetic alterations that
cause altered activities of signal transduction pathways, as occurs
in mastocytosis).21 If this were the case, it would be likely that the
condition would be systemic rather than confined to the skin.
Therefore it is more likely that skin mast cells in patients with
CSU are not intrinsically abnormal but become increasingly sensitive or ‘‘unstable’’ or activated as the result of certain abnormal
factors present in their surroundings.
Although there are many nonimmunologic factors that might
influence mast cell function in the skin, such as components of the
complement system22 and neuropeptides, particularly those
related to stress,23 because this review is primarily concerned
with the mechanisms by which omalizumab might be effective,
nonimmunologic factors will not be considered in detail.
A STATE OF MAST CELL ACTIVATION WITHOUT
DEGRANULATION: PRIMING MAST CELLS FOR
FULL ACTIVATION
Accumulating evidence in the literature suggests that the IgE–
FcεRI–mast cell axis does not merely exist in idled and triggered
states. Before mast cells become productively activated for
mediator release, they exist at some point along a spectrum of
activation states of increasing potency. In other words, the
activation of mast cells does not necessarily lead to their
degranulation but might serve to prime them for subsequent
activation. We will consider 2 possible mast cell–priming
pathways for urticaria, namely the heterogeneous effects of
monomeric IgE and the consideration of CSU as an autoreactive
disease (Fig 2).
MONOMERIC IgE POTENTIATES THE ACTIVITIES
OF MAST CELLS IN THE ABSENCE OF ALLERGEN
CROSS-LINKING
In conventional thinking the involvement of IgE in mast cell
activation requires the cross-linking of FcεRI-bound IgE by
antigen or anti-IgE antibodies. This initiates the aggregation of
FcεRI, leading to tyrosine kinase activation and subsequent mast
cell activation for secretion. However, in 2001, it was suggested
independently by 2 groups24,25 that monomeric IgE in the absence
of antigen can have multiple effects in murine mast cells,
including differentiation, proliferation, survival, and mediator
and cytokine generation. These effects, which involve the binding
of IgE to FcεRI and the aggregation of FcεRI, occur without the
mast cells undergoing degranulation.24
The finding that monomeric IgE can augment mast cell activity
has been confirmed by studies using various techniques. In a
transcriptome analysis of 8793 genes, sensitization of mast cells
with monoclonal IgE alone, without FcεRI cross-linking, was
found to upregulate 58 genes more than 2-fold compared with
their levels in unsensitized mast cells.26 These genes included
those for cytokines, such as IL-1b, IL-6, and colony-stimulating
factor 1; chemokines, such as IL-8 (CXCL8), CCL4, and monocyte chemoattractant protein 1 (CCL7); and cytokine and chemokine receptors. The genes for various immune regulators,
adhesion molecules, antiapoptosis proteins, and cytoskeletal elements, such as RAS protein activator like 1 (RASAL1) and fibronectin leucine-rich transmembrane protein 2 (FLRT2), were also
upregulated.
Other studies have followed the suggestion that mouse
monoclonal IgE molecules are heterogeneous with respect to
their ability to induce survival and activation events in mast
cells.27 At one end of the spectrum, highly cytokinergic (HC)
CHANG ET AL 339
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VOLUME 135, NUMBER 2
FIG 2. The potentiating effects of IgE on mast cell activity. Binding of monomeric IgE to FcεRI, without IgE
cross-linking, potentiates the activities of mast cells in the absence of degranulation. Compared with mast
cells without IgE engagement, the IgE-engaged mast cells become more sensitive as the thresholds for
activation and degranulation (release thresholds) by various factors through their receptors are decreased.
The mast cells also become more potent because they store more mediators and can synthesize more
mediators on degranulation. The mast cells also synthesize an array of factors and cytokines, which
promote both differentiation of progenitors to become mast cells and survival of mast cells, thus
augmenting the pool of mast cells. In subjects with anti-IgE autoantibodies, IgE autoantibodies, or both,
the anti-IgE autoantibodies and presence of cross-reactive self-antigens can cause subthreshold levels of
IgE cross-linking and FcεRI aggregation and augment the IgE-potentiating effect of mast cells.
IgEs induce enhanced survival, degranulation, adhesion, migration, and expression of cytokines, such as IL-6 and TNF-a; at the
other extreme, poorly cytokinergic IgEs mediate these effector
functions inefficiently.28 Interestingly, most murine monoclonal
HC IgEs exhibit polyreactivity to autoantigens, such as
double-stranded DNA (dsDNA), single-stranded DNA
(ssDNA), b-galactosidase, thyroglobulin, and histaminereleasing factor. Autoantibodies to such autoantigens are often
found in patients with autoimmune diseases. By contrast, poorly
cytokinergic IgEs do not react with these antigens.29 This IgE
heterogeneity is not restricted to murine antibodies: Kashiwakura et al29 recently reported that a human monoclonal HC
IgE also shows polyreactivity to dsDNA, ssDNA, and
histamine-releasing factor. Furthermore, sera from patients
with atopic dermatitis showed increased reactivity to ssDNA
and b-galactosidase and increased levels of histaminereleasing factor, suggesting a relationship between HC IgE and
atopic disease.
AUTOREACTIVITY PROBABLY PLAYS A LARGER
ROLE IN CSU THAN CURRENTLY APPRECIATED
There is a strong correlation between CSU and autoimmune
diseases. In a study involving 12,778 patients with CU using data
spanning 17 years,30 it was shown that the odds of patients with
CU to have 1 or more autoimmune diseases, mostly within 10
years of their diagnosis of CU, were 7.7 to 28.8 times higher
than control subjects. These autoimmune diseases include
hypothyroidism, thyroiditis, rheumatoid arthritis, systemic lupus
erythematosus, Sj€ogren syndrome, celiac disease, and type 1 diabetes, among others, which involve autoantibodies. The data indicate that patients with CU have a propensity to autoimmunity and
that in many patients with CU, urticaria appears to be the first or
only manifestation of pathologic autoimmunity.
The autoreactivity in patients with CSU can be described in 2
subtypes. In the first subtype, which is essentially a Coombs and
Gell type II hypersensitivity reaction, affected patients produce
IgG autoantibodies against FcεRI, IgE, or both, which can
cross-link IgE-occupied or barren FcεRI to activate mast cells
and basophils.31 This was originally reported by Grattan et al32
in 1986 after the observation that serum from some patients
with CSU produced a wheal at the site of intradermal injection.
This is the so-called autologous serum skin test (ASST). Interestingly, the IgG subclasses that appear to be pathogenic are
IgG1 and IgG3,22 both of which are capable of activating complement C5a, an established stimulator of skin mast cells, but
not other mast cells, in human subjects.33 In adults the prevalence of positive ASST reactivity in patients with CSU is
approximately 45%.34 Although this IgG autoreactivity is not
definitively proved to be a trigger for urticaria, it is linked to
longer duration of disease and the need for more intensive
treatment.3
In the second subtype patients produce IgE antibodies against
autoantigens. Work in this area stems from the observation that
patients with CSU frequently exhibit increased total IgE levels35
and have autoimmune conditions, especially thyroid autoimmune
disorders, such as Hashimoto thyroiditis.36 Several independent
studies have reported that a significant number of patients with
CSU (up to 33% in some studies) exhibit high levels of autoantibodies to thyroid antigens.37,38 In a study of 478 patients with
CSU, 54% of sera were found to contain significant amounts of
IgE directed against thyroperoxidase (TPO).39 Interestingly, IgE
anti-TPO1 patients also had significantly higher IgG anti-TPO
levels than IgE anti-TPO1 patients. However, there were no differences in disease activity and duration between IgE antiTPO1 and IgE anti-TPO2 patients.
More recently, significantly higher levels than normal of IgE
against dsDNA (IgE anti-dsDNA) have also been found in some
340 CHANG ET AL
patients with CSU.40 No differences between patients with CSU
and healthy subjects were seen in IgG anti-dsDNA levels or IgE
and IgG levels against thioredoxin, peroxiredoxin, and thyroglobulin. There was also no significant difference in levels of IgE antidsDNA between patients with positive and those with negative
ASST results.40 These findings suggest that the ASST cannot
reveal the presence of all autoreactive antibodies and that autoantibodies, such as IgE anti-dsDNA, other than the welldocumented IgG autoantibodies against IgE and FcεRI and IgE
autoantibodies against TPO can also activate basophils to degranulate and play substantial roles in the pathogenesis of CSU.
These findings suggest that this type of autoreactivity is one of
the underlying causes of CSU and that IgE against self-allergen
and the corresponding autoallergen might play important auxiliary roles in the priming of mast cells for activation (without
degranulation) or be a direct stimulus of skin mast cell
degranulation in patients with CSU. If this is the case, then it
might be expected that therapies that reduce autoantibody levels
would be effective in the treatment of CSU. The effectiveness of
omalizumab (anti-IgE) is discussed below. Furthermore, there are
case reports41,42 that rituximab, which binds to B-cell CD20 and
reduces the levels of all classes of antibodies, including autoantibodies, and cyclophosphamide,43,44 which targets B cells
producing autoantibodies, might be effective for treating
autoimmune CSU.
OMALIZUMAB ABOLISHES THE ABILITY OF IgE TO
POTENTIATE MAST CELL ACTIVITY
In a patient with an allergic disease caused by type I hypersensitivity toward specific external antigens, omalizumab induces
multifactorial therapeutic effects. Omalizumab depletes free IgE
in the blood and interstitial space and inhibits IgE binding to
FcεRI on basophils, mast cells, and dendritic cells. Omalizumab
cannot bind to IgE that is already bound to FcεRI and does not
have a direct effect on FcεRI levels. However, the depletion of
free IgE results in the downregulation of FcεRI on cells bearing
the receptor, making those cells insensitive to the stimulation by
incoming allergens. It has also been suggested that the accumulation of omalizumab-IgE immune complexes might help
sequester incoming allergen molecules.16,45 Omalizumab can
also downregulate CD23 (also referred to as FcεRII) on B cells.46
There is also evidence that membrane-bound IgE-expressing B
lymphoblasts and memory B cells can be downregulated, causing
a reduction in the continual generation of IgE-secreting plasma
cells.47,48 This is supported by the finding that IgE production
decreases by 54% annually in omalizumab-treated asthmatic
patients.49 Thus these effects of omalizumab inhibit the allergens
to activate basophils and mast cells and their subsequent release
of inflammatory mediators and cytokines. Omalizumab treatment
ultimately brings down the overall inflammatory state in the body.
But how does omalizumab exert its beneficial effects in patients
with urticaria? As shown in Fig 2, there are 3 possible scenarios
involving IgE. First, omalizumab sequesters monomeric IgE to
reduce its priming effect on mast cells. This would be particularly
relevant if HC IgE is involved in the pathogenesis of urticaria.
Second, in patients with IgG autoantibodies against IgE or
FcεRI, the depletion of mast cell–bound IgE by omalizumab and
the subsequent downregulation of FcεRI on mast cells and
basophils would lead to their decreased state of hyperexcitability.
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FEBRUARY 2015
TABLE I. The potential pharmacologic mechanisms of omalizumab in patients with CSU
Mechanisms
Binding of omalizumab to IgE
Free IgE concentration in blood and interstitial space
FcεRI on mast cells and basophils
IgE-FcεRI engagement
Potentiating of mast cells
Secretion of cytokines (without degranulation)
Mast cell pool
Immune complexes of IgE-omalizumab
Trapping of autologous antigens (eg, TPO)
Trapping of IgE-specific IgG autoantibodies
Binding of omalizumab to membrane-bound IgE on B lymphocytes
Continual synthesis of IgE in extended periods
IgE pool in the immune system
Overall effects
Release thresholds for mast cells for various degranulators
Degranulation of mast cells
Secretion of mediators, cytokines, and chemokines
Recruitment of T cells, macrophages, and eosinophils
Inflammatory manifestation in skin
Vasopermeability, wheal, edema, itch, and erythema
Effects
Y
Y
Y
Y
Y
Y
[
[
[
Y
Y
[
Y
Y
Y
Y
Y
When IgE is bound by omalizumab, forming a complex, IgE cannot bind to FcεRI.
This inhibits TPO-specific IgE autoantibody binding of FcεRI. Because IgE-specific
IgG autoantibodies bind to IgE in accumulating IgE-omalizumab complexes, fewer of
these autoantibodies can bind to IgE on FcεRI.
Third, in those patients with IgE autoantibodies against
autoallergens, the inhibition of IgE binding to FcεRI by
omalizumab and the downregulation of FcεRI would represent
a central mechanism of omalizumab. Furthermore, accumulation of omalizumab-IgE immune complexes15 would sequester
endogenous autoantigens, such as TPO and dsDNA, with which
IgE reacts. In addition to these effects, the binding of omalizumab to IgE on B lymphocytes and memory cells would reduce
the continual generation of IgE-producing plasma cells and
hence IgE synthesis. The overall effect of omalizumab is that
the IgE–FcεRI–mast cell axis is downgraded and the threshold
for activation of mast cells to undergo degranulation by various
factors is increased. This decrease in mast cell sensitivity and
potency and thus increase in mast cell stability causes the
mast cells to undergo less degranulation and secrete smaller
amounts of pharmacologic mediators, thus decreasing the manifestation of urticarial symptoms. A summary of the possible effects is shown in Table I. Also, the decreased release of
inflammatory cytokines and mediators from basophils in the
vasculature as the result of omalizumab treatment would reduce
the inflammatory manifestation in the skin. Such an effect might
be important during the initial period of omalizumab treatment
because the downregulation of FcεRI on basophils is faster than
that on mast cells.
DIFFERENCES IN RESPONSE TO OMALIZUMAB
AMONG PATIENTS WITH CSU AND THOSE WITH
ALLERGIC DISEASES
In patients with CSU, omalizumab has a relatively rapid onset
of action, usually within 4 weeks in most patients and more
rapidly in some.14 Clearly, this is very different from the onset
of action seen in asthmatic patients in whom, although free IgE
is extensively and very rapidly suppressed after commencing
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VOLUME 135, NUMBER 2
omalizumab, optimal benefit with respect to symptoms takes 12
to 16 weeks.50 There are many reasons for this difference. In
some allergic patients allergen-specific IgE accounts for
substantial percentages (eg, >3% to 5%) of total IgE, and it is
difficult to reduce these to levels at which they do not occupy
sufficient FcεRI on basophils and mast cells to sensitize them.
Also, during some episodes of allergic attacks, patients might
be exposed to external allergens, such as dust mites, pollens,
or food antigens, or triggers, levels of which are much greater
than the activation threshold of basophils and mast cells.
Furthermore, in asthmatic patients there is persistent allergic
inflammation in the bronchi, with consequential tissue remodeling.51 The inflammation takes time to resolve before symptoms
improve significantly.50 In contrast, the hives and angioedema
that manifest in the skin of patients with CSU disappear after
each episode. There is no long-lasting damage to the affected
skin.
CONCLUSION
In cases of CSU, in which autoreactive IgG antibodies against
FcεRI, IgE, or both or autoreactive IgE antibodies against
autoallergens are found, these autoantibodies are causative
factors, and IgE, FcεRI, and mast cells are unambiguously at
the center of the pathologic process. For the remaining cases of
CSU, IgE, FcεRI, and mast cells are also likely to play essential
pathologic roles, although the causative factors have not been
identified.
Because the potentiating effect of IgE on mast cell activity
involves the binding of monomeric HC IgE or the aggregation of
FcεRI to a subthreshold level without triggering degranulation, it
is possible that the presence of IgE antibodies with crossreactivity to very low concentrations of self-antigens, such as
dsDNA, ssDNA, and other self-components, might play an
important role in CSU. It should be emphasized that IgG
autoantibodies to IgE and FcεRI, IgE autoantibodies to TPO
and other thyroid antigens, and IgE autoantibodies to dsDNA,
ssDNA, and other self-antigens can all bind to and cross-link
IgE/FcεRI. Although the autoantibodies to individual antigens are
not detectable in immunoassays, their cumulative binding to
IgE/FcεRI might be sufficient to prime mast cells for activation.
If these concepts are correct, autoimmune response and
autoreactive IgE antibodies might play a larger role in patients
with CSU than previously appreciated. In other words, autoimmune processes might be the primary cause of most cases of
CSU. Thus for those cases with a clear autoimmune cause, the
attenuation of the IgE–FcεRI–mast cell axis by the action of
omalizumab yields the observed therapeutic efficacy. Even for
those cases that involve autoimmune response and autoreactive
IgE antibodies subtly, they still involve the central pathologic
axis of IgE–FcεRI–mast cells, as depicted in Fig 2, and omalizumab similarly renders therapeutic effects. The thesis presented here is based on multiple lines of research results from
various investigators. Future studies examining the composition
of autoantibodies and their effects on mast cells in patients with
CSU should help in the evaluation of this thesis. In all, the
development of the anti-IgE therapy has provided a badly
needed therapy for those patients with CU who cannot be
adequately treated with existing standard care. Furthermore,
studies with omalizumab are also advancing our understanding
of the disease process of CU.
CHANG ET AL 341
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342.e2 CHANG ET AL
J ALLERGY CLIN IMMUNOL
FEBRUARY 2015
TABLE E1. Case reports, case series, and clinical trials of omalizumab in patients with CSU
Patients
3 with CSU (2 autoimmune)
12 with CSU
1 with CSU
1 CSU
8 with CSU
1 with CSU
2 with CSU
2 with CSU
3 with CSU
9 with CSU
9 with nonautoimmune CSU
49 with CSU, with IgE anti-TPO
(phase II trial)
5 with CSU
90 with CSU (phase II trial)
14 (2 with chronic angioedema)
19 (6 with CSU, 1 delayed pressure)
51 with CSU
16 with severe CSU
323 with CSU (phase III trial)
14 (3 autoimmune)
15 with CSU
336 with CSU (phase III trial)
110 with CSU (real-life
practice collection)
19 with CSU
1 (CSU 1 CIndU)
Omalizumab treatments
Varying dosages every 2 wk
Ranging from 150 mg every 4 wk to 300 mg every
2 wk; 16 wk
300 mg every 4 wk; 8 wk
150 mg every 4 wk; for 12 mo
Ranging from 150 mg every 4 wk to 300 mg
every 2 wk
300 mg every 2 wk for 6 mo
150 or 300 mg every 4 wk for 32 wk
Ranging from 150 mg every 4 wk to 300 mg
every 2 wk
300 mg every 4 wk for 16 wk
Ranging from 150 mg every 4 wk to 300 mg
every 2 wk
300 mg bimonthly, monthly, or every 3 mo
Two treatment groups (placebo and OM between
75-375 mg every 2 wk or every 4 wk) for 24 wk
300 mg every 2 wk or every 4 wk
Four groups (placebo and 75, 300, and 600 mg;
single dose)
Ranging from 150 mg every 4 wk to 375 mg every
2 wk for 6 mo
150 mg every 2 wk for 1 y
Ranging from 150 mg every 2 wk to 300 mg every
4 wk for 8 wk
150 mg every 2 wk or every 4 wk for various
periods
Four groups (placebo or 75, 150, or 300 mg OM
every 4 wk) for 12 wk
150 mg every 4 wk, 300 mg every 2 wk, or 300 mg
every 4 wk; for 2-37 mo
Ranging from 150 mg every 4 wk to 350 mg every
4 wk for 6 mo
Two groups (placebo and OM 300 mg every 4 wk
for 24 wk)
150 mg every 4 wk or 300 mg every 4 wk for
various periods
Ranging from 150 mg every 2 wk to 300 mg every
4 wk for 1-16 mo
150 mg every 4 wk or 150 mg every 2 wk
Results
Reference
All CR
7 CR, 4 PR, 1 NR
Spector and TanE1
Kaplan et alE2
Positive response
Positive response
Seven positive responses
GodseE3
Maspero et alE4
Magerl et alE5
Positive response
Both positive responses
Both positive responses
Iemoli et alE6
Vestergaard et alE7
Romano et alE8
All positive response
All positive response
Al-AhmadE9
Groffik et alE10
All positive response
Significant improvement
in OM group
All positive response
Significant improvement
in 300- and 600-mg groups
All positive response
Ferrer et alE11
Maurer et alE12
58% CR, 26% PR, 16% NR
83% CR, 10% PR, 7% NR
(30 CAU)
88% positive response
Ivyanskiy et alE16
Metz et alE17
Significant improvement in
150- and 300-mg groups
93% positive response
Maurer et alE19
Lefevre et alE20
87% CR or PR
Armengot-Carbo et alE21
Significant improvement
in OM group
82% CR, 11% PR, 7% NR
Kaplan et alE22
Labrador-Horrillo et alE23
47% CR, 42% PR, 11% NR
Viswanathan et alE24
CR
Vieira Dos Santos et alE25
GodseE13
Saini et alE14
Buyukozturk et alE15
Song et alE18
The order of the list is according to the publication dates of the studies.
CAU, Chronic autoimmune urticaria; CIndU, chronic inducible urticaria; CR, complete response; NR, no response; OM, omalizumab; PR, partial response.