Predicting Pre-Eclampsia in Pregnant Women with Lupus

Newswise — Researchers may be able to predict whether preeclampsia will occur in pregnant women who have SLE, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Boston, Mass.

Systemic lupus erythematosus (also called SLE or lupus) is a chronic autoimmune inflammatory disease that can affect the skin, joints, kidneys, lungs, nervous system, and/or other organs of the body. The symptoms of SLE vary from mild to severe, and typically involve alternating periods of remission and relapse.

Although the risks to pregnant women with SLE themselves are low, the frequency of obstetric complications, such as preeclampsia and impaired fetal growth restriction, are increased in SLE— especially in patients with antiphospholipid antibodies (a cause of vascular inflammation and increased tendency toward blood clotting).

Preeclampsia is associated with insufficient placental blood flow and abnormal placental development, and is a major cause of maternal, fetal and neonatal morbidity and mortality. New blood vessels form in growing tissues through a process known as angiogenesis. In preeclampsia, the presence of anti-angiogenic proteins in the mother's circulation prevents normal growth of blood vessels in the placenta and causes injury to kidneys and blood vessels in the mother. Patients suffering from preeclampsia develop high blood pressure and protein in the urine followed by swelling, weight gain, headaches and, in some cases, seizures. In the fetus, there is poor growth and often severe prematurity.

Researchers recently studied 211 women with SLE and/or APLAs who were less than 12 weeks pregnant, and followed them through pregnancy to determine if increased levels of anti-angiogenic factors in women with lupus would predict the development of preeclampsia later in pregnancy.

Subjects were enrolled in the PROMISSE Study (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus), a multi-center observational study funded by NIAMS.

Each of the 16 patients with SLE and/or increased APLAs who developed preeclampsia were matched based on age and ethnicity to another SLE and/or APLA positive patient who did not develop preeclampsia and a non-autoimmune patient who had an uncomplicated, healthy pregnancy.

Researchers noted that as early as 12 to 15 weeks into their pregnancy, women with SLE and/or APLAs showed higher levels of circulating antiangiogenic factors than participants who had healthy pregnancies. The rate of increase in circulating antiangiogenic factors through pregnancy was significantly higher in the SLE and/or APLA positive patients who went on to develop preeclampsia, and it was higher in participants with SLE and/or antiphospholipid antibodies compared to non-autoimmune participants who had healthy pregnancies. Participants with SLE and/or APLAs who had elevated circulating antiangiogenic factors at 20 to 23 weeks into their pregnancies were at markedly increased risk for preeclampsia later in their pregnancies.

"These findings indicate that circulating antiangiogenic factors are early markers predictive of preeclampsia in patients with SLE," said Jane E. Salmon, MD; Collette Kean Research chair; co-director, Kirkland Center for Lupus Research; Hospital for Special Surgery. "Because inflammatory mediators trigger production of antiangiogenic factors, early intervention to block specific pathways of inflammation could prevent angiogenic imbalance in lupus pregnancies at risk for preeclampsia."

The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see http://www.rheumatology.org/annual.

Editor's Notes: Dr. Salmon will present this research during the ACR Annual Scientific Meeting at the Boston Convention and Exhibition Center from 9:00 " 11:00 am ET on Friday, November 9, 2007, in the Exhibit Hall. Dr. Salmon will be available for media questions and briefing at 8:30 am ET on Thursday, November 8 in the on-site press conference room, Room 251. Presentation Number: L9

Elevated Antiangiogenic Factors Predict Preeclampsia In Pregnant Patients With SLE And/Or APL Antibodies

Jane E. Salmon1, Marta Guerra1, Mimi Kim2, Sarosh Rana3, S. Ananth Karumanchi4, Michael Lockshin1, Ware Branch5, Carl A. Laskin6, T. Flint Porter5, Michelle Petri7, Joan Merrill8, Jill P. Buyon9. 1Hospital for Special Surgery, New York, NY; 2Albert Einstein Coll of Medicine, Bronx, NY; 3Women and Infants' Hospital of Rhode Island/Brown Univ Medical School, Providence, RI; 4Beth Israel Deaconess Med Ctr, Boston, MA; 5Univ of Utah HSC, Salt Lake City, UT; 6Mount Sinai Hospital, Toronto, ON, Canada; 7Johns Hopkins Univ School of Medicine, Baltimore, MD; 8Oklahoma Medical Research Fdn, Oklahoma City, OK; 9New York Univ School of Medicine, New York, NY

Purpose: Pregnant women with lupus and/or antiphospholipid antibodies (APL+) are at increased risk for preeclampsia (PE), a condition associated with insufficient placental vascularization. Elevated levels of circulating antiangiogenic factors (sFlt-1 and sEng) predict PE in healthy women, with highest levels observed close to the onset of clinical disease. We hypothesized that early angiogenic dysregulation would be predictive of PE in women with SLE and/or aPL+.

Methods: We performed a nested case-control study of SLE+ and/or APL+ women within the PROMISSE Study (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus). All patients with SLE and/or APL+ who developed PE (n=16 out of 211) were matched 1:1 by age and ethnicity to a disease control patient (DC) (SLE+ and/or APL+). A healthy control patient (HC) was also matched to each patient. Subjects were evaluated monthly beginning at <12 weeks' gestation.

Results: As early as 12-15 weeks' gestation, levels of circulating sFlt-1 were higher in SLE+ and/or APL+ patients compared to HC (2416±1306 vs. 1670±1120; p = 0.08). The rate of increase in sFlt-1 through pregnancy was significantly higher in patients who went on to develop PE (PE vs. DC; p = 0.0019), and sFlt-1 was higher in DC compared to HC (p=0.0002). Study patients (SLE+ and/or APL+) with elevated levels of sFlt-1 at 20-23 wks gestation (≥75th percentile in HC) were at increased risk for PE later in pregnancy (OR=4.5; 95% CI: 0.97-20.8; p=0.05). Similarly, patients with increased sEng levels at 20-23 weeks' (≥75th percentile in HC) were at higher risk for PE (OR = 14.0, 95% CI: 2.2-87.2; p=0.005).

Conclusions: sFlt-1 and sEng are biomarkers predictive of PE in patients with SLE and/or APL+, suggesting that angiogenic imbalance early in pregnancy increases the vulnerability of SLE and APL+ patients to triggers of PE. Determining the mechanisms of angiogenic dysregulation in these patients will provide insights into the pathogenesis of a major cause of maternal and fetal morbidity and mortality. [Figure 1, available on request]

Disclosure Block: J.E. Salmon, None; M. Guerra, None; M. Kim, None; S. Rana, None; S. Karumanchi, Scios, Inc.; Abbott Diagnostics; Beckman Coulter; J & J; Co-inventor on patents for the diagnosis and treatment of preeclamsia; M. Lockshin, None; W. Branch, None; C.A. Laskin, None; T. Porter, None; M. Petri, None; J. Merrill, None; J.P. Buyon, None.