FarmaCHUSLab Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
Department of Ophthalmology, Bellvitge University Hospital, 08907 Hospitalet de Llobregat, Spain.
Invest Ophthalmol Vis Sci. 2024 Nov 4;65(13):29. doi: 10.1167/iovs.65.13.29.
Adalimumab (ADA) is a systemic biological treatment option approved for the treatment of noninfectious uveitis (NIU); however, up to 40% of patients do not respond to the drug, either in a primary or secondary manner. Here, we evaluated the proteomic profile of patients with NIU who fail to ADA to identify proteins implicated in intraocular inflammation, as well as potential biomarkers for treatment response and novel therapeutic targets.
Cross-sectional observational study of patients with NIU under ADA treatment for six or more months. Tears were collected with microcapillary tubes and protein analyzed by data-independent acquisition/sequential window acquisition of all theoretical mass spectra. Differentially expressed proteins (DEPs) were defined based on the fold change between their expression in nonresponders (NR) and responders (R). Protein network and gene ontology analysis were performed. The χ2 test for trend and receiver operating characteristic (ROC) curves were used to evaluate potential biomarkers of treatment response.
Twenty-nine DEPs, 14 upregulated and 15 downregulated, were detected in NR. These proteins were mainly related to enhanced neutrophil effector functions and redox imbalance. ROC analysis identified defensin-1,3 (DEF-1,3), biotinidase, and ATP-binding cassette transporter A1 as potential biomarkers for treatment response.
This is the first study on a clinical cohort of patients with noninfectious uveitis that identifies tear proteins related to neutrophil hyperactivation as drivers of the persistent intraocular inflammation observed in NR to ADA and provides evidence that targeting interleukin 6, Janus kinases, or the complement cascade could be potential alternative therapeutic strategies in these patients. Our results indicate the potential of high-throughput proteomics to provide insights into the underlying pathological mechanisms of persistent intraocular inflammation observed in patients who do not adequately respond to anti-TNF treatment and the value of tear proteomics as a tool for personalized medicine.
阿达木单抗（ADA）是一种全身性生物治疗药物，已被批准用于治疗非感染性葡萄膜炎（NIU）；然而，高达 40%的患者对该药物没有反应，无论是初次还是再次治疗。在这里，我们评估了对 ADA 治疗无反应的 NIU 患者的蛋白质组学特征，以确定与眼内炎症相关的蛋白质，以及潜在的治疗反应生物标志物和新的治疗靶点。
对接受 ADA 治疗 6 个月或以上的 NIU 患者进行横断面观察性研究。使用微毛细管管收集泪液，通过数据非依赖性采集/所有理论质谱的顺序窗口采集分析蛋白质。根据非应答者（NR）和应答者（R）之间的表达差异，定义差异表达蛋白（DEPs）。进行蛋白质网络和基因本体分析。采用 χ2 趋势检验和受试者工作特征（ROC）曲线评估治疗反应的潜在生物标志物。
在 NR 中检测到 29 个 DEPs，其中 14 个上调，15 个下调。这些蛋白质主要与增强中性粒细胞效应功能和氧化还原失衡有关。ROC 分析确定防御素-1、3（DEF-1、3）、生物素酶和 ATP 结合盒转运蛋白 A1 为治疗反应的潜在生物标志物。
这是第一项针对非感染性葡萄膜炎临床患者队列的研究，该研究确定了与中性粒细胞过度激活相关的泪液蛋白是 ADA 治疗无反应患者持续眼内炎症的驱动因素，并提供了证据表明靶向白细胞介素 6、Janus 激酶或补体级联反应可能是这些患者的潜在替代治疗策略。我们的结果表明，高通量蛋白质组学有可能深入了解对 TNF 治疗反应不足的患者持续眼内炎症的潜在病理机制，以及泪液蛋白质组学作为个体化医学工具的价值。
