Department of Women's & Children's Health, University of Liverpool, Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
Medical Physics and Clinical Engineering, and Department of Physics, University of Liverpool, Liverpool, UK.
Clin Immunol. 2019 Jan;198:71-78. doi: 10.1016/j.clim.2018.10.021. Epub 2018 Nov 2.
BACKGROUND: A urine 'biomarker panel' comprising alpha-1-acid-glycoprotein, ceruloplasmin, transferrin and lipocalin-like-prostaglandin-D synthase performs to an 'excellent' level for lupus nephritis identification in children cross-sectionally. The aim of this study was to assess if this biomarker panel predicts lupus nephritis flare/remission longitudinally. METHODS: The novel urinary biomarker panel was quantified by enzyme linked immunoabsorbant assay in participants of the United Kingdom Juvenile Systemic Lupus Erythematosus (UK JSLE) Cohort Study, the Einstein Lupus Cohort, and the South African Paediatric Lupus Cohort. Monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were also quantified in view of evidence from other longitudinal studies. Serial urine samples were collected during routine care with detailed clinical and demographic data. A Markov Multi-State model of state transitions was fitted, with predictive clinical/biomarker factors assessed by a corrected Akaike Information Criterion (AICc) score (the better the model, the lower the AICc score). RESULTS: The study included 184 longitudinal observations from 80 patients. The homogeneous multi-state Markov model of lupus nephritis activity AICc score was 147.85. Alpha-1-acid-glycoprotein and ceruloplasmin were identified to be the best predictive factors, reducing the AICc score to 139.81 and 141.40 respectively. Ceruloplasmin was associated with the active-to-inactive transition (hazard ratio 0.60 (95% confidence interval [0.39, 0.93])), and alpha-1-acid-glycoprotein with the inactive-to-active transition (hazard ratio 1.49 (95% confidence interval [1.10, 2.02])). Inputting individual alpha-1-acid-glycoprotein/ceruloplasmin values provides 3, 6 and 12 months probabilities of state transition. CONCLUSIONS: Alpha-1-acid-glycoprotein was predictive of active lupus nephritis flare, whereas ceruloplasmin was predictive of remission. The Markov state-space model warrants testing in a prospective clinical trial of lupus nephritis biomarker led monitoring.
背景：尿液“生物标志物小组”包括α-1-酸性糖蛋白、铜蓝蛋白、转铁蛋白和脂联素样前列腺素 D 合酶，在横断面研究中对儿童狼疮肾炎的识别具有“优异”水平。本研究的目的是评估该生物标志物小组是否可以纵向预测狼疮肾炎的发作/缓解。
方法：通过酶联免疫吸附测定法对英国青少年系统性红斑狼疮（UK JSLE）队列研究、爱因斯坦狼疮队列和南非儿科狼疮队列的参与者进行新型尿液生物标志物小组的定量检测。鉴于其他纵向研究的证据，还对单核细胞趋化蛋白-1 和血管细胞黏附分子-1 进行了定量检测。在常规护理过程中收集了一系列尿液样本，并收集了详细的临床和人口统计学数据。使用状态转移的马尔可夫多状态模型进行拟合，通过校正的 Akaike 信息准则（AICc）评分评估预测性临床/生物标志物因素（模型越好，AICc 评分越低）。
结果：该研究包括 80 名患者的 184 个纵向观察结果。狼疮肾炎活动的同质多状态马尔可夫模型 AICc 评分为 147.85。α-1-酸性糖蛋白和铜蓝蛋白被确定为最佳预测因素，分别将 AICc 评分降低至 139.81 和 141.40。铜蓝蛋白与活跃到不活跃的转变相关（危险比 0.60（95%置信区间[0.39,0.93]）），而α-1-酸性糖蛋白与不活跃到活跃的转变相关（危险比 1.49（95%置信区间[1.10,2.02]））。输入个体α-1-酸性糖蛋白/铜蓝蛋白值可提供 3、6 和 12 个月的状态转移概率。
结论：α-1-酸性糖蛋白可预测活跃性狼疮肾炎发作，而铜蓝蛋白可预测缓解。马尔可夫状态空间模型值得在狼疮肾炎生物标志物监测的前瞻性临床试验中进行测试。
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