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Autoimmune-mediated congenital heart block
Journal Pre-proof Autoimmune-Mediated Congenital Heart Block Benjamin Wainwright, Rohit Bhan, Catherine Trad, Rebecca Cohen, Amit Saxena, Jill Buyon, Peter Izmirly PII:
S1521-6934(19)30132-4
DOI:
https://doi.org/10.1016/j.bpobgyn.2019.09.001
Reference:
YBEOG 1973
To appear in:
Best Practice & Research Clinical Obstetrics & Gynaecology
Received Date: 1 August 2019 Accepted Date: 9 September 2019
Please cite this article as: Wainwright B, Bhan R, Trad C, Cohen R, Saxena A, Buyon J, Izmirly P, Autoimmune-Mediated Congenital Heart Block, Best Practice & Research Clinical Obstetrics & Gynaecology, https://doi.org/10.1016/j.bpobgyn.2019.09.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
1 Author query Add reference numbers to table 1
Autoimmune-Mediated Congenital Heart Block
Benjamin Wainwright1, Rohit Bhan1, Catherine Trad1, Rebecca Cohen1, Amit Saxena1, Jill Buyon1, Peter Izmirly1* 1
NYU School of Medicine, New York, NY, USA
*
Benjamin Wainwright Address: 550 1st Ave., MSB 611 New York, NY 10016 Email: [email protected] Phone: 212-263-0743
2 ABSTRACT Autoimmune-mediated congenital heart block (CHB) is a severe manifestation of neonatal lupus in which conduction tissues of the fetal heart are damaged. This occurs due to passive transference of maternal Ro (SSA) and La (SSB) autoantibodies, and subsequent inflammation and fibrosis of the atrioventricular (AV) node. Notably, the disease manifests after the fetal heart has structurally developed, ruling out other anatomical abnormalities that could otherwise contribute to block of conduction. Complete AV block is irreversible and the most common manifestation of CHB, though other cardiac complications such as endocardial fibroelastosis (EFE), a dilated cardiomyopathy, or valvular insufficiency have been observed. In this review, we will detail the classification, prevalence, pathogenesis, and clinical management recommendations for autoimmune CHB.
Keywords: congenital heart block; anti-SSA/Ro autoantibodies; neonatal lupus
3 INTRODUCTION Though the collection of disease pathologies referred to as neonatal lupus can manifest in a number of different ways, autoimmune congenital heart block (CHB) is the most severe diagnosis, bearing a mortality rate of approximately 18% and requiring pacemaker implantation in 70% of survivors [1]. In addition to cardiac complications, neonatal lupus includes cytopenias, cutaneous rash, liver damage, and neuropsychiatric impairment occurring to the child in utero or shortly after birth [2-5]. All of these complications are ascribed to the passive transference of maternal autoantibodies to Ro and La during pregnancy.
Antibodies to Ro and La can transfer to a fetus as early as 11 weeks and are primarily responsible for the observed damage to conduction tissues in the heart [1, 6]. Hearts affected by autoimmune CHB have been shown to present with inflammation, fibrosis, and calcification of the AV node leading to a block in conduction signal [7-9]. This damage occurs after the fetal heart has developed, supported by the lack of structural and anatomical abnormalities observed in CHB hearts. Babies affected by autoimmune CHB predominantly present with complete AV block (also known as third-degree block). The result of the inflammatory response is a significant reduction in fetal ventricular heart rate, as low as 50-70bpm whereas normal is 120160bpm [10].
In this review, we will summarize the different presentations of autoimmune-mediated CHB, including complete heart block, cardiomyopathy, and endocardial fibroelastosis (EFE). We also address the autoantibodies linked to CHB and their proposed mechanism of action. Lastly, we address the clinical management of this disease.
4
PREVALENCE/EPIDEMIOLOGY Autoimmune CHB occurs nearly exclusively in infants whose mothers have autoantibodies to Ro/SSA, most frequently in conjunction with La/SSB. The incidence in the total population of Finland is approximately 1 in 15,000 live births [11]; in a second population-based study, the incidence of autoantibody-related CHB in Stockholm County was approximately 1 in 23,300 [12]. Among the population of patients with Ro antibodies, the risk of having a child with CHB is roughly 2% [13-15]. In Ro-positive mothers who previously had a child affected by cardiac neonatal lupus, the risk of recurrence can approach 19% [1, 16, 17].
Although the association of CHB to autoimmunity is well documented [18-20], active autoimmune disease in the mothers is not a requirement for CHB. Data from the Research Registry for Neonatal Lupus (RRNL) shows that mothers can have SLE, Sjögren’s Syndrome (SS), undifferentiated autoimmune syndrome (UAS), or be completely asymptomatic and still have a child with CHB [21]. In many cases, the mother is unaware she even carries Ro and/or La antibodies prior to the diagnosis of neonatal lupus in an affected child [6, 21].
On a population level, the presence of Ro antibodies in female blood donors has been reported at 0.20% - 0.86% [22, 23]. The prevalence of Ro antibodies specifically is likely even higher, as these approximations were derived from patients who were initially positive for antinuclear antibodies and then tested for Ro antibodies. In patients with SLE the prevalence of Ro antibodies is estimated at 40%, and it is between 60%-100% for patients carrying a diagnosis of SS [24, 25]. Based on the National Vital Statistics Reports, in 2015 there were 3,978,497 live
5 births. Using the estimated prevalence for Ro antibodies of 0.9% and cardiac neonatal lupus of 2%, there could be as many as 700 cases of CHB in a given year. Therefore, though thousands of women could be at risk of having a child with cardiac neonatal lupus, evaluation of Ro and La antibodies are not included in routine prenatal testing.
AUTOANTIBODIES Autoantibodies to Ro and La target the Ro/La ribonucleoprotein complex (52 kD Ro, 60 kD Ro, and 48 kD La). These antibodies are transported across the placenta into fetal circulation facilitated by FcγRn. Both in vitro and in vivo studies provide evidence for the role of Ro and La autoantibodies in pathogenesis [26, 27], as do clinical and epidemiological studies. Antibodies specific for the Ro autoantigen are capable of recognizing one or both isoforms of Ro (52 kD and 60kD). It has been suggested that antibodies to Ro52 are responsible for cardiac injury [28], further supported by the observation that Ro52 antibodies are found more frequently than Ro60 antibodies [20].
Evidence posits a specific epitope on Ro52 (amino acids 200-239, coined p200) as a serological biomarker for increased risk of autoimmune CHB [29]. While the prevalence of anti-p200 antibodies in mothers of children with CHB is well documented, whether or not anti-p200 antibodies can be accurately used as a risk stratification tool for predicting autoimmune CHB remains unclear [30].
Importantly, not all mothers with Ro antibodies run the same risk of having a child with autoimmune CHB. Several studies have shown that the serum levels of Ro and La antibodies are
6 significantly higher in mothers whose children were affected by autoimmune CHB compared to mothers of unaffected children [20]. There is preliminary evidence suggesting that titers of Ro may be a tool to predict risk of autoimmune CHB [31].
It should be noted that there are only 14 cases of La-mediated autoimmune CHB in the published literature [20]. Similar to Ro antibodies, the serum levels of La antibodies have been shown to be significantly higher in affected mothers compared to non-affected mothers. While these cases are intellectually fascinating, they represent <1% of known autoimmune CHB cases, and thereby should not be used as a biomarker to predict autoimmune CHB.
In mothers with children affected by CHB, other autoantibodies are often detected during evaluation for autoimmunity. These include anti-dsDNA and anti-Smith antibodies in SLE, rheumatoid factor in Rheumatoid Arthritis and Sjögren’s Syndrome, and anti-RNP antibodies in Mixed Connective Tissue Disease. At the time of an autoimmune CHB diagnosis, not all mothers fulfill criteria and are thereby not diagnosed with an autoimmune disease. Review of the literature has shown more than half of mothers affected by autoimmune CHB are asymptomatic despite carrying autoantibodies to Ro and La [20]. It is worth noting that there are a few cases in the literature about anti-RNP-associated CHB in the absence of anti-SSA/Ro [25, 32]. Clinicians should consider testing for this antibody in cases who have CHB and do not have anti-SSA/Ro and/or SSB/LA.
MECHANISM OF ACTION
7 The exact mechanism by which Ro/La autoantibodies mediate cardiac injury is unclear. For example, monozygotic twins discordant for the CHB phenotype imply a complexity to disease pathogenesis beyond a mother carrying Ro/La antibodies [33]. This could include fetal genetics, the environment, and other factors.
Antibody-mediated cardiac damage A major challenge in examining the pathophysiology of CHB is explaining the mechanism by which maternal autoantibodies initiate injury to antigen sites that are normally intracellular. One hypothesis is that Ro/La antigens translocate to the surface of cardiomyocytes undergoing normal physiological remodeling, allowing these antigens to be accessed by autoantibodies in circulation and triggering subsequent immune responses [34]. Further, in vitro studies have demonstrated that normal fetal cardiocytes are able to phagocytose apoptotic cardiocytes; immune complex formation on phagocytic cardiocytes may impair their clearance by healthy cardiocytes, hindering a function critical to normal fetal heart development [35]. Indeed, histologic evaluation of normal fetal hearts show virtually no apoptotic cells, whereas hearts of fetuses dying with CHB show exaggerated apoptosis [36]. In turn, the apoptotic cells lead to infiltration by macrophages, the subsequent activation of which causes the release of proinflammatory and fibrotic cytokines such as TNFα and thus results in tissue damage and fibrosis [37].
Another non-mutually exclusive hypothesis suggests there is cross reactivity of Ro antibodies with L-type calcium channels (LTCC) on the surface of cardiomyocytes, disrupting calcium homeostasis and producing abnormalities in conduction [38]. LTCC is critical to the generation
8 of action potential in the sinoatrial and atrioventricular nodes, both of which are prone to injury resulting from neonatal lupus. Another study showed that mouse pups develop sinus bradycardia and heart block when passively immunized to Ro/La antibodies. Further, overexpression of LTCC could rescue the heart block phenotype upon exposure to Ro/La antibodies, suggesting that these antibodies adversely impact LTCC function [39].
Low penetrance of autoimmune CHB in mothers with Ro/La antibodies may indicate protective factors in the fetus. β2-GPI has been shown to bind to apoptotic fetal cardiomyocytes in a dosedependent fashion and prevent opsonization of apoptotic cardiomyocytes by maternal Ro60 IgG [40]. Further, umbilical cord blood of neonates affected by autoimmune CHB showed significantly lower levels of β2-GPI compared to unaffected neonates, suggesting that β2-GPI may be protective to a fetus in a Ro-antibody exposed pregnancy [40].
Further, hearts from fetuses dying of autoimmune CHB showed exaggerated apoptosis compared to electively terminated fetal hearts. Apoptosis was accompanied by increased TGF-β immunoreactivity in the extracellular matrix and infiltrating macrophages [36]. Increased SMAc staining of transdifferentiating myofibroblasts and increased collagen expression in cardiac fibroblasts were shown to be consequences TGF-β activation.
Evaluating maternal and cord levels of prospective biomarkers has proven challenging, but analysis of mothers and infants in the Research Registry for Neonatal Lupus has provided avenues for future exploration. Drawing from the literature on inflammation and fibrosis in CHB and similar conditions, levels of the following potential biomarkers were evaluated in 135
9 maternal serum samples and 139 cord serum samples, 59 of which were from cases of advanced block: C-reactive protein (CRP); NT-pro-B-type natriuretic peptide (NT-proBNP); troponin I; matrix metalloproteinase (MMP)-2; urokinase plasminogen activator (uPA); urokinase plasminogen activator receptor (uPAR); plasminogen; and vitamin D [41]. Regardless of maternal medications and rheumatic disease diagnosis, increased levels of cord CRP, NTproBNP, MMP-2, uPA, uPAR, and plasminogen were associated with CHB manifestations. The investigators concluded that MMP-2 and uPA/uPAR/plasminogen pathway could serve as clues for future treatment given their known associations with inflammation, and monitoring levels of CRP and NT-proBNP after birth could provide prognostic information regarding heart deterioration in early life.
Nonetheless, linking anti-Ro autoantibodies to the maternal inflammatory profile has remained challenging. Despite the fact that rheumatic diseases commonly associated with anti-Ro also show significantly elevated levels of interferon alpha (IFNα) [42, 43], research has only recently turned to investigating the ways in which the IFN profile might affect the maternal-fetal dyad in CHB. In one pivotal study, it was determined that IFNα levels were significantly higher in antiRo positive pregnant women whose fetuses were affected by CHB than their counterparts with the same antibody profile but healthy pregnancies (though the authors were not able to test IFN levels in the infants themselves via cord blood) [44]. The same study showed that sialic acid binding Ig like lectin 1, a protein responsive to IFN also known as sialoadhesin or SIGLEC-1, was similarly upregulated in CHB mothers.
10 Given that increased monocyte levels of SIGLEC-1 are a known biomarker for lupus activity [45] and its upregulation has been linked with fibrotic autoimmune diseases such as systemic sclerosis [46], Clancy et al. investigated its genetic and protein expression profile in CHB [47]. Compared to electively terminated controls, heart tissue from fetuses dying with CHB showed significantly increased SIGLEC-1 expression (among other IFN stimulated genes), and histologic evaluation of the septal cross-sections confirmed the presence of SIGLEC-1’s corresponding protein in CHB hearts. Taken together, these studies strongly posit anti-Ro autoantibodies, IFN, and downstream inflammatory consequences as primary mediators of this complex immune response, leading to fibrotic damage in fetal conduction tissues.
Genetic Contributions to Autoimmune CHB Examining the role of genetics in autoimmune CHB was initially based on the finding that a variant of the TNF-α promoter (rs1800629), associated with increased cytokine production, was found to be significantly increased in all family members of a child with autoimmune CHB compared to population controls [48]. Moreover, a polymorphism in the TGF-β gene associated with increased fibrosis was significantly higher in children with autoimmune CHB compared to controls and unaffected offspring [48]. Given that fetal hearts dying with CHB consistently demonstrate an inflammatory infiltrate, these polymorphisms warrant further investigation.
A genome-wide association study of 116 autoimmune CHB-affected children of European ancestry and 3,351 controls was conducted to investigate novel genetic associations with disease. The most significant associations were found in the human leukocyte antigen (HLA) region at 6p21.3 [49]. The strongest association was found at rs3099844, near the class-III major
11 histocompatibility complex (MHC) region and 94 kb from the TNF-α gene containing the rs1800629 polymorphism. Moreover, a cluster of SNPs at 21q22 were in proximity to the REGETS2/WDR4 transcription factor, which can slow apoptosis and inflammation, repress IL-8 expression, and is involved in augmenting the expression of TGF-β receptor type 2 [49]. Further study within this region has shown that the C2 epitope of HLA-C is significantly enriched in children with CHB compared with their unaffected siblings, potentially implicating an impairment in normal natural killer cell function in this disease’s pathogenesis [50].
AUTOIMMUNE HEART BLOCK AND OTHER CLINICAL MANIFESTATIONS CHB covers a spectrum of severity ranging from first-degree block (prolonged PR interval) to second and third-degree block (fibrosis at the AV node blocking conduction). Despite the difference in severity, all manifestations are strongly associated with maternal anti-SSA/Ro autoantibodies. Importantly, CHB is predominantly diagnosed during pregnancy, and typically within a specific timeframe. Isolated cases have been reported as early as 16 weeks, though a systematic review showed that 75% of cases were diagnosed during weeks 20-29 [20].
There is discordant data as to whether first-degree block progresses to complete heart block (i.e., third degree), in part due to the cutoffs and measurements used for normal ranges. A recent study based on serial echocardiograms of 156 anti-SSA/Ro exposed fetuses concluded that first degree block does not reliably predict progressive heart block [51]. However, progression from first or second-degree block to complete block has been reported [52]. Presently, third-degree block is not reversible.
12 Although AV block is the most common form of autoimmune CHB (sometimes being used interchangeably), other electrophysiological abnormalities have been reported. These include sinus node dysfunction, ventricular and junctional tachycardia, long QT interval, atrial flutter, valvular disease, and dilated cardiomyopathy [20, 53]. However, reliably associating these disease pathologies with the presence of maternal anti-Ro and anti-La antibodies has been substantially more challenging.
Endocardial fibroelastosis (EFE) merits particular mention as a form of myocardial fibrosis that is found in 7% of autoimmune CHB children, though a clear association between the two conditions has not been shown. EFE can lead to end-stage heart failure and subsequent death: a prior study showed that babies with EFE had a 51% mortality rate, and those with concomitant cardiomyopathy was 100% [1]. EFE can be detected on echocardiograms by areas of patchy echogenicity on the endocardial surfaces on the fetal heart [20]. Valvular disease is another rare but severe complication of autoimmune CHB, with tensor apparatus dysfunction arising in 1.6% of cases. Echocardiographic studies show patchy echogenicity at the papillary muscle detected between 19-22 weeks involving the tricuspid and mitral valves. Valvular insufficiency developed both prenatally and postnatally, ranging from 34 weeks of gestation to 26 weeks after birth. All babies required urgent valve surgery [54].
Dilated cardiomyopathy (DCM) is the other significant albeit rare cardiac complication found in babies affected by autoimmune CHB that is associated with a high mortality rate [1, 55]. In DCM, the left ventricle is enlarged and weakened, resulting in a decreased ability of the heart to pump blood. DCM can be diagnosed in utero alongside CHB, but also can manifest after birth as
13 postnatal DCM. The risk factors for DCM remain unclear, though a recent study analyzed the prevalence and outcomes of DCM in 187 children with autoimmune CHB. 35 children (18%) were found to have DCM, and 22 (11.8%) died at a median age of 7 years. Further, it was shown that there were two distinct types of DCM: neonatal DCM and late-onset DCM. Hydrops, EFE, and pericardial effusion were all factors associated with neonatal DCM; factors associated with late-onset DCM were non-European origin, pacemaker implantation, and valvular insufficiency. Notably, use of fluorinated steroids had no protective effect against late-onset DCM, and none of the risk factors associated with neonatal DCM were predictive of late-onset DCM [53].
CLINICAL MANAGEMENT OF AUTOIMMUNE CHB Presently, antibody screening for Ro/SSA and La/SSB is not part of routine prenatal care. However, all women carrying a diagnosis of SLE, SS, or UAS should be screened for these antibodies prior to pregnancy or early during pregnancy. This is true particularly for those women who previously had a child with any form of autoimmune CHB or even cutaneous manifestations of neonatal lupus, as will be discussed in the following sections. This is critical as many women whose infants develop neonatal lupus are themselves asymptomatic.
Pregnancy Outcomes Autoimmune CHB carries a mortality rate of 17%-19%, with 70% of deaths occurring in utero [20]. Of the live births, the mean 10-year survival rate was 86%, with a mean gestational age of delivery between 34-37 weeks and a Caesarean section rate of 75%. Fetal echocardiographic risk factors associated with mortality included EFE, hydrops, earlier diagnosis of CHB, and decreased ventricular rate. Analysis of deaths in the RRNL showed that severe cardiomyopathy
14 was the cause of death in two-thirds of cases. Compared to isolated cases of autoimmune CHB, the mortality rate was greater than 50% in babies with concomitant EFE or DCM, and was 100% in babies with both EFE and DCM [20].
By age 10, the probability of CHB-affected children requiring a pacemaker was approximately 70%. Almost all children were paced within the first year of life and nearly two-thirds were within 10 days of birth [20]. A significant challenge for pediatric cardiologists treating CHBaffected children is determining which patients require pacemaker implantation, and at what age a pacemaker should be introduced [56].
In addition to increased risks of cardiac events later in life, however, children with CHB appear to face worse outcomes in other aspects of their health as well. A recent paper using the Swedish National Patient Register looked at long term outcomes in patients with congenital heart block and found that affected individuals had a significantly increased risk of cardiovascular comorbidity and a higher risk of infections [57]. They also noted an increased risk for a systemic connective tissue disorder. Accordingly, close follow-up is required for all children affected by autoimmune CHB.
Therapy Recommendations Fluorinated steroids such as dexamethasone cross the placenta and have the potential to mitigate inflammation in autoimmune-CHB affected children, but there are conflicting reports regarding the drug’s efficacy for either treatment or prophylaxis. Jaeggi et al. investigated the use of dexamethasone and β-agonists on fetuses with complete atrioventricular block (as measured by
15 heart rates less than 55bpm) [58] and concluded that CHB-affected fetuses treated with both dexamethasone and β-agonists had improved survival at one year and reduced morbidity. However, data from the RRNL showed that fluorinated steroids did not prevent disease progression, improve survival, or delay pacemaker placement when given shortly after the detection of isolated advanced block [59]. Other groups later confirmed the finding that in isolated cases of autoimmune CHB, prenatal corticosteroid treatment showed no significant difference for in utero progression, survival to birth, pacemaker implantations, or long-term DCM [53, 60]. Thus, though dexamethasone has been proposed as a potential therapeutic for CHB and is often given when block is detected, mounting evidence from the US, France and the Netherlands have shown that fluorinated steroids have no significant effect in improving fetal outcomes when prescribed alone and some have now questioned their use [59-62].
A recent study evaluated the outcomes of autoantibody-mediated fetal cardiomyopathy/EFE following treatment with IVIG and corticosteroids [63]. Twenty affected patients were referred at a median gestational age of 23 weeks with atrioventricular block. IVIG was administered at 1g/1kg between one and three times. The results indicated that 16 of 20 (80%) of patients were alive at median follow-up of 2.9 years, with none requiring cardiac transplantation. Though the study did not identify the ideal schedule or dosage for administration of IVIG, it suggests the drug could in fact be efficacious after further investigation.
Because it is known to inhibit Toll-like receptor signaling, hydroxychloroquine (HCQ) has been proposed as a potential preventive for autoimmune CHB (Table 1). A case-control study explored the hypothesis that HCQ might reduce the risk of Ro-mediated cardiac injury [64]. The
16 study was limited to children born to anti-Ro positive mothers with a confirmed diagnosis of SLE, with 50 CHB cases and 151 controls. Seven (14%) CHB-affected children were exposed to HCQ compared to 56 (37%) of the controls. Although HCQ use was not a statistically significant predictor of autoimmune CHB, the study suggested a protective benefit from HCQ [64]. A subsequent study from the RRNL and other registries from France and the U.K. showed that HCQ reduced the recurrence rate by 64% in subsequent pregnancies [65]. These findings were corroborated by Martínez-Sánchez et al., who reported the prevalence of CHB was much lower in patients taking HCQ compared to untreated patients, providing further support for the drug as preventative therapy against CHB [66]. HCQ had a similarly beneficial effect in another symptom of anti-Ro-mediated infant autoimmunity, cutaneous neonatal lupus (NL) [67].
Insert Table 1 here.
Cutaneous NL manifests as a skin rash, most often circling the eyes and spanning the infant’s cheeks across the bridge of the nose, though occasionally other parts of the body are affected simultaneously [3]. The rash clears concurrently with maternal antibodies exiting the neonate’s circulation around eight months of age [68], rarely scarring or leaving permanent skin damage. Though cutaneous manifestations are transient and inarguably less severe than their cardiac counterparts, it bears noting in the context of this review that mothers who give birth to a child with cutaneous neonatal lupus are 6 – 10 times more likely to have subsequent children with CHB [69]. Among 58 mothers enrolled in the Research Registry for Neonatal Lupus who gave birth to a child with cutaneous NL, the disease recurred in 23 (29.9%) of 77 subsequent pregnancies, and 14 (18.2%) were affected by CHB. Accordingly, mothers of infants with
17 neonatal lupus rashes should be counseled about their increased risk of CHB in future pregnancies, as these mothers might even be unaware of their anti-Ro status.
Given the evident epidemiological and pathological connections between cutaneous and cardiac NL, recent research has investigated whether or not HCQ’s efficacy in CHB can be translated to preventing rash as well. In a case-control study of anti-Ro positive mothers with confirmed systemic autoimmune diagnoses (including systemic lupus erythematosus and Sjögren’s syndrome, among others), investigators found that HCQ was used in 34% of pregnancies that resulted in healthy infants (146/434) compared to only 16% of infants who developed a rash (20/122), showing that the drug is significantly associated with a reduction in cutaneous NL incidence (OR 0.4 [95% CI 0.2 to 0.6]; p<0.01) [67]. Infants exposed to the drug in utero also trended (p=0.21) towards developing the rash later after birth than their unexposed counterparts.
Based on these and other limited but encouraging results, a prospective, open label study was initiated using Simon’s two-stage design to determine whether HCQ significantly reduces the risk of recurrent CHB. To ensure all enrollees were of sufficiently high titer to be at risk, participants were eligible only if they had previously experienced a pregnancy affected by antiRo-mediated cardiac manifestations. The study is currently enrolling with the goal of 54 total patients (https://clinicaltrials.gov/ct2/show/NCT01379573).
Monitoring for CHB All pregnant women who carry Ro and/or La antibodies are considered to be high risk, particularly those who have previously had a child with autoimmune CHB or neonatal lupus.
18 These women should be referred to an obstetric unit specialized in high-risk pregnancies. While first-degree block may be detected via auscultation, some manifestations of CHB, including more advanced block and extranodal disease, can be undetectable without additional testing. Though slightly more burdensome, fetal echocardiograms are a safe, noninvasive method of screening for CHB. Accordingly the current standard of care mandates weekly echocardiograms for all women managing anti-Ro pregnancies within the window of vulnerability for CHB (i.e., weeks 16 – 26).
However, recent studies have called the practicality of weekly echocardiograms into question. Treatment efficacy for first-degree block is currently controversial, rendering an early diagnosis as possibly another source of maternal stress, and even complete block can arise within 24 hours [70]. Further complicating management strategies, evidence suggests that prompt treatment of second degree block with corticosteroids and IVIG in conjunction can reverse the diagnosis and revert the fetus back to normal sinus rhythm [71]. As a supplementary surveillance technique, Cuneo et al. have proposed fetal heart rate and rhythm monitoring (FHRM), a process by which the pregnant person self-evaluates every 12 hours using a handheld Doppler; should any abnormality be discovered, the patient is seen for an urgent confirmatory echo followed by treatment with dexamethasone and/or IVIG [70].
The FHRM pilot study evaluated 273 completed anti-Ro pregnancies, with mothers detecting one case of second degree block and two cases of third [72]. Throughout the course of the study, there were 21 perceived aberrant rhythms, three of which were confirmed to be heart block. Upon confirmatory echo, the rest of the 21 rhythms were premature atrial contractions (6),
19 repeated sinoatrial arrest (1), and normal sinus rhythm (11). Ultimately the second-degree case responded to treatment and regressed to normal sinus rhythm at birth, but there was unfortunately no improvement in the more advanced cases. It is worth noting, however, that these cases did not receive a confirmatory echo and treatment until more than 24 hours elapsed; further research will be required to know if prompter treatment can avert adverse outcomes.
As for feasibility, only six of the participants did not complete the course of home monitoring per the protocol, four of which were due to the protocol design per se (one experienced unmanageable stress, and three felt the process was unduly time-consuming); one terminated her pregnancy due to extremely low gestational weight, and the final participant was lost to followup [72]. Within this cohort there was a 5% false positive rate, but the false negative rate was 0% - i.e., no mothers failed to detect an irregular rhythm that led to a cardiac event. Thus, preliminary FHRM data suggest that the increased surveillance can detect and treat fetuses with second degree block, improving outcomes at birth without creating a large burden of unnecessary urgent echos for health care providers.
Practice Points •
Current data on HCQ suggest it may reduce the likelihood of developing CHB.
•
Recent data on fluorinated steroids do not show an improvement in mortality.
•
A handheld Doppler has shown preliminary efficacy as a screening method to supplement weekly echocardiograms.
Research Agenda
20 •
There is an ongoing prospective study evaluating whether HCQ reduces the recurrence rate of CHB.
•
Further evidence is being sought regarding the efficacy of prompt IVIG and dexamethasone administration within 12 hours of CHB detection.
•
Recent research into the pathophysiology of CHB suggest that it may be interferonstimulated.
ACKNOWLEDGEMENTS: The Research Registry for Neonatal Lupus was supported by NIH/NIAMS AR042220 and AR42271; it is currently ongoing through private philanthropy.
Conflicts of Interest The authors have no conflicts of interest.
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25 [31] Jaeggi E, Laskin C, Hamilton R, Kingdom J, Silverman E. The importance of the level of maternal anti-Ro/SSA antibodies as a prognostic marker of the development of cardiac neonatal lupus erythematosus a prospective study of 186 antibody-exposed fetuses and infants. J Am Coll Cardiol. 2010;55:2778-84. [32] Radin M, Schreiber K, Cuadrado MJ, Cecchi I, Andreoli L, Franceschini F, et al. Pregnancy outcomes in mixed connective tissue disease: a multicentre study. Rheumatology (Oxford). 2019. [33] Cooley HM, Keech CL, Melny BJ, Menahem S, Morahan G, Kay TW. Monozygotic twins discordant for congenital complete heart block. Arthritis Rheum. 1997;40:381-4. [34] Clancy RM, Alvarez D, Komissarova E, Barrat FJ, Swartz J, Buyon JP. Ro60-associated single-stranded RNA links inflammation with fetal cardiac fibrosis via ligation of TLRs: a novel pathway to autoimmune-associated heart block. J Immunol. 2010;184:2148-55. [35] Clancy RM, Neufing PJ, Zheng P, O'Mahony M, Nimmerjahn F, Gordon TP, et al. Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis of congenital heart block. J Clin Invest. 2006;116:2413-22. [36] Clancy RM, Kapur RP, Molad Y, Askanase AD, Buyon JP. Immunohistologic evidence supports apoptosis, IgG deposition, and novel macrophage/fibroblast crosstalk in the pathologic cascade leading to congenital heart block. Arthritis Rheum. 2004;50:173-82. [37] Miranda-Carus ME, Askanase AD, Clancy RM, Di Donato F, Chou TM, Libera MR, et al. Anti-SSA/Ro and anti-SSB/La autoantibodies bind the surface of apoptotic fetal cardiocytes and promote secretion of TNF-alpha by macrophages. J Immunol. 2000;165:5345-51. [38] Xiao GQ, Hu K, Boutjdir M. Direct inhibition of expressed cardiac l- and t-type calcium channels by igg from mothers whose children have congenital heart block. Circulation. 2001;103:1599-604.
26 [39] Karnabi E, Qu Y, Mancarella S, Boutjdir M. Rescue and worsening of congenital heart block-associated electrocardiographic abnormalities in two transgenic mice. J Cardiovasc Electrophysiol. 2011;22:922-30. [40] Reed JH, Clancy RM, Purcell AW, Kim MY, Gordon TP, Buyon JP. beta2-glycoprotein I and protection from anti-SSA/Ro60-associated cardiac manifestations of neonatal lupus. J Immunol. 2011;187:520-6. [41] Saxena A, Izmirly PM, Han SW, Briassouli P, Rivera TL, Zhong H, et al. Serum Biomarkers of Inflammation, Fibrosis, and Cardiac Function in Facilitating Diagnosis, Prognosis, and Treatment of Anti-SSA/Ro-Associated Cardiac Neonatal Lupus. J Am Coll Cardiol. 2015;66:930-9. [42] Emamian ES, Leon JM, Lessard CJ, Grandits M, Baechler EC, Gaffney PM, et al. Peripheral blood gene expression profiling in Sjogren's syndrome. Genes Immun. 2009;10:28596. [43] Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100:2610-5. * [44] Lisney AR, Szelinski F, Reiter K, Burmester GR, Rose T, Dorner T. High maternal expression of SIGLEC1 on monocytes as a surrogate marker of a type I interferon signature is a risk factor for the development of autoimmune congenital heart block. Ann Rheum Dis. 2017;76:1476-80. [45] Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a
27 potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58:1136-45. [46] York MR, Nagai T, Mangini AJ, Lemaire R, van Seventer JM, Lafyatis R. A macrophage marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists. Arthritis Rheum. 2007;56:1010-20. * [47] Clancy RM, Halushka M, Rasmussen SE, Lhakhang T, Chang M, Buyon JP. Siglec-1 Macrophages and the Contribution of IFN to the Development of Autoimmune Congenital Heart Block. J Immunol. 2019;202:48-55. [48] Clancy RM, Backer CB, Yin X, Kapur RP, Molad Y, Buyon JP. Cytokine polymorphisms and histologic expression in autopsy studies: contribution of TNF-alpha and TGF-beta 1 to the pathogenesis of autoimmune-associated congenital heart block. J Immunol. 2003;171:3253-61. [49] Clancy RM, Marion MC, Kaufman KM, Ramos PS, Adler A, International Consortium on Systemic Lupus Erythematosus G, et al. Identification of candidate loci at 6p21 and 21q22 in a genome-wide association study of cardiac manifestations of neonatal lupus. Arthritis Rheum. 2010;62:3415-24. [50] Ainsworth HC, Marion MC, Bertero T, Brucato A, Cimaz R, Costedoat-Chalumeau N, et al. Association of Natural Killer Cell Ligand Polymorphism HLA-C Asn80Lys With the Development of Anti-SSA/Ro-Associated Congenital Heart Block. Arthritis Rheumatol. 2017;69:2170-4. [51] Jaeggi ET, Silverman ED, Laskin C, Kingdom J, Golding F, Weber R. Prolongation of the atrioventricular conduction in fetuses exposed to maternal anti-Ro/SSA and anti-La/SSB antibodies did not predict progressive heart block. A prospective observational study on the effects of maternal antibodies on 165 fetuses. J Am Coll Cardiol. 2011;57:1487-92.
28 [52] Askanase AD, Friedman DM, Copel J, Dische MR, Dubin A, Starc TJ, et al. Spectrum and progression of conduction abnormalities in infants born to mothers with anti-SSA/Ro-SSB/La antibodies. Lupus. 2002;11:145-51. [53] Morel N, Levesque K, Maltret A, Baron G, Hamidou M, Orquevaux P, et al. Incidence, risk factors, and mortality of neonatal and late-onset dilated cardiomyopathy associated with cardiac neonatal lupus. Int J Cardiol. 2017;248:263-9. [54] Cuneo BF, Fruitman D, Benson DW, Ngan BY, Liske MR, Wahren-Herlineus M, et al. Spontaneous rupture of atrioventricular valve tensor apparatus as late manifestation of antiRo/SSA antibody-mediated cardiac disease. Am J Cardiol. 2011;107:761-6. [55] Moak JP, Barron KS, Hougen TJ, Wiles HB, Balaji S, Sreeram N, et al. Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela. J Am Coll Cardiol. 2001;37:238-42. [56] Capone C, Buyon JP, Friedman DM, Frishman WH. Cardiac manifestations of neonatal lupus: a review of autoantibody-associated congenital heart block and its impact in an adult population. Cardiol Rev. 2012;20:72-6. [57] Mofors J, Eliasson H, Ambrosi A, Salomonsson S, Skog A, Fored M, et al. Comorbidity and long-term outcome in patients with congenital heart block and their siblings exposed to Ro/SSA autoantibodies in utero. Ann Rheum Dis. 2019;78:696-703. [58] Jaeggi ET, Fouron JC, Silverman ED, Ryan G, Smallhorn J, Hornberger LK. Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation. 2004;110:1542-8.
29 * [59] Izmirly PM, Saxena A, Sahl SK, Shah U, Friedman DM, Kim MY, et al. Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system. Ann Rheum Dis. 2016;75:1161-5. [60] Van den Berg NW, Slieker MG, van Beynum IM, Bilardo CM, de Bruijn D, Clur SA, et al. Fluorinated steroids do not improve outcome of isolated atrioventricular block. Int J Cardiol. 2016;225:167-71. [61] Levesque K, Morel N, Maltret A, Baron G, Masseau A, Orquevaux P, et al. Description of 214 cases of autoimmune congenital heart block: Results of the French neonatal lupus syndrome. Autoimmun Rev. 2015;14:1154-60. [62] Brucato A, Tincani A, Fredi M, Breda S, Ramoni V, Morel N, et al. Should we treat congenital heart block with fluorinated corticosteroids? Autoimmun Rev. 2017;16:1115-8. [63] Trucco SM, Jaeggi E, Cuneo B, Moon-Grady AJ, Silverman E, Silverman N, et al. Use of intravenous gamma globulin and corticosteroids in the treatment of maternal autoantibodymediated cardiomyopathy. J Am Coll Cardiol. 2011;57:715-23. [64] Izmirly PM, Kim MY, Llanos C, Le PU, Guerra MM, Askanase AD, et al. Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis. 2010;69:1827-30. * [65] Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim MY, Saxena A, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent antiSSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation. 2012;126:7682.
30 [66] Martinez-Sanchez N, Perez-Pinto S, Robles-Marhuenda A, Arnalich-Fernandez F, Martin Camean M, Hueso Zalvide E, et al. Obstetric and perinatal outcome in anti-Ro/SSA-positive pregnant women: a prospective cohort study. Immunol Res. 2017;65:487-94. * [67] Barsalou J, Costedoat-Chalumeau N, Berhanu A, Fors-Nieves C, Shah U, Brown P, et al. Effect of in utero hydroxychloroquine exposure on the development of cutaneous neonatal lupus erythematosus. Ann Rheum Dis. 2018. [68] Lee LA. Maternal autoantibodies and pregnancy--II: The neonatal lupus syndrome. Baillieres Clin Rheumatol. 1990;4:69-84. [69] Izmirly PM, Llanos C, Lee LA, Askanase A, Kim MY, Buyon JP. Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block. Arthritis Rheum. 2010;62:11537. [70] Cuneo BF, Ambrose SE, Tworetzky W. Detection and successful treatment of emergent anti-SSA-mediated fetal atrioventricular block. Am J Obstet Gynecol. 2016;215:527-8. [71] Kan N, Silverman ED, Kingdom J, Dutil N, Laskin C, Jaeggi E. Serial echocardiography for immune-mediated heart disease in the fetus: results of a risk-based prospective surveillance strategy. Prenat Diagn. 2017;37:375-82. * [72] Cuneo BF, Sonesson SE, Levasseur S, Moon-Grady AJ, Krishnan A, Donofrio MT, et al. Home Monitoring for Fetal Heart Rhythm During Anti-Ro Pregnancies. J Am Coll Cardiol. 2018;72:1940-51.
31 Table 1. Citation
Methodology
CHB HCQ
CHB No HCQ
P value
Izmirly,
Case-Control
7/50 (14%)
56/151 (37%)
0.10
Historical Cohort
3/40 (7.5%)
46/217 (21.2%)
0.05
Chart Review
1/14 (7%)
7/19 (35%)
0.09
Prospective Cohort
1/18 (6%)
6/22 (27%)
0.10
Retrospective Cohort
1/73 (1%)
12/195 (6%)
0.20
Rash HCQ
Rash No HCQ
20/122 (16%)
146/434 (34%)
Ann Rheum Dis, 2010 Izmirly, Circulation, 2012 Tunks, Am. J. Ob Gyn, 2013 Martínez-Sánchez, Immunol. Res,2017 Barsalou, Rheumatology, 2017
Barsalou,
Case-Control
Ann Rheum Dis, 2018
Table 1. Published studies evaluating the efficacy of HCQ in neonatal lupus.
< 0.01
S1521-6934(19)30132-4
DOI:
https://doi.org/10.1016/j.bpobgyn.2019.09.001
Reference:
YBEOG 1973
To appear in:
Best Practice & Research Clinical Obstetrics & Gynaecology
Received Date: 1 August 2019 Accepted Date: 9 September 2019
Please cite this article as: Wainwright B, Bhan R, Trad C, Cohen R, Saxena A, Buyon J, Izmirly P, Autoimmune-Mediated Congenital Heart Block, Best Practice & Research Clinical Obstetrics & Gynaecology, https://doi.org/10.1016/j.bpobgyn.2019.09.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
1 Author query Add reference numbers to table 1
Autoimmune-Mediated Congenital Heart Block
Benjamin Wainwright1, Rohit Bhan1, Catherine Trad1, Rebecca Cohen1, Amit Saxena1, Jill Buyon1, Peter Izmirly1* 1
NYU School of Medicine, New York, NY, USA
*
Benjamin Wainwright Address: 550 1st Ave., MSB 611 New York, NY 10016 Email: [email protected] Phone: 212-263-0743
2 ABSTRACT Autoimmune-mediated congenital heart block (CHB) is a severe manifestation of neonatal lupus in which conduction tissues of the fetal heart are damaged. This occurs due to passive transference of maternal Ro (SSA) and La (SSB) autoantibodies, and subsequent inflammation and fibrosis of the atrioventricular (AV) node. Notably, the disease manifests after the fetal heart has structurally developed, ruling out other anatomical abnormalities that could otherwise contribute to block of conduction. Complete AV block is irreversible and the most common manifestation of CHB, though other cardiac complications such as endocardial fibroelastosis (EFE), a dilated cardiomyopathy, or valvular insufficiency have been observed. In this review, we will detail the classification, prevalence, pathogenesis, and clinical management recommendations for autoimmune CHB.
Keywords: congenital heart block; anti-SSA/Ro autoantibodies; neonatal lupus
3 INTRODUCTION Though the collection of disease pathologies referred to as neonatal lupus can manifest in a number of different ways, autoimmune congenital heart block (CHB) is the most severe diagnosis, bearing a mortality rate of approximately 18% and requiring pacemaker implantation in 70% of survivors [1]. In addition to cardiac complications, neonatal lupus includes cytopenias, cutaneous rash, liver damage, and neuropsychiatric impairment occurring to the child in utero or shortly after birth [2-5]. All of these complications are ascribed to the passive transference of maternal autoantibodies to Ro and La during pregnancy.
Antibodies to Ro and La can transfer to a fetus as early as 11 weeks and are primarily responsible for the observed damage to conduction tissues in the heart [1, 6]. Hearts affected by autoimmune CHB have been shown to present with inflammation, fibrosis, and calcification of the AV node leading to a block in conduction signal [7-9]. This damage occurs after the fetal heart has developed, supported by the lack of structural and anatomical abnormalities observed in CHB hearts. Babies affected by autoimmune CHB predominantly present with complete AV block (also known as third-degree block). The result of the inflammatory response is a significant reduction in fetal ventricular heart rate, as low as 50-70bpm whereas normal is 120160bpm [10].
In this review, we will summarize the different presentations of autoimmune-mediated CHB, including complete heart block, cardiomyopathy, and endocardial fibroelastosis (EFE). We also address the autoantibodies linked to CHB and their proposed mechanism of action. Lastly, we address the clinical management of this disease.
4
PREVALENCE/EPIDEMIOLOGY Autoimmune CHB occurs nearly exclusively in infants whose mothers have autoantibodies to Ro/SSA, most frequently in conjunction with La/SSB. The incidence in the total population of Finland is approximately 1 in 15,000 live births [11]; in a second population-based study, the incidence of autoantibody-related CHB in Stockholm County was approximately 1 in 23,300 [12]. Among the population of patients with Ro antibodies, the risk of having a child with CHB is roughly 2% [13-15]. In Ro-positive mothers who previously had a child affected by cardiac neonatal lupus, the risk of recurrence can approach 19% [1, 16, 17].
Although the association of CHB to autoimmunity is well documented [18-20], active autoimmune disease in the mothers is not a requirement for CHB. Data from the Research Registry for Neonatal Lupus (RRNL) shows that mothers can have SLE, Sjögren’s Syndrome (SS), undifferentiated autoimmune syndrome (UAS), or be completely asymptomatic and still have a child with CHB [21]. In many cases, the mother is unaware she even carries Ro and/or La antibodies prior to the diagnosis of neonatal lupus in an affected child [6, 21].
On a population level, the presence of Ro antibodies in female blood donors has been reported at 0.20% - 0.86% [22, 23]. The prevalence of Ro antibodies specifically is likely even higher, as these approximations were derived from patients who were initially positive for antinuclear antibodies and then tested for Ro antibodies. In patients with SLE the prevalence of Ro antibodies is estimated at 40%, and it is between 60%-100% for patients carrying a diagnosis of SS [24, 25]. Based on the National Vital Statistics Reports, in 2015 there were 3,978,497 live
5 births. Using the estimated prevalence for Ro antibodies of 0.9% and cardiac neonatal lupus of 2%, there could be as many as 700 cases of CHB in a given year. Therefore, though thousands of women could be at risk of having a child with cardiac neonatal lupus, evaluation of Ro and La antibodies are not included in routine prenatal testing.
AUTOANTIBODIES Autoantibodies to Ro and La target the Ro/La ribonucleoprotein complex (52 kD Ro, 60 kD Ro, and 48 kD La). These antibodies are transported across the placenta into fetal circulation facilitated by FcγRn. Both in vitro and in vivo studies provide evidence for the role of Ro and La autoantibodies in pathogenesis [26, 27], as do clinical and epidemiological studies. Antibodies specific for the Ro autoantigen are capable of recognizing one or both isoforms of Ro (52 kD and 60kD). It has been suggested that antibodies to Ro52 are responsible for cardiac injury [28], further supported by the observation that Ro52 antibodies are found more frequently than Ro60 antibodies [20].
Evidence posits a specific epitope on Ro52 (amino acids 200-239, coined p200) as a serological biomarker for increased risk of autoimmune CHB [29]. While the prevalence of anti-p200 antibodies in mothers of children with CHB is well documented, whether or not anti-p200 antibodies can be accurately used as a risk stratification tool for predicting autoimmune CHB remains unclear [30].
Importantly, not all mothers with Ro antibodies run the same risk of having a child with autoimmune CHB. Several studies have shown that the serum levels of Ro and La antibodies are
6 significantly higher in mothers whose children were affected by autoimmune CHB compared to mothers of unaffected children [20]. There is preliminary evidence suggesting that titers of Ro may be a tool to predict risk of autoimmune CHB [31].
It should be noted that there are only 14 cases of La-mediated autoimmune CHB in the published literature [20]. Similar to Ro antibodies, the serum levels of La antibodies have been shown to be significantly higher in affected mothers compared to non-affected mothers. While these cases are intellectually fascinating, they represent <1% of known autoimmune CHB cases, and thereby should not be used as a biomarker to predict autoimmune CHB.
In mothers with children affected by CHB, other autoantibodies are often detected during evaluation for autoimmunity. These include anti-dsDNA and anti-Smith antibodies in SLE, rheumatoid factor in Rheumatoid Arthritis and Sjögren’s Syndrome, and anti-RNP antibodies in Mixed Connective Tissue Disease. At the time of an autoimmune CHB diagnosis, not all mothers fulfill criteria and are thereby not diagnosed with an autoimmune disease. Review of the literature has shown more than half of mothers affected by autoimmune CHB are asymptomatic despite carrying autoantibodies to Ro and La [20]. It is worth noting that there are a few cases in the literature about anti-RNP-associated CHB in the absence of anti-SSA/Ro [25, 32]. Clinicians should consider testing for this antibody in cases who have CHB and do not have anti-SSA/Ro and/or SSB/LA.
MECHANISM OF ACTION
7 The exact mechanism by which Ro/La autoantibodies mediate cardiac injury is unclear. For example, monozygotic twins discordant for the CHB phenotype imply a complexity to disease pathogenesis beyond a mother carrying Ro/La antibodies [33]. This could include fetal genetics, the environment, and other factors.
Antibody-mediated cardiac damage A major challenge in examining the pathophysiology of CHB is explaining the mechanism by which maternal autoantibodies initiate injury to antigen sites that are normally intracellular. One hypothesis is that Ro/La antigens translocate to the surface of cardiomyocytes undergoing normal physiological remodeling, allowing these antigens to be accessed by autoantibodies in circulation and triggering subsequent immune responses [34]. Further, in vitro studies have demonstrated that normal fetal cardiocytes are able to phagocytose apoptotic cardiocytes; immune complex formation on phagocytic cardiocytes may impair their clearance by healthy cardiocytes, hindering a function critical to normal fetal heart development [35]. Indeed, histologic evaluation of normal fetal hearts show virtually no apoptotic cells, whereas hearts of fetuses dying with CHB show exaggerated apoptosis [36]. In turn, the apoptotic cells lead to infiltration by macrophages, the subsequent activation of which causes the release of proinflammatory and fibrotic cytokines such as TNFα and thus results in tissue damage and fibrosis [37].
Another non-mutually exclusive hypothesis suggests there is cross reactivity of Ro antibodies with L-type calcium channels (LTCC) on the surface of cardiomyocytes, disrupting calcium homeostasis and producing abnormalities in conduction [38]. LTCC is critical to the generation
8 of action potential in the sinoatrial and atrioventricular nodes, both of which are prone to injury resulting from neonatal lupus. Another study showed that mouse pups develop sinus bradycardia and heart block when passively immunized to Ro/La antibodies. Further, overexpression of LTCC could rescue the heart block phenotype upon exposure to Ro/La antibodies, suggesting that these antibodies adversely impact LTCC function [39].
Low penetrance of autoimmune CHB in mothers with Ro/La antibodies may indicate protective factors in the fetus. β2-GPI has been shown to bind to apoptotic fetal cardiomyocytes in a dosedependent fashion and prevent opsonization of apoptotic cardiomyocytes by maternal Ro60 IgG [40]. Further, umbilical cord blood of neonates affected by autoimmune CHB showed significantly lower levels of β2-GPI compared to unaffected neonates, suggesting that β2-GPI may be protective to a fetus in a Ro-antibody exposed pregnancy [40].
Further, hearts from fetuses dying of autoimmune CHB showed exaggerated apoptosis compared to electively terminated fetal hearts. Apoptosis was accompanied by increased TGF-β immunoreactivity in the extracellular matrix and infiltrating macrophages [36]. Increased SMAc staining of transdifferentiating myofibroblasts and increased collagen expression in cardiac fibroblasts were shown to be consequences TGF-β activation.
Evaluating maternal and cord levels of prospective biomarkers has proven challenging, but analysis of mothers and infants in the Research Registry for Neonatal Lupus has provided avenues for future exploration. Drawing from the literature on inflammation and fibrosis in CHB and similar conditions, levels of the following potential biomarkers were evaluated in 135
9 maternal serum samples and 139 cord serum samples, 59 of which were from cases of advanced block: C-reactive protein (CRP); NT-pro-B-type natriuretic peptide (NT-proBNP); troponin I; matrix metalloproteinase (MMP)-2; urokinase plasminogen activator (uPA); urokinase plasminogen activator receptor (uPAR); plasminogen; and vitamin D [41]. Regardless of maternal medications and rheumatic disease diagnosis, increased levels of cord CRP, NTproBNP, MMP-2, uPA, uPAR, and plasminogen were associated with CHB manifestations. The investigators concluded that MMP-2 and uPA/uPAR/plasminogen pathway could serve as clues for future treatment given their known associations with inflammation, and monitoring levels of CRP and NT-proBNP after birth could provide prognostic information regarding heart deterioration in early life.
Nonetheless, linking anti-Ro autoantibodies to the maternal inflammatory profile has remained challenging. Despite the fact that rheumatic diseases commonly associated with anti-Ro also show significantly elevated levels of interferon alpha (IFNα) [42, 43], research has only recently turned to investigating the ways in which the IFN profile might affect the maternal-fetal dyad in CHB. In one pivotal study, it was determined that IFNα levels were significantly higher in antiRo positive pregnant women whose fetuses were affected by CHB than their counterparts with the same antibody profile but healthy pregnancies (though the authors were not able to test IFN levels in the infants themselves via cord blood) [44]. The same study showed that sialic acid binding Ig like lectin 1, a protein responsive to IFN also known as sialoadhesin or SIGLEC-1, was similarly upregulated in CHB mothers.
10 Given that increased monocyte levels of SIGLEC-1 are a known biomarker for lupus activity [45] and its upregulation has been linked with fibrotic autoimmune diseases such as systemic sclerosis [46], Clancy et al. investigated its genetic and protein expression profile in CHB [47]. Compared to electively terminated controls, heart tissue from fetuses dying with CHB showed significantly increased SIGLEC-1 expression (among other IFN stimulated genes), and histologic evaluation of the septal cross-sections confirmed the presence of SIGLEC-1’s corresponding protein in CHB hearts. Taken together, these studies strongly posit anti-Ro autoantibodies, IFN, and downstream inflammatory consequences as primary mediators of this complex immune response, leading to fibrotic damage in fetal conduction tissues.
Genetic Contributions to Autoimmune CHB Examining the role of genetics in autoimmune CHB was initially based on the finding that a variant of the TNF-α promoter (rs1800629), associated with increased cytokine production, was found to be significantly increased in all family members of a child with autoimmune CHB compared to population controls [48]. Moreover, a polymorphism in the TGF-β gene associated with increased fibrosis was significantly higher in children with autoimmune CHB compared to controls and unaffected offspring [48]. Given that fetal hearts dying with CHB consistently demonstrate an inflammatory infiltrate, these polymorphisms warrant further investigation.
A genome-wide association study of 116 autoimmune CHB-affected children of European ancestry and 3,351 controls was conducted to investigate novel genetic associations with disease. The most significant associations were found in the human leukocyte antigen (HLA) region at 6p21.3 [49]. The strongest association was found at rs3099844, near the class-III major
11 histocompatibility complex (MHC) region and 94 kb from the TNF-α gene containing the rs1800629 polymorphism. Moreover, a cluster of SNPs at 21q22 were in proximity to the REGETS2/WDR4 transcription factor, which can slow apoptosis and inflammation, repress IL-8 expression, and is involved in augmenting the expression of TGF-β receptor type 2 [49]. Further study within this region has shown that the C2 epitope of HLA-C is significantly enriched in children with CHB compared with their unaffected siblings, potentially implicating an impairment in normal natural killer cell function in this disease’s pathogenesis [50].
AUTOIMMUNE HEART BLOCK AND OTHER CLINICAL MANIFESTATIONS CHB covers a spectrum of severity ranging from first-degree block (prolonged PR interval) to second and third-degree block (fibrosis at the AV node blocking conduction). Despite the difference in severity, all manifestations are strongly associated with maternal anti-SSA/Ro autoantibodies. Importantly, CHB is predominantly diagnosed during pregnancy, and typically within a specific timeframe. Isolated cases have been reported as early as 16 weeks, though a systematic review showed that 75% of cases were diagnosed during weeks 20-29 [20].
There is discordant data as to whether first-degree block progresses to complete heart block (i.e., third degree), in part due to the cutoffs and measurements used for normal ranges. A recent study based on serial echocardiograms of 156 anti-SSA/Ro exposed fetuses concluded that first degree block does not reliably predict progressive heart block [51]. However, progression from first or second-degree block to complete block has been reported [52]. Presently, third-degree block is not reversible.
12 Although AV block is the most common form of autoimmune CHB (sometimes being used interchangeably), other electrophysiological abnormalities have been reported. These include sinus node dysfunction, ventricular and junctional tachycardia, long QT interval, atrial flutter, valvular disease, and dilated cardiomyopathy [20, 53]. However, reliably associating these disease pathologies with the presence of maternal anti-Ro and anti-La antibodies has been substantially more challenging.
Endocardial fibroelastosis (EFE) merits particular mention as a form of myocardial fibrosis that is found in 7% of autoimmune CHB children, though a clear association between the two conditions has not been shown. EFE can lead to end-stage heart failure and subsequent death: a prior study showed that babies with EFE had a 51% mortality rate, and those with concomitant cardiomyopathy was 100% [1]. EFE can be detected on echocardiograms by areas of patchy echogenicity on the endocardial surfaces on the fetal heart [20]. Valvular disease is another rare but severe complication of autoimmune CHB, with tensor apparatus dysfunction arising in 1.6% of cases. Echocardiographic studies show patchy echogenicity at the papillary muscle detected between 19-22 weeks involving the tricuspid and mitral valves. Valvular insufficiency developed both prenatally and postnatally, ranging from 34 weeks of gestation to 26 weeks after birth. All babies required urgent valve surgery [54].
Dilated cardiomyopathy (DCM) is the other significant albeit rare cardiac complication found in babies affected by autoimmune CHB that is associated with a high mortality rate [1, 55]. In DCM, the left ventricle is enlarged and weakened, resulting in a decreased ability of the heart to pump blood. DCM can be diagnosed in utero alongside CHB, but also can manifest after birth as
13 postnatal DCM. The risk factors for DCM remain unclear, though a recent study analyzed the prevalence and outcomes of DCM in 187 children with autoimmune CHB. 35 children (18%) were found to have DCM, and 22 (11.8%) died at a median age of 7 years. Further, it was shown that there were two distinct types of DCM: neonatal DCM and late-onset DCM. Hydrops, EFE, and pericardial effusion were all factors associated with neonatal DCM; factors associated with late-onset DCM were non-European origin, pacemaker implantation, and valvular insufficiency. Notably, use of fluorinated steroids had no protective effect against late-onset DCM, and none of the risk factors associated with neonatal DCM were predictive of late-onset DCM [53].
CLINICAL MANAGEMENT OF AUTOIMMUNE CHB Presently, antibody screening for Ro/SSA and La/SSB is not part of routine prenatal care. However, all women carrying a diagnosis of SLE, SS, or UAS should be screened for these antibodies prior to pregnancy or early during pregnancy. This is true particularly for those women who previously had a child with any form of autoimmune CHB or even cutaneous manifestations of neonatal lupus, as will be discussed in the following sections. This is critical as many women whose infants develop neonatal lupus are themselves asymptomatic.
Pregnancy Outcomes Autoimmune CHB carries a mortality rate of 17%-19%, with 70% of deaths occurring in utero [20]. Of the live births, the mean 10-year survival rate was 86%, with a mean gestational age of delivery between 34-37 weeks and a Caesarean section rate of 75%. Fetal echocardiographic risk factors associated with mortality included EFE, hydrops, earlier diagnosis of CHB, and decreased ventricular rate. Analysis of deaths in the RRNL showed that severe cardiomyopathy
14 was the cause of death in two-thirds of cases. Compared to isolated cases of autoimmune CHB, the mortality rate was greater than 50% in babies with concomitant EFE or DCM, and was 100% in babies with both EFE and DCM [20].
By age 10, the probability of CHB-affected children requiring a pacemaker was approximately 70%. Almost all children were paced within the first year of life and nearly two-thirds were within 10 days of birth [20]. A significant challenge for pediatric cardiologists treating CHBaffected children is determining which patients require pacemaker implantation, and at what age a pacemaker should be introduced [56].
In addition to increased risks of cardiac events later in life, however, children with CHB appear to face worse outcomes in other aspects of their health as well. A recent paper using the Swedish National Patient Register looked at long term outcomes in patients with congenital heart block and found that affected individuals had a significantly increased risk of cardiovascular comorbidity and a higher risk of infections [57]. They also noted an increased risk for a systemic connective tissue disorder. Accordingly, close follow-up is required for all children affected by autoimmune CHB.
Therapy Recommendations Fluorinated steroids such as dexamethasone cross the placenta and have the potential to mitigate inflammation in autoimmune-CHB affected children, but there are conflicting reports regarding the drug’s efficacy for either treatment or prophylaxis. Jaeggi et al. investigated the use of dexamethasone and β-agonists on fetuses with complete atrioventricular block (as measured by
15 heart rates less than 55bpm) [58] and concluded that CHB-affected fetuses treated with both dexamethasone and β-agonists had improved survival at one year and reduced morbidity. However, data from the RRNL showed that fluorinated steroids did not prevent disease progression, improve survival, or delay pacemaker placement when given shortly after the detection of isolated advanced block [59]. Other groups later confirmed the finding that in isolated cases of autoimmune CHB, prenatal corticosteroid treatment showed no significant difference for in utero progression, survival to birth, pacemaker implantations, or long-term DCM [53, 60]. Thus, though dexamethasone has been proposed as a potential therapeutic for CHB and is often given when block is detected, mounting evidence from the US, France and the Netherlands have shown that fluorinated steroids have no significant effect in improving fetal outcomes when prescribed alone and some have now questioned their use [59-62].
A recent study evaluated the outcomes of autoantibody-mediated fetal cardiomyopathy/EFE following treatment with IVIG and corticosteroids [63]. Twenty affected patients were referred at a median gestational age of 23 weeks with atrioventricular block. IVIG was administered at 1g/1kg between one and three times. The results indicated that 16 of 20 (80%) of patients were alive at median follow-up of 2.9 years, with none requiring cardiac transplantation. Though the study did not identify the ideal schedule or dosage for administration of IVIG, it suggests the drug could in fact be efficacious after further investigation.
Because it is known to inhibit Toll-like receptor signaling, hydroxychloroquine (HCQ) has been proposed as a potential preventive for autoimmune CHB (Table 1). A case-control study explored the hypothesis that HCQ might reduce the risk of Ro-mediated cardiac injury [64]. The
16 study was limited to children born to anti-Ro positive mothers with a confirmed diagnosis of SLE, with 50 CHB cases and 151 controls. Seven (14%) CHB-affected children were exposed to HCQ compared to 56 (37%) of the controls. Although HCQ use was not a statistically significant predictor of autoimmune CHB, the study suggested a protective benefit from HCQ [64]. A subsequent study from the RRNL and other registries from France and the U.K. showed that HCQ reduced the recurrence rate by 64% in subsequent pregnancies [65]. These findings were corroborated by Martínez-Sánchez et al., who reported the prevalence of CHB was much lower in patients taking HCQ compared to untreated patients, providing further support for the drug as preventative therapy against CHB [66]. HCQ had a similarly beneficial effect in another symptom of anti-Ro-mediated infant autoimmunity, cutaneous neonatal lupus (NL) [67].
Insert Table 1 here.
Cutaneous NL manifests as a skin rash, most often circling the eyes and spanning the infant’s cheeks across the bridge of the nose, though occasionally other parts of the body are affected simultaneously [3]. The rash clears concurrently with maternal antibodies exiting the neonate’s circulation around eight months of age [68], rarely scarring or leaving permanent skin damage. Though cutaneous manifestations are transient and inarguably less severe than their cardiac counterparts, it bears noting in the context of this review that mothers who give birth to a child with cutaneous neonatal lupus are 6 – 10 times more likely to have subsequent children with CHB [69]. Among 58 mothers enrolled in the Research Registry for Neonatal Lupus who gave birth to a child with cutaneous NL, the disease recurred in 23 (29.9%) of 77 subsequent pregnancies, and 14 (18.2%) were affected by CHB. Accordingly, mothers of infants with
17 neonatal lupus rashes should be counseled about their increased risk of CHB in future pregnancies, as these mothers might even be unaware of their anti-Ro status.
Given the evident epidemiological and pathological connections between cutaneous and cardiac NL, recent research has investigated whether or not HCQ’s efficacy in CHB can be translated to preventing rash as well. In a case-control study of anti-Ro positive mothers with confirmed systemic autoimmune diagnoses (including systemic lupus erythematosus and Sjögren’s syndrome, among others), investigators found that HCQ was used in 34% of pregnancies that resulted in healthy infants (146/434) compared to only 16% of infants who developed a rash (20/122), showing that the drug is significantly associated with a reduction in cutaneous NL incidence (OR 0.4 [95% CI 0.2 to 0.6]; p<0.01) [67]. Infants exposed to the drug in utero also trended (p=0.21) towards developing the rash later after birth than their unexposed counterparts.
Based on these and other limited but encouraging results, a prospective, open label study was initiated using Simon’s two-stage design to determine whether HCQ significantly reduces the risk of recurrent CHB. To ensure all enrollees were of sufficiently high titer to be at risk, participants were eligible only if they had previously experienced a pregnancy affected by antiRo-mediated cardiac manifestations. The study is currently enrolling with the goal of 54 total patients (https://clinicaltrials.gov/ct2/show/NCT01379573).
Monitoring for CHB All pregnant women who carry Ro and/or La antibodies are considered to be high risk, particularly those who have previously had a child with autoimmune CHB or neonatal lupus.
18 These women should be referred to an obstetric unit specialized in high-risk pregnancies. While first-degree block may be detected via auscultation, some manifestations of CHB, including more advanced block and extranodal disease, can be undetectable without additional testing. Though slightly more burdensome, fetal echocardiograms are a safe, noninvasive method of screening for CHB. Accordingly the current standard of care mandates weekly echocardiograms for all women managing anti-Ro pregnancies within the window of vulnerability for CHB (i.e., weeks 16 – 26).
However, recent studies have called the practicality of weekly echocardiograms into question. Treatment efficacy for first-degree block is currently controversial, rendering an early diagnosis as possibly another source of maternal stress, and even complete block can arise within 24 hours [70]. Further complicating management strategies, evidence suggests that prompt treatment of second degree block with corticosteroids and IVIG in conjunction can reverse the diagnosis and revert the fetus back to normal sinus rhythm [71]. As a supplementary surveillance technique, Cuneo et al. have proposed fetal heart rate and rhythm monitoring (FHRM), a process by which the pregnant person self-evaluates every 12 hours using a handheld Doppler; should any abnormality be discovered, the patient is seen for an urgent confirmatory echo followed by treatment with dexamethasone and/or IVIG [70].
The FHRM pilot study evaluated 273 completed anti-Ro pregnancies, with mothers detecting one case of second degree block and two cases of third [72]. Throughout the course of the study, there were 21 perceived aberrant rhythms, three of which were confirmed to be heart block. Upon confirmatory echo, the rest of the 21 rhythms were premature atrial contractions (6),
19 repeated sinoatrial arrest (1), and normal sinus rhythm (11). Ultimately the second-degree case responded to treatment and regressed to normal sinus rhythm at birth, but there was unfortunately no improvement in the more advanced cases. It is worth noting, however, that these cases did not receive a confirmatory echo and treatment until more than 24 hours elapsed; further research will be required to know if prompter treatment can avert adverse outcomes.
As for feasibility, only six of the participants did not complete the course of home monitoring per the protocol, four of which were due to the protocol design per se (one experienced unmanageable stress, and three felt the process was unduly time-consuming); one terminated her pregnancy due to extremely low gestational weight, and the final participant was lost to followup [72]. Within this cohort there was a 5% false positive rate, but the false negative rate was 0% - i.e., no mothers failed to detect an irregular rhythm that led to a cardiac event. Thus, preliminary FHRM data suggest that the increased surveillance can detect and treat fetuses with second degree block, improving outcomes at birth without creating a large burden of unnecessary urgent echos for health care providers.
Practice Points •
Current data on HCQ suggest it may reduce the likelihood of developing CHB.
•
Recent data on fluorinated steroids do not show an improvement in mortality.
•
A handheld Doppler has shown preliminary efficacy as a screening method to supplement weekly echocardiograms.
Research Agenda
20 •
There is an ongoing prospective study evaluating whether HCQ reduces the recurrence rate of CHB.
•
Further evidence is being sought regarding the efficacy of prompt IVIG and dexamethasone administration within 12 hours of CHB detection.
•
Recent research into the pathophysiology of CHB suggest that it may be interferonstimulated.
ACKNOWLEDGEMENTS: The Research Registry for Neonatal Lupus was supported by NIH/NIAMS AR042220 and AR42271; it is currently ongoing through private philanthropy.
Conflicts of Interest The authors have no conflicts of interest.
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31 Table 1. Citation
Methodology
CHB HCQ
CHB No HCQ
P value
Izmirly,
Case-Control
7/50 (14%)
56/151 (37%)
0.10
Historical Cohort
3/40 (7.5%)
46/217 (21.2%)
0.05
Chart Review
1/14 (7%)
7/19 (35%)
0.09
Prospective Cohort
1/18 (6%)
6/22 (27%)
0.10
Retrospective Cohort
1/73 (1%)
12/195 (6%)
0.20
Rash HCQ
Rash No HCQ
20/122 (16%)
146/434 (34%)
Ann Rheum Dis, 2010 Izmirly, Circulation, 2012 Tunks, Am. J. Ob Gyn, 2013 Martínez-Sánchez, Immunol. Res,2017 Barsalou, Rheumatology, 2017
Barsalou,
Case-Control
Ann Rheum Dis, 2018
Table 1. Published studies evaluating the efficacy of HCQ in neonatal lupus.
< 0.01