Faculty Bibliography

BACKGROUND: Cardiac manifestations of neonatal lupus (cardiac NL) include congenital heart block and cardiomyopathy. Several candidate biomarkers were evaluated in cases at risk for cardiac NL on the basis of potential roles in inflammation, fibrosis, and cardiac dysfunction: C-reactive protein (CRP); NT-pro-B-type natriuretic peptide (NT-proBNP); troponin I; matrix metalloproteinase (MMP)-2; urokinase plasminogen activator (uPA); urokinase plasminogen activator receptor (uPAR); plasminogen; and vitamin D. OBJECTIVES: Identification of maternal and fetal biomarkers associated with development and morbidity of cardiac NL should provide clues to pathogenesis with translational implications for management. METHODS: Cord (139) and maternal (135) blood samples collected during pregnancies at risk for cardiac NL were available for study. Levels of cord and maternal CRP, cord NT-proBNP, and cord troponin I were evaluated using multiplex assays. Cord and maternal vitamin D were assessed by liquid chromatography-mass spectrometry. MMP-2, uPA, uPAR, and plasminogen were evaluated using ELISA. RESULTS: Cord CRP, NT-proBNP, MMP-2, uPA, uPAR, and plasminogen levels were higher in cardiac NL-affected fetuses than in unaffected cases, independent of maternal rheumatic disease, season at highest risk of cardiac NL development, and medications taken during pregnancy. These biomarkers were positively associated with a disease severity score derived from known risk factors for mortality in cardiac NL. Maternal CRP and cord troponin I levels did not differ between the groups. Cord and maternal vitamin D levels were not significantly associated with cardiac NL, but average maternal vitamin D level during pregnancy was positively associated with longer time to postnatal pacemaker placement. CONCLUSIONS: These data support the association of fetal reactive inflammatory and fibrotic components with development and morbidity of cardiac NL. Following CRP and NT-proBNP levels after birth can potentially monitor severity and progression of cardiac NL. MMP-2 and the uPA/uPAR/plasminogen cascade provide therapeutic targets to decrease fibrosis. Although decreased vitamin D did not confer increased risk, given the positive influence on postnatal outcomes, maternal levels should be optimized.

Transplacental transfer of maternal anti-Ro and/or anti-La autoantibodies can result in fetal cardiac disease including congenital heart block and cardiomyopathy, called cardiac Neonatal Lupus (NL). Thousands of women are faced with the risk of cardiac NL in their offspring, which is associated with significant morbidity and mortality. There are no known therapies to permanently reverse third degree heart block in NL, although several treatments have shown some effectiveness in incomplete heart block and disease beyond the atrioventricular node. Fluorinated steroids taken during pregnancy have shown benefit in these situations, although adverse effects may be concerning. Published data are discordant on the efficacy of fluorinated steroids in the prevention of mortality in cardiac NL. beta-agonists have been used to increase fetal heart rates in utero. The endurance of beta-agonist effect and its impact on mortality are in question, but when used in combination with other therapies, they may provide benefit. No controlled experiments regarding the use of plasmapheresis in cardiac NL have been performed, despite its theoretical benefits. Intravenous immunoglobulin was not shown to prevent cardiac NL at a dose of 400 mg/kg, although it has shown effectiveness in the treatment of associated cardiomyopathy both in utero and after birth. Retrospective studies have shown that hydroxychloroquine may prevent the recurrence of cardiac NL in families with a previously affected child, and a prospective open-label trial is currently recruiting patients in order to fully evaluate this relationship.