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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Special Emphasis Panel (ZAR1-AAA-B (03))
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Witter, James
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Hospital for Special Surgery
New York
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Kim, Mimi Y; Guerra, Marta M; Kaplowitz, Elianna et al. (2018) Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies. Ann Rheum Dis 77:549-555
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Yelnik, Cecile M; Porter, T Flint; Branch, D Ware et al. (2016) Brief Report: Changes in Antiphospholipid Antibody Titers During Pregnancy: Effects on Pregnancy Outcomes. Arthritis Rheumatol 68:1964-9
Kim, Mimi Y; Buyon, Jill P; Guerra, Marta M et al. (2016) Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study. Am J Obstet Gynecol 214:108.e1-108.e14
Buyon, Jill P; Kim, Mimi Y; Salmon, Jane E (2016) Predictors of Pregnancy Outcomes in Patients With Lupus. Ann Intern Med 164:131
Yelnik, Cecile M; Laskin, Carl A; Porter, T Flint et al. (2016) Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results. Lupus Sci Med 3:e000131
Buyon, Jill P; Kim, Mimi Y; Guerra, Marta M et al. (2015) Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study. Ann Intern Med 163:153-63

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