Predictors of Pregnancy Outcome in SLE and APS

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，特别是在抗磷脂(APL)抗体存在的情况下。APL抗体导致血管事件，特别是导致复发性胎儿丧失的体内机制在很大程度上尚不清楚。我们在抗磷脂抗体综合征(APS)小鼠模型上的研究表明，体内补体激活对于APL抗体导致的胎儿丢失是必要的。 这项建议是首次将补体激活在APL抗体介导的妊娠丢失的发病机制中的潜在作用的新的研究观察转化为临床相关的人类研究。尚未有研究调查APL相关不良妊娠结局患者(伴有或不伴有SLE)的补体是否被激活，以及补体激活的特定模式是否具有特征性，从而可以将这些患者与无APL抗体或胎儿丢失的SLE患者以及正常妊娠患者区分开来。我们在小鼠APS中的初步数据，更准确的补体激活测试的可用性，以及有效和特异的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得到检验。因此，这项研究的具体目的是：确定替代或经典补体途径激活产生的分裂产物升高是否预测抗磷脂抗体和/或系统性红斑狼疮患者的不良胎儿结局。我们建议对6个主要临床中心登记的400多名孕妇进行前瞻性观察研究，并根据APL和既往存在的SLE的存在与否进行分组和分析。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。我们将在怀孕期间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液样本，并对这些数据进行分析，以确定不良胎儿结局的预测因素。我们将对胎盘进行研究，以确定组织病理学和损伤介质的特征。RNA、DNA、血清和尿液将被储存用于研究，以阐明复杂和非复杂妊娠过程中基因表达的时间变化，并调查遗传多态。 我们相信，我们的研究将为补体介导的炎性疾病的机制提供洞察力，并提出预防、阻止或改变这些条件的方法。临床上可用于预测不良妊娠结局的替代标志物的特征将使我们能够在有APL抗体相关胎儿丧失风险的患者中启动补体抑制的介入性试验。在APL和SLE患者中鉴定这些替代标记物也可能被证明普遍适用于无疾病妇女孕期并发症的预测。

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.