Effects of Mepolizumab and Systemic Corticosteroids on Airway Gene Expression Patterns Post-exacerbation in Urban Children With Asthma
Recommended Citation
Gaberino CL, Dill-McFarland K, Bacharier LB, Gill M, Stokes J, Liu AH, Cohen R, Kumar R, Lang A, Khurana Hershey GK, Sherenian M, Zoratti EM, Teach S, Kattan M, Becker PM, Togias A, Busse WW, Altman MC, Jackson DJ. Effects of Mepolizumab and Systemic Corticosteroids on Airway Gene Expression Patterns Post-exacerbation in Urban Children With Asthma. Am J Respir Crit Care Med 2025; 211:2.
Document Type
Conference Proceeding
Publication Date
5-1-2025
Publication Title
Am J Respir Crit Care Med
Abstract
Rationale: Systemic corticosteroids are standard-of-care treatment for asthma exacerbations; however, little is known about whether corticosteroid effects on airway inflammatory pathways differ when added to biologic therapies targeting type 2 inflammation. Methods: 290 urban children (6-17 years) with exacerbation-prone eosinophilic asthma were randomized (1:1) to q4 week placebo or mepolizumab injections added to guideline-based care for 52 weeks. Nasal lavage samples were collected at baseline (before treatment), post-exacerbation (5-10 days after starting systemic corticosteroids), and on treatment for RNA-sequencing. Differentially expressed genes (DEGs) were assessed using mixed effects modeling (significance threshold FDR<0.05). Results: 98 participants were evaluated following 170 exacerbation events (placebo:105, mepolizumab:65). In the placebo group, there were no significant differentially expressed genes comparing on treatment to before treatment timepoints. In the placebo group, there were 6363 significant DEGs (2734 increased, 3629 decreased) comparing post-exacerbation to on treatment. In the mepolizumab group, there were 1404 significant DEGs (664 increased, 740 decreased) comparing on treatment to before treatment (Fig1A: x-axis). In the mepolizumab group, there were 1111 significant DEGs (413 increased, 698 decreased) comparing post-exacerbation to on treatment (Figure 1A: y-axis). In the post-exacerbation versus on treatment contrasts, there were 885 overlapping significant DEGs (348 increased, 537 decreased) between the placebo and mepolizumab participants. Mepolizumab reduced expression of eosinophil-associated genes (CCL23, GATA1, CLC, PRSS33, PTGDR2, ADORA3, THBS4) on treatment, with a larger decrease post-corticosteroid (more reduced than placebo) (FDR<0.05) (Fig1B). Mepolizumab did not significantly alter expression of mast cell/T2 cytokine-related genes (HDC, CPA3, GATA2, TPSAB2, IL5, IL13, IL1RL1, ALOX15) on treatment; however, expression of these genes significantly decreased post-corticosteroid (more reduced than placebo) (FDR<0.05) (Fig1B). Mepolizumab increased expression of genes associated with epithelial and airway inflammation (CFTR, ERBB2, BMP3, TRPV4) on treatment; however, expression of these genes returned to baseline levels post-corticosteroid (FDR<0.05) (Fig1B). Conclusions: By comparing differential gene expression across treatment groups and time points, we identified overlapping DEGs related to systemic corticosteroid effects, DEGs related only to mepolizumab treatment, and clusters of functionally related genes with additive effects of mepolizumab plus systemic corticosteroids. Mepolizumab enhances the actions of oral corticosteroids on eosinophil related pathways in relation to exacerbations. Oral corticosteroids provide the added benefit of down-regulating mast cell and T2 cytokine pathways. Finally, oral corticosteroids reverse the up-regulation of epithelial inflammatory pathways that occurred during mepolizumab treatment.
Volume
211
First Page
2
