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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]

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]

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]

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]

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.

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]

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]

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 (). 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. [ABSTRACT FROM AUTHOR]

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. [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]