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-? was a critical downstream effector of abnormal placental development and fetal damage, and that TNF-? 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-? blockade in our mouse models, we hypothesize that TNF-? 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-? 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-? 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-? 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.

Public Health Relevance

Pregnancies in patients with antiphospholipid syndrome who have a lupus anticoagulant in their blood have a high likelihood of ending in fetal death or very premature delivery because of poor placental development and preeclampsia. At present, there is no effective treatment for women with these high-risk pregnancies, but our work in an animal model that mimics this human condition shows that blockade of TNF-? , a pivotal mediator of inflammation, prevents adverse outcomes. Our proposed study will determine whether treatment during pregnancy with certolizumab, a TNF-? inhibitor that does not cross the placenta, reduces the rate of poor pregnancy outcomes in women with clinical antiphospholipid syndrome; and, if successful, it will provide a new approach to protecting pregnancies in women with antiphospholipid syndrome and a rationale for trials of TNF-? blockade in women with other conditions who are at risk for preeclampsia or placental insufficiency.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZAR1-HL (M1))
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Witter, James
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Hospital for Special Surgery
New York
United States
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