IMPACT Study

Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women and presents during their childbearing years. Pregnancy in women with SLE is dangerous both for mother and offspring, and, in many cses women with SLE have been  advised not to have children.  Among complications frequently seen in women with lupus are preeclampsia (also known as toxemia of pregnancy), preterm birth, growth restricted fetuses, and pregnancy loss. All of these complications are manifestations of placental failure. 

Preeclampsia, the maternal response to toxic substances produced by a dysfunctional placenta, is characterized by hypertension, kidney damage, and dysfunction of other organs, including seizures and strokes. Severe preeclampsia therefore is an absolute indication for emergent delivery, regardless of the gestational age of the fetus, and is a major cause of maternal and fetal morbidity and mortality. Because there is no other effective treatment for preeclampsia or placental insufficiency, which can also lead to inadequate nutrition and oxygenation of the developing fetus, 10-20% of SLE patients are delivered at 24-28 weeks.  

Such preterm births pose substantial risk for cerebral palsy and neurodevelopmental delay. Restriction of fetal growth may also have long-term effects on cognitive development and an increased risk of hypertension and type 2 diabetes in adulthood. Moreover, considering only in- hospital medical costs for the first year of life, the average cost for a premature infant born at 28 weeks is $86,000; at 24 weeks it is more than $200,000. Among survivors, the rate of neurodevelopmental delay and other disabilities is at least 15%. Thus, the long-term financial and medical burden to society is substantial, and the emotional cost to patient and family immeasurable. Treatments designed to avoid these complications are critically needed. 

There is currently no effective treatment for women with these high-risk pregnancies, but previous research in an animal model that mimics the human condition shows that a blockade of tumor necrosis factor-α (TNF-α), a pivotal mediator of inflammation, prevents adverse outcomes. Further research conducted through the IMPACT study will determine whether treatment during pregnancy with a TNF-α inhibitor that does not cross the placenta reduces the rate of poor pregnancy outcomes in women with lupus and lupus-like illnesses. This is the first clinical trial of a biologic therapy to prevent pregnancy complications in lupus patients. If successful, it will provide a new approach to protecting pregnancies in such patients and a rationale for trials of TNF-α blockade in non-autoimmune women at high risk for preeclampsia or placental insufficiency, including those with hypertension, diabetes or carrying twins. 

The study will also provide the basis to expand the capacity to predict pregnancy outcomes and identify pathways that go awry by analyzing patterns of activated genes in immune cells in the blood of women with healthy pregnancies and babies, and in those who develop serious complications. 

Based on observations of the PROMISSE and favorable results of TNF-α blockade in mouse models, the IMPACT Trial (IMprove Pregnancy in APS with Certolizumab Therapy) research team hypothesized that TNF-α blockade in pregnancy would significantly decrease the rate of fetal death and/or preterm delivery due to PE or PI in women with APS and LAC. They expect that TNF-α blockade will result in a reduction in the devastating and costly complications attributable to preterm births in these challenging high-risk obstetric patients. With the clinical and biomarker risk stratification models and infrastructure created for PROMISSE, the IMPACT researchers have implemented the first trial of a biologic therapy to prevent adverse pregnancy outcomes in high-risk pregnancies in patients with APS with or without SLE. 

• To determine whether TNF-α blockade added to a regimen of heparin and low dose aspirin during pregnancy reduces the rate of adverse pregnancy outcomes in women with APS5 (prior vascular thrombosis or pregnancy morbidity) and LAC, the researchers are conducting an open label single-stage Phase II trial to evaluate the effect of certolizumab, a TNF-α inhibitor that does not cross the placenta and has been shown to be well tolerated in pregnancy, on reducing the risk of adverse pregnancy outcome in pregnant women with APS and LAC.  The study enrolls patients at 8 weeks’ gestation and follows them every 2 weeks with a phone call and monthly with a study visit through pregnancy, and follow their babies through the first year of life.  
• To determine whether TNF-α blockade during pregnancy favorably alters angiogenic markers of poor placental vascularization in women with APS and LAC, researchers are obtaining blood specimens from patients in the trial. Given that angiogenic dysregulation at 12-15 weeks gestation was highly predictive of adverse pregnancy outcome in PROMISSE, angiogenic marker levels may provide an early measure of efficacy in this and future trials. 
• To identify genes that predict poor fetal and/or maternal outcomes and that block TNF-alpha response. The study will analyze blood samples from IMPACT patients.  Identification of genes related to response and lack of response to certolizumab may reveal new targets for treatment of patients with SLE/APS and will also allow the researchers to monitor effectiveness of treatments. 

SIGNIFICANCE
This proof-of-concept translational clinical trial and the exploration of gene expression signatures in blood that distinguish healthy from complicated pregnancies hold the promise of significant advances in the understanding and treatment of complications in pregnant lupus patients.  Importantly, this work also has implications for the prevention and treatment of complications in women without autoimmune disease who are destined for poor placental development and ensuing preeclampsia and fetal morbidity associated with preterm birth.  A reduction of severe adverse pregnancy outcomes in certolizumab-treated patients would provide a rationale for trials of TNF-α blockade in pregnant women without APS, but at risk for severe preeclampsia, and extend the benefits of measuring biomarkers in early pregnancy to many more patients.

CONCLUSION
For millions of women around the world affected by lupus and countless others at risk of poor placental development and preeclampsia, treatments to avoid these pregnancy complications are desperately needed.  Dr. Jane Salmon, the study’s lead investigator explains, “have dedicated my life’s work to meet this urgent need, and I am poised at a critical juncture to: complete the first clinical trial of a biologic therapy that promises to prevent these pregnancy complications in high-risk women, enabling them to deliver healthy, full-term babies. This work promises to build a better future in which women with lupus and other high-risk pregnancies can fulfill their dreams of motherhood.  I am deeply grateful for the Lupus Foundation of America’s partnership in advancing this important research.”

The main investigator of the study is Dr. Jane Salmon, who is the Collette Kean Research Professor at Hospital for Special Surgery.  Dr. Salmon is also a Director of the Lupus and APS Center of Excellence at Hospital for Special Surgery and Co-Director of the Mary Kirkland Center for Lupus Research. She is Professor of Medicine and Professor of Medicine in Obstetrics and Gynecology and Associate Dean, Faculty Affairs at Weill Cornell College of Medicine. 

Dr. Salmon has worked with her Co-PI, Dr. Ware Branch, Professor of Obstetrics and Gynecology at the University of Utah and the Medical Director of Women and Newborn Clinical Program for the Urban Central Region of Intermountain Healthcare, on the IMPACT study since 2017, which was previously funded by NIAMS.

For over 20 years, Dr. Salmon’s laboratory has focused on the mechanisms by which placental injury occurs in lupus patients. Dr. Salmon assembled a team of investigators and launched the NIH-funded PROMISSE Study (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus) to determine which pregnancies were at highest risk for adverse outcomes and the correlates of poor outcome.  Over the course of 10 years, Dr. Salmon and her colleagues collected data and blood samples every month of pregnancy from 750 women and assessed their clinical status and markers of inflammation in the blood.  Over 20% of pregnancies in patients with SLE resulted in an adverse pregnancy outcome related to abnormal growth and development of the placenta inside the uterus, including 5% with stillbirth or neonatal death. 

The results of the PROMISSE Study provide models for early risk stratification to allow physicians to identify patients at low risk early in pregnancy and reassure them that their pregnancies were likely to be uncomplicated and their babies healthy. Conversely and importantly, they are working to offer patients at highest risk with an experimental therapy to prevent placental dysfunction. 

The IMPACT trial represents the next critically important “bench to bedside” phase of this work– translation of experiments in mice into therapies for patients.  If it is successful, this study will have major implications for enabling women with lupus and others at-risk of poor placental development and preeclampsia to have healthy pregnancies and babies. 

Angiogenic Factors - proteins that circulate in blood, promote proper placenta development, and are required to maintain the health of the mother’s vascular system.

Antiphospholipid Syndrome (APS) - an autoimmune disease caused by antiphospholipid antibodies that provoke blood clots in arteries and veins and pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia.  Over 25% of patients with lupus have antiphospholipid antibodies.

Gene expression profiles, signatures, transcripts, RNAseq - products of activated genes; used to identify pathways associated with initiators (causes) of disease or mechanisms by which diseases cause damage to organs.

Lupus Anticoagulant (LAC) - a type of antiphospholipid antibody associated with pregnancy complications and blood clots.

Systemic Lupus Erythematosus, Lupus (SLE) - is a systemic autoimmune disease in which the body’s immune system mistakenly attacks healthy tissue. SLE affects many internal organs leading to damage in the joints, skin, lungs, blood vessels, heart, kidneys, and nervous system.  SLE is a disease more frequent in women (9:1 female:male) with typical onset during the childbearing years (ages 20-40).

Preeclampsia - is a disorder of pregnancy characterized by high blood pressure and kidney dysfunction. Preeclampsia increases the risk of poor outcomes for both the mother and the baby.  It is a major cause of maternal deaths and preterm birth with associated complications of lung disease, blindness and developmental delay. 

Tumor necrosis factor-α (TNF-α) - a protein secreted by activated immune cells that causes inflammation and tissue injury.