Metabolomic and lipidomic alterations in atopic dermatitis patients with dupilumab-associated ocular surface disease

Background Atopic dermatitis (AD) is an inflammatory skin disease characterized by chronic pruritic eczema with an estimated prevalence of 10% in adults, with 50% suffering moderate to severe manifestations. Dupilumab, an IL-4/IL-13 inhibitor, is approved for treating moderate to severe AD. Dupilumab-associated ocular surface disease (DAOSD) emerges in up to 60% of dupilumab-treated patients, constituting a major AD-specific adverse event. DAOSD pathogenesis has not been fully understood yet. Objective To elucidate metabolic changes occurring after dupilumab treatment in AD patients, particularly focusing on those who develop DAOSD. Methods In this prospective single-center cohort study, 20 AD patients underwent dupilumab therapy, with six developing DAOSD. Plasma and serum samples were collected at baseline, 4- and 16-weeks post-treatment initiation, and during the conjunctivitis episode. Additionally, 10 age- and sex-matched healthy controls were sampled solely at baseline. High resolution mass spectrometry was employed for metabolomic and lipidomic analysis of all blood samples. Results Targeted metabolomics and lipidomics identified 138 metabolites and lipids, while untargeted analysis revealed 7931 features in plasma or serum. Multivariate analysis unveiled significant metabolic and lipidic disparities between untreated AD patients and healthy controls, notably in AD patients who later developed DAOSD. The metabolic and lipidic profiles and their associated pathways were significantly influenced by ongoing treatment, with distinct kinetics differing between AD and DAOSD patients. Conclusion Metabolomics and lipidomics analysis further deepen our comprehension of DAOSD pathogenesis. Financial support: This project was financially supported by the City of Graz to VP and NW and the Dr. Adele-Rabensteiner Foundation of the Austrian Association of Ophthalmology to NW and by the Austrian Science Fund FWF (W1241) to PW. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. No conflicting relationship exists for any author.背景 特应性皮炎（Atopic Dermatitis, AD）是一种以慢性瘙痒性湿疹为特征的炎症性皮肤病，成人患病率约为10%，其中50%患者表现为中重度临床症状。度普利尤单抗（Dupilumab）是一种IL-4/IL-13抑制剂，已获批用于治疗中重度特应性皮炎。在接受度普利尤单抗治疗的患者中，度普利尤单抗相关眼表疾病（Dupilumab-associated Ocular Surface Disease, DAOSD）的发生率可达60%，是特应性皮炎治疗相关的主要不良事件。目前DAOSD的发病机制尚未完全阐明。 研究目的 本研究旨在阐明特应性皮炎患者接受度普利尤单抗治疗后的代谢变化，重点关注发生DAOSD的患者亚群。 研究方法 本研究为单中心前瞻性队列研究，共纳入20名接受度普利尤单抗治疗的特应性皮炎患者，其中6名后续发生DAOSD。分别于治疗基线、治疗启动后第4周、第16周以及结膜炎发作时采集血浆与血清样本。另纳入10名年龄与性别匹配的健康对照，仅在基线时采集样本。采用高分辨质谱技术对所有血液样本进行代谢组学与脂质组学分析。 研究结果 靶向代谢组学与脂质组学共鉴定出138种代谢物及脂质，而非靶向分析则在血浆或血清中检出7931个特征峰。多变量分析显示，未接受治疗的特应性皮炎患者与健康对照之间存在显著的代谢与脂质组差异，在后续发生DAOSD的特应性皮炎患者中尤为显著。治疗进程显著影响代谢与脂质组特征及其相关通路，且特应性皮炎患者与DAOSD患者的代谢动力学特征存在显著差异。 研究结论 代谢组学与脂质组学分析进一步深化了我们对DAOSD发病机制的认知。 经费支持 本项目由格拉茨市资助VP与NW，奥地利眼科学会阿德莱·拉本施泰纳博士基金会资助NW，奥地利科学基金FWF（W1241）资助PW。资助方未参与研究设计、数据采集与解读，亦未干预论文投稿与发表决策。所有作者均无利益冲突。