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。 与严重的发病率和死亡率相关。目前的临床实验室标记物缺乏足够的敏感性 和特异性，以优化个体患者护理，创造了为LN开发新的生物标记物的需要。至 针对这一未得到满足的需求，狼疮研究界已经做出了重大努力，以确定 新的LN生物标志物，但到目前为止还没有一种符合临床使用条件。我们推测其中一个 这些失败的重要原因是没有一个单一的生物标志物可以解释SLE或LN的异质性。 在假设多种生物标志物可以代表LN风险的不同方面的假设下，我们 建议评估分类为疾病易感性、系统性疾病的生物标记物 炎症和肾间室/细胞损伤，以建立风险预测模型。我们的目标是发展 用于早期检测肾功能不全、慢性肾损害和LN治疗反应的复合生物标志物 病人。为了实现这一目标，我们将使用来自纵向观察队列和临床的生物标本。 拥有注解良好的患者样本的试验。南卡罗来纳医科大学(MUSC)团队 因此建议与俄亥俄州立大学(OSU)团队合作，将每个小组的纵向 SLE队列，并创建适合生物标记物发现的表型良好的患者资源，并且足够大 充分支持验证研究。OSU-MUSC合并后的队列将有大约500个LN 曾就诊风湿科/肾病科并每隔两至六年收集一次生物制品的患者 几个月，长达十年。利用这些样本，我们的集体团队已经描述了几个DNA， 与疾病活动性、治疗反应或器官损害相关的血清和尿液生物标志物 LN，并在开发LN结果的生物标记物面板方面拥有相当丰富的经验。我们已经回顾了 近十年的文献，系统地对新的生物标志物进行了排名，并提出了测试表现最好的LN 本提案中的生物标记物涉及：(I)与活动性LN相关的生物标记物是否可用于 在前瞻性纵向队列中预测即将出现的肾耀斑；(2)复合板的基线测量 尿液或血清生物标志物可以区分谁会和谁不会对肾功能产生反应 用霉酚酸酯进行一年的常规治疗；(Iii)发展遗传风险概况 在患者中识别那些容易发展为慢性肾脏损害的人。我们还将比较 预测LN疾病结局的生物标记物与非肾性SLE的生物标记物相比，致力于发展LN 指示炎症活动和/或损伤增加的特定生物标记物与一般生物标记物。我们的 最终目标是验证具有足够灵敏度和特异度的LN预测指标，使其在临床上具有相关性。 而且在大多数临床服务实验室中可以很容易地检测到这一点，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.