Skip to main content

Advertisement

SpringerLink
Log in

Identification and management of fetuses at risk for, or affected by, congenital heart block associated with autoantibodies to SSA (Ro), SSB (La), or an HsEg5-like autoantigen

  • Original Article
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

The congenital heart block (CHB), diagnosed in structurally normal hearts, is strongly associated with, if not caused by, maternal SSA/SSB antibodies (Abs). It develops between 16 and 24 weeks’ gestation, coincidentally with the increased transplacental IgG passage, and a window of unique cardiac vulnerability. Less is known about rare CHB cases in which neither cardiac malformations nor SSA/SSB Abs are detectable. We report on four pregnant women: patient 1 at high CHB risk (owing to Sjögren’s syndrome (SS) and recurrent pregnancy losses), and patients 2–4 with already established CHB (aggravated by hydrops in patient 2). Abs were found directed to SSA/SSB (patients 1–3) or to an HsEg5-like autoantigen instead (patient 4). During preventive immunoadsorption (IA) from week 19 throughout (patient 1), or therapeutic IA (plus dexamethasone), commenced at week 25 (patient 2), SSA Ab levels decreased per session by 47±7 or 80±16%, respectively, and hydropic changes resolved. Patient 1 delivered a healthy boy, while patients 2–4 gave birth to CHB-affected children at need for permanent pacing. The irreversibility of complete CHB may justify (a) early ANA screening in all pregnancies (thereby also considering specificities as anti-HsEg5), and (b) preventive immmunoadsorption in high-risk pregnancies (before/during the critical cardiac development phase). This implies controversy, because factors converting risk to disease (in only ~2%) are unknown, and prospective randomized treatment studies are not available, given the rarity of CHB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Brucato A, Jonzon A, Friedman D, Allan LD, Vignati G, Gasparini M, Stein JI, Montella S, Michaelsson M, Buyon J (2003) Proposal for a new definition of congenital complete atrioventricular block. Lupus 12:427–435

    Article  PubMed  CAS  Google Scholar 

  2. Buyon JP, Clancy RM (2003) Neonatal lupus: review of proposed pathogenesis and clinical data from the US-based Research Registry for Neonatal Lupus. Autoimmunity 36:41–50

    Article  PubMed  CAS  Google Scholar 

  3. Julkunen H, Miettinen A, Walle TK, Chan EK, Eronen M (2004) Autoimmune response in mothers of children with congenital and postnatally diagnosed isolated heart block: a population based study. J Rheumatol 31:183–189

    PubMed  Google Scholar 

  4. Buyon JP, Waltuck J, Caldwell K, Crawford B, Slade SG, Copel J, Chan EKL (1994) Relationship between maternal and neonatal levels of antibodies to 48-kDa SSB (La), 52-kDa SSA (Ro), and 60-kDa SSA (Ro) in pregnancies complicated by congenital heart block. J Rheumatol 21:1943–1947

    PubMed  CAS  Google Scholar 

  5. Tseng CE, Buyon JP (1997) Neonatal lupus syndromes. Rheum Dis Clin North Am 23:31–54

    Article  PubMed  CAS  Google Scholar 

  6. Horsfall AC, Venables PJ, Taylor PV, Maini RN (1991) Ro and La antigens and maternal anti-La idiotype on the surface of myocardial fibres in congenital heart block. J Autoimmun 4:165–176

    Article  PubMed  CAS  Google Scholar 

  7. Reichlin M, Brucato A, Frank MB, Maddison PJ, McCubbin VR, Wolfson-Reichlin M, Lee LA (1994) Concentration of autoantibodies to native 60-kd Ro/SS-A and denatured 52-kd Ro/SS-A in eluates from the heart of a child who died with congenital complete heart block. Arthritis Rheum 37:1698–1703

    Article  PubMed  CAS  Google Scholar 

  8. Garcia S, Nascimento JHM, Bonfa E, Levy R, Oliveira SF, Tavares AV, Campos de Carvalho AC (1994) Cellular mechanisms of the conduction abnormalities induced by serum from anti-Ro/SSA-positive patients in rabbits hearts. J Clin Invest 93:718–724

    Article  PubMed  CAS  Google Scholar 

  9. Boutjdir M, Chen L, Zhang Z-H, Tseng C-E, DiDonato F, Rashbaum W, Morris A, El-Sherif N, Buyon JP (1997) Arrhythmogenicity of IgG and anti-52-kD SSA/Ro affinity-purified antibodies from mothers of children with congenital heart block. Circ Res 80:354–362

    PubMed  CAS  Google Scholar 

  10. Mazel JA, El-Sherif N, Buyon JP, Boutjdir M (1999) Electrocardiographic abnormalities in a murine model injected with IgG from mothers of children with congenital heart block. Circulation 99:1914–1918

    PubMed  CAS  Google Scholar 

  11. Miranda-Carús ME, Boutjdir M, Tseng C-E, DiDonato F, Chan EKL, Buyon JP (1998) Induction of antibodies reactive with SSA/Ro-SSB/La and development of congenital heart block. J Immunol 161:5886–5892

    PubMed  Google Scholar 

  12. Salomonsson S, Sonesson S, Ottosson L, Muhallab S, Olsson T, Sunnerhagen M, Kuchroo VK, Thorén P, Herlenius E, Wahren-Herlenius M (2005) Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block. J Exp Med 201:11–17

    Article  PubMed  CAS  Google Scholar 

  13. Miranda ME, Tseng CE, Rashbaum W, Ochs RL, Casino CA, Di Donato F, Chan EK, Buyon JP (1998) Accessibility of SSA/Ro and SSB/La antigens to maternal autoantibodies in apoptotic human fetal cardiac myocytes. J Immunol 161:5061–5069

    PubMed  CAS  Google Scholar 

  14. Ayukawa K, Taniguchi S, Masumoto J, Hashimoto S, Sarvotham H, Hara A, Aoyama T, Sagara J (2000) La autoantigen is cleaved in the COOH terminus and loses the nuclear localization signal during apoptosis. J Biol Chem 275:34465–34470

    Article  PubMed  CAS  Google Scholar 

  15. Baboonian C, Venables PJ, Booth J, Williams DG, Roffe LM, Maini RN (1989) Virus infection induces redistribution and membrane localization of the nuclear antigen La (SS-B): a possible mechanism for autoimmunity. Clin Exp Immunol 78:454–459

    PubMed  CAS  Google Scholar 

  16. Furukawa F, Lyons MB, Lee LA, Coulter SN, Norris DA (1988) Estradiol enhances binding to cultured human keratinocytes of antibodies specific for SS-A/Ro and SS-B/La. Another possible mechanism for estradiol influence of lupus erythematosus. J Immunol 141:1480–1488

    PubMed  CAS  Google Scholar 

  17. Horsfall AC, Rose LM (1992) Cross-reactive maternal autoantibodies and congenital heart block. J Autoimmun 5:479–493

    Article  PubMed  CAS  Google Scholar 

  18. Qu Y, Xiao G-Q, Chen L, Boutjdir M (2001) Autoantibodies from mothers of children with congenital heart block downregulate cardiac L-type Ca channels. J Mol Cell Cardiol 33:1153–1163

    Article  PubMed  CAS  Google Scholar 

  19. Scofield RH, Dickey WD, Jackson KW, James JA, Harley JB (1991) A common autoepitope near the carboxyl terminus of the 60-kD Ro ribonucleoprotein: sequence similarity with a viral protein. J Clin Immunol 11:378–388

    Article  PubMed  CAS  Google Scholar 

  20. Clancy RM, Kapur RP, Molad Y, Askanase AD, Buyon JP (2004) Immunohistologic evidence supports apoptosis, IgG deposition, and novel macrophage/fibroblast crosstalk in the pathologic cascade leading to congenital heart block. Arthritis Rheum 50:173–182

    Article  PubMed  CAS  Google Scholar 

  21. Herreman G, Galezowski N (1985) Maternal connective tissue disease and congenital heart block (letter). N Engl J Med 312:1329

    Article  PubMed  Google Scholar 

  22. Alexander E, Buyon JP, Provost TT, Guarnieri T (1992) Anti-Ro/SS-A antibodies in the pathophysiology of congenital heart block in neonatal lupus syndrome, an experimental model. Arthritis Rheum 35:176–189

    Article  PubMed  CAS  Google Scholar 

  23. Sonesson SE, Salomonsson S, Jacobsson LA, Bremme K, Wahren-Herlenius M (2004) Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA/Ro 52-kd antibodies. Arthritis Rheum 50:1253–1261

    Article  PubMed  CAS  Google Scholar 

  24. Brucato A, Frassi M, Franceschini F, Cimaz R, Faden D, Pisoni MP, Muscara M, Vignati G, Stramba-Badiale M, Catelli L, Lojacono A, Cavazzana I, Ghirardello A, Vescovi F, Gambari PF, Doria A, Meroni PL, Tincani A (2001) Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women. Arthritis Rheum 44:1832–1835

    Article  PubMed  CAS  Google Scholar 

  25. Solomon DG, Rupel A, Buyon JP (2003) Birth order, gender and recurrence rate in autoantibody-associated congenital heart block: implications for pathogenesis and family counseling. Lupus 12:646–647

    Article  PubMed  Google Scholar 

  26. Hickstein H, Külz T, Claus R, Stange J, Schmidt R (2005) Autoimmune-associated congenital heart block: treatment of the mother with immunoadsorption. Ther Apher Dial 9:148–153

    Article  PubMed  CAS  Google Scholar 

  27. Vitali C, Bombardieri S, Moutsopoulos HM, Balestrieri G, Bencivelli W, Bernstein RM et al (1993) Preliminary criteria for the classification of the Sjögren’s syndrome: results of a prospective concerted action supported by the European Community. Arthritis Rheum 36:340–347

    Article  PubMed  CAS  Google Scholar 

  28. Claus R, Lenschow U, Külz T, Kotitschke A, Meiske D, Thiesen HJ, Lorenz P (2005) Congenital heart block associated with a maternal anti-HsEg5-like autoantibody. Rheumatology 44:691–693

    Article  PubMed  CAS  Google Scholar 

  29. Andrade LE, Chan EK, Peebles CL, Tan EM (1996) Two major autoantigen-antibody systems of the mitotic spindle apparatus. Athritis Rheum 39:1643–1653

    Article  CAS  Google Scholar 

  30. Whitehead CM, Winkfein RJ, Fritzler MJ, Battner JB (1996) The spindle kinesin-like protein HsEg5 is an autoantigen in systemic lupus erythematosus. Arthritis Rheum 39:1635–1642

    Article  PubMed  CAS  Google Scholar 

  31. Blangy A, Lane HA, d’Hérin P, Harper M, Kress M, Nigg EA (1995) Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83:1159–1169

    Article  PubMed  CAS  Google Scholar 

  32. Michaëlsson M, Engle MA (1972) Congenital heart block: an international study of the natural history. In: Brest AN, Engle MA (eds) Cardiovascular clinics. Davis, Philadelphia, pp 85–101

    Google Scholar 

  33. Ramsey-Goldman R, Hom D, Deng JS, Ziegler GC, Kahl LE, Steen VD, LaPorte RE, Medsger TA Jr (1986) Anti-SS-A antibodies and fetal outcome in maternal systemic lupus erythematosus. Arthritis Rheum 29:1269–1273

    Article  PubMed  CAS  Google Scholar 

  34. 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

    Article  PubMed  CAS  Google Scholar 

  35. Mavragani CP, Ioannidis JPA, Tzioufas AG, Hantoumi EE, Moutsopoulos HM (1999) Recurrent pregnancy loss and autoantibody profile in autoimmune diseases. Rheumatology 38:1228–1233

    Article  PubMed  CAS  Google Scholar 

  36. Gordon P, Khamashta MA, Rosenthal E, Simpson JM, Sharland G, Brucato A, Franceschini F, De Bosschere K, Meheus L, Meroni PL, Hughes GRV, Buyon J (2004) Anti-52 kDa Ro, anti-60 kDa Ro, and anti-La antibody profiles in neonatal lupus. J Rheumatol 31:2480–2487

    PubMed  CAS  Google Scholar 

  37. Buyon JP, Winchester RJ, Slade SG, Arnett F, Copel J, Friedman D, Lockshin MD (1993) Identification of mothers at risk for congenital heart block and other neonatal lupus syndromes in their children. Comparison of enzyme-linked immunosorbent assay and immunoblot for measurement of anti-SS-A/Ro and anti-SS-B/La antibodies. Arthritis Rheum 36:1263–1273

    Article  PubMed  CAS  Google Scholar 

  38. Dörner T, Chaoui R, Feist E, Göldner B, Yamamoto K, Hiepe F (1995) Significantly increased maternal and fetal IgG autoantibody levels to 52 kD Ro (SS-A) and La (SS-B) in complete congenital heart block. J Autoimmun 8:675–684

    Article  PubMed  Google Scholar 

  39. Salomonsson S, Dörner T, Theander E, Bremme K, Larsson P, Wahren-Herlenius M (2002) A serologic marker for fetal risk of congenital heart block. Arthritis Rheum 46:1233–1241

    Article  PubMed  CAS  Google Scholar 

  40. McCauliffe DP, Yin H, Wang LX, Lucas L (1994) Autoimmune sera react with multiple epitopes on recombinant 52 and 60kDa Ro (SSA) proteins. J Rheumatol 21:1073–1080

    PubMed  CAS  Google Scholar 

  41. Fritsch C, Hoebeke J, Dali H, Ricchiuti V, Isenberg DA, Meyer O, Muller S (2006) 52-kDa Ro/SSA epitopes preferentially recognized by antibodies from mothers of children with neonatal lupus and congenital heart block. Arthritis Res Ther 8(1): R4. DOI 10.1186/ar1848

    Article  PubMed  CAS  Google Scholar 

  42. Benson DW (2004) Genetics of atrioventricular conduction disease in humans. Anat Rec 280A(2):934–939

    Article  Google Scholar 

  43. Whitehead CM, Rattner JB (1998) Expanding the role of HsEg5 within the mitotic and post-mitotic phases of the cell cycle. J Cell Sci 111:2551–2561

    PubMed  CAS  Google Scholar 

  44. Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E, Fritsch A, Lee Y, Mak J, Moody R, Turincio R, Chabala JC, Gonzales P, Roth S, Weitman S, Wood KW (2004) Antitumor activity of a kinesin inhibitor. Cancer Res 64:327–3280

    Article  Google Scholar 

  45. Harley JB, Kaine JL, Fox OF, Reichlin M, Gruber B (1985) Ro (SS-A) antibody and antigen in a patient with congenital complete heart block. Arthritis Rheum 28:1321–1325

    Article  PubMed  CAS  Google Scholar 

  46. Julkunen H, Eronen M (2001) Long-term outcome of mothers of children with isolated heart block in Finland. Arthritis Rheum 44:647–652

    Article  PubMed  CAS  Google Scholar 

  47. Saleeb S, Copel J, Friedman D, Buyon JP (1999) Comparison of treatment with fluorinated glucocorticoids to the natural history of autoantibody-associated congenital heart block: retrospective review of the research registry for neonatal lupus. Arthritis Rheum 42:2335–2345

    Article  PubMed  CAS  Google Scholar 

  48. Shinohara K, Miyagawa S, Fujita T, Aono T, Kidoguchi K (1999) Neonatal lupus erythematosus: results of maternal corticosteroid therapy. Obstet Gynecol 93:952–957

    Article  PubMed  CAS  Google Scholar 

  49. Derksen RHW, Meilof JF (1992) Anti-Ro/SSA and anti-La/SSB autoantibody levels in relation to systemic lupus erythematosus disease activity and congenital heart block. Arthritis Rheum 35:953–959

    Article  PubMed  CAS  Google Scholar 

  50. Van der Leij JN, Visser GH, Bink-Boelkens MT, Meilof JF, Kallenberg CG (1994) Successful outcome of pregnancy after treatment of maternal anti-Ro (SSA) antibodies with immunosuppressive therapy and plasmapheresis. Prenat Diagn 14:1003–1007

    Article  PubMed  Google Scholar 

  51. Barclay CS, French MA, Ross LD, Sokol RJ (1987) Successful pregnancy following steroid therapy and plasma exchange in a woman with anti-Ro (SSA) antibodies. Case report. Br J Obstet Gynaecol 94:369–371

    PubMed  CAS  Google Scholar 

  52. Buyon JP, Swersky SH, Fox HE, Bierman FZ, Winchester RJ (1987) Intrauterine therapy for presumptive fetal myocarditis with acquired heart block due to systemic lupus erythematosus. Experience in a mother with a predominance of SSB (La) antibodies. Arthritis Rheum 30:44–49

    Article  PubMed  CAS  Google Scholar 

  53. Arroyave CM, Puente Ledezma F, Montiel Amoroso G, Martinez Garcia AC (1995) Myocardiopathy diagnosed in utero in a mother with SSA antibodies treated with plasmapheresis. Ginecol Obstet Mex 63:134–137

    PubMed  CAS  Google Scholar 

  54. Feist E, Dörner T, Wagenmann A, Chaqui R, Rohde W, Burmester GR, Hiepe F (1996) High risk pregnancy in primary Sjögren’s syndrome—successful management by plasmapheresis and dexamethasone. Z Rheumatol 55:127–132

    PubMed  CAS  Google Scholar 

  55. Buyon J, Roubey R, Swersky S, Pompeo L, Parke A, Baxi L, Winchester R (1988) Complete congenital heart block: risk of recurrence and therapeutic approach to prevention. J Rheumatol 15:1104–1108

    PubMed  CAS  Google Scholar 

  56. Müller-Ladner U, Benning K, Röther E, Lang B (1992) Neonatal lupus erythematosus as an example of passively acquired autoimmunity. Immun Infekt 20:117–121

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank Eva Lorbeer and Marlies Dettmer for their excellent technical assistance and the EU for funding (LSHM-CT-2004-005264 “Autorome”).

Author information

Authors and Affiliations

  1. Department of Immunology, Medical Faculty, University of Rostock, Schillingallee 70, 18057, Rostock, Germany

    Renate Claus, Doris Meiske, Andrea Kotitschke, Hans-Jürgen Thiesen & Peter Lorenz

  2. Department of Internal Medicine, Medical Faculty, University of Rostock, Rostock, Germany

    Heiko Hickstein

  3. Department of Obstetrics and Gynecology, Medical Faculty, University of Rostock, Rostock, Germany

    Thomas Külz

  4. Department of Pediatrics, Medical Faculty, University of Rostock, Rostock, Germany

    Ute Lenschow

Authors
  1. Renate Claus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heiko Hickstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Külz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ute Lenschow
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Doris Meiske
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea Kotitschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hans-Jürgen Thiesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter Lorenz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Renate Claus.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Claus, R., Hickstein, H., Külz, T. et al. Identification and management of fetuses at risk for, or affected by, congenital heart block associated with autoantibodies to SSA (Ro), SSB (La), or an HsEg5-like autoantigen. Rheumatol Int 26, 886–895 (2006). https://doi.org/10.1007/s00296-005-0101-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-005-0101-4

Keywords

Search

Navigation