Clinical Investigator
Clin Investig (1992) 70:492-496
Original ArticJe
© Springer-Verlag 1992
Investigations into Ro-specific antibody-associated congenital cardiac conduction defects T. D6rner 1, F. Hiepe ~, B. G61dner 2, and E. Apostoloff 1 1 Klinik ffir Innere Medizin und z Kinderklinik der CharitY, Humboldt-Universit/it zu Berlin
Summary. Forty-two babies with different congenital cardiac conduction defects, and in 12 cases the mothers, were tested for autoantibodies to Ro, La, U~RNP and Sin. Ro-specific antibodies were detected most frequently. They were to be found in 16 sera from infants and in 8 maternal serum sampies. The occurrence of anti-Ro was associated preferentially with several atrioventricular conduction blocks. The sex relation of anti-Ro associated congential heart block did not show a typical preference (6male/10 female). At the time of giving birth, 5 anti-Ro-positive mothers did not have any clinical symptoms of rheumatic autoimmune diseases. Three of them had a first degree atrioventricular block. Our findings indicate that all pregnant women at risk for anti-Ro like connective tissue disease or cardiac conduction defects should be tested for these autoantibodies because of the suspicion of cardiac conduction abnormalities in the offspring. Anti-Ro-positive infants should be examined for structural heart disease by echocardiography. Key words: Ro(SS-A)-specific autoantibodies Autoantibodies - Neonatal lupus erythematosus Congenital heart block - Systemic lupus erythematosus
In 1977 McCue et al. [21] reported infants with congenital heart block (CHB) who were born to mothers with connective tissue diseases. Looking for characteristics associated with immunologic features, Scott et al. [26] and Reed et al. [24] independently detected a correlation of CHB and maternal Ro-specific antibodies. There are also reports about an association of CHB and isolated Abbreviations: anti-EBV VCA IgG=anti-viral capsid antigens immunoglobulin G; AV = atrioventricular; CHB = congenital heart block; CIE = counter immunoelectrophoresis; EBV = Epstein-Barr virus; N L E = n e o n a t a l lupus erythematosus; S L E = systemic lupus erythematosus
U1RNP-specific [2, 30] and La-specific antibodies [9, 29]. We investigated 42 sera from newborns with CHB and in 12 cases the corresponding maternal serum samples for autoantibodies to Ro, La, Sm and U1RNP in a retrospective study. The coexisting type of cardiac conduction defects were analysed, and all infants were examined for structural heart disease by echocardiography.
Methods Forty-two serum samples from babies (18 male/ 24 female) with isolated congenital cardiac conduction defects and in 12 cases the maternal sera were obtained within 3 months of birth. None of the infants showed symptoms of isolated or associated cutaneous lupus. Sera were selected at the Department of Pediatric Medicine and the Department of Internal Medicine (Charit6 Berlin) from 6/1986 to 8/1991. The mean age of the mothers was 24.17 years (range: 20-30 years) at the end of pregnancy, and only 3 of them suffered from systemic lupus erythematosus (SLE) fulfilling the 1982 revised criteria [28]. Nine mothers did not have any clinical symptoms. Ro-specific antibodies were detected using pig spleen extract in counter immunoelectrophoresis (CIE) as reported [7]. La-, Sin- and U1RNP-specific antibodies were detected using rabbit thymus extract in CIE as described previously [10, 11, 12]. All infants were examined for morphological abnormalities using echocardiography, and each baby and mother were examined using electrocardiography routinely.
Results Ro-specific antibodies were detected in 16 of 42 babies (10 female/6 male) suffering from heart rhythm disorders and in 8 of the 12 maternal sera. The results of autoantibody detection in all 54 serum samples are summarized in Table 1. Ro- and
493 Table 1. Prevalence of La-, U1RNP- and Sin-specific antibodies of 16 infants and 8 mothers with Ro-specific antibodies and 26 babies and 4 mothers without anti-Ro using counter immunoelectrophoresis
Anti-La Anti-UIRNP Anti-Sin
Anti-Ro-positive
Anti-Ro-negative
Babies (n = ] 6)
Mothers (n = 8)
Babies (n = 26)
Mothers (n = 4)
3 0 0
1 1 0
0 0 0
0 0 0
Table 3. Distribution of cardiac conduction defects of 26 antiRo-negative infants and associated individual findings Cardiac conduction defects
Number of patients
Associated findings
First degree of AV heart block
4
1 patient's serum possessed IgArheumatoid factor
Third degree of AV heart block
5
1 patient with anti-viral capsid antigen immunoglobulin G (anti-EBV VCA IgG) 1 case Ebstein's disease 1 case respiratory insufficiency
Transient fetal bradyarrhythmia
9
I case with atrial aneurysm
Sinus arrhythmia and second degree sinuatrial block
1
None
Table 2. Distribution of cardiac conduction defects of 16 anti-
Ro-positive babies and associated individual findings Cardiac conduction defect
Number of patients
Associated findings
First degree of atrioventricular (AV) heart block with bradyarrhythmia
2
None
First degree AV heart block
6
1 patient's serum possessed anti-La
Third degree AV heart block
5
2 patients' sera possessed anti-La
Transient fetal bradyarrhythmia
2
None
Tachyarrhythmia
1
Atrium secundum defect
La-specific antibodies coincided in 3 infant cases and I maternal serum. The distribution of cardiac conduction defects in anti-Ro-positive and -negative infants with associated findings are shown in Tables 2 and 3. Three sera contained Ro- and La-specific antibodies. Two of these cases were infants with third degree atrioventricular (AV) block. In one anti-Ro-positive baby with tachyarrhythmia, an atrium septum secundum defect was found by echocardiography. La-, U1RNP- and Sm-specific antibodies were not detected in the anti-Ro-negative group. Strikingly, the sera of babies without anti-Ro possessed other serological abnormalities like Epstein-Barr virus-specific viral capsid antigens immunoglobulin G (VCA IgG) antibodies in one and IgA rheumatoid factor in another case, respectively. Furthermore, there was one anti-Ro-negative patient with respiratory insufficiency and third degree AV heart block, and 1 infant with transient fetal bradyarrhythmia had an atrial aneurysm. Another
Sinus arrhythmia
4
None
Fetal bradyarrhythmia and ventricular extrasystoles
1
None
Inconstant ventricular extrasystoles
2
None
AV = atrioventricular
baby without anti-Ro suffered from Ebstein's disease with third degree AV heart block. The types of cardiac conduction defects and corresponding antibody prevalence in the 12 mothers and their infants are shown in Table 4. In 6 cases we found Ro-specific antibodies in both the sera of the mother and the baby with congenital conduction defects. One anti-Ro-positive SLE mother with associated first degree AV block gave birth to a baby with a transient fetal bradyarrhythmia (pair 3). The infant's serum did not show Rospecific antibodies. One healthy anti-Ro-positive mother had an anti-Ro-negative child with Ebstein's disease and associated third degree AV block as mentioned above (pair 8). Another antiRo-positive infant with transient fetal bradyarrhythmia had an anti-Ro-negative healthy mother (pair 9). Three mothers' and the corresponding babies' sera did not contain Ro-specific autoantibodies. Discussion In this study we have examined humoral autoimmunological features and the occurrence of congenital cardiac rhythm disorders. Our results underline the diagnostic importance of Ro-specific
494 Table 4. Associated serological findings and cardiac conduction disorders in 12 mother and infant pairs Number of pair
1
Mother
Infant
Autoimmune disease
Cardiac conduction defect
Antibodies against
Sex
Cardiac conduction defect
Antibodies against
SLE
No
Ro, La
Female
AV block III
Ro, La
2
SLE
AV block I
Ro, U 1 R N P
Female
AV block III
Ro
3
SLE
AV block I
Ro
Male
Transient fetal bradyarrhythmia
-
4
No
AV block I
Ro
Male
AV block I
Ro
5
No
AV block I
Ro
Female
AV block I
Ro, La
6
No
No
Ro
Female
AV block III
Ro
7
No
No
Ro
Male
AV block III
Ro
8
No
AV block I
Ro
Female
Ebstein's disease, AV block III
9
No
No
Male
Transient fetal bradryarrhythmia
Ro
10
No
No
Female
Transient fetal bradyarrhythmia
-
11
No
No
Male
Sinus arrhythmia
12
No
No
Male
AV block III
SLE = systemic lupus erythematosus
autoantibodies for cardiac conduction defects in contrast to La-, Sm- and UiRNP-specific antibodies. The infants we examined partly represented a selected group with severe cardiac conduction defects. Electrocardiographically, 13 of 16 anti-Ropositive infants showed AV conduction defects. In contrast, we found only 9 of 26 babies without anti-Ro and coinciding AV blocks. In patients without anti-Ro, other abnormalities involving serological (anti-EBV VCA-IgG, IgA rheumatoid factor), pathomorphological (Ebstein's disease) or pathophysiological (respiratory insufficiency) findings were present. The majority of the anti-Ronegative group was characterized by sinus arrhythmias or ventricular extrasystoles. The sera of this patient group did not contain any other investigated autoantibodies either. The findings support the hypothesis that Ro-specific antibodies preferentially affect the AV myocardiac cells or primarily lead to functional defects at the AV node. Furthermore, we found in 3 healthy and in two SLE mothers a first degree AV block with associated anti-Ro. Logar et al. [19] demonstrated in 36 anti-Ro-positrive adult SLE patients a significantly higher prevalence of conduction defects and myocarditis. The pathogenic mechanisms of Ro-specific antibodies, which may lead to cardiac conduction defects, are not completely clear. Immunohistologically, the Ro antigen was detected in conduction system cells [5, 6, 16], and they could lead to fibrosing alterations of the cardiac conduction
system [14]. Other atrial and ventricular myocardial cells may also be affected [5]. It was postulated that the cardiac damage is caused by anti-Ro [1, 19], and its presence may serve as a marker for heart involvement. La-specific antibodies coincided with anti-Ro in 3 infants' and 1 maternal serum most frequently. Silverman et al. [27] demonstrated that anti-Ro/La define the immune response which is associated with congenital heart block. Strikingly, 5 anti-Ro-positive mothers were healthy and gave birth to infants with conduction disorders. McCune et al. [22] reported the importance of congenital heart block (CHB) infants' birth followed by the manifestation of a SLE/ Sj6gren's syndrome overlap after a 10-year period. Further investigations are necessary to determine if anti-Ro-associated CHB babies and/or electrocardiographic abnormalities are primary signs for an elevated risk for maternal connective tissue disease manifestation. Among the anti-Ro-positive children we found I case of a tachyarrhythmia and atrium septum secundum defect. Previously, several reports described the presence of anti-Ro and ductus arteriosus Botalli persistens, total transposition of the outlet tracts, septum defects and subendocardial fibroelastosis [3, 8, 13, 21]. Machado et al. [20] reported 37 fetuses with complete heart block, 16 with isolated heart block and 21 with coinciding structural heart disease, in a series of 6000 fetal
495
echos done because of a suspicion of different increased risks. Infants with heart block and associated structural abnormalities have an increased mortality compared with those with isolated CHB [4, 201. None of the three SLE cases showed disease activity in pregnancy. One corresponding infant manifested a transient fetal bradyarrrhythmia, but the serum did not possess Ro-specific antibodies in contrast to the maternal serum sample. In our experience anti-Ro-positive SLE mothers could have normal healthy infants (data not shown). On the other hand, an important number of children with CHB or neonatal lupus (NLE) are born of mothers who are prospectively identifiable as having SLE or SLE overlap syndromes [18, 25]. Ramsey-Goldman et al. [23] reported the relative risk of 1:20 for anti-Ro-positive SLE patients and a 14-fold elevated risk of anti-Ro healthy mothers having infants with NLE. One baby of a healthy anti-Ro-negative mother also manifested a transient bradyarrhythmia with coinciding anti-Ro. An explanation could be an anti-Ro de novo synthesis in the child, but different results of anti-U1RNP (pair 2) and anti-La (pair 5) were also found in the corresponding maternal and fetal sera. The question remains whether or not Ro-, Laor U,RNP-specific antibodies can be detected at higher frequencies using enzyme immunoassay and/or immunoblot with their increased sensitivity and different detection conditions. The immunofluorescence pattern only supports the possibility that isolated CHB may be causally related to autoantibodies [15]. Thus, the presence of other hitherto unknown antibodies could play a pathological role. The sex relation in our anti-Ro-positive CHB infants (6 male/10 female) shows no preference of females in contrast to connective tissue diseases. We conclude that the maternal role of antibody production and the placental transport are of outstanding importance in CHB. The comprehensive guidelines for SLE treatment in pregnancy with consideration of the issues has been recently reviewed by Lockshin [17]. After birth, CHB most frequently leads to chronic heart failure. Finally, most of the patients, especially with a third degree AV block, had pacemakers implantated after ineffective drug therapy. In our opinion all pregnant women at risk for anti-Ro like connective tissue disease or cardiac conduction defects should be tested for these autoantibodies because of the elevated risk of having CHB infants. Furthermore, infants, especially in
association with Ro-specific antibodies, should be examined for pathomorphological disorders by echocardiography. In this study we have compared the occurrence of congenital cardiac conduction defects and the association of different maternal and fetal autoantibodies. The diagnostic importance of anti-Ro for congenital cardiac rhythm disorders was documented. La-specific antibodies were detected with anti-Ro most frequently. Further examinations of serological characteristics of pregnant women could help to increase the predictive value for NLE and congenital cardiac conduction defects in the children. Acknowledgement. We are grateful to Miss I. Herbrand for her technical assistance in autoantibody detections.
References 1. Behan WM, Behan PO, Gairns J (1987) Cardiac damage in polymyositis associated with antibodies to tissue ribonucleoprotein. Br Heart J 57:176-180 2. Borenstein DG, Fye WB, Arnett FC, Stevens MB (1978) The myocarditis of systemic lupus erythematosus: association with myositis. Ann Intern Med 89:619-624 3. Chameides L, Truex RC, Yetter V, Rashkind W J, Galioto FM Jr, Noonan JA (1977) Association of maternal lupus erythematodes with congenital heart block. N Engl J Med 297:1204 4. Davison MB, Radford DJ (1989) Fetal and neonatal congenital complete heart block. Aust N Z J Med 150:192-197 5. Deng JS, Sontheimer RD, Gilliams JN (1985) Expression of Ro/SS-A antigen in human skin and heart. J Invest DermatoI 85:412416 6. Deng JS, Bait LW Jr, Shen-Schwartz S, Ramsey-Goldman R, Medsger T Jr (1987) Localization of Ro(SS-A) antigen in the cardiac conduction system. Arthritis Rheum 30 : 1232-1238 7. D6rner T, Hiepe F, Mielke F, Kiessig ST, Lukowsky A, Apostoloff E (1991) Development of a solid phase enzyme immunoassay for the detection of anti-Ro autoantibodies. Scand J Rheumatol 20: 267-273 8. Esscher E, Scott JS (1979) Congenital heart block and maternal systemic lupus erythematosus. Br Med J 2:1235-1238 9. Franceschini F, Bertoli MT, Martinelli M, Tincani A, Malagoli A, Faden D, Tarantini M, Balestrieri G, Cattaneo R (1990) The neonatal lupus erythematosus associated with isolated La(SSB) antibodies. J Rheumatol 17: 415-416 10. Hiepe F (1988) Einftihrung und Weiterentwicklung moderher immunologischer Methoden und ihre Bedeutung ffir die Immungenese, Diagnostik und Therapie yon Autoimmunerkrankungen des rheumatischen Formenkreises unter Berficksichtigung gerontologischer Aspekte. Dissertation B Humboldt-Universit/it, Berlin 11. Hiepe F, Kiessig ST, Yamamoto K, Prokop G, Mielke F, Lukowsky A, Schlaak B, Miyamoto T, Apostoloff E (1990) Nachweis yon Autoantik6rpern gegen extrahierbare nukle~ire Antigene (ENA) bei Autoimmunerkrankungen des rheumatischen Formenkreisesmittels I m m u n o b l o t t i n g Vergleich mit der Gegenstromelektrophorese. Z Rheumatol 49: 304-309
496 12. Hiepe F, Yamamoto K, Takeuchi A, Apostoloff E, Miyamoto T (1990) Heterogeneity of RNP and Sm autoantigens in relation to the cell sources and the activated state of the cells. Rheumatol Int 10:121-126 13. Hull D, Binns BAO, Joyce D (1966) Congenital heart block and widespread fibrosis due to natural lupus erythematosus. Arch Dis Child 41 : 688-690 14. Lee LA (1988) Anti-Ro (SS-A) and anti-La (SS-B) antibodies in lupus erythematosus and in Sj6gren's syndrome. Arch Dermatol 124: 233-236 15. Lee LA, Harmon C, Huff JC, Norris DA, Weston WL (1985) The demonstration of SS-A antigen in human fetal tissues and in neonatal and adult skin. J Invest Dermatol 85:143-146 16. Litsey SE, Noonan JA, O'Connor WN, Cottril CM, Mitchell B (1985) Maternal connective tissue disease and congenital heart block: demonstration of immunoglobulin in cardiac tissue. N Engl J Med 312:98-100 17. Lockshin MD (1990) Pregnancy associated with systemic lupus erythematosus. Semin Perinatol 14:130-138 18. Lockshin MD, Bonfa E, Elkon EKL, Druzin ML (1988) Neonatal lupus risk to newborns of mothers with systemic lupus erythematosus. Arthritis Rheum 31:697-701 19. Logar D, Kvedre T, Rozman B, Dobvisek J (1990) Possible association between anti-Ro antibodies and myocarditis or cardiac conduction defects in adults with systemic lupus erythematosus. Ann Rheum Dis 49 : 627-629 20. Machado MV, Tynan MJ, Curry PVL, Allan LD (1988) Fetal complete heart block. Br Heart J 60:512-515 21. McCue CM, Mantakas ME, Tringlestad JB, Ruddy S (1977) Congenital heart block in newborns of mothers with connective tissue disease. Circulation 56 : 82-90 22. McCune AB, Weston WL, Lee LA (1987) Maternal and fetal outcome in neonatal lupus erythematosus. Ann Intern Med 106:518-523 23. Ramsey-Goldman R, Hom D, Deng JS, Ziegler GC, Kahl LE, Steen VD, LaPorte RE, Medsger TA Jr (1986) Anti-SSA antibodies and fetal outcome in maternal systemic lupus erythematosus. Arthritis Rheum 29:1269-1273
24. Reed BR, Lee LA, Harmon C, Wolfe R, Wiggins J, Peebles C, Weston WL (1983) Autoantibodies to SS-A/Ro in infants with congenital heart block. J Pediatr 103:889-891 25. Reichlin M, Friday K, Harley JB (1988) Complete congenital heart block followed by anti-Ro/SS-A in adult life. Studies of an informative family. Am J Med 84:33%344 26. Scott JS, Maddison PJ, Taylor PV, Esscher E, Scott O, Skinner RP (1983) Connective tissue disease, antibodies to ribonucleo-protein and congenital heart block. N Engl J Med 309:20%212 27. Silverman E, Mamula M, Hardin JA, Laxer R (1991) Importance of the immune response to Ro/La particle in the developement of congenital heart block and neonatal lupus erythematosus. J Rheumatol 18:120-124 28. Tan EM, Cohen AS, Fries JF, Masi AT, McShane JG, Talal N, Winchester RJ (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271-1277 29. Taylor PV, Taylor KF, Norman A, Griffiths S, Scott JS (1988) Prevalence of maternal Ro(SS-A) and La(SS-B) autoantibodies in relation to congenital heart block. Br J Rheumatol 27:128-132 30. Watson RM, Lane AT, Barnett NK, Bias WB, Arnett FC, Provost TT (1984) Neonatal lupus erythematosus : a clinical, serological and immunogenetic study with review of the literature. Medicine (Baltimore) 63 : 362 378 Received: October 30, 1991 Returned for revision: January 30, 1992 Accepted: March 12, 1992 Dr. reed. T. D6rner Humboldt-Universitfit zu Berlin Univer sitS.tsklinikum Charit6 Klinik ffir Innere Medizin Schumannstrasse 20/21 O-1040 Berlin, FRG
Clin Investig (1992) 70:492-496
Original ArticJe
© Springer-Verlag 1992
Investigations into Ro-specific antibody-associated congenital cardiac conduction defects T. D6rner 1, F. Hiepe ~, B. G61dner 2, and E. Apostoloff 1 1 Klinik ffir Innere Medizin und z Kinderklinik der CharitY, Humboldt-Universit/it zu Berlin
Summary. Forty-two babies with different congenital cardiac conduction defects, and in 12 cases the mothers, were tested for autoantibodies to Ro, La, U~RNP and Sin. Ro-specific antibodies were detected most frequently. They were to be found in 16 sera from infants and in 8 maternal serum sampies. The occurrence of anti-Ro was associated preferentially with several atrioventricular conduction blocks. The sex relation of anti-Ro associated congential heart block did not show a typical preference (6male/10 female). At the time of giving birth, 5 anti-Ro-positive mothers did not have any clinical symptoms of rheumatic autoimmune diseases. Three of them had a first degree atrioventricular block. Our findings indicate that all pregnant women at risk for anti-Ro like connective tissue disease or cardiac conduction defects should be tested for these autoantibodies because of the suspicion of cardiac conduction abnormalities in the offspring. Anti-Ro-positive infants should be examined for structural heart disease by echocardiography. Key words: Ro(SS-A)-specific autoantibodies Autoantibodies - Neonatal lupus erythematosus Congenital heart block - Systemic lupus erythematosus
In 1977 McCue et al. [21] reported infants with congenital heart block (CHB) who were born to mothers with connective tissue diseases. Looking for characteristics associated with immunologic features, Scott et al. [26] and Reed et al. [24] independently detected a correlation of CHB and maternal Ro-specific antibodies. There are also reports about an association of CHB and isolated Abbreviations: anti-EBV VCA IgG=anti-viral capsid antigens immunoglobulin G; AV = atrioventricular; CHB = congenital heart block; CIE = counter immunoelectrophoresis; EBV = Epstein-Barr virus; N L E = n e o n a t a l lupus erythematosus; S L E = systemic lupus erythematosus
U1RNP-specific [2, 30] and La-specific antibodies [9, 29]. We investigated 42 sera from newborns with CHB and in 12 cases the corresponding maternal serum samples for autoantibodies to Ro, La, Sm and U1RNP in a retrospective study. The coexisting type of cardiac conduction defects were analysed, and all infants were examined for structural heart disease by echocardiography.
Methods Forty-two serum samples from babies (18 male/ 24 female) with isolated congenital cardiac conduction defects and in 12 cases the maternal sera were obtained within 3 months of birth. None of the infants showed symptoms of isolated or associated cutaneous lupus. Sera were selected at the Department of Pediatric Medicine and the Department of Internal Medicine (Charit6 Berlin) from 6/1986 to 8/1991. The mean age of the mothers was 24.17 years (range: 20-30 years) at the end of pregnancy, and only 3 of them suffered from systemic lupus erythematosus (SLE) fulfilling the 1982 revised criteria [28]. Nine mothers did not have any clinical symptoms. Ro-specific antibodies were detected using pig spleen extract in counter immunoelectrophoresis (CIE) as reported [7]. La-, Sin- and U1RNP-specific antibodies were detected using rabbit thymus extract in CIE as described previously [10, 11, 12]. All infants were examined for morphological abnormalities using echocardiography, and each baby and mother were examined using electrocardiography routinely.
Results Ro-specific antibodies were detected in 16 of 42 babies (10 female/6 male) suffering from heart rhythm disorders and in 8 of the 12 maternal sera. The results of autoantibody detection in all 54 serum samples are summarized in Table 1. Ro- and
493 Table 1. Prevalence of La-, U1RNP- and Sin-specific antibodies of 16 infants and 8 mothers with Ro-specific antibodies and 26 babies and 4 mothers without anti-Ro using counter immunoelectrophoresis
Anti-La Anti-UIRNP Anti-Sin
Anti-Ro-positive
Anti-Ro-negative
Babies (n = ] 6)
Mothers (n = 8)
Babies (n = 26)
Mothers (n = 4)
3 0 0
1 1 0
0 0 0
0 0 0
Table 3. Distribution of cardiac conduction defects of 26 antiRo-negative infants and associated individual findings Cardiac conduction defects
Number of patients
Associated findings
First degree of AV heart block
4
1 patient's serum possessed IgArheumatoid factor
Third degree of AV heart block
5
1 patient with anti-viral capsid antigen immunoglobulin G (anti-EBV VCA IgG) 1 case Ebstein's disease 1 case respiratory insufficiency
Transient fetal bradyarrhythmia
9
I case with atrial aneurysm
Sinus arrhythmia and second degree sinuatrial block
1
None
Table 2. Distribution of cardiac conduction defects of 16 anti-
Ro-positive babies and associated individual findings Cardiac conduction defect
Number of patients
Associated findings
First degree of atrioventricular (AV) heart block with bradyarrhythmia
2
None
First degree AV heart block
6
1 patient's serum possessed anti-La
Third degree AV heart block
5
2 patients' sera possessed anti-La
Transient fetal bradyarrhythmia
2
None
Tachyarrhythmia
1
Atrium secundum defect
La-specific antibodies coincided in 3 infant cases and I maternal serum. The distribution of cardiac conduction defects in anti-Ro-positive and -negative infants with associated findings are shown in Tables 2 and 3. Three sera contained Ro- and La-specific antibodies. Two of these cases were infants with third degree atrioventricular (AV) block. In one anti-Ro-positive baby with tachyarrhythmia, an atrium septum secundum defect was found by echocardiography. La-, U1RNP- and Sm-specific antibodies were not detected in the anti-Ro-negative group. Strikingly, the sera of babies without anti-Ro possessed other serological abnormalities like Epstein-Barr virus-specific viral capsid antigens immunoglobulin G (VCA IgG) antibodies in one and IgA rheumatoid factor in another case, respectively. Furthermore, there was one anti-Ro-negative patient with respiratory insufficiency and third degree AV heart block, and 1 infant with transient fetal bradyarrhythmia had an atrial aneurysm. Another
Sinus arrhythmia
4
None
Fetal bradyarrhythmia and ventricular extrasystoles
1
None
Inconstant ventricular extrasystoles
2
None
AV = atrioventricular
baby without anti-Ro suffered from Ebstein's disease with third degree AV heart block. The types of cardiac conduction defects and corresponding antibody prevalence in the 12 mothers and their infants are shown in Table 4. In 6 cases we found Ro-specific antibodies in both the sera of the mother and the baby with congenital conduction defects. One anti-Ro-positive SLE mother with associated first degree AV block gave birth to a baby with a transient fetal bradyarrhythmia (pair 3). The infant's serum did not show Rospecific antibodies. One healthy anti-Ro-positive mother had an anti-Ro-negative child with Ebstein's disease and associated third degree AV block as mentioned above (pair 8). Another antiRo-positive infant with transient fetal bradyarrhythmia had an anti-Ro-negative healthy mother (pair 9). Three mothers' and the corresponding babies' sera did not contain Ro-specific autoantibodies. Discussion In this study we have examined humoral autoimmunological features and the occurrence of congenital cardiac rhythm disorders. Our results underline the diagnostic importance of Ro-specific
494 Table 4. Associated serological findings and cardiac conduction disorders in 12 mother and infant pairs Number of pair
1
Mother
Infant
Autoimmune disease
Cardiac conduction defect
Antibodies against
Sex
Cardiac conduction defect
Antibodies against
SLE
No
Ro, La
Female
AV block III
Ro, La
2
SLE
AV block I
Ro, U 1 R N P
Female
AV block III
Ro
3
SLE
AV block I
Ro
Male
Transient fetal bradyarrhythmia
-
4
No
AV block I
Ro
Male
AV block I
Ro
5
No
AV block I
Ro
Female
AV block I
Ro, La
6
No
No
Ro
Female
AV block III
Ro
7
No
No
Ro
Male
AV block III
Ro
8
No
AV block I
Ro
Female
Ebstein's disease, AV block III
9
No
No
Male
Transient fetal bradryarrhythmia
Ro
10
No
No
Female
Transient fetal bradyarrhythmia
-
11
No
No
Male
Sinus arrhythmia
12
No
No
Male
AV block III
SLE = systemic lupus erythematosus
autoantibodies for cardiac conduction defects in contrast to La-, Sm- and UiRNP-specific antibodies. The infants we examined partly represented a selected group with severe cardiac conduction defects. Electrocardiographically, 13 of 16 anti-Ropositive infants showed AV conduction defects. In contrast, we found only 9 of 26 babies without anti-Ro and coinciding AV blocks. In patients without anti-Ro, other abnormalities involving serological (anti-EBV VCA-IgG, IgA rheumatoid factor), pathomorphological (Ebstein's disease) or pathophysiological (respiratory insufficiency) findings were present. The majority of the anti-Ronegative group was characterized by sinus arrhythmias or ventricular extrasystoles. The sera of this patient group did not contain any other investigated autoantibodies either. The findings support the hypothesis that Ro-specific antibodies preferentially affect the AV myocardiac cells or primarily lead to functional defects at the AV node. Furthermore, we found in 3 healthy and in two SLE mothers a first degree AV block with associated anti-Ro. Logar et al. [19] demonstrated in 36 anti-Ro-positrive adult SLE patients a significantly higher prevalence of conduction defects and myocarditis. The pathogenic mechanisms of Ro-specific antibodies, which may lead to cardiac conduction defects, are not completely clear. Immunohistologically, the Ro antigen was detected in conduction system cells [5, 6, 16], and they could lead to fibrosing alterations of the cardiac conduction
system [14]. Other atrial and ventricular myocardial cells may also be affected [5]. It was postulated that the cardiac damage is caused by anti-Ro [1, 19], and its presence may serve as a marker for heart involvement. La-specific antibodies coincided with anti-Ro in 3 infants' and 1 maternal serum most frequently. Silverman et al. [27] demonstrated that anti-Ro/La define the immune response which is associated with congenital heart block. Strikingly, 5 anti-Ro-positive mothers were healthy and gave birth to infants with conduction disorders. McCune et al. [22] reported the importance of congenital heart block (CHB) infants' birth followed by the manifestation of a SLE/ Sj6gren's syndrome overlap after a 10-year period. Further investigations are necessary to determine if anti-Ro-associated CHB babies and/or electrocardiographic abnormalities are primary signs for an elevated risk for maternal connective tissue disease manifestation. Among the anti-Ro-positive children we found I case of a tachyarrhythmia and atrium septum secundum defect. Previously, several reports described the presence of anti-Ro and ductus arteriosus Botalli persistens, total transposition of the outlet tracts, septum defects and subendocardial fibroelastosis [3, 8, 13, 21]. Machado et al. [20] reported 37 fetuses with complete heart block, 16 with isolated heart block and 21 with coinciding structural heart disease, in a series of 6000 fetal
495
echos done because of a suspicion of different increased risks. Infants with heart block and associated structural abnormalities have an increased mortality compared with those with isolated CHB [4, 201. None of the three SLE cases showed disease activity in pregnancy. One corresponding infant manifested a transient fetal bradyarrrhythmia, but the serum did not possess Ro-specific antibodies in contrast to the maternal serum sample. In our experience anti-Ro-positive SLE mothers could have normal healthy infants (data not shown). On the other hand, an important number of children with CHB or neonatal lupus (NLE) are born of mothers who are prospectively identifiable as having SLE or SLE overlap syndromes [18, 25]. Ramsey-Goldman et al. [23] reported the relative risk of 1:20 for anti-Ro-positive SLE patients and a 14-fold elevated risk of anti-Ro healthy mothers having infants with NLE. One baby of a healthy anti-Ro-negative mother also manifested a transient bradyarrhythmia with coinciding anti-Ro. An explanation could be an anti-Ro de novo synthesis in the child, but different results of anti-U1RNP (pair 2) and anti-La (pair 5) were also found in the corresponding maternal and fetal sera. The question remains whether or not Ro-, Laor U,RNP-specific antibodies can be detected at higher frequencies using enzyme immunoassay and/or immunoblot with their increased sensitivity and different detection conditions. The immunofluorescence pattern only supports the possibility that isolated CHB may be causally related to autoantibodies [15]. Thus, the presence of other hitherto unknown antibodies could play a pathological role. The sex relation in our anti-Ro-positive CHB infants (6 male/10 female) shows no preference of females in contrast to connective tissue diseases. We conclude that the maternal role of antibody production and the placental transport are of outstanding importance in CHB. The comprehensive guidelines for SLE treatment in pregnancy with consideration of the issues has been recently reviewed by Lockshin [17]. After birth, CHB most frequently leads to chronic heart failure. Finally, most of the patients, especially with a third degree AV block, had pacemakers implantated after ineffective drug therapy. In our opinion all pregnant women at risk for anti-Ro like connective tissue disease or cardiac conduction defects should be tested for these autoantibodies because of the elevated risk of having CHB infants. Furthermore, infants, especially in
association with Ro-specific antibodies, should be examined for pathomorphological disorders by echocardiography. In this study we have compared the occurrence of congenital cardiac conduction defects and the association of different maternal and fetal autoantibodies. The diagnostic importance of anti-Ro for congenital cardiac rhythm disorders was documented. La-specific antibodies were detected with anti-Ro most frequently. Further examinations of serological characteristics of pregnant women could help to increase the predictive value for NLE and congenital cardiac conduction defects in the children. Acknowledgement. We are grateful to Miss I. Herbrand for her technical assistance in autoantibody detections.
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