Tomio Fujita

Neonatal lupus erythematosus: results of maternal corticosteroid therapy

OBJECTIVEnTo assess the possibility of preventing cardiac or cutaneous manifestations of neonatal lupus erythematosus or treating the fetus with congenital heart block by administering corticosteroid therapy to the mother.nnnMETHODSnEighty-seven offspring of 40 anti-Ro/SSA-positive mothers, followed up from 1979 to 1996, were evaluated. Autoantibodies against Ro/SSA and La/SSB antigens were detected by immunodiffusion and enzyme-linked immunosorbent assay.nnnRESULTSnNone of 26 neonates whose mothers received corticosteroid maintenance therapy initiated before 16 weeks gestation demonstrated congenital heart block, whereas 15 of 61 neonates whose mothers received no corticosteroids during pregnancy or began receiving steroid therapy after 16 weeks gestation had congenital heart block. Complete congenital heart block, once developed, did not respond to corticosteroid treatment in utero. Four infants whose mothers received steroid treatment before 16 weeks gestation had skin lesions of neonatal lupus erythematosus.nnnCONCLUSIONnOnce established, complete congenital heart block was irreversible and maternal corticosteroid therapy did not effectively prevent cutaneous lupus erythematosus. However, prenatal maintenance therapy with prednisolone or betamethasone given to the mother starting early in pregnancy (before 16 weeks gestation) might reduce the risk of developing antibody-mediated congenital heart block in the offspring.

A1C but Not Serum Glycated Albumin Is Elevated Because of Iron Deficiency in Late Pregnancy in Diabetic Women

OBJECTIVE We have already reported that A1C is elevated because of iron deficiency in late pregnancy among nondiabetic pregnant women. This report examined whether the same phenomenon is observed in pregnant women with diabetes. RESEARCH DESIGN AND METHODS This longitudinal study was conducted in 17 pregnant women with diabetes (20–35 weeks of pregnancy). A1C, serum glycated albumin, erythrocyte indexes, and iron metabolism indexes were measured. RESULTS A1C levels were significantly increased in late pregnancy, whereas serum glycated albumin showed no significant changes. Glycated albumin/A1C ratio, mean corpuscular hemoglobin, serum transferrin saturation, and serum ferritin were significantly decreased in late pregnancy. Serum transferrin saturation showed a significant positive correlation with glycated albumin/A1C ratio. CONCLUSIONS A1C levels, but not serum glycated albumin levels, are elevated in late pregnancy because of iron deficiency in diabetic women. Serum glycated albumin may offer an adequate marker for glycemic control during pregnancy.

Polymorphisms of HLA class II genes and autoimmune responses to Ro/SS-A-La/SS-B among Japanese subjects

OBJECTIVEnTo investigate HLA class II allele associations with autoantibody responses to Ro/SS-A and La/SS-B among Japanese subjects.nnnMETHODSnHaplotype and allele distributions, along with molecular polymorphisms, of HLA class II genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism in 41 Japanese women with precipitating autoantibodies to Ro/SS-A and/or La/SS-B.nnnRESULTSnAmong women with both Ro/SS-A and La/SS-B antibodies, the HLA class II haplotype DRB1*08032/DQA1*0103/DQB1*0601 and DRB1*08032 allele showed significantly increased frequencies compared with patients with anti-Ro/SS-A alone or with normal controls. All women with both anti-Ro/SS-A and anti-La/SS-B, but not those with anti-Ro/SS-A alone, carried DRB1 alleles that shared the same amino acid residues at positions 14-31 and 71 of the hypervariable regions of the DRB1 chain. All anti-Ro/SS-A positive women carried 1 or 2 alleles of DQB1*06 and DQB1*03 subtypes that shared the same amino acid residues at positions 71-77 of the DQB1 chain. HLA class II allele distributions did not differ among 3 anti-Ro/SS-A positive groups with different disease expressions, i.e., patients with systemic lupus erythematosus, patients with primary Sjögrens syndrome, and women with no apparent symptoms of rheumatic disease.nnnCONCLUSIONnHLA class II allele distributions differ among anti-Ro/SS-A positive subjects according to the presence or absence of coexisting anti-La/SS-B antibodies, but not according to disease expression. Our findings suggest that different HLA class II molecules might control the development of anti-Ro/SS-A and/or anti-La/SS-B antibodies in the autoimmune response to the Ro/SS-A-La/SS-B complex.

Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss

Recent findings have raised the possibility that polymorphisms within the annexin A5 gene (ANXA5) promoter contribute to the etiology of recurrent pregnancy loss (RPL). In our present study, 243 Japanese women who had suffered more than three fetal losses and a group of 119 fertile controls were genotyped for four ANXA5 gene promoter single-nucleotide polymorphisms (SNPs; SNP1-4: g.-467G >A, g.-448A>C, g.-422T>C, g.-373G>A) previously reported to be associated with this disorder. An additional two SNPs located within the 5-untranslated region of the ANXA5 (SNP5 and 6: g.-302T>G, g.-1C>T) were also evaluated. Our case--control study revealed that the minor allele was significantly more frequent in the RPL group than controls for all six of these SNPs, among which SNP5 showed the highest significance (P= 0.002). As with the M2 haplotype for SNP1-4 (A-C-C-A) for a western population in previous reports, a haplotype comprising all of the minor alleles for SNP1-6 (A-C-C-A-G-T), the third major haplotype in the Japanese population, showed a significantly higher frequency in our current RPL subjects than in controls (P= 0.025). In addition, the second major haplotype (G-A-T-G-G-C) was found to confer a significant risk of RPL (P= 0.036), implicating SNP5 as a major risk determinant for this disease. Our present findings support the hypothesis that genomic variations within the ANXA5 gene upstream region impact upon the disease susceptibility to RPL. Our data indicate that SNP5 is a novel risk factor for this disease in the Japanese population.

Clinical Significance and Treatment of Massive Intervillous Fibrin Deposition Associated with Recurrent Fetal Growth Retardation

Retrospective examinations of 8,139 placentae were performed to clarify the relationship between placental disorders with massive intervillous fibrin deposition (MIFD) and intrauterine growth retardation (IUGR). Although the incidence of MIFD was low (0.4%), the small-for-date (SFD) birth rate in the MIFD group was significantly higher than that in the control group (62.9 vs. 8.3%; p < 0.001). Seventeen of 35 patients in the MIFD group had no clinical complications. MIFD itself was thought to be the main cause of IUGR in these patients. 78.4% of multiparae in the MIFD group have unsuccessful obstetrical histories such as intrauterine fetal death and fetal growth retardation. Four of 6 patients with a history of MIFD and SFD delivery in a previous pregnancy repeated the same episode. These data indicate that the MIFD recurrence rate in subsequent pregnancies must be high. Patients with a history of both SFD delivery and MIFD in previous pregnancies were defined as high-risk patients and they were given orally 30 mg of aspirin and 150 mg of dipyridamole daily and/or daily intravenous injection of 10,000 IU heparin during pregnancy. As a result, MIFD did not recur in all cases of the treated group and 87.5% (7/8) of the treated group could deliver approximate-for-date infants compared with 33.3% (2/6) of the untreated group (p < 0.05). These results indicate that anticoagulant and antiplatelet therapies are extremely effective for prevention of MIFD and IUGR due to MIFD.

Neonatal lupus erythematosus: Analysis of HLA class II alleles in mothers and siblings from seven Japanese families

BACKGROUNDnNeonatal lupus erythematosus (NLE) is a syndrome characterized by dermatitis and congenital heart block. The disease is mostly associated with transplacental passage of maternal anti-Ro(SS-A) or anti-La(SS-B) antibodies. Maternal HLA-DR3 and DQ2 alleles are associated with NLE in white and North American black populations.nnnOBJECTIVEnWe sought evidence of a potential genetic disposition to NLE in mothers with a relatively homogeneous ethnic background.nnnMETHODSnClass II human major histocompatibility complex HLA-DRB1, DQA1, DQB1, and DPB1 alleles were determined by polymerase chain reaction-restriction fragment length polymorphism in anti-Ro(SS-A)-positive mothers as well as in infants from seven Japanese families with siblings concordant or discordant for disease expression of NLE.nnnRESULTSnAll seven mothers had two or three DQ alleles of DQA1 and DQB1 possessing specific amino acid residues, which are reportedly associated with anti-Ro(SS-A) autoantibody response in white and black populations. There was no class II HLA profile that distinguished disease manifestations of NLE in infants.nnnCONCLUSIONnThe HLA class II allele associations with anti-Ro(SS-A) autoantibodies that have been noted in other ethnic groups were also found in Japanese anti-Ro(SS-A)-positive mothers whose infants had NLE, suggesting shared susceptibility factors across racial barriers in maternal predisposition to Ro(SS-A) autoimmune response.

Neonatal lupus erythematosus: studies on HLA class II genes and autoantibody profiles in Japanese mothers.

Neonatal lupus erythematosus (NLE) is a rare disorder of neonates characterized by two major clinical manifestations: congenital heart block and cutaneous lupus lesions. The disease is associated with placentally transferred maternal anti-Ro/SSA and/or La/SSB antibodies. To clarify possible class II HLA associations with maternal autoantibody responses, haplotypic and allelic distributions, along with the polymorphism of the MHC class II HLA alleles, were analyzed based on PCR-RFLP results in 25 Japanese mothers of two groups defined by precipitating autoantibody profiles. Among mothers with both anti-Ro/SSA and anti-La/SSB antibodies, but not those with anti-Ro/SSA alone, the class II haplotypes DRB1*1101-DQA1*0501-DQB1*0301 and DRB1*08032-DQA1*0103-DQB1*0601 as well as individual class II alleles DRB1*1101, DRB1*08032 and DQB1*0301 showed significantly increased frequencies compared to those in normal controls. All anti-Ro/SSA and anti-La/SSB positive mothers carried DRB1 alleles that shared the same amino acid residues at positions 14-31 and 71 of the DRB1 chain. These mothers also carried homozygous or heterozygous DQ6 and DQ3 alleles that shared the same amino acid residues at positions 27-36 and 71-77 of hypervariable regions of the DQB1 chain. Furthermore, all mothers with both anti-Ro/SSA and anti-La/SSB were homozygous for DPB1*0501. Nine of 10 anti-Ro/SSA and anti-La/SSB-positive mothers, but only 6 of 15 mothers with anti-Ro/SSA alone, had affected infants. Thus, our findings suggest that there may be immunogenetic differences among mothers according to their autoantibody profiles, and that mothers with both anti-Ro/SSA and anti-La/SSB are more likely to have infants with NLE than mothers with anti-Ro/SSA alone.

Genetic analysis of patients with deep vein thrombosis during pregnancy and postpartum

Deep vein thrombosis (DVT) is a serious pregnancy-related complication. Recent studies indicate that the genetic background for DVT differs with ethnicity. In our study, we enrolled 18 consecutive Japanese patients who had developed DVT during pregnancy and postpartum. We performed a genetic analysis of three candidate genes for DVT, protein S, protein C and antithrombin, in these patients. We found that four patients had missense mutations in the protein S gene, including the K196E mutation in two patients, the L446P mutation in one patient, and the D79Y and T630I mutations in one patient, as well as one patient with the C147Y mutation in the protein C gene. All five patients with genetic mutations had DVT in their first two trimesters. Nine of the patients without genetic mutations developed DVT in the first two trimesters, and four in the postpartum period. Thus, genetic mutations in the protein S gene were predominant in pregnant Japanese DVT women, and DVT in pregnant women with genetic mutations occurred more frequently at the early stage of pregnancy than postpartum. Considering the rapid decrease in protein S activity during pregnancy, we may need to assess thrombophilia in women before pregnancy.

Nonsynonymous mutations in three anticoagulant genes in Japanese patients with adverse pregnancy outcomes

BACKGROUNDnHereditary thrombophilias may associate with uteroplacental thrombosis leading to adverse pregnancy outcomes. The present study was conducted to reveal the frequency of the low-frequency thrombophilic protein S K196E mutation, as well as the frequency of very rare nonsynonymous mutations in protein S, protein C, and antithrombin genes, in patients with adverse pregnancy outcomes.nnnPATIENTS AND METHODSnWe enrolled 330 Japanese patients with adverse pregnancy outcomes and divided them into 233 patients with two or more miscarriages and 114 patients with fetal growth restriction (FGR) and/or intrauterine fetal death (IUFD); 17 patients belonged to both groups. We sequenced the entire coding regions of three anticoagulant genes in all 330 patients.nnnRESULTSnWe found that protein S K196E mutation was identified in 4 out of 233 patients with recurrent miscarriage and in 2 out of 114 patients with FGR and/or IUFD. The frequencies of this mutation in these patient groups were not different from that in a Japanese general population. Very rare nonsynonymous mutations were identified in 3.3% (11 out of 330) of patients with adverse pregnancy outcomes.nnnCONCLUSIONSnAlthough the low-frequency protein S K196E mutation can increase the risk for venous thromboembolism, it did not increase the risk for adverse pregnancy outcomes even in Japanese.

Effect of amnionitis on the complement system of preterm infants

The development of the complement system was studied by quantitation of total hemolytic complement activity (CH50), C1q, C3, C4, and C3 split product (C3d) in cord plasma of nine human fetuses (17-22 weeks of gestation), 110 preterm (24-36 weeks of gestation) and 30 term neonates. The complement levels were analyzed in relation to various illnesses of preterm infants. Histological examination of the placenta revealed a higher incidence of amnionitis in the placenta of less than 34 gestational weeks. In cases without amnionitis, there were significant correlations between complement levels and gestational age. In cases with amnionitis, the complement system was activated even in infants of less than 28 weeks gestation. The complement levels correlated with the extent of the inflammation in the placentas and umbilical cords except for C1q. In infants with Wilson-Mikity syndrome, complement levels other than C1q were significantly elevated in comparison with those of infants with respiratory distress syndrome. In the group of preterm infants without amnionitis, no differences were found between infants with intrauterine growth retardation and those with growth appropriate for gestational age.