Title: Real-life study in non-atopic severe asthma patients
achieving disease control by omalizumab treatment
To the Editor,
Severe asthma is defined as asthma requiring treatment with
guidelines-suggested medications for Global Initiative for Asthma (GINA)
steps 4 or 5 or systemic corticosteroids for ≥50% of the previous year
to prevent it from becoming ‘uncontrolled’ or which remains
‘uncontrolled’ despite this therapy.1 Up to 34%–50%
of severe asthmatic patients have non-atopic (also called non-allergic)
asthma. 2 A significant proportion of these patients
have severe uncontrolled asthma, which requires high doses of inhaled
corticosteroids (ICS) or even oral corticosteroids
(OCS).2 Until the advent of biologics, treatment
options in these patients have been very limited. For many years, both
the pathogenesis knowledge and the results of clinical trials supported
the view that anti-IgE treatment is specifically effective in allergic
asthma. Interestingly, recent molecular and clinical evidence suggests
that anti-IgE treatment might also be effective in patients with
non-allergic asthma.2 Omalizumab
(Xolair®) is an anti-IgE monoclonal antibody that
selectively binds to human IgE and prevents the binding of IgE to its
receptors. Although omalizumab is indicated in Europe in patients with
severe persistent allergic asthma, several case reports and short series
have provided data on the value of omalizumab in patients with
non-atopic asthma.3,4
The observational, multicenter, retrospective, real-life FENOMA study
specifically evaluated patients who achieved full asthma control after
one year of treatment with omalizumab.5 The study
included 345 patients, 80 (23.2%) of whom had non-atopic asthma. The
present post-hoc sub-analysis aims to describe the clinical
improvement of patients with non-atopic asthma. Socio-demographic and
asthma-related characteristics were collected at baseline. Outcomes
analyzed at baseline and after one year of treatment were those included
in the definition of asthma control by GEMA
guidelines.5 Medical records were reviewed between
February 2015 and June 2016. For statistical comparisons, the 2-sided
Wilcoxon signed-rank test was used. A P-value of <0.05 was
considered to be statistically significant. All analyses were performed
with the SAS statistical package (version 9.4; SAS Institute, Cary, NC).
The primary outcome of this post-hoc sub-analysis was to describe
the baseline characteristics and clinical improvement of non-atopic
asthma patients who achieved full disease control after one-year of
treatment with omalizumab through i) frequency of daytime symptoms, ii)
changes in use of ICS or OCS iii) need for rescue therapy, iv) pulmonary
function (forced expiratory volume in 1 second
[FEV1]), v) number of non-severe exacerbations and
vi) use of healthcare resources, i.e. unplanned visits to primary care
or specialists and the number of days of school or workplace absenteeism
due to asthma worsening. Non-severe asthma exacerbations were defined as
those that did not require OCS, emergency assistance or hospitalization.
Secondary outcomes include an assessment of the percentage of eosinophil
blood count and exhaled nitric oxide fraction (FeNO) before and after
treatment.
Demographic, clinical characteristics and asthma history (before
starting treatment with omalizumab) are shown in Table 1 . Mean
(SD) age of patients was 58.7 (12.2) years and 65% were female. Almost
all patients had daytime symptoms, 92% of patients needed rescue
medication, and the mean (SD) initial dose of omalizumab was 338.7
(153.1) mg.
After one year of treatment with omalizumab 50.0% (n=40) of patients
had no daytime symptoms, while 37.5% (n=30) and 12.5% (n=10) had
symptoms 1 and 2 days per week, respectively. Forty-one (51.2%) of the
54 patients who were receiving OCS at entry, stopped treatment
(P<0.0001). Of those continuing on OCS, the average reduction
of the daily dose was not statistically significant (P=0.2132). More
than half of patients (53.7%, n=43) needed no rescue medication. Median
FEV1 increase was 15% and there was a reduction in the
number of non-severe asthma exacerbations. After one year of treatment
with omalizumab, a great reduction in unplanned visits and absenteeism
from school or workplace (P<0.0001; Table 2 ) was
observed.
Of note, the effectiveness of omalizumab was previously assessed in a
Spanish multicenter registry, which evaluated 29 non-atopic severe
asthma patients over 2 years.6 However, our series is
the most extensive study in patients with non-atopic asthma published to
date in Spain, and provides data on full disease control. There have
been several potential suggestions to explain the effectiveness of
omalizumab in non-atopic patients.7 In a
proof-of-concept study in non-atopic asthma patients, treatment with
omalizumab resulted – as per in atopic patients – in a significant
reduction of high-affinity IgE receptor (FcεRI) expression on blood
basophils and plasmacytoid dendritic cells (pDC2), which hampered IgE
binding and the subsequent production on proinflammatory
mediators.8 Additionally, omalizumab treatment was
associated with an increase in FEV1 with a positive
trend in some relevant clinical endpoints, such as asthma
exacerbations.8 In another proof-of-concept trial,
omalizumab therapy (but not placebo) reduced IgE expression and IgE
sensitization of target cells within the bronchial mucosa, and increased
FEV1 versus baseline despite withdrawal of conventional
therapy.9 Interestingly, it has been hypothesized that
patients labelled as ‘non-allergic’ might in fact have a localized
allergy to an unrecognized allergen, with elevated concentrations of
allergen-specific IgE antibodies in the airways.7
Our study has several limitations. Its single-arm retrospective nature
relies on the accuracy and completeness of the information entered into
the clinical records. This has especially affected predictors of
response such as FeNO and the level of eosinophils, which were not
routinely assessed in the clinical practice at the time of the study.
The benefits of omalizumab presented here are those observed in the
population of non-atopic patients who achieved disease control after one
year of treatment with omalizumab. It is unknown how many other patients
classified as non-atopic in the clinical practice did not benefit from
this treatment.
In summary, in the population of patients with non-atopic severe asthma
who achieved full disease control after one year of treatment with
omalizumab, the clinical and pulmonary benefits were remarkable and
similar to those described for atopic patients. A reduction in the use
of healthcare resources was also documented. Large randomized controlled
trials are warranted to confirm the value of omalizumab in this
population of patients.