Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS)

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. Studies in a mouse model of antiphospholipid antibody syndrome (APS)
indicate that in vivo complement activation is necessary for fetal loss caused by aPL
antibodies. This study represents an effort to translate these research observations on the
potential role of complement activation in the pathogenesis of aPL antibody-mediated
pregnancy loss to a clinically relevant human study.

In addition, studies in humans and mice have shown 1) that the balance of circulating
angiogenic and antiangiogenic factors predicts preeclampsia and fetal growth restriction in
healthy women, 2) circulating antiangiogenic factors cause endothelial dysfunction and
abnormal placental development in animal models, and 3) complement activation leads to
elevated levels of circulating antiangiogenic factors and complement inhibition prevents
increased levels of antiangiogenic factors, placental dysfunction and fetal growth
restriction in a mouse model of APS. This study will permit testing the hypothesis that, like
in healthy women, the balance of circulating angiogenic and antiangiogenic factors predict
complications in women with SLE and APS and to translate the findings in animal models into
humans.

The PROMISSE Study is a prospective observational study that will follow 700 pregnant
patients who will be grouped and analyzed according to the presence or absence of aPL
antibodies and preexisting SLE. The patients are followed regularly during the course of the
pregnancy, collecting medical and obstetrical information as well as serial blood specimens
for complement and cytokine assays. The data obtained will be analyzed and used to identify
mechanisms and predictors of poor fetal outcome. We expect that the insights provided through
this study will suggest means to prevent, arrest or modify these conditions.

Inclusion Criteria:

- Patient pregnant with live intrauterine pregnancy, as defined by positive test for
elevated β-HCG, but ≤ 12 weeks by gestation (for subjects without aPL antibodies) and
≤18 weeks (for subjects with aPL antibodies)

- Patient between the ages of 18-45 and able to give informed consent, or age < 18 years
with parental consent

- Hematocrit > 26%

- For APL positive:

- aCL: IgG >= 40 GPL units; IgM >= 40 MPL units

- Positive LAC (RVVT, Kaolin, dilute TTI or PTT LA)

- Anti-β2GPI: IgG >= 40 GPL units; IgM >= 40 MPL units

- For control subjects:

- At least one successful pregnancy

- No history of fetal death (death of conceptus ≥ 10 weeks' gestation)

- No more than 1 miscarriage < 10 weeks' gestation

- No history of positive aPL in local lab or positive aPL in core labs at screening

- Not currently a smoker

- No medical problems requiring chronic treatment

Exclusion Criteria:

- Diabetes mellitus (Type I and Type II) antedating pregnancy

- Known or suspected hereditary complement deficiency (defined by CH50 = 0)