Faculty Bibliography

PURPOSE OF REVIEW: Cardiac manifestations of neonatal lupus include anti-SSA/Ro-SSB/La-mediated conduction system disease and endocardial/myocardial damage resulting in cardiomyopathy. This review will focus on recent data regarding updates on the proposed pathogenesis of disease, morbidity and mortality, and preventive and treatment therapies. RECENT FINDINGS: Evidence from animal models suggests that reactivity to the p200 region of the Ro52 protein, as well as antibody targeting of L-type calcium channels may be important in the development of cardiac neonatal lupus. In-vitro studies support a protective role of beta-2 glycoprotein 1 (prevents anti-Ro binding to apoptotic cells) and pathologic roles of the urokinase-plasminogen activator/receptor system (leads to activation of TGF-beta), and endothelin-1 secretion by macrophages in mediating tissue injury. Genetic studies highlight the fetal major histocompatibility complex in the development of disease, and a multigenerational study demonstrates that mothers of neonatal lupus children accumulate genetic risk factors preferentially from the neonatal lupus child's grandparents. Retrospective studies identify demographic and echocardiographic risk factors for morbidity and mortality and address the role of fluorinated steroids, intravenous immunoglobulin and hydroxychloroquine for prevention and treatment of disease. SUMMARY: Animal studies, in-vitro experiments, genetic analysis and clinical-translational research in cardiac neonatal lupus reveal novel insights and targets for therapy in this often devastating disease.

OBJECTIVE: Maternal anti-Ro autoantibodies are associated with cardiac manifestations of neonatal lupus (cardiac NL), yet only 2% of women with this reactivity have an affected child. Identification of a more specific marker would channel intense monitoring to fetuses at greater risk. This study aimed to determine whether autoantibodies against Ro 52 amino acids 200-239 (p200) confer added risk over autoantibodies to full-length Ro 52, Ro 60, or La. METHODS: Anti-Ro-exposed pregnancies resulting in cardiac NL or no cardiac manifestations were identified from the Research Registry for Neonatal Lupus and the PR Interval and Dexamethasone Evaluation study. Umbilical cord (n = 123) and maternal (n = 115) samples were evaluated by enzyme-linked immunosorbent assay. RESULTS: The frequencies of p200, Ro 52, Ro 60, and La autoantibodies were not significantly different between affected and unaffected children. However, neonatal anti-Ro 52 and Ro 60 titers were highest in cardiac NL and their unaffected siblings compared to unaffected neonates without a cardiac NL sibling. Although both maternal anti-Ro 52 and p200 autoantibodies were less than 50% specific for cardiac NL, anti-p200 was the least likely of the Ro autoantibodies to be false-positive in mothers who have never had an affected child. Titers of anti-Ro 52 and p200 did not differ during a cardiac NL or unaffected pregnancy from the same mother. CONCLUSION: Maternal reactivity to p200 does not confer an added risk to fetal conduction defects over full-length Ro 52 or Ro 60 autoantibodies. Mothers who may never be at risk for having an affected child have lower anti-Ro 60 titers and may require less stringent echocardiographic monitoring compared to women with high-titer autoantibodies.