Received: 8 June 2022 Revised: 19 September 2022 Accepted: 11 October 2022

DOI: 10.1111/dth.15928

REVIEW ARTICLE

Comparison between chronic spontaneous urticaria and

chronic induced urticaria on the efficacy of omalizumab
treatment: A systematic review and meta-analysis

Zhu-Han He 1,2 | Shuo-Cheng Qiu 3 | Zhi-Wei Huang 3 | Guo-Qiang Zhang 4,5 |

Qing-Qing An 3 | Feng Qu 1 | Na Wang 1

1
Cancer Institute, The Fourth Hospital of
Hebei Medical University, Shijiazhuang, China Abstract
2
Department of Pharmacology, School of Basic This meta-analysis aimed to assess the efficacy of omalizumab in the treatment of
Medical Sciences, Shandong University, Jinan,
China
refractory-to-antihistamines chronic induced urticaria (CIndU) in comparison with
3
School of Pharmacy, Hebei Medical that of refractory-to-antihistamines chronic spontaneous urticaria (CSU). We
University, Shijiazhuang, China
retrieved interventional studies and observational studies on omalizumab efficacy to
4
Department of Dermatology, The First
Hospital of Hebei Medical University,
CIndU patients and efficacy comparison between CSU and CIndU both refractory to
Shijiazhuang, China H1-antihistamines in electronic databases (accessed till May 2022). The odd ratio
5
Department of Dermatology, Candidate (OR) and 95% confidence interval (CI) was calculated with a random-effect model in
Branch of National Clinical Research Center
for Skin Diseases, Shijiazhuang, China this meta-analysis. The majority of patients with different CIndU subtypes gained
complete or partial response and good safety after omalizumab treatment. A total of
Correspondence
Feng Qu and Na Wang, Cancer Institute, The five studies with 355 CSU patients and 103 CIndU patients were included for the
Fourth Hospital of Hebei Medical University, meta-analysis. There was no significant difference in the efficacy of omalizumab in
Shijiazhuang, China.
Email: qufeng327968@126.com and the treatment of CSU and CIndU (OR -0.83, 95% CI [0.84, 2.21], P > 0.05). Based on
hbykdxwn@163.com the validity of omalizumab in the treatment of various CIndU subtypes and non-
differential efficacy between CSU and CIndU, it is reasonable to list omalizumab as a
third-line treatment of refractory CIndU.

KEYWORDS
chronic induced urticaria, chronic spontaneous urticaria, meta-analysis, omalizumab, systematic
review

1 | I N T RO DU CT I O N (ContactU), and aquagenic urticaria (AquaU) belong to non-physical

Chronic urticaria (CU) is a condition featuring the progress of
wheals, angioedema or both lasting for more than 6 weeks.1 Accord-
ing to the guidelines, CU is divided into two main categories: chronic
spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU).
CSU appears for unknown reasons, whereas CIndU is induced by a
variety of physical or non-physical stimuli. Symptomatic dermo-
graphism (SDerm), heat urticaria (HU), cold contact urticaria (CCU),
delayed-pressure urticaria (DPU), solar urticaria (SU), exercise-
induced urticaria and vibratory angioedema are defined as physical
urticarias, while cholinergic urticaria (CholU), contact urticaria
urticarias.2
The current management for CU aimed to release and prevent
symptom is recommended to use a stepwise approach: standard-
dosed, second-generation H1-antihistamines(sgAHs) as the first-line
therapy3,4 and then updosing sgAHs to four-fold as a second-line
therapy.5 Still and all, more than 50% patients seem to be resistant to
sgAHs.6
Omalizumab (Xolair, Novartis, Switzerland and Genentech, USA),
a recombinant humanized anti-IgE monoclonal antibody, was the first
drug approved by the Food and Drug Administration (FDA) for the
treatment of patients with CSU,7 but not for the treatment of CIndU.

Dermatologic Therapy. 2022;35:e15928. wileyonlinelibrary.com/journal/dth © 2022 Wiley Periodicals LLC. 1 of 11

https://doi.org/10.1111/dth.15928
2 of 11
The European Academy of Allergology and Clinical Immunology/
Global Allergy and Asthma European Network/European Dermatol-
ogy Forum/World Allergy Organization has recommended omalizu-
mab as a third line treatment.8 Although a few studies have reported
that difficult-to-treat CIndU can benefit from omalizumab,3,9–11 the
large-scale trials are rare, and the reference value of the conclusions
obtained is limited.
Therefore, we attempted to review the available evidence of the
efficacy of omalizumab in the treatment of CIndU and compare the
efficacy of omalizumab in both refractory CSU and CIndU by meta-
analysis, in order to determine the rationality of omalizumab in CIndU.
2 | MATERAILS AND METHODS
The main efficacy outcomes, urticaria control test (UCT) and urticarial
activity score over 7 days (UAS7), were used to assess disease control
in all patients with CSU and CIndU.12,13 This meta-analysis was con-
ducted and registered according to the Cochrane Collaboration and
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) (CRD42022338111).
2.1 | Data source and search
From inception to May 2022, we searched published studies with the
terms: (“omalizumab” OR “Xolair”) AND one of the different kinds of
CIndU, such as “systematic dermographism”, as well as (“Chronic
spontaneous urticaria” OR “chronic idiopathic urticaria” OR “CSU”
OR “CIU”) AND (“Chronic inducible urticaria” OR “CIndU”) AND
(“omalizumab” OR “Xolair”) in MEDLINE (via PubMed), Cochrane
Library, Metstr, CNKI, Wanfang Database, and Chinese Biomedical
Literature Database (SinoMed).
2.2 | Inclusion and exclusion criteria
Inclusion criteria were: (1) observational studies and interventional
studies on omalizumab in the treatment of CIndU alone in the system-
atic review; (2) observational studies and interventional studies on
omalizumab in the treatment of both CSU and CIndU in the meta-
analysis; (3) patients diagnosed with CSU or CIndU were unresponsive
to sgAHs and had never previously received omalizumab treatment.
Exclusive criteria: (1) repeatedly published literatures; (2) reviews,
conference abstracts; (3) irrelevant to the research topic; (4) animal
and cell experiments; (5) meta-analysis; (6) case reports (fewer than
five patients); (7) no case data. Language was limited in English or
Chinese.
2.3 | Definition of “outcomes”
The efficacy outcomes of omalizumab in the treatment of patients
with CSU or CIndU were UCT and UAS7. UAS7 reduction of more
HE ET AL.
than 90%, UCT score ≥12 points or the advent of wheals after respec-
tive provocation testing or the advent of symptoms by patient global
assessment in CIndU was defined as “complete response” and UAS7
reduction of less than 90% or a UCT score <12 points was defined as
“incomplete response” when omalizumab was used to treat CSU and
CIndU.14,15
2.4 | Data extraction
Two authors (He and Qiu) extracted the basic information of the origi-
nal studies: the surname of the author, publication year, study design,
duration of intervention, type of disease, sample size and treatment
plan, independently. Disagreements were resolved by discussions
between two authors and handed over to the third author (Huang) for
decision.
2.5 | Quality assessment
we used the “Risk Of Bias In Non-randomized Studies - of Interven-
tions” (ROBINS-I) tool to assess the risk of bias in non-RCT.16 The
ROBINS-I tool assesses the risk of bias via three major domains: pre-
intervention bias (due to confounding or in selection of participants),
intervention bias (in classification), and post-intervention bias (due to
deviations from intended interventions or missing data; in measure-
ment of outcomes and reported results). We should answer the “sig-
naling questions” provided in each domain factually with the
responses of “Yes”; “Probably yes”; “Probably no”; “No”; and “No
information” and then judge domain-level risk of bias including “Low
risk”, “Moderate risk”, “Serious risk”, “Critical risk” of bias and “no
information”. Finally, we can make the overall risk of bias judgment
after evaluating the risk of bias in all seven domains. The quality of
other four observational studies was evaluated in three parameters
(selection, comparability, and exposure) by the modified version of the
Newcastle-Ottawa Scale (NOS). The modified version of the NOS
employs the semiquantitative principle of star systems with scores
ranging from 0 (worst) to 9 (best) stars to cohort studies and ranging
from 0 (worst) to 7 (best) stars to cross-sectional studies. Studies pre-
senting 7 or more stars were considered high quality (good), while the
stars between 5 and 7 were defined as median-quality (fair). Two
investigators (He and Qiu) conducted all searching and evaluation
independently based on the eligibility criteria. Any disagreement was
adjudicated by a third investigator (Huang) after discussion.
2.6 | Statistical analysis
Our statistical analysis was performed using Review Manager
(RevMan) (V.5.4.1) according to the Meta-analysis of Observational
Studies in Epidemiology group (MOOSE). Odds ratio (OR) and 95%
confidence interval (95% CI) were used for dichotomous data. Statisti-
cal heterogeneity among studies was qualitatively and quantitatively
analyzed by the Cochran's Q-test and Higgins' I2 statistics. A p value
 HE ET AL.

TABLE 1 Interventional studies of omalizumab treatment in patients with chronic induced urticaria (CIndU) subtypes
Author/year/country Study design Population (n) Intervention (n) Duration Primary endpoints Primary outcomes Safety (n%-AEs; serious AEs)

Marcus Maurer/2017/Germany17,18 Multicenter randomized SDerm (61) (1) OMZ150 mg (19). (2) OMZ 300 mg 10 w CFT ( C) Changes of CFT in (1) (1) OMZ150 mg (89%; 5%).
double-blinded placebo-controlled (21). (3) PBO (21) every 4 w OMZ150 mg: (2) OMZ300 mg (81%; 5%).
1.8 ± 0.4; (3) PBO: (90%; 5%)
p = 0.014). (2)
OMZ300 mg: 2.0
± 0.4;
p = 0.004.
(3) PBO: 0.6 ± 0.3

Martin Metz/2017/Germany18,19 Multicenter randomized CCU (31) (1) OMZ 150 mg (10). (2) OMZ 10 w CTT ( C) Changes of CTT in (1) (1) OMZ150 mg (70%; 0%). (2) OMZ300 mg
double-blinded 300 mg (9). (3) PBO (12) every 4 w OMZ150 mg: (78%; 0%). (3) PBO: (75%; 0%)
placebo-controlled 10.6 ± 2.4;
parallel p = 0.001; (2)
OMZ300 mg:
10.4 ± 3.1;
p = 0.013; (3) PBO:
0.3 C ± 1.1
9,10
Gabriel Gastaminza/2019/Spain Multicenter randomized CholU (22) (1) OMZ300 mg (13); (2) PBO (9) 16 w Negative rate of ECT 16 w: p = 0.544. (1) OMZ300 mg (69%). (2) PBO: (44%)
mixed double-blind and first 16-w blinded followed by (1) OMZ:8%
open-label placebo-controlled 32-w open label negative. (2) PBO:
parallel 22%
negative 48 w:
p = 0.02. (1)
OMZ:31%
negative. (2) PBO:
11% negative

Emek Kocatürk /2017/Turkey13,14 non-RCT SDerm (10), CholU(2), 150 mg OMZ/2 w or 300 mg/4 w (17) 24 w UCT DLQI Mean UCT: 13 mean One patient reported flu-like symptoms
CCU (2), CIndU(2), DLQI: 2 after each injection
AU (1)

Francois Aubin/2016/France18,19 Non-RCT SU (10) 300 mg OMZ /4 w, 8 w in total (10) 20 w MUD, DLQI, UAS7, 2/10 (20%) increase in No serious AEs
VAS50 MUD 4/10 (40%)
DLQI score <6
4/10 (40%) have
VAS50 3/10 (30%)
UAS7 score = 0

Shun Chi Ryan Lo/2019/Canada20,21 Non-RCT SU (3), CholU (6), CCU (2), 300 mg OMZ/4 w (450 mg and 600 mg 3m CR and remission rates 15/21(71.43%) CCR Not mention
SDerm (5), DPU (3), HU if unsatisfied) (21) 10/21(47.62%)
(1) and AquaU (1) remission

Peña Arellano MI/2019/Spain21,22 Non-RCT CCU (8) 150 mg OMZ/m (4), 300 mg OMZ/m (2), Not mention CR 6/8 (75%) CCR 1/8 Not mention
600mgOMZ/m (1), 300 mg /15 days (1) (12.5%) PCR 1/8
(12.5%) NCR

Gordon Sussman MD/2014/Canada22,23 Non-RCT CCU (6) 150 mg OMZ/m (6) 25 m CR (cold stimulation tolerance 6/6 (100%) CCR No serious AEs
test)

Abbreviations: AE, adverse event; CCR, complete clinical response; CFT, critical friction thresholds; CR, clinical response; CTT, critical temperature threshold; DLQI, Dermatology Life Quality Index; ECT, exercise challenge test; m, months; MUD, minimal urticarial dose;
NCR: no clinical response; OMZ, omalizumab; PBO, placebo; PCR: partial/mild clinical response; UAS7, urticarial activity score over 7 days; UCT, urticaria control test; VAS50, 50% improvement from baseline in solar urticaria severity as measured on a visual analog scale;
w, weeks.
3 of 11
 4 of 11

TABLE 2 Observational studies of omalizumab treatment in patients with chronic induced urticaria (CIndU) subtypes
Primary
Author/year/country Study design Population (n) Intervention (n) Duration endpoints Primary outcomes Safety
10,11
Sabine Altrichter/2019/Germany Cross-sectional study CholU (16) 300 mg OMZ/2 w (15) 0.5–26 m CR 6/16 (37%) CCR 5/16 Not mention
450 mg OMZ/2 w (1) (31%) MCR
2/16(13%) PCR
3/16(19%) NCR
25,26
Ghazanfar/2016/Denmark Cross-sectional study SU (1), CholU (4), CCU (5), 150 mg OMZ/2 w or 3–6 m CR 9/17 (52.94%) CCR 14% patients reported AEs. Mainly
SDerm (2) and DPU (5) 300 mg OMZ/4 w 7/17 (41.18%) about allergic, gastrointestinal symptoms
PCR 1/17 (5.88%)
NCR

Martin Metz/2014/Germany23,24 Cohort study SU (4), CholU (8), CCU (6), 150, 225, or 300 mg OMZ/2–4 w 4–8 w CR 24/34 (70.59%) CCR Not reported unwanted effects, except one
SDerm (7), DPU (8) and HU (1) 4/34 (11.76%) patient stopped treatment after reproducibly
MCR 6/34 (17.65%) developing mild cutaneous angioedema
NCR

Daniel Morgado-Carrasco/2019/Spain26,27 Cross-sectional study SU (20) 300 mg OMZ /4 w (19) 150 mg 4–86 m, median UAS7, UCT, CR 18/20 (90%) CCR No moderate/severe AEs were reported
OMZ/4 w (1) 24.5 m 2/20 (10%) NCR

Snast/2019/Israel24,25 Cohort study SU (6) 75–150 mg OMZ/4 w (2) 150–300 mg 2–39 m, median 9 m CR 5/6 (83.33%) CCR 1/6 No severe AEs, but 5/6 (83%) patients had an
OMZ/4 w (4) (16.67%) PCR atopic background

Emilia Mellerowicz/2019/Germany27,28 Cross-sectional study CholU (6) Not mention Not mention CR 3/6 (50%) CCR 2/6 2/6 (33.33%) patients reported AEs, mainly
(33.33%) PCR 1/6 about fatigue, headache
(16.67%) NCR

Ji Hye Kim/2020/Korea28,29 Cross-sectional study CholU (21) 150 mg OMZ/4 w 2–75 m CR (VAS: 0–10) 1/21 (4.8%) CCR Not mention
(VAS = 0) 12/21
(57.1%)
PCR(VAS = 1–5)
8/21 (38.1%) NCR
(VAS = 6–10)

Can/2021/Turkey29,30 Cross-sectional study CholU (9), CCU (5), SDerm (30), 150 mg OMZ/2 w or 300 24 w UCT, CR 40/51 (78.43%) CCR No serious AEs
DPU (5), ContactU (1) and AquaU (1) mg OMZ/4 w

Fialek/2021/France30,31 Cross-sectional study CholU (9), CCU (14) and DPU (9) 300 mg OMZ/4 w 3–6 m CR 15/32 (46.88%) CCR 7/29 (24%) patients reported mild AEs
31,32
Voukelatou V/2019/Greece Cross-sectional study CholU (4), CCU (4), CCU & CholU 150–300 mg OMZ/4 w Not mention CR 5/12 (41.6%) CCR No AEs was reported
(3) and SDerm (1) 6/12 (50%) MCR

Abbreviations: AE, adverse event; CCR, complete clinical response; CR, clinical response; DLQI, Dermatology Life Quality Index; LRA, leukotriene receptor antagonist; m, months; MCR, major clinical response; MUD, minimal urticarial dose; NCR, no clinical response;
OMZ, omalizumab; PCR, partial/mild clinical response; UAS7, urticarial activity score over 7 days; UCT, urticaria control test; VAS, visual analogue scale; VAS50, 50% improvement from baseline in solar urticaria severity as measured on a visual analog scale; w, weeks.
HE ET AL.
HE ET AL.
FIGURE 1 Flow diagram of search results based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines
less than 0.05 was considered as statistically significant and then
I2 < 25%, 25%–75% and >75% are considered low, moderate, and
2
high heterogeneity. When p value less than 0.05 and I greater than
75%, the random-effect model is chosen for it while the fixed-effect
model is used for low heterogeneity (I2 < 25% and p > 0.05).17 The
funnel plot was applied to investigate the bias of the included studies.
3 | RESULTS
3.1 | The efficacy and safety of omalizumab for
CIndU in interventional studies
There are only three phase II randomized placebo-controlled trials
10,18,19
(RCTs) focus on the efficacy and safety of omalizumab in CIndU
(Table 1). The results all showed that even with different clinical end-
points of different clinical subtypes, the omalizumab group had a sig-
nificant effect on CIndU compared with the placebo group. Besides,
5 of 11
no statistical discrepancy in efficacy was observed between the differ-
ent omalizumab dose groups. The occurrence of adverse events (AEs)
was similar among all groups. Most AEs reported in omalizumab-
treated patients were mild to moderate, serious AEs were rare and
even not likely to be related to the omalizumab. In addition, five non-
randomized controlled trials (non-RCTs)14,20–23 showed that a large
proportion of CIndU patients achieved complete clinical remission
after observing various efficacy outcomes, thus highlighting substan-
tial clinical efficacy (Table 1). The details of safety were not mentioned
in two non-RCTs,21,22 and no serious AEs were reported in the other
three studies.14,20,23
3.2 | The efficacy and safety of omalizumab for
CIndU in observational studies
We retrieved two cohort studies24,25 and eight cross-sectional stud-
ies11,26–32 (Table 2). The difference of clinical response (CR) rate
 6 of 11

TABLE 3 General characteristics of included studies in meta-analysis

Clinical phenotype

Author/year/country Study design CSU, n (%) CIndU, n (%) Population Intervention Follow-up duration Clinical outcomes

Kocatürk/2017/Turkey13,14 Non-RCT 13 (22.7) 14 (25.4) After 2nd line treatment 150 mg every 2 w or CSU (15), CIndU (17): 12 w UCT and DLQI
(combination 300 mg every 4 w CSU (13), CIndU (15): 24 w
or updosing two different
sgAHs)
for 4 w, UCT < 12

Ghazanfar /2016/Denmark25,26 Cross-sectional study 137 (89.0) 17 (11.0) At least 1 injection of OMZ 150 mg every 2 w or 24 m The degree of relief of
300 mg every 4 w symptoms

Giovanni Damiani /2018/Itlay32,33 Cohort study 88 (69.3) 5 (3.9) (1) A history of urticaria longer 300 mg every 4 w First cycle: 24 w; intermission: 8 w UCT and UAS7
than 6 w. second cycle: 24 w (25 patients
(2) Unresponsive to sgAHs. not needed)
(3) UAS7 >27

Martin Metz /2014/Germany24,33,34 Cohort study 30 (46.9) 34 (53.1) Unresponsive to sgAHs (up to Before 2011, 150,225 or One cycle: 6–12 m UAS7and the absence of
fourfold higher 300 mg every 2–4 w, wheals
than the licensed dose) according to weight and
circulating IgE levels;
In 2011, 150 mg regardless
of weight and circulating IgE levels
24,34
Yudi Chen/2021/China Cross-sectional study 87 (63.0) 33 (23.9) At least 1 injection of OMZ and Not mentioned CSU:7.0 (IQR: 4.0–12.0) m CIndU:5.0 (IQR:2.5–8.0) m UCT and DLQI
at least 1 follow-up visit

Abbreviations: DLQI, dermatology life quality index; IQR, interquartile range; m, month; OMZ, omalizumab; sgAH, second-generation H1-antihistamine; UAS, urticarial activity score; UAS7, 7-day urticarial activity score; UCT, urticaria control test; w, week.
HE ET AL.
HE ET AL.
TABLE 4 Results of ROBINS-1 assessment of the risk of bias in non-RCT
Selection of Classification of
Non-RCT Confounding participants interventions
Kocatürk13,14 Low risk Low risk Low risk
among each subtype was seen clearly. Most of observational studies
demonstrated that more than a half CIndU patients achieved com-
plete clinical rate (CCR) after treating with omalizumab and reported
low incidence of AEs. Considering various subtypes of CIndU, for
example, it was indicated obvious clinical efficacy with about
26 (83.9%)patients achieving CCR in four studies on SU including
31 patients. There were 77 CholU patients in eight studies offering a
great response rate of 64.9% after omalizumab treatment. A total of
eight observational studies mentioned the occurrence of AEs with
omalizumab treatment. From the only data, we calculated that the
incidence of AEs ranged from 14% to 83%, without serious AEs.
3.3 | Meta-analysis: comparison of the efficacy of
omalizumab between CSU and CIndU
14,24,26,33,34
We included five eligible studies in the meta-analysis.
screening process was shown in Figure 1. The characteristics of the
five studies were presented in Table 3. The studies were published
between 2014 and 2021 and conducted in Italy, Turkey, China,
Denmark, and Germany respectively. It involved one non-randomized
study of intervention, two cohort studies and two cross-sectional
studies. A total of 492 patients were enrolled in these studies, of
which 34 patients with both CSU and CIndU were excluded, and
458 cases were finally included in this meta-analysis.
To evaluate the effectiveness of omalizumab for the treatment of
both CSU and CIndU from E. Kocatürk's non-RCT, we determined low
risk of bias within most domains by ROBINS-1. A moderate risk of
bias due to missing data in the post-intervention was observed
because 10 of CIndU and six of CSU patients were unwilling for oma-
lizumab therapy. Besides, bias in measurement of outcomes in the
post-intervention was considered at moderate risk, which may result
from outcome assessors' awareness of intervention condition. Thus,
the overall risk can be judged as low, which corresponds to the risk of
bias in a high-quality study.16 The NOS scale was used to evaluate the
cohort studies and the modified version for cross-sectional studies.
The two cohort studies were both considered high quality (8 and
9 scores). Moreover, we evaluated two cross-sectional studies good
since they got full 7 scores. The details of methodological quality
assessments are shown in Tables 4 and 5.
A total of five articles reported the therapeutic effect of omalizu-
mab in the treatment of CSU and CIndU. Based on the low heteroge-
neity (I2 = 0%, p = 0.74 > 0.1), the fixed-effect model combined with
statistics was adopted for the meta-analysis, which demonstrated that
the efficacy of omalizumab was not significantly different in CSU and
CIndU (OR = 1.36, 95% CI [0.79, 2.32], p = 0.27, Figure 2).
The funnel plot results showed that the left and right sides of the
five included articles were mainly symmetrical, which meant there
7 of 11
Deviations from Measurement Selection of the
intended interventions Missing data of outcomes reported result Overall
Low risk Moderate risk Moderate risk Low risk Low risk
was quite a small bias in this meta-analysis and the results were rela-
tively stable, as shown in Figure 3.
4 | DI SCU SSION
To the best of our knowledge, this is the first meta-analysis to evalu-
ate the efficacy difference of omalizumab between CSU and CIndU
patients combined with the systematic review about the efficacy in
the treatment of patients with CIndU. The systematic review collected
eight interventional studies (three RCTs and five non-RCTs) and
10 observational studies (two cohort studies and eight cross-sectional
studies), including 391 patients with various CIndU, giving the proof
to the efficacy of omalizumab in the treatment of CIndU. Five studies
were included in our meta-analysis, which verified the consistent effi-
cacy of omalizumab treatment between CIndU and CSU.
The The exact etiology of CU remains unclear but existing studies
have indicated that the high affinity IgE receptor (FcεRI) on mast cells
can always be induced and activated through type I and IIb autoim-
mune mechanisms, and subsequently the downstream of these cells
release histamine and other inflammatory mediators, which may play
a crucial role in the occurrence of CU.35–38 A real-world study from
Taiwan reported that nearly half of CSU patients were not controlled
with standard-dosed sgAHs, and 22% have inadequate response even
if the dose was increased by four times, which indicated a vast major-
ity of patients with CSU were dissatisfied with the first-line and even
the second-line treatment.6 Omalizumab can reduce the levels of free
IgE in the blood and interstitial space by binding to free IgE, thus pre-
venting IgE binding to FcεRI. This results in mast cells decreasing the
sensitivity to the upcoming allergens, intervening their degranulation,
and hence inhibiting inflammatory manifestations.4,39 At present,
omalizumab has been successfully licensed as a third-line treatment
option for CSU patients who remain symptomatic after fourfold doses
of sgAHs. As known in the study, omalizumab shows excellent effi-
cacy, quite low incidence of adverse reactions and improves quality of
life in patients with refractory CSU.40 The recommended dose of
omalizumab for CSU is 300 mg every 4 weeks.1 Dosing varies by total
serum IgE levels and body weight.1,41 The duration is about 2–5 years
on average.42 However, the use of omalizumab for refractory CIndU
has so far been considered “off-label”. In fact, over 76% of patients
with CSU coexist with CIndU,4 which may imply that CIndU patients
have already been treated with omalizumab. Therefore, it may be fea-
sible to apply omalizumab as a third-line treatment for CIndU.
We searched for eight interventional studies to validate the effi-
cacy of omalizumab in patients with CIndU. These studies included all
subtypes except exercise-induced urticaria and vibratory angioedema,
because studies on the latter two were case reports or case series and
lacked sufficient evidence. In three RCTs, disease activity is usually
8 of 11 HE ET AL.

measured by threshold tests such as critical friction thresholds (CFT),

Total scores
follow-up of cohorts Total scores
critical temperature thresholds (CTT) and exercise challenge test
(ECT). The studies showed the markable improvement in CFT, CTT

7
8

9
and negative ECT rates in 150 and 300 mg omalizumab group in con-
trast to placebo group, which clarified that initiating omalizumab was

Statistical test
favorable and well tolerated. Moreover, these studies also investi-
Comparability of cohorts on the Assessment of enough for outcomes Adequacy of gated the efficacy of different omalizumab doses and found no statis-
tical discrepancy. Besides, it revealed that a notably increased clinical

★
★

★
response rates to omalizumab in the treatment of patients with CIndU
Was follow-up long

in five non-RCTs. Except interventional studies, another 10 observa-

Assessment of the outcome

tional studies exhibited that a large body of CIndU patients can
achieve complete or major symptom remission and greatly improved
to occur

their quality of life after omalizumab therapy. To sum up, omalizumab

★

can offer considerable benefits to CIndU patients.

Outcome

For safety of omalizumab in CIndU patients, two RCTs on CCU

Outcome

outcome

and SDerm displayed frequency of AEs similar to placebo groups at

about 70%–80%, while another RCT on CholU showed higher inci-
★

Comparability

dence of AEs in omalizumab group (69.2%) than placebo groups

interest was not present at start of study basis of the design or analysis
Results of quality assessment using the modified version of the Newcastle-Ottawa Scale (NOS) for observational studies

(44.4%). However, most of AEs were reported mild or moderate, even

control

★★

★★

considered not related to the study. Apart from that, three non-RCTs
informed no serious AEs while other studies did not mention it. No
severe AEs were mentioned in 10 observational studies, and most
Comparability

Ascertainment of exposure (risk factor)

AEs were mild such as fatigue and headache. However, the frequency
of AEs had a wide range between 14% and 83% probably due to the
★☆

★★

dose and the tolerance of omalizumab in different subtypes. Overall,

the omalizumab can be well safe and tolerated in refractory-to-sgAHs
CIndU patients.
Ascertainment Demonstration that outcome of

Moreover, we applied a meta-analysis to compare the efficacy of

omalizumab in the treatment of CSU and CIndU patients refractory to
sgAHs. The results demonstrated no significant difference in the effi-
★

cacy of omalizumab in the treatment of CSU compared with CIndU

(OR = 1.36, 95% CI [0.79, 2.32], p = 0.27 > 0.05) and the results were
Non-respondents

stable. The present evidence indicated that in the case of ineffectual

antihistamines, not only CSU but also CIndU which has not yet been
★

approved for use does omalizumab exert terrific healing power

Cohort study (range 0-9) of the exposed cohort non-exposed cohort of exposure

to. Hence, for refractory CU (including CSU and CIndU), omalizumab

can be recommended no matter in the revision of guidelines and spec-
Representativeness of the sample
★

ification or in clinical application. From the information available, oma-

lizumab can maintain an overall response rate of 70%–90% for both
Selection of the

CSU and CIndU patients13,34,43 and most adverse reactions were

reported mild-to-moderate intensity, which confirmed its good safety.
Although the drug price and Medicare policies vary from countries,
★

Kanters et al.44 have demonstrated that omalizumab has more cost-

Selection
Representativeness

effectiveness for CSU than standard of care (up to four times of

★

sgAHs) from pharmacoeconomic perspective. In this case, omalizumab

treatment for CIndU is expected to be in accordance with CSU from
Selection

Cross-sectional studies (range 0-7)

Note: One blastar means one score.

both therapeutic and economical perspective.

Giovanni Damiani (2018) ★

Our study has some potential limitations: (1) Although three RCTs
were searched in our study, they were mainly based on the small sam-
Martin Metz (2014)

ple. If possible, future larger-size multicenter RCTs on CIndU are

Yudi Chen (2021)

Ghazanfar (2016)

essential to strongly validate the efficacy of omalizumab. (2) Due to

TABLE 5

the incomplete safety data on omalizumab treatment in the five

included studies, it is difficult to make an overall evaluation of its
treatment in patients with CSU and CIndU from perspective of safety.
HE ET AL.
F I G U R E 2 Forest chart of the significant efficacy of omalizumab in the treatment of chronic spontaneous urticaria (CSU) and chronic induced
urticaria (CIndU)
F I G U R E 3 Funnel plot of the efficacy of omalizumab in the
treatment of chronic spontaneous urticaria (CSU) and chronic induced
urticaria
(3) Since there are differences in the treatment of CU between chil-
dren and adults, while the included study only involved people aged
over 12 years old, so it is not clear whether our conclusions are appli-
cable to children under 12 years old.
Nonetheless, we analyzed various published studies on the effi-
cacy of omalizumab in the treatment of CIndU, including interven-
tional and observational studies. We also compared the treatment
effect of omalizumab in the two subtypes of CU (CIndU vs. CSU) and
concluded that there was no significant difference between omalizu-
mab in the treatment of CIndU and CSU. The analysis of the results is
comprehensive and reliable. We believe that it is reasonable to use
omalizumab as the third-line treatment for refractory CIndU, and it is
expected to provide a basis for clinical treatment guidance and policy
decision-making.
5 | C O N CL U S I O N
In conclusion, omalizumab has efficacy and safety in the treatment of
patients with CIndU unresponsive to sgAHs, with no statistically sig-
nificant difference compared with the treatment of patients
with CSU.
9 of 11
AUTHOR CONTRIBU TIONS
Zhu-Han He: study design; literature searching; title and abstract
screening; full text screening; judging the risk of bias in the studies;
article drafting; article revising. Shuo-Cheng Qiu: literature searching;
title and abstract screening; full text screening; data collection and
analysis; article drafting. Zhi-Wei Huang: title and abstract screening;
full text screening; assisted with data analysis. Guo-Qiang Zhang:
design of study; revising article. Qing-Qing An: assisted with full text
screening; assisted with literature searching. Feng Qu: conception and
design of study; revising article. Na Wang: conception and design of
study; full text screening; revising article; final approval of article to be
submitted.
CONFLIC T OF INT ER E ST
The authors declare no conflict of interest.
DATA AVAILABILITY STAT EMEN T
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
OR CID
Na Wang https://orcid.org/0000-0002-2574-9515
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