Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase.
ABSTRACT A subgroup of patients with chronic spontaneous urticaria (CU) exhibits IgE antibodies directed against autoantigens, such as thyroperoxidase (TPO). We conducted this study to investigate whether such patients with CU with IgE against TPO benefit from treatment with omalizumab, a humanized anti-IgE mAb licensed for the treatment of severe persistent allergic (IgE-mediated) asthma.
We sought to assess the efficacy of omalizumab treatment in patients with CU with IgE autoantibodies against TPO.
In this multicenter, randomized, double-blind, placebo-controlled study patients with CU (male/female, 18-70 years of age) with IgE autoantibodies against TPO who had persistent symptoms (wheals and pruritus) despite standard antihistamine therapy were randomized to receive either omalizumab (75-375 mg, dose determined by using the approved asthma dosing table) or placebo subcutaneously once every 2 or 4 weeks for 24 weeks. The primary end point was the change from baseline in mean weekly urticaria activity score after 24 weeks of treatment, as calculated from patients' diaries. The safety and tolerability of omalizumab were also assessed.
Of the 49 randomized patients (omalizumab, n = 27; placebo, n = 22), 42 completed the study. At week 24, patients demonstrated a mean reduction in the weekly urticaria activity score from baseline of 17.8 with omalizumab and 7.9 with placebo (P = .0089). Complete protection from wheal development was observed in 19 (70.4%) patients in the omalizumab group compared with only 1 (4.5%) patient in the placebo group. The rate of adverse events was similar in both groups.
The results of this study indicate that omalizumab is an effective treatment option for patients with CU with IgE autoantibodies against TPO who are refractory to conventional treatment.
- SourceAvailable from: Torsten Zuberbier[show abstract] [hide abstract]
ABSTRACT: This guideline, together with its sister guideline on the management of urticaria [Zuberbier T, Asero R, Bindslev-Jensen C, Canonica GW, Church MK, Giménez-Arnau AM et al. EAACI/GA(2)LEN/EDF/WAO Guideline: Management of urticaria. Allergy, 2009; 64:1427-1443] is the result of a consensus reached during a panel discussion at the 3rd International Consensus Meeting on Urticaria, Urticaria 2008, a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2)LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO). Urticaria is a frequent disease. The life-time prevalence for any subtype of urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria do not only cause a decrease in quality of life, but also affect performance at work and school and, as such, are members of the group of severe allergic diseases. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors, and pathomechanisms. In addition, it outlines evidence-based diagnostic approaches for different subtypes of urticaria. The correct management of urticaria, which is of paramount importance for patients, is very complex and is consequently covered in a separate guideline developed during the same consensus meeting. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS).Allergy 10/2009; 64(10):1417-26. · 5.88 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: This guideline, together with its sister guideline on the classification of urticaria (Zuberbier T, Asero R, Bindslev-Jensen C, Canonica GW, Church MK, Giménez-Arnau AM et al. EAACI/GA(2)LEN/EDF/WAO Guideline: definition, classification and diagnosis of urticaria. Allergy 2009;64: 1417-1426), is the result of a consensus reached during a panel discussion at the Third International Consensus Meeting on Urticaria, Urticaria 2008, a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2)LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO). As members of the panel, the authors had prepared their suggestions regarding management of urticaria before the meeting. The draft of the guideline took into account all available evidence in the literature (including Medline and Embase searches and hand searches of abstracts at international allergy congresses in 2004-2008) and was based on the existing consensus reports of the first and the second symposia in 2000 and 2004. These suggestions were then discussed in detail among the panel members and with the over 200 international specialists of the meeting to achieve a consensus using a simple voting system where appropriate. Urticaria has a profound impact on the quality of life and effective treatment is, therefore, required. The recommended first line treatment is new generation, nonsedating H(1)-antihistamines. If standard dosing is not effective, increasing the dosage up to four-fold is recommended. For patients who do not respond to a four-fold increase in dosage of nonsedating H(1)-antihistamines, it is recommended that second-line therapies should be added to the antihistamine treatment. In the choice of second-line treatment, both their costs and risk/benefit profiles are most important to consider. Corticosteroids are not recommended for long-term treatment due to their unavoidable severe adverse effects. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS).Allergy 10/2009; 64(10):1427-43. · 5.88 Impact Factor
- New England Journal of Medicine 02/2002; 346(3):175-9. · 51.66 Impact Factor
Efficacy and safety of omalizumab in patients with chronic
urticaria who exhibit IgE against thyroperoxidase
Marcus Maurer, MD,aSabine Altrichter, MD,aThomas Bieber, MD,bTilo Biedermann, MD,cMatthias Br€ autigam, PhD,d
Stefan Seyfried, PhD,eRandolf Brehler, MD,fJ€ urgen Grabbe, MD,gNicolas Hunzelmann, MD,hThilo Jakob, MD,i
Andreas Jung, MD,jJ€ org Kleine-Tebbe, MD,kMartin Mempel, MD,lMichael Meurer, MD,mKristian Reich, MD,n
Franziska Ru€ eff, MD,oKnut Sch€ akel, MD,pKaushik Sengupta, BDS, MScD,qChristian Sieder, MSc,dJan C. Simon, MD,r
Bettina Wedi, MD,sTorsten Zuberbier, MD,aVera Mahler, MD,tand Petra Staubach, MDu
M€ unster, L€ ubeck, K€ oln, Freiburg, Gießen, G€ ottingen, Munich, Dresden, Hamburg, Heidelberg, Leipzig, Hannover, Erlangen, and Mainz,
Germany, Basel, Switzerland, and Hyderabad, India
Berlin, Bonn, T€ ubingen, N€ urnberg,
Background: A subgroup of patients with chronic spontaneous
urticaria (CU) exhibits IgE antibodies directed against
autoantigens, such as thyroperoxidase (TPO). We conducted
this study to investigate whether such patients with CU with IgE
against TPO benefit from treatment with omalizumab, a
humanized anti-IgE mAb licensed for the treatment of severe
persistent allergic (IgE-mediated) asthma.
Objectives: We sought to assess the efficacy of omalizumab
treatment in patients with CU with IgE autoantibodies against
Methods: In this multicenter, randomized, double-blind,
placebo-controlled study patients with CU (male/female, 18-70
years of age) with IgE autoantibodies against TPO who had
persistent symptoms (wheals and pruritus) despite standard
antihistamine therapy were randomized to receive either
omalizumab (75-375 mg, dose determined by using the
approved asthma dosing table) or placebo subcutaneously once
every 2 or 4 weeks for 24 weeks. The primary end point was the
change from baseline in mean weekly urticaria activity score
after 24 weeks of treatment, as calculated from patients’
diaries. The safety and tolerability of omalizumab were also
Results: Of the 49 randomized patients (omalizumab, n 5 27;
placebo, n 5 22), 42 completed the study. At week 24, patients
demonstrated a mean reduction in the weekly urticaria activity
score from baseline of 17.8 with omalizumab and 7.9 with placebo
(P 5.0089). Complete protection from wheal development was
observed in 19 (70.4%) patients in the omalizumab group
of adverse events was similar in both groups.
Conclusions: The results of this study indicate that omalizumab
is an effective treatment option for patients with CU with IgE
autoantibodies against TPO who are refractory to conventional
treatment. (J Allergy Clin Immunol 2011;128:202-9.)
Key words: Urticaria, wheals, pruritus, mast cells, anti-IgE, anti-
disease characterized by recurrent, itchy, wheal and flare–type
skin reactions; angioedema; or both.1H1-antihistamines are the
mainstay of symptomatic therapy. However, less than half of pa-
tients with CU achieve sufficient symptom control with antihista-
mines at standard doses, the only licensed treatment for CU.2,3
CU symptoms are brought about by the degranulation of skin
mast cells. During the past decade, several mechanisms of mast
cell activation in CU have been identified. For example, IgG
autoantibodies directed against IgE, which are detectable in a
subset of patients with CU, can cause cross-linking of mast cell–
bound IgE and subsequent mast cell degranulation.4,5Another
subgroup of patients with CU exhibits IgG autoantibodies di-
rected against the a-subunit of the high-affinity IgE receptor
FceRI on mast cells.4,6,7Very recently, we have identified a sub-
group ofpatients with CUwho exhibit IgE autoantibodies against
thyroperoxidase (TPO), and IgE antibodies against TPO (IgE–
anti-TPO)–positive patients with CU exhibit significantly higher
Dermatologie, Venerologie und Allergologie, Berlin;bUniversit€ atsklinikum Bonn,
Klinik und Poliklinik f€ ur Dermatologie und Allergologie, Bonn;cUniversit€ ats-Haut-
klinik,EberhardKarlsUniversityT€ ubingen;dNovartisPharmaAG,N€ urnberg;eNovar-
tis Pharma AG, Basel;
Hautkrankheiten,M€ unster;gUniversit€ atsklinikumSchleswig-Holstein,Klinikf€ urDer-
matologie,VenerologieundAllergologie,L€ ubeck;hKlinikundPoliklinikf€ urDermato-
logie und Venerologie des Universit€ atsklinikums K€ oln;iAllergy Research Group,
Department of Dermatology, University Medical Center Freiburg, Freiburg;jZentrum
der Dermatologie und Andrologie (Hautklinik), Universit€ atsklinikum Gießen und
Marburg GmbH, Gießen;kUntersuchungszentrum Dermatologie, Allergologie und
Asthma (UZDAA), Berlin;
pUniversit€ ats-Hautklinik, Universit€ atsklinikum Heidelberg, Heidelberg;
Healthcare Pvt Ltd, Hyderabad;rKlinik f€ ur Dermatologie,Venerologie und Allergolo-
gie, Universit€ atsklinikum Leipzig A€ oR, Leipzig;stheDepartment ofDermatology and
Allergy, Hannover Medical School, Hannover;
aCharit? e–Universit€ atsmedizin Berlin, Allergie-Centrum-Charit? e, Klinik f€ ur
fUniversit€ atsklinikum M€ unster, Klinik und Poliklinik f€ ur
lthe Department of Dermatology, Venereology, UMG
mUniversit€ ats Allergie Centrum Dresden, Klinik und Poliklinik f€ ur
oKlinik und Poliklinik f€ ur
tthe Department of Dermatology,
University Hospital Erlangen; anduthe University Medical Center of the Johannes
Gutenberg-University Mainz, Department of Dermatology and Allergy, Mainz.
Sponsored by Novartis Pharma GmbH, Germany.
B. Wedi receive research support from Novartis. M. Br€ autigam, S. Seyfried, and
K. Sengupta are Novartis employees. R. Brehler, M. Maurer, and K. Sch€ akel received
honoraria for lectures and research support from Novartis. T. Zuberbier has recieved
honoraria for consulting for Novartis. The rest of the authors have declared that they
have no conflict of interest.
Received for publication September 1, 2010; revised March 22, 2011; accepted for pub-
lication April 1, 2011.
Available online June 6, 2011.
Reprint requests: Marcus Maurer, MD, Allergie-Centrum-Charit? e, Department of Der-
matology and Allergy, Charit? e–Universit€ atsmedizin Berlin, Charit? eplatz 1, 10117
Berlin, Germany. E-mail: firstname.lastname@example.org.
? 2011 American Academy of Allergy, Asthma & Immunology
AE: Adverse event
AUC: Area under the curve
CU: Chronic spontaneous urticaria
CU-Q2oL: Chronic Urticaria Quality of Life Questionnaire
DLQI: Dermatological Life Quality Index
EAACI: European Academy of Allergology and Clinical
EDF: European Dermatology Forum
GA2LEN: Global Allergy and Asthma European Network
IgE–anti-TPO: IgE antibodies against TPO
UAS: Urticaria activity score
UAS7: Weekly urticaria activity score
WAO: World Allergy Organization
C4 complement levels.8
Omalizumab isa recombinant humanizedmAbthatselectively
binds to the C3 domain of the IgE heavy chain (ie, the site where
serum.9,10In addition, because occupancy of FceRI by IgE deter-
mines the levels of surface FceRI expression, reduced binding of
IgE to FceRI leads to a downregulation of FceRI expression on
mast cells and basophils.11-13Thus in patients with CU with
IgE antibodies against TPO, omalizumab could reduce or inhibit
mast cell activation by reducing the levels of these IgE autoanti-
bodies, decreasing IgE receptor density on cutaneous mast cells,
or both. Therefore the present study was conducted to assess the
efficacy of omalizumab in patients with CU who exhibit IgE an-
tibodies against TPO. In addition, the safety and tolerability of
omalizumab were also assessed.
Male and female patients aged 18 to 70 years with a clinical diagnosis of
moderate-to-severe CU (as classified by the latest consensus guidelines from
the European Academy of Allergology and Clinical Immunology [EAACI],
the Global Allergy and Asthma European Network [GA2LEN], the European
Dermatology Forum [EDF], and the World Allergy Organization [WAO]1; ie,
those with persistent symptoms for > _6 weeks despite receiving maximal in-
label antihistamine therapy) at screening, body weight between 20 and 150
kg, a total serum IgE level between 30 IU/mL or greater and 700 IU/mL or
less, a specific serum IgE–anti-TPO antibody level of 5.0 IU/mL or greater
within the last 3 months before randomization, and a weekly urticaria activ-
ity score (UAS) of 10 or greater at the end of screening were eligible for en-
rollment in the study. Serum IgE–anti-TPO levels were determined by using
a site-directed human IgE capture ELISA, as previously described.8The
UAS is a composite scoring system based on the patient’s diary by using nu-
meric severity ratings from 0 to 3 (0, none; 3, intense) for the number of
wheals per 24 hours and the intensity of pruritus. The total daily score
(sum of the wheal and pruritus scores) could therefore assume any value
between 0 and 6.1,14
Patients were excluded from the study if they had acute urticaria, chronic
diarrhea, severe renal dysfunction, or increased serum IgE levels for reasons
other than allergy or urticaria. Patients with a history of epilepsy, allergy to
antibiotics, malignancy within the past 5 years, or cerebrovascular attacks or
ischemia or who had taken oral or parenteral corticosteroids, methotrexate,
cyclosporine, or other immunosuppressant medications during the 4 weeks
before screening were also excluded.
Study design and treatments
This randomized, double-blind, placebo-controlled, parallel-group study
was conducted at 16 centers in Germany. It was approved by the ethics
with the International Conference on Harmonisation Guidelines for Good
Clinical Practice, the ethical principles embodied in the Declaration of
Helsinki (1989), and applicable local regulations. Written informed consent
was obtained from all patients before their participation in the study.
The study comprised a prescreening visit, a 3-week screening period
(divided into 2 phases), and a 24-week double-blind treatment period. At the
prescreening visit,informedconsentwas obtained,and patientswere assessed
for eligibility. Patients received 10 mg/d loratadine and 1 mg clemastine as
rescue medication (maximum of 3 tablets per day) for 1 week during the first
phase of the screening period to select for patients with CU with symptoms
Patients demonstrating uncontrolled disease activity (UAS >0) during any of
these 7 days were subsequently entered into the second phase of screening,
during which they received antihistamines (10 mg of loratadine on demand
and, if still symptomatic, up to 3 tablets of 1 mg/d clemastine) for 2 weeks.
Those demonstrating a weekly UAS of 10 or greater at the end of the second
phase of screening were subsequently entered into the randomized, double-
blind treatment period.
At baseline, eligible patients were randomized (1:1) to treatment with
omalizumab or placebo. Randomization was performed by using a validated
system that automated the random assignment of the treatments to random-
ization numbers in the specified ratio. Omalizumab (75-375 mg) or placebo
was administered subcutaneously once every 2 or 4 weeks for 24 weeks. The
doses were individualized for the patients based on their body weights and
dosing table for omalizumab.15Treatment allocation was concealed from the
patients, investigating staff, and clinical trial team by using study drugs that
were identical in packaging, labeling, schedule of administration, and
No medications other than H1-blocking antihistamines, such as 10 mg of
loratadine on demand and 1 mg of clemastine as rescue medication, were
During the screening and treatment periods, patients were asked to record
daily scores (based on duration, size, number, and/or intensity) for wheals,
(loratadine and clemastine) by using a paper diary.
Efficacy assessments included calculation of UAS from the patients’ dia-
ries. Because of frequent variations in disease intensity during the course of
a day, the assessment of overall disease activity was based on a weekly aggre-
gate UAS (ie, the sum of the daily UAS self-evaluation scores of 7 individual
days, which could range between 0 and 42 per week, as described previ-
ously).16,17The primary efficacy end point was the change from baseline in
mean weekly UAS after 24 weeks of treatment. Secondary efficacy end points
daily scores for wheals, pruritus, erythema, and angioedema; use of concom-
itant medication; and the patient’s and investigator’s global assessment of
symptoms using a graded Likert scale (0, none; 1, mild; 2, moderate; and 3,
severe). In addition, the patient’s health-related quality of life was evaluated
ity Index (DLQI),18Skindex-29,19and the Chronic Urticaria Quality of Life
Questionnaire (Cu-Q2oL).20The DLQI is a compact questionnaire consisting
of 10 items under 6 headings: symptoms and feelings, daily activities, leisure,
work/school, personal relationships, and treatment. Each item is scored on a
4-point scale ranging from 0 to 3. An overall DLQI score (range, 0-30) is cal-
culated by summing the scores for each item. A higher score is considered an
indicator of greater impairment in health-related quality of life.18Skindex-29
social functioning, and emotional state. An overall quality-of-life index score
(range, 0-100) is obtained by adding the scores from the 3 domains, with
higher scores indicating poorer quality of life.19Although the DLQI and
J ALLERGY CLIN IMMUNOL
VOLUME 128, NUMBER 1
MAURER ET AL 203
Skindex-29 are instruments used to measure the health-related quality of life
of any dermatology patient, the Cu-Q2oL has been specifically developed for
use in patients with CU and encompasses the physical, emotional, social, and
practical domains that characterize this condition. The German version of the
Cu-Q2oL consists of 23 items categorized under the following scales: limits
looks, swelling/eating, functioning, sleep, mental status, and itching/embar-
rassment.20,21Each item is scored on a 5-point Likert-type scale.
Safety assessments included the recording of adverse events (AEs) and
serious AEs, along with evaluationof their severity, duration, and relationship
to the study drug. In addition, urinalysis, regular monitoring of hematology
body weight were performed.
This trial was designed as a proof-of-concept trial with a clear focus on
power by using a 2-sided 5% significance level if the treatment effect (ie, the
difference between the treatment groups) was at least as large as its SD
(standardized effect size, >1). This was considered a very large effect.
All efficacy analyses were performed on the intention-to-treat population,
which included all randomized patients who received at least 1 dose of study
drug and had postrandomization primary efficacy data. Demographic and
baseline characteristics were summarized for all patients in the safety
population, which consisted of all patients who received at least 1 dose of
randomized study drug and had at least 1 postbaseline safety assessment. The
primary end point (mean weekly UAS) was evaluated by using an analysis of
covariance model with the factors of treatment and center and with the
baseline score as the covariate. For the treatment contrast between omalizu-
mab and placebo, a 95% CI and a 2-sided P value were calculated.
Similar analysis of covariance models were used to analyze the standard-
ized UAS AUC and the daily scores for wheals, pruritus, erythema, and
angioedema. The other secondary variables (the DLQI, Skindex-29, and
Cu-Q2oL questionnaires; concomitant and rescue medication use; and the
patient’s and investigator’s global symptom assessments) were summarized
descriptively. AEs, laboratory data, and measurements of vital signs were
summarized descriptively by treatment group. Data were analyzed with
SAS version 8.2 statistical software for Windows (SAS Institute, Inc,
Patient disposition is presented in Fig 1. Between May 2007
and May 2009, 341 patients were screened for this study; of those
were screened but not randomized were not included in the study
specific serum IgE–anti-TPO antibody levels were less than
5.0 IU/mL, the recruitment of patients for the study was stopped,
assigned medication, and no patient received the study drug in
error; thus the safety population was identical to the intention-
to-treat population. Forty-two (85.7%) patients completed the
study. Major protocol deviations were reported in 18 (36%)
patients, which mainly consisted of premature discontinuations
(Fig 1), lost diary data (n 5 6), or deviations from the visit
schedule (n 5 5). Table I represents the demographics and base-
line clinical characteristics of all randomized patients. The mean
ageofall patients was40.5years. Allpatientswerewhite, and the
majority (77.6%) of them were female. The mean IgE–anti-TPO
antibody level was 6.9 6 4.25 IU/mL.
Patients experienced a reduction in UAS7 scores from baseline
squares means); the difference of 9.9 points between treatment
groups was statistically significant (95% CI, 2.7-17.1; P 5.0089)
and clinically relevant (Fig 2, A). The actual UAS7 values (means
FIG 1. Organizational flow chart.
J ALLERGY CLIN IMMUNOL
204 MAURER ET AL
6 SDs) for the omalizumab group were 24.6 6 7.4 at baseline
line and 15.5 6 11.0 after treatment). Fig 2, B, shows the mean
daily UASs over the 24-week treatment period. In contrast to pla-
cebo, those receiving omalizumab experienced a marked reduc-
tion in UAS during the first week of therapy, and the mean
UASs in the omalizumab group continued to decrease through
week 24 (day 169). The standardized UAS AUC over 24 weeks
was significantly lower for omalizumab than placebo (P <.001).
The number and intensity of wheals, pruritus, erythema, and
Online Repository at www.jacionline.org). After week 24, pa-
tients receiving omalizumab demonstrated a significant reduction
in the score for wheals (least squares mean, 29.2 vs 23.3; P 5
.0019), and a complete protection from wheal development was
observed in 19 (70.4%) patients in the omalizumab group com-
pared with only 1 (4.5%) patient in the placebo group. Similarly,
complete absence of pruritus, erythema, and angioedema was ob-
tively, in the omalizumab group compared with only 2 (9.1%), 4
(18.2%), and 8 (36.4%) patients, respectively, in the placebo
Treatment with omalizumab resulted in a substantial decrease
in mean concomitant medication use, from 2.9 loratadine tablets
and 6 clemastine tablets taken in the 7 days before randomization
to 0.3 loratadine tablets and 0.7 clemastine tablets taken during
week 24 (see Fig E1 in this article’s Online Repository at www.
jacionline.org). The corresponding values in the placebo group
for loratadine and clemastine use were 3.5 and 6.1, respectively,
in the 7 days before randomization and 3.3 and 1.4, respectively,
at week 24 (Fig E1).
According to patients’ global assessments of symptoms, 59%
of those in the omalizumab group reported being symptom free at
the end of the study compared with 14% in the placebo group
(Fig 3). The investigator’s global assessment of the patients’
symptoms corroborated the patients’ own assessment of symp-
toms. Substantial differences were again apparent between the
2 treatment groups; 67% of patients receiving omalizumab were
assessed as having achieved a complete resolution of urticaria-
related symptoms after week 24 compared with 4% of placebo
recipients (Fig 3).
Fig 4 and Figs E2 and E3 (available in this article’s Online Re-
in the quality of life of the study participants as measured by the
revealed a significantly greater improvement of quality-of-life for
patients receiving omalizumab compared with placebo (P <.01).
The overall incidence of AEs during the treatment phase was
81.5% (22/27) with omalizumab compared with 86.4% (19/22)
with placebo. The most frequent AEs (>5% of all AEs) were
diarrhea (omalizumab, n 5 4 [14.8%]; placebo, n 5 2 [9.1%]),
nasopharyngitis (omalizumab, n 5 9 [33.3%]; placebo, n 5 11
[50%]), and headache (omalizumab, n 5 10 [37%]; placebo, n 5
6 [27.3%]). The incidence of suspected drug-related AEs was
similar between those receiving omalizumab and placebo (22.2%
and 22.7%, respectively). One patient receiving placebo experi-
enced SAEs (eye infection and angioedema) during the treatment
phase and was withdrawn from the study. There were no deaths
reported during the study. The number of patients with notable
was no evidence of any clinically meaningful trends in the
laboratory estimates or vital signs associated with omalizumab
An increasing number of reports demonstrating the utility of
omalizumab in patients with refractory CU have appeared
recently in the medical literature.22,23However, the majority of
these are observational case reports and uncontrolled studies in-
volving relatively few patients. We explored the clinical efficacy
and safety of omalizumab in patients with CU exhibiting IgE
against TPO by using a randomized, double-blind, placebo-con-
trolled study design. The dose and dosing frequency of omalizu-
mab were based on the total serum IgE level and body weight,
which is consistent with those used for patients with allergic
asthma eligible for omalizumab therapy. The results of this study
showed that omalizumab significantly reduced disease activity,
decreased the need for additional medication to control symp-
toms, and improved patients’ health-related quality of life.
The significant benefit observed in IgE–anti-TPO–positive
patients with CU treated with anti-IgE suggests that IgE–anti-
TPO is critical for the development of urticarial symptoms in
thesepatients and thatanti-IgEprotects fromurticarial symptoms
by reducing IgE–anti-TPO autoantibodies. Further studies, such
as skin testing or mast cell activation studies, are needed to
confirm and prove that IgE–anti-TPO does induce mast cell
degranulation and urticarial symptoms. Further studies are also
needed to test IgE–anti-TPO–negative patients with urticaria for
their response to anti-IgE treatment and to explain the mecha-
nisms and speed of action of anti-IgE in IgE–anti-TPO–positive
patients with CU. The current EAACI/GA2LEN/EDF/WAO
guidelines1recommend assessing disease activity in patients
with CU by using 24-hour self-evaluation scores based on the
lizumab in this study was 3 times that of placebo. A decrease in
UASs was observed during the first week of therapy and contin-
ued until the end of the study. This rapid improvement in disease
activity was observed in previous studies as well. Significant
clearing of urticaria within 1 week of starting omalizumab ther-
apy was reported by Spector and Tan24in patients with refractory
CU who had earlier received different combinations of antihista-
with little or no success. In this case series, however, omalizumab
TABLE I. Patients’ demographics and baseline characteristics
(n 5 27)
(n 5 22)
Age (y), mean 6 SD (range)
Sex, no. (%)
Race, no. (%), white
Height (cm), mean 6 SD (range)
39.1 6 9.0 (24-57) 42.3 6 15.0 (20-69)
171.0 6 7.2
81.9 6 20.2
164.1 6 6.6
71.2 6 12.4
Weight (kg), mean 6 SD (range)
IgE–anti-TPO (IU/mL), mean 6 SD
Total IgE (IU/mL), mean 6 SD
7.3 6 4.6
211 6 158
6.2 6 3.7
181 6 136
J ALLERGY CLIN IMMUNOL
VOLUME 128, NUMBER 1
MAURER ET AL 205
was used at higher doses than recommended in patients with
In this study, in addition to significant reductions in weekly
UASs, omalizumab resulted in complete protection against the
appearance of wheals in 70% of the treated patients based on data
from the patients’ diaries. Similar observations were made with
regard to the complete resolution of pruritus, erythema, and angi-
oedema. In addition, according to the patients’ global assessment
of symptoms, more than half of those in the omalizumab group
weresymptom free attheend ofthestudy comparedwith approx-
imately one tenth of those in the placebo group. These observa-
tions were paralleled by the investigator’s global assessment of
symptoms. Kaplan et al25studied the effects of omalizumab in
12 patients with chronic autoimmune urticaria refractory to anti-
complete remission by the end of the 16-week treatment period.
10 years,26the first injection of omalizumab yielded 90% control
of symptoms, and after the second injection, which was adminis-
tered 4 weeks after the first, the patient was totally symptom free.
The frequency of use of rescue medication for symptomatic
relief provides an indication of the degree of clinical impairment.
use from baseline to the conclusion of their study in patients re-
ceiving omalizumab(P 5.004). In our study treatment with oma-
lizumab markedly reduced the burden of repeated rescue
medication use. The use of omalizumab was associated with an
overall reduction in the use of loratadine and clemastine from 3
and 6 times, respectively, per week at the beginning of the study
to less than once a week at the end of the treatment period.
Available data suggest that CU has a detrimental effect on both
objective functioning and subjective well-being.2Furthermore,
both health status and subjective satisfaction are lower in patients
with CU than in healthy subjects and patients with respiratory
FIG 2. A, Change in UASs after 24 weeks of treatment. Difference between omalizumab and placebo 5 29.9
(95% CI, 2.7-17.1). Population for analysis: intention-to-treat population. Analysis of covariance model:
variables 5 baseline, center, and treatment. Least squares mean after adjusting the covariates, such as
center, baseline value, and treatment group. B, Mean daily UAS. The standardized UAS over 24 weeks
was significantly lower for omalizumab than placebo (P 5 .0002). Population for analysis: intention-to-
J ALLERGY CLIN IMMUNOL
206 MAURER ET AL
allergies.27By providing rapid control of symptoms and decreas-
ing the burden of additional medications, omalizumab can pro-
vide benefits that are relevant to patients, offering them the
prospect of significant amelioration of their disease experience.
Indeed, assessment of health-related quality of life by using eval-
uative instruments specifically designed for skin diseases, such as
the DLQI and Skindex-29, suggested that the observed clinical
benefits with omalizumab might translate into improvements in
the patients’ quality of life. In particular, the DLQI and Skindex
assessments revealed a significantly greater improvement of
45% to 50% in the quality of life of patients receiving
omalizumab compared with 6% to 11% in those receiving pla-
cebo. Similar improvements in the functional capacity and
well-being of patients with CU have been demonstrated previ-
ously by using the DLQI25and Skindex-2928questionnaires.
A banding system has been suggested to assist the clinical
interpretation of DLQI scores.29Based on this system, in the cur-
rent study omalizumab decreased the influence of CU on the
patients’ lives from a very large effect to a small one. On the con-
trary, there was no such change in patients receiving placebo.
Moreover, in patients with CU, a difference in overall DLQI
FIG 3. Patients’ and investigator’s global assessment of symptoms at study’s end. Population for analysis:
FIG 4. Percentage improvement in quality of life (QoL). Population for analysis: intention-to-treat
J ALLERGY CLIN IMMUNOL
VOLUME 128, NUMBER 1
MAURER ET AL 207
4.8, which exceeded the minimum clinically important differ-
ence. In addition, assessment of the effect of treatment on the in-
dividual Skindex-29 domains also demonstrated that all scores
were significantly improved after 24 weeks of treatment with
omalizumab in contrast to placebo, with the degree of improve-
ment of functional impairment being similar to the improvement
in the burden on symptoms and emotions.
In addition to the DLQI and Skindex questionnaires, a disease-
specific questionnaire, namely CU-Q2oL, was used in this study.
The results observed with the CU-Q2oL questionnaire (55%
improvement with omalizumab vs 6% with placebo) were similar
a significant enhancement in the overall quality of life of patients
those treated with placebo. Interestingly, the distribution of the
different CU-Q2oL domain scores indicated that the extent of
improvement with omalizumab was of a higher magnitude on the
functioning and itching/embarrassment item bundles than on the
other scales. Each of the CU-Q2oL scales discriminated clearly
between omalizumab and placebo, with the effect sizes for
omalizumab being markedly superior to those for placebo.
In terms of overall safety, all treatments in this study were safe
and well tolerated. The overall rate of AEs was comparable
between omalizumab and placebo. The most frequent AEs were
nasopharyngitis, diarrhea, and headache. In patients with allergic
airway disease, local injection-site symptoms, most commonly
bruising and itching, and anaphylaxis, presenting as broncho-
such AEs in this study was very low or nil. In addition, therewere
or any clinically relevant differences in vital signs between the
the effect of omalizumab across all defined outcome measures,
which underlines the internal validity of the study and suggests
that omalizumab might be a useful therapeutic option in patients
with CU with high levels of IgE–anti-TPO autoantibodies.
Other related clinical scenarios in which omalizumab has shown
promise include cold urticaria,33cholinergic urticaria,34solar
urticaria,35,36heat urticaria,37,38and symptomatic dermogra-
phisms.39However, it should be emphasized that omalizumab is
and thepotentialsideeffects of thismedication,includingtherisk
for anaphylaxis, should be evaluated thoroughly.22
In conclusion, the results of this study demonstrate that
omalizumab is an effective treatment option for patients with
CU. In addition, omalizumab had a good overall safety and
tolerability profile in these patients. The results of this study
EDF guidelines2to use omalizumab in the treatment of patients
with CU who do not sufficiently respond to standard therapy.
We thank Jodie Urcioli for proofreading the manuscript.
Clinical implications: Omalizumab shows strong efficacy and a
very good safety profile in the treatment of patients with CU
with IgE autoantibodies against TPO.
1. Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK,
Gimenez-Arnau AM, et al. EAACI/GA2LEN/EDF/WAO guideline: definition,
classification and diagnosis of urticaria. Allergy 2009;64:1417-26.
2. Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK,
Gimenez-Arnau AM, et al. EAACI/GA2LEN/EDF/WAO guideline: manage-
ment of urticaria. Allergy 2009;64:1427-43.
3. Kaplan AP. Clinical practice. Chronic urticaria and angioedema. N Engl J Med
4. Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy Clin Immunol
5. Goh CL, Tan KT. Chronic autoimmune urticaria: Where we stand? Indian J Der-
6. Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW. Autoanti-
bodies against the high-affinity IgE receptor as a cause of histamine release in
chronic urticaria. N Engl J Med 1993;328:1599-604.
7. Fiebiger E, Maurer D, Holub H, Reininger B, Hartmann G, Woisetschl€ ager M,
et al. Serum IgG autoantibodies directed against the a chain of FceRI: a selective
marker and pathogenetic factor for a distinct subset of chronic urticaria patients?
J Clin Invest 1995;96:2606-12.
8. Altrichter S, Peter HJ, Pisarevskaja D, Metz M, Martus P, Maurer M. IgE mediated
autoallergy against thyroid peroxidase—a novel pathomechanism of chronic
spontaneous urticaria? Plos One 2011;6:e14794.
9. Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. The anti-
inflammatory effects of omalizumab confirm the central role of IgE in allergic
inflammation. J Allergy Clin Immunol 2005;115:459-65.
10. Babu KS, Arshad SH, Holgate ST. Omalizumab, a novel anti-IgE therapy in aller-
gic disorders. Expert Opin Biol Ther 2001;1:1049-58.
11. Chang TW, Shiung YY. Anti-IgE as a mast cell-stabilizing therapeutic agent.
J Allergy Clin Immunol 2006;117:1203-12.
12. MacGlashan D Jr, Xia HZ, Schwartz LB, Gong J. IgE-regulated loss, not IgE-
J Leukocyte Biol 2001;70:207-18.
13. Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced
reductions in mast cell FceRI expression and function. J Allergy Clin Immunol
14. M1ynek A, Zalewska-Janowska A, Martus P, Staubach P, Zuberbier T, Maurer M.
How to assess disease activity in patients with chronic urticaria? Allergy 2008;63:
15. Hochhaus G, Brookman L, Fox H, Johnson C, Matthews J, Ren S, et al. Pharmaco-
dynamics of omalizumab: implications for optimised dosing strategies and clinical
efficacy in the treatment of allergic asthma. Curr Med Res Opin 2003;19:491-8.
16. Grattan CE, O’Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed PT, et al.
Randomized double-blind study of cyclosporin in chronic ‘idiopathic’ urticaria.
Br J Dermatol 2000;143:365-72.
immunoglobulin in autoimmune chronic urticaria. Br J Dermatol 1998;138:101-6.
18. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)—a simple practical
measure for routine clinical use. Clin Exp Dermatol 1994;19:210-6.
19. Chren MM, Lasek RJ, Flocke SA, Zyzanski SJ. Improved discriminative and eval-
uative capability of a refined version of Skindex, a quality-of-life instrument for
patients with skin diseases. Arch Dermatol 1997;133:1433-40.
20. Baiardini I, Pasquali M, Braido F, Fumagalli F, Guerra L, Compalati E, et al. A new
tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria
quality of life questionnaire (CU-QoL). Allergy 2005;60:1073-8.
21. M1ynek A, Magerl M, Hanna M, Lhachimi S, Baiardini I, Canonica GW, et al. The
German version of the chronic urticaria quality-of-life questionnaire: factor analy-
sis, validation, and initial clinical findings. Allergy 2009;64:927-36.
22. Spector SL, Tan RA. Omalizumab also successful in chronic urticaria. J Allergy
Clin Immunol 2008;121:784.
23. Magerl M, Staubach P, Maurer M. Effective treatment of therapy resistant chronic
spontaneous urticaria with omalizumab. J Allergy Clin Immunol 2010;126:665-6.
24. Spector SL, Tan RA. Effect of omalizumab on patients with chronic urticaria. Ann
Allergy Asthma Immunol 2007;99:190-3.
25. Kaplan AP, Joseph K, Maykut RJ, Geba GP, Zeldin RK. Treatment of chronic au-
toimmune urticaria with omalizumab. J Allergy Clin Immunol 2008;122:569-73.
26. Godse KV. Omalizumab in severe chronic urticaria. Indian J Dermatol Venereol
27. Baiardini I, Giardini A, Pasquali M, Dignetti P, Guerra L, Specchia C, et al. Quality
of life and patients’ satisfaction in chronic urticaria and respiratory allergy. Allergy
28. Gober LM, Sterba PM, Eckman JA, Saini SS. Effect of anti-IgE (omalizumab)
in chronic idiopathic urticaria (CIU) patients. J Allergy Clin Immunol 2008;
J ALLERGY CLIN IMMUNOL
208 MAURER ET AL
29. Dermatology Life Quality Index. Information and conditions concerning use. Depart-
ment of Dermatology, Cardiff University. Available at: http://www.dermatology.org.
uk/quality/quality-dlqi-info.html. Accessed January 20, 2010.
30. Shikiar R, Harding G, Leahy M, Lennox RD. Minimal Important Difference (MID)
of the Dermatology Life Quality Index (DLQI): results from patients with chronic
idiopathic urticaria. Health Qual Life Outcomes 2005;3:36.
31. Holgate ST, Chuchalin AG, H? ebert J, L€ otvall J, Persson GB, Chung KF, et al. Ef-
ficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab)
in severe allergic asthma. Clin Exp Allergy 2004;34:632-8.
32. British Thoracic Society and Scottish Intercollegiate Guidelines Network. British
guideline on the management of asthma. A national clinical guideline. Thorax
33. Boyce JA. Successful treatment of cold-induced urticaria/anaphylaxis with anti-
IgE. J Allergy Clin Immunol 2006;117:1415-8.
34. Metz M, Bergmann P, Zuberbier T, Maurer M. Successful treatment of cholinergic
urticaria with anti-immunoglobulin E therapy. Allergy 2008;63:247-9.
35. G€ uzelbey O, Ardelean E, Magerl M, Zuberbier T, Maurer M, Metz M. Successful
treatment of solar urticaria with anti-immunoglobulin E therapy. Allergy 2008;63:
36. Waibel KH, Reese DA, Hamilton RG, Devillez RL. Partial improvement of solar
urticaria after omalizumab. J Allergy Clin Immunol 2010;125:490-1.
37. Bullerkotte U, Wieczorek D, Kapp A, Wedi B. Effective treatment of refractory
severe heat urticaria with omalizumab. Allergy 2010;65:931-2.
38. Bindslev-Jensen C, Skov PS. Efficacy of omalizumab in delayed pressure urticaria:
a case report. Allergy 2010;65:138-9.
39. Krause K, Ardelean E, Keßler B, Magerl M, Metz M, Siebenhaar F, et al. Antihis-
tamine-resistant urticaria factitia successfully treated with anti-immunoglobulin
E therapy. Allergy 2010;65:1494-5.
J ALLERGY CLIN IMMUNOL
VOLUME 128, NUMBER 1
MAURER ET AL 209
FIG E1. Reduction in concomitant and rescue medication use from baseline to week 24. Population for
analysis: intention-to-treat population.
J ALLERGY CLIN IMMUNOL
209.e1 MAURER ET AL
FIG E2. Percentage improvement in the quality-of-life subdomains of the
J ALLERGY CLIN IMMUNOL
VOLUME 128, NUMBER 1
MAURER ET AL 209.e2
FIG E3. Percentage improvement in the subdomains of the Cu-Q2oL. Population for analysis: intention-to-
J ALLERGY CLIN IMMUNOL
209.e3 MAURER ET AL
TABLE E1. Number of wheals and episodes of erythema during
week 24 of treatment
Population for analysis: intention-to-treat population; missing assessments not
J ALLERGY CLIN IMMUNOL
VOLUME 128, NUMBER 1
MAURER ET AL 209.e4
TABLE E2. Intensity of pruritus and angioedema during week 24
Population for analysis: intention-to-treat population; missing assessments not
J ALLERGY CLIN IMMUNOL
209.e5 MAURER ET AL