TNF-alpha Blockade with Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with APS

使用 Certolizumab 阻断 TNF-α 可预防 APS 高危患者的妊娠并发症

• 批准号: 9331440
• 负责人: D.Ware Branch
• 金额: $ 22.44万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331440
• 关键词: Abnormal placentation; Age; Anaphylatoxins; Angiogenic Factor; Animal Model; Animals; Antibodies; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Aspirin; Autoimmune Diseases; Biological Markers; Biological Response Modifier Therapy; Blood; Blood Vessels; Cardiolipins; Clinical; Complement; Diagnosis; Discipline of obstetrics; Dose; Emotional; Equilibrium; Failure; Family; Fetal Death; Fetus; Functional disorder; Future; Generations; Gestational Age; Heparin; High-Risk Pregnancy; Human; Hypoxia; Immunoglobulin G; Immunoglobulin M; Individual; Infant; Inflammation; Inflammation Mediators; Inflammatory; Injury; Inpatients; Life; Lupus Coagulation Inhibitor; Measures; Mediator of activation protein; Medical; Modeling; Morbidity - disease rate; Neutrophil Infiltration; Observational Study; Outcome; Pathway interactions; Patient risk; Patients; Placenta; Placental Insufficiency; Placentation; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Premature Birth; Public Health; Regimen; Research Infrastructure; Risk; Risk stratification; Societies; Spiral Artery of the Endometrium; Survivors; Systemic Lupus Erythematosus; TNF gene; Testing; Thromboplastin; Thrombosis; Tissues; Vascular Endothelial Growth Factor Receptor-1; Vascularization; Woman; Work; adverse outcome; adverse pregnancy outcome; base; beta 2-glycoprotein I; clinical biomarkers; clinical effect; clinical predictors; cost; disability; effective therapy; fetal; high risk; hypoperfusion; mouse model; novel strategies; open label; phase II trial; pregnant; prevent; prospective; reproductive; standard care; therapy design; tumor necrosis factor-alpha inhibitor

Project Summary/Abstract Antiphospholipid syndrome (APS) is an autoimmune disorder that occurs most commonly in women of reproductive-age and is associated with thrombosis and adverse pregnancy outcomes (APOs), such as fetal loss and preterm birth due to severe preeclampsia (PE) or placental insufficiency (PI). The diagnosis of APS requires the presence of antiphospholipid antibodies (aPL), including the lupus anticoagulant (LAC). Therapy for APS focuses on preventing thrombosis, but thromboprophylaxis has not effectively prevented poor pregnancy outcomes. In PROMISSE, a prospective multicenter observational study of 724 patients, 44% of pregnancies in women with APS and LAC resulted in APOs despite treatment with heparin and low dose aspirin. Angiogenic dysregulation early in pregnancy predicted APOs, most of which were due to failure of adequate vascularization of the developing placenta and underperfusion of the fetus. Mouse models show that poor placental vascularization in APS is due to inflammation: aPL target placental tissue, and activate complement, leading to recruitment of neutrophils and release of inflammatory mediators and anti-angiogenic factors. We found that TNF-α was a critical downstream effector of abnormal placental development and fetal damage, and that TNF-α blockade restored angiogenic balance, normalized placentation and spiral artery remodeling, and rescued pregnancies. Based on our observations in PROMISSE and the favorable results of TNF-α blockade in our mouse models, we hypothesize that TNF-α blockade will significantly decrease the rate of preterm delivery due to PE and PI in women with APS and LAC. With the infrastructure created for PROMISSE, we are poised to conduct the first trial of a biologic therapy to prevent APOs in high-risk APS pregnancies. Our specific aims are to determine whether TNF-α blockade during pregnancy, added to a regimen of heparin and low dose aspirin, (1) reduces the rate of APOs in women with clinical APS and LAC, and (2) alters angiogenic markers of poor placental vascularization. We will conduct an open label single stage Phase II trial of certolizumab (a TNF-α inhibitor that does not cross the placenta). The potential public health impact of this trial extends beyond the population of women with APS. A reduction of severe APOs in certolizumab-treated patients would provide a rationale for trials of TNF-α blockade in pregnant women without APS, but at risk for severe PE or PI, and extend the benefits of measuring angiogenic factor biomarkers in early pregnancy to many more patients.

项目摘要/摘要 抗磷脂综合征（APS）是一种自身免疫性疾病，通常发生在女性中 生殖年龄，与血栓形成和不良妊娠结局（APO）有关，例如胎儿 由于严重的前青（PE）或占地不足（PI）而导致的损失和早产。 AP的诊断 需要存在抗磷脂抗体（APL），包括狼疮抗凝剂（LAC）。治疗 因为APS专注于预防血栓形成，但是血栓预防并未有效防止贫困 怀孕结果。在Promisse中，一项对724名患者的前瞻性多中心观察研究，其中44％ 患有AP和LAC女性的妊娠导致APOS目的地治疗肝素和低剂量 阿司匹林。怀孕早期的血管生成失调预测了APO，其中大多数是由于失败 小鼠模型表明，发育中的斑点的充分血管化和胎儿的灌注不足。 AP中的占地去血管化较差是由于炎症引起的：APL靶位置组织，并激活 完成，导致中性粒细胞的募集和炎症介质和抗血管生成的释放 因素。我们发现TNF-α是异常位置发育和胎儿的关键下游效应。 损坏，TNF-α封锁恢复了血管生成平衡，归一化位置和螺旋伪影 改建，并回应怀孕。基于我们对Promisse的观察和有利的结果 TNF-α阻断在我们的小鼠模型中，我们假设TNF-α封锁将显着降低速率 APS和LAC女性的PE和PI引起的早产。与为 Prosisse，我们被毒死了为预防高风险APS的APO进行的第一次试验 怀孕。我们的具体目的是确定TNF-α在怀孕期间是否封锁，添加到 肝素和低剂量阿司匹林方案，（1）降低了患有临床APS和LAC的女性的APO率 （2）改变不良的斑点血管形成的血管生成标记。我们将进行一个开放式标签单 CERTOLIZUMAB的II期试验（不穿越多余的TNF-α抑制剂）。潜在的公众 该试验的健康影响范围超出了APS女性的人口。减少严重的APO 经过certolizumab治疗的患者将为孕妇的TNF-α块试验提供理由 APS，但面临严重PE或PI的风险，并扩展了测量血管生成因子生物标志物的好处 早期怀孕给更多患者。