Budesonide

In severe asthma, intensive (“supratherapeutic”) doses of inhaled corticosteroids (ICS) are often used. The prevalence of supratherapeutic ICS use and its impact on corticosteroid-related comorbidities is poorly understood. We aimed to describe the prevalence of supratherapeutic ICS use in severe asthma, its relation to corticosteroid-related comorbidities, and changes in prescribed and redeemed ICS dose after 12 months of biologic therapy.

Patients from the nationwide Danish Severe Asthma Register (DSAR) receiving biologic therapy > 12 months were included. Supratherapeutic doses were defined as > 1600 µg budesonide daily. Baseline characteristics, comorbidity burden, and change in ICS use after 12 months of biologic therapy was stratified according to ICS use at baseline.

We included 652 patients in our analyses and 156 (24%) were supratherapeutic ICS users prior to initiation of biologic therapy. Supratherapeutic ICS users had a higher baseline prevalence of cataracts at 14 vs 8.1%; p = 0.025. No differences in other corticosteroid-related comorbidities were observed.No change in prevalence of prescribed supratherapeutic ICS was seen after 12 months of biologic therapy. However, a reduction in ICS adherence among supratherapeutic users was observed with 72% of patients demonstrating > 80% adherence at 12 months, compared to 83% at baseline (p < 0.001).

Supratherapeutic doses of ICS were used by almost one-fourth of the patients prior to initiation of biologic therapy and were associated with a higher prevalence of cataracts. Physician-driven ICS reduction was rare, yet supratherapeutic ICS users were found to self-regulate ICS therapy when treated with biologic therapy.

Macrophage extracellular traps (METs) are crucial for initiating airway inflammation and modulating the immune microenvironment of asthmatic airways. Metrnl/IL-41 is a negative regulator of airway inflammatory responses. However, the role of Metrnl/IL-41 in the cross-talk between METs and airway epithelial cells, as well as its effect on the pathophysiology of asthma airway remodeling, are still unclear. We aimed to elucidate the role of METs and Metrnl/IL-41 in airway epithelial cells and chronic asthma. Immunofluorescence and scanning electron microscopy were used to visualize METs formation. The effects of Metrnl/IL-41 on the proliferation, epithelial‒mesenchymal transition (EMT), and migration of METs-treated 16-HBE cells were determined. The role of Metrnl/IL-41 in macrophage polarization was analyzed. A chronic asthmatic murine model was established to explore the effects of rm-Metrnl/IL-41 and budesonide on lung histopathology changes, airway hyperresponsiveness, and airway inflammation and airway remodeling. Exposure to house dust mite (HDM) induced METs production in macrophages. Metrnl/IL-41 partially abrogated METs-mediated migration and EMT in 16-HBE cells by inhibiting the nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. Rm-Metrnl/IL-41 reduced airway inflammation, airway hyperresponsiveness, mucus secretion, collagen deposition, transforming growth factor-β1 (TGF-β1) levels, and EMT-related protein levels in asthmatic mice. Additionally, Metrnl/IL-41 significantly reduced neutrophils, M1 macrophages, and Th17 cells numbers in the lungs of asthmatic mice. METs play critical roles in EMT and airway remodeling, inhibiting METs formation may constitute a prospective therapeutic approach for asthma. Metrnl/IL-41 is a crucial protective cytokine against airway inflammation, indicating its potential as a therapeutic target in asthma.