Outcome of pregnancies in patients with anti-SSA/Ro antibodies: a study of 165 pregnancies, with special focus on electrocardiographic variations in the children and comparison with a control group

OBJECTIVE: Aside from congenital heart block (CHB), sinus bradycardia and prolongation of the corrected QT (QTc) interval have been reported in infants born to mothers with anti-SSA antibodies. To assess the pathologic nature of these manifestations, this study focused on electrocardiographic (EKG) variations in these children, comparing them with findings in a control group. METHODS: We studied 165 consecutive pregnancies in 106 anti-SSA-positive women with connective tissue diseases (CTDs). EKGs obtained on 58 children of this group were compared with those obtained on 85 infants born to mothers with CTD who were negative for both anti-SSA and anti-SSB. RESULTS: No statistically significant difference was seen between the 2 study groups with regard to gestational age, prematurity, birth weight, age of the children at the time of EKG, age of the mothers, or treatments received by the mothers during their pregnancies. Seven of 137 children developed cutaneous neonatal lupus syndrome; 1 child developed CHB (CHB risk of 1 in 99 [1%] if only the first prospectively observed pregnancy in women without a history of CHB is included in the analysis). For EKGs recorded during the first 2 months of life, the mean +/- SD PR interval was 96 +/- 16 msec in the anti-SSA-positive group and 96 +/- 13 msec in the anti-SSA-negative group (P = 0.84), with mean QTc values of 397 +/- 27 and 395 +/- 25 msec (P = 0.57) and mean heart rates of 141 +/- 23 and 137 +/- 21 beats per minute (P = 0.20), respectively. No difference in the PR interval, QTc interval, or heart rate was observed for EKGs obtained between 2 and 4 months of life. When EKGs obtained at 0-2 months were compared with those obtained at 2-4 months, a physiologic prolongation of the QTc interval was observed in both study groups. No sudden infant death or symptomatic arrhythmia occurred during the first year of life. CONCLUSION: The EKG findings in children of anti-SSA-positive and anti-SSA-negative mothers were not significantly different. Our results suggest that the prolongation of the QTc interval and sinus bradycardia that have recently been reported in children of mothers with anti-SSA antibodies occur independently of the anti-SSA antibodies. The pathologic nature of these EKG variations was not confirmed by our controlled study.     

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.

     

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.     

A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti–Jo‐1 or anti–Ro 52/anti–Ro 60 autoantibodies

Objective

To investigate type I interferon (IFN) system activation and its correlation with autoantibodies and organ manifestations in polymyositis (PM), dermatomyositis (DM), and inclusion body myositis.

Methods

Sera from 30 patients and 16 healthy controls, or purified IgG, were combined with material released from necrotized cells to stimulate IFNα production by peripheral blood mononuclear cells (PBMCs) from healthy blood donors. Muscle biopsy specimens from 25 patients and 7 healthy controls were investigated for blood dendritic cell antigen 2 (BDCA‐2)–positive plasmacytoid dendritic cells (PDCs) and IFNα/β‐inducible myxovirus resistance 1 (MX‐1) protein.

Results

Sera from 13 patients who were positive for anti–Jo‐1 or anti–Ro 52/anti–Ro 60 autoantibodies induced IFNα production in PBMCs when combined with necrotic cell material. In addition, IgG prepared from anti–Jo‐1–positive PM sera induced IFNα with necrotic material, but not when the latter was treated with RNase. BDCA‐2 expression in PDCs in muscle tissue was increased in PM patients with anti–Jo‐1 autoantibodies, while MX‐1 staining in capillaries was increased in DM patients, compared with healthy individuals. IFNα‐inducing capacity correlated with interstitial lung disease, while MX‐1 expression in the capillaries correlated with DM.

Conclusion

Immune complexes containing anti–Jo‐1 or anti–Ro 52/anti–Ro 60 autoantibodies and RNA may act as endogenous IFNα inducers that activate IFNα production in PDCs. These PDCs could be of importance for inducing myositis, whereas in DM patients without autoantibodies the presence of MX‐1 protein in capillaries suggests another cellular IFNα source and induction mechanism. Consequently, the type I IFN system may be of importance in both PM and DM, but via different pathways.

     

Prolongation of the corrected QT interval in adult patients with anti‐Ro/SSA–positive connective tissue diseases

Objective

Newborns of mothers positive for anti‐Ro/SSA autoantibodies may develop a series of electrocardiographic (EKG) disturbances. Prolongation of the corrected QT (QTc) interval was recently reported in a significant proportion of children with maternally acquired anti‐Ro/SSA antibodies, with a concomitant disappearance of EKG abnormalities and acquired maternal autoantibodies during the first year, suggesting a direct, reversible electrophysiologic effect of anti‐Ro/SSA antibodies on the ventricular repolarization. On this basis, we investigated whether these antibodies may also affect cardiac repolarization in anti‐Ro/SSA–positive adult patients with connective tissue diseases.

Methods

Fifty‐seven patients with connective tissue diseases were selected: 31 had anti‐Ro/SSA antibodies and 26 did not (controls). In all subjects, we analyzed the QTc interval, heart rate variability, and signal‐averaged high‐resolution EKG recording.

Results

Anti‐Ro/SSA–positive patients showed a significant prolongation of the mean QTc interval compared with the controls (mean ± SD 445 ± 21 versus 419 ± 17 msec; P = 0.000005). Eighteen of the 31 anti‐Ro/SSA–positive patients (58%) and none of the 26 anti‐Ro/SSA–negative patients had QTc values above the upper limit of normal (440 msec). Both groups had a reduction in heart rate variability, with a prevalence for the sympathetic nervous system and a high incidence of ventricular late potentials; these values were not significantly different between the 2 groups.

Conclusion

Adult patients with anti‐Ro/SSA–positive connective tissue diseases showed a high prevalence of QTc interval prolongation. This feature, with the concomitant abnormalities in the autonomic tone and ventricular late excitability observed in all patients studied, suggests that anti‐Ro/SSA–positive patients may have a particularly high risk of developing life‐threatening arrhythmias.

     

High titer of anti–phosphatidylserine‐prothrombin complex antibodies in patients with cutaneous polyarteritis nodosa

Objective

To investigate possible correlations between cutaneous polyarteritis nodosa (CPN) and antiphospholipid syndrome–associated antibodies.

Methods

Sixteen patients were referred with CPN features. To investigate the possible role of antiphospholipid antibodies (aPL) in CPN, we measured serum lupus anticoagulant (LAC), IgG and IgM anticardiolipin (aCL) and anti–phosphatidylserine‐prothrombin complex (anti‐PS/PT) antibodies, and anti–β₂‐glycoprotein I–dependent cardiolipin (anti‐β₂GPI/CL) antibodies in the 16 CPN patients, 8 microscopic polyangiitis (MPA) patients, 33 systemic lupus erythematosus (SLE) patients, and 23 healthy controls. LAC was determined according to the Subcommittee on Lupus Anticoagulant/Phospholipid Dependent Antibody guidelines. Anti‐PS/PT, aCL, and anti‐β₂GPI/CL antibodies were measured by enzyme‐linked immunosorbent assay.

Results

Anti‐PS/PT antibodies and/or LAC were detected in all CPN patients, but not in any controls. Serum IgM anti‐PS/PT antibody was found in 13 (81.3%) CPN patients. The mean ± SD serum anti‐PS/PT IgM level (19.9 ± 12.4 units/ml) in CPN patients was significantly elevated compared with SLE patients (5.7 ± 5.9 units/ml). IgG anti‐PS/PT antibody was detected in 5 (31.3%) CPN patients, but not in any controls. The IgG PS/PT antibody titers were similar in CPN patients (12.3 ± 12.0 units/ml) and SLE patients (13.8 ± 14.3 units/ml). Three (18.8%) CPN patients were positive for IgG aCL antibody and 2 (12.5%) for IgM aCL antibody. No MPA patients had aPL. CPN skin manifestations included livedo reticularis (14 [87.5%]). Direct immunofluorescence (DIF) revealed C3 within the affected vessels in 7 (77.8%) of 9 CPN patients.

Conclusion

Our study demonstrated that presence of anti‐PS/PT antibodies and/or LAC could serve as markers in CPN patients. CPN could be dependently associated with the presence of anti‐PS/PT antibody. Clinicians need to recognize these titers to permit early accurate diagnosis and treatment. We believe that anti‐PS/PT antibodies will become widely recognized as a new factor when diagnosing CPN.