Abstract
Recent developments in therapeutic strategies have provided alternatives to corticosteroids as the cornerstone treatment for managing airway inflammation in asthma. The past two decades have witnessed a tremendous boost in the development of anti-cytokine monoclonal antibody (mAb) therapies for the management of severe asthma. Novel biologics that target eosinophilic inflammation (or type 2, T2 inflammation) have been the most successful at treating asthma symptoms, though there are a few in the drug development pipeline for treating non-eosinophilic or T2-low asthma. There has been significant improvement in clinical outcomes for asthmatics treated with currently available monoclonal antibodies (mAbs), including anti-immunoglobulin (Ig) E, anti-interleukin (IL)-4 receptor α subunit, anti-IL-5, anti-IL-5Rα, anti-IL-6, anti-IL-33, and anti-thymic stromal lymphopoietin (TSLP). Despite these initiatives in precision medicine for asthma therapy, a significant disease burden remains, as evident from modest reduction of exacerbation rates, i.e., approximately 40–60%. There are numerous studies that highlight predictors of good responses to these biologics, but few have focused on those who fail to respond adequately despite targeted treatment. Phenotyping asthmatics based on blood eosinophils is proving to be inadequate for choosing the right drug for the right patient. It is therefore pertinent to understand the underlying immunology, and perhaps, carry out immune endotyping of patients before prescribing appropriate drugs. This review summarizes the immunology of asthma, the cytokines or receptors currently targeted, the possible mechanisms of sub-optimal responses, and the importance of determining the immune make-up of individual patients prior to prescribing mAb therapy, in the age of precision medicine for asthma.
Highlights
Asthma is defined by reversible airflow obstruction, hyperresponsiveness, and inflammation, that manifests as wheeze, dyspnea, and cough
Increased C1-q/IgG levels and C1-qIgG/IL-5-IgG dual-positive cells in sputum plugs were found in those who worsened on mepolizumab. This is supported by a case report where we described a severe asthmatic treated with mepolizumab had worsening of symptoms, and molecular analysis revealed increased anti-eosinophil peroxidase (EPX) and IL-5+innate lymphoid cell type 2 (ILC2), suggesting that increased T helper 2 (Th2) signaling leads to activation of IL-5-producing ILC2s and subsequent eosinophilia (Mukherjee et al, 2017)
Studies looking at moderate-severe asthma with type 2 (T2)-high inflammation have shown that treatment with lebrikizumab resulted in 60% reduction of asthma exacerbation rates (AAER) and improved FEV1, but no effect on symptoms (Corren et al, 2011)
Summary
Asthma is defined by reversible airflow obstruction, hyperresponsiveness, and inflammation, that manifests as wheeze, dyspnea, and cough. Despite a wide array of treatments available for asthma, 5–10% of patients have poor response to inhaled corticosteroids, and remain on high doses of systemic corticosteroids (Heffler et al, 2019). At first glance, this may seem like a non-significant percentile; this subgroup contributes substantially to the economical disease burden, accounting for 56 billion US dollars annually, due to frequent exacerbations with need for acute care (Barnett and Nurmagambetov, 2011). This review will summarize the immunology of asthma, the cytokines or receptors currently targeted, and potential mechanisms of sub-optimal responses
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