The heart and skin of neonatal lupus: does maternal health matter?

Abstract

Despite the rarity of neonatal lupus erythematosus—most internists are unlikely to encounter more than a few mothers with affected children—the disease has attracted great interest. Perhaps this is because it is a fascinating model of passively acquired autoimmunity. It is currently hypothesized that maternal autoantibodies reactive with components of the SSA/Ro-SSB/La ribonucleoprotein complex are actively transported across the trophoblast and injure the fetal cardiac conducting system and neonatal skin (1,2). The target antigens have been extensively characterized at the molecular level (3). Yet the how and why of antibodymediated insult remain largely unanswered: the main problem is finding a reasonable explanation for accessibility of these intracellular antigens to extracellular maternal antibodies. Evidence is emerging to support a role for physiologic apoptosis as a mechanism of translocating these antigens to the cell surface where they can be bound by cognate maternal antibodies (4). Additionally, several laboratories have demonstrated that the candidate antibodies are arrhythmogenic and inhibit inward calcium fluxes across membranes (5). Mice actively immunized with SSA/Ro antigens have given birth to pups with varying conduction disturbances (6). The nearly universal finding of these specific antibodies in the serum of mothers—who may either be asymptomatic or have a rheumatic disease— of children who are diagnosed with congenital heart block is astonishing. However, viewed from the opposite perspective, the penetrance of disease in the offspring of mothers with these candidate autoantibodies is quite low: only 1% to 2% of children have neonatal lupus. Even more curious are the striking differences between the two major manifestations of the disease, both of which are linked to the same broad antibody responses. Cardiac injury is most often detected between 18 and 24 weeks of gestation. In contrast, cutaneous injury frequently occurs 6 weeks after birth, following sun exposure. The signature cardiac lesion is atrioventricular block, which can be first-, second-, or third-degree block (the last being most common) in a structurally normal heart; in 10% of cases there is an associated cardiomyopathy. The cutaneous lesions are generally annular or elliptical, and are present on the scalp, face, chest, and extremities. The maternal heart is not targeted, but the rash closely resembles subacute cutaneous lupus in the adult. Importantly, third-degree heart block is permanent, while the cutaneous lesions disappear by 8 months, coincident with the clearance of maternal antibodies from the neonate’s circulation. Provided with these clinical clues, one is likely to ask the obvious: might the health status of the mother herself be linked to the discordant manifestations? Such a connection would aid in defining risk for a given mother, an enormous benefit to the practitioner faced with family counseling, and in identifying a pathogenetic mechanism of injury, the holy grail to the basic researcher. Maternal disease might reflect the fine specificity of an antibody response, which in turn could account for the preferential vulnerability of one particular organ versus another. In this issue of the Journal, Lawrence et al (7) address this question and compare a newly described cohort of 24 women with anti-SSA/Ro-SSB/La antibodies whose children had only cutaneous manifestations of neonatal lupus with their previously published cohort of 32 mothers with similar antibodies whose children had only cardiac manifestations (8). Maternal health status was considered as either symptomatic (inclusive of varied rheumatic diseases such as systemic lupus erythematosus, Sjogren’s syndrome, and undifferentiated autoimmune diseases) or completely asymptomatic. A significantly greater number of mothers whose children had congenital heart block were asymptomatic (75%), compared with mothers of children with skin rash alone (42%). At follow-up, mothers of children with congenital heart block were more likely to remain asymptomatic (59%) than were mothers of children with skin rash (25%). This same question has also recently been addressed by review of data in the Research Registry for Neonatal Lupus (9) of 105 mothers whose children had only congenital heart block and 47 mothers whose children had only a skin rash (10). All mothers had documented antibodies to SSA/Ro or SSB/La. Initially, 37% of the “congenitalheart-block mothers” and 28% of the “skin mothers” were asymptomatic. After at least 5 years of follow-up, Am J Med. 2000;108:741–743. From the Department of Rheumatology, Hospital for Joint Diseases, New York University School of Medicine, New York, New York. Requests for reprints should be addressed to Jill P. Buyon, MD, Department of Rheumatology, Hospital for Joint Diseases, New York University School of Medicine, 301 East 17th Street, New York, New York 10003.