Neonatal lupus syndromes.

The neonatal lupus syndromes (NLS), while quite rare, carry significant mortality and morbidity in cases of cardiac manifestations. Although anti-SSA/Ro-SSB/La antibodies are detected in > 85% of mothers whose fetuses are identified with congenital heart block (CHB) 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 CHB was at or below 1 in 50. While 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 (e.g., TGFbeta) from the scavenging macrophages and modulation of cardiac fibroblasts to a myofibroflast scarring phenotype. The spectrum of cardiac abnormalities continues to expand, 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 which 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. In order to achieve advances at both the bench and bedside, national research registries established in the US and Canada are critical.

Neonatal outcome in patients with rheumatic disease.

Rheumatic autoimmune diseases have a higher prevalence in women, particularly during their childbearing age. Due to improved management, an increasing number of patients plan and carry out one or more pregnancies. Therefore, a growing interest is being paid to the possible consequences of maternal disease and associated treatment on the fetus and newborn infant. If maternal disease is characterized by the presence of IgG isotype autoantibodies, these can cross the placenta with possible antibody-mediated damage to the fetus. This is typically the case of the so called neonatal lupus erythematosus (NLE); a similar mechanism has been shown in infants of patients with immune thrombocytopenic purpura (ITP) and, less frequently, in those from mothers with antiphospholipid syndrome (APS). Indeed, this last condition is often responsible for placental, rather than neonatal, pathology. In addition, immunosuppressive and other drugs administered to the mothers during pregnancy and lactation might affect the fetal and neonatal immune system development. Finally, mothers disease and/or treatment could be related to neuropsychological alteration reported in some of their children.

Neonatal lupus syndromes.

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.

Neonatal lupus.

Congenital heart block (CHB), defined as an atrioventricular block diagnosed in utero, at birth, or within the neonatal period (0-27 d after birth), is a rare disorder closely linked to transplacental transport of maternal antibodies anti-Ro/SSA and anti-La/SSB. These antibodies may induce a myocarditis, or interact directly with calcium channel proteins with disturbance of transmembrane signaling at the level of the conduction tissue, or interfere with apoptosis. Depending on the severity of the process, the fetus may die in utero or a few days after birth or survive to the perinatal period and have a near-normal life; in most survivors a pace-maker must be implanted. Skin lesions, haematological disorders, and hepatic cholestasis are other transient clinical features of the syndrome. Sinus bradycardia and QT interval prolongation may be observed as well in babies born from anti-Ro/SSA positive mothers. The risk of recurrence of complete block ranges from 10-17%. Most of the mothers are asymptomatic at delivery and are identified only by the birth of an affected child. Their long-term outcome generally is more reassuring than previously assumed and arthralgias and dry eyes are the most common symptoms. A standard therapy for blocks detected in utero still does not exist. The prevalence of complete CHB in newborns of anti-Ro/SSA positive women and with known connective-tissue disease was 2%. Serial echocardiograms and obstetric sonograms, performed at least every 2 wk starting from the 16 wk gestation, are recommended in anti-Ro/SSA positive pregnant women.

Comparison of treatment with fluorinated glucocorticoids to the natural history of autoantibody-associated congenital heart block: retrospective review of the research registry for neonatal lupus.

OBJECTIVE: To compare intervention with fluorinated glucocorticoids to the natural history of untreated congenital heart block (CHB) with respect to conduction abnormalities, associated effusions, ascites, and hydrops fetalis, and the requirement for a pacemaker. METHODS: Records of all mothers enrolled in the Research Registry for Neonatal Lupus were reviewed. The cohort includes 47 mothers whose sera contain anti-SSA/Ro or anti-SSB/La antibodies, and their 50 offspring with CHB, in whom at least 4 echocardiograms were performed after in utero diagnosis. In 28 pregnancies, mothers received dexamethasone 4-9 mg/day for 3-19 weeks or betamethasone 12-24 mg/week for >6 weeks (group A). In 22 pregnancies, fluorinated steroids were not used (group B). RESULTS: Third-degree block was present in 21 fetuses in group A and 18 fetuses in group B; none were reversible despite steroid treatment. Three fetuses in group A and 2 in group B progressed from second-degree block, alternating with third-degree block, to permanent third-degree block at birth and postnatally. Of 4 fetuses in group A with second-degree block at presentation, all reverted to first-degree block by birth; 2 remain so at age 4 years, 1 alternates between first-degree and second-degree block at 2 years, and the fourth is in second-degree block at age 4 years. Of 2 fetuses in group B with second-degree block at presentation, both progressed to permanent third-degree block postnatally. Initial echocardiographic evaluation revealed pericardial effusions in 13 group A versus 4 group B fetuses, pleural effusions in 2 group A versus 0 group B, ascites in 8 group A versus 0 group B (P < 0.007), hydrops fetalis in 8 group A versus 0 group B (P < 0.007), and intrauterine growth restriction in 1 group A versus 1 group B. Pericardial effusions resolved and reappeared in both groups. Steroid therapy was most effective in the resolution of pleural effusions (2 of 2), ascites (6 of 8), and hydrops fetalis (5 of 8). Oligohydramnios ensued in 9 group A and 2 group B fetuses. Although fetuses in group A had more complications at presentation than those in group B, there were no significant differences in the duration of pregnancy (35.7 weeks versus 37.0 weeks), the number of deaths (4 versus 1), final degree of heart block, or requirement for a pacemaker (14 versus 11). CONCLUSION: While prospective trials are needed, these data suggest that fluorinated steroids should be considered for fetuses with incomplete block or hydropic changes. Serial echocardiograms are recommended to monitor fetal progress. It remains to be determined whether third-degree block is reversible if therapy is initiated immediately upon detection.

Neonatal lupus syndromes.

Neonatal lupus is a model of passively acquired autoimmunity in that immune abnormalities in the mother lead to the production of antibodies that cross the placenta and injure the developing fetus. Congenital complete heart block (CCHB), a permanent manifestation of neonatal lupus, is detectable after 18 wk gestation. Transient manifestations include cutaneous, hepatic, and hematologic abnormalities that occur at variable frequency. To date, there is a universal association of CCHB with maternal antibodies to SSA/Ro-SSB/La ribonucleoproteins, detectable by high ratio monomer:crosslinker SDS-immunoblot. Intriguingly, cardiac disease and often other manifestations are not present in the mother, raising the hypothesis that there is differential expression and/or accessibility of SSA/Ro-SSB/La antigens in fetal vs. adult tissues. CCHB may be a final consequence of a more widespread inflammatory response in the heart, including the existence of an associated myocarditis. In contrast to the in utero onset of CCHB, skin lesions generally become apparent after birth. Ultraviolet exposure may be an initiating factor and exacerbate an existing rash. Several studies have documented the predominance of DR3 alleles in mothers of affected offspring, frequently associated with the extended haplotype A1,B8. Available evidence suggests that fetal genetic differences in the major histocompatibility complex (MHC) do not influence susceptibility. The recommended clinical approach includes obstetric and rheumatologic management of both the fetus identified with CCHB and the fetus with a normal heart beat but at high risk of developing CCHB. Fetal echocardiogram is essential in diagnosing and following disease and may suggest the presence of an associated myocarditis.(ABSTRACT TRUNCATED AT 250 WORDS)

New findings in neonatal lupus syndrome.

Neonatal lupus is a syndrome characterized by cutaneous lupus and/or congenital heart block (CHB). This report reviews our original observations on patients with neonatal lupus during the past five years: (1) Sicca syndrome (SS-A) (Ro) autoantibodies were found in the serum of the mothers and infants, were of maternal origin, and constituted a marker for the syndrome. (2) SS-A autoantibodies were found in the majority of the cases of "idiopathic" CHB and may have been the most common cause of all CHBs. (3) Mothers who had one child affected were at risk for having a second child affected. (4) Mothers were often asymptomatic. (5) HLA associations in this syndrome were HLA-DR3, HLA-B8, HLA-MB2, and HLA-MT2, and these occurred in mothers but not infants. Thus, the HLA association was with autoantibody production rather than tissue injury, a finding that may help clarify genetic and environmental roles in autoantibody-mediated disease.