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Effects on pregnancy - Neonatal Lupus

SLE = Systemic Lupus Erythematosus

This illness of the fetus and neonate is currently considered a model of passively acquired autoimmunity, in which immune abnormalities in the mother (who may have SLE, SS, or be totally asymptomatic) lead to the production of antibodies to SSA/Ro-SSB/La ribonucleoproteins that cross the placenta and presumably injure fetal tissue [reviewed in ref. 60].

The most serious manifestation is damage to the cardiac conducting system, resulting in congenital heart block (CHB). Cutaneous involvement (frequently photosensitive) and, to a lesser extent, hepatic and hematologic involvement, are also associated with maternal and fetal anti-SSA/Ro-SSB/La antibodies and are now grouped under the heading of neonatal lupus syndromes.

Cardiac and dermatological manifestations are the hallmarks of the syndrome and can occur separately or together. Neonatal lupus was so termed because the dermatological lesions of the neonate resembled those seen in SLE. The name neonatal lupus is a misnomer in that only a third of mothers of affected children actually have SLE, and the neonatal disease is frequently only manifest as heart block, a problem rarely reported in adults with lupus.

To date, complete heart block is irreversible. In contrast, the non-cardiac manifestations are transient, resolving at about 6 months of life coincident with the disappearance of maternal autoantibodies from the neonatal circulation.

The incidence of neonatal lupus in an offspring of a mother with anti-SSA/Ro antibodies is estimated at 1–2% [61]. Although there is no serologic profile that is unique to mothers of affected children compared with mothers of healthy children, anti-SSA/Ro antibodies are usually of high titer and associated with anti-SSB/La antibodies [62]. Anti-52-kDa SSA/Ro antibodies are more prevalent by immunoblot in sera of mothers of children with heart block, although all these sera are likely to have anti-60-kDa SSA/Ro antibodies by immunoprecipitation.

Reports of discordant dizygotic and monozygotic twins and lowrecurrence rates [63] (10 of 52 pregnancies subsequent to a child with CHB in our series from the Research Registry for Neonatal Lupus), indicate that factors (likely fetal) in addition to anti-SSA/Ro and SSB/La antibodies contribute to the development of neonatal lupus.

Experiments using a rabbit model have provided insights into the pathogenicity of maternal anti-SSA/Ro and anti- SSB/La antibodies. Perfusion of rabbit hearts with isolated IgG fractions from sera containing anti-SSA/Ro-SSB/La antibodies results in the electrocardiographic demonstration of atrioventricular (AV) block [64]. We have recently reproduced these conduction abnormalities in human fetal hearts by use of affinity-purified anti-52-kDa SSA/Ro antibodies [65]. Moreover, sera with anti-SSA/Ro-SSB/La reactivities and affinitypurified anti-52-kDa SSA/Ro induce a reduction in the L-type calcium channel current (ICa) in patch-clamp experiments of isolated rabbit and human fetal ventricular myocytes. Thus, the inhibitory effect of ICa at the single myocyte level correlates with the induction of AV block in the EKG of whole working hearts. These data support a major role of ICa in the electrogenesis and propagation of the action potential at the AV node and indicate that anti-SSA/Ro-SSB/La antibodies may interact (directly or indirectly) with these putative ion channels. It is important to note that the AV node, which is absent and replaced by fibrotic or adipose tissue in autopsy studies of CHB, is rich in conducting cells that contain high concentrations of calcium channels.

An antibody-specific murine model to correlate arrhythmogenic effects of maternal autoantibodies with the in vivo genesis of CHB has been recently developed. Complete heart block has been observed in offspring of BALB/c mice immunized with 52-kDa SSA/Ro [66].

Substantial mortality and morbidity are associated with CHB: one-fifth to one-third of those affected die, some in utero, and the majority of children require pacing [63]. Because CHB is most often identified in the mid to late second trimester, intrauterine therapy is possible, but guidelines are empiric. The rationale for treatment of identified heart block and prevention of potential heart block is to diminish a presumed inflammatory insult to the heart and to lower the titer of maternal autoantibodies.

Several intrauterine therapeutic regimens have been attempted, including dexamethasone, which is not metabolized by the placenta and is available to the fetus in an active form, and plasmapheresis [67]. Anecdotal reports suggest that associated pleuropericardial effusions and ascites resolve, presumably secondary to a decrease in fetal cardiac inflammation independent of a decrease in maternal or fetal antibody titer. It is encouraging, however, that heart block, once established, is not absolutely immutable, since incomplete block has reverted to sinus rhythm and third degree blocks have transiently improved in the degree of block [68]. The administration of maternal prednisone (at least in low and moderate doses) early in pregnancy does not prevent the development of CHB. Given the rarity of neonatal lupus, prophylactic therapies are not justified at this time. Frequent echocardiograms (two-dimensional and M-mode techniques) between 16 and 30 weeks of gestation, the presumed window of cardiac vulnerability, to identify an incomplete block or myocardial dysfunction, may be the optimal approach.

REFERENCES

61. Lee, L. A. (1993) Neonatal lupus erythematosus. J. Invest. Dermatol. 100, 9S–13S.
62. Buyon, J. P.,Winchester, R. J., Slade, S. G., Arnett, F., Copel, J., Friedman, D., Lockshin, M. D. (1993) Identification of mothers at risk for congenital heart block and other neonatal lupus syndromes in their children:Comparison of ELISA and immunoblot to measure anti-SSA/Ro and anti-SSB/La antibodies. Arthr. Rheumatol. 36, 1263–1273.
63. Waltuck, J., Buyon, J. P. (1994) Autoantibody associated complete heart block: Outcome in mothers and children. Ann. Intern. Med. 120, 544–551.

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