A Rosy Outlook for Pregnancy and Lupus

Biomarkers and Potential Treatments

Medscape: What specific biomarkers are showing promise in helping risk-stratify patients?

Dr Salmon: One class of biomarkers that we were interested in are complement activation products. They tend to be higher throughout pregnancy in those destined for poor outcomes.

There are also antiangiogenic factors in the circulation of pregnant women. As the placenta develops, there is a remodeling of spiral arteries and extensive vasculogenesis. This is impaired in patients who will develop preeclampsia or growth-restricted fetuses. When the placenta doesn't develop properly, there is profound hypoxia owing to its underperfusion. Hypoxia drives production of antiangiogenic factors by the placenta, which are secreted into the maternal circulation and injure the maternal vasculature.

The clinical manifestations of preeclampsia in mothers—hypertension, proteinuria, edema, seizures, abnormal liver function—are a consequence of endothelial damage. And the treatment of severe preeclampsia is delivering the baby and placenta to end the release of these antiangiogenic factors into the maternal circulation.

We discovered that in pregnant patients with lupus and patients with antiphospholipid antibodies who are destined for severe adverse outcomes, there is already evidence of an imbalance between pro- and antiangiogenic factors at 12-15 weeks' gestation. And if you follow these patients over time, the rate of rise and the levels of antiangiogenic factors are dramatically increased in women who will manifest preeclampsia many weeks later. The balance between angiogenic and antiangiogenic factors measured in our biomarker panel was dramatically abnormal early in gestation, at a time when the clinical parameters of pregnancy appeared to fine.

If a patient has a lupus anticoagulant or a history of hypertension has angiogenic dysregulation at 16 weeks as detected by our biomarker panel, her risk for a severe adverse pregnancy outcome is 94%. In contrast, if the levels of angiogenic factors are normal, the risk can be as low as 5%, similar to that of pregnancies in healthy women. It's really outstanding.

Medscape: What's next for you and your lab?

Dr Salmon: Now that we can identify very high-risk pregnant lupus patients, we are embarking on an interventional clinical trial to prevent serious complications.

We have been funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, to perform an open-label phase 2b study to test whether inhibition of tumor necrosis factor (TNF) alpha in pregnant women at very high risk—beginning at 8 weeks of pregnancy—can prevent preeclampsia and rescue pregnancies.

We are using TNF-alpha as our first therapeutic target because in mice treated with antiphospholipid antibodies, we were able to prevent placental and fetal injury with TNF-alpha blockade. In addition, we performed studies on other preeclampsia-prone mice, and we found that treatment with a TNF inhibitor also prevented preeclampsia and fetal death. With evidence from two mouse models, along with some clinical data showing higher TNF levels in the placentas of women with preeclampsia, we could propose this interventional trial.

Part of my excitement about our trial is that if it is successful in patients with lupus, such an approach can be tested to prevent pregnancy complications in non-autoimmune women at high risk for preeclampsia.

Medscape: Any final comments to clinicians managing patients with lupus?

Dr Salmon: I am thrilled that we now can tell most patients with lupus that if their disease is inactive and well-controlled, they can have normal pregnancies. The onus is on us, their physicians, to counsel them as to when it's safe to become pregnant. It must be a dialogue that every physician, rheumatologist, primary care doc, and obstetrician has with her or his patients with lupus: Pregnancy can be fine, but try to conceive at a time when lupus disease is inactive.

The other message is that there is a subset of women with lupus who are at very high risk for serious pregnancy complications. We must identify them, follow them carefully, and determine which interventions will help them. I believe prevention will be possible in the not-too-distant future, because we have an understanding of the pathologic pathways causing the placental and fetal damage. I'm very hopeful.

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