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