Faculty Bibliography

BACKGROUND: Based on the potential involvement of Toll-like receptor (TLR) signalling in the pathogenesis of neonatal lupus (NL), it was hypothesised that fetal exposure to hydroxychloroquine (HCQ), a TLR inhibitor, might reduce the risk of anti-SSA/Ro/SSB/La antibody-associated cardiac manifestations of NL (cardiac-NL). METHODS: Cardiac-NL children (N=50) and controls (N=151) were drawn from the following overlapping pregnancy studies: Research Registry for NL; PR Interval and Dexamethasone Evaluation in Cardiac-NL; and Predictors of Pregnancy Outcomes: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus (SLE). Pregnancies met the following inclusion criteria: documentation of maternal anti-SSA/Ro/SSB/La antibodies at pregnancy, confirmation of medication use and child's outcome, a diagnosis of SLE before pregnancy and birth by 31 December 2007. RESULTS: Seven (14%) of the cardiac-NL children were exposed to HCQ compared with 56 (37%) of the controls (p=0.002; OR 0.28; 95% CI 0.12 to 0.63). Cases and controls were similar with respect to demographic and antibody status. Multivariable analysis adjusting for birth year, maternal race/ethnicity, antibody status, non-fluorinated steroid use and prior cardiac-NL risk yielded an OR associated with HCQ use of 0.46 (95% CI 0.18 to 1.18; p=0.10). CONCLUSION: This case-control study suggests that, in mothers with SLE with anti-SSA/Ro/SSB/La antibodies, exposure to HCQ during pregnancy may decrease the risk of fetal development of cardiac-NL. Prospective studies are needed for confirmation

Rationale: Binding of maternal anti-Ro/La antibodies to cognate antigen expressed on apoptotic cardiocytes decreases clearance by healthy cardiocytes, which may contribute to the development of autoimmune associated congenital heart block and fatal cardiomyopathy. Objective: Given recent evidence implicating the urokinase plasminogen activator receptor (uPAR) as a 'don't eat me' signal during efferocytosis, experiments addressed whether surface bound anti-Ro antibodies inhibit apoptotic cell removal via an effect on the expression/function of the urokinase-type plasminogen activator protease uPA/uPAR system. Methods and Results: As assessed by flow cytometry and confocal microscopy, uPAR colocalizes and interacts with Ro60 on the surface of apoptotic human fetal cardiocytes. Blocking of uPAR enhances phagocytosis of apoptotic cardiocytes by healthy cardiocytes and reverses the anti-Ro60-dependent impaired clearance of apoptotic cardiocytes. Binding of anti-Ro60 antibodies to apoptotic cardiocytes results in increased uPAR expression, as well as enhanced uPA activity. The binding of anti-Ro60 did not alter other surface molecules involved in cell recognition (calreticulin, CD31, or CD47). Conclusions: These data suggest that increased uPAR expression and uPA activity induced by anti-Ro60 binding to the apoptotic fetal cardiocyte provide a molecular basis by which these antibodies inhibit efferocytosis and ultimately lead to scar of the fetal conduction system and working myocardium

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with premature atherosclerosis but the mechanisms underlying this association are not understood. The role of endothelial dysfunction is hypothesized. METHODS: In predominantly non-Caucasian patients with SLE (N=119) and controls (N=71), carotid ultrasonography was performed and circulating endothelial cells (CECs), soluble endothelial protein C receptor and gene polymorphism at A6936G, soluble E-selectin (sE-selectin), and adiponectin were assessed. RESULTS: Carotid plaque was more prevalent among patients than controls (43% vs 17%, p=0.0002). Mean CCA IMT was greater in patients compared to controls (0.59+/-0.19 mm vs 0.54+/-0.11 mm, p=0.03). Among SLE patients, plaque was not associated with smoking, body-mass index, LDL, triglycerides, homocysteine, C-reactive protein, anti-ds DNA antibody, C3, C4, SLE activity, or medications. Age and levels of soluble E-selectin and adiponectin were significantly higher in the SLE patients with plaque compared to those without plaque in univariate and multivariate analyses. sE-selectin and adiponectin were found to serve as independent predictors of carotid plaque and that elevations were persistent over more than one visit. Unexpectedly, these biomarkers were present despite clinical quiescence. CONCLUSION: Premature atherosclerosis is a consistent feature of SLE and extends across ethnicities. Higher levels of adiponectin may represent a physiological attempt to limit further endothelial damage already reflected by the elevation in sE-selectin and the observed increase in plaque represents overwhelming of this reparative process by atherogenic stimuli

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

OBJECTIVE: The recurrence rate of anti-SSA/Ro-associated congenital heart block (CHB) is 17%. Sustained reversal of third-degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB. METHODS: A multicenter, prospective, open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included the presence of anti-SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with < or = 20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second-degree or third-degree CHB. RESULTS: Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues. CONCLUSION: This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers

Neonatal lupus is a model of passively acquired autoimmunity whereby anti-SSA/Ro-SSB/La antibodies target the fetal heart and neonatal skin in a minority of cases. Since neuro-psychiatric impairment has been reported in humans and mice exposed prenatally to a variety of maternal autoantibodies including anti-Ro/La, this study was initiated to evaluate the potential neurotoxic effects of these specific autoantibodies and the overall frequency of autoimmune diseases, general health, and somatic growth of children with neonatal lupus and their unaffected siblings. In addition to the general health questionnaires maintained on family members enrolled in the Research Registry for Neonatal Lupus (RRNL), specific questionnaires related to neuro-psychiatric development were sent to all mothers whose children (both affected and unaffected) were older than 5 years of age. Controls consisted of healthy friends. Of 121 anti-Ro exposed children meeting the inclusion criteria, information was returned on 104 (33 cardiac manifestations of neonatal lupus, 20 rash, and 51 unaffected siblings) and 22 of the friend controls. The mean age of all of the children was 14.5 years (range 5-39). In total, 42 (40%) of the 104 anti-Ro exposed children were reported to have a neuro-psychiatric disorder, compared with 6 (27%) of the friend controls (p = 0.34). For 8 (24%) of the congenital heart block (CHB) children (6 boys, 2 girls) the mothers reported attention problems. Four, all boys, were on stimulants. Of the rash children, 4 (20%) (2 boys, 2 girls) had attention problems with one boy on Ritalin. Of the unaffected siblings, 9 (18%) (8 boys and 1 girl) had attention problems with 3 boys on stimulants. One (5%) of the control children (a girl) had attention problems, not requiring therapy. There was no statistical difference in attention problems between the groups (p = 0.120). Behavioral problems were present in all groups with no statistical differences noted. The prevalence of depression, anxiety, developmental delays, learning, hearing, and speech problems were not significantly different between groups. In the CHB children, one boy has nephrotic syndrome and one girl has psoriasis. In the rash children, one girl has juvenile rheumatoid arthritis. In the unaffected group there are five children with autoimmune diseases, two with inflammatory bowel diseases (one boy and one girl), one boy has a spondyloarthropathy, one girl has alopecia areata and one young woman has Antiphospholipid syndrome. In the control group one boy has Henoch Schonlein purpura. There were four cases of hypothyroidism, possibly secondary to Hashimoto's thyroiditis, three in boys with CHB and one in a girl with rash. None of the unaffected siblings or controls had hypothyroidism. Parental reporting of neuro-psychiatric abnormalities was high in anti-Ro exposed children regardless of the neonatal lupus manifestation. However, medication use was limited and although the frequency of this reporting was greater than friend controls, it did not reach significance