Barbara Mendez1, Amit Saxena2, Jill P. Buyon3 and Peter M. Izmirly4
(1)
Albert Einstein College of Medicine, Department of Rheumatology, Montefiore Medical Specialists, 495 Central Park Avenue, Scarsdale, NY 10583, USA
(2)
NYU Langone Medical Center, Center for Musculoskeletal Care, 333 East 38th Street, 4th Floor, New York, NY 10016, USA
(3)
Department of Rheumatology, New York University School of Medicine, 301 East 17th Street, Suite 1410, New York, NY 10003, USA
(4)
Department of Rheumatology, New York University School of Medicine, 301 East 17th Street, Room 1611B, New York, NY 10003, USA
Peter M. Izmirly
Email: Peter.izmirly@nyumc.org
Abbreviations
Anti-TG
Anti-thyroglobulin
Anti-TPO
Anti-thyroperoxidase
CHB
Congenital heart block
EFE
Endocardial fibroelastosis
HCQ
Hydroxychloroquine
La48
48 kDa SSB/La
LTCC
L-type cardiac calcium channels
MHC
Major histocompatibility complex
NL
Neonatal lupus
Ro52
52 kDa SSA/Ro
Ro60
60 kDa SSA/Ro
RRNL
Research registry for neonatal lupus
SLE
Systemic lupus erythematosus
SS
Sjögren’s syndrome
UAS
Undifferentiated autoimmune syndrome
Introduction
Fetuses exposed to maternal anti-SSA/Ro and anti-SSB/La antibodies can develop a syndrome known as neonatal lupus (NL), which is comprised of cardiac, cutaneous, hepatic, and hematologic abnormalities [1–8]. The term “neonatal lupus” originated with the observation that the cutaneous lesions of the neonate resemble those associated with systemic lupus erythematosus (SLE) [3, 4]. The clearance of maternal autoantibodies in the 6–8 months of postnatal life is accompanied by the resolution of the cutaneous, hematologic, and hepatic abnormalities. In contrast, cardiac manifestations of NL, most typically congenital heart block (CHB), are often irreversible and associated with significant morbidity and mortality [9]. The term cardiac-NL is used to denote the varied spectrum of cardiac disease, inclusive of heart block (complete or incomplete), cardiomyopathy, and endocardial fibroelastosis (EFE). While CHB may result in long-term sequelae, the pathophysiologic processes leading to disease occur during the pre- and postnatal period in which maternal anti-SSA/SSB autoantibodies are present in the fetal or neonatal circulation. This concordance between antibody presence and disease manifestations implicates NL as a disease of passively acquired humoral autoimmunity.
Epidemiology
Cardiac-NL occurs exclusively in infants born to mothers with anti-SSA/Ro and/or anti-SSB/La antibodies, while the cutaneous manifestations can be seen when the mother has these antibodies or antibodies to RNP [10, 11]. The population prevalence of CHB is approximately 1:15,000 live births [12, 13]. In children born with CHB in the absence of documented structural abnormalities, antibodies to anti-SSA/Ro are found in over 85 % [11]. Among anti-SSA/Ro positive mothers, prospective studies show that approximately 2 % of pregnancies will result in infants affected by cardiac disease [14–17] and the recurrence rate is approximately 8- to 9-fold this risk [12, 18–22]. The risk of developing cutaneous manifestations of NL is 7–16 % in offspring of anti-Ro and anti-La positive mothers [15, 17]. The recurrence rate of cutaneous NL is estimated to be between 23 and 29 %, and having an initial child with cutaneous NL appears to increase the risk of a subsequent child developing cardiac-NL [23]. Mothers of children with either cutaneous NL or CHB may be asymptomatic themselves, or they may have an autoimmune disease such as Sjögren’s syndrome (SS), SLE, or an undifferentiated autoimmune syndrome (UAS). In many cases, the presence of anti-SSA/Ro and/or anti-SSB/La antibodies is only detected after the diagnosis of NL is made in an affected child [24]. Studies show that presence of maternal rheumatic disease does not appear to influence the recurrence of the NL [12, 25]. However, about half of asymptomatic mothers of NL offspring will go on to later develop an autoimmune disease, the most common being SS [26].
Cutaneous NL
The rash of NL is transient and can be present at birth, but is more often observed at a mean of 6 weeks after birth [27]. An association with UV exposure suggests that a skin response to UV light may liberate antigenic elements that then permit the onset of the local autoimmune rash [27]. Once begun, the mean duration of the rash is 17 weeks [27]. The rash is characterized by erythematous annular lesions or arcuate macules with slight central atrophy and raised active margins, which are located primarily on the scalp and periorbital area. A review of the corporeal distribution of rash among 57 infants with cutaneous NL enrolled in the research registry for neonatal lupus (RRNL) revealed that 100 % had facial involvement. Other areas of involvement included the scalp, trunk, extremities, neck, intertriginous areas and rarely the palms or soles, in descending order [27]. NL lesions resemble those of subacute cutaneous lupus erythematosus seen in adults, with basal cell damage in the epidermis and a superficial monocyte cell infiltrate in the upper dermis [28]. Immunofluorescence staining of skin biopsies reveals IgG deposition within the epidermis [28]. The rash is usually self-limiting and almost always resolves by 6–8 months of age, when the maternal antibodies are cleared from the affected child [28]. Although residual skin abnormalities are rare, some that have been documented include atrophy, scarring, pitting, hypopigmentation or hyperpigmentation, and telangiectasias [27, 28]. In rare instances, cutaneous NL has been seen in the presence of an autoantibody other than anti-SSA and/or anti-SSB. In that instance, the mother produced an autoantibody to RNP [10].
Management and Treatment of Cutaneous NL
Once identified, infants with NL should be protected from excessive exposure to sun and/or other sources of UV radiation. In fact, just the presence of anti-SSA/Ro and/or anti-SSB/La antibodies in the mother should prompt counseling with regard to sun exposure, for both herself and the neonate, even if no rash is observed. Topical steroids, preferably those that are non-fluorinated, have been used on infants who have developed cutaneous NL. However, the efficacy of such steroids has been questioned. Neiman and colleagues looked at steroid treated or untreated cutaneous NL and reported no significant differences in outcome; however, the study was limited by a small number of cases [27]. Systemic therapies are not recommended given the transience and almost universal benignity of NL skin lesions.
Hepatic Abnormalities
It is likely that the prevalence of hepatic involvement as a manifestation of NL has been underestimated, since neonatal evaluation does not routinely include a liver enzyme profile [29]. One prospective study did show that 26 % of children born to mothers with anti-SSA/Ro had elevated liver enzymes [15]. Laxer described NL associated with significant hepatic involvement in four infants, three living and one who died postnatally [1]. The clinical picture in these neonates was cholestatic. Pathologic changes included giant cell transformation, ductal obstruction, and extramedullary hematopoiesis [1]. Lee described an additional three infants with hepatic dysfunction, all with abnormal hepatic panels and histologic evidence of cholestasis [30]. One of these three infants had concurrent CHB and congestive heart failure. Post-mortem immunofluorescence studies of the liver tissue revealed widespread IgG deposition. The second infant had hepatosplenomegaly and thrombocytopenia at birth, followed by a cutaneous eruption at 3 weeks of age. His liver biopsy revealed hepatocellular cholestasis, lobular disarray, and mild pseudoacinar formation. The third neonate developed a typical NL rash at 2 weeks and transaminitis with jaundice by 8 weeks. Liver biopsy revealed canalicular and hepatocellular cholestasis [30]. Lee further investigated the incidence of hepatobiliary manifestations among 219 NL patients in the RRNL and noted that recognized hepatobiliary disease occurred in 19 of 219 infants (9 %), usually in conjunction with either cardiac or cutaneous involvement [29]. Three clinical variants were observed: 1—severe liver failure present during gestation or in the neonatal period (least common); 2—conjugated hyperbilirubinemia with mild or no elevations of aminotransferases occurring in the first few weeks of life; and 3—mild elevations of aminotransferases occurring at approximately 2–3 months of life. The prognosis for the children in the last two categories was excellent [29].
Hematologic Abnormalities
Hematologic manifestations of NL include thrombocytopenia, neutropenia, anemia, and rarely, aplastic anemia [15]. Thrombocytopenia usually comes to recognition as a result of petechial or purpuric eruptions. Thrombocytopenia was present in 10 % of the neonates referred to Lee and her colleagues [28]. Gastrointestinal bleeding was rare, occurring in only one child [28]. While NL thrombocytopenia is presumed to be autoimmune in nature, its exact pathogenesis remains unclear, and it is uncertain if it is mediated via anti-platelet antibodies or anti-SSA/Ro-SSB/La antibodies targeting the surface of fetal platelets.
Neutropenia has also been documented in NL [31]. In vitro, exposure of intact neutrophils to anti-SSA/Ro positive maternal and/or infant serum from affected families results in immunoglobulin deposition on neutrophils, suggesting a possible immune-mediated basis for NL neutropenia [31]. Indeed, the neutrophil/immunoglobulin interactions were neutralized by pre-incubating the sera with 60 kDa Ro antigen that bound the autoantibody, suggesting that anti-60 kDa SSA/Ro directly drives the pathogenesis of neutropenia [31]. NL neutropenia has been shown to resolve as maternal antibodies are cleared from the neonate without known sequelae to the child [31]. In one prospective study, 25 of 107 infants born to mothers with anti-SSA/Ro or anti-SSB/La antibodies had neutropenia but no cases of neonatal sepsis occurred [15]. Wolach described a 5-month-old child with typical cutaneous NL and complete marrow aplasia that resolved at 8 months, which coincided with the clearance of anti-SSA/Ro antibodies [32]. This child died at 16 months from sepsis.
Neuropsychological Impairment
Since the blood–brain barrier is not fully formed in utero, it seems reasonable to speculate that neurologic dysfunction might also be a part of the spectrum of anti-SSA/Ro associated injury. Boros and colleagues reported results from a Canadian cohort of 87 infants exposed to maternal anti-SSA/Ro and/or anti-SSB/La antibodies [33] . Five of 47 infants with a manifestation of NL and two of the children without any manifestation of NL had hydrocephalus resulting in a prevalence of 8 % in the entire cohort. This is considerably higher than in the general population. The authors suggested that hydrocephalus is a manifestation of NL that tends to resolve spontaneously, with only one child requiring surgical intervention.
Maternal immunological dysfunction has been associated with reports of developmental language delay, learning difficulties, and left-handedness [34]. A self-report survey of 468 children and their parents suggested that parents with reported immunologic disorders described a higher prevalence of learning and behavior problems in their male children than did parents without immunologic disease [35]. In one study an association was found between dyslexia and CHB lesions in the children of women with SLE [36]. In a second study of 45 mothers of dyslexic children, anti-SSA/Ro sera levels were found to be 20 times greater than those of controls [37]. More recently Ross evaluated 58 children of mothers with SLE during pregnancy and found that 26 % of the children had some form of learning disability [38]. Boys were more affected than girls. The presence of anti-SSa/Ro and/or anti-SSB/La antibodies and disease activity during pregnancy were significantly related to the higher prevalence of learning disability in the offspring.
Askanase and colleagues evaluated the prevalence of neuropsychological disorders in children known to be exposed to anti-SSA/Ro and/or anti-SSB/La antibodies in utero [39]. This retrospective study used detailed questionnaires, telephone interviews, and reviews of medical records of children with NL, their unaffected siblings, and healthy controls who were friends of similar age. It was noted that behavioral problems, either isolated or associated with attention disorder, were present in all groups with no statistical difference. The prevalence of depression, anxiety, developmental delays, learning disability, hearing and speech problems, and use of stimulants were also not significantly different between groups. The authors suggested that parental reporting of neuropsychiatric abnormalities was high in antibody-exposed children; however, it did not meet statistical significance when compared to the controls. Further evaluation with neurocognitive testing is needed to characterize the potential brain injury by autoantibodies seen in NL [39].
Cardiac Manifestations
The most serious manifestation of NL is cardiac disease, including heart block (complete or incomplete), associated cardiomyopathy, EFE and valvular abnormalities [9]. The risk of having a child with cardiac-NL is approximately 2 % for an anti-SSA/Ro positive woman who has either never been pregnant or has previously had only healthy offspring [14–17]. If an anti-SSA/Ro positive mother has a previous child affected with cardiac-NL, the risk increases nearly tenfold to roughly 18 % in her next pregnancy [12, 19, 20, 40, 41]. If an anti-SSA/Ro antibody-positive mother has had a previous child with cutaneous NL, the chance of having a subsequent child with cardiac-NL is 13 % [23].
The incidence of CHB appears to be more common in offspring of women with high titers of anti-SSA/Ro and anti-SSB/La compared with mothers with low titers [42]. However, there is considerable overlap in antibody titers between affected and unaffected cases and most women have high titers that remain stable over time. In one study, the risk of CHB was slightly higher if a mother had antibodies to both anti-SSA/Ro and anti-SSB/La [43]. In any event, it is clear that antibodies to anti-SSA/Ro remain the primary drivers of the condition.
Second degree heart block detected in utero, and first or second degree heart block identified in infants at birth, can progress to complete heart block [18, 22, 44]. It is unclear whether first degree heart block detected in utero also progresses to more advanced heart block. In a prospective study of 95 RRNL cases, all reported patients with in utero prolonged PR interval that were treated or not had spontaneous resolution of the prolong PR interval [17]. A recent study questioned the significance of first degree block, as serial echocardiograms in 165 anti-SSA/Ro antibody-exposed fetuses with AV prolongation did not reliably predict progression to second or third degree heart block [45]. These distinctions are important, because there is evidence for the efficacy of treatment in cases of low-grade heart block, whereas third degree heart block is currently irreversible [46].
Other documented arrhythmias and conduction abnormalities seen in NL include sinus node dysfunction, long QT interval, ventricular and atrial ectopy, ventricular and junctional tachycardia, and atrial flutter, but generally these arrhythmias have not been clinically significant [47, 48]. Autoantibody-mediated heart block in NL is typically associated with a structurally normal heart; however, structural abnormalities such as flail mitral valve secondary to chordal disruption from EFE have been reported [49]. In an evaluation of 18 autopsies of cardiac-NL cases from the RRNL, fibrosis of the AV node and distal conduction system was the most characteristic histopathological finding [50]. However, fibrosis of the SA node and bundle of His, EFE, and valvular damage were also part of the spectrum of anti-SSA/Ro injury. Valvular pathology was identified at the tricuspid, mitral, aortic, and pulmonary valves. One of these fetuses had aortic insufficiency and stenosis together with severe pulmonary valve stenosis and mild hypoplasia of the mitral and tricuspid valve leaflets. Pre-mortem echocardiograms did not consistently predict the pathological findings on autopsy [50].
Another cardiac abnormality that may be associated with NL is congestive heart failure due to cardiomyopathy, which is often associated with EFE. EFE has been reported both in isolation and in association with conduction defects [9, 51–54]. In addition, a few cases of late onset cardiomyopathy have been reported in infants with CHB despite receiving early pacemaker implantation [52].
Morbidity and Mortality of Cardiac-NL
Two recent large studies addressed the morbidity and mortality of cardiac-NL [9, 55]. The first, from the U.S.-based RRNL, addressed mortality rates and associated risk factors [9]. In this study, in which all cases of cardiac-NL were due to exposure to maternal anti-SSA/Ro and/or anti-SSB/La antibodies, the case fatality rate was 17.5 % [9]. In utero deaths accounted for one third of the fatalities, with most occurring before 30 weeks. Fetal echocardiographic risk factors associated with increased mortality included EFE, hydrops, earlier diagnosis of cardiac-NL, and lower ventricular rate. The additional presence of EFE and dilated cardiomyopathy was associated with increased case fatality rates of 51.9 and 53.3, respectively, compared to those with only isolated advanced heart block [9]. The majority of postpartum deaths occurred before 1 year of life. Of the children born alive, the cumulative probability of survival at 10 years was 86 %. By age 10 the cumulative probability of requiring a pacemaker was approximately 70 %. Although rare, some children do require cardiac transplant. There also was a trend toward increased mortalities in children of mothers who had established diagnosis of SLE and/or SS at the time of pregnancy, which became significant in the multivariable analysis. In addition there was a significantly higher case fatality rate in minorities compared to Caucasians, possibly because they had a higher risk for developing hydrops and EFE [9].
In a second multicenter study of advanced heart block from Europe and Brazil, of which the majority were exposed to anti-SSA/Ro and/or anti-SSB/La antibodies, 91 % resulted in live births and 93 % of those were alive after the neonatal period [55]. They found similar risk factors associated with mortality as reported in the U.S. RRNL, including a gestational age <20 weeks at diagnosis, ventricular rate <50 bpm, fetal hydrops, and impaired left ventricular function at diagnosis. In that study at 1 year of life, 69 % of children were paced [55].
Proposed Mechanisms for Cardiac-NL
The precise mechanisms through which maternal anti-SSA/Ro-SSB/La antibodies contribute to the pathogenesis of autoantibody-mediated cardiac tissue injury remains unclear. Discordance of CHB in monozygotic twins of mothers with anti-SSA/Ro and/or anti-SSB/La antibodies implies that a combination of fetal genetics, the passive transfer of anti-SSA/Ro and anti-SSB/La antibodies, and the environment are needed for the CHB phenotype. Two non-mutually exclusive hypotheses have been proposed to explain the mechanism by which maternal autoantibodies to normally sequestered intracellular antigens initiate injury, one based on apoptosis and the other on direct calcium channel effects [56, 57].
Apoptosis, Antibodies, and Tissue Inflammation and Injury
In vitro studies have demonstrated that apoptosis results in translocation of the SSA/Ro and SSB/La antigens to the surface of the fetal cardiomyocytes [58–60]. It has been shown that healthy fetal cardiocytes in cell culture are capable of phagocytosing neighboring apoptotic cardiocytes, which implies that during embryogenesis of the human heart this is a physiologic property of healthy cardiocytes [61]. However, during this critical period of remodeling, SSA/Ro and SSB/La antigens may become accessible to the cognate maternal autoantibodies with the subsequent formation of immune complexes.
In vitro data generated both from cultured human fetal cardiocytes and from in vivo work in a murine model confirms the binding of anti-SSA/Ro and anti-SSB/La antibodies to the surface of apoptotic cells [59, 60]. The autoantibody binding to apoptotic cardiocytes results in inhibition of phagocytosis and clearance by neighboring healthy cardiocytes. It has been proposed that this leads to pathologic clearance of the apoptotic cardiocytes opsonized with anti-SSA/Ro and anti-SSB/La by infiltrating macrophages [61]. In contrast to the physiologic clearance by neighboring cardiocytes, phagocytosis by macrophages results in macrophage activation and secretion of pro-inflammatory cytokines and fibrotic cytokines, resulting in inflammation-induced tissue damage and fibrotic scarring [58].
Consistent with this model, a study which examined four available autopsy specimens from patients enrolled in the RRNL revealed exaggerated apoptosis, IgG deposition, and macrophage/fibroblast cross talk [62]. Apoptosis was extensive in fetuses dying early, and most pronounced in regions containing conduction tissue. Deposition of IgG was observed in hearts from fetuses with CHB/myocarditis, but not in control hearts, and was co-localized with apoptotic cells. Giant cells and macrophages were present in septal and thickened fibrous sub-endocardial regions. Septal tissue revealed extensive areas of fibrosis and microcalcification, in which predominant smooth muscle actin infiltrates (myofibroblast scarring phenotype) were observed [62].
Direct Calcium Channel Effects
In addition to inducing tissue damage, anti-SSA/Ro and /or anti-SSB/La antibodies cross-react with L-type cardiac calcium channels (LTCC), resulting in channel inhibition [63–65]. L-type channel function is crucial for the generation of action potentials in AV and SA nodes—both areas of NL vulnerability. A recent study showed that mouse pups passively immunized with anti-SSA/Ro and anti SSB/La antibodies developed sinus bradycardia and heart block, but that pups could be protected from these arrhythmias by transgenic over-expression of LTCC, suggesting that the antibodies adversely impact LTCC function. LTCC knockout pups born to immunized mothers had sinus bradycardia, advanced heart block and decreased fetal parity, confirming that these channels are necessary for normal cardiac function [65].
Target Antigens of the SSA/Ro-SSB/La System
The candidate antigens and their cognate antibodies have been extensively characterized at the molecular level. Initial cloning of 60 kDa SSA/Ro (Ro60) identified a zinc finger and an RNA-binding protein consensus motif [66–69]. It has been suggested that Ro60 may function as part of a novel quality control for ribosome biogenesis [70]. Xue et al. [71] reported that autoimmunity develops in a murine Ro60-knockout model and UVB irradiation results in significantly increased numbers of apoptotic keratinocytes compared to wild-type mice. This model suggested that Ro60 plays a role in preventing autoimmunity, possibly by removing defective ribonucleoproteins from cells, allowing them to escape immune surveillance, thus Ro60 could be involved in cell survival. However, an alternative explanation is that the increased numbers of keratinocytes present after photoprovocation represent a defect in clearance of these cells, either because anti-Ro60 antibodies inhibit phagocytic uptake or the Ro60 ligand for uptake is absent.
Anti-SSB/La antibodies recognize a 48 kDa polypeptide (La48) that does not share antigenic determinants with either 52 kDa Ro (Ro52) or Ro60 [72, 73]. Anti-SSB/La antibodies facilitate maturation of RNA polymerase III transcripts, directly bind a spectrum of RNAs, and associate at least transiently with Ro60 [74, 75].
In addition to the well-characterized Ro60 and La48 autoantigens, another target of the autoimmune response in mothers whose children have CHB is Ro52 [76, 77]. Like several other TRIM proteins, Ro52 has E3 ligase activity and functions in the process of ubiquitination [78].
There was recent excitement regarding the autoantibody response against the p200 epitope, which spans Ro 52 amino acids 200–239, as a candidate biomarker conferring an increased risk for the development of cardiac-NL in an offspring [79, 80]. While several groups have confirmed the high prevalence of the p200 response in women giving birth to a child with cardiac-NL, there have been inconsistencies regarding its utility in high-risk assessment relative to the pregnancy exposure [81]. It has not been determined whether antibodies to the p200 region of Ro52 confer any added risk over that observed to full length Ro52.
Joanne Reed and colleagues addressed some of these limitations by assessing umbilical blood from both affected and unaffected siblings, or simultaneously evaluating maternal and neonatal sera for anti-Ro60, anti-Ro52, anti-p200, and anti-La antibodies [82]. They noted that the presence of both anti-Ro52 and p200 antibodies was more common in mothers pregnant with a child with cardiac-NL or who had a previous child with cardiac-NL compared to mothers who never had a child with cardiac-NL. However, both anti-Ro52 and p200 autoantibodies were of low specificity for cardiac-NL [82]. Based on the 2 % prevalence of cardiac-NL in anti-Ro60 positive mothers [14–17], the presence of anti-Ro52 and anti-p200 minimally increases the risk of cardiac-NL to 2.2 and 2.6 %, respectively [82]. Overall the presence of p200 antibodies was common in each group, suggesting that p200 is a dominant epitope in the anti-Ro52 response regardless of fetal outcome [82].
In a murine study, passive transfer of anti-SSA/Ro and anti-SSB/La antibodies from mothers of children with heart block resulted in bradycardia and PR interval prolongation in 70 and 90 % of pups, respectively [83]. In contrast, active immunization with p200 peptide results in 20 % of rat pups with first degree block and none with complete heart block [84]. These data suggest that anti-p200 antibodies are not sufficient to account for all cases of cardiac-NL.
Environmental Contribution
A recent study in a Swedish population-based cohort of 190 pregnancies identified maternal age and seasonal timing of pregnancy as being novel risk factors for CHB in mothers with anti-SSA/Ro and/or anti-SSB/La antibodies [85]. Older maternal age (29.5 vs. 26.6) was significantly associated with cardiac-NL. This study also demonstrated that cardiac-NL was present in 58.5 % of births in which weeks 18–24 occurred during January–March, compared with 39 % of all births during the remainder of the year. The study authors posited that a decrease in sun exposure and vitamin D levels during the winter months in Sweden may explain this phenomenon. The average vitamin D level in each month, calculated based on samples from healthy Swedish woman, was inversely correlated with the number of heart block pregnancies in autoantibody positive women [85]. The authors acknowledged that other winter-related events such as viral infections might also contribute to the above observation [85].
Genetic Contributions
The initial genetic approach to NL exploited the finding that a variant in the TNFα promoter (rs1800629) associated with high cytokine production [86, 87] and was considered a potential candidate for risk of disease. In a study of 40 children with cardiac-NL, 17 with cutaneous NL, 31 unaffected siblings, and their 74 mothers, the frequency of the risk allele at rs1800629 was greatest in the mothers and affected siblings, although the frequency was significantly increased in all family members compared to population controls [88]. Furthermore, a polymorphism at codon 10 of the TGF-β gene that is associated with increased fibrosis was significantly higher in CHB children compared to unaffected offspring and controls [88]. Cimaz et al. studied the TNFα and TGF-β polymorphisms in two families, one with a cardiac-NL affected child among a set of twins, and another with an affected child among a set of triplets. No differences regarding TNFα polymorphisms were observed [89].
A focus on variation at the major histocompatibility complex (MHC) was a logical choice for genetic studies, since the extended HLA-A1;B8;DR3 haplotype block contains risk alleles for inflammation and certain autoimmune diseases, and is strongly associated with anti-SSA/Ro-SSB/La antibodies [90–93]. Allelic variants within the MHC may influence not only the development of the requisite pathogenic antibodies in the mother, but separately confer susceptibility to fetal injury in response to these antibodies. For example, Strandberg et al. demonstrated in a rodent model that maternal MHC regulated the generation of anti-Ro52 antibodies and that fetal MHC determined susceptibility to the development of a prolonged PR interval [94].
The role of fetal genetics in development of human disease was investigated in a genome-wide association study of 116 Caucasian cardiac-NL children and 3,351 controls, using a 370,000 SNP platform [95]. The 17 most significant associations were found in the HLA region at 6p21.3. The strongest association, found at rs3099844, is near the class-III MHC region and 94 kb from the TNFα gene, which contains the rs1800629 polymorphism previously associated with cardiac-NL [88]. Outside of the HLA, no individual locus previously implicated in autoimmune diseases achieved genome-wide significance. However, a cluster of associated SNPs at 21q22 were in proximity to the REG-ETS2/WDR4 transcription factor that serves as a “brake” to both apoptosis and inflammation, represses the expression of interleukin-8, and plays a role in augmenting the expression of TGF-β receptor type-2 [95] .
A missense variant at rs7775397 within the C6orf10 gene, which codes for an uncharacterized protein and lies in the Class III–Class II boundary was also associated with cardiac-NL in the GWAS [95]. This SNP and the TNFα promoter rs1800629 were evaluated in a multigenerational family study to determine the role of maternal grandparents in the development of the autoimmune phenotype of NL mothers [96]. Genotyping was performed in families consisting of 41 NL mothers, 38 grandmothers, and 29 grandfathers. There was an increased frequency of the two candidate genetic variants in the NL-mothers compared to HAPMAP controls. The clustering of each genetic variant in NL-mothers was related to a preferential skewing of inheritance from grandparents, as shown by a transmission disequilibrium test (TDT). These results imply that mothers accumulate genetic determinants specific to NL, which are not present in grandparents. The preferential transmission of risk alleles represents a selection pattern which demonstrates the “perfect storm” of events leading to cardiac-NL [96].
Clinical Management of Neonatal Lupus: Screening, Diagnosis, Monitoring, and Treatment
Screening
Presently, anti-SSA/Ro and anti-SSB/La antibody screening is not part of routine prenatal care. However, all women with SLE, SS, or UAS should be screened for these antibodies prior to pregnancy or early in pregnancy, as should women with a prior child having a neonatal rash or heart block, even if not previously recognized as NL. If antibodies are identified in an asymptomatic woman, she should be referred to a rheumatologist for evaluation. In a review of the RRNL, 50 % of mothers had progression of autoimmune symptoms. The probability of an asymptomatic mother developing SLE or SS by 10 years is roughly 19 and 28 %, respectively [26]. The NL manifestation of the child was not predictive of maternal disease progression [26].
In a prospective study of 87 women with anti-SSA/Ro and/or anti-SSB/La antibodies, Spence and colleagues found a 10 % prevalence of thyroid abnormalities (nine either had hypothyroidism or had a history of hypothyroidism) [97]. The children of these nine women with hypothyroidism had a significantly higher incidence of CHB when compared to mothers without hypothyroidism (55 vs. 13 %) [97]. Within the RRNL, 11 of 69 mothers (16 %) with NL children had clinical thyroid disease [98]. Thirty-three percent of these mothers had anti-thyroglobulin (anti-TG) antibodies and 22 % had anti-thyroperoxidase (anti-TPO) antibodies [98]. Thus, evaluation of thyroid disease may be warranted in mothers of NL-affected children or possibly even individuals with anti-SSA/Ro and anti-SSB/La antibodies [98].
Diagnosis
The diagnosis of cardiac-NL is made when a fetus or newborn of a mother with anti-SSA/Ro and/or anti-SSB/La antibodies develops heart block and/or evidence of cardiomyopathy, EFE, or hydrops fetalis. The most vulnerable period for the onset of cardiac-NL occurs between 18 and 24 weeks of gestation, correlating with an increase in transplacental passage of IgG autoantibodies from the maternal to the fetal circulation [99, 100].
Monitoring for CHB
There are no formal guidelines for the type and the frequency of testing to detect fetal heart block, but performing weekly pulsed Doppler fetal echocardiography from 18 to 26 weeks of gestation and every other week until 32 weeks should be strongly considered. Normal sinus rhythm can progress to complete heart block in 1 week during this vulnerable period [17, 40]. New onset heart block is less likely during the 26th through the 30th week, and it rarely develops after 30 weeks of pregnancy [18]. Incident heart block is much less likely to occur after the neonatal period [18].
Children with conduction abnormalities in utero should have an EKG and echocardiogram at birth. A prolonged PR interval in utero or at birth warrants the child being followed by a cardiologist for at least the first year of life. Fetal echocardiogram is essential for diagnosis and following the course of disease. Although not absolute, one can generally reassure the mother that if there is no evidence of cardiac injury by 1 week of postnatal life, the chances of developing a cardiac problem are quite slim [18]. Any conduction defect should also trigger immediate testing of the mother for anti-SSA/Ro antibodies regardless of whether the mother has symptoms.
Antibody Testing
Commercial testing is usually done by ELISA but laboratories may differ in the source of antigen. Certain laboratories identify only anti-Ro60, while others test anti-Ro60 and anti-Ro52. Isolated anti-Ro52 is extremely uncommon [101] and thus a positive anti-Ro60 finding is sufficient to place a pregnancy at risk. A negative anti-Ro60 finding is likely sufficient to rule out NL, although certain investigators suggest specific testing of anti-Ro52, which may or may not be available commercially. The finding of an isolated anti-SSB/La antibody is extremely unusual [9]. The recently adapted BioPlex 2200 assay for ANA screening will report antibodies for SSA/Ro60, SSA/Ro52 and SSB/La antigens.
Maternal antibodies to other antigens may cause neonatal disease in some cases. Anti-U1 RNP antibodies in the absence of anti-SSA/Ro or anti-SSB/La antibodies were found in a few instances of NL [102]. These cases had the classic rash of NL, but not CHB. There was one report of cardiac injury associated with anti-RNP in the absence of anti-SSA/Ro-SSB/La, which presented as transient first degree block that spontaneously reversed [103].
Prophylaxis and Treatment
Fluorinated steroids such as dexamethasone cross the placenta and may play a role in mitigating inflammation in affected NL individuals. Beta-agonists, such as terbutaline, can increase fetal heart rates in those affected by CHB. Jaeggi and colleagues [104] investigated the treatment impact of dexamethasone and beta-agonists on heart rates less than 55 bpm in patients with fetal complete atrioventricular block. The study concluded that both treatments improved 1 year survival and reduced morbidity. However, Eliasson and colleagues [55] noted no significant effect on mortality of fetuses based on treatment with fluorinated corticosteroids. In a large U.S.-based study [9], fluorinated steroids were associated with an increased mortality in fetuses dying in utero, which was attributed to their use in cases with more severe disease. At present there is no consensus on treatment guidelines.
The use of prophylactic treatment of pregnancies at risk for cardiac-NL with maternal steroids has been previously evaluated but this study combined fluorinated steroids with non-fluorinated steroids, the latter of which are not active in the fetus [105]. Accordingly, the interpretation of their benefit in reducing the risk of cardiac-NL is limited [106]. Two other studies restricted to fluorinated steroids showed that their prophylactic use did not associate with a reduction in recurrent cases of cardiac-NL [25, 107].
Steroids can cause many adverse effects in both the mother and the fetus. In the mother they may result in hypertension (and preeclampsia), gestational diabetes, bone death and bone loss, and increased risk of infection. The fetus can be affected by intra-uterine growth restriction, oligohydramnios (probably independent of CHB), increased risk of pre-term labor, increased post natal activity of the hypothalamus pituitary axis, and possible increased neurodevelopmental disabilities [105]. The side effects to the mother and fetus outweigh the potential unproven benefit of using steroids as prophylaxis against cardiac-NL.
Two prospective studies evaluated intravenous gamma globulin (IVIG) to prevent CHB in mothers who were anti-SSA/Ro positive and had a previous child with CHB [40, 41]. These patients were given IVIG at 400 mg/kg every 3 weeks from 12 to 24 weeks of gestation. The trials were terminated early, and it was concluded that IVIG at the above dose was ineffective at reducing the recurrence rate of cardiac-NL [40, 41]. It is unknown whether higher doses, such as 1 g/kg, would be efficacious.
A recent study evaluated outcomes of maternal autoantibody-mediated fetal cardiomyopathy/EFE following IVIG and corticosteroid therapy [108]. Twenty patients were treated with IVIG at approximately 1 g/kg administered between one and three times. Their results indicated that 16/20 (80 %) patients were alive at a median follow-up of 2.9 years and none required cardiac transplantation. This suggested a possible benefit of IVIG in patients with fetal cardiomyopathy/EFE related to NL.
A potentially promising approach to prevention of cardiac-NL is the use of hydroxychloroquine (HCQ). A case–control study explored the hypothesis that HCQ might reduce the risk of disease [109]. This initial study was limited to children born to mothers with SLE and anti-SSA/Ro antibodies, and comprised 50 cardiac-NL cases and 151 non-cardiac-NL controls. Seven (14 %) cardiac-NL children were exposed to HCQ compared with 56 (37 %) controls (p = 0.002; OR 0.28). A multivariable analysis yielded an OR associated with HCQ use of 0.46 (p = 0.10). Although HCQ was no longer a statistically significant predictor of cardiac-NL, the estimate of the OR remained in the direction of a protective effect, consistent with the results from the overall unadjusted analysis [109]. A subsequent study was performed to evaluate whether HCQ reduces the increased risk of recurrence of cardiac-NL, independent of maternal health status [25]. Using an international cohort, 257 pregnancies subsequent to the birth of a child with cardiac-NL were evaluated (40 exposed and 217 unexposed to HCQ). The recurrence rate of cardiac-NL in fetuses exposed to HCQ was 7.5 % (3/40) compared to 21.2 % (46/217) in the unexposed group (p = 0.05). There were no deaths in the HCQ exposed group compared to a case fatality rate of 22 % in the unexposed group. In both multivariable and propensity score analyses, the latter an alternative approach to adjust for possible confounding by indication, HCQ use remained significantly associated with a decreased risk of cardiac-NL. These data suggest that HCQ may protect the fetus from disease in those exposed to the pathogenic antibody as evidenced by a previous sibling with CHB [25].
Recommendations
In affected children with first degree heart block in utero, a watchful approach should include a repeat echocardiogram within 24 h. If there is a persistent prolonged PR, dexamethasone at 4 mg/day is a consideration to be discussed with the team of obstetricians, pediatric cardiologists, and rheumatologists. The echocardiogram should be repeated within a week, and if the PR interval returns to normal, the decision to discontinue dexamethasone and follow with weekly echocardiograms may be reasonable. If there is persistence of first degree block after several weeks, a watchful approach without dexamethasone would be reasonable. The reluctance in making a firm recommendation is that the abnormal PR interval may in fact revert spontaneously. Second degree block may progress to complete heart block, and treatment with dexamethasone is likewise reasonable. Treatment with dexamethasone is also suggested for cases with cardiomyopathy, EFE, and hydrops fetalis. If there is no change after 2 weeks of therapy, there may be no justification for continuation. IVIG in addition to steroids can be considered in cases where disease extends beyond the AV node.
Breastfeeding
A study examined breast milk in mothers with SSA/Ro and/or SSB/La antibodies [110]. Based on ELISA and immunoblot, the antibody profiles of the breast milk paralleled those observed in the serum. Two hundred and sixty-six children of mothers with SSA/Ro and/or SSB/La antibodies in the RRNL were studied, of which 136 were breastfed. NL was present in 149 of the children (55 rash only, 72 CHB only, 22 rash and CHB). Fisher’s exact test revealed no significant differences between the breastfed and non-breastfed NL-affected children compared to the unaffected children. There was a trend for the children who were breastfed to have cutaneous manifestations at a later age than those who had rashes and were formula fed; the difference in mean age at presentation of the rash was not statistically significant. The duration of the rash was not influenced by breastfeeding. In a second study of 32 children of mothers with anti-SSA/Ro, Ro and La specific IgM and IgA levels were low or nondetectable in children raised with and without breastfeeding. Cutaneous NL lesions developed independent of breastfeeding. The available data do not suggest that breastfeeding has pathologic consequences [111]. The maternal antibodies transferred to the fetus during gestation are present for several months postpartum, and the additional antibodies from breast milk are inconsequential. Mothers should be advised that autoantibodies are present in the breast milk but reassured that, at least within the limits of published literature, breastfeeding is not associated with postnatal NL [110, 111].
Long-term Follow-Up of Children with Varied Manifestations of NL
Little is known about the health outcomes of children with NL and their unaffected siblings. Martin and colleagues [112] obtained information on the health of children >8 years of age, 49 who had a manifestation of NL and 45 of their unaffected siblings. ANA positivity was found in 2 of 33 children with NL and 2 of 22 unaffected siblings. Six children with NL were noted to develop an autoimmune process (2 with juvenile rheumatoid arthritis, 1 psoriasis and iritis, 1 diabetes and psoriasis, 1 congenital hypothyroidism and nephrotic syndrome) despite the absence of anti-SSA/Ro or anti SSB/La antibodies in these individuals. All, however, had mothers who likewise had an autoimmune disease (four mothers had Sjögren’s syndrome (SS), one SLE/SS, one with undifferentiated autoimmune disease). Likewise, Esscher and Scott reported a 15-year-old girl who developed SLE [113]. Jackson, Fox, and Waterworth also reported three other patients with NL who developed SLE (2 at age 13 and 1 at age 19) [114–116]. Lanham reported 2 other children with CHB, one which developed SS at age 23 and in the other had arthritis with a positive ANA and dsDNA at age 19 [117] .
In contrast, Brucato followed 13 children with CHB for a mean of 18 years and none developed clinical symptoms or serologic abnormalities suggesting immune disease [118]. Despite this encouraging report, the data suggest that NL-affected children of mothers who have an autoimmune disease may require continued follow-up prior to adolescence. During adolescence and young adulthood, individuals with NL and their unaffected siblings do not appear to have an increased risk of developing systemic rheumatic disease [118].
Acknowledgments
The authors are grateful to Amanda Zink for assistance in preparing the manuscript.
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