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

Обзор

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.

Подробное описание

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.

Первичные конечные точки

• Otherwise unexplained fetal death occurring after 12 weeks gestation [Срок оценки: End of pregnancy]
• Neonatal death [Срок оценки: Time of neonatal death]
• Preterm delivery prior to 36 weeks' gestation [Срок оценки: End of pregnancy]
• Small for gestational age (SGA) <5th %ile [Срок оценки: End of pregnancy]

Вторичные конечные точки (4)

• Gestational age [Срок оценки: End of pregnancy]
• Birth weight [Срок оценки: End of pregnancy]
• Number of days neonate requires positive pressure ventilation [Срок оценки: Neonate discharge from hospital]
• Total number of days neonate is hospitalized [Срок оценки: Neonate discharge from hospital]

Критерии участия

Критерии включения

• 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

Критерии исключения

• Diabetes mellitus (Type I and Type II) antedating pregnancy
• Known or suspected hereditary complement deficiency (defined by CH50 = 0)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Случай-контроль

Центры проведения

США · 8 центров

• Northwestern University — Chicago
• University of Chicago — Chicago
• Johns Hopkins Hospital — Baltimore
• NYU Langone Medical Center/Hospital for Joint Diseases — New York
• Hospital for Special Surgery — New York
• Columbia University Medical Center — New York
• Oklahoma Medical Research Foundation — Oklahoma City
• University of Utah Salt Lake City — Salt Lake City

Канада · 1 центр

• Mt. Sinai Hospital — Toronto

Великобритания · 1 центр

• Guy's & St Thomas' NHS Foundation Trust — London

Публикации

• 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. doi: 10.1038/nm1121. Epub 2004 Oct 17. PMID 15489858
• 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. doi: 10.1172/JCI18817. PMID 14660741
• 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. doi: 10.1084/jem.200116116. PMID 11805148
• 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. PMID 22275304
• Buyon JP, Kim MY, Guerra MM, Laskin CA, Petri M, Lockshin MD, Sammaritano L, Branch DW, Porter TF, Sawitzke A, Merrill JT, Stephenson MD, Cohn E, Garabet L, Salmon JE. Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study. Ann Intern Med. 2015 Aug 4;163(3):153-63. doi: 10.7326/M14-2235. PMID 26098843
• Kim MY, Buyon JP, Guerra MM, Rana S, Zhang D, Laskin CA, Petri M, Lockshin MD, Sammaritano LR, Branch DW, Porter TF, Merrill JT, Stephenson MD, Gao Q, Karumanchi SA, Salmon JE. Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study. Am J Obstet Gynecol. 2016 Jan;214(1):108.e1-108.e14. doi: 10.10 PMID 26432463
• Yelnik CM, Laskin CA, Porter TF, Branch DW, Buyon JP, Guerra MM, Lockshin MD, Petri M, Merrill JT, Sammaritano LR, Kim MY, Salmon JE. Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results. Lupus Sci Med. 2016 Jan 12;3(1):e000131. doi: 10.1136/lupus-2015-000131. eCollection 2016. PMID 26835148
• Yelnik CM, Porter TF, Branch DW, Laskin CA, Merrill JT, Guerra MM, Lockshin MD, Buyon JP, Petri M, Sammaritano LR, Stephenson MD, Kim MY, Salmon JE. Brief Report: Changes in Antiphospholipid Antibody Titers During Pregnancy: Effects on Pregnancy Outcomes. Arthritis Rheumatol. 2016 Aug;68(8):1964-9. doi: 10.1002/art.39668. PMID 26990620

Идентификаторы

NCT: NCT00198068 · 2014-309 · R01AR049772

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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