Airway autoimmunity, asthma exacerbations, and response to biologics

Abstract

Monoclonal antibodies (mAb) directed against T2 cytokines are increasingly becoming the standard of care for severe asthma. Six biologics are currently approved by the US FDA to treat patients with severe asthma. Omalizumab targets IgE, mepolizumab and reslizumab, are neutralizing antibodies against ligand IL-5, benralizumab targets IL-5Rα, dupilumab is directed against IL-4Rα, and tezepelumab blocks the epithelial-derived alarmin, TSLP. 1,2 They are very effective to reduce asthma exacerbations and the need for maintenance of oral corticosteroids (OCS) in most patients whose asthma severity is driven by the corresponding target protein.However, suboptimal responses to these biologics are being gradually recognized. [3][4][5][6] Several reasons might explain asthma exacerbations when patients are being treated with biologics, after initial good responses (Figure 1), including inadequate efficacy of the biologic or other unrelated causes such as airway infections or a new co-morbid process. The sub-optimal responses could be related to

TNF Superfamily and ILC2 Activation in Asthma

“…For example, airway autoantibodies are associated with the formation of eosinophil extracellular traps, which were resistant to treatment with dexamethasone [ 91 ]. In addition, increased levels of anti-EPX IgG were observed in severe asthmatics who did not respond to anti-IL-5 therapy, and severe asthmatics with two or more autoantibodies, such as anti-EPX, MARCO, and nuclear/extractable nuclear antigens, were at a higher risk of exacerbations and were likely not to respond to biologics, as their titers were not attenuated by current anti-inflammatory treatment, regardless of eosinophil suppression [ 92 , 94 , 95 ]. Specifically, mixed granulocytic (>2% sputum eosinophils and >64% sputum neutrophils) asthma patients with anti-MARCO IgG antibodies had higher risk of subsequent asthma exacerbation triggered by infection.…”

The United Airways Clinic: roadmap of a patient‐centred multidisciplinary approach to the complex airways patient: the Sydney model

“…The UAC aimed to improve collaboration between specialists leading to improved health outcomes, timely access to care and accordingly more appropriate health care resource utilisation 8 . Furthermore, this approach supports a patient‐centred care approach that is not only collaborative but also cost‐effective 9 .…”

Role of club cell 16‐kDa secretory protein in asthmatic airways

“…Eosinophils, mast cells and neutrophils are major effector cells driving chronic airways inflammation, while epithelial cells and smooth muscles are major structural cells contribute to initiating symptoms. 1,2 Airways epithelial cells (AECs) closely interacting with eosinophils are the first defence cells to initiate, maintain and augment long-standing airways inflammation; therefore, epitheliumcentred endotypes in response to external/endogenous stimuli may be key factors to determine persistent airways inflammation and progressive airways remodelling. Living cells release reactive oxygen species (ROS), which cause oxidative stress such as metabolic consequences in combat with invading allergens, wound healing and repairing processes.…”