BACKGROUND:Asthma remission is a feasible treatment goal. However, remission definitions vary, and predictive biomarkers remain underexplored. METHODS:We conducted a post hoc analysis of ATLANTIS (NCT02123667), a multinational prospective study including 684 adult asthmatics. Remission was defined by 3-component (3C) and 4-component (4C) criteria. 3C remission included: (1) ACQ-6 < 1.5, (2) no maintenance oral corticosteroids, (3) no exacerbations. An absolute decline < 10% in pre-bronchodilator FEV1% predicted, was added for the 4C definition. Multivariate logistic regression identified remission predictors. A novel Low Disease Activity (LDA) score was developed using factor analysis of five clinical variables (ACQ-6, FeNO, BEC, and FEV1) including an innovative small airways dysfunction questionnaire tool (SADT). Nasal transcriptomics were analysed for differential gene expression and pathway enrichment and were replicated in U-BIOPRED (NCT01976767) using sputum transcriptomics. U-BIOPRED was included only to study omics replication of remission pathways identified in ATLANTIS. FINDINGS:Remission occurred in 48% (3C) and 45% (4C) of patients. Predictors included male sex, better lung function, fewer previous exacerbations, and higher SADT (fewer small airways symptoms). LDA identified milder disease and was associated with remission [OR 3C 4.43 (2.80, 7.10) and 4C 3.46 (2.23, 5.43)], improved QoL [OR 2.07 (1.65, 2.60)], and fewer future exacerbations [OR 0.43 (0.22, 0.85)]. Transcriptomic analyses revealed remission-associated upregulation of interleukin 4/13 signalling and downregulation of coagulation pathways, in both ATLANTIS and U-BIOPRED. INTERPRETATION:SAD was associated with reduced asthma remission. A novel LDA tool demonstrated clinical utility in stratifying prospective asthma risk. Key immunologic and haemostatic pathways may underpin remission, offering potential targets for future intervention.
BACKGROUND:Biologics targeting type 2 cytokines can inhibit airway inflammation and improve lung function in moderate-to-severe asthma; however, their impact on airway mucosal inflammatory cells is unclear. This study assessed the effects of dupilumab on airway mucosal and systemic inflammation, and related gene expression in patients with persistent asthma. METHODS:In the phase 2a EXPEDITION study (NCT02573233), patients aged 18-65 years were randomised to add-on dupilumab 300 mg (n = 20) or placebo (n = 22) every 2 weeks for 12 weeks. Pre- and post-treatment bronchial biopsies, bronchial brushings, bronchoalveolar lavage (BAL) fluid and blood samples were collected. Clinical and patient-reported outcomes, gene expression, type 2 biomarkers and safety outcomes were assessed. RESULTS:Dupilumab versus placebo improved lung function and asthma control. No significant changes in eosinophils, mast cells or type 2 helper cells were observed in bronchial biopsies. Downregulation of M2 macrophage- and eosinophil-associated gene sets was observed in BAL and brushing samples after dupilumab. Dupilumab decreased multiple circulating type 2 biomarkers in peripheral blood (punadj < 0.001, padj < 0.01), goblet cell numbers (punadj = 0.0336; padj = 0.2554) and mucus area (punadj = 0.0426; padj = 0.2554) in bronchial biopsies versus placebo. The safety profile was consistent with the known safety profile of dupilumab. CONCLUSION:Dupilumab improved lung function and asthma control while reducing circulating type 2 biomarkers. No measurable impact was observed on type 2-associated inflammatory cell numbers in airway bronchial biopsies; however, dupilumab modulated the expression of inflammation-associated gene sets. These findings provide cellular and molecular data that may explain dupilumab-driven mechanisms of improved lung function in patients with type 2 asthma.
