CE-52 Biologic and clinical effects of autoimmunity on the maternal/fetal dyad

Background Progress in the management of pregnancy in patients with lupus and asymptomatic women with anti-Ro antibodies has been made on several fronts in the last year. Results Data from the PROMISSE study ( P redictors of P R egnancy O utcome: Bio M arkers I n Antiphospholipid S yndrome and S ystemic Lupus E rythematosus) under the leadership of Dr. Jane Salmon which enrolled 389 women with or without anti-phospholipid antibodies, identified several important and potentially actionable baseline predictors of adverse pregnancy outcomes (APO). These include: taking hypertensive medications, having a platelet count less than 100 k, being positive for the lupus anticoagulant (LAC), and having a physician global assessment of lupus activity at >1. The absence of a rise in C3 during the second trimester also constituted a risk factor. Being non-Hispanic white was protective. Both mild/moderate and severe flares were infrequent, 13% and 3%, respectively. De novo renal disease was rare, occurring in 3/265 patients who never met ACR renal criteria. Overall, in patients with no risk factors at baseline, the APO rate was 7.8%; fetal/neonatal mortality 3.9%. In contrast, in patients who are either LAC positive, or LAC negative but non-White and treated with antihypertensives, the APO rate was 58%; fetal/neonatal mortality 22%. With regard to clinical and basic translational work in neonatal lupus, there have been several advances. Based on review of 156 cases of heart block absent any extra-nodal involvement the use of fluorinated steroids did not reverse the block, influence the cumulative probability of extranodal disease, the cumulative probability of survival, or the cumulative probability of pacemaker implantation. Accordingly, these data do not support the use of dexamethasone in isolated block for the sole purpose of preventing more progressive disease. Evaluation of umbilical cord blood from 139 anti-Ro exposed neonates with and without heart block suggests innate and parenchymal immune cell activation in the affected fetus. Specifically, cord CRP, NT-proBNP, MMP-2, uPA, uPAR, and plasminogen levels were higher in affected fetuses than in unaffected cases, independent of maternal rheumatic disease, season at highest risk of heart block, and medications taken during pregnancy. These biomarkers were positively associated with a disease severity score derived from known risk factors for mortality. Based on the consistent demonstration of fibrosis of the atrioventricular node surrounded by macrophages and multinucleated giant cells in anti-Ro antibody exposed fetuses dying with heart block, investigational studies focused on macrophage signalling stimulated by ssRNA associated (hY3) with the Ro60 protein and the impact of antagonising innate cell drivers such as TLR7/8. Ligation of TLR7/8 resulted in increased histone methylation as measured by increased H3K4me2, a requirement for binding of NF-κB at certain promoters, specifically the kB1 region in the TNF promoter which was significantly decreased by hydroxychloroquine. Conclusion Translation of these finding to the bedside suggests that hydroxychloroquine may be efficacious in preventing heart block. An ongoing study is currently addressing secondary prevention.