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

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: 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

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

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

Purpose: To analyze whether quantitative scores on a multidimensional health assessment questionnaire (MDHAQ) provide clues to the likelihood of inflammatory versus non-inflammatory symptoms and concomitant fibromyalgia, an important challenge in clinical care, according to a global scale for noninflammatory symptoms completed by a rheumatologist in 50 patients with SLE seen in usual care. Methods: A cross-sectional study was performed in 50 consecutive SLE patients of one rheumatologist seen in usual care. On arrival at the clinic, patients completed a multidimensional health assessment questionnaire (MDHAQ) which includes scales for physical function (FN), 0-10 visual analog scales for pain (PN), global estimate (PTGL) and fatigue (FT), and a review of systems symptom checklist (SX). SLE patients also completed a self-report Systemic Lupus Assessment Questionnaire (SLAQ). The rheumatologist, unaware of MDHAQ and SLAQ scores, recorded a physician global estimate (MDGL) and an estimate of non-inflammatory symptoms, each scored on a 0-3 scale in 0.1 increments, as well as four SLE indices: SLEDAI-2K (SLE Disease Activity Index), BILAG (British Isles Lupus Assessment Group index), SLAM (SLE Activity Measure) with and without laboratory tests, and ECLAM (European Consensus Lupus Activity Measurement). SLE patients with scores of <0.5 on the noninflammatory symptom scale were regarded as low and those with scores >=0.5 high noninflammatory symptoms; the two groups were compared using the Mann-Whitney statistic. Results: The study included 45 women and 5 men, mean age 38.7 years, mean disease duration 7.3 years. Of the 50 patients, 16 had high and 34 low scores for non-inflammatory symptoms. Those with high scores for non-inflammatory symptoms had significantly higher scores for FN, PN, FT, PTGL, SX, SLAQ, and SLAM without laboratory tests, as well as significantly lower CRP. No significant differences were seen patients estimated as high and low scoring patients for SLEDAI, BILAG, SLAM, ECLAM, C3, C4, antiDsDNA, or ESR. Fewer than 50% of low patients had FN, PN, PTGL, or FT >=2, while 100% of high patients had FT >2, and 94% PTGL >2. All patients with high non-inflammatory symptoms (16/16) reported more than 5 SX, compared to 15/34 (44%) low patients, and 12/16 (75%) high patients reported >10 SX, compared to 6/34 (18%) low patients. (Table Presented) Conclusion: High scores for dysfunction, pain, fatigue, global estimates, and number of symptoms are common in SLE patients with high versus low levels of non-inflammatory symptoms. SLE indices do not distinguish between patients with high versus low levels of non-inflammatory symptoms. A simple global scale to estimate non-inflammatory symptoms may be informative in therapeutic decisions, particularly if consistent with patient questionnaire patterns

Purpose: Coagulation is one of the first pathways to be elicited by vascular injury, and its activation is followed by proinflammatory phenomena, in part due to loss of the anti-inflammatory activity of both the Protein C pathway and membrane Endothelial Protein C receptor (mEPCR). It has been recently demonstrated that mEPCR is highly expressed in the cortical peritubular capillaries of kidneys from patients (pts) with active lupus nephritis compared to normal human kidney. Profound upregulation of mEPCR was observed even in areas absent tubulointerstitial damage. This study addressed the hypothesis that changes in the microvasculature extend beyond the clinically targeted organ and that dysregulation is a fundamental characteristic of SLE. Methods: The study included SLE pts in whom renal disease was considered active as assessed by proteinuria and urinary sediment. Renal biopsies were performed in all pts. Thirty skin biopsies from non-lesional nonsunexposed skin (buttocks) were obtained in 26 pts (23 females, 3 males) and five healthy controls (4 females, 1 male). The paraffin skin sections were individually stained with specific antibodies against mEPCR and adiponectin (protective markers), ICAM-1 (proinflammatory) and CD31 (pan endothelial marker). Immunohistochemistry (IHC) was scored by counting peroxidase-brown labeled blood vessels (10-20 microns in diameter) without knowledge of the clinical information associated with the biopsy. The number of blood vessels with an intensity of at least 1+ were quantitatively scored with ranges 1-12. To account for the number of blood vessels per slide, the CD31 count had to be 12 to be included in the analysis. Results: The 28 renal biopsies comprised the following ISN/RPS classifications: 4 Class III, 7 Class IV, 8 Class V, I Class VI, 3 Class III/V, 3 Class IV/V. Nineteen percent of the pts had a GFR <60 (mean GFR, 82 ml/min). Abnormal laboratory values for complement and anti-dsDNA antibodies were reported in 72% and 75% of pts, respectively. Nephrotic range proteinuria was present in 37%. For IHC skin assessments of the controls, the mean score for mEPCR was 1 (highest 2), ICAM-1 was 4 (highest 7) and adiponectin was 1 (highest 2). In 17/25 (68%) of the SLE non-lesional non-sun exposed skin sections, mEPCR was expressed above the highest control. In 16/30 (53%) ICAM-1 staining exceeded 7. In contrast, only 6/25 (19%) expressed adiponectin above 2. For each specific stain there were no apparent differences between biopsy class, degree of proteinuria, presence of anti dsDNA or low complement levels. However, pts with mEPCR staining above 2 had higher GFR measurements than those with staining < 2 (88 ml/min +/- 31 versus 53 +/- 32, p= 0.0168). In contrast, GFR was unrelated to ICAM-1 and adiponectin expression. Conclusion: These data are consistent with the notion that there is widespread activation of the microvasculature. The capacity of endothelial cells to utilize anticoagulation pathways is not restricted to the kidney and expression of mEPCR in the microcirculation likely represents an attempt to limit microvascular inflammation in kidney and skin

Purpose: Despite weekly monitoring of fetuses exposed to maternal anti-SSA/Ro antibodies, immediate treatment has never permanently reversed complete heart block. This irreversibility strongly supports an emphasis on preventative strategies. A recent case-control study revealed that fetal exposure to Hydroxychloroquine (HCQ), which prevents endosomal acidification and Toll-Like Receptor ligation (proposed pathway involved in cardiac inflammation and scarring), decreases the risk of cardiac manifestations of neonatal lupus (cardiac-NL) in Systemic Lupus Erythematosus (SLE) mothers with anti-SSA/Ro antibodies. That study did not address the effect of HCQ on the recurrence rate in subsequent pregnancies which is nearly 10 fold the frequency in anti-SSA/Ro positive women who have not had an affected child. Accordingly, this study explores whether HCQ prevents the development of cardiac-NL in these highest risk pregnancies. Methods: Twenty-four pregnancies of 22 mothers satisfied the inclusion criterion: exposure to HCQ in a pregnancy of a mother whose previous child had either cardiac or cutaneous-NL. Exposure was defined as the sustained use of HCQ throughout pregnancy with initiation prior to 6 weeks gestation. In 19 of these 22 families the previous child had cardiac-NL (1-isolated cardiomyopathy and 18-advanced congenital heart block (CHB) 8 of whom died from complications of the disease) and in 3 families the prior child had cutaneous-NL. Of these 22 previous NL pregnancies, 15 were unexposed to HCQ (13 CHB, 1 cardiomyopathy and 1 rash), 6 were exposed to HCQ (4 CHB and 2 rash) and in 1 CHB child, exposure to HCQ was unknown. Results: Sixty-eight percent of the mothers were Caucasian. The maternal health status was SLE in 41%, Sjogren's Syndrome (SS) in 32%, SLE with secondary SS in 18%, and Undifferentiated Autoimmune Syndrome in 9%. Sixty-four percent (14/22) of the mothers were positive for both anti-SSA/Ro and anti-SSB/La antibodies. The mean daily dose of HCQ was 352.6 mg. Using prospective data from the Research Registry for Neonatal Lupus, the recurrence rate of cardiac-NL following a child with cardiac-NL is 18% (based on 161 pregnancies following a previous child with CHB) and the occurrence rate of cardiac-NL following a child with cutaneous-NL is 13% (based on 39 pregnancies following a previous child with cutaneous-NL). These data suggest that the expected rate of cardiac-NL in this cohort should be approximately 17.2%. Of the 24 subsequent pregnancies exposed to HCQ in this study only one fetus developed cardiac-NL (3^rd degree) and this mother's previous child had cutaneous-NL. Thus, the recurrence/occurrence rate was 4.2% (95% CI:(0.11% - 21.1%), a reduction of 75.7%. In addition to HCQ, 25% (6/24) of the mothers received intermittent low dose IVIG, 75% (18/24) non-fluorinated steroids, 17 of whom were on <= 10 mg of Prednisone, and 8.3% (2/24) fluorinated steroids, one after the diagnosis of CHB. Conclusion: This case series suggests that in mothers with anti-SSA/Ro antibodies and a previous child with NL, exposure to HCQ during a subsequent pregnancy may decrease the risk for fetal development of cardiac-NL

Purpose: The classic cardiac manifestations of neonatal lupus (cardiac-NL) include a spectrum of conduction dysfunction (1^st, 2^nd, or 3^rd degree heart block (CHB)) and more rarely cardiomyopathy which can be absent any conduction disease. This study was undertaken to update the mortality data of cardiac-NL in a large US based cohort and identify associated risk factors to further understand the pathogenesis of anti-SSA/Ro mediated injury and provide evidence based data for counseling women with these antibodies. Methods: Three hundred and one children with cardiac-NL (295 with CHB and 6 with isolated cardiomyopathy) enrolled in the Research Registry for Neonatal Lupus (RRNL) had sufficient medical records for review. The RRNL database was analyzed for the following potential mortality maternal risk factors: age at pregnancy, race/ethnicity, anti-SSB/La antibody status, health status and fetal risk factors: time of diagnosis, exposure to maternal non-fluorinated and fluorinated steroids during pregnancy, method of delivery, and gender. In addition, morbidity was assessed by the frequency of pacemaker placement and cardiac transplant. Results: Follow up of the children ranged from in utero death to adulthood. Of the 301 children with cardiac-NL, 53 (17.6%) died. Thirty percent died in utero or at birth, 41% died prior to six months of postnatal life and the remaining 29% died after 6 months. Mortality was higher among children born to non-Caucasian mothers compared to Caucasian mothers (33% vs 15% p=.0003). Maternal age was equivalent between the groups (29.1 dead vs 29.7 live). The maternal presence of anti-SSB/La antibodies was 74% for those whose children died and 63% for those whose children survived, which was not significant. A maternal diagnosis of Sjorgen's Syndrome and/or Systemic Lupus Erythematosus was not significantly associated with cardiac-NL death (53% in death vs 44%) suggesting that prior knowledge of maternal antibody status did not influence mortality. With regard to fetal factors, 86% of those who died were diagnosed with cardiac-NL during pregnancy compared to 85% who survived. For those diagnosed during pregnancy there was a trend towards early gestational diagnosis for those children that died compared to those that survived (21 vs 23.5 weeks p=.09). There was also a trend toward higher exposure to maternal fluorinated steroids after the diagnosis in children that died (53% vs 40% p=.09), however there was no difference in maternal use of non-fluorinated steroids in those that died vs those that survived (19% vs 16%). Most fetuses were delivered by C-section and this was not significantly associated with death (70% dead vs 75% live). Female gender was also not associated with outcome (49% who died were female vs 52% live). Eighty-five percent of children received a pacemaker, 43% within 9 days of birth, 20% between 9 days and one year. Five children (2%) received a heart transplant. Conclusion: Based on data from this large cohort, 17.6% of children born with cardiac-NL die from complications of the disease. Eighty-five percent required pacing and two percent required cardiac transplantation. Mortality was more prevalent in children born to non Caucasian mothers