RESUMEN
BACKGROUND: Mepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids remain the main treatment for these residual exacerbations. OBJECTIVE: Our study aimed to explore the corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms beyond the IL-5 pathway. METHOD: The MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in 27 patients treated with mepolizumab for SEA. We analysed paired sputum (n=16) and plasma (n=25) samples from the MAPLE trial using high-throughput Olink® proteomics. We also analysed additional sputum proteins using ELISA. RESULTS: In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Neutrophilic pathways were upregulated. Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated. CONCLUSION: At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab. These effects are heterogeneous and may be clinically relevant in residual exacerbations.
RESUMEN
BACKGROUND: Mucus plugs in asthmatic airways are associated with airway obstruction and the activity of inflammatory cytokines, specifically interleukin (IL)-5 and IL-13, and they may provide an opportunity for targeted therapy. This analysis of the CASCADE (Study to Evaluate Tezepelumab on Airway Inflammation in Adults With Uncontrolled Asthma) placebo-controlled trial used computed tomography (CT) imaging to assess mucus plugs in patients with moderate-to-severe, uncontrolled asthma who received tezepelumab or placebo. METHODS: CASCADE was an exploratory, double-blind, placebo-controlled trial examining the anti-inflammatory effect of tezepelumab. Patients (aged 18 to 75 years old) were randomly assigned 1:1 to 210 mg tezepelumab or placebo every 4 weeks subcutaneously for at least 28 weeks. An expert radiologist, blinded to treatment groups and time points, objectively scored 18 lung segments for the presence of mucus plugs in CT scans obtained before and after treatment; greater numbers of mucus plugs resulted in higher mucus plug scores. RESULTS: Absolute change from baseline (mean [±standard deviation]) in mucus plug score was −1.7±2.6 in patients receiving tezepelumab (n=37) and 0.0±1.4 in patients receiving placebo (n=45). At baseline, mucus plug scores correlated positively with levels of inflammatory biomarkers (blood eosinophils, eosinophil-derived neurotoxin, fractional exhaled nitric oxide, IL-5, and IL-13) and negatively with lung function measures (prebronchodilator forced expiratory volume in 1 second and forced mid-expiratory flow). In tezepelumab recipients, reductions in mucus plug scores were correlated with improvements in lung function and reductions in blood eosinophil count and levels of eosinophil-derived neurotoxin, a biomarker of eosinophilic degranulation. CONCLUSIONS: Tezepelumab was associated with a reduction in occlusive mucus plugs versus placebo in a randomized controlled trial in patients with moderate-to-severe, uncontrolled asthma. (Funded by AstraZeneca and Amgen Inc.; ClinicalTrials.gov number, NCT03688074.)
