Predictors of Pregnancy Outcome In SLE and APS

描述(由申请人提供)： 患有抗磷脂综合征(APS)和/或系统性红斑狼疮(SLE)的妇女的妊娠并发症包括反复流产、先兆子痫、胎盘功能不全和宫内生长受限(IUGR)。体内导致胎盘和胎儿损伤的机制还不完全清楚，治疗仍然不太理想。我们在APS小鼠模型中发现补体是妊娠丢失和/或与胎盘炎症相关的IUGR的早期影响因素，并表明补体激活导致抗血管生成因子的释放和胎盘发育异常。PROMISSE研究(妊娠结局的预测因素：抗磷脂抗体综合征和系统性红斑狼疮的生物标记物)是首次将我们在小鼠身上的新发现转化为人类，并确定补体分裂产物的升高是否预测抗磷脂(APL)抗体和/或SLE患者的妊娠并发症。在这项前瞻性观察研究的前4年中，我们在7个中心招募了342名孕妇，按有无APL抗体和既往SLE进行分组和分析，每月获得详细的医疗和产科信息，并连续采集血浆、血清、DNA、RNA和尿液。初步数据表明，补体激活产物水平的升高预示着不良的胎儿结局，这与我们的假设一致，即补体是胎儿丢失和IUGR的近端介体。我们建议将我们的目标样本量从400名孕妇增加到700名孕妇，以保持研究的力量，因为转化率低于预期，并通过扩大不良妊娠结局的生物标志物和范围来利用基础设施和丰富的患者数据和样本收集。具体地说，在目标1中，我们将确定补体途径激活产生的分裂产物的升高是否预测APL抗体和/或SLE患者的不良胎儿和/或母亲结局，以及在目标2中，循环血管生成和抗血管生成因子的平衡是否预测先兆子痫或IUGR婴儿的出生。在目标3，一个新的方向，我们将使用PROMISSE队列在人类中确认我们在小鼠身上的最新发现，某些抗DNA抗体与N-甲基D-天冬氨酸受体(NMDAR)发生交叉反应，并导致神经元死亡，从而导致认知和行为障碍。我们建议量化PROMISSE SLE患者整个孕期的抗NMDAR抗体水平，并通过评估12个月和3.5岁儿童的皮质功能任务来验证在宫内暴露于母体抗NMDAR抗体会改变子代行为和认知发育的假设。这项PROMISSE研究的竞争性更新和扩展提供了一个绝佳的机会，将知识从小鼠模型转化为患者，定义发病机制，确定APL和/或SLE不良妊娠结局的预测因素，并定义预防此类结果的新治疗目标。患有系统性红斑狼疮(SLE)和/或抗磷脂(APL)抗体的患者流产、先兆子痫和胎儿生长受限的风险增加，这些是美国和世界范围内孕产妇、胎儿和新生儿发病率和死亡率的主要原因，其病因和机制尚不清楚，治疗有限。除了导致胎盘功能障碍外，母体自身抗体还可能直接损害胎儿的大脑发育。识别预测这些患者不良妊娠结局的生物标志物将阐明疾病机制，确定治疗患者的目标，并产生临床适用的指标，以允许在妊娠并发症风险最高的患者中启动介入试验。

DESCRIPTION (provided by applicant): Pregnancy complications in women with the antiphospholipid syndrome (APS) and/or SLE include recurrent miscarriage, preeclampsia, placental insufficiency, and intrauterine growth restriction (IUGR). The mechanisms leading to placental and fetal injury in vivo are incompletely understood and treatment remains sub-optimal. We have identified complement as an early effector in pregnancy loss and/or IUGR associated with placental inflammation in a mouse model of APS and shown that complement activation causes the release of anti- angiogenic factors and abnormal placental development. The PROMISSE Study (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus) is a first-time effort to translate our novel findings in mice to humans and determine if elevations of complement split products predict pregnancy complications in patients with antiphospholipid (aPL) antibodies and/or SLE. In the first 4 years of this prospective, observational study of pregnant patients grouped and analyzed according to the presence or absence of aPL antibodies and preexisting SLE, we have enrolled 342 pregnant patients in 7 centers, obtained detailed medical and obstetrical information monthly, and serially collected plasma, serum, DNA, RNA, and urine. Preliminary data suggest that elevated levels of complement activation products antecede and predict poor fetal outcome, consistent with our hypothesis that complement is a proximal mediator of fetal loss and IUGR. We propose to increase our target sample size from 400 to 700 pregnant patients to maintain study power given lower than expected outcome rates, and to leverage the infrastructure and rich collection of patient data and samples by expanding the array of biomarkers and scope of adverse pregnancy outcomes. Specifically, in Aim 1 we will determine whether elevations of split products generated by activation of complement pathways predict poor fetal and/or maternal outcome in patients with aPL antibodies and/or SLE and, in Aim 2, whether the balance of circulating angiogenic and antiangiogenic factors predicts preeclampsia or delivery of IUGR infants. In Aim 3, a new direction, we will use the PROMISSE cohort to affirm in humans our recent findings in mice, that certain anti-DNA antibodies cross-react with N-methyl D- aspartate receptors (NMDAR) and cause neuronal death with ensuing cognitive and behavioral impairment. We propose to quantitate anti-NMDAR antibody levels throughout pregnancy in PROMISSE SLE patients and test the hypothesis that in utero exposure to maternal anti-NMDAR antibodies alters behavior and cognitive development in offspring by evaluating cortical function tasks in 12 month and 3.5 year old children. This competitive renewal and extension of the PROMISSE Study provides an outstanding opportunity to translate knowledge from mouse models to patients, define pathogenic mechanisms, identify predictors of poor pregnancy outcome in APL and/or SLE, and define novel therapeutic targets to prevent such outcomes.Patients with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies are at increased risk for miscarriage, preeclampsia and fetal growth restriction - major causes of maternal, fetal, and neonatal morbidity and mortality in the US and worldwide - whose etiology and mechanism remain unknown and for which therapy is limited. In addition to causing placental dysfunction, maternal autoantibodies may also directly impair fetal brain development. Identification of biomarkers that predict poor pregnancy outcome in these patients will elucidate mechanisms of disease, define targets for treating patients, and generate clinically applicable indicators to permit initiation of interventional trials in patients at greatest risk for pregnancy complications.