Predictive Biomarkers for disease activity and organ damage in patients with lupus

摘要 狼疮性肾炎（LN）是系统性红斑狼疮（SLE）最严重的表现之一， 与显著的发病率和死亡率相关。目前临床实验室标志物缺乏足够的灵敏度 和特异性来优化个体患者护理，从而需要开发新的LN生物标志物。到 为了解决这一未满足的需求，狼疮研究界做出了重大努力， 新的LN生物标志物，但迄今为止还没有一个有资格用于临床使用。我们推测其中一个 这些失败的重要原因是没有单一的生物标志物可以解释SLE或LN的异质性。 假设多种生物标志物可以代表LN风险的不同方面，我们 建议评估分类为疾病易感性、系统性 炎症和肾室/细胞损伤，以建立风险预测模型。我们的目标是发展 用于早期检测肾耀斑、慢性肾损害和LN治疗反应的复合生物标志物 患者为了实现这一目标，我们将使用来自纵向观察队列和临床研究的生物标本。 有注释良好的患者样本的试验。南卡罗来纳州医科大学（MUSC）团队 因此，建议与俄亥俄州州立大学（OSU）团队合作，联合收割机将每个小组的纵向 SLE队列，并创建适合生物标志物发现的良好表型患者资源， 充分把握验证研究。合并的OSU-MUSC队列将有大约500 LN 每隔2 - 6天进行一次风湿病学/肾脏病学门诊访视并采集生物标本的患者 几个月到十年。利用这些样本，我们的团队已经描述了几种DNA， 与疾病活动、治疗反应或器官损伤相关的血清和尿液生物标志物， LN，并在开发LN结局的生物标志物组方面具有相当丰富的经验。我们已审阅 过去十年的文献，系统地排名新的生物标志物，并提出测试表现最好的LN 生物标志物，以解决是否：（i）与活动性LN相关的生物标志物可用于 在前瞻性纵向队列中预测即将发生的肾耀斑;（ii）复合组的基线测量 尿液或血清生物标志物的检测可以区分谁将和谁将不会达到肾反应， 一年的常规治疗与霉酚酸酯;（iii）遗传风险的发展， LN患者，以确定那些谁是倾向于发展慢性肾损伤。我们还将比较 预测LN疾病结局的生物标志物与非肾性SLE的生物标志物， 特异性生物标志物组与一般生物标志物组，其指示活动性炎症和/或损伤累积。我们 最终目标是获得具有足够灵敏度和特异性的有效LN预测因子， 并且可以在大多数临床服务实验室中容易地测定以改善患者护理。

Abstract Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE) and is associated with significant morbidity and mortality. Current clinical laboratory markers lack sufficient sensitivity and specificity to optimize individual patient care creating a need to develop novel biomarkers for LN. To address this unmet need there has been a significant effort within the lupus research community to identify novel LN biomarkers, but to date none have been qualified for clinical use. We speculate that one of the important causes of these failures is that no single biomarker can account for the heterogeneity of SLE or LN. Under the hypothesis that multiple categories of biomarkers can represent different aspects of risk for LN, we propose to assess biomarkers that are classified into categories of disease susceptibility, systemic inflammation, and kidney compartment/cell injury to build models for risk prediction. Our objective is to develop composite biomarkers for early detection of renal flares, chronic renal damage, and treatment response of LN patients. To accomplish this goal we will use biospecimens from longitudinal observational cohorts and clinical trials that have well-annotated patient samples. The Medical University of South Carolina (MUSC) team therefore proposes to partner with the Ohio State University (OSU) team to combine each group's longitudinal SLE cohorts and create a well-phenotyped patient resource suited to biomarker discovery and large enough to adequately power validation studies. The combined OSU-MUSC cohort will have approximately 500 LN patients who have had rheumatology/nephrology clinic visits and biospecimens collected every two to six months for up to ten years. Using these samples, our collective team has already described several DNA, serum and urine biomarkers that are associated with disease activity, treatment response or organ damage in LN, and has considerable experience in developing biomarker panels for outcomes in LN. We have reviewed the last decade's literature, systematically ranked novel biomarkers, and propose to test the top performing LN biomarkers in this proposal to address whether: (i) Biomarkers associated with active LN can be used to predict impending renal flares in prospective longitudinal cohorts; (ii) Baseline measures of composite panels of urine or serum biomarkers can distinguish between who will and who will not achieve a renal response to one year of conventional therapy with mycophenolate mofetil; (iii) The development of genetic risk profiles of LN patients to identify those who are predisposed to develop chronic kidney damage. We will also compare biomarkers predictive of disease outcomes in LN to those in non-renal SLE, working towards developing LN specific vs general biomarker panels that are indicative of active inflammation and/or damage accrual. Our ultimate goal is to have validated LN predictors of sufficient sensitivity and specificity to be clinically relevant, and that can be easily assayed in most clinical service laboratories to improve patient care.