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Rheumatology Advance Access originally published online on July 10, 2007
Rheumatology 2007 46(8):1221-1222; doi:10.1093/rheumatology/kem148
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIALS

Predicting autoimmune congenital heart block: is it feasible and how?

A. G. Tzioufas and H. M. Moutsopoulos

Department of Pathophysiology, Medical School, University of Athens, Greece

Correspondence to: A. G. Tzioufas. E-mail: agtzi{at}med.uoa.gr

Autoimmune congenital heart block (CHB) is the most serious complication of neonatal lupus syndrome (NLS), a rare disorder afflicting fetuses of mothers with circulating autoantibodies to Ro/SSA and La/SSB ribonucleoproteins. The syndome is considered a model of passively acquired autoimmunity since during pregnancy maternal autoantibodies are transferred across the placenta, bind onto tissues of the developing fetus and eventually produce the pathology of NLS. NLS develops in 2–5% of fetuses of Ro/SSA and La/SSB autoantibody-positive pregnant women. Two thirds of mothers have Sjögren's syndrome, systemic lupus erythematosus or undifferentiated connective tissue disease and the remainder are asymptomatic. Although NLS can affect the skin, liver, blood cells and heart, almost all extra-cardiac manifestations subside when the maternal autoantibodies are cleared from the circulation of the offspring [1]. NLS has certain characteristics that distinguish it from other autoimmune diseases. These include a unique causative factor (antibodies against Ro/SSA and La/SSB), well-defined study population, short observation period for initiation of the autoimmune tissue injury and finally a relatively short follow-up time compared to other autoimmune diseases. These features may allow the design of studies, functional or immunological, to identify specific predictors associated with development of the syndrome.

Functional studies

Functional studies aim to determine predicting factor(s) for heart involvement in high-risk pregnancies of women positive for anti-Ro/SSA and/or anti-La/SSB antibodies. Cardiac involvement and particularly permanent congenital heart block is, by far, the most serious manifestation of NLS. CHB without structural cardiac abnormalities affects 1/20 000 neonates in the general population [2], and virtually all cases are associated with maternal autoantibodies to Ro/SSA and La/SSB. It usually appears during the 18–24 week of gestation and manifests as fetal bradycardia. Deposition of antibodies and complement components, lymphocytic infiltrates, as well as fibrosis and micro-calcifications are common histological findings in the affected fetal heart, resulting in CHB. The perinatal mortality of affected fetuses is around 30% [3] or even higher when CHB is associated with endocardial fibroelastosis (EFE) or cardiomyopathy [4–6]. The latter findings appear to be the worst outcome variables. A carefully performed retrospective study has suggested that EFE may occur despite adequate ventricular pacing and be associated with significant mortality. This finding implies a similar pathogenetic mechanism rather than a CHB related sequel. However, these observations will need confirmation by prospective studies.

The majority of living children need permanent pacemakers [7]. Evaluation of fetuses by echocardiograms in shorter intervals or pulsed Doppler-derived PR interval measurements has shown that CHB can be of first, second or third degree. In this issue, Gerosa et al. [8] report the results of a four-centre study of electrocardiographic abnormalities in fetuses of 96 pregnant women with autoimmune diseases (of whom 60 had anti-Ro/SSA antibodies). They found that 2/60 anti-Ro/SSA positive children had 2nd or 3rd degree CHB—a finding similar to those reported previously—whereas a rather high proportion had transient 1st degree heart block (as attested by the PR prolongation time). Interestingly, children of anti-Ro/SSA negative mothers had the same frequency of 1st degree related abnormalities. Although the study did not include a normal control population of similar gestational age, the PR intervals were more prolonged in early gestational ages, compared to late pregnancy or at birth. Also it should be noted that the threshold for PR prolongation in this study was set at 140 ms, whereas in other studies varied from 135 ms [9] to 150 ms [10].

Definition and identification of 1st degree CHB block is of particular importance, mainly for two reasons: (i) it might very well indicate that the disease process is already underway and, therefore, serve as predictive factor for future irreversible damage of fetus heart and (ii) it may prove useful in identifying candidates for early therapeutic intervention. In this regard, Sonesson et al. [9] reported a high frequency of 1st degree CHB (30%) in fetuses of anti Ro52-KD positive mothers. One of the fetuses in this study progressed from first to complete CHB. In a retrospective study, Askanase et al. [11] reported that 9 of 187 children with CHB had a first-degree block that was discovered at birth. The block progressed after birth in four of these children. Four other newborn infants had a second-degree block; in two of them it progressed to a complete heart block. These observations suggest that CHB constitutes a spectrum of disorders, where at least in some cases the disease may start as a first-degree block and end up as a complete block. On the other hand, other authors described a lower frequency of first-degree CHBs [12]. The discrepancy of these results is likely related to differences in defining the upper limit cut-off point for PR. Therefore, a consensus agreement of a ‘pathogenic’ threshold of PR is mandatory for predicting CHB in high risk pregnancies.

Immunological studies

Over the past several years, clinical and experimental studies have convincingly demonstrated the pivotal role of maternal anti-Ro/SSA and/or anti-La/SSB antibodies in the pathogenesis of NLS. More than 90% of mothers have circulating autoantibodies to one or more RoRNP protein components such as Ro60Kd, La or Ro52Kd and the majority of them have autoantibodies against all three [1, 13]. CHB occurs in ~2% of anti-Ro/SSA positive mothers but in presence of anti-La/SSB antibodies the risk of CHB increases to 5% [14]. In subsequent pregnancies, the recurrence rate of CHB increases 9 to 10-fold compared to risk for CHB in a primigravida with anti-Ro/SSA and/or anti-La/SSB antibodies [15]. This indicates that ‘pathogenic’ autoantibodies may still be present but also other factors contribute to disease expression. A recent study demonstrated that clearance of apoptotic cardiocytes opsonized by maternal autoantibodies, from resident cardiocytes was largely impaired, leading to accumulation of apoptotic cells, inflammation and ultimately to tissue injury [16].

The ultimate goal of prediction is to define high or low risk groups of mothers, prior to pregnancy. Disease predictors linked tightly with a particular autoantibody system, such as NLS, can be generated from two sources: (i) the autoantibody population and (ii) regulatory mechanisms involved in perpetuation of the autoimmune response. The summary of data presented in the opening lines of this section suggests that the fine specificity of antibodies binding onto the affected heart, as well as the regulation of their production are particularly important for definition of putative predictive factors. Recent observations have shown that transferred anti Ro52Kd antibodies, targeting a particular epitope spanning the region 200–239aa, termed p200, may initiate cardiac injury in NLS by binding to fetal cardiomyocytes and inducing apoptosis by calcium imbalance [17]. The presence of anti-p200 as a dominant epitope of anti-Ro52 response was also confirmed in 156 anti-Ro52 positive sera but this study failed to disclose any relation with CHB [18]. Another recent study revealed a preferential recognition of antibodies to different components of RoRNP proteins in different phases of apoptosis in Jurkat and HeLa cells [19], but this study did not use apoptotic cardiocytes. The use of autoantibodies as predictive tools is hampered because important information is still missing. In fact, systematic epitope mapping studies involving autoantibody fine patterning, post-translational modification of autoantigens, that is known to occur in autoimmune lesions [20], the characterization of the relative avidity of pathogenic autoantibodies and most importantly the investigation whether these autoantibodies are presented in non-pregnant women are still largely unknown.

An important regulatory mechanism involved in perpetuation of antibody response is through anti-idiotypic antibodies. Anti-idiotypic antibodies react with idiotypes within the F(ab)2 fragment of antibodies through complementary interactions contributing to homeostasis of the adaptive immune response [21]. Anti-idiotypic antibodies have been described in association with a variety of autoantibodies, but their role in autoimmune diseases, as well as their overall clinical utility, has been largely unexplored. The main reason is the difficulty in isolating and handling anti-idiotypic antibodies from autoimmune sera, where a diverse autoimmune response against different B-cell epitopes occurs. Epitope mapping studies revealed structures within the autoantigens that have two characteristics: they are recognized preferentially by autoantibodies in the majority of patients’ sera and exhibit high affinity for the epitope. These tools enabled studies in a narrowed spectrum of circulating autoantibodies from patients with different autoimmune diseases [22]. Complementary epitopes have the potential to adopt structures that are complementary to B-cell epitopes and mimic the shape of the paratopes of the antibodies recognizing these epitopes. Therefore, complementary peptides can be efficiently used for detection of anti-idiotypic antibodies. Previous studies in our laboratory [23] disclosed that: (i) both major B-cell epitopes 289–308 and 349–364 of La/SSB and their complementary epitopes are recognized by sera containing anti-La/SSB antibodies, (ii) highly purified antibodies to these complementary epitopes are anti-idiotypic antibodies binding onto the F(ab)2 fragment of antibodies to epitopes of La/SSB, and (iii) by using the complementary epitopes as inhibitors of the anti-idiotypic antibodies, the anti-La/SSB reactivity can be recovered in anti-Ro/SSA-positive, anti-La/SSB-negative autoimmune sera. Using this approach in sera of anti-Ro/anti-La positive women during pregnancy or within 6 months after delivery, Stea et al. [24] demonstrated that mothers giving birth to a healthy child and having no history of a child with NLS exhibited a statistically significant higher anti-idiotypic antibody activity compared with mothers carrying a child with NLS. These results suggest that anti-idiotypic antibodies to autoantibodies against La/SSB may protect the fetus by blocking pathogenic maternal autoantibodies. Furthermore, testing for these anti-idiotypic responses might be useful in predicting a decreased risk of NLS.

In conclusion, these observations point the need for launching large multicentre prospective studies involving sequential sera from women before, during pregnancy and after the delivery as well as other epitopes (as for example, the epitope p200 of Ro52KD) which will address the predictive value of anti-idiotypic antibodies in NLS. Furthermore, the use of complementary peptides that trigger the production of anti-idiotypic antibodies to autoantibodies against Ro/SSA and La/SSB might prove an important therapeutic tool for preventing NLS in women with anti-Ro/SSA and anti-La/SSB autoantibodies.

The authors have declared no conflicts of interest.

References

  1. Buyon JP, Rupel A, Clancy RM. Neonatal lupus syndromes. Lupus (2004) 13:705–12.[Abstract/Free Full Text]
  2. Michaelsson M, Engle MA. Congenital complete heart block: an international study of the natural history. Cardiovasc Clin (1972) 4:85–101.[Medline]
  3. Waltuck J, Buyon JP. Autoantibody-associated congenital heart block: outcome in mothers and children. Ann Intern Med (1994) 120:544–51.[Abstract/Free Full Text]
  4. Nield LE, Silverman ED, Taylor GP, et al. Maternal anti-Ro and anti-La antibody-associated endocardial fibroelastosis. Circulation (2002) 105:843–8.[Abstract/Free Full Text]
  5. Jaeggi ET, Hamilton RM, Silverman ED, Zamora SA, Hornberger LK. Outcome of children with fetal, neonatal or childhood diagnosis of isolated congenital atrioventricular block. A single institution's experience of 30 years. J Am Coll Cardiol (2002) 39:130–7.[Abstract/Free Full Text]
  6. Moak JP, Barron KS, Hougen TJ, et al. Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela. J Am Coll Cardiol (2001) 37:238–42.[Abstract/Free Full Text]
  7. Buyon JP, Hiebert R, Copel J, et al. Autoimmune-associated congenital heart block: demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol (1998) 31:1658–66.[Abstract/Free Full Text]
  8. Gerosa M, Cimaz R, Stramba-Badiale M, et al. Electrocardiographic abnormalities in infants born from mothers with autoimmune diseases: a multicenter prospective study. Rheumatology (2007) 46:1285–9.[Abstract/Free Full Text]
  9. Sonesson SE, Salomonsson S, Jacobsson LA, Bremme K, Wahren-Herlenius M. Signs of first degree heart block occur in one third of fetuses of pregnant women with anti-SSA/Ro 52-kd antibodies. Arthritis Rheum (2004) 50:1253–61.[CrossRef][Web of Science][Medline]
  10. Buyon JP, Askanase AD, Kim MY, Copel JA, Friedman DM. Identifying an early marker for congenital heart block: when is a long PR interval too long? Arthritis Rheum (2005) 52:1341–2.[Web of Science][Medline]
  11. Askanase AD, Friedman DM, Copel J, 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.[Abstract/Free Full Text]
  12. Friedman D, Buyon J, Copel J, Kim M. PR interval and dexamethasone evaluation: an ongoing prospective fetal echocardiographic study in neonatal lupus. I – observational. [Abstract]. Lupus (2004) 13:760.
  13. Wahren-Herlenius M, Sonesson SE. Specificity and effector mechanisms of autoantibodies in congenital heart block. Curr Opin Immunol (2006) 18:690–6.[CrossRef][Web of Science][Medline]
  14. Gordon P, Khamashta MA, Rosenthal E, et al. Anti-52 kDa Ro, anti-60 kDa Ro, and anti-La antibody profiles in neonatal lupus. J Rheumatol (2004) 31:2480–7.[Abstract/Free Full Text]
  15. Brucato A, Frassi M, Franceschini F, et al. Risk of congenital heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis. Arthritis Rheum (2001) 44:1832–5.[CrossRef][Web of Science][Medline]
  16. Clancy RM, Neufing PJ, Zheng P, 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.[CrossRef][Web of Science][Medline]
  17. Salomonsson S, Sonesson SE, Ottosson L, et al. Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block. J Exp Med (2005) 201:11–17.[Abstract/Free Full Text]
  18. Clancy RM, Buyon JP, Ikeda K, et al. Maternal antibody responses to the 52-kd SSA/Ro p200 peptide and the development of fetal conduction defects. Arthritis Rheum (2005) 52:3079–86.[CrossRef][Web of Science][Medline]
  19. Reed JH, Neufing PJ, Jackson MW, et al. Different temporal expression of immunodominant Ro60/60 kDa-SSA and La/SSB apotopes. Clin Exp Immunol (2007) 148:153–160.[Web of Science][Medline]
  20. Stea EA, Routsias JG, Samiotaki M, et al. Analysis of parotid glands of primary Sjogren's syndrome patients using proteomic technology reveals altered autoantigen composition and novel antigenic targets. Clin Exp Immunol (2007) 147:81–9.[Web of Science][Medline]
  21. Jerne NK. Towards a network theory of the immune system. Ann Immunol (1974) 125C:373–89.
  22. Routsias JG, Vlachoyiannopoulos PG, Tzioufas AG. Autoantibodies to intracellular autoantigens and their B-cell epitopes: molecular probes to study the autoimmune response. Crit Rev Clin Lab Sci (2006) 43:203–48.[CrossRef][Web of Science][Medline]
  23. Routsias JG, Touloupi E, Dotsika E, et al. Unmasking the anti-La/SSB response in sera from patients with Sjogren's syndrome by specific blocking of anti-idiotypic antibodies to La/SSB antigenic determinants. Mol Med (2002) 8:293–305.[Medline]
  24. Stea EA, Routsias JG, Clancy RM, Buyon JP, Moutsopoulos HM, Tzioufas AG. Anti-La/SSB antiidiotypic antibodies in maternal serum: a marker of low risk for neonatal lupus in an offspring. Arthritis Rheum (2006) 54:2228–34.[CrossRef][Web of Science][Medline]
Accepted 30 April 2007


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