Signs of first‐degree heart block occur in one‐third of fetuses of pregnant women with anti–SSA/Ro 52‐kd antibodies

Objective

To prospectively investigate the development of fetal heart block in anti–SSA/Ro 52‐kd–positive women, and to evaluate the usefulness of serial Doppler echocardiography in detecting early signs of congenital heart block.

Methods

Twenty‐four women with anti–SSA/Ro 52‐kd antibodies and consequently increased risk for fetal heart block were followed up weekly, between 18 and 24 weeks of gestation, with two Doppler echocardiographic methods designed to estimate the time delay between hemodynamic events caused by atrial and ventricular depolarizations. Two hundred eighty‐four women with normal pregnancies served as controls. Anti–Ro 52‐kd, anti–Ro 60‐kd, and anti‐La antibodies were investigated by immunoblotting and enzyme‐linked immunosorbent assay using recombinant proteins.

Results

In anti–Ro 52‐kd–positive women, fetal atrioventricular (AV) time intervals were longer and heart rates were slightly lower compared with those in controls. Eight of 24 fetuses had signs of first‐degree block. One of these fetuses had progression to complete block, and another showed recovery from second‐degree block to first‐degree block with betamethasone treatment. In the remaining 6 fetuses, spontaneous normalization occurred before or shortly after birth. Fetuses with normal AV time intervals at 18–24 weeks had normal electrocardiographic results at birth.

Conclusion

Anti–Ro 52‐kd–positive pregnant women frequently carry fetuses with Doppler echocardiographic signs of first‐degree AV block. These blocks revert spontaneously in the majority of fetuses, but progression to a more severe degree of block may occur in some. Serial Doppler echocardiographic measurement of AV time intervals is suggested as a useful method for surveillance of these high‐risk pregnancies.

     

Ro52, Ro60 and La IgG autoantibody levels and Ro52 IgG subclass profiles longitudinally throughout pregnancy in congenital heart block risk pregnancies

Congenital heart block occurs in fetuses of Ro/SSA and La/SSB positive women. To investigate the stability of maternal autoantibody levels during pregnancy, we followed Ro52, Ro60 and La autoantibody IgG level variation and Ro52 subclass profiles longitudinally in selected congenital heart block risk pregnancies. Serum samples were obtained from 12 Ro/La positive women diagnosed with a systemic rheumatic disease and followed on average 60 months (range two to 84) which included 13 pregnancies. Seven children were affected by neonatal lupus, whereof four developed complete congenital heart block. Serum was also collected from the babies at birth. Ro52, Ro60 and La IgG as well as subclass antibodies were analysed by ELISA using recombinant antigens. Six Ro/La negative rheumatic patients were included as controls for antibody levels during pregnancy. Ro52, Ro60 and La IgG levels decreased progressively from early to late pregnancy, significantly for Ro52 and Ro60 (P < 0.01). No peaks or persistent elevation of antibody levels were noted in any of the CHB risk pregnancies. Ro52 IgG1 antibody levels were significantly higher than IgG2 (P < 0.01), IgG3 (P < 0.01) and IgG4 (P < 0.05) levels in the mothers during pregnancy. Ro52 IgG1 and IgG4 levels decreased significantly from early to late pregnancy (P = 0.02), while levels of IgG2 and IgG3 were low and the decrease was not significant. All IgG subclasses were transferred to the children. We conclude that maternal levels of Ro52, Ro60 and La autoantibodies tended rather to decrease than to increase during pregnancy.     

First‐degree heart block in the fetus of an anti‐SSA/Ro–positive mother: Reversal after a short course of dexamethasone treatment

Isolated congenital heart block is almost invariably associated with the presence of antibodies to SSA/Ro and SSB/La antigens in the maternal circulation. Once established, third‐degree congenital heart block is permanent. However, a lesser degree of autoantibody‐associated heart block in a fetus can be reversed if it is recognized and treated early enough with fluorinated glucocorticosteroids. The only method available clinically for the recognition of first‐degree heart block in a fetus is measurement of the mechanical PR interval by pulsed Doppler echocardiography. This is the first report of a fetus in whom a diagnosis of first‐degree heart block and the consequent decision to intervene were based solely on this technique. In addition, the first‐degree heart block resolved completely after only 2 weeks of dexamethasone treatment, and the heart rhythm remained stable throughout the remainder of the pregnancy despite early discontinuation of therapy due to oligohydramnios.     

Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies: a prospective controlled study

Anti-Ro/SSA antibodies are associated with neonatal lupus but are also considered a possible cause for unexplained pregnancy loss and adverse pregnancy outcome. In a large multicentres cohort study we have prospectively followed 100 anti-Ro/SSA positive women (53 systemic lupus erythematosus (SLE)) during their 122 pregnancies and 107 anti-Ro/SSA negative women (58 SLE) (140 pregnancies). Anti-Ro/SSA antibodies were tested by immunoblot and counterimunoelectrophoresis. Mean gestational age at delivery (38 vs 37.9 weeks), prevalence of pregnancy loss (9.9 vs 18.6%), preterm birth (21.3 vs 13.9%), cesarean sections (49.2 vs 53.4%), premature rupture of membranes (4.9 vs 8.1%), preeclampsia (6.6 vs 8%), intrauterine growth retardation (0 vs 2.3%)and newborns small for gestational age (11.5 vs 5.8%) were similar in anti-Ro/SSA positive and negative SLE mothers; findings were similar in non-SLE women. Two cases of congenital heart block were observed out of 100 anti-Ro/SSA positive women. In conclusion, anti-Ro/SSA antibodies are responsible for congenital heart block but do not affect other pregnancy outcomes, both in SLE and in non-SLE women. The general outcome of these pregnancies is now very good, ifprospectively followed by multidisciplinary teams with ample experience in this field.     

Anti-Ro/SSA-associated corrected QT interval prolongation in adults: the role of antibody level and specificity

Objective

Recent evidence suggests that anti‐Ro/SSA antibodies, strongly associated with the development of congenital heart block, may also be arrhythmogenic for the adult heart. In fact, anti‐Ro/SSA–positive patients with connective tissue disease (CTD) frequently display corrected QT (QTc) prolongation associated with an increase in ventricular arrhythmias. However, QTc prolongation prevalence markedly differs throughout the studies (10–60%), but the reason why is not yet clear. The aim of this study was to evaluate whether anti‐Ro/SSA–associated QTc prolongation in adult patients with CTD is related to antibody level and specificity.

Methods

Forty‐nine adult patients with CTD underwent a resting 12‐lead electrocardiogram recording to measure QTc interval, and a venous withdrawal to determine anti‐Ro/SSA antibody level and specificity (anti–Ro/SSA 52 kd and anti–Ro/SSA 60 kd) by immunoenzymatic methods and Western blotting.

Results

In our population, a direct correlation was demonstrated between anti–Ro/SSA 52‐kd level and QTc duration (r = 0.38, P = 0.007), patients with a prolonged QTc had higher levels of anti–Ro/SSA 52 kd with respect to those with a normal QTc (P = 0.003), and patients with a moderate to high level (≥50 units/ml) of anti–Ro/SSA 52 kd showed a longer QTc interval (P = 0.008) and a higher QTc prolongation prevalence (P = 0.008) than those with a low positive/negative level (<50 units/ml). On the contrary, no association was found between QTc and anti–Ro/SSA 60‐kd level.

Conclusion

In anti‐Ro/SSA–positive adult patients with CTD, the occurrence of QTc prolongation seems strictly dependent on the anti–Ro/SSA 52‐kd level. This finding, possibly explaining the different QTc prolongation prevalence reported, strengthens the hypothesis that an extremely specific autoimmune cross‐reaction is responsible for the anti‐Ro/SSA–dependent interference on ventricular repolarization.     

First-degree heart block in the fetus of an anti-SSA/Ro-positive mother: reversal after a short course of dexamethasone treatment

Isolated congenital heart block is almost invariably associated with the presence of antibodies to SSA/Ro and SSB/La antigens in the maternal circulation. Once established, third-degree congenital heart block is permanent. However, a lesser degree of autoantibody-associated heart block in a fetus can be reversed if it is recognized and treated early enough with fluorinated glucocorticosteroids. The only method available clinically for the recognition of first-degree heart block in a fetus is measurement of the mechanical PR interval by pulsed Doppler echocardiography. This is the first report of a fetus in whom a diagnosis of first-degree heart block and the consequent decision to intervene were based solely on this technique. In addition, the first-degree heart block resolved completely after only 2 weeks of dexamethasone treatment, and the heart rhythm remained stable throughout the remainder of the pregnancy despite early discontinuation of therapy due to oligohydramnios.     

Passively acquired anti‐SSA/Ro antibodies are required for congenital heart block following ovodonation but maternal genes are not

Anti‐SSA/Ro antibodies are necessary but not sufficient to provoke autoimmune‐associated congenital heart block (CHB). Genetic factors are likely contributory. Accordingly, HLA‐related candidates and single‐nucleotide polymorphisms in the promoter region of tumor necrosis factor α and codon 10 in transforming growth factor β1 (TGFβ1) were evaluated in a unique family: the surrogate mother (anti‐SSA/Ro positive), the biologic father, and the CHB‐affected child (product of ovodonation). There was an HLA mismatch between the affected child and the surrogate mother. However, both the biologic and the surrogate mothers shared DQ2 and the profibrosing leucine polymorphism at codon 10 of TGFβ. In conclusion, we observed that CHB can develop in a genetically unrelated child exposed in utero to anti‐SSA/Ro antibodies. Testing for anti‐SSA/Ro antibodies might be considered in women undergoing artificial fertilization. It is possible that there is no direct association of maternal genes beyond a contributory role in generating the autoantibody.     

Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA/Ro 52-kd antibodies

OBJECTIVE: To prospectively investigate the development of fetal heart block in anti-SSA/Ro 52-kd-positive women, and to evaluate the usefulness of serial Doppler echocardiography in detecting early signs of congenital heart block. METHODS: Twenty-four women with anti-SSA/Ro 52-kd antibodies and consequently increased risk for fetal heart block were followed up weekly, between 18 and 24 weeks of gestation, with two Doppler echocardiographic methods designed to estimate the time delay between hemodynamic events caused by atrial and ventricular depolarizations. Two hundred eighty-four women with normal pregnancies served as controls. Anti-Ro 52-kd, anti-Ro 60-kd, and anti-La antibodies were investigated by immunoblotting and enzyme-linked immunosorbent assay using recombinant proteins. RESULTS: In anti-Ro 52-kd-positive women, fetal atrioventricular (AV) time intervals were longer and heart rates were slightly lower compared with those in controls. Eight of 24 fetuses had signs of first-degree block. One of these fetuses had progression to complete block, and another showed recovery from second-degree block to first-degree block with betamethasone treatment. In the remaining 6 fetuses, spontaneous normalization occurred before or shortly after birth. Fetuses with normal AV time intervals at 18-24 weeks had normal electrocardiographic results at birth. CONCLUSION: Anti-Ro 52-kd-positive pregnant women frequently carry fetuses with Doppler echocardiographic signs of first-degree AV block. These blocks revert spontaneously in the majority of fetuses, but progression to a more severe degree of block may occur in some. Serial Doppler echocardiographic measurement of AV time intervals is suggested as a useful method for surveillance of these high-risk pregnancies.     

Neonatal lupus syndromes

Children born from mothers positive for autoantibodies against SSA/Ro and/or anti‐SSB/La ribonucleoproteins may develop heart conduction tissue damage resulting in atrioventricular block and/or transient skin rash, liver enzyme abnormalities and anaemia/thrombocytopenia. Additional transient electrocardiographic abnormalities (sinus bradycardia, QT interval prolongation) have been reported. Such clinical and laboratory manifestations are included in the so‐called neonatal lupus syndromes, independently whether the mother is suffering from a systemic autoimmune disease or is totally asymptomatic. The prevalence of the congenital heart block is around 2%, of neonatal rash around 20%, while laboratory abnormalities in asymptomatic babies can be detected in up to 40% of cases. The risk of recurrence of complete heart block is almost 10 times higher in the following pregnancies. Most of the mothers are asymptomatic at delivery and are identified only by the birth of an affected child. Their long‐term outcome is generally more reassuring than previously assumed and arthralgias and xerophtalmia are the most common symptoms. A standard therapy for heart blocks detected in uterus is still a matter of investigation, although fluorinated corticosteroids have been reported to be effective on myocarditic signs when present. Serial echocardiograms and obstetric sonograms, performed at least every two weeks, starting from the 16 weeks gestation, are recommended in anti‐Ro/SSA positive pregnant women: the goal is to detect early fetal abnormalities, that might precede complete atrioventricular block and that might be a target of preventive therapy. Transplacental passage of maternal anti‐SSA/Ro ‐SSB/La IgG is thought to be pivotal in inducing tissue damage. However, the discordant appearance of the syndrome in twins does suggest a role also for fetal or environmental factors.     

Anti-Ro52 antibody level is an important marker of fetal congenital heart block risk in anti-Ro/SSA antibody positive pregnancy

Objective: The aims of this study are to determine the incidence of congenital heart block (CHB) in the Japanese population and identify maternal factors predicting fetal CHB in anti-Ro/SSA antibody positive pregnancy.

Methods: A retrospective study was performed using 52,147 clinical records of pregnancies followed in a single center. For 183 anti-Ro/SSA antibody-positive women, anti-Ro52 and Ro60 antibodies were measured, and the odds of CHB in relation to maternal clinical features were calculated by multivariate analysis. The receiver-operating characteristic (ROC) curves for predicting CHB were constructed for the titers of anti-Ro/SSA, anti-Ro52 and anti-Ro60 antibodies.

Results: Fetal CHB occurred in two pregnancies among those without known risks such as positive anti-Ro/SSA antibody or previous CHB-affected pregnancy, suggesting an incidence similar to that in Caucasian populations. As for the anti-Ro/SSA antibody positive pregnancies, the titers of anti-Ro/SSA, anti-Ro52 and anti-Ro60 antibodies were independent risk factors for fetal CHB and the use of corticosteroids before 18 gestational weeks was an independent protective factor. The area under the ROC was 0.84, 0.73 and 0.74 for anti-Ro52, anti-Ro60 and anti-Ro/SSA antibodies, respectively.

Conclusion: CHB occurred in two among approximately 50,000 pregnancies without known risks such as positive anti-Ro/SSA antibody or previous delivery of CHB-affected babies. Measurement of anti-Ro52 antibody levels may be helpful in extracting a risk group of delivering CHB infants in the anti-Ro/SSA antibody positive pregnancy.     

Pregnancy in lupus.

Patients with systemic lupus erythematosus with established disease have poorer pregnancy outcomes than do women with later onset disease. Active renal disease and maternal hypertension are important predictors of fetal loss and premature birth, respectively. Placental pathology in SLE patients is characterized by decidual vasculopathy and infarction, and in APLS patients, infarction can be extensive. Maternal anti-52 kD SSA/Ro by immunoblot continues to be an important risk factor for having a child with heart block. The risk of having a subsequent child with congenital heart block ranges between 12-16%. Childhood morbidity with heart block is high, with 63% eventually requiring pacemakers. In APLS, antiB2GP-I antibodies can have a significant role in the diagnosis, especially when the traditional assays for aCL antibodies and LAC are negative. Some obstetricians have found that IVIG improves the birthrate in aPL positive women who have recurrent spontaneous abortions after IVF.     

A serologic marker for fetal risk of congenital heart block

OBJECTIVE: To analyze the humoral immune response to Ro/SSA and La/SSB antigens in detail, in order to identify markers in mothers at high risk of having children with congenital heart block (CHB). METHODS: Serum samples were obtained from 9 Ro/La-positive mothers who gave birth to affected children, from their 8 newborns with CHB, and from 26 Ro/La-positive mothers whose children were healthy. Antibodies against Ro 52-kd, Ro 60-kd, and La were analyzed by enzyme-linked immunosorbent assay and immunoblotting, using recombinant proteins and synthetic peptides. RESULTS: IgG anti-Ro 52-kd antibodies were detected in all mothers who gave birth to children with CHB, as well as in their affected children, but were less frequent and at lower levels in control mothers. Fine mapping revealed a striking difference in which the response in mothers with affected children was dominated by antibodies to amino acids 200-239 of the Ro 52-kd protein (P = 0.0002), whereas the primary activity in control mothers was against amino acids 176-196 (P = 0.001). Furthermore, 8 of 9 mothers of children with CHB had antibody reactivity against amino acids 1-135 of the Ro 52-kd protein, containing 2 putative zinc fingers reconstituted under reducing conditions. CONCLUSION: The results suggest that development of CHB is strongly dependent on a specific antibody profile to Ro 52-kd, which may be a useful tool to identify pregnant Ro/La-positive women at risk of delivering a baby with CHB. Close monitoring of mothers at high risk would enable early detection of a block that is still developing and allow early treatment to combat more serious complications.     

Late neonatal lupus erythematosus onset in a child born of a mother with primary Sjögren's syndrome

BACKGROUND: The neonatal lupus syndrome can be present as congenital heart block (CHB) or as neonatal lupus erythematosus (NLE), both seldom passively acquired autoimmune diseases. CHB starts around week 20 of pregnancy and is a lifelong event, whereas NLE is self limiting and usually starts at the 6th week of the child's age-the maximum recorded up to week 20. CASE REPORT: An asymptomatic mother with primary Sjogren's syndrome and anti-SSA/Ro52, anti-SSA/Ro60, and anti-SSB/La autoantibodies is described who, at gestational week 23 during her first pregnancy, was diagnosed as having a male fetus with CHB due to third degree atrioventricular block. The boy from the second pregnancy developed skin eruptions which clinically and by biopsy were compatible with NLE at week 20+1 post partum. CONCLUSIONS: Our case of NLE, starting at week 20+1 of age, seems to be the latest reported clinical case of NLE. Development of CHB and NLE in two consecutive boy pregnancies is unusual.     

Autoimmune associated congenital heart block: integration of clinical and research clues in the management of the maternal / foetal dyad at risk

One of the strongest associations with autoantibodies directed to components of the SSA/Ro‐SSB/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. This risk is 10‐fold higher in women who have had a previously affected child with CHB. Anti‐Ro/La antibodies are necessary but insufficient to cause disease. In vitro and in vivo experiments suggest that the pathogenesis involves exaggerated apoptosis, macrophage/myfibroblast crosstalk, TGFβ expression and extensive fibrosis in the conducting system and in some cases surrounding myocardium. A disturbing observation is the rapidity of disease progression, with advanced heart block and life‐threatening cardiomyopathy observed <2 weeks from normal sinus rhythm. Once 3rd degree (complete) block is identified, reversal has never been achieved, despite dexamethasone. Current strategies include the evaluation of an early echocardiographic marker of injury, such as a prolonged PR interval and the use of IVIG as a preventative measure for pregnancies of mothers with previously affected children.     

Low titer,isolated anti Ro/SSA 60 kd antibodies is correlated with positive pregnancy outcomes in women at risk of congenital heart block

Clinical Rheumatology - Congenital heart block (CHB) is an autoantibody mediated disorder presumably caused by placental transmission of maternal autoantibodies to Ro/SSA 52 kd, p200, Ro/SSA 60 kd,...     

Anti-SSA/Ro and anti-SSB/La antibodies. What's new?

Anti-SSA/Ro and anti-SSB/La autoantibodies recognize different epitopes on polypeptides associated with small RNAs called scYRNA situated mostly in the cytoplasmic compartment (70%) and few in the nuclear compartment (30%). These hYRNPs (h=human) can be found on the cytoplasmic membrane or in small blebs during apoptosis after various stimuli such as UVB, 17-beta-estradiol, viral infection, TNF alpha and other cellular apoptosis inducing molecules. At least two major different proteins are called SSA/Ro: a 52 kDa Ro (with two subtypes alpha and beta) and a 60 kDa Ro. There is only one SSB/La protein of 48 kDa. In some circumstances, other proteins such as calreticuline (MW 57 kDa) join Ro/SSA proteins on some YRNAs. Anti-SSA/Ro antibodies are detected in the sera of 30% of patients with SLE, even during preclinical setting; anti-Ro/SSA are strongly associated (90%) with some subtypes of SLE such as old-onset (>50 y) SLE, subacute lupus erythematosus, drug-induced subacute lupus erythematosus and in patients with hereditary C2 or C4 or C1q deficiency with lupus or lupus-like disease. Anti-SSA/Ro are also associated with primary Sj?gren syndrome (50% to 60%) and with undifferenciated connective tissue disease (UCTD). Anti-SSA/Ro antibodies are almost always present in sera of mothers with babies with neonatal lupus syndrome (NNL) and with complete congenital heart block (CCHB). This last event is very unusual in pregnant patients with anti-Ro/SSA antibodies (1% to 2% of primigeste women). Some good evidences such as experimental models in vitro or ex-vivo, argue for the responsibility of maternal anti-Ro/SSA 52 kDa and/or anti-La/SSB antibodies (or associated IgG antibodies) as major etiologic factor of CCHB and NNL. IgG anti-Ro 52 beta kDa has been shown able to interrupt the atrioventricular conduction as well as the L calcium channel influx of fetal cardiocytes. Other factors must be taken into account to explain discordant twins (with and without CCHB). More recently anti-Ro/SSA antibodies were associated with QT interval prolongation in newborns without CCHB.     

Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: Results of a multicenter,prospective, open‐label clinical trial

Objective

The recurrence rate of anti‐SSA/Ro–associated congenital heart block (CHB) is 17%. Sustained reversal of third‐degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB.

Methods

A multicenter, prospective, open‐label study based on Simon's 2‐stage optimal design was initiated. Enrollment criteria included the presence of anti‐SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with ≤20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second‐degree or third‐degree CHB.

Results

Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues.

Conclusion

This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.

     

Prevention of congenital heart block in children of SSA-positive mothers

The incidence of congenital heart block (CHB) in the offspring of anti-Ro-positive women is approximately 1-2%, and the risk of recurrence is 10 times higher in the following pregnancies. Non-fluorinated steroids (prednisone, prednisolone and methylprednisolone) are recommended only for maternal indications, not for prevention of CHB in anti-Ro/SSA-positive women. Fluorinated steroids (dexamethasone or bethametasone) are not metabolized by the placenta and are available to the fetus in an active form. Routine prophylactic therapy with fluorinated steroids is not recommended even in women who previously had children with CHB or skin rash since this therapy has its own side-effects. Intravenous immunoglobulin had been used to prevent the development of CHB in 8 high risk mothers (anti-Ro/SSA positive and previous pregnancy with CHB), and in one case CHB recurred (12.5%). At present, the only sure recommendation that can be made in these women is that in the presence of reliable positivity for anti-Ro/SSA antibodies serial echocardiograms and obstetric sonograms should be performed at least every 2 weeks starting from the 16th week of gestational age: the goal is to detect early fetal abnormalities, such as premature atrial contractions or moderate pericardial effusion, that might precede complete atrioventricular block and that might be a target of preventive therapy. Fluorinated steroids should not be used in the absence of symptoms; in the presence of alarming symptoms, betamethasone seems safer than dexamethasone.     

Recurrent pregnancy loss and autoantibody profile in autoimmune diseases

OBJECTIVE: To explore the association of non-organ-specific autoimmune responses against three distinct Ro antigen-related reactivities (Ro52, Ro60, p57) with a history of pregnancy loss in women with autoimmune disorders. Materials and methods. Seventy unselected anti-Ro/SSA-positive women were studied in a retrospective cohort study. Forty anti-Ro/SSA-positive women were age matched to an equal number of women with autoimmune disorders who were anti-Ro/SSA negative in a case-control study. The association of reactivities against three distinct antigen specificities (Ro52, Ro60, p57) with recurrent pregnancy loss was investigated. Independence and modification of these associations from the effect of antithyroglobulin, antithyroid peroxidase and anticardiolipin antibodies were also examined. RESULTS: In the cohort study, reactivity against each of the three antigen specificities (Ro52, Ro60, p57) was independently associated with a history of recurrent pregnancy loss. In the case-control study, the effects were still independent and were not modified when other autoantibodies were considered. In particular, the number of reactivities against Ro52, Ro60 and p57 peptides, and the presence of antithyroglobulin antibodies, were independent predictors of recurrent pregnancy loss (odds ratios 3.35 per each additional reactivity and 5.54 in the presence of antithyroglobulin; P=0.002 and 0.025, respectively). CONCLUSIONS: In women with autoimmune disorders, a history of recurrent pregnancy loss is independently associated with reactivity against each of the three antigen specificities (Ro52, Ro60, p57) and also with the presence of antithyroglobulin antibodies, suggesting that cumulative autoimmune responses against these non-organ-specific and organ-specific antigens correlate with the risk of stillbirth and spontaneous abortion.     

Epidemiology, etiology, detection, and treatment of autoantibody-associated congenital heart block in neonatal lupus

Neonatal lupus syndrome is a model of passively acquired autoimmunity in which the pregnant woman’s serum contains specific antibodies to 52 or 60 kd SSA/Ro and/or 48 kd SSB/La, which cross the placenta and are associated with the development of congenital heart block in the fetus and/or a transient rash or various liver and blood cell abnormalities in the newborn. To date, congenital heart block is a permanent condition that entails significant morbidity and mortality, with nearly all affected infants requiring pacemakers and with an 80% cumulative probability of survival at 3 years of age. An intensive search is on for the specific etiopathophysiology and for new clinical tools to approach and treat this disease.