Faculty Bibliography

The neonatal lupus syndromes, although quite rare, provide an excellent opportunity to examine disease from bench to bedside. During the past year numerous publications have reported basic and clinical research. Although anti-SSA/Ro-SSB/La antibodies are detected in more than 85% of mothers whose fetuses are identified with conduction abnormalities in a structurally normal heart, when clinicians applied this testing to their pregnant patients, the risk for a woman with the candidate antibodies to have a child with congenital heart block was at or below one in 50. Although the precise pathogenic mechanism of antibody-mediated injury remains unknown, it is clear that the antibodies alone are insufficient to cause disease, and fetal factors are likely contributory. In vivo and in vitro evidence supports a pathologic cascade involving apoptosis of cardiocytes, surface translocation of Ro and La antigens, binding of maternal autoantibodies, secretion of profibrosing factors from the scavenging macrophages, and transdifferentiation of cardiac fibroblasts to a myofibroblast scarring phenotype. Cross-reactivity of anti-52-kD SSA/Ro antibodies with a serotoninergic cardiac receptor, 5-hydroxytryptamine (HT)4, has been suggested but remains unconfirmed. The spectrum of cardiac abnormalities continues to grow, with varying degrees of block identified in utero and reports of late-onset cardiomyopathy (some of which display endocardial fibroelastosis). Moreover, there is now clear documentation that incomplete blocks (including those improving in utero with dexamethasone) can progress postnatally, despite the clearance of the maternal antibodies from the neonatal circulation. Better echocardiographic measurements that identify first-degree block in utero may be the optimal means of approaching pregnant women at risk. Prophylactic therapies, including treatment with intravenous immunoglobulin, await larger trials. Reassuringly, most children with neonatal lupus syndromes do not develop rheumatic diseases, although follow-up is limited to late adolescence. To further efforts both at the bench and bedside, national research registries established in the United States and Canada are critical

Congenital heart block (CHB), a life-threatening manifestation of neonatal lupus, offers aunique opportunity to study the effect or arm of immunity and define the pathogenicity of an autoantibody in mediating tissue injury. This review focuses on our recent in vitro model which supports a cascade from antibody insult to unchecked fibrosis. In brief, it is proposed that the fetal cardiac myocyte undergoes apoptosis which facilitates transfer of intracellular Ro and La antigens to the surface where they are bound by circulating maternal autoantibodies (anti-SSA/Ro-SSB/La antibodies). Scavenging macrophages phagocytose these inadvertently 'opsonized' cardiocytes, leading to the secretion of pro-inflammatory and pro-fibrotic cytokines, the latter of which transdifferentiate fibroblasts into myofibroblasts and thereby promote scarring. Immunohistologic study of a heart from a neonate dying of CHB supports this model in that macrophages and myofibroblasts were demonstrated. To facilitate both basic and clinical research, a Research Registry for Neonatal Lupus was established in 1994 by the U.S. National Institute of Arthritis, Musculoskeletal and Skin Diseases. Maternal and fetal outcomes are addressed as well as recurrence rates. Laboratory evaluation and management decisions during pregnancy are provided