Dupilumab‐associated ocular surface disease is characterized by a shift from Th2/Th17 toward Th1/Th17 inflammation

• Published in: Allergy (Copenhagen) Vol. 79; no. 4; pp. 937 - 948
• Main Authors: Thormann, Kathrin, Lüthi, Anne‐Sophie, Deniau, Felix, Heider, Anja, Cazzaniga, Simone, Radonjic‐Hoesli, Susanne, Lehmann, Mathias, Schlapbach, Christoph, Herzog, Elio L., Kreuzer, Marco, Zinkernagel, Martin S., Akdis, Cezmi A., Zysset‐Burri, Denise C., Simon, Hans‐Uwe, Simon, Dagmar
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.04.2024
• Subjects: Antibodies, Monoclonal, Humanized; Atopic dermatitis; Dermatitis, Atopic - diagnosis; Dermatitis, Atopic - drug therapy; Dermatitis, Atopic - metabolism; dry eye disease; dupilumab; Eczema; Eye Diseases; Fibrosis; Helper cells; Humans; Inflammation; Lymphocytes T; Microbiomes; Monoclonal antibodies; Next-generation sequencing; ocular surface disease; Pilot Projects; Proteomics; remodeling; Severity of Illness Index; Side effects; Treatment Outcome; type 1 inflammation; Up-regulation; ocular surface disease; atopic dermatitis; remodeling; dry eye disease; type 1 inflammation; dupilumab
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.16045

Background Dupilumab is used for the treatment of atopic dermatitis (AD). Approximately one third of AD patients develop a dupilumab‐associated ocular surface disease (DAOSD), of which the pathomechanism is poorly understood. This study aimed at investigating inflammatory markers in tear fluids of patients on dupilumab therapy. Methods Tear fluids were collected from AD patients with DAOSD (ADwDAOSD), AD patients without DAOSD (ADw/oDAOSD), and non‐AD patients before and during dupilumab therapy, and analyzed using a specialized proteomic approach quantifying inflammatory markers. The ocular surface microbiome was determined by next generation sequencing technology. Results Upon dupilumab therapy, an upregulation of 31 inflammatory markers was observed in DAOSD tear fluids compared to baseline in AD patients. While IL‐12B was upregulated in both ADwDAOSD and ADw/oDAOSD groups, the pattern of inflammatory markers significantly differed between groups and over time. In the ADwDAOSD group, a shift from a mixed Th2/Th17 pattern at baseline toward a Th1/Th17 profile under dupilumab was observed. Furthermore, an upregulation of remodeling and fibrosis markers was seen in DAOSD. Semantic map and hierarchical cluster analyses of baseline marker expression revealed four clusters distinguishing between AD and non‐AD as well as ADwDAOSD and ADw/oDAOSD patient groups. In a pilot study, dupilumab therapy was associated with a decrease in richness of the ocular surface microbiome. Conclusions DAOSD is characterized by a Th1/Th17 cytokine profile and an upregulation of markers known to promote remodeling and fibrosis. The expression pattern of inflammatory markers in tear fluids at baseline might serve as a prognostic factor for DAOSD. Dupilumab therapy affects the expression of inflammatory markers in tear fluids and the microbiome of ocular surfaces of AD patients. A high expression of Th2/Th17 inflammatory markers in tear fluids at baseline is characteristic for AD patients later developing DAOSD. In patients developing DAOSD, a shift from a Th2/Th17 toward a Th1/Th17 inflammation pattern at ocular surfaces is observed.Abbreviations: AD, atopic dermatitis; CCL, C‐C motif chemokine ligand; DAOSD, dupilumab‐associated ocular surface disease; IFN, interferon; IL, interleukin; LIF, leukemia inhibitory factor; MMP‐1, matrix metalloprotease 1; NPX, normalized protein expression; OSM, oncostatin; TGF, transforming growth factor; Th, T helper; TNF, tumor necrosis factor; TNSF14, TNF super family member 14.