Novel treatments driven by asthma endotypes
Precision medicine, which is fitting very well asthma’s heterogeneity
and complex pathogenesis, is becoming an overarching medical discipline
that requires a good understanding of biomarkers, phenotypes, endotypes,
genotypes, regiotypes, and theratypes of
diseases.2 ICS have been the foundation for asthma
treatment, however, inhaled or systemic corticosteroids can be
ineffective in many patients with asthma. Few treatment options exist
for patients with steroid resistant asthma. The recent development of a
new class of biological agents that target airway type 2 inflammation
has provided an opportunity for treating patients with corticosteroid
refractory asthma (Figure 1).153
A significant amount of research supports the separation into type 2 and
non-type
2 asthma endotypes.8,154,155 Type 2 asthma usually has
high sputum and blood eosinophil counts, high FeNO. The diagnosis of
non-type 2 patients, who are usually unresponsive to the inhaled
corticosteroids treatment, remains a challenge. Some studies have
suggested that elevated levels of circulating interleukin(IL)-17, IL-6,
IL-23 or other factors, such as, bacterial infection, obesity are all
involved in the pathogenesis of the non-type 2
asthma.156 Neutrophilia observed in these non-type 2
patients was related to recurrent respiratory tract infection
facilitated probably by a deficiency of local airway immunoglobulins.
Asthma patients who received intravenous immunoglobulin exhibited higher
levels of serum IgA and fewer infection exacerbations 12 months
afterwards.157
Several earlier studies have highlighted the impact of high altitude
treatment in atopic dermatitis and asthma.158,159 A
recent study by Boonpiyathad et al.160 described the
clinical and immunological changes after high altitude treatment in
asthma patient subgroups and showed that clinical improvement is
dependent on the asthma phenotype. Furthermore, high altitude treatment
reduced the type 2 immune response and corrected the elevated CRTH2
expression and its dysregulated functions.160
Severe asthma is defined by the ERS/ATS criteria as either asthma
requiring escalation to step 5 medical therapy (= high-dose ICS in
combination with a second controller and/or additional systemic
corticosteroid therapy) to maintain asthma control or asthma that
remains uncontrolled despite step 5 therapy.161,162Only 5-10% of asthma patients fulfil these criteria, but they are
responsible for >80% of the total asthma healthcare costs.
Adverse effects due to an overload of corticosteroid therapy (resulting
from an often combined nasal, cutaneous and/or inhaled therapy) are
recognized as a major contributor to the immense healthcare
costs.161 Voorham et al. showed in a matched,
historical cohort study that patients undergoing long-term systemic
corticosteroid treatment suffered annually increasing healthcare costs
compared to patients who do not receive systemic.163
Targeted therapies play a critical role in severe and difficult-to-treat
asthma in adults, including monoclonal antibodies against IgE, blockage
of IL-4 and IL-13 signaling, anti-IL5 and anti-IL-5 receptor
therapies.164,165 This is partly why optimization of
severe asthma therapy (i.e. by reducing steroid use) received
considerable attention in the past decades, with targeted approaches
(e.g. biologicals) (Figure 1).161 Currently, there are
five biologicals approved for difficult-to-control asthma, targeting IgE
(omalizumab), IL-5 (mepolizumab and resilizumab), IL-5Rα (benralizumab)
and IL-4Rα (dupilumab). These drugs were shown to have steroid sparing
effects and reduce asthma exacerbations, as well as hospital admissions,
in randomized control trials.105 Biological treatment
of severe asthma also comes with a high cost for the healthcare system
(it exceeds the recommended maximal cost per quality-adjusted life-year
by far); thus, the selection of the patient is required to be
rigurous.105,161 One difficulty in patient selection
is due to the overlapping severe asthma phenotypes, such as severe
allergic asthma and severe eosinophilic asthma. A multi-center,
open-label, single-arm study conducted by Chapman et al. showed that a
direct switch from omalizumab to mepolizumab (within 2-4 weeks of the
last biologic dose) is possible without any tolerability issues and can
be highly beneficial for patients with severe eosinophilic asthma not
optimally controlled by omalizumab.166,167 As crucial
as the patient selection is for the initiation of biological treatment,
the decision in which patients to discontinue it after long-term usage
is equally important. In a real-life study involving children with
severe allergic asthma, Deschildre et al. demonstrated that omalizumab
discontinuation could be safely proposed after at least 24 months of
treatment in children with prolonged controlled asthma and no severe
exacerbations for at least one year. They also showed that some
phenotypic markers (female gender, allergic multimorbidity, and
decreased lung function) should be taken into account, consistent with
the findings from the persistency of response after long-term therapy
(XPORT) trial assessing omalizumab discontinuation effects in an adult
population.168
The identification of treatment responders is of great significance for
patient selection; however, validated biomarkers are currently scarce.
For benralizumab Mathur et al. found several indicators of enhanced
response of the drug in two phase III trials in patients with elevated
blood eosinophil counts, decreased lung function, long-term oral
corticosteroid use and nasal polyposis.169 In a small
prospective study Antonicelli et al. showed that forced oscillation
technique (a non-invasive method that provides information of the degree
of obstruction of the respiratory system) could detect specific
mepolizumab-induced changes in peripheral airway function in patients
undergoing treatment for severe eosinophilic
asthma.170
EAACI recently launched its guidelines for the use of biologicals in
severe asthma. Recommendations follow the GRADE approach for each
biological and each outcome. In addition, a management algorithm for the
use of biologicals in the clinic is proposed, together with future
approaches and research priorities.171
Fokkens et al. stated that it is likely that biologics will become an
alternative for sinus surgery in chronic rhinosinusitis with nasal
polyposis, which is a frequent co-morbidity of severe
asthma.105
Optimizing patient empowerment and satisfaction by allowing
self-injection of currently approved biologicals administered
subcutaneously is another approach.172 Another key
future development could be optimization of airway delivery of
biological agents by using nebulized monoclonal
antibodies.162
Another promising new approach is the use of arginase inhibitors which
lead to an increase in nitric oxide levels, thus promoting
bronchodilatation and inhibiting airway inflammation. Currently, drugs
based on arginase inhibition are under development.81Other possible future targets in personalized asthma therapy include the
epithelial-cell-derived cytokines, (e.g. IL-33 or TSLP), kinases (e.g.
JAK, Pi3K) and the PGD2 (acts as a pro-inflammatory mediator) (Figure
1).161,162 A comprehensive review by an EAACI task
force173 highlighted the complex roles of eicosanoids
in asthma and allergy.
Type 2 inflammation-independent asthma represents a critical unmet
medical need in the search for potential drug targets, as such patients
show a decreased response to asthma therapies targeting type 2
cytokines. By generating a noncompetitive inhibitory anti-tryptase
antibody in humanized mouse and cynomolgus monkey models, Maun et al.
provided the scientific rationale for clinical testing of such
antibodies.174
Kere et al. examined the association between biologicals,
corticosteroids and DNA methylation in peripheral blood cells from
asthmatic children and found no evidence that ICS or other asthma
medications affect peripheral blood cell DNA methylation
levels.175 However, the usage of biologicals
provides therapeutic options when conventional approaches fail.
Allergen-specific immunotherapy. The only causal treatment in
allergic asthma is AIT, the role of which has been largely explored in
recent clinical and experimental research. In a large cohort study
involving 39,167 asthmatic subjects, a remarkable reduction of
symptomatic medication was observed among 4,111 patients treated by AIT
during a 8-year follow-up. This outcome, which was mainly observed in
young subjects, suggests that AIT might play a role in preventing
progression from mild to more severe asthma.176Moreover, AIT was shown to decrease serum IgE levels, while increasing
serum levels of Der p 2-specific IgG4 and Der p 2-specific IgD in
HDM-sensitized asthmatic patients. The longitudinal change in Der p
2-specific IgE/IgD ratio was similar to that in Der p 2-specific
IgE/IgG4 ratio. Asthma symptoms were improving during the AIT process,
which also correlated with allergen-specific B cell
responses.177
Many retrospective AIT studies investigated the risk of new-onset
asthma, the relative risk of medication dispensing for asthma and its
potential progression among multimorbid allergic subjects. It was found
that use of sublingual allergen immunotherapy tablets for pollen allergy
for the treatment of allergic rhinitis could reduce the prevalence of
asthma, decrease asthma medication usage and also slow progression of
asthma in comparison to a group receiving only symptomatic allergic
rhinitis medication.178-180 Moreover, AIT with grass
allergen peptide over 3 weeks before the beginning of grass pollen
season was considered as an efficient and safe modality to protect
patients with rhino conjunctivitis and asthma from symptom
onset.181 Additionally, it was suggested that in
patients with both allergic asthma and allergic rhinitis, compared to
standard care, sublingual allergen immunotherapy may have a
cost-effective benefit with an incremental cost-effectiveness ratio of
£10,726 per quality-adjusted life year which is nearly half of the
(English) National Institute for Health and Clinical Excellence
threshold.182
Studies have been continued to develop novel vaccines for
allergen-specific immunotherapy. In a HDM-driven allergic asthma mouse
model purified Der p1 and 2, similar to crude HDM extract, demonstrated
a suppressive effect on AHR, eosinophilic inflammation, type 2 cytokines
and activation of lung structural cells.183 These
optimal results based on purified natural allergens from animal studies
suggest further research focusing on novel vaccines due to high demands
in the field of allergic asthma.
A systematic review summarized recent updates about nonpharmacological
asthma management. This review epitomised the methods used in studies,
highlight the importance of education and self-management and called for
a through description of methods in future studies.184