Lela A. Lee

Autoimmune-Associated Congenital Heart Block: Demographics, Mortality, Morbidity and Recurrence Rates Obtained From a National Neonatal Lupus Registry

OBJECTIVES The present study describes the demographics, mortality, morbidity and recurrence rates of autoimmune-associated congenital heart block (CHB) using information from the Research Registry for Neonatal Lupus. BACKGROUND Isolated CHB detected at or before birth is strongly associated with maternal autoantibodies to 48-kD SSB/La, 52-kD SSA/Ro and 60-kD SSA/Ro ribonucleoproteins and is a permanent manifestation of the neonatal lupus syndromes (NLS). Available data are limited by the rarity of the disease. RESULTS The cohort includes 105 mothers whose sera contain anti-SSA/Ro or anti-SSB/La antibodies, or both, and their 113 infants diagnosed with CHB between 1970 and 1997 (56 boys, 57 girls). Of 87 pregnancies in which sufficient medical records were available, bradyarrhythmia confirmed to be CHB was initially detected before 30 weeks of gestation in 71 (82%) (median time 23 weeks). There were no cases in which major congenital cardiac anatomic defects were considered causal for the development of CHB; in 14 there were minor abnormalities. Twenty-two (19%) of the 113 children died, 16 (73%) within 3 months after birth. Cumulative probability of 3-year survival was 79%. Sixty-seven (63%) of 107 live-born children required pacemakers: 35 within 9 days of life, 15 within 1 year, and 17 after 1 year. Forty-nine of the mothers had subsequent pregnancies: 8 (16%) had another infant with CHB and 3 (6%) had a child with an isolated rash consistent with NLS. CONCLUSIONS Data from this large series substantiate that autoantibody-associated CHB is not coincident with major structural abnormalities, is most often identified in the late second trimester, carries a substantial mortality in the neonatal period and frequently requires pacing. The recurrence rate of CHB is at least two- to three-fold higher than the rate for a mother with anti-SSA/Ro-SSB/La antibodies who never had an affected child, supporting close echocardiographic monitoring in all subsequent pregnancies, with heightened surveillance between 18 and 24 weeks of gestation.

Maternal and Fetal Outcome in Neonatal Lupus Erythematosus

Maternal health, childrens health, and obstetric histories were assessed in a follow-up study of 21 families with children with neonatal lupus erythematosus; this group constituted approximately 15% of all reported cases. Twenty-one mothers had twenty-four children with the disease. Twelve children had congenital heart block (5 boys, 7 girls), 10 had cutaneous lupus lesions (1 boy, 9 girls), and 2 girls had both heart block and cutaneous lesions. Although half of the mothers were initially asymptomatic, 18 of 21 have developed symptoms during the follow-up period (range, 0.25 to 9.5 years). Three of the children died in the neonatal period. The 21 children who survived have been asymptomatic during follow-up, although 5 of 11 with heart block have pacemakers. The mothers did not have an increased risk for spontaneous abortions. Three of twelve livebirths after the birth of the first child with neonatal lupus erythematosus resulted in another affected child.

Subacute Cutaneous Lupus Erythematosus Associated with Hydrochlorothiazide Therapy

Photosensitive eruptions with clinical and histologic features of subacute cutaneous lupus erythematosus and antibodies to SS-A(Ro) antigen occurred in five patients taking hydrochlorothiazide. After drug therapy was discontinued, the eruptions cleared. In one patient anti-SS-A antibodies disappeared after discontinuation of thiazide, and in another rechallenge with hydrochlorothiazide produced an acute dermatitis with a photodistribution. These eruptions may represent a new type of photosensitive drug reaction in which the photoactive drug may be synergistic with anti-SS-A antibody in producing cutaneous lesions of photosensitive subacute cutaneous lupus erythematosus.

Immunogenetics of the Neonatal Lupus Syndrome

Abstract Infants with neonatal lupus erythematosus have congenital heart block, transient cutaneous lesions, or both. Mothers of these infants have SSA/Ro autoantibodies that are passed across the ...

Autoantibodies to SS-A/Ro in infants with congenital heart block

Antibodies to SS-A/Ro have been proposed to be a serologic marker for the neonatal lupus syndrome, which is characterized by congenital heart block or cutaneous lupus or both. The antibodies occur in the mother and are transiently found in the childs serum. We examined an unselected series of 12 children with idiopathic CHB, isolated in 10 children and with cutaneous lupus lesions in two. Six of these children and their mothers were studied during the childs neonatal period, and six were studied retrospectively. All six neonates had SS-A/Ro autoantibodies. Nine of 12 mothers had SS-A/Ro autoantibodies. Of the seropositive mothers, one had systemic lupus erythematosus, two had sicca syndrome, one had photosensitivity, one had arthralgias, and four were asymptomatic. We propose that congenital heart block may be related to transplacental passage of maternal SS-A/Ro antibodies and that neonatal lupus may be the most common cause.

Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus

The 1982 ACR classification criteria have become de facto diagnostic criteria for systemic lupus erythematosus (SLE), but a review of the criteria is necessary to include recent diagnostic tests. The criteria were not developed with the help of dermatologists, and assign too much weight to the skin as one expression of a multiorgan disease. Consequently, patients with skin diseases are classified as SLE based mostly on skin symptoms. We discuss specific problems with each dermatologic criterion, but changes must await a new study. We suggest the following guidelines for such a study, aimed at revision of the criteria. 1) The SLE patient group should be recruited in part by dermatologists. 2) The study should evaluate an appropriate international ethnic/racial mix, including late onset SLE as well as pediatric patients. 3) All patients should have current laboratory and clinical evaluations, as suggested in the paper, to assure the criteria can be up-to-date. This includes anti-SS-A and anti-SS-B antibodies and skin biopsies for suspected cutaneous lupus erythematosus except for nonscarring alopecia and oral ulcers. 4) The study should be based on a series of transparent power calculations. 5) The control groups should represent relevant differential diagnoses in numbers large enough to assess diagnostic problems that might be specific to these differential diagnoses. In order to demonstrate specificity of the criteria with a 95% confidence interval between 90 and 100%, each control group of the above should have at least 73 patients.

Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block

OBJECTIVE Cutaneous disease associated with placental transport of maternal anti-SSA/Ro or anti-SSB/La antibodies is transient, and children often appear to be otherwise healthy. However, the impact of this manifestation of neonatal lupus (NL) on the risk of cardiac disease occurring in a future pregnancy is critical for family counseling and for powering preventive trials. The purpose of this study was to determine the recurrence rates of NL, with specific focus on cardiac NL following cutaneous NL in a child enrolled in the Research Registry for Neonatal Lupus (RRNL). METHODS Fifty-eight families who were enrolled in the RRNL met the following inclusion criteria for our study: maternal anti-SSA/Ro or anti-SSB/La antibodies, a child with cutaneous NL, and a pregnancy subsequent to the child with cutaneous NL. RESULTS The majority of the 58 mothers (78%) were Caucasian. Of 77 pregnancies that occurred following the birth of a child with cutaneous NL, the overall recurrence rate for any manifestation of NL was 49% (95% confidence interval [95% CI] 37-62%); 14 pregnancies (18.2%) were complicated by cardiac NL, 23 (29.9%) by cutaneous NL, and 1 (1.3%) by hematologic/hepatic NL. A subset analysis was restricted to the 39 children who were born after the initial child with cutaneous NL had been enrolled in the RRNL. The overall recurrence rate for NL was 36% (95% CI 20-52%); 5 pregnancies (12.8%) were complicated by cardiac NL and 9 (23.1%) by cutaneous NL. There were no significant differences in the following maternal risk factors for having a subsequent child with cardiac or cutaneous NL: age, race/ethnicity, anti-SSB/La status, diagnosis, use of nonfluorinated steroids, or breastfeeding. The sex of the subsequent fetus did not influence the development of cardiac or cutaneous NL. CONCLUSION Based on data from this large cohort, the identification of cutaneous NL in an anti-SSA/Ro antibody-exposed infant is particularly important, since it predicts a 6-10-fold risk of a subsequent child developing cardiac NL.

Comparison of the reliability and validity of outcome instruments for cutaneous dermatomyositis

Background  Reliable and validated measures of skin disease severity are needed for cutaneous dermatomyositis (DM). Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Dermatomyositis Skin Severity Index (DSSI) and Cutaneous Assessment Tool (CAT) skin indices have been developed as outcome instruments.

Neonatal lupus liver disease.

Neonatal lupus erythematosus (NLE) is an autoimmune disease characterized by complete congenital heart block and/or transient skin lesions of subacute cutaneous lupus erythematosus. We report that in approximately 10% of cases of NLE with heart block or skin disease, liver disease also occurs (4 of 35 cases in our series). Cholestasis was the major feature in our cases. Although the cholestasis may be severe, the disease process appears to be transient and surviving babies have been healthy on follow-up. In one liver examined for antibody deposition, IgG antibody deposits, presumably of maternal origin, were present. Three maternal sera were examined for autoantibodies, including liver-specific autoantibodies. No liver-specific autoantibodies were found. Rather, the maternal autoantibodies too were the ubiquitous Ro/SSA-associated autoantigens. The autoantibodies bound the 60 kDa SSA/Ro ribonuclear protein (three of three sera), the 52kDa SSA/Ro protein (two of three sera) and the SSB/La ribonuclear protein (two of three sera).

CUSP/p63 expression in rat and human tissues

The human homolog of KET, p63, bears strong homology to the tumor suppressor p53 and plays an essential role in epithelial development. CUSP, the most abundant cutaneous product of p63, has been identified as an autoantigen in chronic ulcerative stomatitis (CUS). The original report of KET expression at least partially contradicts p63 expression subsequently reported by many different groups. We have examined p63 expression by Northern analysis of RNA from multiple human tissues and by indirect immunofluorescence of rat tissue with CUS patient sera. Northern analysis reveals p63 RNA in skin, thymus, placenta, skeletal muscle, kidney, and lung, with non-transactivating p63 RNA in skin, thymus, and placenta. Reverse transcriptase polymerase chain reaction (rtPCR) assays show abundant non-transactivating p63 RNA, and little to no transactivating p63 RNA, in human basal cell carcinoma as well as in normal skin adjacent to the tumors. p63 RNA expression was not detected in brain, heart, colon, spleen, liver, or small intestine. Immunofluorescence reveals p63 expression in skin, oral epithelium, tongue, kidney, and trachea, but not in liver, large intestine, testis, skeletal muscle, or heart. Focal p63 expression within tissues, the complex array of isoforms encoded by the gene, and the specificity of the probes and antibodies utilized, may all contribute to contradictory accounts of CUSP/p63 expression.