Department of Rheumatology and Immunology, Peking University International Hospital, Beijing, China.
Department of Retroperitoneal Tumor Surgery, Peking University International Hospital, Beijing, China.
Ann Rheum Dis. 2023 May;82(5):688-697. doi: 10.1136/ard-2022-223736. Epub 2023 Jan 31.
Retroperitoneal fibrosis (RPF) is a rare autoimmune disease with fibrous tissue growth and inflammation in retroperitoneum. Its current treatments involve long-term uptake of glucocorticoids (e.g., prednisone) for controlling inflammation; however, side effects are common. We strived for an improved therapy for fibrosis remission while reducing side effects.
We surveyed gene-disease-drug databases and discovered that mammalian target of rapamycin (mTOR) was a key signalling protein in RPF and the mTOR inhibitor compound sirolimus affected many RPF pathways. We designed a therapy combining a gradual reduction of prednisone with a long-term, stable dosage of sirolimus. We then implemented a single-arm clinical trial and assessed the effects in eight RPF patients at 0, 12 and 48 weeks of treatment by measuring fibrous tissue mass by CT, markers of inflammation and kidney functions by lab tests, immune cell profiles by flow cytometry and plasma inflammatory proteins by Olink proteomics.
With the combined therapy, fibrous tissue shrunk about by half, markers of acute inflammation reduced by 70% and most patients with abnormal kidney functions had them restored to normal range. Molecularly, fibrosis-related T cell subsets, including T2, T17 and circulating T cells, were reduced and tumour necrosis factor and related cytokines restored to healthy levels. No severe long-term side effects were observed.
Our combined therapy resulted in significant fibrosis remission and an overall regression of the immune system towards healthy states, while achieving good tolerance. We concluded that this new therapy had the potential to replace the steroid monotherapy for treating RPF.
腹膜后纤维化（RPF）是一种罕见的自身免疫性疾病，其特征是腹膜后纤维组织增生和炎症。目前的治疗方法包括长期服用糖皮质激素（如泼尼松）来控制炎症；然而，副作用很常见。我们努力寻找一种改善纤维化缓解的治疗方法，同时减少副作用。
我们调查了基因-疾病-药物数据库，发现哺乳动物雷帕霉素靶蛋白（mTOR）是 RPF 的关键信号蛋白，mTOR 抑制剂西罗莫司影响许多 RPF 途径。我们设计了一种联合治疗方案，即逐渐减少泼尼松的用量，同时长期稳定剂量使用西罗莫司。然后，我们进行了一项单臂临床试验，在 0、12 和 48 周的治疗期间，通过 CT 测量纤维组织质量、实验室检测炎症标志物和肾功能、流式细胞术检测免疫细胞谱和 Olink 蛋白质组学检测血浆炎症蛋白，评估了 8 例 RPF 患者的治疗效果。
联合治疗后，纤维组织缩小了约一半，急性炎症标志物降低了 70%，大多数肾功能异常的患者肾功能恢复正常。从分子水平上看，纤维化相关的 T 细胞亚群，包括 T2、T17 和循环 T 细胞，减少了，肿瘤坏死因子和相关细胞因子恢复到健康水平。未观察到严重的长期副作用。
我们的联合治疗方案显著缓解了纤维化，并使免疫系统整体向健康状态回归，同时具有良好的耐受性。我们得出结论，这种新的治疗方法有可能替代类固醇单药治疗 RPF。
