Background

Mepolizumab is an anti-interleukin-5 monoclonal antibody for severe eosinophilic asthma (SEA). The effects of mepolizumab, or the addition of oral corticosteroids (OCS) to mepolizumab, on molecular mechanisms in the airway epithelium are poorly understood.

Aim

Determine the transcriptional effects of mepolizumab followed by prednisolone or placebo on the nasal epithelium in patients with SEA.

Methods

MAPLE was a randomized, double-blind, placebo-controlled crossover trial of prednisolone at stable state in adults with SEA after mepolizumab (Yang F, JACI Pract 2022;10:2925-34.e12). OCS had a minor effect on FEV1 but not on symptoms. Nasal scrape samples were taken before mepolizumab, and after OCS and placebo. RNA was extracted using Qiagen kits and sequenced on good quality samples using Illumina Novaseq.

Results

5 paired samples comparing pre- to post- mepolizumab on placebo revealed 377 differentially expressed genes (DEG) for gene ontology analysis (adj p <0.1, abs log2fold >0.5). Genes down-regulated by mepolizumab related to the structure and function of cilia. Genes up-regulated by mepolizumab related to extracellular matrix structure and keratinisation.

6 paired samples comparing OCS to placebo on mepolizumab revealed 30 DEGs. Genes down-regulated by OCS included leukocyte chemotaxis, mast cell tryptase, and the 15-lipoxygenase pathway.

Conclusions

Mepolizumab affects transcription of genes related to nasal epithelial cell structure, but it is unclear how this relates to epithelial function. Prednisolone in addition to mepolizumab suppresses additional biology unaffected by IL-5 inhibition. The relationship of these additional effects to clinical outcome is unresolved.

Funder

GSK