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Introduction: Antibody-mediated complete atrioventricular block (CAVB) is considered irreversible. We sought to examine the effects of transplacental steroids on fetal AV conduction. Methods: Fifty-nine fetuses diagnosed with CAVB at our center from 1996 to 2018 were reviewed. Routine dexamethasone administration to birth was used to limit cardiac inflammatory damage. Restoration of fetal AV conduction was classified as "unexpected" treatment response. Results: CAVB resolved in 5/29 (17%) fetuses first treated =24-week gestation with 8 mg/day of dexamethasone, when compared with 0/30 (0%) when treatment was initiated later and/or at a starting dose of 4 mg/day (odds ratio 13.69; 95% confidence interval 0.72-260.13; p = 0.024). Treatment response was also associated with a faster ventricular rate at diagnosis (median [range]: 80 [60-97] beats per minute [bpm] vs. 58 [38-92] bpm; p = 0.0036). CAVB reappeared in all 5 responders either prenatally (n = 1) or postnatally before (n = 3) or after (n = 1) the first year of life. When compared with infants with treatment-resistant CAVB (median followup 10.3 years), responders (median follow-up 12.3 years) required postnatal pacing less frequent (2/5 [40%] vs. 45/49 [92%]; p = 0.013). Conclusions: In a subgroup of CAVB fetuses, dexamethasone transiently restored AV conduction. This was associated with a lower rate of postnatal pacing when compared with nonresponders. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: A single-center cohort study of consecutive children diagnosed with non-proliferative MLN was performed. Clinical and laboratory measures and treatment regimens were obtained in prospective standardized assessments. Renal outcome was measured by renal parameters and steroid requirement. Predictors for remission and time to remission were determined. Results: A total of 30 children were identified with a median follow-up time 4.1 years. Of 21 patients followed for more than 2 years, 19 (90 %) achieved clinical remission, and 16 (76 %) achieved a state of maintained clinical remission on low-dose prednisone. Three patients developed proliferative nephritis on subsequent renal biopsy. Lower albumin at the time of biopsy was correlated with a lower rate of remission and longer time to remission. Conclusions: Among our paediatric patient cohort the outcome of non-proliferative MLN in systemic lupus erythematosus was good. The majority of patients did not require aggressive immunosuppressive treatment to reach a stable disease state on low-dose steroid treatment. [ABSTRACT FROM AUTHOR]

Key Clinical Message Systemic 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. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that affects various organs. Lupus nephritis is one of the most common, and most important, serious manifestations of SLE. Antimalarial agents are part of the immunomodulatory regimen used to treat patients with SLE; however, their role in the treatment of patients with lupus nephritis in particular is less well recognized, especially by nephrologists. Not all antimalarial agents have been used in the treatment of lupus; this Review will focus on studies using chloroquine and hydroxychloroquine. In addition, this Review will briefly describe the history of antimalarial drug use in patients with SLE, the theorized mechanisms of action of the agents chloroquine and hydroxychloroquine, their efficacy in patients with SLE and those with lupus nephritis, their use in pregnancy, and potential adverse effects. The Review will also cover the latest recommendations regarding monitoring for hydroxychloroquine-associated or chloroquine-associated retinopathy. Overall, antimalarial drugs have numerous beneficial effects in patients with SLE and lupus nephritis, and have a good safety profile. [ABSTRACT FROM AUTHOR]

Objectives: We prospectively examined the prevalence and outcome of untreated fetal atrioventricular (AV) prolongation in the presence of maternal anti-Ro antibodies. Background: It has been suggested that antibody-mediated congenital complete atrioventricular block (CAVB) may be preventable if detected and treated early when low-grade block is present. With this rationale in mind, dexamethasone has been advocated by others to treat prolonged fetal AV conduction >2 z-scores, consistent with first-degree heart block. Methods: Between July 2003 and June 2009, 165 fetuses of 142 anti-Ro/La antibody–positive women were referred to our center for serial echocardiography. Our protocol included weekly evaluation of the fetal AV conduction between 19 (range 17 to 23) and 24 (range 23 to 35) gestational weeks. AV times were compared with institutional reference data and with post-natal electrocardiograms. Results: Of 150 fetuses with persistently normal AV conduction throughout the observation period, a diagnosis of CAVB was subsequently made in 1 at 28 weeks, after the serial evaluation had ended. Of 15 untreated fetuses either with AV prolongation between 2 and 6 z-scores or with type 1 second-degree block, progressive heart block developed in none of them. Three of these 15 fetuses (20%) had a neonatal diagnosis of first-degree block that spontaneously resolved (n = 2) or has not progressed (n = 1) on follow-up examinations. No other cardiac complications were detected. Conclusions: Fetal AV prolongation did not predict progressive heart block to birth. Our findings question the rationale of a management strategy that relies on the early identification and treatment of fetal AV prolongation to prevent CAVB. [ABSTRACT FROM AUTHOR]

Abstract: Autoantibodies to topoisomerase I (topo-I, also referred to as Scl-70, ATA) have historically been considered a specific marker for systemic sclerosis (SSc). Although found in ∼20% of SSc sera, other evidence indicated that ATA also occur in up to 25% of systemic lupus erythematosus (SLE). Given that SLE is approximately 100 times more prevalent than SSc, the number of ATA positive SLE patients is at least 2–3 orders of magnitude greater than the prevalence of ATA in SSc. These observations have raised questions about the disease specificity and clinical value of ATA. Therefore, our objective was to analyse the prevalence of ATA in different disease conditions with a special focus on SLE employing a systematic literature review (meta-analysis) in combination with our experimental investigations. [Copyright &y& Elsevier]

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease with a highly variable clinical course. Pediatric-onset SLE (pSLE) represents 10-20% of all SLE cases, and is associated with higher disease severity, including more-rapid damage accrual, than adult-onset SLE. As in adults, pSLE disease expression varies according to ethnicity, with a milder disease course in white patients. The majority of pSLE patients will have developed damage within 5-10 years of disease onset, most frequently involving the musculoskeletal, ocular, renal and neuropsychiatric systems. Owing to improvements in disease management and recognition over the past 20-30 years, patients now live longer, but as a result have increased disease damage. Premature atherosclerosis and osteoporosis have become increasingly prevalent morbidities in pSLE patients. Early atherosclerosis leads to a considerable rise in cardiovascular and cerebrovascular events, and failure to develop adequate peak bone mass during adolescence--a crucial period of bone accrual--is likely to lead to early osteoporosis and fractures. Patients with pSLE have an incurable, potentially devastating disease that occurs during a vulnerable period of psychosocial development, leading to specific and unique psychosocial stressors. Additional large, long-term follow-up studies in pSLE are needed to better understand the disease prognosis and to facilitate development of tailored treatments. [ABSTRACT FROM AUTHOR]

: ObjectivesThis study was designed to document the association of endocardial fibroelastosis (EFE) and maternal autoantibodies.: BackgroundNeonatal 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.: MethodsWe 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.: ResultsTwo 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.: ConclusionsThese 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. [Copyright &y& Elsevier]

Abstract. Renal failure occurred in a 14-year-old girl with peripheral arthritis associated with inflammatory bowel disease while she was being treated with naproxen. She had previously received aspirin and tolmetin sodium and had no complications. A renal biopsy showed a severe tubulointerstitial nephritis. Although her renal function improved somewhat with corticosteroid treatment, it worsened when the steroids were discontinued. This case emphasizes that renal failure can develop insidiously in children on nonsteroidal anti-inflammatory drug therapy and that such children must be monitored closely for signs of nephrotoxicity. [ABSTRACT FROM AUTHOR]

Electrocardiograms taken at rest of 2 children with transplacental exposure to anti-Ro antibody but 1:1 atrioventricular conduction demonstrated sinus node disease. Treadmill exercise testing of 28 patients with congenital complete heart block found 3 patients with chronotropic incompetence of the sinus node. [ABSTRACT FROM AUTHOR]

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) [ABSTRACT FROM AUTHOR]

Objective Childhood-onset SLE (cSLE) manifests differently than adult-onset SLE (aSLE). This study determined whether ethnic differences contribute to the differences in clinical presentation between the two groups. Methods This cross-sectional study used data from a multi-centred registry from eight adult and four paediatric Canadian centres gathered at study entry. We compared the frequency of clinical manifestations and autoantibodies between aSLE and cSLE. For those with a significant difference, a multivariable logistic regression was performed, adjusting for ethnicity, SLE onset (cSLE vs aSLE), disease duration and centre. Disease activity and damage between aSLE and cSLE were compared after stratifying by disease duration. Results Of 552 aSLE subjects, 502 (90.9%) were female and 381 (69.0%) were Caucasian. Mean age at diagnosis was 37.0 ± 13.6 years and disease duration 10.9 ± 9.6 years. Of 276 cSLE subjects, 231 (83.7%) were female and 101 (36.6%) were Caucasian. Mean age at diagnosis was 12.7 ± 3.3 years and disease duration 5.6 ± 8.2 years. In multivariable regression analysis, aSLE was associated with decreased odds of having a neurologic disorder (odds ratio = 0.49) and increased odds of having aCL antibodies (odds ratio = 1.85). Disease activity and damage accrual scores were higher in aSLE than cSLE within the same disease duration strata, although the differences were not clinically significant. Ethnicity was not associated with any differences in clinical manifestations or autoantibody frequency between aSLE and cSLE. Conclusion Although a crude comparison of aSLE and cSLE yielded several differences in clinical symptoms and autoantibodies, this difference was not attributable to ethnic differences between aSLE and cSLE. [ABSTRACT FROM AUTHOR]

Objectives Genome-wide association studies (GWAS) have identified loci associated with estimated glomerular filtration rate (eGFR). Few LN risk loci have been identified to date. We tested the association of SLE and eGFR polygenic risk scores (PRS) with repeated eGFR measures from children and adults with SLE. Methods Patients from two tertiary care lupus clinics that met ≥4 ACR and/or SLICC criteria for SLE were genotyped on the Illumina MEGA or Omni1-Quad arrays. PRSs were calculated for SLE and eGFR, using published weighted GWA-significant alleles. eGFR was calculated using the CKD-EPI and Schwartz equations. We tested the effect of eGFR- and SLE-PRSs on eGFR mean and variance, adjusting for age at diagnosis, sex, ancestry, follow-up time, and clinical event flags. Results We included 1158 SLE patients (37% biopsy-confirmed LN) with 36 733 eGFR measures over a median of 7.6 years (IQR: 3.9–15.3). LN was associated with lower within-person mean eGFR [LN: 93.8 (s. d. 26.4) vs non-LN: 101.6 (s. d. 17.7) mL/min per 1.73 m2 ; P  < 0.0001] and higher variance [LN median: 157.0 (IQR: 89.5, 268.9) vs non-LN median: 84.9 (IQR: 46.9, 138.2) (mL/min per 1.73 m2)2; P  < 0.0001]. Increasing SLE-PRSs were associated with lower mean eGFR and greater variance, while increasing eGFR-PRS was associated with increased eGFR mean and variance. Conclusion We observed significant associations between SLE and eGFR PRSs and repeated eGFR measurements, in a large cohort of children and adults with SLE. Longitudinal eGFR may serve as a powerful alternative outcome to LN categories for discovery of LN risk loci. [ABSTRACT FROM AUTHOR]

Objectives Cardiac involvement in neonatal lupus erythematosis (NLE) can present as myocarditis/endocardial fibroelastosis (EFE). It is unknown whether high-sensitivity cardiac troponin T (hs-cTnT) is useful in identifying subclinical myocardial inflammation in infants exposed prenatally to anti-Ro antibodies. This study reports hs-cTnT levels in infants exposed to anti-Ro antibodies with/without cardiac NLE and reports cardiac MRI (CMR) findings in a subset of these children. Methods The study included 45 consecutive infants exposed prenatally to anti-Ro antibodies with (n  = 7) or without (n  = 38) cardiac NLE, who were seen at the SickKids NLE Clinic between 2012 and 2014. Hs-cTnT levels were measured at least once, and those infants with values of ≥30 ng/l were offered the opportunity to undergo CMR. Descriptive statistics were performed. Results Of 38 infants without cardiac NLE, 25 had a hs-cTnT level of ≥30 ng/l (including 1 of >113 ng/l); of these, 8 underwent CMR (all without myocarditis/EFE). All 7 infants with cardiac NLE had at least one hs-cTnT level of ≥30 ng/l, but only 2/7 had a level of >113 ng/l; 4/7 infants with cardiac NLE had CMR (all without myocarditis/EFE); 6/7 infants with cardiac NLE had their steroid treatment adjusted based on the trend in their hs-cTnT levels. Conclusion Only 3/45 anti-Ro antibodies–exposed infants had hs-cTnT values outside the reference range reported in healthy infants. None of 12 infants who had CMR had subclinical myocarditis/EFE. Routine measurement of hs-cTnT in every anti-Ro antibody–exposed infant is not indicated. Further studies are needed to define the role of hs-cTnT as a biomarker for cardiac NLE. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives Genetics plays an important role in SLE risk, as well as osteonecrosis (ON), a significant and often debilitating complication of SLE. We aimed to identify genetic risk loci for ON in people with childhood-onset (cSLE) and adult-onset (aSLE) SLE. Methods We enrolled participants from two tertiary care centres who met classification criteria for SLE. Participants had prospectively collected clinical data and were genotyped on a multiethnic array. Un-genotyped single nucleotide polymorphisms (SNPs) were imputed, and ancestry was inferred using principal components (PCs). Our outcome was symptomatic ON confirmed by imaging. We completed time-to-ON and logistic regression of ON genome-wide association studies (GWASs) with covariates for sex, age of SLE diagnosis, five PCs for ancestry, corticosteroid use and selected SLE manifestations. We conducted separate analyses for cSLE and aSLE and meta-analysed results using inverse-variance weighting. Genome-wide significance was P  < 5 × 10−8. Results The study included 940 participants with SLE, 87% female and 56% with cSLE. ON was present in 7.6% (n  = 71). Median age of SLE diagnosis was 16.9 years (interquartile range [IQR]: 13.5, 29.3), with median follow-up of 8.0 years (IQR: 4.2, 15.7). Meta-GWAS of cSLE and aSLE time-to-ON of 4 431 911 SNPs identified a significant Chr.2 SNP, rs34118383 (minor allele frequency = 0.18), intronic to WIPF1 (hazard ratio = 3.2 [95% CI: 2.2, 4.8]; P  = 1.0 × 10−8). Conclusion We identified an intronic WIPF1 variant associated with a 3.2 times increased hazard for ON (95% CI: 2.2, 4.8; P   =  1.0 × 10−8) during SLE follow-up, independent of corticosteroid exposure. The effect of the SNP on time-to-ON was similar in cSLE and aSLE. This novel discovery represents a potential ON risk locus. Our results warrant replication. [ABSTRACT FROM AUTHOR]

Objective: Anti‐Ro antibody–positive mothers are frequently referred for serial echocardiography due to the fetal risk of developing heart block and endocardial fibroelastosis. Little is known why only some and not all offspring develop these cardiac manifestations of neonatal lupus (CNL). This prospective study examined associations between anti‐Ro antibody titers and fetal CNL. Methods: Antibody‐positive mothers referred since 2018 for fetal echocardiography at risk of CNL (group 1; n = 240) or with CNL (group 2; n = 18) were included. Maternal antibody titers were measured with a chemiluminescent immunoassay (CIA). Additional testing on diluted serum samples was used to quantify anti–Ro 60 antibody titers above the analytical measuring range (AMR) of the standard CIA (≥1,375 chemiluminescent units [CU]). Results: Among 27 total mothers with a fetal diagnosis of CNL, all displayed anti–Ro 60 antibody titers that exceeded the AMR of the CIA at least 10‐fold. Of 122 mothers in group 1 who underwent additional anti–Ro 60 antibody testing, event rates of CNL (n = 9) were 0% (0 of 45) among mothers with anti–Ro 60 antibody titers from 1,375–10,000 CU, 5% (3 of 56) among mothers with titers from 10,000–50,000 CU, but 29% (6 of 21) among mothers with titers >50,000 CU (odds ratio 13.1, P = 0.0008). Of mothers in group 2 with a primary diagnosis of CNL, 0% (0 of 18 mothers) had anti–Ro 60 antibody titers <10,000 CU, 44% (8 of 18 mothers) had titers from 10,000–50,000 CU, and 56% (10 of 18 mothers) had titers >50,000 CU. Conclusion: CNL is associated with substantially higher anti‐Ro antibody titers than are obtained using a standard CIA. Enhancing the assay measuring range allows an improved specificity of identifying pregnancies at risk of CNL. [ABSTRACT FROM AUTHOR]

Background: We compared the safety and efficacy of leflunomide with that of methotrexate in the treatment of polyarticular juvenile rheumatoid arthritis in a multinational, randomized, controlled trial. Methods: Patients 3 to 17 years of age received leflunomide or methotrexate for 16 weeks in a double-dummy, blinded fashion, followed by a 32-week blinded extension. The rates of American College of Rheumatology Pediatric 30 percent responses (ACR Pedi 30) and the Percent Improvement Index were assessed at baseline and every 4 weeks for 16 weeks and every 8 weeks during the 32-week extension study. Results: Of 94 patients randomized, 86 completed 16 weeks of treatment, 70 of whom entered the extension study. At week 16, more patients in the methotrexate group than in the leflunomide group had an ACR Pedi 30 response (89 percent vs. 68 percent, P=0.02), whereas the values for the Percent Improvement Index did not differ significantly (–52.87 percent vs. –44.41 percent, P=0.18). In both groups, the improvements achieved at week 16 were maintained at week 48. The most common adverse events in both groups included gastrointestinal symptoms, headache, and nasopharyngeal symptoms. Aminotransferase elevations were more frequent with methotrexate than with leflunomide during the initial study and the extension study. Conclusions: In patients with polyarticular juvenile rheumatoid arthritis, methotrexate and leflunomide both resulted in high rates of clinical improvement, but the rate was slightly greater for methotrexate. At the doses used in this study, methotrexate was more effective than leflunomide. N Engl J Med 2005;352:1655-66. [ABSTRACT FROM AUTHOR]

Background: Rheumatic diseases are associated with an increased fracture risk. The tissue level characteristics of the bone involvement in children have not been well elucidated. Our objectives were to describe the bone micro-architectural characteristics in children with rheumatic diseases on chronic glucocorticoids, and to determine associations between micro-architectural findings with clinical and radiological variables. Methods: Children on chronic glucocorticoids for an underlying rheumatic disease were referred for evaluation of bone fragility given the presence of vertebral compression fractures. A trans-iliac bone biopsy was performed as part of the clinical assessment. Histomorphometric analysis and quantitative backscattered electron imaging (qBSE) of the biopsy samples were undertaken. Results: Data of 15 children (14.0 ± 3.2 years) with a duration of glucocorticoid exposure of 6.2 ± 4.1 years and average prednisone dose of 14.1 ± 6.2 mg/m2/day were assessed. Histomorphometric analyses demonstrated significant decrease in trabecular thickness (p = 0.01), osteoid thickness (p < 0.01), osteoblast surface (p = 0.02) and increase in trabecular separation (p = 0.04) compared to published age-matched normative data. Severity of the trabecular deficit was correlated to glucocorticoid dose, height and body mass index Z score, but not bone mineral density or measures of disease activity. Using qBSE to measure bone mineralization, the subjects were shown to have a heterogeneous and hypermineralized profile, with higher cumulative glucocorticoid dose being associated with greater mineralization (p < 0.01). Conclusions: In children with rheumatic diseases presenting with vertebral fractures, there is evidence of abnormal bone matrix mineralization and impairments of bone micro-architecture that correlate to glucocorticoid dose. [ABSTRACT FROM AUTHOR]

: ObjectivesWe reviewed our institution’s experience with isolated (congenital) third-degree atrioventricular block (CAVB) to identify pre- and post-natal predictors of mortality and the requirement for pacemakers in infancy and childhood.: BackgroundBecause of the relative rarity of the disease, there is a paucity of data concerning the outcome of fetuses and children with isolated CAVB.: MethodsThe medical records of all cases of CAVB encountered at our institution from January 1965 to December 1998 were analyzed.: ResultsOf 102 cases identified, 29 were diagnosed in utero (F) at 26.1 ± 5.6 weeks gestation, 33 as neonates (N; ≤28 days), and 40 as children (C) at 5.7 ± 4.8 years of age. Anti-Ro and/or anti-La were present in 95% of F and 90% of N, but only in 5% of C mothers tested (p < 0.0001). Patients with CAVB having F, N and C diagnosis had a mortality of 43%, 6% and 0%, respectively, in the first two decades of life. Increased mortality risk was associated with a fetal diagnosis of CAVB (13/15 deaths; p < 0.05), fetal hydrops (6/6 cases; p < 0.0001), endocardial fibroelastosis (5/5 cases; p < 0.0001) and delivery at ≤32 weeks (4/6 cases; p < 0.05). Timing of pacemaker implantation differed significantly among F versus N (p < 0.05) and N versus C (p < 0.001) cases. At 20 years of age only 11% and 12% of CAVB patients with N and C diagnosis, respectively, were not paced.: ConclusionsPre-natal diagnosis of CAVB is associated with high fetal and neonatal mortality. Among survivors, whether the diagnosis is made before or after birth, most undergo pacemaker implantation by adulthood, with earlier intervention and a significantly greater need for reintervention among those diagnosed in utero. [Copyright &y& Elsevier]

Background: There are no validated screening measures for depressive or anxiety disorders in childhood Systemic Lupus Erythematosus (cSLE). We investigated cross-sectionally (1) the prevalence of depressive and anxiety disorder in cSLE. (2) the validity of the Centre for Epidemiologic Studies Depression Scale for Children (CES-DC) and the Screen for Childhood Anxiety and Related Disorders (SCARED) measures in identifyingthese disorders. Methods: Participants 8-18 years with cSLE/incipient cSLE completed CES-DC, SCARED, and Quality OfMy Life (QOML) measures. Parents completed the SCARED-Parent measure. Diagnosis was by gold-standard psychiatric interview and determined prevalence of psychiatric disorder. Receiver Operating Characteristics Area under the Curve (ROCAUC) evaluated screening measure diagnostic performance. Results: Ofseventy-two parent-child dyads, 56 interviews were completed. Mean screen scores were: CES-DC = 15 (range 1-49, SD 12), SCARED-C = 22 (range 2-61, SD 14), SCARED-P = 13 (range 0-36, SD 8). Depressive disorder screen positivity (CES-DC ≥ 15) was 35% (vs. prevalence 5%). Anxiety disorder screen positivity (SCARED ≥ 25) was 39% (vs. prevalence 16%). CES-DC ROCAUC = 0.98 and SCARED-C ROCAUC = 0.7 (cut-points 38 and 32 respectively). Conclusions: Diagnostic thresholds for depressive and anxiety disorderscreening measures are high for both CES-DC and SCARED-C in cSLE. Brief focused interview should follow to determine whether psychiatric evaluation is warranted. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To report the 2‐year efficacy and safety of tocilizumab (TCZ) in patients with polyarticular‐course juvenile idiopathic arthritis (JIA). Methods: Patients ages 2–17 years with active polyarticular‐course JIA, in whom treatment with methotrexate was unsuccessful, received 16 weeks of open‐label intravenous TCZ in part 1 (once every 4 weeks: 8 mg/kg or 10 mg/kg for body weight [BW] <30 kg; 8 mg/kg for BW ≥30 kg). Assessments were based on the JIA–American College of Rheumatology (ACR) response (defined as percentage of improvement in ≥3 of the 6 JIA core response variables [CRVs]). Patients with at least a JIA‐ACR30 response (defined as ≥30% improvement in ≥3 of the 6 JIA CRVs without worsening in >1 of the remaining JIA CRVs by >30%) at week 16 were randomly assigned (1:1) to receive TCZ or placebo in part 2. Patients remained in part 2 until either week 40 or the occurrence of JIA flare. Upon starting part 3, all patients received open‐label TCZ. At week 104 of the study, efficacy was assessed using JIA‐ACR50/70/90 response rates (defined as 50%, 70%, or 90% improvement, respectively), achievement of inactive disease, and the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS‐71). Safety was assessed in the all‐exposure population per 100 patient‐years of exposure. Results: Overall, 188 patients entered part 1, 166 patients entered part 2, and 160 patients entered part 3. By week 104, among the 188 patients in the modified intent‐to‐treat group who received TCZ, JIA‐ACR50/70/90 response rates were 80.3%/77.1%/59.6%, respectively, the median JADAS‐71 score decreased from 3.6 at week 40 to 0.7 at week 104, 51.1% of patients had achieved inactive disease, and 31 of 66 patients who had been receiving glucocorticoids discontinued them. Adverse event (AE) and serious AE rates were 406.5 per 100 patient‐years and 11.1 per 100 patient‐years, respectively. The infection rate was 151.4 per 100 patient‐years, and the serious infection rate was 5.2 per 100 patient‐years. Conclusion: Patients treated with TCZ for polyarticular‐course JIA showed high‐level disease control for up to 2 years. The TCZ safety profile was consistent with that previously reported. [ABSTRACT FROM AUTHOR]

Objective LN is one of the most common and severe manifestations of SLE. Our aim was to test the association of SLE risk loci with LN risk in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE). Methods Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed <18 years) and aSLE patients (diagnosed ⩾18 years). Patients met ACR and/or SLICC SLE criteria and were genotyped on the Illumina Multi-Ethnic Global Array or Omni1-Quad arrays. We identified those with and without biopsy-confirmed LN. HLA and non-HLA additive SLE risk-weighted genetic risk scores (GRSs) were tested for association with LN risk in logistic models, stratified by cSLE/aSLE and ancestry. Stratified effect estimates were meta-analysed. Results Of 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk [odds ratio (OR) = 1.26; 95% CI 1.09, 1.46; P = 0.0006], as was increasing HLA GRS in Europeans (OR = 1.55; 95% CI 1.07, 2.25; P = 0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. When restricting cases to proliferative LN, the magnitude of these associations increased for both the non-HLA (OR = 1.30; 95% CI 1.10, 1.52; P = 0.002) and HLA GRS (OR = 1.99; 95% CI 1.29, 3.08; P = 0.002). Conclusion We observed an association between known SLE risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future studies will include SLE-risk single nucleotide polymorphisms specific to non-European ancestral groups and validate findings in an independent cohort. [ABSTRACT FROM AUTHOR]

The authors reflect on ghost authorship in publishing. They present the criteria for authorship under the International Committee of Medical Journal Editors focusing on contribution, drafting, final approval and accountability. They explain the agreement made by the International Rheumatology Editors during the American College of Rheumatology Annual Meeting in October 2013 on the restriction of ghost authorship in rheumatology-related publications.

The article offers the authors insights on ghost authorship in biomedical publishing. Topics discussed include the criteria to become an author from the policy of International Committee of Medical Journal Editors (ICMJE), the study published by the "British Medical Journal" (BMJ) on the assessment of prevalence of honorary authorship and ghost authorship in general medical journals, and the American College of Rheumatology (ACR) Annual Meeting on October 27, 2013.

Objective: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long‐term kidney survival. This study was undertaken to identify short‐term end points that predict long‐term kidney outcomes for use in clinical trials. Methods: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long‐term outcomes in a 36‐month follow‐up period. The long‐term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression. Results: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction‐period CKD status, 12‐month proteinuria, and 12‐month serum creatinine level. The SKI HIT variables included prediction‐period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12‐month proteinuria, 12‐month serum creatinine level, race, and an interaction between ISN/RPS class and 12‐month proteinuria. The RRT HIT included age at diagnosis, 12‐month proteinuria, and 12‐month serum creatinine level. Each HIT validated well internally (c‐indices 0.84–0.92) and in an independent LN cohort (c‐indices 0.89–0.92). Conclusion: HITs, derived from short‐term kidney responses to treatment, correlate with long‐term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials. [ABSTRACT FROM AUTHOR]

Objective: To describe the features and treatment of macrophage activation syndrome (MAS) in a single‐center cohort of patients with childhood‐onset systemic lupus erythematosus (SLE), and to compare childhood‐onset SLE manifestations and outcomes between those with and those without MAS. Methods: We included all patients with childhood‐onset SLE followed up at The Hospital for Sick Children from 2002 to 2012, and identified those also diagnosed as having MAS. Demographic, clinical, and laboratory features of MAS and SLE, medication use, hospital and pediatric intensive care unit (PICU) admissions, as well as damage indices and mortality data were extracted from the Lupus database. Student's t‐tests and Fisher's exact tests were used to compare continuous and categorical variables, respectively. We calculated incidence rate ratios of hospital and PICU admissions comparing patients with and those without MAS, using Poisson models. Kaplan‐Meier survival analysis was used to examine the time to disease damage accrual. Results: Of the 403 patients with childhood‐onset SLE, 38 (9%) had MAS. The majority (68%) had concomitant MAS and SLE diagnoses. Fever was the most common MAS clinical feature. The frequency of renal and central nervous system disease, hospital admissions, the average daily dose of steroids, and time to disease damage were similar between those with and those without MAS. We observed a higher mortality rate among those with MAS (5%) than those without MAS (0.2%) (P = 0.02). Conclusion: MAS was most likely to develop concomitantly with childhood‐onset SLE diagnosis. The majority of the MAS patients were successfully treated with corticosteroids with no MAS relapses. Although the numbers were small, there was a higher risk of death associated with MAS compared to SLE without MAS. [ABSTRACT FROM AUTHOR]

Objective. Recent studies have suggested that prenatal exposure to HCQ reduces the risk of cardiac neonatal lupus. The aim of this study is to assess if maternal intake of antimalarials (AMs) throughout pregnancy lowered the risk of cardiac and non-cardiac neonatal lupus. Methods. Consecutive children seen between 1 January 1984 to 1 October 2013 born to women with a CTD and positive anti-Ro and/or anti-La antibodies were eligible for this single-centre retrospective cohort study. A total of 315 individuals were screened and 268 participants were included. Exposure to AMs was defined as HCQ or chloroquine throughout pregnancy. Outcomes were cardiac and non-cardiac neonatal lupus. Frequentist and Bayesian analyses were performed. We hypothesized that prenatal AM exposure would decrease the risk of cardiac but not non-cardiac neonatal lupus. Results. A total of 268 pregnancies were included; 73 were exposed to AMs throughout pregnancy. Ninety-nine children developed neonatal lupus, 117 remained unaffected and 52 children did not develop cardiac neonatal lupus but could not be categorized as unaffected since their full non-cardiac neonatal lupus status was unknown. Logistic regression suggested a protective effect of AM on cardiac neonatal lupus, but results were not statistically significant [odds ratio (OR) 0.21; P = 0.07]. Bayesian analysis showed that the probability of obtaining a protective effect (OR<1.0) for cardiac neonatal lupus was significant (98.7%). The effect of AMs on non-cardiac neonatal lupus was not significant (OR 0.78; P = 0.21). Conclusion. In this large single-centre cohort study, exposure to AMs throughout pregnancy was asso- ciated with a decreased probability of developing cardiac but not non-cardiac neonatal lupus. [ABSTRACT FROM AUTHOR]

Most outcome studies of rheumatic diseases report outcomes ascertained on a single occasion. While single assessments are sufficient for terminal or irreversible outcomes, they may not be sufficiently informative if outcomes change or fluctuate over time. Consequently, longitudinal studies that measure non-terminal outcomes repeatedly afford a better understanding of disease evolution. Longitudinal studies require special analytic methods. Newer longitudinal analytic methods have evolved tremendously to deal with common challenges in longitudinal observational studies. In recent years, an increasing number of studies have used longitudinal design. This review aims to help readers understand and apply the findings from longitudinal studies. Using a cohort of children with juvenile dermatomyositis (JDM), we illustrate how to study evolution of disease activity in JDM using longitudinal methods. [ABSTRACT FROM AUTHOR]

Objective To determine whether longer disease duration negatively impacts carotid intima-media thickness (CIMT), flow-mediated dilation (FMD), and pulse wave velocity (PWV) in a cohort of patients with childhood-onset systemic lupus erythematosus (SLE), and to compare CIMT, FMD, and PWV in patients with childhood-onset SLE with those in healthy children and explore determinants of vascular test results in childhood-onset SLE. Methods Cross-sectional analysis was performed in a prospective longitudinal cohort of patients with childhood-onset SLE at the latest followup visit. Clinical and laboratory data were collected for patients with childhood-onset SLE. CIMT, FMD, and PWV were measured using standardized protocols in patients with childhood-onset SLE and healthy children. Correlations between disease duration and results of the 3 vascular tests were performed. Vascular data in patients with childhood-onset SLE were compared with those in healthy children. Multivariable linear regression was used to identify determinants of CIMT, FMD, and PWV in childhood-onset SLE. Results Patients with childhood-onset SLE (n = 149) and healthy controls (n = 178) were enrolled. The median age of the patients was 17.2 years (interquartile range [IQR] 15.7-17.9 years), and their median disease duration was 3.2 years (IQR 1.8-4.9 years). The median age of the healthy children was 14.7 years (IQR 13.1-15.9 years). Longer disease duration correlated with worse FMD (r = −0.2, P = 0.031) in patients with childhood-onset SLE. Patients with childhood-onset SLE had smaller (better) CIMT, higher (better) FMD, and similar PWV compared with healthy controls. Linear regression analysis explained <24% of the variation in vascular test results in patients with childhood-onset SLE, suggesting that other variables should be explored as important determinants of CIMT, FMD, and PWV. Conclusion In this cohort of 149 patients with childhood-onset SLE, patients did not have worse CIMT, FMD, or PWV than did healthy controls. Longer disease duration was associated with worse FMD, suggesting progressive endothelial dysfunction over time. [ABSTRACT FROM AUTHOR]

Objective Systemic lupus erythematosus (SLE) is characterized by increased cardiovascular risk in adult-onset and childhood-onset SLE. Type I interferons (IFNs) appear to play a prominent role in premature vascular damage in adult-onset SLE, at least in part, by inducing impairments in the phenotype and function of endothelial progenitor cells (EPCs), thereby hampering vascular repair. It is not clear whether EPC dysfunction is present in childhood-onset SLE in association with a type I IFN signature. Methods The phenotype and numbers of EPCs were quantified in patients with childhood-onset SLE, patients with juvenile idiopathic arthritis (JIA), and matched healthy control subjects. In a separate cohort of patients with childhood-onset SLE, markers of subclinical atherosclerosis and endothelial dysfunction were quantified using standardized protocols and analyzed for associations with serum type I IFN activity. Results EPC numbers and function were significantly decreased in patients with childhood-onset SLE compared with patients with JIA and healthy control subjects. Serum from patients with childhood-onset SLE impaired differentiation of EPCs into mature endothelial cells in healthy controls, and this effect was blocked by inhibition of the type I IFN pathway. Type I IFN activity in serum was not significantly associated with subclinical atherosclerosis and endothelial function in patients with childhood-onset SLE. Conclusion As in adult-onset SLE, childhood-onset SLE is characterized by phenotypic and functional EPC abnormalities, which are likely triggered by type I IFNs. Although cross-sectional analysis revealed no global association between type I IFN signatures and vascular measures of subclinical atherosclerosis, longitudinal assessments are needed to evaluate whether progression of vascular damage in patients with childhood-onset SLE is associated with type I IFNs, as observed in patients with adult-onset SLE. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB. Methodology/Principal Findings: We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18–22.6 weeks gestation). Using human fetal hearts (20–22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305–319 of the extracellular loop linking transmembrane segments S5–S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells. Conclusions/Significance: Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets. [ABSTRACT FROM AUTHOR]

Objectives: Physicians often assess the effectiveness of treatments on a small number of patients. Multiple-baseline designs (MBDs), based on the Wampold--Worsham (WW) method of randomization and applied to four subjects, have relatively low power. Our objective was to propose another approach with greater power that does not suffer from the time requirements of the WW method applied to a greater number of subjects. Study Design and Setting: The power of a design that involves the combination of two four-subject MBDs was estimated using computer simulation and compared with the four- and eight-subject designs. The effect of a delayed linear response to treatment on the power of the test was also investigated. Results: Power was found to be adequate (>80%) for a standardized mean difference (SMD) greater than 0.8. The effect size associated with 80% power from combined tests was smaller than that of the single four-subject MBD (SMD = 1.3) and comparable with the eight-subject MBD (SMD = 0.6). A delayed linear response to the treatment resulted in important reductions in power (20--35%). Conclusions: By combining two four-subject MBD tests, an investigator can detect better effect sizes (SMD = 0.8) and be able to complete a comparatively timelier and feasible study. [ABSTRACT FROM AUTHOR]

Background: Following the introduction of the ILAR criteria for juvenile idiopathic arthritis, juvenile psoriatic arthritis (JPsA) has become a better recognized category within the inflammatory arthritides of childhood. There are fewer reports describing the characteristics and long-term outcome of patients with JPsA than other subtypes of JIA. The aim of our study was to determine the long-term outcome and clinical course of patients with juvenile psoriatic arthritis (JPsA) and to define subgroups of JPsA. Methods: Clinical records of all patients meeting criteria for JPsA were reviewed and divided into 4 groups depending on their clinical features and onset type. Patient characteristics and clinical features at onset and during follow-up were determined. Results: The cohort consisted of 119 patients: 65 with oligoarticular-onset (55%; persistent 44 and extended 21), 34 (29%) with RF(-) and 4 (3%) RF(+) polyarticular and 16 (13%) enthesitis-related arthritis (ERA). At diagnosis patients with ERA were oldest and more commonly male (p=0.001 and =0.01 respectively). Patients with a polyarticular course had more involvement of small joints of the hands and wrist when compared to patients with persistent oligoarticular and ERA (p<0.001) while patients with ERA had more hip and sacroiliac arthritis (p<0.001 for both). Nail changes were seen in 66 patients (57%) and were associated with DIP involvement (p=0.0034). Outcome: Time to first inactive disease on, but not off, therapy was significantly longer among patients with polyarticular course when compared to oligoarticular and ERA (p=0.016 and p=0.48 respectively). Patients with polyarticular course more frequently had contractures during follow-up than other groups (p=0.01). Conclusion: The long-term outcome of with JPsA was generally good. Patients with JPsA did not appear to form distinct sub-group of patients but rather resembled JIA patients with onset types without psoriasis. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to evaluate the outcome of maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis following intravenous gamma globulin (IVIG) and corticosteroid therapy. Background: We have previously shown that 85% of fetuses and infants with maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis suffer demise or need for transplant. In an attempt to improve this outcome, in 1998, we began to empirically treat affected patients with IVIG and corticosteroids. Methods: We reviewed the clinical records and echocardiograms of 20 affected patients encountered in our institutions and treated with IVIG and corticosteroids from 1998 to 2009. Results: All 20 were initially referred at a median gestational age of 23 weeks (range 18 to 38 weeks). Nineteen mothers were anti-Ro antibody positive, 8 anti-La antibody positive, and 7 had clinical autoimmune disease. Endocardial fibroelastosis was seen in 16 and was not obvious in 4 others with reduced ventricular function, and 16 (80%) had reduced or borderline ventricular shortening fraction (≤30%) before or after birth. Eighteen had atrioventricular block at referral (16 in 3°). During pregnancy, maternal IVIG was given in 9 and dexamethasone in 17. After birth, 17 infants received IVIG (n = 14) and/or corticosteroids (n = 15). Twelve underwent pacemaker implantation. Four with hydrops at presentation died perinatally, despite initial improvement in function in 3. At a median follow-up of 2.9 years (1.1 to 9.8 years), 16 (80%) patients are currently alive with normal systolic ventricular function and 6 are not paced. Conclusions: Treatment of maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis with IVIG and corticosteroids potentially improves the outcome of affected fetuses. Further studies are needed to determine the optimal dose and timing of IVIG administration. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to determine whether cardiac complications of neonatal lupus erythematosus (NLE) are related to maternal anti-Ro and anti-La autoantibody-levels. Background: Autoantibody-positive mothers are frequently referred for serial echocardiography because of the elevated fetal risk of developing immune-mediated heart block. Little is known why only some and not all offspring are affected. Methods: All cases referred since 2000 for serial fetal echocardiography or cardiac complications related to maternal antibodies were included. Patients without cardiac NLE (group 1) and with cardiac NLE (group 2) were compared. Antibody levels were measured by enzyme-linked immunosorbent assay with a cutoff value of 8 U/ml for a positive test result. Results: Group 1 included 146 serially screened fetuses with normal pregnancy outcomes. Group 2 consisted of 40 fetuses/neonates with a diagnosis of heart block or endocardial fibroelastosis or both, and included 4 fetuses diagnosed during serial screening. All cardiac complications were associated with moderate (≥50 U/ml; 15%) or high (≥100 U/ml; 85%) maternal anti-Ro levels, independently of anti-La antibody titres. The event rate of complete heart block was 5% for prospectively screened fetuses with Ro-values ≥50 U/ml (odds ratio: 7.8) and 0% for fetuses with lower titres (p < 0.0001). Infants with pre-natal exposure to high-titre anti-La levels ≥100 U/ml were the most likely to have noncardiac features of NLE (event rate: 57%; odds ratio: 4.7). Conclusions: Our findings support that the amount of maternal antibodies, rather than their presence, is associated with fetal tissue injury. As anti-Ro levels correlate with the risk of cardiac complications, serial echocardiography should be limited to women with high anti-Ro-titres. [Copyright &y& Elsevier]

Objective: Barriers to medical care may influence health status. It is unclear whether problems with access can predict clinical outcomes in lupus. This study aimed to determine whether care barriers are associated with increased disease activity and damage in a multi-center, multiethnic SLE cohort. We also compared concordance between care barriers as reported by the patient and lupus specialist. Methods: Data from SLE patients in 12 Canadian centers collected at annual visits, including demographics, treatment, disease activity and damage were analyzed. Results: 654 patients were enrolled with ethnic groups being Caucasian [CC] (64%), Aboriginal [ABO] (9%), Asian [AS] (21%), and Black [BLK] (6%). 50.8% had at least one barrier to care including travel to a rheumatologist (32.0%), waiting to see a rheumatologist and cost of medications. Access to medication and costs were signifi cantly associated with co-morbidity (p < 0.001, p = 0.04). There were significant associations between ethnicity and any physician perceived care barrier (p < 0.001), mostly in Aboriginal. Doctors identified half of patients who had access to medication problems (p = 0.003) and the relationship between doctors and patients identifying similar care barriers was weak (r = 0.09). A lower total household income significantly predicted the presence of any care barrier (p < 0.001). Conclusions: Despite access to a lupus specialist many care barriers were identified, although we found few associations between care barriers and patient outcomes. The cost of medication was related to SLE disease activity; however, we cannot determine if this was cause or effect. Care barriers identified by lupus patients are significantly underestimated by physicians. [ABSTRACT FROM AUTHOR]

The article examines the ability of neutrophil gelatinase-associated lipocalin (NGAL) to predict worsening of renal disease activity in childhood-onset systemic lupus erythematosus (SLE). It highlights a longitudinal prospective study which was conducted to 111 patients with childhood-onset SLE. According to the article, serial measurement of urinary and plasma NGAL levels can be important in the prediction of global renal SLE disease activity.

The article focuses on the study that evaluates the risk factors for subclinical atherosclerosis in a population of patients with pediatric systemic lupus erythematosus (SLE). It is concluded that both traditional and nontraditional risk factors are linked with increased carotid intima-media thickness (CIMT) in the cohort of patients in the Antherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. Azathioprine treatment is also linked with increased CIMT.

A combined forward and reverse genetic approach was undertaken to test the candidacy of IRAK1 (interleukin-1 receptor associated kinase-1) as an X chromosome-encoded risk factor for systemic lupus erythematosus (SLE). In studying ≈5,000 subjects and healthy controls, 5 SNPs spanning the IR.4K1 gene showed disease association (P values reaching 10[sup-10], odds ratio >1.5) in both adultand childhoodonset SLE, in 4 different ethnic groups, with a 4 SNP haplotype (GGGG) being strongly associated with the disease. The functional role of IRAK1 was next examined by using congenic mouse models bearing the disease loci: S/el or S1e3. IRAK1 deficiency abrogated all lupusassociated phenotypes, including 1gM and lgG autoantibodies, lymphocytic activation, and renal disease in both models. In addition, the absence of IRAK1 reversed the dendritic cell "hyperactivity" associated with S!e3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establish IRAK1 as a disease gene in lupus, capable of modulating at least 2 key checkpoints in disease development. This demonstration of an X chromosome gene as a disease susceptibility factor in human SLE raises the possibility that the gender difference in SLE may in part be attributed to sex chromosome genes. [ABSTRACT FROM AUTHOR]

The article focuses on the genotyping of STAT4 which reveals multiple haplotypic associations with systematic lupus erythematosus (SLE). SLE is a prototypical systematic autoimmune disorder with complex etiology and strong genetic component. STAT-1 and STAT-4 are transcription factors that play a key role in the interferon and Th1 signalling pathways. An additional haplotypic association across STAT4 was identified to have common risk haplotype found in multiple racial groups.

Objective: Barriers to medical care may influence health status. It is unclear whether problems with access can predict clinical outcomes in lupus. This study aimed to determine whether care barriers are associated with increased disease activity and damage in a multi-center, multiethnic SLE cohort. We also compared concordance between care barriers as reported by the patient and lupus specialist. Methods: Data from SLE patients in 12 Canadian centers collected at annual visits, including demographics, treatment, disease activity and damage were analyzed. Results: 654 patients were enrolled with ethnic groups being Caucasian [CC] (64%), Aboriginal [ABO] (9%), Asian [AS] (21%), and Black [BLK] (6%). 50.8% had at least one barrier to care including travel to a rheumatologist (32.0%), waiting to see a rheumatologist and cost of medications. Access to medication and costs were signifi cantly associated with co-morbidity (p < 0.001, p = 0.04). There were signifi cant associations between ethnicity and any physician perceived care barrier (p < 0.001), mostly in Aboriginal. Doctors identifi ed half of patients who had access to medication problems (p = 0.003) and the relationship between doctors and patients identifying similar care barriers was weak (r = 0.09). A lower total household income signifi cantly predicted the presence of any care barrier (p < 0.001). Conclusions: Despite access to a lupus specialist many care barriers were identifi ed, although we found few associations between care barriers and patient outcomes. The cost of medication was related to SLE disease activity; however, we cannot determine if this was cause or effect. Care barriers identifi ed by lupus patients are signifi cantly underestimated by physicians. [ABSTRACT FROM AUTHOR]

The article discusses a study on the difference between systemic lupus erythematosus (SLE) that occurred during childhood and those during adulthood. Patients were examined using SLE Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). It was found that children with SLE have more diseases than adults with SLE.

The article presents a study which identified susceptibility genes contributing to systemic lupus erythematosus (SLE), using a novel candidate gene pathway microarray platform. A platform of single-nucleotide polymorphisms (SNPs) from genes was designed and validated. The authors said the overall findings demonstrate that the platform used provides an novel and powerful approach which is applicable to determining genetic foundations of complex diseases.