Serum free IgE guided dose reduction of omalizumab: a case report
Gon et al.
Allergy Asthma Clin Immunol
Serum free IgE guided dose reduction of omalizumab: a case report
Yasuhiro Gon 0
Reiko Ito 0
Shuichiro Maruoka 0
Kenji Mizumura 0
Yutaka Kozu 0
Hisato Hiranuma 0
Yuko Iida 0
Sotaro Shikano 0
Shu Hashimoto 0
0 Division of Respiratory Medicine, Nihon University School of Medicine , 30-1 Ohyaguchi-Kamicho, Itabashiku, Tokyo 173-8610 , Japan
Background: Omalizumab is a human IgG1 antibody against IgE used as a therapy for sever asthmatic patients with asthma. According to the guidelines of the Global Initiative for Asthma, omalizumab is an add-on drug at treatment step 5 that is used for severe asthma patients who are allergic to perennial allergens. The effects of omalizumab for severe asthma therapy have been validated in multiple clinical studies. However, the long-term effects of omalizumab on IgE production and possibility of resetting of administration dose of omalizumab remain unknown. Case Presentation: The serum total and free IgE levels were measured over time in a 63-year-old female patient with allergic asthma who was administered 375 mg omalizumab biweekly for 36 months. Her symptoms did not worsen and clinical course remained favorable after reducing the dose to 375 mg per month. The serum free IgE levels temporarily increased following a dose reduction of omalizumab. The serum free IgE trough level temporarily increased at 4 weeks after capable to reduce the dosage; however, thereafter, the serum free IgE level decreased to desired levels (below 30 ng/mL). Conclusions: The present case shows the possibility of reducing the dose following the long-term use of omalizumab. Considering the high medical cost of omalizumab, the dose reduction may be a viable option. It may be useful to measure the serum free IgE level to appropriately identify patients in whom the dose can be reduced, and to carefully monitor the clinical course.
Bronchial asthma; Omalizumab; IgE
To the editor
Omalizumab is a human IgG1 antibody against IgE used
to treat patients with severe allergic asthma with
symptoms that are poorly controlled with high doses of inhaled
steroids. Numerous clinical studies have demonstrated
the effectiveness of omalizumab therapy on intractable
atopic asthma, and this has become one of the few
available treatment modalities. The goal of omalizumab
therapy is to achieve free IgE (unbound IgE that can bind to
IgE receptors) of ≤25 ng/mL [
]; however, it is
impossible to distinguish between free IgE and IgE-omalizumab
complexes using conventional measurements of serum
total IgE. Conventionally, the serum free IgE levels could
not be assessed after administering omalizumab [
To overcome this issue, we previously developed ELISA
with solid-phase soluble FcεRI to allow for the
measurement of serum free IgE levels in patients undergoing
omalizumab treatment [
]. Here we report the case of a
patient who was able to reduce the dose of omalizumab
supported by the measurement of the serum free IgE
A 63-year-old female patient developed bronchial
asthma at approximately 5 years of age. Her asthma did
not spontaneously resolve and she subsequently
suffered from regular asthma attacks. Specific IgE testing
was positive for house dust, Dermatophagoides
pteronyssinus, Chironomid midges, and negative for
Aspergillus fumigatus, Candida albicans, Penicillium notatum
and other common allergens. Despite the treatment with
the combination of budesonide 1280 μg and formoterol
36 μg per day, a leukotriene receptor antagonist, and
lowdose theophylline, she experienced exacerbations several
times. The asthma control test (ACT) score was 18, and
%FVC 86.7%, FEV1.0 0.88 mL, %FEV1 46.1% at 2 month
before omalizumab therapy which initiated the year at
in September 2013. Table 1 presents the term-course of
her clinical data. She has a height of 157 cm and a weight
of 66 kg, and her serum total IgE level was 580 IU/mL.
Based on the omalizumab dose table, she was started
on a biweekly administration of 375 mg omalizumab. At
week 16, we conducted an evaluation to assess whether
the drug should be continued. We observed an
improvement in the patient’s subjective symptoms and morning
peak expiratory flow levels. The level of airway
obstruction had improved according to the respiratory function
tests, and because there were no exacerbations within
16 weeks, we decided to continue omalizumab
administration. Because there were no clear aggravations, we
continued treatment with omalizumab at the same dose
for 36 months. We measured her serum free IgE levels
at 2, 4, 8, and 26 weeks after initiating omalizumab and
found that the serum free IgE levels were extremely low
at 72.8, 40.50, 18.1, and 11.3 ng/dL, respectively (Fig. 1).
Because her symptoms had stabilized after initiating
omalizumab with no exacerbations, she inquired whether
it was possible to reduce the frequency of
administration from once every 2 weeks to once every 4 weeks.
Her ACT scores in the past 6 months were 23–25, her
morning peak expiratory flow was stable, and there were
no exacerbations in the past year; hence, we accepted
her request and reduced the frequency of administration
from biweekly to monthly without changing the dose of
375 mg omalizumab per administration beginning from
August 2016. Therefore, the dosage was reduced by half.
The serum free IgE trough level transiently increased to
129.3 ng/mL at 4 weeks after reducing the dosage;
however, thereafter, the serum free IgE level decreased to
Asthma control test (ACT) assesses the frequency of shortness of breath and general asthma symptoms, use of rescue medications, the effect of asthma on daily
functioning, and overall self-assessment of asthma control. ACT score 25 points indicates complete control of asthma, under 18 points indicates poor-controlled
93.6 ng/mL within 4 weeks and gradually to 20.6 ng/mL,
which is well below the desired level, 30 ng/mL (Fig. 1).
She experienced no exacerbations during this period, and
her ACT score remained at 25. FEV1 measured via
pulmonary function testing almost unchanged after
reduction of omalizumab (Fig. 1). Moreover, her asthma was
controlled over the 9-month period since the dosage was
At present, free IgE and IgE-omalizumab complexes
cannot be distinguished using current clinical methods
for measuring serum total IgE levels, like ImmunoCAP
(Thermo Fisher Scientific, Uppsala, Sweden); thus, serum
total IgE levels appear to increase following the
administration of omalizumab [
]. This is because of the
2.4day half-life of human serum IgE compared to the 20-day
half-life of IgE, which is longer because of IgE binding to
the IgG1 antibody omalizumab.
Lowe et al. [
] have used mathematical models to
predict that long-term omalizumab treatment may lower IgE
production levels in their study of pharmacokinetic data
from past clinical trials. According to the assessment
using this model, the IgE production level is inhibited to
a greater extent as the duration of omalizumab
administration increases [
]. A prospective study measuring
the free IgE level of 30 patients undergoing omalizumab
therapy over time, using the method of free IgE
measurement that we developed, demonstrated that free IgE
levels 1 year after initiating administration had gradually
]. Furthermore, the speed at which the free
IgE level decreases after initiating omalizumab has been
demonstrated to have a possible association with the
reactivity to omalizumab therapy [
]. In the present case,
the total IgE levels also gradually declined beginning at
4 weeks. I suggested that the IgE production levels were
observed to gradually decrease after initiating
omalizumab administration, but it is difficult to fully grasp the
quantitative relationship because the total IgE level
temporarily increases after initiating omalizumab (Fig. 1).
While the mechanism underlying the decrease in the
serum total IgE level due to the continuation of
omalizumab therapy remains unknown, there are several
possible explanations. First, decrease of free IgE levels by
omalizumab can lead to down regulation of FcεRI on
mast cell and dendritic cells [
]. Second, IgE production
is promoted by Th2 cytokines and CD40 [
therapy may suppress the activation Th2 cells indirectly,
thereby lowering IgE production. Third, the decreased
expression of low-affinity IgE receptors on dendritic cells
is also suggested to be potentially involved in decreasing
]. Third, the decreased expression of CD23/FcεRII,
one of the low-affinity IgE receptors, may also be involved
in suppressing IgE production. CD23/FcεRII is known to
play an important role in maintaining IgE homeostasis.
Past clinical research on the anti-human CD23/FcεRII
monoclonal antibody lumiliximab has demonstrated that
the inhibition of CD23/FcεRII controls the human serum
IgE level [
]. The binding of CD23/FcεRII to IgE is
reportedly inhibited by omalizumab bound to IgE [
Moreover, sCD23/FcεRII expression is reported to increase in
response to inflammation [
]; thus, it is also possible that
the improvement in allergic inflammation lowers soluble
CD23/FcεRII, which then decreases the induction of IgE
production via CD23/FcεRII.
The serum free IgE levels would be the most reliable
marker reflect the IgE production status in the patients
treated with omalizumab. One of the benefits of the
longterm use of omalizumab is the improvement of patients’
atopic status by reducing IgE productivity. Moreover,
if IgE production can be suppressed, it is possible to
readjust and reduce the dosage.
The present case shows the possibility of reducing the
dose of omalizumab following its. Considering the high
medical cost of omalizumab, reduction of the dose may
be a viable option. In such a case, it is useful to measure
the serum free IgE level to appropriately identify patients
in whom the dose can be reduced. Because there are
patients similar to the present study in whom serum free
IgE levels temporarily increase following a dose
reduction of omalizumab, it is recommended that their clinical
courses be carefully monitored by observing their serum
free IgE levels.
YG wrote the manuscript. YG, RI, SM, HH, YK provided clinical care to the
patient. YG, RI and SM performed the experiments. SS, KM, IY, and SH revised
the manuscript. All authors approved the final manuscript for publication. All
authors read and approved the final manuscript.
YG and SH: personal fees/other from: AstraZeneka, Kyorin Pharma, Novartis
Pharma, Boehringer Ingelheim, outside the submitted work. All other authors
have declared no competing interests.
Availability of data and materials
Please contact author for data requests.
Consent for publication
The individual described in the above case report has completed and signed a
consent form for publication and presentation.
We obtained written consent from the patient to have the measurement
of serum free IgE. The measurement of serum free IgE was taken with the
approval of the ethics committee of the Nihon University Itabashi Hospital
(RK-120413-9, approved in 27 April 2012).
The measurement of the free IgE was supported by the Strategic Research
Base Development Program for Private Universities subsidized by MEXT
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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