Dr. Jane Salmon is a Professor of Medicine and Professor of Obstetrics and Gynecology at Weill Cornell Medical College and the Collette Kean Research Professor at Hospital for Special Surgery in New York, USA. She is the principle investigator in the PROMISSE study, which has generated very important data and received great attention.
– Professor Jane Salmon, what does the acronym PROMISSE stand for?
– PROMISSE stands for Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus study. PROMISSE is the largest multicenter, multiethnic, and multiracial study to prospectively assess the frequency of adverse pregnancy outcomes and clinical and laboratory variables (including research biomarkers) that predict them, in women with or without high titer antiphospholipid antibodies (APL) and inactive SLE or mild or moderate SLE activity at conception. We enrolled over 700 patients from 2003 to 2014.
– What are the main results of the study?
– There have been many discoveries as result of the PROMISSE Study, and there are more to come. Our first report showed that in APL-positive patients, LAC is the primary predictor of adverse pregnancy outcome (Lockshin et al Arthritis Rheum 2012). ACL and anti-β2-GP-I, if LAC is not also present, did not predict APO. We recently confirmed these findings in an independent group of aPL-positive patients from PROMISSE (Yelnick et al, Lupus Science and Medicine, 2016). We also found that in pregnant SLE patients with inactive or stable mild or moderate SLE, severe flares are infrequent, and absent specific risk factors (LAC, antihypertensive medications, non-white or Hispanic) outcomes are favorable (Buyon et al, Ann Int Med 2015). With the knowledge from PROMISSE, we can counsel patients considering lupus pregnancy to wait until disease is quiescent. Timely risk stratification of patients is important for effective clinical care and optimal allocation of health care resources.
– Recently, your research group reported in LS&M that lupus anticoagulant is the main predictor of adverse pregnancy events in patients with aPL. What is the clinical significance of this finding, and what kind of intervention do you suggest for aPL-positive pregnant women in order to prevent adverse pregnancy events? Would you treat patients with aCL and/or anti-β2-GPI differently compared with patients with LAC?
– Pregnant women who are LAC-positive require close monitoring. I cannot recommend that treatments beyond those based on historic evidence, because PROMISSE was not designed to assess different therapies. Interventional trials in well-defined groups of high risk patients are needed to identify the best therapies to prevent complications.
– Were the patients with aPL who developed adverse pregnancy events on anticoagulants and/or antimalarials during their pregnancy?
– Treatment decisions for patients enrolled in the PROMISSE Study were determined by the patient’s physicians. Thus, we cannot assess contributions of therapy without biased as to why a patient was treated with a certain medication. The majority of the patients with aPL received anticoagulants. Those receiving aspirin tended to have better outcomes, while those receiving heparin trended toward worse outcomes. It is likely that heparin was prescribed for patients felt by their physicians to be at high risk or had histories of APS (thrombosis or obstetric complications). We do not know whether the frequency of adverse outcomes would have been even greater had these women not received heparin. More than half of our patients received hydroxychloroquine through their pregnancies, and this therapy was not associated with differences in pregnancy outcome.
– Professor Salmon, what are your visions for future therapeutic approaches in APS and in aPL-positive pregnant women without history of thrombotic events? Do you see any future for other treatments apart from anticoagulants?
– PROMISSE showed us that current therapies are not adequate for these patients. Yet, many of these patients have uncomplicated pregnancies and healthy newborns. We now have the capacity to risk stratify based on APL tests and other clinical features (history of thrombosis, presence of SLE). Future studies will test interventions that block the inflammatory pathways that contribute to APL-induced injury to the developing placenta. Both human and experimental mouse models indicate a key role for complement activation as a proximal mediator of poor fetal outcome. In addition, mouse models suggest that TNF-alpha may be an attractive downstream target to inhibit.
– Thank you very much for your valuable insights!