Persistent Neutrophil Infiltration and Unique Ocular Surface Microbiome Typify Dupilumab–Associated Conjunctivitis in Patients with Atopic Dermatitis
Vijaykumar Patra, Nora Woltsche, Urban Čerpes, Danijela Bokanovic, Maria Repelnig, Aaroh Joshi, Isabella Perchthaler, Manuela Fischl, Marc Vocanson, Natalie Bordag, Marija Durdević, Johannes Woltsche, Franz Quehenberger, Franz J. Legat, Andreas Wedrich, Jutta Horwath‐Winter, Peter Wolf
Abstract
ObjectiveTo elucidate the pathogenesis of dupilumab [Dupixent®]-associated ocular surface disease (DAOSD).DesignProspective single-centre cohort study.Subjects and ControlsTwenty patients with moderate to severe atopic dermatitis (AD) who received dupilumab and ten age- and sex-matched healthy controls were enrolled in the study.MethodsThe study cohort underwent a thorough slit lamp and whole-body dermatologic examination. Conjunctival swabs and smears were collected at baseline, four and sixteen weeks after treatment initiation, and during the conjunctivitis episode. 16S rRNA sequencing was performed to analyse the ocular surface microbiome, smears were H&E stained, and serum cytokines were measured by using a multiplex immunobead assay.Main Outcome MeasuresComposition of ocular surface microbiome and cellular component, as well as serum cytokine levels.ResultsSix of the twenty AD patients developed DAOSD after dupilumab initiation; these patients responded after a delay to treatment as quantified by Eczema Area and Severity Index (EASI) and Investigator’s Global Assessment (IGA). Conjunctival smears showed massive neutrophilic infiltration and serum analysis revealed increased systemic levels of neutrophil-priming pro-inflammatory cytokines, in particular IL -1β and TNF-α in patients with DAOSD compared to those without it. The ocular surface microbiome of patients with DAOSD was characterised by a diverse and persistent microbial colonisation, and particularly by Acetobacter aceti. In contrast, microbial diversity decreased in AD patients without DAOSD after the initiation of dupilumab treatment, and especially the abundance of Staphylococcus aureus. In vitro experiments substantiated the potential role of the microbiome, showing increased growth of Acetobacter aceti and decreased growth of Staphylococcus aureus in presence of dupilumab.ConclusionsPersistent neutrophilic infiltration and a unique microbial landscape on the ocular surface associated with elevated levels of systemic pro-inflammatory cytokines typify DAOSD.