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

• Otherwise unexplained fetal death occurring after 12 weeks gestation [ Time Frame: End of pregnancy ] [ Designated as safety issue: No ]
  Fetal death occurring after 12 weeks' gestation and not explained by chromosomal abnormalities, anatomic malformations, or congenital infections.
• Neonatal death prior to hospital discharge and due to complications of prematurity [ Time Frame: Time of neonatal death ] [ Designated as safety issue: No ]
• Indicated preterm delivery prior to 36 weeks' gestation because of gestational hypertension, preeclampsia-eclampsia or placental insufficiency [ Time Frame: End of pregnancy ] [ Designated as safety issue: No ]
• Small for gestational age (SGA) <5th %ile in the absence of anatomical or chromosomal abnormalities and/or delivery before 36 weeks because of intrauterine growth restriction (IUGR). [ Time Frame: End of pregnancy ] [ Designated as safety issue: No ]

• Gestational age [ Time Frame: End of pregnancy ] [ Designated as safety issue: No ]
• Birth weight [ Time Frame: End of pregnancy ] [ Designated as safety issue: No ]
• Number of days neonate requires positive pressure ventilation [ Time Frame: Neonate discharge from hospital ] [ Designated as safety issue: No ]
• Total number of days neonate is hospitalized [ Time Frame: Neonate discharge from hospital ] [ Designated as safety issue: No ]

The PROMISSE Study is an observational study of 700 pregnant patients, enrolled at nine major clinical centers. The purpose of the study is 1) to determine whether certain proteins (called complement split products) that can injure healthy organs can be used to predict poor pregnancy outcome in patients with systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS), and/or 2) to determine whether elevated levels of circulating antiangiogenic factors predict pregnancy complications in patients with aPL antibodies and/or SLE.

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.

Pregnant patients identified by investigators at each study site

• Systemic Lupus Erythematosus
• Antiphospholipid Syndrome

• Group 1: aPL+/SLE-
  Positive antiphospholipid antibodies (aPL) defined as positive LAC and/or anti cardiolipin IgG/IgM >= 40 units and/or anti-beta 2 glycoprotein I IgG or IgM >= 40 units; no SLE
• Group 2: aPL+/SLE+
  Positive antiphospholipid antibodies (aPL) defined as positive LAC and/or anti cardiolipin IgG/IgM >= 40 units and/or anti-beta 2 glycoprotein I IgG or IgM >= 40 units AND SLE defined as four or more American College of Rheumatology criteria for SLE.
• Group 3: aPL-/SLE+
  No antiphospholipid antibodies; SLE defined as four or more American College of Rheumatology criteria for SLE.
• Group 4: aPL-/SLE-
  Healthy controls: no antiphospholipid antibodies; no SLE

• Lockshin MD, Kim M, Laskin CA, Guerra M, Branch DW, Merrill J, Petri M, Porter TF, Sammaritano L, Stephenson MD, Buyon J, Salmon JE. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum. 2012 Jul;64(7):2311-8. doi: 10.1002/art.34402.
• Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med. 2004 Nov;10(11):1222-6. Epub 2004 Oct 17.
• Girardi G, Berman J, Redecha P, Spruce L, Thurman JM, Kraus D, Hollmann TJ, Casali P, Caroll MC, Wetsel RA, Lambris JD, Holers VM, Salmon JE. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003 Dec;112(11):1644-54. Erratum in: J Clin Invest. 2004 Feb;113(4):646.
• Holers VM, Girardi G, Mo L, Guthridge JM, Molina H, Pierangeli SS, Espinola R, Xiaowei LE, Mao D, Vialpando CG, Salmon JE. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med. 2002 Jan 21;195(2):211-20.
• Michael D Lockshin, Cohn E, Aslam A, Buyon JP, Salmon JE. Sex ratios among children of lupus pregnancies. Arthritis Rheum. 2013 Jan;65(1):282. doi: 10.1002/art.37718.
• Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D, Roumenina L, Branch DW, Goodship T, Fremeaux-Bacchi V, Atkinson JP. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 2011 Mar;8(3):e1001013. Epub 2011 Mar 22.

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
• Multiple fetal gestations
• Known or suspected hereditary complement deficiency (defined by CH50 = 0)