Small Airways Dysfunction and Remission in Adults With Asthma: A Longitudinal Exploratory Analysis of the <scp>AssessmenT</scp> of <scp>smalL</scp> Airways <scp>involvemeNT</scp> In <scp>aSthma</scp> ( <scp>ATLANTIS</scp> ) Study

ABSTRACT 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 FEV 1 % 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 FEV 1 ) 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.