Faculty Bibliography

Despite a now reasonable large body of developed information, critical gaps are apparent. Pregnancy is the only naturally occurring event in which an individual is exposed to nonself HLA. How the HLA mismatched fetus escapes rejection remains a biologic enigma. More definitive evidence is needed to determine if TH2 bias occurs in normal human pregnancy and how this impacts on established autoimmune diseases. With regard to specific autoantibody-associated placental and fetal disease, why aren't all pregnancies affected when the putative maternal antibodies are present? Future studies of maternal-fetal immunology, inclusive of information on cytokine regulation, should yield insights not only into the maintenance of normal pregnancy but also into the disproportionate increase of autoimmune diseases in females and the variable course of these diseases during pregnancy

Isolated congenital heart block (CHB) detected in utero is strongly associated with autoantibodies reactive with the intracellular soluble ribonucleoproteins 48 kD SSB/La, 52 kD SSA/Ro, and 60 kD SSA/Ro. An erythematous skin rash with a predilection for the scalp and periorbital area, most often apparent in the first few postnatal months, is also highly associated with these maternal antibodies. The permanent cardiac disease and transient cutaneous disease are the most common manifestations of the neonatal lupus syndromes. Fetal and neonatal disease are presumed to be due to the transplacental passage of these IgG autoantibodies from the mother, who may have systemic lupus erythematosus (SLE), Sjogren's syndrome, or be entirely asymptomatic, into the fetal circulation. The fetal heart appears to be uniquely vulnerable, since complete block has never been described in the mothers despite exposure to identical circulating levels of the autoantibodies. Extensive work from several laboratories has resulted in the molecular characterization of the maternal autoantibody responses and the cloning of genes expressing the cognate antigens whose structural features suggest a role in transcriptional regulation. While the precise pathogenetic mechanism of autoantibody mediated tissue injury is not defined it has been demonstrated in adult rabbit and human fetal hearts that sera containing anti-SSA/Ro antibodies induce atrioventricular block and inhibit L-type calcium currents (ICa) in isolated ventricular myocytes. From a clinical perspective the current data suggest that there is not a unique profile of maternal antibody response that predicts the development of neonatal lupus. However, a low risk profile is one in which the titer of anti-SSA/Ro antibodies is low and neither the 60 kD or 52 kD component is recognized on SDS-immunoblot and there are no detectable anti-SSB/La antibodies. Although the fetal disease is called neonatal lupus, this is clearly a misnomer since only about 25% of mothers actually fulfill criteria for the diagnosis of SLE. Furthermore, asymptomatic mothers do not invariably become ill and if an asymptomatic mother does develop SLE it is generally not life-threatening. The recurrence rare of CHB is low, about 15%, but this is nearly three times higher than the risk for CHB in a primigravida with the putative antibodies. CHB carries a significant mortality, 15-30%, and morbidity; two thirds of children require permanent pacing. While prospective clinical trials of fluorinated steroids in women with anti-SSA/Ro and/or anti-SSB/La antibodies is not likely to be initiated given the very low rate of CHB in these mothers, such trials in fetuses with heart block identified in utero are required before definitive recommendations can be made. Numerous anecdotal cases support the use of dexamethasone for treatment of effusions and hydrops and possibly incomplete block. To further efforts both at the bench and bedside, national registries have been established in the U.S. and Canada

Oral contraceptives (OCs) are generally not prescribed for women with SLE due to the widely-held view that they may activate disease. This practice is based on the greater incidence of SLE in women than in men, biologic abnormalities od estrogen metabolism, murine models of lupus, several anecdotes of patients having disease flares while receiving exogenous hormones, and a single retrospective study in patients with pre-existing renal disease. In contrast, recent retrospective patient surveys, albeit limited by the absence of formal analyses of disease activity, suggest that the rate of flare is not significantly increased in patients taking OCs. The preexisting data are insufficient to warrant the dismissal of a potentially important birth control option in a disease which predominantly affects women in their reproductive years and whose fertility is not altered by the disease. In counseling patients regarding lupus and pregnancy, there are clinical predictors of pregnancy outcome; patients in remission tend to do well. The same principles may be true regarding advice on the use of OCs; patients with inactive or stable/moderate disease and at low risk for thrombosis may benefit without a change in lupus activity. OCs with the lowest estrogen content should be used and consideration given to progestin only pills in situations where there is some risk of increased clotting. Large prospective double-blind placebo-controlled studies inclusive of all ethnic groups should provide the basis for more definitive recommendations

Autoantibodies to SS-A/Ro are among the most common found in sera of patients with systemic rheumatic diseases. These autoimmune diseases can affect various organ systems of the body and are variable in their manifestations and presentation. One of the autoimmune targets is the 60 kDa SS-A/Ro protein known to be associated with small cytoplasmic Y RNAs. To study systematically the expression of the protein, we have cloned the mouse full length 60 kDa SS-A/Ro cDNA using 5' RACE based on a cDNA sequence reported in the mouse genome project. The recombinant protein derived from the putative full-length construct was shown to react with human prototype anti-SS-A/Ro serum Ge in western blot and immunoprecipitation and comigrated with cellular 60 kDa SS-A/Ro protein in 3T3 cells. Cellular expression, measured by RT-PCR, was highest in mouse brain, followed by lung, muscle, kidney and heart. Lower levels were found in testis, liver and spleen. Like the human 60 kDa SS-A/Ro protein, the deduced mouse homolog has 538 amino acids. Sequence analysis showed 89.9% identity and 95.0% similarity between the mouse and human proteins

Fourteen patients were enrolled in a placebo-controlled double-blind randomized trial of 8 weeks of treatment for active lupus nephritis. Seven patients received prednisone at a dose of 1 mg kg(minus sign1) day(minus sign1) plus misoprostol at a dose of 200 &mgr;g P.O. Q.I.D.; 7 patients received prednisone plus placebo. The patients included 12 females, 2 males; 3 African-Americans, 3 Asians, 5 Hispanics, and 3 Caucasians. There were no serious side effects associated with prednisone or misoprostol treatment during the 8-week study period. Laboratory measures obtained at baseline, 4, 8, and 12 weeks included complete blood count (CBC), ESR, C reactive protein (CRP), serum creatinine, creatinine clearance, 24-h urine protein excretion, C3, C4, and anti-double stranded DNA (anti-dsDNA). Statistical analysis was conducted assessing change in measures over time in the entire study group by paired t-tests. The effect of treatment on change over time was examined by analysis of covariance. Log transformation of the variables was performed prior to statistical analysis. For the entire study group, the mean levels of ESR, CRP, 24-h protein excretion, C3, C4, and anti-dsDNA were improved at 4, 8, and 12 weeks. The mean ESR at baseline was 70 plus minus 8 compared to 42 plus minus 8 at 12 weeks (p < 0.01). The mean CRP at baseline was 0.6 plus minus 0.2 compared to 0.2 plus minus 0.1 at 12 weeks (p < 0.01). The 24-h protein excretion was 4367 plus minus 769 mg at baseline compared to 2512 plus minus 709 mg at 12 weeks (p = 0.02). The mean C3 at baseline was 40 plus minus 4 mg dl(minus sign1) compared to 60 plus minus 4 mg dl(minus sign1) at 12 weeks (p < 0.01). The mean C4 at baseline was 14 plus minus 1 mg dl(minus sign1) compared to 23 plus minus 2 mg dl(minus sign1) at 12 weeks (p < 0.01). The mean anti-dsDNA at baseline was 4268 plus minus 1780 compared to 316 plus minus 111 at 12 weeks (p < 0.001). The baseline serum creatinine (1.12 plus minus.15 mg dl(minus sign1)) and creatinine clearance (82 plus minus 15 ml min(minus sign1)) were not significantly changed at 12 weeks (1.10 plus minus 0.2 mg dl(minus sign1) and 80 plus minus 17 ml min(minus sign1), respectively). Comparing the misoprostol treatment group to the placebo group, there were no statistically significant differences for ESR, CRP, creatinine, creatinine clearance, 24-h protein excretion, C3, C4, or anti-dsDNA at any time points. However, comparing the misoprostol treatment group at 4 weeks to the placebo group, a more rapid decrease in anti-dsDNA (reduction of 3297 plus minus 2374) was observed in the misoprostol treatment group versus 304 plus minus 409 in the placebo group), as well as lower mean anti-dsDNA levels (464 plus minus 140) in the misoprostol treatment group versus 4118 plus minus 3834 in the placebo group). Also, the C3 and C4 levels at 12 weeks in the misoprostol treatment group (67 plus minus 5 and 27 plus minus 3 mg dl(minus sign1), respectively) were greater than levels in the placebo group (52 plus minus 4 and 19 plus minus 3 mg dl(minus sign1), respectively). The data demonstrate that oral prednisone is effective in reducing proteinuria and improving the biological markers of disease activity (i.e., ESR, CRP, C3, C4, and anti-dsDNA) following short-term treatment of active lupus nephritis. Additionally, the more rapid change in anti-dsDNA levels and superior normalization of complement levels in the treatment group, although not statistically significant, are consistent with a biologic effect of misoprostol on lymphocyte function and the production of a pathogenic autoantibodies

OBJECTIVE: Congenital complete heart block is associated with maternal autoantibodies to Ro and La proteins, which injure the fetal cardiac conduction system. We administered dexamethasone to the mothers of five fetuses with heart block caused by maternal antibodies. STUDY DESIGN: We diagnosed five cases of fetal heart block at 20 to 23 weeks and treated all mothers with dexamethasone 4 mg orally each day for the remainder of the pregnancy. All patients were positive for anti-SS-A (anti-Ro) and/or anti-SS-B (anti-La) antibodies. RESULTS: Four patients had complete heart block, and one had second-degree block. In two patients (one with complete heart block, one with second-degree heart block) the degree of block lessened with treatment. Hydrops in three complete heart block patients resolved after treatment. Maternal antibody levels did not change. Matched maternal and cord samples at delivery showed similar antibody levels. CONCLUSIONS: Complete heart block can respond to transplacental glucocorticoid therapy with improved cardiac conduction. Because there may be a concurrent myocarditis, treatment in utero may also improve cardiac contractility, leading to the observed rapid resolution of hydrops. Treatment with steroids that cross the placenta should be considered for newly diagnosed cases of complete heart block with positive antibody screens