5 Maternal autoantibodies and pregnancy The neonatal lupus syndrome LELA

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A. LEE

Neonatal lupus erythematosus (NLE) is an autoimmune disease of the fetus or newborn that is typified by cutaneous lupus lesions and/or congenital complete heart block. Babies with NLE have circulating maternal autoantibodies, which are usually anti-Ro/SSA and anti-La/SSB. The first case report of what, in retrospect, was probably NLE was a report of two siblings with congenital heart block born to a mother with Sj6gren's syndrome (Aylward, 1928). The first report of what was actually recognized as NLE was that of a baby with cutaneous lupus lesions born to a mother who later developed systemic lupus erythematosus (McCuistion and Schoch, 1954). Since the baby's lesions were transient, whereas the mother developed a persistent autoimmune disease, McCuistion and Schoch postulated that the primary abnormality lay in the mother, and that a diseasecausing maternal factor, probably autoantibodies, had been transmitted across the placenta to the child. A few years after the report of cutaneous lupus in a newborn, a relationship between congenital heart block in infants and autoimmune disease in the mother was noted (Hogg, 1957; Hull et al, 1966). The next major event in the history of NLE was the discovery of the association of NLE with maternal anti-Ro/SSA autoantibodies (Franco et al, 1980; Weston et al, 1982). These autoantibodies occur in almost every case of NLE and thus are of great diagnostic assistance. Shortly after this discovery, it was determined that most babies who would previously have been classified as having 'idiopathic' congenital heart block had maternal anti-Ro/SSA autoantibodies and NLE (Reed et al, 1983; Scott et al, 1983). The availability of a serological test which facilitates making the diagnosis of NLE and the increased awareness of the clinical findings in NLE has led to an improved recognition of NLE and a substantial increase in the number of cases reported. The exact incidence of NLE is still not known. It has been estimated that the incidence of congenital heart block is about i in 20 000 live births (Micha61sson and Engle, 1972). Since NLE is a common cause of congenital heart block, and since heart block accounts for perhaps half of NLE cases, it can be estimated that the incidence of NLE is probably at least 1 in 20 000 live births. Baillibre's Clinical Rheumatology-Vol. 4, No. 1, April 1990 ISBN 0-7020-1481-8

69 Copyright 9 1990, by Bailli6re Tindall All rights of reproduction in any form reserved

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CLINICAL A N D DIAGNOSTIC FINDINGS Infants

About half NLE cases reported have been of skin disease and about half have been of congenital heart block. In about 10% of cases, skin disease and heart block coexisted in the same infant. Liver disease and thrombocytopenia can also occasionally be part of NLE. In our group, we have observed the combinations of skin and heart disease occurring in the same infant: skin and liver disease; liver disease and heart block; skin disease, heart block, and thrombocytopenia; and skin disease, liver disease and thrombocytopenia. Thus, while most babies have either skin disease or heart disease only, some have a combination of findings. Skin disease Cutaneous lesions in NLE are superficial inflammatory plaques that are analogous to subacute cutaneous lupus lesions in adults (Lee and Weston, 1988; Lee and David, 1989). Hypopigmentation is common and may be prominent. Erythema and scaling are typical, and the shape of the lesions is often annular or elliptical. Follicular plugging, dermal atrophy, and scarring, features typical of well-established discoid lupus lesions, are not characteristics of NLE. Lesions occur most often on the face and scalp, but may occur in any location and may cover virtually the entire body. In some cases, lesions have been brought on or exacerbated by sun exposure. The usual time of appearance of the first skin lesions is a few weeks after birth, although lesions can be present at birth. The disease activity generally lasts for a few weeks or months, and resolves by about 6 months of age in most cases. Although disease activity, as evidenced byinflammation (erythema) or the continued appearance of new lesions, resolves by about 6 months of age, the lesions may have persistent hypopigmentation for 1-2 years. It is important, therefore, when evaluating the child's skin for persistent changes, that the child be followed at least to the age of 2 years. In our group of children with NLE skin disease for whom we have adequate follow-up (n = 14), we have observed two children with persistent telangiectasias and one child with a small but persistent patch of hyperpigmentation. The remainder of the children, including some who had very extensive skin disease, now have normal-appearing skin. We have not observed scarring in any child with NLE. The diagnosis of NLE skin disease is often made by a combination of the clinical and serological findings. Children who have skin disease should be examined by a practitioner who is familiar with the cutaneous findings in NLE and who is also familiar with the clinical manifestations of those diseases in the differential diagnosis (e.g. eczema, seborrhoeic dermatitis). Photographs of the skin lesions can serve as an important documentation of the disease. A baby who is suspected of having NLE skin disease should be examined for autoantibodies, as should his mother. In about 95% of cases of NLE to date, the autoantibodies are anti-Ro/SSA (Lee and Weston, 1988). In many

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of those cases, anti-La/SSB antibodies have been found as well and may possibly occur in the absence of detectable quantities of anti-Ro/SSA (Lee et al, 1987b). There have been two cases of cutaneous NLE in which the babies had anti-UiRNP antibodies but not anti-Ro/SSA or anti-La/SSB (Provost et al, 1987). Skin biopsy for histology and immunofluorescence can be very helpful in making the diagnosis of cutaneous NLE. The lesional histology is that of cutaneous lupus, consisting primarily of basal cell damage in the epidermis and a superficial mononuclear cell infiltrate in the upper dermis. This is the type of histology more typical of subacute cutaneous lupus rather than discoid lupus (Bangert et al, 1984; David et al, 1989). Immunofluorescence of the skin lesions is also positive, in our experience. The major findings are those of subacute cutaneous lupus, namely, a particulate pattern of IgG in the epidermis (David et al, 1989; Lee et al, 1989). Although biopsies can add valuable diagnostic information, many parents elect not to have a biopsy done. Fortunately, in most cases, biopsies are not absolutely necessary for the diagnosis. It should be noted, though, that with less data documenting the diagnosis, the clinical experience of the examining physician carries even more weight. Heart disease

The usual cardiac finding in NLE is isolated congenital heart block, that is, heart block in the absence of structural abnormalities such as septal defects. The block is almost always complete, or third degree, but it may be possible for lesser degrees of heart block to be present (Stephensen et al, 1981). The disease begins in utero and may be detected as early as the 16th week of gestation. It is possible for the disease to appear later in gestation. In one instance, a fetus followed closely throughout gestation did not develop heart block until the 24th week of gestation (Buyon et al, 1987). In addition, a case has been reported in which heart block progressed from a second degree block, present at birth, to complete heart block by 9 weeks of age (Geggel et al, 1988). On histological examination, there is scarring in the conduction system with fibrosis and calcifications at the atrioventricular node (Lev et al, 1971; Ho et al, 1986) and in some cases the sinoatrial node as well (Chameides et al, 1977; Bharati et al, 1987). There may also be patchy infiltrates of lymphoid cells in the myocardium (Bharati et al, 1987; Lee et al, 1987a) or endocardial fibroelastosis (Hogg, 1957; Hull et al, 1966). There have been a few cases noted of persistent patent ductus arteriosus in babies who had probable or certain cardiac NLE with heart block (Chameides et al, 1977; Esscher and Scott, 1979; Stephensen et al, 1981; Kasinath and Katz, 1982). Because of scarring in the conduction system, heart block is almost always permanent. There has been one case of presumptive NLE in which a baby had transient atrioventricular dissociation, followed by first degree heart block, then a normal sinus rhythm (McCue et al, 1977). The immediate outcome for babies born with heart block due to NLE is that about half do not require treatment and about half need pacemakers. A small but signifi-

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cant number, about 10%, do not respond to pacer implantation, probably because of coexistent cardiac muscle disease. These babies with recalcitrant disease usually die in infancy. The diagnosis of congenital heart block due to NLE can be suspected first by detecting a slow heart rate in the fetus. The slow heart rate can be confirmed to be related to heart block by ultrasound, where the atria can be shown to be beating at a different rate from the ventricles. Ultrasound can also be used to determine whether there are major structural abnormalities of the heart. In addition, for fetuses suspected of having NLE cardiac disease, the mothers should be tested for autoantibodies. The combination of isolated congenital heart block plus maternal autoantibodies is sufficient to establish the diagnosis of NLE.

Other findings There have been a few well-documented cases of non-infectious hepatitis (Laxer et al, 1987; McCune et al, 1987). In those cases of hepatitis, other causes of hepatitis, primarily infectious diseases, were ruled out by extensive testing. Although NLE liver disease is transient, lasting a few weeks or months, it may be quite severe. Non-infectious hepatitis has occurred in three of 30 babies with NLE referred to our group to date. Three decades ago, thrombocytopenia was observed to occur in a baby whose mother had systemic lupus erythematosus and thrombocytopenia (Nathan and Snapper, 1958). More recently, thrombocytopenia has been observed together with other findings of neonatal lupus (Vonderheid et al, 1976; Winkler et al, 1977; McCune et al, 1987; Watson et al, 1988). Some of the babies had a petechial or purpuric eruption as a presenting finding. Although thrombocytopenia is a relatively common 'non-specific' finding in seriously ill newborns, many or most of the cases reported appear likely to be directly related to NLE. Thrombocytopenia was present in three of 30 babies referred to our group, including two siblings. Gastrointestinal bleeding occurred in one of these babies. It is possible, though not conclusively shown, that autoimmune haemolytic anaemia, leukopenia, splenomegaly and pneumonitis may also be part of the neonatal lupus syndrome. There has been one case of NLE and transient hypocalcaemia with seizures (Moudgil et al, 1987). One case of NLE and persistent myelopathy has been reported (Kaye et al, 1987). Mothers

Maternal symptoms At the time of delivery of their first baby with NLE, about half of the mothers in our series were healthy and had no symptoms suggestive of connective tissue disease. With time, more mothers develop symptoms. When 21 mothers were questioned about symptoms, an average of about 5 years after the birth of their first child with NLE, 18 had symptoms suggestive of autoimmune disease (McCune et al, 1987). These symptoms

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were dry eyes (n = 12), dry mouth (n = 11) and arthralgias (n = 13). One mother had systemic lupus erythematosus, and one had subacute cutaneous lupus erythematosus. Two had transient cutaneous lesions suggestive of leukocytoclastic vasculitis, although that diagnosis was not documented. Thus, the clinical findings of mothers are, in our group, more typical of Sj6gren's syndrome than of systemic lupus erythematosus. It should be emphasized that, while most of the mothers now have symptoms, they are, on the whole, mild symptoms and the women appear to be reasonably healthy. As noted previously, mothers of babies with NLE have autoantibodies. Almost all have anti-Ro/SSA and/or anti-La/SSB, but anti-UiRNP antibodies can be found in some NLE mothers.

Pregnancy outcomes As a group, mothers of babies with NLE do not appear to be at a high risk for spontaneous abortions. Of 53 evaluable pregnancies in 21 mothers, six resulted in spontaneous abortion (McCune et al, 1987). This gives a percentage which is not different from that of normal control groups. In 11 of the 21 women we questioned about pregnancy outcomes, 13 pregnancies occurred subsequent to their delivering their first baby with NLE. One of these pregnancies resulted in a spontaneous abortion, nine resulted in apparently normal babies, and three resulted in babies with NLE (McCune et al, 1987). One of the women had seven children: the fourth and the seventh baby had congenital heart block, while the others were apparently normal. Thus, a woman who has had one baby with NLE may certainly have another affected baby, but the risk appears to be considerably less than 100% and may be about 25%. MANAGEMENT

Screening tests during pregnancy Anti-Ro/SSA antibodies detectable by double immunodiffusion in agarose occur in about 0.5% of all pregnant women, and anti-La/SSB in about 0.1% (Harmon et al, 1984). It is not recommended that all pregnant women be screened for autoantibodies. However, screening can be done in a selected group. These are women who have signs or symptoms that often occur in individuals with anti-Ro/SSA or anti-La/SSB antibodies, namely, Sj6gren's symptoms, arthralgias, photosensitivity, subacute cutaneous lupus erythematosus or systemic lupus erythematosus. In addition, a woman who has previously had a baby with signs or symptoms consistent with NLE should be screened for autoantibodies. Testing for autoantibodies should include specific testing for anti-Ro/SSA, anti-La/SSB and anti-U1RNP antibodies. At this time, it is not known whether other autoantibodies may be associated with NLE. Whether or not a woman is known to have autoantibodies, a fetal heart

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rate should be measured frequently during gestation. If the fetal heart rate is low, heart block should be considered in the differential diagnosis. As previously discussed, the diagnosis of heart block related to NLE can be made in utero by ultrasound and by testing the mother for IgG autoantibodies. Treatment during pregnancy

When considering therapeutic interventions during pregnancy, certain facts should be kept in mind. First, most mothers who have anti-Ro/SSA or anti-La/SSB antibodies will have normal babies. The exact risk for a mother with anti-Ro/SSA or anti-La/SSB having a baby with NLE is not known. Taking into account what is known about the number of pregnant women with those autoantibodies and the number of babies born with congenital heart block, a reasonable guess for the risk for a mother with anti-Ro/SSA or anti-La/SSB antibodies is about 1-2%. Whether or not this guess is accurate, it nevertheless appears that most mothers with anti-Ro/SSA or anti-La/SSB will have normal babies. It is possible that certain women with anti-Ro/SSA or anti-La/SSB have a higher risk than the 1-2% estimate. When examining a group of women with systemic lupus erythematosus and anti-Ro/SSA, one group found that six of 96 pregnancies (6%) resulted in babies with congenital heart block (Ramsey-Goldman et al, 1986). In another study examining women with systemic lupus erythematosus and anti-Ro/SSA, three of 24 babies (13%) had definite NLE and six of 24 (25%) had definite or possible NLE (Lockshin et al, 1988). Including in this group the SLE mothers who had anti-La/SSB or anti-RNP (plus the ones with anti-Ro/SSA), three of their 38 babies (8%) had definite NLE and eight of 38 (21%) had definite or possible NLE. (All three babies in this study with 'definite' NLE had cutaneous NLE but not heart block. 'Possible' NLE in this study consisted of thrombocytopenia only, Coombs' negative haemolytic anaemia only, or equivocal carditis without heart block.) In addition, as mentioned previously, mothers who have already had one child with NLE may have about a 25% risk of having a baby with NLE in subsequent pregnancies (McCune et al, 1987). Nevertheless, in both potentially high-risk groups, anti-Ro positive women with systemic lupus erythematosus and women who have already had one baby with NLE, the majority of babies born to them do not have NLE. Second, of those babies who do develop NLE, perhaps half will have skin disease, a transient disease with little potential for long-term morbidity and no potential for mortality. Third, even in those babies who have potentially life-threatening disease, most will do well despite having no treatment during gestation. Recently, a case was reported in which cardiac NLE was treated during gestation with serial plasmapheresis of the mother plus systemic steroids (Buyon et al, 1987). Therapy was begun at about 26 weeks of gestation. At that time, the fetus had complete heart block, dilated heart chambers, and pericardial and pleural effusions. The effusions gradually regressed during the next several weeks, although the dilated heart chambers and complete

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heart block persisted. At 31 weeks of gestation, the mother experienced a flare of her systemic lupus erythematosus, the volume of amniotic fluid was noted to be markedly decreased, and fetal movements were decreased. An elective caesarean section was done at that point. The baby had complete heart block but no evidence of heart failure, and did well in the neonatal period. It is possible, but not clear, that the decreased pleural and pericardial effusions during treatment indicated a beneficial effect of treatment. More information is needed before recommending this type of treatment during pregnancy for all fetuses with severe NLE cardiac disease. In summary, given the considerations mentioned above, it is not appropriate at this time to attempt treatment during pregnancy unless the fetus has a demonstrable, life-threatening manifestation of N L E (e.g. cardiac disease with hydrops fetalis), and, even so, such treatment should be considered experimental. Any experimental treatment given should be administered in a setting where the effect of treatment on the fetus can be monitored by a physician who has expertise in paediatric cardiology.

Management in the newborn period

Screening evaluation All babies who are known to have anti-Ro/SSA or anti-La/SSB autoantibodies or who have N L E should be examined for the presence of cutaneous lupus, heart disease, liver disease and thrombocytopenia. Laboratory evaluation should include electrocardiography, liver function tests (such as serum bilirubin, glutamic oxaloacetic transaminase and alkaline phosphatase) and blood count (including platelet count).

Treatment of skin disease All babies who have N L E should be protected from excessive sun exposure, even if they have not developed skin lesions. Sun protective measures need not be drastic, but should include appropriate use of clothing and a reasonable avoidance of sun exposure, at least until 8-12 months of age. If babies are unavoidably to be in the sun for more than a brief period, sunscreen can be applied to the areas that will receive exposure. For those babies who develop lesions, topical steroids are appropriate. In many cases, a non-fluorinated topical steroid can be used. For more severe cases, the physician may opt for a brief course of a somewhat more potent topical steroid, but that treatment should be given only under the supervision of a physician knowledgeable in skin diseases and topical steroid use, and should be given for a limited period in order to avoid cutaneous atrophy. It should also be kept in mind that administration of high potency topical steroids to the skin of an infant can result in systemic effects. Given the benign nature of skin disease in NLE, systemic therapies should not be used. Cardiopulmonary arrest has been reported in children after accidental ingestion of five or fewer chloroquine tablets (DiMaio and Henry, 1974). Thus, it appears that antimalarials have a low toxic to

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therapeutic ratio in young children and are not recommended for treatment of skin disease.

Treatment of internal disease Treatment of cardiac disease consists largely of pacemaker implantation when necessary, as previously mentioned. In addition, some children require medical management of heart failure. Systemic steroids are sometimes used for children with severe internal manifestations of NLE. The effect of such treatment is difficult to assess, particularly in a situation where the disease activity typically regresses spontaneously. LONG-TERM PROGNOSIS Infants

Babies with NLE generally do well later in childhood. In a follow-up study of 24 babies followed for an average of about 5 years (range 0.25-9.5 years), three babies with heart disease died in infancy (McCune et al, 1987). The 21 surviving children consisted of nine babies who had skin disease only, nine who had heart block only, one who had skin and liver disease, one who had skin disease and heart block, and one who had skin disease, heart block, and thrombocytopenia. All of these children were in good health on follow-up although five of the children with heart block have permanent pacemakers. In another report of 27 cases of congenital heart block, most or all of whom probably had NLE, it was noted that most children were free of symptoms (Esscher and Scott, 1979). However, three babies died in the neonatal period and one died at age 6 months from Stokes-Adams attacks. One other child had Stokes-Adams attacks at age 2 years and required a pacemaker at that point. Finally, another child had a pacemaker inserted at age 3, but was experiencing increasing heart failure at age 8 years. Thus, the prognosis for childhood is quite good in those babies who survive infancy, but some babies with heart block may have persistent difficulties and many require permanent pacemaker implantation. The longer-term prognosis for individuals who have had NLE is not known. There have been two cases reported of individuals who had cutaneous NLE and developed connective tissue disease in adulthood (Fox et al, 1979; Jackson and Gulliver, 1979), and five cases of individuals with congenital heart block who developed connective tissue disease in adulthood (McCue et al, 1977; Esscher and Scott, 1979; Waterworth, 1980; Lanham et al, 1983). At this time, most of the babies reported with NLE are still children. More information about this issue will be available when a cohort of children has been followed into adulthood. Mothers

As noted previously, most mothers eventually develop symptoms of con-

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nective tissue disease. In our group, these consisted typically of mild symptoms of Sj6gren's syndrome. Whether most will develop more serious symptoms with further time is not known. PATHOGENESIS OF NEONATAL LUPUS Autoantibodies

It has been hypothesized that in NLE an autoimmune mother transfers autoantibodies to her fetus, who then develops NLE as a result of those autoantibodies. The following points favour this hypothesis. (1) The mother usually has persistent autoimmunity, while the baby with NLE has no clinical or serological signs of autoimmunity later in childhood. Thus, the mother appears to be the source of the autoimmunity. (2) The placenta is selective in its transfer of substances from the mother to the fetus. IgG is transferred well, for example, whereas maternal leukocytes are not. Thus, immunoglobulins are a good candidate for the putative pathogenic factor transmitted from mother to baby. (3) Maternal autoantibodies are found in virtually all cases of NLE. (4) The skin disease resolves at about the time that maternal autoantibodies can no longer be detected in the child's serum. (5) Fraternal twins, one of whom had heart block and the other of whom was normal, were examined for autoantibodies. The affected baby had low titres of circulating maternal anti-Ro/SSA antibodies, while the unaffected baby had high titres of maternal anti-Ro/SSA in her serum. The titres of antiLa/SSB and anti-Sm autoantibodies were similar in both babies. These data were offered in support of the hypothesis that the affected baby had substantial amounts of anti-Ro/SSA autoantibodies selectively deposited in his heart (Harley et al, 1985). To examine the hypothesis that autoantibodies are important in the genesis of NLE, certain basic questions need to be addressed. First, are there antibodies in NLE lesions? Our findings of particulate IgG deposition in the epidermis of NLE skin lesions have been discussed in a previous section. Cardiac tissue from babies with fatal NLE heart disease has been examined by three different groups. All found antibody deposition in the heart, although the patterns of deposition and the immunoreactants found were somewhat different. One group examined the right atrial appendage and found diffuse staining for IgG and IgA and diffuse staining for IgG in the epicardium (Litsey et al, 1985). Another described diffuse cytoplasmic IgG, IgM and complement staining in multiple areas of the heart (Taylor et al, 1986). We observed particulate deposits of IgG and complement, but not IgM or IgA, in multiple areas of the heart (Lee et al, 1987a). Although the number of tissue samples examined is quite small, the evidence is that NLE lesions do have antibody deposits. The second basic question is, what are the antibodies that are deposited? To examine the specificity of antibodies deposited in the skin, we have used an animal model: immunodeficient mice with grafted human skin. The mice are injected with human antiserum or purified antibodies; the skin grafts are

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then examined for human Ig deposits. In initial studies, when anti-Ro/SSA but not control antiserum was injected, human IgG was deposited in a particulate pattern in the epidermis of the human skin grafts (Lee et al, 1986a). This pattern is the same as that we observed in NLE lesions and in lesions of subacute cutaneous lupus in adults. In later studies, particulate IgG deposits in the epidermis were observed when affinity purified antiRo/SSA antibodies were injected, but not when anti-Ro/SSA serum was preadsorbed to a Ro/SSA affinity column to remove selectively the antiRo/SSA antibodies (Lee et al, 1989). Thus, the antibodies bound to the skin in patients with anti-Ro/SSA antibodies appear to be anti-Ro/SSA. (These studies used sera that did not contain significant amounts of anti-La/SSB. The deposition of anti-La/SSB in the skin has not yet been addressed, nor has the deposition of anti-UiRNP.) Preliminary studies looking at the specificity of antibodies deposited in various organs have also provided evidence that anti-Ro/SSA is deposited in multiple internal organs (Lee et al, 1986b). In these studies, newborn guinea-pigs were injected with anti-Ro/SSA or control serum and organs were examined for human Ig deposits. In addition, pregnant guinea-pigs were injected with human anti-Ro/SSA serum or control serum, and the offspring examined for human Ig deposits. In both cases, newborn guineapigs had particulate deposits of IgG in internal organs and skin when anti-Ro/SSA but not control sera were injected. The pattern of these deposits was particulate and was the same pattern that we had observed in the heart of a baby with cardiac NLE (Lee et al, 1987a). A third question that may be important in NLE is: to what antigen(s) do the antibodies bind? This question has not been answered conclusively. Ro and La are normally present in the heart and skin (Lee et al, 1985; Coulter et al, 1988; Jones et al, 1988), and there is some evidence that the antigens to which the antibodies bind are Ro/SSA and/or La/SSB (Lee et al, 1987b; Coulter et al, 1988; Buyon et al, 1989). However, the studies that have been done to date have examined antibody-antigen interactions using cellular lysates and have not examined antibody-antigen interactions at the cell surface, which is presumably the point at which the antibodies first bind to the cell. Why are the heart and skin involved so often in NLE, and what determines whether heart will be affected or skin will be affected? As mentioned, the information currently available from studies in guinea-pigs indicates that antibody binding probably occurs in multiple organs, even those apparently never affected in NLE (Lee et al, 1986b). We have not, as yet, found major antigenic differences among various human tissues, including tissues commonly involved and tissues not clinically involved in NLE (Coulter et al, 1988). Further, sera from mothers of babies with heart disease are indistinguishable from sera from mothers of babies with skin disease in their reactivity with heart and skin in Western blotting experiments (Coulter et al, 1988). Finally, we have examined the IgG subclasses represented in N L E heart block sera and NLE skin disease sera (Bennion et al, 1989). Both heart and skin disease sera contain predominantly IgG1, a subclass that can cross the placenta relatively early during gestation. Thus,

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babies with skin disease alone probably were exposed to anti-Ro/SSA and/or anti-La/SSB antibodies at a time when heart block typically develops, but for unknown reasons they failed to develop heart block. Does antibody binding lead directly to tissue injury? There is some evidence that maternal autoantibodies cannot by themselves cause NLE. Not every baby of a mother with anti-Ro/SSA or anti-La/SSB antibodies will develop NLE. Even among siblings, some may be affected while others are not. Furthermore, antibody binding is probably more widespread than is tissue injury. In the skin of adults when anti-Ro/SSA and subacute cutaneous lupus, antibody binding is regularly present in uninvolved skin (David et al, 1989). In guinea-pigs injected with human anti-Ro/SSA serum, antibody binding was not |imited to heart and skin but rather was present in every organ examined (Lee et al, 1986b). If autoantibodies are involved in the pathogenesis of NLE, how might they cause disease? Antibodies can lead to disease by several mechanisms. Binding of antibodies to a cellular antigen can disrupt the structure and/or function of that antigen. Alternatively, antibody binding can lead to complement activation or to antibody-dependent cellular cytotoxicity (ADCC). The evidence for any of these mechanisms being operative in NLE is scant. The presumed cellular targets of autoantibodies in NLE, Ro/SSA and La/SSB antigens, are RNA-binding proteins that may play an integral role in normal cellular function. La protein binds transcripts of RNA polymerase III, which include transfer RNAs, and La/SSB may be important in RNA processing. The function of Ro/SSA protein is not known. As opposed to La/SSB, which binds innumerable RNAs, Ro/SSA has been found with only four RNAs. 'Ro/SSA' itself actually appears to be not just one antigen but rather a polymorphic set of antigens ranging in molecular weight from about 52-60 kDa (Ben-Chetrit et al, 1988; Rader et al, 1989). It is probable that Ro and La are important for normal cellular operations, and it is doubtful whether autoantibodies to Ro/SSA and La/SSB cause disease by interfering directly with their functions. It is certainly conceivable that complement activation and/or ADCC are important in the pathogenesis of NLE lesions. Complement is present in lesions of NLE, and cells that could serve as effectors of ADCC are present in lesions. However, there is no conclusive evidence supporting either mechanism. Other factors

As mentioned above, complement and mononuclear cells are present in lesions and may contribute to lesion formation. The means by which mononuclear cells (largely lymphocytes) contribute to lesion formation is not known. One possibility (that is unlikely) is that the mononuclear cells alone are causing disease. Since in NLE the mother is persistently autoimmune, while the child has a transient disease, and since maternal autoimmune leukocytes would not be expected to be present in the fetal circulation, it is quite unlikely that autoimmune leukocytes are directly causing disease in the fetus or newborn.

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Ultraviolet light is a contributing factor in many cases of cutaneous NLE. It is probably not required for skin disease to occur, since in some cases lesions have been present at birth and since lesions can occur in sunprotected sites. It has been described that exposure of keratinocytes to ultraviolet light will augment anti-Ro/SSA binding to the keratinocytes (LeFeber et al, 1984). This is one potential means by which exposure to ultraviolet light could lead to the initiation or exacerbation of skin disease. Also, experiments measuring the effect of a local injection of anti-Ro/SSA serum on cutaneous blood flow in guinea-pigs, showed that anti-Ro/SSA serum can increase microvascular blood flow in skin exposed to ultraviolet light (Davis et al, 1989). Sex steroids are probably important in NLE, just as they are in adult lupus. The ratio of females to males with cardiac NLE is about even, but the ratio of females to males with cutaneous N L E is about 3 : 1. The reason for this discrepancy is not known, but it should be considered that the hormonal milieu in which heart disease occurs (pregnancy) is quite different from that in which skin disease occurs (infancy). The mechanisms by which sex steroids influence lupus are complex (Lahita, 1985). One proposed mechanism is that oestradiol enhances binding of anti-Ro/SSA and anti-La/SSB antibodies to keratinocytes (Furukawa et al, 1988). Genetic factors are important in NLE, although no genetic factors have been identified that aid in determining which fetus will develop disease. Mothers of babies with NLE have an increased likelihood of being HLA-BS, DR3 positive, while babies apparently have no associated H L A type (Lee et al, 1983; Watson et al, 1984). The association of an H L A type with maternal autoimmunity is probably a reflection of the role that H L A proteins play in antigen recognition. It is not surprising that individuals with anti-Ro/SSA or anti-La/SSB antibodies have appropriate H L A proteins for the optimal recognition of Ro/SSA or La/SSB antigens. Complement genes are also being examined in NLE. There is preliminary evidence that abnormal C4 genes may be present in a significant number of N L E mothers (Watson et al, 1989). Abnormal C4 genes may simply be a marker of disease and may lie near the relevant NLE gene(s) on the chromosome, or, alternatively, abnormal C4 genes may result in abnormal C4 function, which could in some way be related to disease. SUMMARY

N L E is manifested most typically as transient subacute cutaneous lupus lesions or isolated complete congenital heart block. Babies with NLE have maternal anti-Ro/SSA, anti-La/SSB, or anti-U1RNP autoantibodies. It is presumed, but not proven, that transmission of these autoantibodies through the placenta to the baby has resulted in disease. However, other factors such as inflammatory cells or complement activation may be necessary for disease to be expressed. About half of babies reported with NLE have had heart disease and about half have had skin disease. There have been a few reports of liver disease and

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a few of thrombocytopenia. A n y combination of these findings is possible in a given infant. Possibly, other haematologic abnormalities, pneumonitis or neurological disease could occur, but the evidence that these other abnormalities are part of N L E is scant. Mortality in N L E has occurred in babies with severe cardiac disease. It is estimated that 10% or more of babies with cardiac N L E die in infancy. Of the remainder, perhaps half will require permanent pacemaker implantation. Thus, there is substantial morbidity and mortality with cardiac NLE. The skin disease, by contrast, is not serious and typically leaves little or no residua. Individuals who have had N L E may develop connective tissue disease in adulthood. Whether this is a c o m m o n or an unusual occurrence is not yet known, since a large cohort of individuals with N L E has not yet been followed into adulthood. Mothers of babies with N L E are often initially asymptomatic. With time, they frequently develop connective tissue disease symptoms. In our experience, these have been largely symptoms of Sj6gren's syndrome and have generally not been debilitating. Most babies of mothers with anti-Ro/SSA, anti-La/SSB, or anti-U1RNP autoantibodies do not develop NLE. There is no way to determine prospectively which fetus or infant will be affected and which of those affected will have life-threatening disease. Systemic therapies should be reserved for those infants who have life-threatening manifestations of NLE. It is not yet known whether treatment of the mother during gestation will be beneficial or harmful to fetuses with severe N L E cardiac disease.

Acknowledgements This work has been supported in part by grant AR-01487fromthe National Institutes of Health.

REFERENCES Aylward RD (1928) Congenital heart-block. British Medical Journal 1: 943. Bangert JL, Freeman RG, Sontheimer RD & Gilliam JN (1984) Subacute cutaneous lupus erythcmatosus and discoid lupus erythematosus: comparative histopathologic findings. Archives of Dermatology 120: 332-337. Ben-Chetrit E, Chan EKL, Stdlivan KF & Tan EM (1988) A 52-kD protein is a novel component of the SS-A/Ro antigenic particle. Journal of Experimental Medicine 167: 1560-1571. Bennion SD, Mercill DB, Lieu T-S, Reimer C & Lee LA (1989) Cutaneous IgG subclass deposition in neonatal lupus (NLE) and subacute cutaneous lupus (SCLE). Clinical Research 37: 745A (abstract). Bharati S, SwerdlowMA, Vitullo D, ChiemmongkoltipP & Lev M (1987) Neonatal lupus with congenital atrioventricular block and myocarditis. Pace 10: 1058--1070. BuyonJP, SwerskySH, Fox HE, Bierman FZ & WinchesterRJ (1987) Intrauterine therapy for presumptive fetal myocarditiswith acquired heart block due to systemiclupus erythematosus. Arthritis and Rheumatism 30: 44-49. Buyon JP, Ben-Chetrit E, Karp Set al (1989) Acquired congenital heart block. Pattern of maternal antibody response to biochemically defined antigens of the SSA/Ro-SSB/La system in neonatal lupus. Journal of Clinical Investigation 84: 627-634. Chameides L, Truex RC, Vetter V e t al (1977) Association of maternal systemic lupus

82

t.A.

LEE

erythematosus with congenital complete heart block. New England Journal of Medicine 297: 1204-1207. Coulter SN, Smith ML & Lee LA (1988) A 50 kD protein reactive with anti-La (SSB) sera is more abundant in neonatal than in adult tissues. Clinical Research 36: 248A (abstract). David KM, Bennion SD, DeSpain JD, Golitz LE & Lee LA (1989) Immunoreactants in lesions and uninvolved skin in lupus. Clinical Research 37: 748A (abstract). Davis TL, Lyde CB, Davis BM & Sontheimer RD (1989) Perturbation of experimental ultraviolet light-induced erythema by passive transfer of serum from subaeute cutaneous lupus erythematosus patients. Journal oflnvestigative Dermatology 92: 573-577. Di Maio VJM & Henry LD (1974) Chloroquine poisoning. Southern Medical Journal 67: 1031-1035. Esscher E & Scott JS (1979) Congenital heart block and maternal systemic lupus erythematosus. British Medical Journal 1: 1235-1238. Fox RJ, McCuistion CH & Schoch EP (1979) Systemic lupus erythematosus: association with previous neonatal lupus erythematosus. Archives of Dermatology 115: 340. Franco HL, Weston WL, Tan EM et al (1980) Association of antibodies to sicca syndrome antigens in newborns with lupus erythematosus and their mothers. Clinical Research 28: 134A (abstract). Furukawa F, Lyons MB, Lee LA, Coulter SN & Norris D A (1988) Estradiol enhances binding to cultured human keratinocytes of antibodies specific for SS-A/Ro and SS-B/La. Journal oflmmunology 141: 1480-1488. Geggel RL, Tucker L & Szer I (1988) Postnatal progression from second- to third-degree heart block in neonatal lupus syndrome. Journal of Pediatrics 113: 1049-1052. Harley JB, Kaine JL, Fox OF, Reichlin M & Gruber B (1985) Ro/SSA antibody and antigen in a patient with congenital complete heart block. Arthritis and Rheumatism 28: 1321-1325. Harmon CE, Lee LA, Huff JC, Norris DA & Weston WL (1984) The frequency of antibodies to the SSA/Ro antigen in pregnancy sera. Arthritis and Rheumatism 28:$20 (abstract). Ho SY, Esscher E, Anderson RH & Micha~lsson M (1986) Anatomy of congenital complete heart block and relation to maternal anti-Ro antibodies. American Journal of Cardiology 58" 291-294. Hogg GR (1957) Congenital, acute lupus erythematosus associated with subendocardial fibroelastosis. American Journal of Clinical Pathology 28: 648-654. Hull D, Binns BAO & Joyce D (1966) Congenital heart block and widespread fibrosis due to maternal lupus erythematosus. Archives of Diseases of Childhood 41: 688--690. Jackson R & Gulliver M (1979) Neonatal lupus erythematosus progressing into systemic lupus erythematosus. British Journal of Dermatology 101: 81-86. Jones SK, Coulter S, Harmon C et al (1988) Ro/SSA antigen in human epidermis. British Journal of Dermatology 118: 363--367. Kasinath BS & Katz AI (1982) Delayed maternal lupus after delivery of offspring with congenital heart block. Archives of Internal Medicine 142: 2317. Kaye EM, Butler IJ & Conley S (1987) Myelopathy in neonatal and infantile lupus erythematosus. Journal of Neurology, Neurosurgery and Psychiatry 50: 923-926. Lahita R G (1985) Sex steroids and the rheumatic diseases. Arthritis and Rheumatism 28: 121-126. Lanham JG, Walport MJ & Hughes GRV (1983) Congenital heart block and familial connective tissue disease. Journal of Rheumatology 10: 823-825. Laxer RM, Roberts EA, Cutz E et al (1987) Cholestatic jaundice and hepatitis in neonatal lupus erythematosus (NLE). Arthritis and Rheumatism 29:$81 (abstract). Lee L A & David KM (1989) Cutaneous lupus erythematosus. Current Problems in Dermatology 1: 161-200. Lee LA & Weston WL (1988) Neonatal lupus erythematosus. Seminars in Dermatology 7: 66-72. Lee LA, Bias WB, Arnett FC et al (1983) Immunogenetics of the neonatal lupus syndrome. Annals of lnternal Medicine 99: 592-596. Lee LA, Harmon CE, Huff JC, Norris DA & Weston WL (1985) The demonstration of SS-A/Ro antigen in human fetal tissues and in neonatal and adult skin. Journal of Investigative Dermatology 85: 143-146. Lee LA, Weston WL, Krueger G G et al (1986a) An animal mode[ of antibody binding in cutaneous lupus. Arthritis and Rheumatism 29: 782-788.

NEONATAL LUPUS SYNDROME

83

Lee LA, Coulter S, Norris D & Weston W (1986b) An animal model for studying transplacental passage and tissue deposition of antibody in neonatal lupus. Clinical Research 34: 161A (abstract). Lee LA, Coulter S, Erner S & Chu H (1987a) Cardiac immunoglobulin deposition in congenital heart block associated with maternal anti-Ro autoantibodies. American Journal of Medicine 83: 793-796. Lee LA, Lekan C & Coulter S (1987b) Characterization of autoantibodies associated with neonatal lupus. Clinical Research 35: 699A (abstract). Lee LA, Gaither KK, Coulter SN, Norris D A & Harley JB (1989) Pattern of cutaneous immunoglobulin G deposition in subacute cutaneous lupus erythematosus is reproduced by infusing purified anti-Ro (SSA) autoantibodies into human skin-grafted mice. Journal of Clinical Investigation 83: 1556-1562. LeFeber WP, Norris DA, Ryan SB et al (1984) Ultraviolet light induces binding of antibodies to selected nuclear antigens on cultured human keratinocytes. Journal of Clinical Investigation 74: 1545-1551. Lev M, Silverman J, Fitzmaurice FM et al (1971) Lack of connection between the atria and the more peripheral conduction system in congenital atrioventricular block. American Journal of Cardiology 27: 481488. Litsey SE, Noonan JA, O'Connor WN, Cottrill CM & Mitchell B (1985) Maternal connective tissue disease and congenital heart block: demonstration of immunoglobulin in cardiac tissue. New England Journal of Medicine 312: 98-100. Lockshin MD, Bonfa E, Elkon K & Druzin ML (1988) Neonatal lupus risk to newborns of mothers with systemic lupus erythcmatosus. Arthritis and Rheumatism 31: 697-701. McCue CM, Mantakas ME, Tingelstad JB & Ruddy S (1977) Congenital heart block in newborns of mothers with connective tissue disease. Circulation 56: 82-90. McCuistion CH & Schoch EP (1954) Possible discoid lupus erythematosus in a newborn infant: report of a case with subsequent development of acute systemic lupus erythematosus in mother. Archives of Dermatology 70: 782-785. McCune AB, Weston WL & Lee LA (1987) Maternal and fetal outcome in neonatal lupus erythematosus. Annals of Internal Medicine 106: 518-523. Micha61sson M & Engle MA (1972) Congenital complete heart block: an international study of the natural history. Cardiovascular Clinics: 85-101. Moudgil A, Kishore K & Srivastava RN (1987) Neonatal lupus erythematosus, late onset hypocalcaemia, and recurrent seizures. Archives of Diseases of Childhood 62: 736-739. Nathan DJ & Snapper I (1958) Simultaneous placental transfer of factors responsible for L.E. cell formation and thrombocytopenia. American Journal of Medicine 25: 647-653. Provost TT, Watson R, Gammon WR et al (1987) Neonatal lupus syndrome associated with U1 RNP (nRNP) antibodies. New England Journal of Medicine 316: 1135-1138. Rader MD, O'Brien C, Liu Y, Harley JB & Reichlin M (1989) Heterogeneity of the Ro/SSA antigen: different molecular forms in lymphocytes and red blood cells. Journal of Clinical Investigation 83: 1293-1298. Ramsey-Goldman R, Horn D, Deng J-S et al (1986) Anti-SS-A antibodies and fetal outcome in maternal systemic lupus erythematosus. Arthritis and Rheumatism 29: 1269-1273. Reed BR, Lee LA, Harmon C et al (1983) Autoantibodies to SS-A/Ro in infants with congenital heart block. Journal of Pediatrics 103: 889-891. Scott JS, Maddison PJ, Taylor PV et al (1983) Connective-tissue disease, antibodies to ribonucleoprotein, and congenital heart block. New England Journal of Medicine 309: 209-212. Stephensen O, Cleland WP & Hallidie-Smith K (1981) Congenital complete heart block and persistent ductus arteriosus associated with maternal systemic lupus erythematosus. British Heart Journal 46: 104-106. Taylor PV, Scott JS, Gerlis LM, Esscher E & Scott O (1986) Maternal antibodies against fetal cardiac antigens in congenital complete heart block. New England Journal of Medicine 315: 667-672. Vonderheid EC, Koblenzer PJ, Ming PML & Burgoon CF (1976) Neonatal lupus erythematosus: report of four cases with review of the literature. Archives of Dermatology 112: 698-705. Waterworth RF (1980) Systemic lupus erythematosus occurring with congenital complete heart block. New Zealand Medical Journal 92:311-312.

84

L . A . LEE

Watson RM, Lane AT, Barnett NK et al (1984) Neonatal lupus erythematosus: a clinical, serological and immunogenetic study with review of the literature. Medicine 63: 362-378. Watson R, Kang JE, May Met al (1988) Thrombocytopenia in the neonatal lupus syndrome. Archives of Dermatology 124: 560-563. Watson RM, Lee LA, Bias WB & McLean RH (1989) Increased C4A deficiency and C4A gene deletion in mothers of infants with neonatal lupus erythematosus (NLE). ClinicalResearch 37: 769A (abstract). Weston WL, Harmon C, Peebles C et al (1982) A serological marker for neonatal lupus erythematosus. British Journal of Dermatology 107: 377-382. Winkler RB, Nora AH & Nora JJ (1977) Familial congenital complete heart block and maternal systemic lupus erythematosus. Circulation 56: 1103-1107.