Faculty Bibliography

This study was undertaken to determine the role of antibodies against both recombinant Ro (r-Ro) and La (r-La) proteins and polypeptides derived from the recombinant La protein in predicting fetal and neonatal outcome in children at risk to develop neonatal lupus erythematosus (NLE). All sera were obtained in the perinatal period and quantitative ELISA assays were used. We collected 41 maternal sera within 2 months of delivery of a child with NLE (21 with congenital heart disease block (CHB) and 20 with dermatologic NLE) and 19 sera from anti-Ro and/or anti-La antibody-positive mothers with systemic lupus erythematosus (SLE) who delivered a child without NLE. All sera were tested for anti-r-La and anti-r-Ro antibodies by ELISA, and most sera were tested for antibodies directed against La polypeptides by immunoblot. We found significantly higher anti-r-La antibody levels in the sera from mothers of children with NLE compared with sera from mothers of unaffected children (0.67 +/- 0.43 versus 0.14 +/- 0.30; P < 0.0001). There was a statistically significant difference in the mean anti-r-La levels between the sera of mothers of children with CHB compared with dermatologic NLE (0.51 +/- 0.45 versus 0.83 +/- 0.37 respectively; P = 0.0091). When we examined antibodies directed against the recombinant 52-kD Ro protein, there was a statistically significant elevation of titres in the sera of mothers of NLE children (0.77 +/- 0.35) compared with non-NLE mothers (0.29 +/- 0.39; P < 0.0001). There was no difference in the r-Ro levels between mothers of children with dermatologic NLE compared with CHB (0.82 +/- 0.37 versus 0.71 +/- 0.74; P = 0.32). When we examined polypeptides derived from the recombinant La protein, the mean number of polypeptides recognized by sera from mothers of children with NLE was significantly higher than the mean number of polypeptides recognized by sera from mothers of unaffected children (5.1 +/- 0.54 versus 2.3 +/- 0.54 respectively; P < 0.001). More importantly, when we examined the individual polypeptides, we found that only sera from mothers of children with NLE and not from mothers of unaffected children recognized a polypeptide designated DD (30% versus 0%, respectively). These studies indicate that the autoantibody response to the Ro/La particle can differentiate sera from mothers of children with NLE and sera from mothers of unaffected children. Furthermore, there was a difference in the anti-La autoantibody response between mothers of children with CHB and dermatologic NLE.(ABSTRACT TRUNCATED AT 400 WORDS)

The medical records of patients receiving cyclophosphamide for lupus nephritis between 1987 and 1993 at the New York University/Hospital for Joint Diseases Lupus Study Group Institutions were retrospectively reviewed. We identified 45 patients (38 female, seven male) who received a mean of 9 +/- 1 (range 2-23) pulses of intravenous cyclophosphamide for diffuse proliferative glomerulonephritis (n = 28), focal proliferative glomerulonephritis (n = 7), membranous nephropathy (n = 5), mesangial nephropathy with sclerosis (n = 1) or nephritis without biopsy (n = 4). Forty-two of the 45 patients received cyclophosphamide after failing steroid therapy. During a follow-up period of 52 +/- 3 months, nine patients progressed to end-stage renal disease (ESRD) with three additional patients experiencing a doubling of the creatinine and two patients persistent nephrotic range proteinuria. There were no deaths directly attributable to cyclophosphamide and no patients developed hemorrhagic cystitis or malignancy. Ten of 37 women had ceased menstruating prior to cyclophosphamide therapy. Treatment-associated amenorrhea occurred in only three patients all over 27 years of age. Intermittent intravenous cyclophosphamide therapy of lupus nephritis is well tolerated and usually effective in maintaining renal function in patients unresponsive to steroids although, in our experience, 20% of patients developed ESRD and a total of 14 of 45 (30%) patients had unsatisfactory outcomes

To determine the feasibility and effectiveness of prenatal therapy of congenital heart block (CHB), information was sought regarding the timing of identification of CHB in 72 pregnancies and the outcome of those pregnancies in which the mothers were administered corticosteroids. Mailed questionnaires with telephone follow-up, data from primary physicians and chart review were utilized. In 38 (53%) of affected pregnancies CHB was identified between 16 and 24 weeks of gestation, in 17 (24%) between 25 and 30 weeks of gestation, in 8 (11%) between 31 and 37 weeks, and in 5 (7%) between 38 and 40 weeks. In four pregnancies the timing was unknown. Five women were taking prednisone for disease activity prior to the discovery of CHB and in six other women prednisone therapy was initiated at or about the time CHB was identified. In 19 pregnancies, women were given fluorinated steroids (available to the fetus in an active form) as attempted therapy after the discovery of CHB. Of these, one fetus with second degree block reverted to sinus rhythm and two with third degree block exhibited an improvement in the degree of block. In eight fetuses pleural and/or pericardial effusions resolved. In conclusion, the gestational period of heightened fetal vulnerability for the development of heart block is in the mid second to early third trimester. Although there is no evidence that maternal prednisone should be used prophylactially, fluorinated steroids may be efficacious after the identification of heart block, particularly with regard to an associated myocarditis

Five cases of benign fetal arrhythmias presented with dramatic pictures of sustained irregular bradycardias. These cases were not associated with structural heart disease, the development of hydrops fetalis, or maternal autoantibodies. In all but one case, the arrhythmias resolved before delivery. Two fetuses had 2:1 atrioventricular block and the other three showed group beating due to blocked atrial trigeminy. With regular intermittent reevaluation, and if no signs of hydrops occur, watchful waiting is the suggested therapeutic modality

OBJECTIVE: Nitric oxide, a potent vasodilator released by endothelial cells, inhibits platelet aggregation and adhesion to vascular endothelial surfaces. Because endothelial cell damage is considered pivotal in the pathogenesis of preeclampsia, this study was initiated to determine whether nitric oxide production is decreased in patients with preeclampsia. STUDY DESIGN: Twenty-six patients with preeclampsia (as defined by a blood pressure > or = 140 mm Hg systolic or 90 mm Hg diastolic plus proteinuria, > or = 300 mg per 24 hours or > or = 2+ by dipstick, both occurring on two occasions > or = 4 hours apart) and 26 normotensive women with singleton gestations in the third trimester were studied. Because nitric oxide is spontaneously oxidized to both nitrite and nitrate, two analytic assays were used serially. Serum nitrite levels were initially determined with the Greiss reagent and subsequently analyzed with Escherichia coli nitrate reductase. RESULTS: With the Greiss reagent alone the mean +/- SEM of serum nitrite level in 26 patients with preeclampsia was significantly decreased compared with 26 normotensive patients (3.46 +/- 1.43 mumol/L vs 4.65 +/- 0.85 mumol/L, p = 0.02). With the addition of the nitrate reductase enzyme of Escherichia coli the mean +/- SEM of serum nitrite level in 26 preeclamptic patients was again significantly decreased compared with 26 normotensive patients (20.04 +/- 1.25 mumol/L vs 27.38 +/- 2.23 mumol/L, p = 0.02). One patient with the syndrome of hemolysis, elevated liver enzymes, and low platelets demonstrated a concurrent decrease in serum nitrite over a 2-week period, emphasizing the relationship of nitric oxide to the pathophysiologic features of the syndrome. CONCLUSIONS: Circulating levels of nitrite are decreased in patients with preeclampsia. These data support the concept that diminished nitric oxide synthesis contributes to the pathophysiologic changes seen in preeclampsia

OBJECTIVE. Since there is suggestive but, to date, indirect evidence that maternal anti-SSA(Ro) and SSB(La) antibodies are pathogenic in congenital heart block (CHB), we explored the hypothesis that binding to fetal tissues would result in selective depletion of autoantibodies from the neonatal circulation. METHODS. Maternal and umbilical cord levels of anti-48 kDa SSB(La), anti-52 kDa SSA(Ro) and anti-60 kDa SSA(Ro) antibodies were measured by ELISA and immunoprecipitation at parturition in 15 pregnancies complicated by CHB. A control group consisted of 13 pregnancies in which the mother was known to have antibodies to either SSA(Ro) and/or SSB(La) and the children did not have CHB. RESULTS. The ratios of maternal to cord serum levels of anti-48 SSB(La), anti-52 SSA(Ro) and anti-60 kDa SSA(Ro) antibodies ranged from 0.71 to 2.38 in both affected and unaffected pregnancies. The mean ratio obtained for each of the 3 autoantibodies was not significantly different between the 2 groups. Moreover these ratios did not significantly differ from the mean ratios obtained for total IgG levels in either group. CONCLUSION. These data demonstrate that maternal antibodies to all components of the SSA(Ro) SSB(La) system are efficiently transported across the placenta and are not selectively depleted in the circulation of neonates with CHB

Neonatal lupus continues to generate considerable interest despite its rarity; more than 15 original contributions were made to the literature in the past year. Diverse aspects of this 'syndrome' of passively acquired autoimmunity have been covered. Experiments using a rabbit model provided insights into the pathogenicity of maternal anti-Ro/SS-A and anti-La/SS-B antibodies. Perfusion of rabbit hearts with anti-Ro/SS-A and anti-La/SS-B sera resulted in conduction abnormalities in whole adult rabbit hearts and induced a reduction in the peak slow inward current in patch-clamp experiments of isolated rabbit ventricular myocytes, suggesting involvement of calcium channels. Clinical investigations are moving away from case reports, and recent studies now include substantial entries. Assuming that patients reported from the United States, Finland, and England are all separate, sera from at least 100 different mothers of infants with congenital heart block have been studied. Although there is apparently no serologic profile that is unique to mothers of affected children, compared with mothers of healthy children, anti-Ro/SS-A antibodies (anti-52-kD antibodies are more prevalent by immunoblot in congenital heart block, although all these sera are likely to have anti-60-kD antibodies by immunoprecipitation) are usually of high titer and associated with anti-La/SS-B antibodies. To date, the only maternal autoantibodies that have been associated with congenital heart block recognize Ro/SS-A or La/SS-B antigens. Mothers of affected infants are often asymptomatic, and when symptomatic, the clinical features are frequently characteristic of Sjogren's syndrome. Although treatment of affected fetuses with dexamethasone has successfully diminished associated effusions, there has been no report of reversal of established third-degree heart block

Previous studies have shown that neutrophils in the circulation of patients with active systemic lupus erythematosus (SLE) are activated as judged by their increased surface expression of the beta 2-integrin CD11b/CD18. Since activation of neutrophils leads to altered expression of another adhesion molecule, L-selectin (LS), we examined neutrophils from patients with SLE for changes in the expression of CD11b/CD18 and LS by cytofluorographic analysis of immunofluorescent-labeled cells. Overall there was no difference between surface expression of CD11b/CD18 on neutrophils from SLE patients or controls [mean fluorescence 225 +/- 26 vs 225 +/- 13 relative fluorescence units (RFU), respectively]. However, as previously reported, neutrophils from patients with more active disease (activity score > or = 3, UCH Middlesex activity score) expressed greater CD11b/CD18 than neutrophils from controls (319 +/- 40 RFU, P < 0.03, n = 9) or from patients with less active disease (193 +/- 10 RFU, P < 0.006). Indeed, CD11b/CD18 expression correlated directly with disease activity (r = 0.54, P < 0.02). Stimulation of neutrophils ex vivo with the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (100 nM) induced up-regulation of CD11b/CD18 in cells from both SLE patients and controls (205 +/- 12% vs 239 +/- 15% of basal, respectively), but neutrophils from the most active patients (score > or = 3) increased CD11b/CD18 expression less than controls (175 +/- 12% of basal, P < 0.003, n = 9). The magnitude of the stimulated increment in expression of CD11b/CD18 on neutrophils correlated inversely with SLE activity (r = -0.64, P < 0.003, n = 20). Surprisingly, we observed no change in LS expression on neutrophils from SLE patients compared to controls (143 +/- 14 vs 141 +/- 16 RFU, respectively) even in patients with the highest activity indices (154 +/- 21 RFU). In contrast to CD11b/CD18, there was no correlation between LS expression and disease activity (r = 0.12, P = NS). Stimulation of neutrophils reduced the expression of LS similarly in both controls and SLE patients (67 +/- 3% vs 58 +/- 4% reduction, respectively) and did not correlate with disease activity (r = 0.07, P = NS, n = 20). These results show, for the first time, that changes in CD11b/CD18 expression do not correlate with LS expression on neutrophils from patients with active SLE.(ABSTRACT TRUNCATED AT 400 WORDS)