SAN DIEGO – Alteration in the balance of placentally secreted angiogenic factors early in pregnancy provides a potent new predictor of subsequent preeclampsia and other poor outcomes in pregnant women with systemic lupus erythematosus and/or antiphospholipid antibody syndrome.
Patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibody syndrome (APS) who had an elevated ratio of a splice variant of vascular endothelial growth factor R1 called sFLT1 to placental growth factor (PlGF) when measured at 16-19 weeks’ gestation were at 13.8-fold increased relative risk of preeclampsia before 34 weeks, compared with patients with an sFLT1/PlGF ratio below that cut-point in the large, multicenter, observational PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and SLE) study, Dr. Jane E. Salmon reported at the annual meeting of the American College of Rheumatology.
Dr. Jane Salmon
"Nearly half of the patients with an SFLT1/PlGF ratio greater than 3.45 when measured at 16-19 weeks’ gestation will develop early preeclampsia. On the other hand, a low ratio, as well as low levels of sFLT1 or high levels of PlGF, can reassure physicians and patients that preterm preeclampsia is unlikely: a 3% chance," said Dr. Salmon, professor of medicine and of ob.gyn. at Cornell University and a rheumatologist at the Hospital for Special Surgery, both in New York.
Pregnancy in patients with lupus is associated with obstetric complications placing both mother and fetus at great risk. Yet, until now it hasn’t been possible to predict which patients will have poor outcomes.
The key to identifying those at high risk lies in a recognition that preeclampsia and other poor outcomes are dramatic manifestations of placental insufficiency, which actually begins, initially silently, early in pregnancy. The maternal hypertension, proteinuria, thrombocytopenia, and other end-organ manifestations of preeclampsia are caused by maternal endothelial dysfunction mediated by placental secretion of antiangiogenic factors. Angiogenic growth factors, such as PIGF and vascular endothelial growth factor (VEGF), are essential to a healthy endothelium. But placentally secreted sFLT1 binds to these two angiogenic growth factors, rendering them unavailable to the endothelium, she explained.
Overexpression of sFLT1 in multiple animal models results in hypertension and proteinuria, the hallmarks of preeclampsia. Moreover, cancer patients treated with VEGF inhibitors often develop these two conditions. Based in part on these observations, Dr. Salmon and her coinvestigators turned to the PROMISSE study to test their hypothesis that elevated levels of antiangiogenic factors early in pregnancy predict poor outcomes in patients with SLE and/or APS. The prospective study involved 503 pregnant women with SLE and/or APS and 204 healthy controls, all with monthly blood draws starting before 12 weeks’ gestation.
The composite outcome of preeclampsia, small for gestational age, indicated preterm delivery, and other adverse events occurred in 37% of SLE patients who also had APS. The rate was 16% in patients with SLE alone, 26% in those with APS alone, and 3% in controls.
Subjects with SLE and/or APS who developed preeclampsia and other pregnancy complications displayed significantly higher levels of sFLT1 beginning at 12 weeks and sustained through 31 weeks’ gestation, compared with those with normal pregnancies. Moreover, PlGF levels were significantly lower during weeks 16-31 in the patients with pregnancy complications. The investigators determined that the best predictor of pregnancy complications was the ratio of antiangiogenic sFLT1 to angiogenic PlGF. And the optimal cut-point was 3.45.
Audience members said that while a predictive test for preeclampsia is most welcome, the fact remains that physicians don’t have a lot to offer in terms of prevention or treatment of this feared pregnancy complication. Dr. Salmon responded that the SFLT1/PlGF ratio can be used to risk-stratify pregnant lupus patients for future interventional trials with new drugs looking at new pathways. Already, for example, other investigators have reported some success using a strategy targeting sFLT1 itself. In a small study, they found that women with severe preeclampsia who had their blood run through a heparin column that binds and removes sFLT1 were able to maintain their pregnancies for up to 2 weeks.
"It’s a tiny, open-label trial involving a device, but I think that will move forward," she predicted.
The PROMISSE study was funded by the National Institutes of Health, the Alliance for Lupus Research, and the Mary Kirkland Center for Lupus Research at the Hospital for Special Surgery. Dr. Salmon reported having received research grants from and/or serving as a consultant to Alexion, Novartis, and Roche.