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Predicting Adverse Pregnancy Outcomes in Patients with Lupus

In pregnant patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (aPL), increased levels of complement activation products, specifically Bb and sC5b-9, early in pregnancy is strongly predictive of adverse pregnancy outcomes. These findings from the PROMISSE study, published in the X issue of the Annals of Rheumatic Disease, should help researchers develop treatments for women at high-risk for adverse pregnancy outcomes.

"The complement activation pathway is involved in the pathogenesis of pregnancy complications in patients with lupus and antiphospholipid antibodies. Higher levels of complement activation are associated with problems in pregnancy," said lead study author Jane Salmon, MD, Collette Kean Research Chair at Hospital for Special Surgery, in New York City. The study is confirmatory of mice studies that have implicated inflammation, particularly complement activation and recruitment of neutrophils, as a causative factor in placental insufficiency, fetal loss, and growth restriction.

Currently, Dr. Salmon said, the findings cannot be used to identify women at risk in the clinic, because the tests measuring complement activation are only available for research and they don’t have the sensitivity or specificity to be used alone to predict outcome. However, said Dr. Salmon, the identification of biomarkers that put patients with lupus or aPL at risk will allow the identification of a subset of patients who can be considered for an intervention trial.

"What I would most like to do is a trial to block complement activation in high-risk patients. There are many companies developing such drugs," said Dr. Salmon.

Lupus is a chronic inflammatory disease, in which the body’s own immune system attacks tissues of the body and can cause complications during pregnancy. Antiphospholipid antibodies interfere with phospholipids, a type of fat found in all living cells and cell membranes, including blood cells and the lining of blood vessels. Patients with these antibodies are at risk for blood clots, stroke and pregnancy complications, but some patients with these antibodies can be completely healthy.

The multicenter, prospective PROMISSE trial has been comparing the pregnancies of women with aPL, lupus, both aPL and lupus, and healthy controls. Between 20 percent and 25 percent of patients with lupus and/or aPL have pregnancy complications and the study aimed to identify which patients are at risk.

The study enrolled 487 pregnant women with SLE and/or aPL and 204 pregnant healthy controls (n=204) who were less than 12 weeks from gestation and evaluated them monthly. Researchers measured complement activation products, including Bb and sC5b-9, on serial blood samples at each monthly visit. They tracked adverse pregnancy outcomes, which were defined as fetal/neonatal death, preterm delivery less than 36 weeks because of placental insufficiency or preeclampsia and/or growth restriction less than the fifth percentile.

Adverse pregnancy outcomes occurred in 20.5 percent of patients with SLE and/or aPL. As early as 12 to 15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with adverse pregnancy outcomes and remained elevated through 31 weeks, compared with those with normal outcomes. When analyses were restricted to patients with aPL, associations between Bb at 12 to 15 weeks and adverse pregnancy outcomes were stronger.

"Low levels of complement activation go on in many patients with lupus, but higher levels of complement activation are associated with problems in pregnancy," explained Dr. Salmon. "There are many pathways to activate complement. Our identification of Bb strongly argues that this alternative pathway to activate complement is very important in disease, supporting the mouse studies, but it also focuses a potential therapy on this pathway as opposed to some of the others." She said researchers can test the benefits of an intervention by measuring whether it can decrease levels of complement activation.

The PROMISSE study was funded by the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the National Institutes of Health in 2003 to identify biomarkers that would predict poor pregnancy outcomes in lupus patients. PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) involves nine centers in North America.