E D Silverman

SickKids, Toronto, Ontario, Canada

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Publications (277)1262.91 Total impact

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    ABSTRACT: To evaluate and determine the most effective immunosuppressive therapy for the induction treatment of proliferative lupus nephritis (PLN) based on renal remission.
    The Journal of rheumatology. 09/2014;
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    ABSTRACT: Key Clinical MessageSystemic lupus erythematosus should be included in the differential diagnosis of every adolescent with pancytopenia. An accurate diagnosis with the appropriate therapy is vital and can cause lasting reversal of this condition.
    Clinical Case Reports. 09/2014;
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    ABSTRACT: Studies of paediatric patients with membranous lupus nephritis (MLN) have yielded variable results, mostly due to the inclusion of mixed, i.e. proliferative nephritis. The aim of this study was to describe clinical and laboratory findings at the diagnosis of paediatric non-proliferative MLN, report the outcome and identify predictors of remission.
    Pediatric nephrology (Berlin, Germany). 07/2014;
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    ABSTRACT: Objective: To evaluate the influence of ethnicity on self-reported health related quality of life (HRQOL) in the Canadian childhood-onset systemic lupus Erythematosus (cSLE) population.Methods: Patients with cSLE at 4 pediatric centers were consecutively enrolled. Sociodemographics and multiple disease activity measures were collected. The Child Health Questionnaire (CHQ) was administered and analysed by ethnicity.Results: We enrolled 213 cSLE patients, and complete data from 196 patients with these ethnicities were analysed: White (33%), Asian (32%), South Asian (16%), Black (11%), Latino/Hispanic (5%), and Aboriginal (4%). Compared to healthy children, cSLE patients rated their HRQOL significantly more poorly in 9 of 10 individual domains, and in 4 of 10 domains when compared to a cohort of juvenile arthritis. Within the cSLE cohort, CHQ scores were lower in 5 of 10 domains in white patients versus nonwhite ethnicities (p<0.05 for each). Physical summary scores (PhS) were lower for white patients compared to the other ethnicities aggregated together (46.0 ± 11.9 vs. 50.4 ± 10.1, p = 0.009); however, psychosocial summary scores (PsS) were similar among the groups (40.5 ± 14.6 vs. 42.8 ± 12.7, p = 0.26). Disease activity measures, including Systemic Lupus Disease Activity Index, Systemic Lupus Activity Measure and physician global visual analogue scale were similar across ethnicities. However, patient reported Systemic Lupus Activity Questionnaire symptom scores were greater in patients of white ethnicity compared to those of Asian ethnicity (8.2 ± 5.8 vs. 4.5 ± 4.7, p=0.004).Conclusion: The self- and parent-reported health status of Canadian cSLE patients differed across ethnicities, with white patients reporting lower HRQOL, despite similar and overall low disease activity. © 2014 American College of Rheumatology.
    Arthritis Care & Research. 05/2014;
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    ABSTRACT: Objective: To determine the impact of prenatal exposure to maternal anti-Ro antibodies, slow fetal heart rate and/or chronic dexamethasone therapy for immune-mediated congenital atrio-ventricular heart block (CAVB) on cognitive and academic performance at school age.Methods: Prospective, blinded assessment of cognitive functioning of 3 cohorts of children aged 6-16 years with in-utero exposure to maternal anti-Ro antibodies and with: 1) no CAVB and no prenatal dexamethasone (n=14); 2) CAVB without prenatal treatment (n=10); and 3) CAVB with prenatal dexamethasone therapy (n=16). Domains assessed included intelligence, visual perceptual and visual motor skills, auditory and visual attention, verbal learning and memory, visual memory, executive function and behavior.Results: All cohorts scored within the normal range and were not significantly different in intelligence scores, verbal comprehension, perceptional reasoning, working memory, and processing speed. For prenatally treated children with CAVB, there were no significant associations between neurocognitive function scores, minimal fetal heart rate (range: 47 – 80 beats/min) and the duration and dosage (2-15 weeks; 56 – 824 mg) of dexamethasone therapy.Conclusion: CAVB and transplacental prenatal treatment with dexamethasone was not associated with neurocognitive impairment in school-age children. Larger numbers are required to validate our observation and assessment of other cognitive abilities is warranted. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 04/2014;
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    ABSTRACT: Background/Purpose:Childhood-onset systemic lupus erythematous (cSLE) has a more severe clinical course with higher disease activity and involvement of major organs compared to adult-onset SLE. Avascular necrosis (AVN) is a significant morbidity causing pain and disability, sometimes requiring joint replacement surgery. Our objective was to examine the frequency and risk factors for symptomatic AVN in cSLE.Methods:A single center matched case-control design was used. 617 patients with cSLE followed at SickKids Lupus Clinic between July 1982 and June 2013 were included in the study. The AVN cohort consisted of 37 patients identified with clinical findings of symptomatic AVN and diagnosis confirmed by one or more imaging modalities. Three controls were matched to each AVN patient by date and age at diagnosis (± 1 year). Baseline clinical, laboratory and treatment characteristics were compared between the patients with AVN and the controls by univariate analyses and if statistically significant, were included in a multivariable logistic regression model.Results:A total of 37/617 (6%) patients developed symptomatic AVN during follow-up at SickKids. The majority was female (30/37, 81%) and of Asian descent (20/37, 54%). The mean age at diagnosis was 16.1 years (±2.1), with median time to AVN of 1.52 years. Only 2/37 (5%) of patients developed AVN prior to the onset of puberty. The hip was the most commonly involved joint (26/37, 70%) with bilateral involvement in 49% (18/37) of patients. Compared to the matched non-AVN cohort, patients with AVN had higher incidence of CNS disease (p = 0.003), nephritis (p < 0.001), acute or chronic renal failure (p = 0.029), but less frequent photosensitivity (p = 0.006). Patients with AVN also required greater cumulative prednisone from cSLE diagnosis to AVN (364 ± 53 vs. 232 ± 36 mg/kg, p < 0.001), higher prednisone dose at time of AVN diagnosis (±3 months, 0.30 ± 0.25 vs. 0.19 ± 0.24 mg/kg, p = 0.012), maximal daily prednisone dose (1.25 ± 0.36 vs. 0.71 ± 0.53 mg/kg, p < 0.001) and more frequent use of pulse methylprednisolone therapy (39% vs. 10%, p < 0.001). The median prednisone dose at time of AVN was 0.27 vs. 0.09 mg/kg. Multivariable regression analysis confirmed nephritis, CNS disease, maximal daily prednisone dose and use of pulse methylprednisolone as significant predictors of symptomatic AVN development. Overall disease activity from SLE diagnosis to AVN diagnosis as measured by adjusted mean SLEDAI was not significantly different (6310 ± 976 vs. 4994 ± 440, p = 0.165).Conclusion:cSLE patients with severe organ involvement including nephritis and CNS disease, higher maximal daily dose of prednisone, and more frequent use of pulse methylprednisolone are more likely to develop symptomatic AVN.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Background/Purpose:Biologic therapies have revolutionized the management of rheumatic diseases of childhood. However, these medications are associated with adverse effects including the possible development of neoplasms. The aim of our study was to determine the rate as well as risk factors for the development of neoplasms in patients with JIA treated with biologics.Methods:We performed a retrospective review of the rheumatology biologic registry (RBR) at The Hospital for Sick Children (SickKids), Toronto, Canada, one of the largest quarternary pediatric referral centres in North America. Demographic and neoplastic data, clinical course and medication history were extracted from the RBR and clinical charts. Unless specified, data was expressed as median (IQR). The study was approved by the SickKids Ethics Review Board.Results:The cohort consisted of 357 patients with rheumatic diseases who were on one or more biologics between January 1997 and August 2013. Juvenile Idiopathic Arthritis (JIA) was the most common diagnosis [302/357 (84.5%)]. A total of 6/357 (1.68%) patients developed a neoplasm: 4 with JIA, 1 each with idiopathic uveitis and polyarteritis nodosa. (Refer to t87) 1Table 1. Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6NeoplasmNasopharyngeal carcinoma1. Tonsillar lymphoproliferative disorder (LD) in 2006Clear cell renal carcinomaHepatosplenic lymphomaSmall blue cell sarcoma, undifferentiatedPilomatricoma 2. Renal carcinoma in 2011 Rheumatic Disease (RD)Idiopathic UveitisPolyarteritis NodosaPoly JIA (RF negative)Systemic JIAOligo JIA (extended)Oligo JIA (extended)Age of onset of RD (years), Cytotoxic agentsMTX (4.7)MTX (1.2);MTX (6.2);MTX (3.6);MTX (7.2);CSA (3.2);(Time (years)) AZA (NA);LFN(0.2);CSA (0.9);LFN (0.2)AZA (4.3);Abbreviations: -Methotrexate (MTX), CYC (1.5)CSA (1.5);Tacrolimus (5.0); MTX (6.0);-Azathioprine (AZA), AZA (1.2);Etoposide (6 cycles over 34 days); LFN (2.8)-Leflunomide (LFN), SSA (0.9)Thalidomide (0.6) Cyclophosphamide (CYC), -Cyclosporine (CSA), -Sulfasalazine (SSA) -Not available (NA) Biologic(s)Infliximab (3.3)Infliximab (7.5)Etanercept (4.8)Etanercept (0.1);Etanercept (5.2)Infliximab (8.2);(Time (years)) Infliximab (1.7); Etanercept (1.5) Anakinra (1.9) Time to neoplasm (years)5.31. 14.115.811.816.712.7 2. 18.6 Time from DMARD to neoplasm (years)4.71. 6.817.611.88.412.6 2. 11.4 Time from Biologic to neoplasm (years)3.31. 4.810. 2. 9.3 Family history of neoplasmMaternal grandfather: lung cancer; Maternal grandmother: cervical cancerMother died due to breast cancer.NANANAStrong family history of colon cancerAmongst patients with neoplasms, the median (IQR) age at rheumatic disease onset was 3.4 (1.7–7.3) years and the age of diagnosis of the neoplasm was 16.3 (15.3–17.9) years. All cancers were malignant except in patient 6 which was of a benign nature. On average, patients had exposure to 3 DMARDs (range 1–5), with methotrexate as the commonest DMARD used in 5/6 patients prior to diagnosis of the neoplasm. The time from the disease onset to initiation of DMARD was 3.9 (0.4–7.9) years. The time from the DMARD initiation and the diagnosis of a neoplasm was 10.1 (7.2–12.3) years. For methotrexate alone, the duration of use was 5.4 (3.9–6.1) years. All patients diagnosed with a neoplasm, had received both, DMARD(s) and biologic(s). 2 patients were on infliximab alone, 2 on etanercept alone and 2 on multiple biologics of which etanercept and infliximab were both used. The time between onset of a biologic and diagnosis of a neoplasm was 5.0 (3.6–7.7) years. Two patients (2 and 4) also received medications which are associated with the development of the neoplasms (cyclophosphamide or etoposide).Conclusion:Majority of neoplasms were of uncommon morphology and site as well as aggressive in nature. The neoplasms developed late after drug exposure with a median duration to diagnosis of neoplasm of 10.1 years on a DMARD and 5.5 years on a biologics. Whilst DMARDs and biologics are effective for the management of rheumatic diseases, patients with refractory disease requiring ongoing drug therapies should have malignancy/ neoplasm surveillance included as part of routine clinical care. Comparison of patients on biologics with and without neoplasms is in progress.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Background/Purpose:Little is known about the long-term morbidity and mortality of childhood-onset SLE (cSLE) after transition to adult care; however, linking clinical data to administrative databases enables study of previously unknown outcomes. Our objectives were to describe long-term outcomes in young adults with cSLE, including: i) cardiovascular outcomes; ii) renal outcomes; iii) joint replacement surgery due to avascular necrosis; iv) malignancies; and v) pregnancies and births.Methods:A retrospective chart review of all cSLE patients (<18 years at diagnosis) diagnosed between Jan 1, 1984 and Dec 31, 2011 and followed for ≥1 year was conducted after contacting all pediatric and adult rheumatologists and nephrologists practicing in Ontario. Clinical data and Ontario Health Insurance Plan (OHIP) numbers were securely transferred to the Institute for Clinical Evaluative Sciences (ICES). OHIP numbers were transformed into an encrypted ICES key number (IKN) used to link the cohort to multiple administrative datasets to determine the outcomes of interest. Outcomes were determined using validated definitions. Means ± standard deviations are given unless noted.Results:622 cSLE patients are included in this inception cohort. The cohort was predominantly female (81%) with mean follow-up of 10.7 ± 7.3 years, representing 6629 person-years of disease. Age at diagnosis was 12.8 ± 3.2 years. There were 34 (6%) hospitalizations for cerebrovascular events, at mean age 18.1 ± 7.7 years, and disease duration 6.7 ± 7.0 years. Fewer than 6 hospitalizations for myocardial infarctions occurred at a median disease duration of 10.7 years. 273 (44%) patients had biopsy-proven lupus nephritis, with end stage renal disease occurring in 20 (7.3%) of these patients at mean age 31.4 ± 8.0 years, and disease duration 17.5 ± 8.7 years. Eight patients underwent renal transplant. Twenty-two (3.5%) patients have had 32 hip replacement surgeries, at mean age 24.2 ± 6.6 years and disease duration 10.1 ± 6.7 years. Fewer than 6 patients have had knee and/or ankle replacement surgery. Fourteen malignancies occurred in 13 (2%) patients, at mean age 28.2 ± 9.2 years and disease duration 16.5 ± 7.2 years. Nine were female reproductive and/or hematologic malignancies. Obstetrical outcomes were examined in females ages 15–45 years. Of 222 pregnancies, there were 82 (37%) live births, occurring at mean age 26.4 ± 4.9 years and disease duration 12.1 ± 5.5 years. Fewer than 6 pregnancies resulted in twins. There were 90 (41%) therapeutic abortions, 39 (18%) miscarriages, and 8 (4%) still births.Conclusion:Myocardial infarction and end-stage renal failure rates in this cohort with universal healthcare appear to be lower than reported in other populations. Cerebrovascular disease, hip replacement surgery and malignancies were significant morbidities in this cohort of young adults. Many women were able to conceive and deliver live infants; however, the miscarriage and stillbirth rates were greater than expected for young women.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Objective: Prognosis studies examine outcomes and/or seek to identify predictors or factors associated with outcomes. Many prognostic factors have been identified in Systemic Lupus Erythematosus (SLE) but few have been consistently found across studies. We hypothesized that this is due to lack of rigor of study designs. This study aimed to systematically assess the methodological quality of prognosis studies in SLE.Methods: A search of prognosis studies in SLE was performed using MEDLINE and EMBASE, from January 1990 to June 2011. A representative sample of 150 articles was selected using a random number generator and assessed by 2 reviewers. Each study was assessed by a risk-of-bias tool according to 6 domains: study participation, study attrition, measurement of prognostic factors, measurement of outcomes, measurement/adjustment for confounders and appropriateness of statistical analysis. Information about missing data was also collected.Results: A cohort design was used in 71% of studies. High risk of bias was found in 65% for confounders, 57% of studies for study participation, 56% for attrition, 36% for statistical analyses, 20% for prognostic factors and 18% for outcome. Missing covariate or outcome information was present in half of the studies. Only 6 studies discussed reasons for missing data and 2 imputed missing data.Conclusions: Lack of rigorous study design— especially in addressing confounding, study participation and attrition, and inadequately handled missing data— has limited the quality of prognosis studies in SLE. Future prognosis studies should be designed with consideration of these factors to improve methodological rigor. © 2014 American College of Rheumatology.
    Arthritis Care & Research. 03/2014;
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    ABSTRACT: Background/Purpose:To assess efficacy and safety of SC golimumab (GLM) in polyarticular pediatric juvenile idiopathic arthritis pts (aged 2 to <18 yrs) with active arthritis despite MTX for ≥3 months.Methods:In GO-KIDS, a 3-part randomized double-blind, PBO-controlled, withdrawal trial in pts with active JIA with a polyarticular course (≥5 active joints) and disease duration of ≥6 months despite current MTX (10–30 mg/m2/wk). In Part 1(wk 0–12), all pts received open-label (OL) 30 mg/m2 GLM SC (max 50 mg) q4 wks with stable MTX dose. At wk 16, pts with ACR JIA 30 response entered Part 2 (wk 16–48). In Part 2, pts were randomized to continue GLM or switch to PBO q4 wks. Upon Part 2 completion at wk 48 or ACR JIA flare in Part 2, pts received OL GLM in Part 3. Primary endpoint was proportion of ACR JIA 30 responders at wk 16 without a JIA flare in Part 2 using wk 16 as baseline measurement. Secondary outcomes were ACR JIA 30/50/70/90 response rates and inactive disease rates at wk 16 and wk 48 by group and safety.Results:173 pts (Caucasian 87.9%, 75.7% females; age [median/range] 12 yrs/2–17 yrs) with moderately active disease were enrolled (Table 1); 19 (11%) were d/c in Part 1 (lack of efficacy n = 14, AE n = 4, withdrawal of consent n = 1). In Part 1, 151 of 173 (87.3%) achieved an ACR JIA 30 response and 36.1% inactive disease status (Table 2). There were 154 pts randomized double-blind in Part 2 (PBO n = 76; continued GLM n = 78). At the end of Part 2, no significant differences between groups in JIA ACR non-flare rates and trial did not meet primary endpoint [PBO-grp vs. GLM-grp: 52.6% vs. 59.0%, p = 0.41) nor were there differences for major secondary endpoints (Table 2). In contrast, sustained response in both groups (PBO, GLM) relative to wk 0 (Table 1 and 2). 6.5% (10 of 154) of pts d/c therapy after wk16 through wk 48. Through wk 48, AEs, serious AE (SAE), and serious infections were reported in 87.9%, 13.3%, and 2.9% of all randomized pts, respectively. Most common SAE was JIA exacerbation. No deaths, active TB or malignancies were reported (1). GLM-treated pt experienced SAE of toxic hepatitis and 1 had SAE of hepatic enzyme increase. One pt switched from PBO to GLM experienced SAE of serum sickness reaction, resulting in GLM d/c. Proportion of pts with ≥1 injection site reaction was 8.1%. None of the reactions were serious, severe, or led to GLM d/c.Table 1. At Baseline (All enrolled patients n=173)At wk16 (All randomized patients prior to randomization, n=154)At wk48Values are medians (interquartile range)PBO + MTX (n=76)GLM + MTX (n=78) Physicians global assessment5.40 (3.90; 7.00)0.50 (0.10; 1.30)0.30 (0.00; 1.00)0.30 (0.00; 1.30)Patient/parent global assessment4.50 (2.80; 6.10)0.90 (0.30, 2.30)0.60 (0.20; 1.65)0.45 (0.10; 1.70)Number of active joints12.0 (8.0; 18.0)1.0 (0.0; 3.0)1.0 (0.0; 3.0)0.0 (0.0; 2.0)Number of joints with limited range of motion8.0 (6.0; 15.0)1.0 (0.0, 4.0)0.5 (0.00; 4.0)1.0 (0.0; 3.0)Physical function by CHAQ0.94 (0.38; 1.50)0.25 (0.00; 0.75)0.13 (0.00; 0.63)0.00 (0.00; 0.63)ESR (mm/hr)16.00 (8.00; 28.00)9.00 (5.00; 19.00)9.50 (5.00; 16.50)10.00 (5.00; 19.00)Methotrexate (mg/wk)15t(5.00; 30.00)15t(5.00; 30.00)15t(5.00; 30.00)15t(5.00; 30.00)Table 2. ACR JIA response and flare ratesPART 1 [WK 0ndash;16] Pts experiencing flares/those considered treatment failures due to protocol violations are considered ACR non-responders from the flair/failure visit to wk 48aObserved dataPercentage of ACR JIA responders at end of Part 1 [WK 16] (n = 173)JIA ACR 3087.3%t(151) JIA ACR 5079.2%t(137) JIA ACR 7065.9%t(114) JIA ACR 9036.4%t(63) Inactive disease36.1%t(62) PART 2 [WK 16ndash;48] Percentage of ACR JIA 30 responders without flare in Part 2 (n = 154)PBO + MTX (n=76)52.6%t(40)P=0.41 GLM + MTXt(n=78)59.0%t(46) Inactive disease21.6%/39.7% Clinical remission11.8%/12.8% Percentage of ACR JIA responders at WK48 (vs. wk0) by treatment in Part 2‡ [PBO +MTX/GLM +MTX]JIA ACR 3095.9%/89.0% JIA ACR 5091.8%/86.3% JIA ACR 7078.1%/78.1% JIA ACR 9053.4%/56.2% Conclusion:JIA pts with active polyarticular dis ease demonstrated rapid response to GLM with 16 wks of OL treatment, resulting in inactive disease in 36% of the pts. The lack of differences in flare rates between GLM and PBO arms from wk 16 to 48 among OL GLM responders needs further evaluation. Safety profile was acceptable and injections well tolerated.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Background/Purpose:1) To determine the longitudinal disease activity trajectory of an inception cohort of Juvenile Dermatomyositis (JDM) patients, 2) To identify predictor(s) for longitudinal disease activity trajectory of JDM.Methods:A single-center, inception cohort of juvenile dermatomyositis (JDM) patients (age of diagnosis <18 years old), recruited within 1 year of their initial presentation was studied. The patients were accrued from January 1991 to December 2010, in a JDM subspecialty clinic. Patients were evaluated at every clinic visit for disease activity with the modified Disease Activity Score (mDAS). Baseline disease features–DASm, swallowing difficulty, skin ulcer, calcinosis, duration of symptoms before evaluation, age and gender–were evaluated as predictors of the longitudinal trajectory of JDM. Time-varying treatment effects were also tested. Longitudinal trajectory modeling was performed with mixed random effects modeling (random slopes).Results:Ninety-five JDM patients (33 males, 35%) were studied. The median age of onset was 7.8 (25th–75th percentile (P): 4.9–12.1) years. The median mDAS score at presentation was 7 (25th–75th P: 6–9), the median skin subscale score was 3 (25th–75th P: 2–4), the median musculoskeletal subscale was 4 (25th–75th P: 3–6). The median duration of follow-up was 4.6 (25th–75th P: 2.4–6.9) years. All patients in the cohort were treated with a standardized protocol comprising prednisone alone (before 2000) or methotrexate (MTX) and prednisone (after 2000). The disease trajectory of mDAS in this inception cohort followed a rapid reduction of activity within the first 2 years with a minor flare in disease activity beyond 2 years. Baseline nailfold abnormality predicted a slower improvement in mDAS trajectory. Higher baseline mDAS predicted faster improvement in mDAS trajectory. Treatment with MTX and prednisone predicted reductions in disease activity 3 and 6 months later respectively.Conclusion:Disease activity trajectory of JDM showed a general rapid reduction of mDAS followed by a small flare of disease activity beyond 2 years. Baseline nailfold abnormality and mDAS predicted future evolution of disease trajectory. The effects of treatment were observed only 3–6 months after.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Background/Purpose:Neonatal lupus erythematosus (NLE) is a passively transferred autoimmune disease that occurs in babies born to mothers with anti-Ro and anti-La antibodies. The most serious complication of NLE is congenital heart block (CHB). In pregnancies of mothers with a known autoimmune condition and positive anti-Ro antibodies, the incidence of heart block is approximately 1-2% of live births. We have previously shown that only mothers with moderate-high titre antibodies are at risk to deliver a child with CHB. However, the rate of anti-Ro positive antibody pregnant women in an otherwise healthy population is unknown or is their risk for delivering a child with CHB.Objectives: Determine the rate of anti-Ro/La antibodies in the general pregnant population. Determine if the incidence of CHB is increased in healthy mothers with positive Ro/La antibodies compared to mothers with known autoimmune disease and positive anti-Ro/La antibodies.Methods:Antibody testing was performed on 15198 pregnant women who were having concurrent Maternal Serum Screening in the Metropolitan Toronto area. Maternal self-reported outcomes of prenatal, pregnancy, and post-natal medical conditions were reported, along with fetal outcomes of pre and post-natal illnesses. Autoantibody titres were stratified into negative, low, moderate, and high positive.Results:1152/151598 (7.6%) of the mothers who had anti-Ro antibodies and 179/15198 (1.18%) had moderate-high titres (at risk to deliver a child with CHB). 779 (5%) had anti-La antibodies with the majority being low titre. During the course of the study there were 13 cases of CHB that were unrelated to our maternal sample population- 10 to well mothers and 3 to mothers with an autoimmune disease. All of these women mothers had moderate-high titre anti-Ro antibodies, while only 31% had moderate-high titre anti-La antibodies. During the course of the study 64 pregnant women with a known autoimmune disease and anti-Ro antibodies (at risk to deliver a child with CHB) were prospectively followed. 3/64 delivered a child with CHB. All 3 of these mothers had moderate-high titre anti-Ro antibodies while 41/61 mothers who delivered a child without CHB had moderate-high titre anti-Ro antibodies. Therefore 3/44 (6.9%) mothers with moderate-high titre anti-Ro antibodies and an autoimmune disease delivered a child with CHB.Conclusion:The incidence of CHB is reported to be between 1:10/N15,000 pregnancies. Therefore, based on our data showing 1.18% of otherwise well pregnant woman had moderate-high titre anti-Ro antibodies (at risk to deliver a child with CHB), for each child with CHB we predict that 117—174 children without CHB will be delivered to otherwise healthy mothers. In contrast, in mothers with a known autoimmune disease and moderate-high anti-Ro antibody titre, we found a 6.9% incidence of CHB and therefore for each child with CHB there were 14 children without CHB born. Therefore the risk for a woman with a known autoimmune disease and moderate-high titre anti-Ro antibodies was approximately 10x that of otherwise healthy pregnant women. These data therefore suggest that the anti-Ro antibody repertoire differs between these 2 groups of pregnant women.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Background/Purpose:Macrophage activation syndrome (MAS), a life-threatening inflammatory emergency of children with rheumatic diseases, is increasingly recognized in pediatric systemic lupus erythematosus (pSLE). The challenge is to differentiate active pSLE from MAS in order to make correct treatment decisions. The purpose of this study is to generate a decision tree for the recognition of MAS in newly diagnosed pSLE and test the performance of these proposed criteria in an independent pSLE cohort.Methods:A retrospective cohort study of consecutive patients requiring admission to SickKids Hospital with newly diagnosed, active pSLE between January 2002 and July 2007 (training cohort) was performed. All patients met ≥4/11 ACR criteria. Data collection on: 1) Clinical features including fever, CNS dysfunction, splenomegaly, hepatomegaly and hemorrhage; 2) laboratory parameters; CBC, ESR, CRP, C3, C4, ferritin, AST, ALT, LDH, albumin, bilirubin, triglycerides, LDL, HDL, urea, creatinine, sodium, coagulation parameters including INR, PTT, fibrinogen and D-Dimer, and soluble IL-2 receptor (sIL-2R) and CD163. Patients were assigned to one of 2 cohorts exclusively (MAS/non-MAS). Putative predictor variables were compared between cohorts. A decision tree analysis for diagnosis of MAS in pSLE was constructed using recursive partitioning, and decision rules were subsequently applied to an independent cohort of newly diagnosed, active pSLE diagnosed and admitted to SickKids between July 2007 and July 2013 (testing cohort) to determine the sensitivity and specificity of the proposed criteria.Results:The training cohort consisted of 56 pSLE patients: 9 (16%) diagnosed with MAS and 47 non-MAS patients. Splenomegaly was more common in the non-MAS cohort, with no other differences in clinical characteristics between cohorts. Of all the available laboratory data, ALT ≥ 45 units/L, neutrophils < 1.65 × 103/mm3 and ferritin < 836 µg/L identified 56% of the patients with MAS (R2 = 0.75) with 100% specificity. The testing cohort consisted of 9 (20%) MAS and 37 non-MAS pSLE patients. The proposed thresholds for ALT, neutrophil count and ferritin demonstrated a sensitivity of 11% and specificity of 97%.Conclusion:MAS is a life threatening complication of pSLE. Early recognition is challenging yet critical for appropriate therapy. PSLE patient with and without MAS have many similar clinical and laboratory features. Using statistical modeling, the initial criteria developed maintained excellent specificity but poor sensitivity for distinguishing MAS from active SLE at diagnosis in the testing cohort. Hence, new validated models are required for the early recognition of MAS among pSLE patients. Future analyses are planned to address these issues.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Background/Purpose:It had been suggested that prenatal exposure to hydroxychloroquine reduced the risk of cardiac NLE. The primary aim was to assess if prenatal exposure to antimalarials (AM) decreased the risk of cardiac NLE. The secondary aim was to analyze the effect of AM exposure on the risk of non-cardiac NLE.Methods:A retrospective cohort study was performed on a large single-center cohort of children exposed to anti-Ro and/or anti-La antibodies on whom prospective data has been collected since 1984. Inclusion criteria were: 1) first child born from a woman positive for anti-Ro and/or anti-La antibodies with a diagnosis of cutaneous lupus, systemic lupus erythematosus, Sjogren's syndrome, dermatomyositis or rheumatoid arthritis, 2) the mother underwent fetal chocardiography screening during pregnancy and/or the child had a postnatal ECG and 3) the child was ≥6 months old as of October 2013. We used Bayesian analysis for the association between prenatal use of AM and NLE.Results:The study population consisted of 265 children, of whom 72 were exposed to AM throughout gestation. Full laboratory data was available on 216 infants: 101 (46.8%) developed NLE and 115 (53.2%) remained unaffected. Forty nine children were classified as having no cardiac NLE but could not be diagnosed as true unaffected children as one or more blood test components were missing. These children were only included when the outcome studied was cardiac NLE. On univariable analysis and under a non-informative prior, the probability that prenatal AM exposure would be protective (RR < 1) was 97.1% for cardiac and 66.9% for non-cardiac NLE. On multivariable analysis, the RRs obtained were numerically higher, but still suggestive of a protective effect (1). Using a more stringent RR cutoff (RR < 0.75), the effect on the outcome cardiac NLE remained significant, unlike for non-cardiac NLE for which probabilities dropped significantly.Table 1. Bayesian Analyses of the Effect of Prenatal Exposure to Antimalarial on the Risk of NLEOutcomePriorSample size (N)RR (95% CrI)Probability of RR <1 (%)Probability of RR <0.75 (%)aIndependent variable: prenatal exposure to AMbIndependent variables: prenatal exposure to AM, anti-Ro ≥50 U/mL, anti-La ≥50 U/mL and maternal diagnosis (Sjogren's syndrome vs all other diagnosis)cNLE: neonatal lupus; RR (95% CrI): relative risk (95% credible interval)Univariable analyses† Cardiac NLENon-informative2650.17 (0.01, 1.05)97.193.8Cardiac NLEInformative2650.34 (0.17, 0.66)99.998.9Non-cardiac NLENon-informative2140.93 (0.64, 1.29)66.912.7Multivariable analyses‡ Cardiac NLENon-informative2300.31 (0.01, 1.91)87.880.0Cardiac NLEInformative2300.36 (0.18, 0.72)99.898.1Non-cardiac NLENon-informative1900.94 (0.65, 1.31)64.011.6Conclusion:In this study of the largest single-center cohort of children born to anti-Ro and/or anti-La antibody positive women with a connective tissue disease, we have shown that the probability that AM exposure was associated with a decreased risk of cardiac NLE was >87%. A clinically significant beneficial effect from AM exposure on non-cardiac NLE features was not present. These findings need to be confirmed in an independent cohort.
    Arthritis & Rheumatology. 03/2014; 66(S11).
  • Mohammed Olfat, Earl D. Silverman, Deborah M. Levy
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    ABSTRACT: Background/Purpose:Cytopenias including thrombocytopenia and autoimmune hemolytic anemia(AIHA) are common in childhood-onset SLE (cSLE) and may be refractory to conventional therapy with corticosteroids, IVIG and/or other immunosuppressives. Rituximab appears to be an effective therapy for cytopenias, although no long term studies have been completed, and few cSLE patients have been reported. Our objectives were to examine our experience, determine the rate and durability of response to rituximab, and evaluate its safety in our cSLE population with refractory cytopenias.Methods:A single center retrospective cohort study of patients diagnosed with cSLE between Jan 1, 2003 and Dec 31, 2012. Inclusion criteria were SLE diagnosed <18th birthday, refractory cytopenia (thrombocytopenia and/or AIHA) with inadequate response to conventional therapy, and treatment with rituximab during the study period. Demographic, clinical, laboratory, and treatment data were examined. Complete response for thrombocytopenia was defined as platelets >100 × 109/L, and for AIHA hemoglobin >120 g/L. B-cell phenotyping was determined at regular intervals. Outcomes examined included the time to clinical response, time to B-cell depletion, and the duration of response. Adverse events studied included the incidence of persistent (>12 months) hypogammaglobulinemia, infusion reactions and infections requiring hospitalization.Results:398 patients were diagnosed with cSLE during the study period; 24 (6%) received rituximab for refractory cytopenia. Rituximab was given either as 4 weekly doses of 375 mg/m2 or 2 doses of 500 mg/m2 separated by 14 days, depending on the year. There was a female predominance (18/24, 75%), the median age was 13.2 y (range 4–18). Fifteen (63%) had thrombocytopenia, 5 (21%) had AIHA, and 4 (17%) had both. The median (IQR) time from cytopenia onset to rituximab therapy was 517 (237, 892) days. Complete response to 1st course of rituximab occurred by 30 days in 15 (63%), by 90 days in an additional 3 (13%) patients, by 180 days in 3 (13%) patients, and by 1 year in 2 (8%) patients; 1 patient failed to respond. For thrombocytopenia, the time to complete response was 17(13, 62) days and for AIHA 54 (24, 98) days. Five (21%) patients had one or more flare episodes at 21 (14.6, 27.3) months. No patient with thrombocytopenia in the absence of AIHA flared following 1st dose of rituximab. All patients who had B cell phenotyping had complete depletion of CD20 B cells at 16 (14, 30) days. The time to B cell reconstitution was 331 (175, 468) days. Transient infusion reactions included fever, erythematous pruritic rash, and hypotension in 2 patients. Four patients had transient hypogammaglobulinemia. Three patients had persistent undetectable IgG and received monthly IVIG replacement; 2 had recurrent infections. One patient (who was not hypogammaglobulinemic) had varicella zoster 10 weeks following rituximab. No other hospitalizations for infection were observed within 1 year of rituximab administration.Conclusion:Rituximab appears to be a well tolerated, safe, and long-lasting therapy for cSLE patients with refractory cytopenias. Longer term data is required to assess the incidence and clinical significance of hypogammaglobulinemia.
    Arthritis & Rheumatology. 03/2014; 66(S11).
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    ABSTRACT: Systemic lupus erythematosus (SLE) frequently has neuropsychiatric involvement including affective disorders, psychosis, and cognitive dysfunction. Evidence suggests that anorexia nervosa (AN) in adolescents with SLE may be triggered by steroid-induced changes in weight and body shape. We propose that AN may be another manifestation of neuropsychiatric SLE and should be considered in this patient population. A retrospective chart review identified 7 children/adolescents diagnosed with SLE and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria for AN, restrictive subtype, at the Hospital for Sick Children in Toronto between January 1989 and January 2011. One patient developed AN 15 months after being diagnosed with SLE that was attributed to prednisone-induced weight gain and cushingoid appearance. Of the remaining 6 patients, the median age at onset of AN symptoms was 12.2 years and diagnosis of AN was 13.6 years. The median age at SLE diagnosis was 14.2 years with median time after onset of AN symptoms of 20 months (7.5-32 months). All patients had evidence of joint symptoms and a positive antinuclear antibody, and 50% had lymphopenia at the time of SLE diagnosis. Treatment of SLE resulted in improvement of AN in all patients. The timing of the clinical presentation of AN in relation to the diagnosis of SLE and response to SLE treatment suggests that AN may be a novel presentation of neuropsychiatric SLE. Patients with AN who present with or develop joint symptoms, a positive antinuclear antibody, or lymphopenia should be investigated and followed for possible SLE.
    PEDIATRICS 01/2014; · 4.47 Impact Factor
  • Bhadran Bose, Earl D Silverman, Joanne M Bargman
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    ABSTRACT: Management of patients with lupus nephritis can be complex and challenging. We suggest that there are some widely held misconceptions about lupus, and unfortunately, these underpin the treatment of many patients. There is little evidence to support the common assumption that intravenous pulse cyclophosphamide is the best treatment for lupus nephritis. Although there is much focus on which immunosuppressive agent to use, too little attention is paid to the proper dose and duration of corticosteroids and concomitant therapy with antimalarial agents. Many clinicians reflexively perform kidney biopsies when these biopsies may be high risk and not influence therapy. There is little emphasis on or awareness of nonadherence to therapy, which is an underappreciated cause of treatment resistance. Resolution of proteinuria and hematuria can take a long time, and immunotherapy should not be intensified based on urine sediment alone. Furthermore, the intensity of the immunosuppression must be considered in the context of lupus nephritis class and duration of kidney damage. Finally, clinicians are aware of the risks of pregnancy in the face of active lupus, but assume that their patients also are aware of this and forget to discuss this with them. With a combined experience of more than 50 years in managing children and adults with lupus, we offer our impression of recurrent mistakes in the management of lupus in general, with a focus on treatment of lupus nephritis.
    American Journal of Kidney Diseases 12/2013; · 5.29 Impact Factor
  • Source
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    ABSTRACT: The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin's lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis. These results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care.
    Arthritis research & therapy 11/2013; 15(6):R198. · 4.27 Impact Factor
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    ABSTRACT: Objectives Hospitalization is a major factor in health care costs and a surrogate for worse outcomes in chronic disease. The aim of this study was to determine the frequency of hospitalization secondary to lupus flare, the causes of hospitalization, and to determine risk factors for hospitalization in patients with systemic lupus erythematosus (SLE).Methods Data were collected as part of the 1000 Canadian Faces of Lupus, a prospective cohort study, where annual major lupus flares including hospitalizations were recorded over a 3-year period.ResultsOf 665 patients with available hospitalization histories, 68 reported hospitalization related to a SLE flare over 3 years of follow-up. The average annual hospitalization rate was 7.6% (range 6.6-8.9%). The most common reasons for hospitalization were: hematologic (22.1%), serositis (20.6%), musculoskeletal (MSK) (16.2%), and renal (14.7%). Univariate risk factors for lupus hospitalization included (OR [95% CI]; p < 0.05): juvenile-onset lupus (2.2 [1.1-4.7]), number of ACR SLE criteria (1.4 [1.1-1.7], baseline body mass index (BMI) (1.1 [1.0-1.1]), psychosis (3.4 [1.2-9.9]), aboriginal race (3.2 [1.5-6.7]), anti-Smith (2.6 [1.2-5.4]), erythrocyte sedimentation rate >25 mm/hr (1.9 [1.1-3.4]), proteinuria >0.5 g/d (4.2 [1.9-9.3], and SLAM-2 score (1.1 [1.0-1.2]). After multivariate regression only BMI, number of ACR criteria, and psychosis were associated with hospitalization for lupus flare.Conclusions The mean annual rate of hospitalization attributed to lupus was lower than expected. Hematologic, serositis, MSK and renal were the most common reasons. In a regression model elevated BMI, more ACR criteria and psychosis were associated with hospitalization.
    Lupus 09/2013; · 2.78 Impact Factor
  • Julie Barsalou, Deborah M Levy, Earl D Silverman
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    ABSTRACT: This manuscript will provide a review of studies published in the last year examining the major disease manifestations, comorbidities, biomarkers and therapeutic trials involving childhood-onset systemic lupus erythematosus (cSLE) patients. Recent multicenter prospective cohort studies supported previous findings that cSLE patients accrue damage early on their disease. Four studies showed that ethnicity altered disease severity and incidence of both cSLE and lupus nephritis. Description of clinical features and response to therapy in a large group of cSLE patients with neuropsychiatric involvement provided useful information on this feature. Advancement in the field of biomarkers was seen but the new biomarkers are not yet ready for clinical use. A randomized placebo-controlled trial of statins to prevent atherosclerosis progression did not meet its primary endpoint but did show a trend in improvement of carotid intima-media thickness, a surrogate marker of atherosclerosis. No other prospective interventional treatment trials designed specifically for cSLE patients were reported in the past year. There is an urgent need to better characterize the long-term outcome of cSLE patients and identify early on those at risk of a worse outcome. Advances in the field of biologics and small molecules will hopefully allow better targeted therapies of the cSLE population.
    Current opinion in rheumatology 07/2013; · 4.60 Impact Factor

Publication Stats

6k Citations
1,262.91 Total Impact Points


  • 1989–2014
    • SickKids
      • • Division of Rheumatology
      • • Division of Cardiology
      • • Division of Hematology/Oncology
      • • Department of Paediatrics
      • • Department of Diagnostic Imaging
      Toronto, Ontario, Canada
  • 1987–2014
    • University of Toronto
      • • Hospital for Sick Children
      • • Centre For Prognosis Studies in the Rheumatic Diseases
      • • Division of Rheumatology
      • • Department of Paediatrics
      Toronto, Ontario, Canada
  • 2011
    • University of California, San Francisco
      San Francisco, California, United States
  • 2009–2011
    • Cincinnati Children's Hospital Medical Center
      • • Division of Rheumatology
      • • Department of Pediatrics
      Cincinnati, OH, United States
    • University of Oklahoma Health Sciences Center
      • Department of Pediatrics
      Oklahoma City, Oklahoma, United States
    • The University of Chicago Medical Center
      Chicago, Illinois, United States
  • 2007–2010
    • University Children's Hospital Basel
      Bâle, Basel-City, Switzerland
    • University of Adelaide
      Tarndarnya, South Australia, Australia
    • Ljubljana University Medical Centre
      • Unit of Allergy, Rheumatology and Clinical Immunology
      Lubliano, Ljubljana, Slovenia
    • University of British Columbia - Vancouver
      • Division of Nuclear Medicine
      Vancouver, British Columbia, Canada
  • 2007–2009
    • IRCCS Istituto G. Gaslini
      Genova, Liguria, Italy
  • 2002–2009
    • University of Cincinnati
      Cincinnati, Ohio, United States
    • Northwestern University
      • Department of Pediatrics
      Evanston, IL, United States
  • 1993–2006
    • Dalhousie University
      • Department of Pediatrics
      Halifax, Nova Scotia, Canada
  • 2003
    • University of Milan
      Milano, Lombardy, Italy
  • 1996
    • University of Saskatchewan
      • Department of Pediatrics
      Saskatoon, Saskatchewan, Canada
  • 1992–1996
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 1985
    • Stanford University
      Palo Alto, California, United States
  • 1984
    • Children's Hospital Los Angeles
      Los Angeles, California, United States