Predictors of Pregnancy Outcome in SLE and APS

SLE 和 APS 妊娠结局的预测因素

• 批准号: 6731292
• 负责人: Jane E Salmon
• 金额: $ 114.54万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-25 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731292
• 关键词: antiphospholipid syndrome; biomarker; blood chemistry; clinical research; complement pathway; enzyme linked immunosorbent assay; genetic polymorphism; human pregnant subject; immunocytochemistry; in situ hybridization; medical complication; microarray technology; outcomes research; pathologic process; pregnancy loss; prognosis; statistics /biometry; systemic lupus erythematosus; urinalysis; western blottings; women's health

DESCRIPTION (provided by applicant): Thrombosis and pregnancy loss are common features of systemic lupus erythematosus (SLE), particularly in the presence of antiphospholipid (aPL) antibodies. The in vivo mechanisms by which aPL antibodies lead to vascular events and, specifically, to recurrent fetal loss are largely unknown. Our studies in a murine model of antiphospholipid antibody syndrome (APS) indicate that in vivo complement activation is necessary for fetal loss caused by aPL antibodies. This proposal represents a first time effort to translate novel research observations on the potential role of complement activation in the pathogenesis of aPL antibody-mediated pregnancy loss to a clinically relevant human study. No study has investigated whether complement is activated in patients with aPL-associated poor pregnancy outcomes (with or without SLE), and whether particular patterns of complement activation characterize and thus can distinguish these patients from SLE patients without aPL antibodies or fetal loss, and from patients with normal pregnancy. Our preliminary data in murine APS, the availability of more accurate tests of complement activation, and the recent development of effective and specific complement inhibitors argue persuasively that the role of complement in aPL associated pregnancy complications shouldnow be examined. Accordingly, the specific aim of the study is: To determine whether elevations of split products generated by activation of the alternative or classical complement pathways predict poor fetal outcome in patients with antiphospholipid antibodies and/or SLE. We propose a prospective observational study of over 400 pregnant patients, enrolled at 6 major clinical centers, and grouped and analyzed according to the presence or absence of aPL and preexisting SLE. We have assembled a core group of investigators with recognized expertise in SLE and aPL pregnancy, high-risk obstetrics, the basic biology of complement, and statistical methods in SLE studies. We will obtain detailed medical and obstetrical information during the course of pregnancy and serial blood specimens for complement and cytokine assays, and analyze these data to identify predictors of poor fetal outcome. We will study placentas to characterize tissue pathology and mediators of injury. RNA, DNA, serum, and urine will be stored for studies to elucidate temporal changes in gene expression during the course of complicated and uncomplicated pregnancies and to investigate genetic polymorphisms. We believe that our study will provide insights into the mechanisms of complement-mediated inflammatory disorders and suggest means to prevent, arrest, or modify these conditions. Characterization of clinically applicable surrogate markers that predict poor pregnancy outcome will enable us to initiate an interventional trial of complement inhibition in patients at risk for aPL antibody-associated fetal loss. The identification of such surrogate markers in aPL and SLE patients may also prove generally applicable to anticipate complications during pregnancy in disease-free women.

描述（由申请人提供）： 血栓形成和妊娠丧失是全身性红斑狼疮（SLE）的常见特征，尤其是在存在抗磷脂（APL）抗体的情况下。 APL抗体导致血管事件的体内机制，尤其是复发性胎儿丧失，这在很大程度上是未知的。我们在抗磷脂抗体综合征（AP）的鼠模型中的研究表明，体内补体激活对于由APL抗体引起的胎儿损失是必不可少的。 该提案是对补体激活在APL抗体介导的妊娠损失中的潜在作用的新研究观察的首次努力，以对临床相关的人类研究。没有研究研究APL相关的妊娠结局（有或没有SLE）的患者是否会激活补体，以及补体激活的特定模式是否具有特征，因此可以将这些患者与没有APL抗体或胎儿丧失的SLE患者区分开来，以及与正常妊娠的患者。我们在鼠AP中的初步数据，更准确的补体激活测试以及最近的有效和特定补体抑制剂的最新发展，有说服力地认为补体在APL相关的妊娠并发症中的作用应检查。因此，该研究的具体目的是：确定通过激活替代或经典补体途径产生的分裂产物的升高预测抗磷脂抗体和/或SLE患者的胎儿预后不良。我们提出了一项针对400多名孕妇的前瞻性观察研究，该患者在6个主要的临床中心招收，并根据APL或不存在APL和先前存在的SLE进行分组和分析。我们已经组建了一个核心研究人员，在SLE和APL妊娠，高风险妇产科，补体的基本生物学以及SLE研究中的统计方法方面具有公认的专业知识。在怀孕过程中，我们将获得详细的医学和产科信息，以及用于补体和细胞因子分析的连续血样，并分析这些数据以识别胎儿不良预后的预测指标。我们将研究胎盘以表征组织病理学和损伤的介体。 RNA，DNA，血清和尿液将用于研究，以阐明复杂和简单怀孕过程中基因表达的时间变化，并研究遗传多态性。 我们认为，我们的研究将提供有关补体介导的炎症性疾病机制的见解，并提出预防，逮捕或修改这些疾病的手段。临床适用的替代标志物的表征预测妊娠结局不佳将使我们能够对有APL抗体相关的胎儿损失的患者进行介入的补体抑制试验。 APL和SLE患者中这种替代标志物的鉴定也可能证明是通常用于预测无病女性怀孕期间并发症。