Journal of Neonatology & Clinical Pediatrics Category: Clinical Type: Review Article
Neonatal Lupus Erythematosus
- Nehad Nasef1*, Mona Hafez2, Ashraf Bakr3
- 1 Department Of Pediatrics, Faculty Of Medicine, University Of Mansoura, Mansoura 35516, Egypt
- 2 Pediatric Cardiology Unit, Faculty Of Medicine, Mansoura University Children’s Hospital, Mansoura, Egypt
- 3 Department Of Pediatrics, Faculty Of Medicine, Pediatric Nephrology Unit, Mansoura University Children’s Hospital, Mansoura, Egypt
*Corresponding Author:Nehad Nasef
Department Of Pediatrics, Faculty Of Medicine, University Of Mansoura, Mansoura 35516, Egypt
Received Date: Jul 01, 2014 Accepted Date: Aug 22, 2014 Published Date: Sep 05, 2014
ANA : Antinuclear Antibody
Anti-RNP : Anti-Ribonucleoprotein
APL : Antiphospholipid
CHB : Congenital Heart Block
CNS : Central Nervous System
IG : Immunoglobulin
IVIG : Intravenous Immunoglobulin
NICU : Neonatal Intensive Care Unit
NLS : Neonatal Lupus Syndrome
SLE : Systemic Lupus Erythematosus
SSA/Ro : Anti-Sjogren’s syndrome A antibody (Anti-Ro antibody)
SSB/La : Anti-Sjogren’s syndrome B antibody (Anti-La antibody)
Congenital NLS presents mainly with cardiac, dermatologic, and hepatic manifestations and to less extent with hematologic, central nervous system, or splenic abnormalities. Primary infantile SLE frequently involves the kidneys, and requires aggressive immunosuppressive therapy.
Congenital complete heart block, diagnosed by mid-trimester fetal echocardiography, was detected in 2% of first-observed pregnancies and 1.8 % of live births to women with positive maternal screening for anti-SSA/Ro antibodies [2-4]. In a prospective study of 98 infants born to mothers with positive anti-SSA/Ro antibodies, three infants had first degree block, three had third degree block, and four had cutaneous neonatal lupus .
Anti-SSA/Ro and anti-SSB/La antibodies were present in 91 % of mothers of infants with complete heart block, 73 % of mothers of infants with transient cutaneous neonatal lupus, and 15 % of mothers with lupus and related autoimmune diseases who gave birth to healthy infants [6,7].
The incidence of cardiac manifestations in neonatal lupus increases to about 17 % in women with anti-SSA/Ro and/or anti-SSB/La antibodies who have had a previous child with congenital heart block , a previous child with cutaneous neonatal lupus without cardiac manifestations , and in women with high titers of anti-SSA/Ro and anti-SSB/La compared to low titers . On the other hand, infants exposed to high titers of anti-SSB/La were more likely to have noncardiac manifestations of neonatal lupus .
Maternal antibodies are of immunoglobulin G (IgG) nature antibodies which cross the placenta to the fetus in the second trimester reaching maternal concentrations by 30 weeks’ gestation, and exceed maternal concentrations by term . Maternal autoantibodies mediate fetal autoimmune disease through formation of antibody complexes with apoptotic antigens in the skin, liver, heart and newly forming bone which when phagocytosed and opsonized initiate proinflammatory process that results in immune-mediated damage to fetal tissues [12,13].
Several studies have established the association between antibodies against the 60 kD extractable nuclear antigens Ro (anti-SSA/Ro) and La (anti-SSB/La) and neonatal lupus. In addition to the traditional Ro antigen of 60kD, another antigen of 52kD has been identified. Antibodies with specificity for the 52 kD component of the SSA/Ro protein (Ro52) are more frequently found and are present at higher concentrations in the serum of children with congenital heart block and their mothers [14,15]. More specifically, maternal anti Ro-52 kD antibodies with primary specificity for a particular peptide fragment (amino acids 200 through 239, p200-239) are significantly associated with the development of CHB [15,16]. Although maternal anti Ro52-p200 antibody exposure was observed in equal frequency in both affected and unaffected offspring , higher levels of Ro52 p200 antibodies were observed in mothers of children with CHB compared to those with normal children . Cutaneous NL was present in 16 % of women with anti-SSA/Ro antibodies and was significantly more frequent in those with both anti-SSA/Ro and anti-SSB/La autoantibodies .
The pathogenesis of heart block results from binding of anti-SSA/Ro and/or anti-SSB/La antibodies to fetal cardiac tissue, leading to autoimmune injury of the atrioventricular (AV) node and its surrounding tissue [19,20]. Apoptosis induced translocation of SSA/Ro and SSB/La to the surface of fetal cardiomyocytes allows anti-SSA/Ro and anti-SSB/La antibodies to bind to the surface of the fetal cardiomyocytes . Apoptotic cardiomyocytes are then phagocytosed by healthy fetal cardiomyocytes diverting these opsonized cardiomyocytes to uptake by macrophages , which release pro-inflammatory cytokines, initiating an inflammation-free physiologic remodelling of the human fetal heart and resulting in inflammation-induced tissue damage . Tumor necrosis factor alpha and transforming growth factor beta may potentiate the inflammatory and fibrosis components respectively . In addition to inducing tissue damage, anti-SSA/Ro and/or anti-SSB/La antibodies may inhibit calcium channel activation or the cardiac L- type calcium channels which are crucial to action potential propagation and conduction in the AV and SA nodes [25,26].
Maternal antibodies to other antigens like anti-U1 ribonuclear protein antibodies in the absence of anti-SSA/Ro or anti-SSB/La antibodies were found to cause classic rash of NL, but not congenital heart block [27,28].
Genetic predisposition, particularly the HLA alleles DQB1*02, DRB1*03, and a polymorphism in the promoter region of the gene for tumor necrosis factor alpha may play a role in skin disease. The frequency of carriage of all three alleles in infants with characteristic lupus rash was twice that of infants with CHB or unaffected infants .
|System||Clinical manifestations||Treatment (Level of Evidence)||Outcome|
|Skin||1. Transient lesions||
||Spontaneously resolve by 6-8 months|
|a. Erythematous, papulosquamous, desquamative rash|
|b. Blueberry muffin rash|
|2. Permanent lesions|
|d. Skin dyspigmentation|
|e. Skin pitting|
|f. Skin scarring|
|g. Skin atrophy|
|Cardiac||2. Conductive system affection||
|a. Congenital Heart Block (CHB)|
|b. Transient sinus bradycardia|
|c. Prolonged QT interval|
|d. Wolff-Parkinson- White syndrome|
|3. Inflammatory manifestations|
|b. Endocardial fibroelastosis|
|4. Structural defect|
|c. Patent foramen ovale|
|d. Pulmonary stenosis|
|e. Pulmonary valvular dysplasia|
||Resolve by 3-6 months with fading of maternal antibodies|
|4. Bone marrow failure|
|5. Disseminated intravascular coagulation|
|6. Hyper-coagulation and thrombosis|
|Hepatobilary||1. Neonatal cholestasis||
||Resolve by 3-6 months with fading of maternal antibodies|
|2. Neonatal hepatitis|
|3. Liver cell failure|
|2. Pulmonary capillaritis|
|2. Nephrotic syndrome|
|Endocrine||2. Adrenal insufficiency|
|Musculoskeletal||Rhizomelic chondrodysplasia punctata|
||Some infants develop
1. Learning disabilities
3. Developmental delay
4. Obsessive compulsive disorders
|4. Truncal hypotonia,|
|5. Spastic paresis|
|7. Intra-cerebral haemorrhages|
Neonatal lupus rash is characterized by round or elliptical erythematous, papulosquamous lesions with central clearing, annular erythema, and a fine scale. Blueberry muffin rashes have been also described in cases of neonatal lupus representing extramedullary dermal erythropoiesis secondary to severe intrauterine anemia mediated by maternal autoantibodies. The rash typically involves the face, scalp, neck, trunk, extremities, and intertriginous areas and is frequently induced or exacerbated by ultraviolet light (sunlight or phototherapy).
The histopathology of the erythematous-desquamative lesions shows vacuolar alterations at the dermoepidermal interface and adnexal structures . Some patients present with urticaria-like lesions that have superficial and deep perivascular and periadnexal lymphocytic infiltrates.
Injury to the conducting system presents mainly with congenital heart block (Figure 1) and to less extent with transient sinus bradycardia, QT interval prolongations, and Wolff-Parkinson- White syndrome [34,35]. Neonatal Lupus Syndrome accounts for 85% of all cases of congenital complete heart block . The incidence of heart block in infants born to mothers who have anti-Ro/SSA or anti-La/SSB antibodies is 1% to 2% in the first pregnancy and increases to 16% to 18% in subsequent pregnancies [37,38]. Injury to fetal and neonatal cardiac conduction tissue occurs as a consequence of a cascade of inflammatory events starts with cardiocyte apoptosis and progress through translocation of SSA/Ro and SSB/La antigens to the cardiocyte surface, binding of maternal autoantibodies, macrophage recruitment, secretion of profibrosing factors, and fibrosis of the cardiac conduction system [34,39]. Most cases of CHB are detected before 30 weeks’ gestation, with a peak incidence between 20 and 24 weeks .
Myocarditis and ventricular endocardial fibroelastosis occur with NLS as a result of inflammatory cell infiltrates and deposition of immunoglobulin, complement, and fibrin in the myocardium . Myocarditis is often followed by the development of postnatal cardiomyopathy in approximately 10% of infants who have NLS leading to poor prognosis .
Neonatal lupus with CHB has been associated with endocardial fibroelastosis which may present early during fetal, during immediate postnatal life, or late as long as five years after the diagnosis of complete heart block [32,41]. Structural heart disease, particularly VSD, has been reported occasionally in association with NL and heart block [42,43]. Other congenital structural cardiac anomalies have been observed in association with NL include persistent patent ductus arteriosus, patent foramen ovale, pulmonary stenosis, pulmonary valvular dysplasia, fusion of chordae tendineae of the tricuspid valve, and ostium secundum type atrial septal defects [42,44].
Anemia and thrombocytopenia are the most common hematologic manifestations, while neutropenia and aplastic anemia are rare. Hemolytic anemia is a rare manifestation of NLS. Immune thrombocytopenic purpura with microangiopathic hemolytic anemia and disseminated intravascular coagulation has been reported in an infant who had NLS .
Bone marrow aspiration is characterised by the presence of teardrop cells and basophilic stippling. Haematological abnormalities are typically worsened over the first days after birth, and resolve after disappearance of maternal autoantibodies.
Hyper-coagulation and thrombosis has been descried with NLS due to transplacentally acquired antiphospholipid (APL) antibodies, especially in the setting of sepsis, indwelling catheters, or other situations where vessel injury predisposes to thromboses .
PULMONARY AND RENAL MANIFESTATIONS
Bilateral massive adrenal hemorrhage and adrenal insufficiency has been previously reported with transplacental acquired antiphospholipid antibodies .
Similar to other NLS manifestation rhizomelic chondrodysplasia punctata occurs as a result of IgG–apoptotic cell complexes presented in the zones of newly forming fetal bones initiating an immune complex-mediated inflammation at growth plates .
Although most infants who have NLS are asymptomatic at birth, seizures, strabismus, opsoclonus, truncal hypotonia, spastic paresis, myelopathies, cerebral haemorrhages, static encephalopathies, and developmental delay have been observed in infancy. Children born to women who have SLE and concurrent APL antibodies showed increased rate of learning disabilities . Infants who have idiopathic lenticulostriate vasculopathies were more likely to have muscle tone abnormalities at 6 months of age and may have an increased risk of developing attention deficits, hyperactivity, obsession/compulsion, and tic disorders [61,62].
Radiologic evaluations have shown evidences of white matter disease, cerebral edema, hypomyelination, echogenic lenticulostriate vessels, basal ganglia calcifications, gangliothalamic vasculopathy, subependymal cysts, haemorrhages, and ventriculomegaly [57,63-65]. Less common radiological findings in infants who had NLS include thalamostriatal malformations, absent septum pellucidum, prominent cavum septum pellucidum, optic chiasm and optic nerve hypoplasia, and cortical dysgenesis. A statistically significant association has been observed between neonatal intraventricular hemorrhage and lenticulostriate vasculopathy in infants with NLS . The prevalence of hydrocephalus and macrocephaly also is increased in infants born to mothers who have anti-SSA/Ro antibodies .
Although the relation between maternal autoantibodies and neonatal neurological diseases is not yet known to be true or confounded, clinical and experimental evidence support a true association. The known connection between autoantibodies, in the setting of SLE, Sjögren syndrome, and APL syndrome, with adult human CNS diseases like CNS vasculitis, white matter lesions, chorea, seizures, and cognitive dysfunction supports the association between neonatal CNS injury and maternal autoantibodies. Additionally, animal studies show that APL, anti-SSA/Ro, and antidsDNA antibodies mediate neurologic dysfunction, potentiate seizures, and lead to excitotoxic injury to the animal brain [67-73].
Fetal congenital heart block occurs mostly during the period from 18 to 24 weeks gestation, less likely during the 26th through the 30th week, and rarely after 30 weeks of pregnancy. Normal sinus rhythm can progress to complete block in seven days during the initial high-risk period.
Complete heart block results in fetal bradycardia which can be detected by routine fetal auscultation, ultrasonography, or pulsed Doppler echocardiography [75,76]. Women who test positive for SSA/Ro and SSB/La autoantibodies should have a more intensive assessment for fetal heart block with frequent fetal echocardiographic testing during pregnancy. Although there are no formal guidelines for the type or the frequency of testing, performing weekly pulsed Doppler fetal echocardiography from the 18th through the 26th week of pregnancy and then every other week until 32 weeks has been strongly considered. Additional diagnostic modalities include fetal magnetocardiography and electrocardiography [77,78].
Infants up to eight months of age with an annular or polycyclic rash and/or any degree of heart block should be tested for anti-SSA/Ro and anti-SSB/La antibodies.
Infants diagnosed with NL who has compatible clinical manifestations and detectable autoantibodies with no electrocardiographic evidence of heart block of any degree at birth, is at very low risk of subsequently developing conducting system disease however they should be followed for later development of cardiomyopathy.
Prenatal treatment: Flourinated corticosteroids, as dexamethasone and betamthasone, and sympathomimetics have been used in mothers of affected fetuses to prevent in utero effusions, hydrops fetalis, and other complications of advanced heart block [80,82,83], however the efficacy and safety of antenatal steroid therapy has been questioned. Previous reports have shown that fetuses with second degree heart block treated with dexamethasone or betamethasone reverted to first degree block by birth, while those who were not treated progressed to complete heart block . In a multicenter study of antenatal dexamethasone therapy, 100 % of fetuses with third degree block did not respond to therapy, 50 % of infants with second degree block remained in second degree block, 30 % reverted to normal sinus rhythm, and 20 % progressed to third degree heart block, while 100 % of fetuses with first degree block converted to normal sinus rhythm within one week . In another multicenter prospective study, fetuses with first degree heart block, diagnosed by tissue velocity-based fetal kinetocardiogram, treated with antenatal dexamethasone had normalization of AV conduction in all affected fetuses within two weeks . In a retrospective series of 37 patients with complete heart block, the one-year survival rate in the 21 patients treated with dexamethasone was 90 %, compared with a survival rate of 46 % in the 16 untreated patients .
Fluorinated glucocorticoids are also considered for signs of cardiomyopathy. However, the effectiveness of these agents in the treatment of endocardial fibroelastosis is unknown . In a retrospective study for the use of glucocorticoids and IVIG (both in utero and after birth), a potential survival benefit was observed in cases with cardiomyopathy/endocardial fibroelastosis based upon comparison to historical control data .
Plasmapheresis and intrauterine placement of a fetal pacemaker also have been attempted [87,88]. Intrapartum IVIG (400 mg/kg given every three weeks from weeks 12 to 24) has also been used to prevent and treat CHB with limited success, but the safety profile maybe better than that of corticosteroids [89,90].
Hydroxychloroquine (400 mg orally once a day) inhibits ligation of endosomal Toll-like receptors. It is often used during pregnancies complicated by lupus and considered of minimal risk to the fetus and mother. It should be initiated between 6 and 10 weeks gestation in women who are not already on the medication. In a case-control study of mothers with SLE treated with hydroxychloroquine, the overall risk of cardiac lupus was decreased . A subsequent retrospective study based upon data from neonatal lupus registries in the United States, France, and the United Kingdom supports the efficacy of hydroxychloroquine in reducing the recurrence rate of cardiac-NL .
Accordingly, prenatal treatment with fluorinated glucocorticoids (oral dexamethasone 4 mg per day, or betamethasone 3 mg per day) is suggested for mothers of fetuses with second degree heart block, beginning as soon after detection and continuing through the end of pregnancy depending upon the response. Glucocorticoid therapy should be discontinued after one week of detection if heart block progresses to third degree block with no other signs of myocarditis. Most patients with third degree block will require cardiac pacing. Treatment of third degree block with glucocorticoids is generally not advised, unless there are other factors as suspected myocarditis and cardiomyopathy, although to date this has not been well evidenced [82,93]. Treatment of isolated first degree block is controversial, because of the risks of therapy, the evidence that first degree block can revert to normal sinus rhythm without therapy, and the absence of consistent evidence that untreated first degree block can progress to more advanced block [85,94]. Preemptive treatment with hydroxychloroquine in pregnant women who have previously given birth to a child with cardiac manifestations of neonatal lupus and who have anti-SSA/Ro antibodies has been shown to be promising.
Postnatal treatment: After delivery, infant electrocardiography should be obtained. When bradyarrhythmias or other arrhythmias are detected perinatally, infants should be monitored closely for progression of conduction abnormalities and cardiomyopathies. Treatment with sympathomimetic agents such as salbutamol and isoprenaline was proved, through case reports, to be effective prenatally in fetuses with congenital heart block  but not in postnatal management . Post natal treatment with IVIG or glucocorticoids was found to be ineffective in neonates with CHB .
Infants born with congenital heart block may be indicated for permanent cardiac pacemaker insertion. Indications of cardiac pacing in cases of congenital heart block are summarized in (Table 2) [98,99].
|Class I (Pacing is indicated)||Congenital complete AV block with|
|a. Ventricular rate less than 50 beats per minute.|
|b. Wide QRS escape rhythm.|
|c. Prolonged QTc interval.|
|d. Complex ventricular ectopy.|
|e. Ventricular dysfunction.|
|f. Ventricular pause > 3 folds the cycle length of the underlying rhythm|
|g. Associated congenital heart disease and a ventricular rate less than 70 beats per minute.|
|Class IIa (Pacing is reasonable)||Congenital complete A-V block beyond the first year of life with|
|a. Average heart rate less than 50 beats per minute.|
|b. Abrupt pauses in ventricular rate of 2 or 3 times the basic cycle length.|
|c. Associated symptoms due to chronotropic incompetence.|
|Class IIb (Pacing is considered)||Congenital complete A-V block in asymptomatic children with an acceptable rate, narrow QRS complex, and normal ventricular function.|
|Class III (Pacing is not indicated)||Asymptomatic type I (Wenckebach) second-degree AV block.|
Pacing devices are divided into either single (conventional right ventricular) or dual (combined right and left ventricular) pace makers. The use of dual pace maker in infants and children was associated with less frequent left ventricular modeling, dilatation, and asymmetrical hypertrophy . Conventional right ventricular pacemaker was found to be associated with significant increase in choronotropic insufficiency, cardiomyopathy, and acute heart failure particularly in infants of mothers with lupus [102,103].
Intravenous immunoglobulins (IVIG) at a dose of 1 g/kg/day for 1 or 2 days and corticosteroids at a dose of 1 to 2 mg/kg/day for 5 days are instituted in cases of persistent, severe hematologic manifestations.
PULMONARY AND RENAL
In cases with heart block, mortality varies with the time of presentation representing 43% when diagnosed in utero by fetal echocardiography . In neonates with congenital NLS, complete CHB is associated with significant morbidity and mortality representing 20% cumulative probability of death at 3 years, and 65% of survivors require pacemakers . In a prospective observational study of infants and children with isolated congenital heart block, 67% were diagnosed before one year of age . In the same study, authors noticed that 46% of infants with isolated congenital heart block secondary to maternal lupus required pacemaker in the first 24 months of life .
Data from Research Registry for Neonatal Lupus revealed an overall mortality of infants with congenital complete heart block, born to mothers with anti-SSA/Ro or anti-SSB/La antibodies, of 19 %; 5 % occurred in utero, 9 % within the first three months of birth, 5 % between the age of three months and three years, no deaths older than the age of three . Of survivors, 63 % ultimately required a pacemaker .
Previously reported fetal risk factors associated with increased mortality include early diagnosis (before 20 weeks gestational age), lower ventricular rate (less than 50 beats per minute), echocardiographic evidence of hydrops, echocardiographic evidence of endocardial fibroelastosis, and impaired left ventricular function at diagnosis [105,106].
Asymptomatic infants with complete heart block remain well until later childhood, adolescence, or adulthood. However, exercise limitation and even death are possible in the absence of pacing.
Children who have had NL may be at increased risk of developing an autoimmune and/or rheumatic disease including pauciarticular and polyarticular onset juvenile idiopathic arthritis, psoriasis, thyroid disease, iritis, type 1 diabetes mellitus, and nephrotic syndrome . None of the children with neonatal disease, nor any of their unaffected siblings, developed systemic lupus erythematosus during at least eight years of follow-up .
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Citation:Nasef N, Hafez M, Bakr A (2014) Neonatal Lupus Erythematosus. J Neonatol Clin Pediatr 1: 002.
Copyright: © 2014 Nehad Nasef, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.