Kraaijvanger Raisa, Janssen Bonás Montse, Paspali Ioanna, Grutters Jan C, Veltkamp Marcel, de Kleijn Dominique P V, van Moorsel Coline H M
ILD Center of Excellence, member of European Reference Network-Lung, St Antonius Hospital, Nieuwegein, The Netherlands.
Department of Vascular Surgery, Division of Surgical Specialties, University Medical Center, Utrecht, The Netherlands.
ERJ Open Res. 2025 Mar 3;11(2). doi: 10.1183/23120541.00672-2024. eCollection 2025 Mar.
∼30% of patients with sarcoidosis, a systemic granulomatous disease of unknown cause, need treatment to alleviate symptoms or prevent organ damage. Prednisone and methotrexate (MTX) are the most commonly used drugs; however, success of treatment varies from patient to patient. In this study, we search for biomarkers and pathways that predict response to treatment with prednisone or MTX in extracellular vesicles (EVs).
A targeted proteomics approach (OLINK Bioscience) was used in which 92 proteins were measured in two baseline EV fractions in 32 patients treated for pulmonary sarcoidosis (eight responders and eight non-responders each for prednisone and MTX). The top three proteins were replicated in 62 prednisone- and 76 MTX-treated patients.
We identified 11 differentially expressed proteins (DEPs) between responders and non-responders to prednisone treatment, and 16 DEPs for patients treated with MTX. Reactome pathway analysis showed DEPs in prednisone to be involved in nuclear factor kappa B and interleukin signalling pathways. The DEPs in MTX were involved in transduction of GPI-anchored proteins and MAPK signalling pathway. CHI3L1 for prednisone and CPA1 for MTX were replicated as significant predictors of response.
This study is the first to show that in pulmonary sarcoidosis the response to treatment with prednisone or MTX can be predicted at baseline by different EV proteins active in different pathways. Using these markers and associated pathways to identify patients with a high probability of response to therapy will aid personalised treatment choice and improve treatment outcome.
结节病是一种病因不明的全身性肉芽肿性疾病，约30%的患者需要治疗以缓解症状或预防器官损害。泼尼松和甲氨蝶呤（MTX）是最常用的药物；然而，治疗效果因人而异。在本研究中，我们在细胞外囊泡（EVs）中寻找可预测对泼尼松或MTX治疗反应的生物标志物和信号通路。
采用靶向蛋白质组学方法（欧林生物科学公司），对32例接受肺结节病治疗的患者（泼尼松和MTX治疗组各有8例反应者和8例无反应者）的两个基线EV组分中的92种蛋白质进行检测。在前62例接受泼尼松治疗和76例接受MTX治疗的患者中重复检测了排名前三的蛋白质。
我们鉴定出泼尼松治疗反应者与无反应者之间有11种差异表达蛋白（DEP），MTX治疗患者有16种DEP。Reactome通路分析显示，泼尼松治疗中的DEP参与核因子κB和白细胞介素信号通路。MTX治疗中的DEP参与糖基磷脂酰肌醇锚定蛋白的转导和丝裂原活化蛋白激酶信号通路。泼尼松治疗中的CHI3L1和MTX治疗中的CPA1被重复确认为反应的显著预测因子。
本研究首次表明，在肺结节病中，泼尼松或MTX治疗反应可在基线时通过不同信号通路中起作用的不同EV蛋白进行预测。利用这些标志物和相关信号通路来识别对治疗反应可能性高的患者，将有助于个性化治疗选择并改善治疗结果。
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