Predictors of Pregnancy Outcome in SLE and APS

SLE 和 APS 妊娠结局的预测因素

• 批准号: 7122478
• 负责人: Jane E Salmon
• 金额: $ 109.67万
• 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/7122478
• 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）： 血栓形成和妊娠丢失是系统性红斑狼疮（SLE）的常见特征，特别是在存在抗磷脂（aPL）抗体的情况下。aPL抗体导致血管事件，特别是导致复发性胎儿丢失的体内机制在很大程度上是未知的。我们在抗磷脂抗体综合征（APS）小鼠模型中的研究表明，体内补体激活是aPL抗体引起的胎儿丢失所必需的。 该提案首次尝试将补体激活在aPL抗体介导的妊娠丢失发病机制中的潜在作用的新研究观察转化为临床相关的人类研究。没有研究调查补体是否在aPL相关的不良妊娠结局（有或没有SLE）患者中被激活，以及补体激活的特定模式是否表征并因此可以将这些患者与没有aPL抗体或胎儿丢失的SLE患者以及正常妊娠的患者区分开。我们在小鼠APS中的初步数据，更准确的补体激活试验的可用性，以及有效和特异性补体抑制剂的最新发展，令人信服地认为，补体在aPL相关妊娠并发症中的作用现在应该被研究。因此，本研究的具体目的是：确定由替代或经典补体途径激活产生的裂解产物升高是否预测抗磷脂抗体和/或SLE患者的胎儿结局不良。我们提出了一个前瞻性的观察性研究，超过400例妊娠患者，在6个主要的临床中心，并根据是否存在aPL和预先存在的SLE进行分组和分析。我们已经组建了一个核心研究小组，他们在SLE和aPL妊娠、高危产科、补体的基础生物学和SLE研究的统计方法方面具有公认的专业知识。我们将在妊娠过程中获得详细的医疗和产科信息，并采集系列血液标本进行补体和细胞因子测定，并分析这些数据以确定不良胎儿结局的预测因素。我们将研究胎盘以表征组织病理学和损伤介质。RNA、DNA、血清和尿液将被储存用于研究，以阐明复杂和简单妊娠过程中基因表达的时间变化，并研究遗传多态性。 我们相信，我们的研究将提供深入了解补体介导的炎症性疾病的机制，并提出预防，逮捕，或修改这些条件的手段。对预测不良妊娠结局的临床适用替代标志物的表征将使我们能够在有aPL抗体相关胎儿丢失风险的患者中启动补体抑制的干预性试验。在aPL和SLE患者中鉴定这种替代标志物也可以证明普遍适用于预测无病妇女怀孕期间的并发症。