Type I interferon gene expression signature as a marker to predict response to cyclophosphamide based treatment in proliferative lupus nephritis.

IF 1.9 4区 医学 Q3 RHEUMATOLOGY Lupus Pub Date : 2024-09-01 Epub Date: 2024-07-20 DOI:10.1177/09612033241266779
Sree Nethra Bulusu, Christina Mary Mariaselvam, Sanket Shah, Vallayyachari Kommoju, Chengappa Kavadichanda, Kotten Thazhath Harichandrakumar, Molly Thabah, Vir Singh Negi
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Abstract

Objectives: To assess the longitudinal effect of cyclophosphamide (CYC) treatment on type-I interferon (IFN) signature in proliferative lupus nephritis (LN) and its role in predicting treatment response.

Methods: Fifty-four biopsy proven proliferative LN patients scheduled to receive high-dose (HD) or low-dose (LD) CYC were recruited and followed up for six months. At six months, patients were classified as clinical responders (CR) or non-responders (NR) to treatment, using the EULAR/EDTA criteria. An IFN-gene based score (IGS) was developed from the mean log-transformed gene expression of MX1, OAS1, IFIT1, OASL, IFIT4, LY6E, IRF7 at baseline, three and six months. Longitudinal changes of IGS within and between groups were assessed and ΔIGS, which is the difference in IGS between baseline and three months was calculated. Independent predictors of non-response were identified and an ROC analysis was performed to evaluate their utility to predict NR.

Results: There was a dynamic change in IGS within the HD, LD, CR, and NR groups. Compared to baseline, there was a significant decrease in IGS at three months in HD and LD groups (HD group: 2.01 to 1.14, p = .001; LD group = 2.01 to 0.81, p < .001), followed by a significant increase from three to six months in LD group (LD: 0.81 to 1.51, p = .03; HD: 1.14 to 1.54, p = .300). A decrease in IGS from baseline to three months was seen in both CR (2.13 to 0.79, p < .001) and NR groups (1.83 to 1.27, p = .046), and a significant increase from three to six months was observed only in the CR group (CR: 0.79 to 1.57, p = .006; NR: 1.27 to 1.46, p = 1). ΔIGS (baseline to three months) was higher in CR compared to NR group (-1.339 vs -0.563, p = .017). ROC analysis showed that the model comprising of 0.81 fold decrease in IGS from baseline to three months, endocapillary hypercellularity and interstitial inflammation on renal histopathology predicted non-response with a sensitivity of 83.3% and specificity of 71.4%.

Conclusion: In proliferative LN, treated with HD or LD-CYC, combined model comprising of decrease in IGS score by 0.81 fold from baseline to three months, along with important histopathological features such as endocapillary hypercellularity and interstitial inflammation had better predictive capability for non-response.

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I型干扰素基因表达特征是预测增殖性狼疮肾炎患者对环磷酰胺治疗反应的标志。
研究目的评估环磷酰胺(CYC)治疗对增殖性狼疮肾炎(LN)I型干扰素(IFN)特征的纵向影响及其在预测治疗反应中的作用:招募了54名经活检证实的增殖性狼疮肾炎患者,计划接受高剂量(HD)或低剂量(LD)CYC治疗,并随访6个月。6个月后,根据EULAR/EDTA标准将患者分为临床应答者(CR)和非应答者(NR)。根据基线、3个月和6个月时MX1、OAS1、IFIT1、OASL、IFIT4、LY6E、IRF7的平均对数变换基因表达量,制定了基于IFN基因的评分(IGS)。评估组内和组间 IGS 的纵向变化,并计算基线和三个月之间 IGS 的差异 ΔIGS。确定了无应答的独立预测因素,并进行了 ROC 分析,以评估其预测无应答的效用:结果:在 HD、LD、CR 和 NR 组中,IGS 发生了动态变化。与基线相比,HD 组和 LD 组的 IGS 在三个月时显著下降(HD 组:2.01 至 1.14,p = .001;LD 组 = 2.01 至 0.81,p < .001),随后,LD 组的 IGS 在三个月至六个月时显著上升(LD 组:0.81 至 1.51,p = .03;HD 组:1.14 至 1.54,p = .300)。从基线到三个月期间,IGS 在 CR 组(2.13 到 0.79,p < .001)和 NR 组(1.83 到 1.27,p = .046)均有所下降,而从三个月到六个月期间,只有 CR 组的 IGS 有显著增加(CR:0.79 到 1.57,p = .006;NR:1.27 到 1.46,p = 1)。与 NR 组相比,CR 组的ΔIGS(基线至三个月)更高(-1.339 vs -0.563,p = .017)。ROC分析显示,由IGS从基线到三个月下降0.81倍、肾组织病理学上的毛细血管内皮细胞增生和肾间质炎症组成的模型预测无应答的敏感性为83.3%,特异性为71.4%:在接受 HD 或 LD-CYC 治疗的增殖性 LN 患者中,由从基线到三个月期间 IGS 评分下降 0.81 倍以及重要的组织病理学特征(如毛细血管内皮细胞增生和间质炎症)组成的联合模型对无应答具有更好的预测能力。
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来源期刊
Lupus
Lupus 医学-风湿病学
CiteScore
4.20
自引率
11.50%
发文量
225
审稿时长
1 months
期刊介绍: The only fully peer reviewed international journal devoted exclusively to lupus (and related disease) research. Lupus includes the most promising new clinical and laboratory-based studies from leading specialists in all lupus-related disciplines. Invaluable reading, with extended coverage, lupus-related disciplines include: Rheumatology, Dermatology, Immunology, Obstetrics, Psychiatry and Cardiovascular Research…
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