Biomedical subjects

Earl D Silverman

Publications and source records attributed to Earl D Silverman.

At least 19 recordsLinked to original sources

PubMed2025

Next generation sequencing analysis reveals complex genetic architecture of childhood-onset systemic lupus erythematosus.

OBJECTIVES: Our current understanding of the genetic architecture of childhood-onset SLE (cSLE) is limited by a dearth of comprehensive genomic studies in cSLE. We have quantified the number of known rare and common SLE risk variants in a diverse cSLE cohort. We characterised type I interferon (IFN) gene expression scores along with genomic data. METHODS: We performed whole genome sequencing on 83 patients with cSLE and 109 unaffected parents and analysed sequences for known common and rare SLE-associated risk variants. Type I IFN gene expression was quantified on a subset of patients. We investigated the relationship between clinical phenotype, genomic profile and type I IFN signatures in this cohort. RESULTS: Patients with cSLE were enriched for common SLE risk variants compared with unaffected parents and controls. We identified rare SLE risk variants in 11% of individuals with cSLE; those with rare variants had earlier disease onset (<12 years) than those without variants. Patients with cSLE had elevated type I IFN gene expression compared with unaffected parents and controls, even though most patients were treated with immunosuppressive therapy. CONCLUSIONS: Patients with cSLE from this ancestrally and geographically diverse cohort are enriched for common cSLE risk variants compared with controls, and 11% carry a rare variant in known monogenic SLE risk genes. The relationship between rare and common risk variant burden is more complex than previously hypothesised. Our findings indicate that studying patients with cSLE is important for understanding genetic contributions to SLE pathogenesis.

Humans↗

PubMed2006

Macrophage activation syndrome as the presenting manifestation of rheumatic diseases in childhood.

We describe 3 patients who presented with features of macrophage activation syndrome (MAS) at the time of presentation of systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis, and Kawasaki disease. Immunohistochemical studies in the patient with SLE demonstrated extensive expression of CD163 on hemophagocytic macrophages, suggesting a possible role as a marker of MAS.

Adolescent↗

PubMed2006

Corticosteroid treatment of refractory Kawasaki disease.

OBJECTIVE: To review the indications for corticosteroids in patients with Kawasaki disease (KD) treated by pediatric rheumatologists in Canada and to determine their efficacy on fever in patients with refractory KD. METHODS: All practicing pediatric rheumatologists in Canada identified KD patients treated with corticosteroids and completed a standard data form that included demographics, clinical and laboratory features, imaging studies, and therapeutic interventions, by chart review. RESULTS: Thirty-two patients with KD (14 female; 18 male: mean age 4.6 years) were treated with corticosteroids. Corticosteroids were used in 26 patients (81%) for persistent fever despite treatment with intravenous immunoglobulin (IVIG) (refractory KD), 5 patients (19%) for congestive heart failure, and 1 patient for persistent acute phase symptoms other than fever. The 26 patients with refractory KD are the primary subject of this report. Twenty-two patients (85%) had rapid, sustained resolution of fever after corticosteroids. There were no serious reported adverse effects. Eight patients (31%) treated with corticosteroids developed coronary artery (CA) aneurysms and 9 (35%) developed CA dilatations without aneurysms. Of those who developed CA aneurysm, 4 had aneurysms detected prior to IV methylprednisolone (MP) on echocardiograms performed on days 6-27 (mean day 13) of illness. The remaining 4 patients had CA aneurysm detected after IVMP therapy, on echocardiograms performed on days 13-49 (mean day 23) of illness, 1-25 days (mean 9 days) after IVMP. In patients with one year or more of followup, 46% had resolution of CA abnormalities. CONCLUSION: Corticosteroids are effective in the treatment of fever in most patients with IVIG-refractory KD. A multicenter prospective study is needed to determine the effect of corticosteroids on CA outcome in patients with refractory KD.

Child↗

PubMed2005

Increased risk of complete congenital heart block in infants born to women with hypothyroidism and anti-Ro and/or anti-La antibodies.

OBJECTIVE: To determine whether the presence of hypothyroidism is associated with an increased incidence of neonatal lupus erythematosus (NLE) in infants of mothers with anti-Ro autoantibodies. METHODS: The cohort consisted of 87 women with anti-Ro antibodies who delivered 102 infants. All infants had a full history and physical examination within 12 weeks of birth, electrocardiogram (echocardiogram when clinically indicated), complete blood cell count with differential, liver function tests, and autoantibody profile. Nine women had hypothyroidism and 78 had normal thyroid function. RESULTS: At least one manifestation of NLE was seen in 7/9 (78%) infants born to mothers with hypothyroidism and 45/78 (58%) infants born to mothers with normal thyroid function. Complete congenital heart block (CCHB) was seen in 5/9 (55%) in the hypothyroid group and 10/78 (13%) of the normal thyroid function group (p < 0.005). Mothers with hypothyroidism had a 9-fold increased risk over women with normal thyroid function of having a child with CCHB (odds ratio 8.63). Twenty-seven (31%) of the women were healthy: 4/9 of the hypothyroid and 23/78 of the normal thyroid function group. Of the 23 infants born to healthy mothers with normal thyroid function, 15/23 (65%) had NLE and 8/23 (35%) of these had CCHB. CONCLUSION: Women with hypothyroidism and anti-Ro antibodies were at increased risk for delivering a child with CCHB compared to women with antibodies alone, irrespective of maternal health. This study indicates that women with hypothyroidism should be tested for anti-Ro antibodies, as they may be at risk to deliver a child with CCHB.

Adult↗

PubMed2005

Effect of maternal autoantibodies on fetal cardiac conduction: an experimental murine model.

The pathogenesis of congenital heart block (CHB) remains unclear. The occurrence rate of neonatal CHB is low, even in murine models of lupus erythematosus. The assessment of heart block in murine maternal lupus models by measuring atrioventricular conduction in neonatal offspring is potentially confounded by fetal wastage. We therefore sought to develop a murine CHB model with a superior immune response and to use embryonic Doppler echocardiography to observe conduction system damage in the fetus. Mature 8-wk-old female C3H/HeJ mice (n=43) were immunized with 60 kD Ro, 48 kD La, or recombinant calreticulin autoantigens. ELISA confirmed that significant serum autoantibodies developed in all three immunized groups when compared with controls. Starting at 13 d of gestation, a significantly lower fetal heart rate (HR) and a higher percentage of fetal bradycardia/atrioventricular block (AVB, nonadvanced second degree) were observed in all immunized groups, compared with controls. There was 9-18% nonadvanced second-degree AVB in immunized groups and 0% in controls at <18 d of gestation. Neonatal electrocardiograms demonstrated only 1 degrees AVB in immunized groups. Maternal immunization with 60 kD Ro, 48 kD La, or recombinant calreticulin autoantigens resulted in AVB in a significant percentage of fetuses, however, lesser degrees of AVB were seen at birth. Significant fetal bradycardia and AVB may be missed by assessment only at birth in murine models of CHB due to fetal wastage.

Animals↗

PubMed2005

Angiography-negative primary central nervous system vasculitis in children: a newly recognized inflammatory central nervous system disease.

Inflammatory central nervous system (CNS) diseases in childhood comprise a wide spectrum of heterogeneous conditions. We studied 4 children with primary CNS vasculitis in whom results of magnetic resonance imaging studies were abnormal but results of conventional angiography were normal. We determined that angiography-negative, biopsy-confirmed primary small-vessel CNS vasculitis is a previously unrecognized distinct disease entity in children. The diagnosis must be considered in a child with a progressive, acquired diffuse or focal neurologic deficit, even if the results of conventional angiography are normal. A lesional brain biopsy is required to confirm the diagnosis. Use of immunosuppressive therapy plus aspirin leads to an excellent neurologic outcome.

Adolescent↗

PubMed2005

Systemic lupus erythematosus.

Systemic lupus erythematosus in children and adolescents is a multisystem autoimmune disease with a great variability in disease presentation and course. This article summarizes available epidemiologic data, clinical patterns, approaches to investigation and treatment, and recent outcome data.

Adolescent↗

PubMed2005

Infections and Kawasaki disease: implications for coronary artery outcome.

OBJECTIVE: We sought to determine the effect of coincident infection, at time of diagnosis of Kawasaki disease (KD), on treatment response and coronary artery outcome. METHODS: A single-center, retrospective study of 129 consecutive patients diagnosed with typical KD between January 1997 and December 1998 was performed. Standardized clinical assessments, laboratory, microbiology, and imaging test results plus treatment regimens were reviewed. Coronary arteries were visualized by using echocardiography, and coronary artery lesions (CALs) were reported as body surface area-adjusted z scores. Infection-positive and -negative groups were identified, and clinical, laboratory, and treatment data were analyzed. The effect of infections and other outcome variables on CAL development was determined by multivariate regression analysis. RESULTS: (1) Concurrent infections: 33% of children with typical KD had > or =1 confirmed infection at KD diagnosis. (2) Treatment response: the presence of infection did not alter the response to treatment with intravenous immunoglobulin, with resolution of fever in 83% of children after 1 dose of intravenous immunoglobulin together with aspirin administration regardless of presence or absence of infection. (3) Coronary outcome: in total, 31% of the patients developed CALs. Both the proven-infection and no-proven-infection groups had a similar CAL frequency. (4) Multivariate regression analysis: proven infection did not increase the risk of coronary artery involvement even after adjusting for other factors impacting on coronary artery outcomes. CONCLUSIONS: Infections are common at diagnosis of KD. A broad spectrum of infectious agents was found. Infections at diagnosis of KD did not affect the patients' response to treatment and coronary artery outcome when compared with those patients without infections.

Adolescent↗

PubMed2005

Longterm outcomes in patients with giant aneurysms secondary to Kawasaki disease.

OBJECTIVE: Kawasaki disease (KD) has potentially serious cardiac complications including coronary artery aneurysms. Children who develop giant aneurysms (GA) are at increased risk of thrombosis and ischemia, and although longterm oral anticoagulation with warfarin is recommended, its efficacy has not been studied. We examined the longterm outcome of patients with GA secondary to KD, to determine if anticoagulation with warfarin aids in the prevention of myocardial ischemia. METHODS: We studied patients with KD followed between May 1990 and April 2000. RESULTS: Thirty-nine GA occurred in 2.2% of patients with KD (22/997 patients), and 33 non-GA were also identified in these patients. Patients were divided into 2 groups, those taking warfarin and no warfarin. Most patients in both groups were also taking antiplatelet agents. The demographics of the 2 groups were statistically similar, except the median duration of followup was significantly longer for patients in the no-warfarin group (6.9 vs 13.3 yrs; p = 0.008). Four early ischemic events (< 1 year after KD diagnosis) occurred (3 myocardial infarctions and one stroke). Screening for late ischemic events by stress nuclear medicine myocardial perfusion imaging revealed only one patient, in the no-warfarin group, with reversible perfusion defects. No patient had clinical signs or symptoms of late myocardial ischemia. Echocardiographic regression of aneurysms was observed in both groups. In the warfarin vs no-warfarin group, the diameters of the GA regressed a median 22% vs 32% (p = 0.27), and non-GA regressed a median of 30% vs 25% (p = 0.61). Compliance with anticoagulation was good, and no major bleeding complication of anticoagulation occurred. CONCLUSION: Regression of GA occurred in most of our patients, and minimal late ischemia was observed. Further studies are required to evaluate the use of oral anticoagulation in patients with GA secondary to KD.

Adolescent↗

PubMed2005

Nasal septal perforation: a novel clinical manifestation of systemic juvenile idiopathic arthritis/adult onset Still's disease.

Nasal septal perforation has been well recognized in patients with various rheumatic diseases. To our knowledge, this condition has not been reported in children with systemic juvenile idiopathic arthritis (SJIA) or patients with adult onset Still's disease (AOSD). We describe 3 patients with persistent SJIA/AOSD who developed nasal septal perforation during the course of their disease. As illustrated by these cases, nasal septal perforation may develop as a rare complication of SJIA/AOSD and can be considered as part of the clinical spectrum of the disease. In one case the nasal septal perforation was associated with vasculitis.

Adolescent↗

PubMed2004

Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease.

BACKGROUND: Untreated isolated fetal complete atrioventricular block (CAVB) has a significant mortality rate. A standardized treatment approach, including maternal dexamethasone at CAVB diagnosis and beta-stimulation for fetal heart rates <55 bpm, has been used at our institutions since 1997. The study presents the impact of this approach. METHODS AND RESULTS: Thirty-seven consecutive cases of fetal CAVB since 1990 were studied. Mean age at diagnosis was 25.6+/-5.2 gestational weeks. In 33 patients (92%), CAVB was associated with maternal anti-Ro/La autoantibodies. Patients were separated into those diagnosed between 1990 and 1996 (group 1; n=16) and those diagnosed between 1997 and 2003 (group 2; n=21). The 2 study groups were comparable in the clinical presentation at CAVB diagnosis but did differ in prenatal management (treated patients: group 1, 4/16; group 2, 18/21; P<0.0001). Overall, 22 fetuses were treated, 21 with dexamethasone and 9 with beta-stimulation for a mean of 7.5+/-4.5 weeks. Live-birth and 1-year survival rates of group 1 were 80% and 47%, and these improved to 95% for group 2 patients (P<0.01). The 21 patients treated with dexamethasone had a 1-year survival rate of 90%, compared with 46% without glucocorticoid therapy (P<0.02). Immune-mediated conditions (myocarditis, hepatitis, cardiomyopathy) resulting in postnatal death or heart transplantation were significantly more common in untreated anti-Ro/La antibody-associated pregnancies compared with patients treated with steroids (0/18 versus 4/9 live births; P=0.007). CONCLUSIONS: A standardized treatment approach, including transplacental fetal administration of dexamethasone and beta-stimulation at heart rates <55 bpm, reduced the morbidity and improved the outcome of isolated fetal CAVB.

Adrenergic beta-Agonists↗

PubMed2003

European Consensus Lupus Activity Measurement is sensitive to change in disease activity in childhood-onset systemic lupus erythematosus.

OBJECTIVES: To evaluate the European Consensus Lupus Activity Measurement (ECLAM) for responsiveness to change in disease activity when used in childhood-onset systemic lupus erythematosus (cSLE). To confirm the construct validity and to characterize the measurement properties of the ECLAM by assessing its ability to predict damage and steroid requirements. METHODS: The disease courses of 66 newly diagnosed cSLE patients were reviewed. The ECLAM and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were scored for all clinic visits and hospitalizations. Damage was assessed at the end of the followup period using the Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index. Disease activity at the time of diagnosis, 6 months after diagnosis, at the time of first flare, and 6 months after first flare was used to estimate responsiveness of the measures. Responsiveness was measured by the effect size, the effect size index, the standardized response mean, and the relative efficiency index (REI). The measurement properties of the ECLAM and SLEDAI over time were examined by comparing the ability of both measures to predict damage and oral steroid requirement. RESULTS: The ECLAM and SLEDAI are both responsive to change in disease activity irrespective of the statistic used. The ECLAM is more sensitive than the SLEDAI using the REI (all >1.9). Cumulative disease activity as measured by the SLEDAI or the ECLAM are important predictors of damage. There are no statistically important differences between the 2 measures with regard to their ability to predict steroid requirements. CONCLUSIONS: The ECLAM has construct validity in cSLE and, like the SLEDAI, is highly sensitive to clinically important change in disease activity. The ECLAM may be more responsive. The quantitative properties of the 2 measures are very similar. The SLEDAI likely remains the preferable disease activity measure for cSLE given its overall measurement properties and ease of use.

Administration, Oral↗

PubMed2003

Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-Ro autoantibodies.

OBJECTIVE: Neonatal lupus erythematosus (NLE) is characterized by complete congenital heart block (CCHB), cutaneous rash, and laboratory abnormalities in infants born to mothers with autoantibodies directed against SSA/Ro, SSB/La, or both. We carried out a prospective study to determine the incidence of individual NLE features. STUDY DESIGN: The study was performed in two centers: Toronto, Canada, and Milano, Italy. Mothers had been referred for the presence of anti-SSA/Ro autoantibodies, regardless of their diagnosis. All the children were seen at least once within the first 6 months of life for clinical evaluation and laboratory testing. The study group consisted of 128 infants born from 124 pregnancies in 112 women with anti-Ro antibodies with or without anti-La antibodies. RESULTS: There were two cases of CCHB for an overall percentage of 1.6%. Twenty-one children (16%) developed cutaneous NLE. Laboratory testing showed hematologic abnormalities in 27% of the babies and elevation of liver enzymes in 26%. CONCLUSIONS: Mothers with autoimmune diseases and anti-Ro antibodies are at risk of delivering a child with NLE but at a low risk of delivering a child with CCHB. Infants born to mothers with anti-Ro or anti-La antibodies should be monitored for other features of NLE in addition to CCHB.

Adolescent↗

PubMed2003

Thrombocytopenia and thromboembolism in pediatric systemic lupus erythematosus.

To define in children with systemic lupus erythematosus (SLE) the incidence, outcome, and association of thrombocytopenia with other SLE manifestations, specifically thromboembolic events (TEs), we retrospectively reviewed 106 pediatric patients with SLE diagnosed between 1992 and 2001. Thrombocytopenia was found in 50%, which was of a moderate or severe degree in 34%. The thrombocytopenia was sustained in 29% of all patients. Twelve patients were diagnosed with autoimmune thrombocytopenic purpura 2 to 69 months before the diagnosis of SLE. Of them, 10 children required treatment, and three patients underwent splenectomy. TEs occurred in 10.4% of the total cohort of 106. Lupus anticoagulant, but not anticardiolipin antibodies and sustained thrombocytopenia, were associated with a higher risk for TEs.

Antibodies↗

PubMed2003

Superantigenic activity is responsible for induction of coronary arteritis in mice: an animal model of Kawasaki disease.

Kawasaki disease (KD) is a multisystem vasculitis and the leading cause of acquired heart disease in children of the developed world. Lactobacillus casei cell wall extract-induced coronary arteritis in mice mirrors KD in children. Here, we report that responses to L. casei cell wall extract possess all the hallmarks of a superantigen-mediated response: marked proliferation of naive T cells, non-classical major histocompatibility restriction with a hierarchy in the efficiency of different class II molecules to present this superantigen, a requirement for antigen presentation, but not processing, and stimulation of T cells in a non-clonal, TCR V(beta) chain-dependent fashion. This superantigenic activity directly correlates with the ability to induce coronary arteritis in mice. Taken together, our findings demonstrate that superantigenic activity in L. casei cell wall extract is responsible for induction of coronary artery disease.

Animals↗

PubMed2003

Are children with Kawasaki disease and prolonged fever at risk for macrophage activation syndrome?

Kawasaki disease (KD) patients are known to be at increased risk for coronary artery lesions. We present evidence of another possible complication associated with KD: macrophage activation syndrome (MAS). In this case, a patient with KD and prolonged fever developed MAS. This case is of particular interest because of the late age of onset and recurrent nature of KD as well as the complication of MAS. We also present a review of the literature that supports the inclusion of MAS as an infrequent complication of KD.

Child↗

PubMed2003

Evaluation of eutectic lidocaine/prilocaine cream (EMLA) for steroid joint injection in children with juvenile rheumatoid arthritis: a double blind, randomized, placebo controlled trial.

OBJECTIVE: To evaluate the efficacy of eutectic lidocaine/prilocaine cream (EMLA) in reducing the pain associated with steroid joint injection in children with juvenile arthritis. METHODS: A randomized, double blind, placebo controlled parallel group trial. Thirty-one children (ages 8-18 yrs) scheduled for steroid injection into a knee were randomized into groups having either 2.5 g lidocaine/prilocaine cream or placebo cream applied to the injection site 60-90 min before the procedure. Patients assessed the pain associated with initial needle insertion and subsequent steroid injection using a 10 cm visual analog scale. RESULTS: No significant difference was found in the pain reported after needle insertion or steroid injection between the lidocaine/prilocaine cream group (n = 17) and the placebo group (n = 14). There was a trend toward an association of lower median scores with the pain of steroid injection in the lidocaine/prilocaine group (6 mm) compared with the placebo group (22 mm). CONCLUSION: Application of 2.5 g lidocaine/prilocaine cream for 60-90 min had no statistically significant analgesic effect on pain associated with injections of steroids into the knees of children with juvenile arthritis.

Adolescent↗

PubMed2002

Endocardial fibroelastosis associated with maternal anti-Ro and anti-La antibodies in the absence of atrioventricular block.

OBJECTIVES: This study was designed to document the association of endocardial fibroelastosis (EFE) and maternal autoantibodies. BACKGROUND: Neonatal lupus erythematosus is associated with the transplacental passage of maternal anti-Ro and anti-La antibodies, leading to complete atrioventricular block (CAVB). In some cases, CAVB is associated with EFE. Isolated EFE may be independently related to maternal anti-Ro and anti-La antibodies. METHODS: We identified three cases (one fetus and two infants, all female) of isolated EFE in infants born to autoantibody-positive mothers in the absence of CAVB. Demographics, echocardiograms, and pathology were reviewed. Immunohistochemical analyses for immunoglobulin (Ig)G, IgM, IgA, T-cell, B-cell, and terminal deoxynucleoleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) (test for cell apoptosis) staining were performed on multiple sections of the heart in each case and compared with negative controls. RESULTS: Two cases died and one received a cardiac transplant. All three cases had histologically confirmed EFE. All cases demonstrated significant diffuse IgG infiltration. To a lesser extent, myocardial tissue was also positive for IgM, CD43, and Granzyme B. None of the specimens were TUNEL positive. CONCLUSIONS: These are the first reported cases of isolated EFE associated with maternal anti-Ro and anti-La antibodies in the absence of CAVB. The diffuse deposition of IgG and the presence of a T-cell infiltrate throughout the myocardium suggest that the transplacental passage of maternal autoantibodies induces an immune reaction within the myocardium, leading to isolated EFE. Autoantibody-mediated EFE may be an etiologic factor in cases of fetal and neonatal "idiopathic" dilated cardiomyopathy.

Antibodies, Antinuclear↗