Delayed dilated cardiomyopathy as a manifestation of neonatal lupus: case reports, autoantibody analysis, and management.

Abstract

Neonatal lupus erythematosus (NLE) is a transient disease consisting of one or more of the following findings: congenital complete heart block with or without congestive heart failure, photosensitive erythematous macular cutaneous lesions, thrombocytopenia, and cholestatic liver disease.1 In almost all cases, mothers of infants who have NLE have anti-Ro/Sjögren's Syndrome A antigen (Ro/SSA) autoantibodies of the immunoglobulin G (IgG) class. NLE is believed to be caused by the placental transmission of these maternal autoantibodies. The heart block typically begins during the second or third trimester. Although the disease process of NLE is transient, the atrioventricular node may be replaced by scar tissue, resulting in permanent heart block. In those infants who have heart block accompanied by heart failure, pacemaker placement is necessary and is usually sufficient to resolve symptoms. However, at least 10% of infants who have heart block due to NLE have heart failure that does not respond adequately to pacing, and it has been presumed that the cardiac muscle may also be affected by the disease process.12 In these most severely affected infants, heart failure is typically apparent at birth or very shortly after birth.We describe two infants who were unique because of the late onset of cardiomyopathy. The infants had congenital complete heart block and pacemaker placement in the perinatal period and did well for the first few months of life. Symptoms of heart failure developed at 8 and 4 months of age, respectively, and they were noted to have dilated cardiomyopathy. We confirm the persistence of substantial quantities of maternal anti-Ro/SSA antibodies in the infants' sera at the time of development of the dilated cardiomyopathy and speculate that the prolonged presence of high levels of maternal autoantibodies in the sera facilitated the unusually prolonged disease course in these children.The patient was diagnosed with complete heart block at 28 weeks' gestation. Her mother reported arthralgia in her hands, photosensitive dermatitis on her upper extremities, thorax, and face, and fatigue for 1 year. Her antinuclear antibody (ANA) test result was positive at a 1:3240 dilution with a nuclear speckled pattern, she had no antinative DNA by a Crithidia assay, and she had anti-Ro/SSA and anti-La/Sjögren's Syndrome B antigen (La/SSB) antibodies by immunodiffusion. The pregnancy subsequently progressed normally until premature rupture of membranes developed in the mother, and she gave birth at 35 weeks' gestation by cesarean section. The infant had Apgar scores of 7 at 1 and 5 minutes, jaundice, and hepatomegaly, and she required intubation for 24 hours for hypoxemia associated with hypotension and a heart rate of 50 beats per minute. Laboratory value abnormalities included a platelet count of 119 000, total bilirubin of 5.4 mg/dL, conjugated bilirubin of 3.4 mg/dL, gamma glutamyl transferase of 439 U/L, and lactate dehydrogenase of 1190 U/L. An echocardiogram revealed no structural abnormality and no evidence of left ventricular dysfunction. Evaluation for infection was negative. The infant required dual chamber pacemaker implantation on day 11 for a heart rate remaining at less than 50 beats per minute and subsequently did well with resolution of the cholestatic jaundice and thrombocytopenia within the first month. A follow-up chest radiograph at 1 month of age showed a normal heart size.At 3 months of age, she was noted to have an increased head circumference, with a change from approximately the 40th percentile at birth to greater than the 95th percentile. Moderate dilation of the ventricular system was observed with computed tomography. Follow-up at 6 months of age revealed resolution of the hydrocephalus.At 8 months of age the patient was noted to have respiratory distress and failure to thrive, with height and weight both below the 5th percentile. A mitral regurgitation murmur was detected, and cardiomegaly with pulmonary vascular congestion was noted on a chest radiograph. Evaluation of the pacemaker revealed normal function, whereas an echocardiogram noted four-chamber dilation with poor contractility and 3+ mitral regurgitation. Left ventricular function parameters were depressed, with an ejection fraction of 27% and a fractional shortening of 12%. A myocardial biopsy showed foci of myocyte necrosis but no inflammatory cells. Cardiac catheterization revealed normal coronary arteries and no additional structural abnormalities. Medical treatment with diuresis and digoxin was initiated. After 1 month she had persistent congestive heart failure, and serologic analysis showed persistent anti-Ro/SSA antibodies and a positive ANA test result at a dilution of 1:120 in a nuclear speckled pattern. Prednisone (1 mg/kg per day) was initiated, and during the ensuing months the infant had resolution of her congestive heart failure and resumed growth. At 13 months an echocardiogram revealed mild improvement in the contractility, with a fractional shortening of 23% and 2+ mitral regurgitation. At 3½ years of age, the patient's cardiac function was unchanged, and she continues to receive digoxin, furosemide, and aspirin. Her height and weight are at the 25th percentile.The patient was found at 22 weeks' gestation to have fetal complete heart block with ventricular rates of 60 to 70 beats per minute and atrial rates of 100 to 110 beats per minute. Her mother was a 25-year-old woman with systemic lupus erythematosus manifested by ANA positive at a 1:1080 dilution, antinative DNA of 1:90 byCrithidia assay, and anti-Ro/SSA antibodies by immunodiffusion. Fetal echocardiography revealed no structural abnormality. Normal spontaneous vaginal delivery occurred at 39 weeks' gestation, and the infant weighed 2800 g. Initial Apgar scores were 7 at 1 minute and 8 at 5 minutes. Electrocardiography demonstrated complete heart block and ventricular escape rhythm. Echocardiography demonstrated normal cardiac anatomy and a normal fractional shortening of 42%. On day 2, the patient's heart rate fell to 38 beats per minute with a minimal response to intravenous isoproterenol. A permanent epicardial dual chamber pacemaker was placed without complication, and she maintained apparent normal sinus node function with paced ventricular response at a rate of 80 to 140 beats per minute. She never had evidence of cutaneous lesions of NLE, thrombocytopenia, or cholestatic liver disease.At 4 months of age the patient was noted at examination to have tachypnea and rales, and a chest radiograph demonstrated cardiomegaly and pulmonary edema. Echocardiography revealed left ventricular enlargement and dysfunction, and a gated blood pool study documented an ejection fraction of 26%. Digoxin and captopril were initiated with some improvement. A gated blood pool study at 5.5 months of age showed an ejection fraction of 35%. Her ANA test result was positive at a 1:40 dilution with a nuclear speckled pattern, and she had anti-Ro/SSA antibodies by immunodiffusion. Myocardial biopsy showed tubuloreticular structures within endothelial cells, no direct evidence of viral infection, and no evidence of mitochondrial myopathy or storage disease. Particulate deposits of IgG were observed in the myocardium at immunofluorescence examination. Double volume exchange transfusion was performed to reduce the level of circulating antibody, and prednisone (2 mg/kg per day) was initiated. One week later she was given intravenous Ig (2 g/kg) to potentially block tissue antibody that was recruited into the circulation. Double volume exchange transfusion was repeated 1 week later, and steroid taper was begun 2 weeks after that. At 6 months 4 days of age, after her second plasma exchange, her ejection fraction was 33% by gated blood pool study. Her cardiac status has remained stable. Gated blood pool studies at 20 and 38 months of age showed ejection fractions of 37%. The heart is at the upper end of the normal range in size, with no evidence of pulmonary edema, and she is growing and developing normally, with normal exercise tolerance. She continues to receive digoxin and captopril.Antibodies to 60-kD Ro/SSA, 52-kD Ro/SSA, La/SSB, and U1RNP were evaluated using standard immunodiffusion, immunoblotting, and enzyme-linked immunosorbent assay (ELISA) techniques.3The ELISAs used native bovine 60-kD Ro/SSA, recombinant human 52-kD Ro/SSA, native bovine La/SSB, and native bovine U1RNP, respectively, as the antigens. Maternal autoantibody specificities have been previously reported.3 For quantitating the anti–60-kD Ro/SSA antibody response, optical density results of serial dilutions of test sera were compared with those obtained with serial dilutions of a prototype serum, and a standard curve was generated to calculate units of activity per milliliter of serum. In this assay, greater than 100 000 U/mL is considered a high titer response and correlates well with the presence of precipitin lines in immunodiffusion. For evaluating anti–60-kD Ro/SSA antibody isotypes, alkaline phosphatase–conjugated antibodies to human polyvalent IgG, IgA, IgM, κ chain, and λ chain (Promega, Madison, WI) were applied at a 1:10 000 dilution for 1 hour in a modification of the anti–60-kD Ro/SSA antibody ELISA.Maternal serum contained antibodies to 60-kD Ro/SSA (27 million U/mL), 52-kD Ro/SSA (45 million U/mL), and La/SSB (610 000 U/mL). Cord blood contained approximately 8 million U/mL anti–60-kD Ro/SSA antibody activity. At 8 months of age, the child's serum contained 77 000 U/mL anti–60-kD Ro/SSA antibodies, and at 11 months of age, her serum contained 8500 U/mL anti–60-kD Ro/SSA antibodies. Antibody isotyping of the anti–60-kD Ro/SSA antibody response revealed the same quantitative and qualitative relationship in the mother and child of κ and λ chains. Neither mother nor child had detectable IgA or IgM anti–60-kD Ro/SSA antibodies.Maternal serum contained antibodies to 60-kD Ro/SSA (120 million U/mL) and 52-kD Ro/SSA (1.2 million U/mL) but not to La/SSB or U1RNP. At 5 months of age, the infant had 460 000 U/mL anti–60-kD Ro/SSA antibodies, consistent with a normal rate of metabolism of maternal antibodies. Immediately before her first plasma exchange, her serum contained 190 000 U/mL anti–60-kD Ro/SSA antibodies, and immediately after, there were 48 000 U/mL. Three days later, her anti–60-kD Ro/SSA antibody titer was 240 000 U/mL. Immediately before the second plasma exchange, her serum contained 90 000 U/mL anti–60-kD Ro/SSA antibodies, and she had 18 000 U/mL immediately afterward. Four days after the second plasma exchange, she had 37 000 U/mL circulating anti–60-kD Ro/SSA antibodies.These two cases of NLE involved late development of cardiomyopathy several months after birth. That the cardiomyopathy was related to maternal autoantibodies rather than endogenous production of autoantibodies by the child was shown by the presence of the same light-chain isotypes of the anti-Ro/SSA antibodies in the mother's and infant's sera in case 1, and the falling autoantibody titers at a rate consistent with metabolism in both cases.Evidence that anti-Ro/SSA autoantibodies are pathogenic in NLE consists of the following: (1) the uniform presence of anti-Ro/SSA antibodies in affected infants,1 (2) the resolution of disease activity coincident with the metabolism of maternal antibodies by the infant,1 (3) the deposition of anti-Ro/SSA antibodies in tissue,4 (4) enrichment of anti-Ro/SSA antibody deposits in the heart in a case of cardiac NLE,5 (5) inhibition of repolarization of isolated rabbit myocardial tissue by anti-Ro/SSA antibody-containing serum,6 and (6) the reproduction of heart block in isolated rabbit heart perfused with anti-Ro/SSA antibody-containing serum.7The autoantibody response in anti–Ro/SSA-positive sera is complex, and several autoantibody specificities may be present. These include antibodies to the originally described Ro/SSA protein of 60 kD, antibodies to a nonhomologous 52-kD Ro/SSA protein, antibodies to La/SSB, and antibodies to a 57-kD protein, p57. In our previous analyses, antibodies to the 60-kD Ro/SSA protein were uniformly present in maternal NLE sera, and antibodies to the 52-kD Ro/SSA protein were present in almost all cases.3 Antibodies to the La/SSB and p57 proteins were present in somewhat less than half of the sera.38 In the subgroup of cardiac NLE, all sera contained antibodies to the 52-kD Ro/SSA protein, although in two sera these were detectable only by a sensitive ELISA technique, whereas the antibodies to 60-kD Ro/SSA were present in high titers in all the maternal sera. Although these findings may indicate that antibodies to the 60-kD protein are the most important specificity in NLE, a preliminary report indicates that antibodies to 52-kD Ro/SSA can cause heart block in an isolated perfused rabbit heart model of NLE.9 Thus, current evidence would support either the anti–60-kD Ro/SSA or the anti–52-kD Ro/SSA specificities (or both specificities) as being pathogenic in NLE.The strong evidence supporting an autoantibody-mediated pathogenesis led us to consider therapy directed at removal of the autoantibodies in case 2. The infant's disease did stabilize after plasma exchange, but there is no way to determine whether the stabilization was related to the treatment or would have occurred anyway. In theory, removal of the autoantibodies should be of use, assuming the autoantibodies are pathogenic, because these antibodies are maternal and, once removed, will not recur. The rise in titers a few days after the plasma exchanges was probably due to the release of antibodies bound in tissue. Both children were also treated with systemic corticosteroids. As was the case for plasma exchange, single-case observations do not allow us to conclude whether the corticosteroids were beneficial.Cardiomyopathy coexisting with anti-Ro/SSA antibody-associated complete heart block has been observed previously but is usually apparent early, during the perinatal period. In the cases we report, the exceptionally high maternal titers of anti-Ro/SSA antibodies resulted in a large quantity of anti-Ro/SSA antibodies being transferred across the placenta to the child. This would result in an unusually long period in which the infant was exposed to substantial quantities of anti-Ro/SSA antibodies. Possibly, the prolonged exposure to anti-Ro/SSA antibodies was a major reason that cardiomyopathy developed in these children. Alternatively, or in addition, the anti-Ro/SSA antibodies may have had a particularly high affinity for cardiac muscle, although our studies do not address this possibility.The possibility of late development of cardiomyopathy should be considered in children who have NLE with heart block. In these children, serial echocardiography might be considered to detect the development of cardiomyopathy in its earliest stages. The children we report had stabilization of cardiac function with treatment but little recovery of cardiac function and had persistent need for cardiac medication. Possibly, discovery and treatment of cardiomyopathy at an earlier stage might result in stabilization of cardiac status at a higher level of function, although further studies will be needed to determine whether any of the treatments used in our cases are efficacious.In summary, cardiomyopathy may be observed in infants with NLE and may develop several months after birth. Therapeutic options in severe cases may include treatment directed at depletion of anti-Ro/SSA antibodies from the child's circulation.This work was supported in part by a grant from the Department of Veterans Affairs (Dr Lee), North Atlantic Treaty Organization grant 951288 (Dr. Lee), National Institutes of Health grants AR43975, AR31133, and AR07590 (Dr Reichlin), and an Arthritis Foundation Biomedical Science grant (Dr Reichlin).We acknowledge the technical assistance of Farideh Movafagh and Sandra Long.