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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.

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] 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.

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 follow-up 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.

The 73rd Annual Meeting of The Canadian Rheumatology Association was held at the Fairmont The Queen Elizabeth, Montreal, Quebec, Canada February 27 – March 2, 2019. The program consisted of presentations covering original research, symposia, awards, and lectures. Highlights of the meeting include the following 2019 Award Winners: Distinguished Rheumatologist, Edward Keystone; Distinguished Investigator, Diane Lacaille; Teacher-Educator, Shirley Tse; Emerging Investigator, Glen Hazlewood; Best Abstract on SLE Research by a Trainee – Ian Watson Award, Alexandra Legge; Best Abstract on Clinical or Epidemiology Research by a Trainee – Phil Rosen Award, Lauren King; Best Abstract on Basic Science Research by a Trainee, Remy Pollock; Best Abstract for Research by an Undergraduate Student, Andrea Carboni-Jimènez; Best Abstract on Research by a Rheumatology Resident, May Choi; Best Abstract by a Medical Student, Leonardo Calderon; Best Abstract by a Post-Graduate Research Trainee, Carolina Munoz-Grajales; Best Abstract by a Rheumatology Post-Graduate Research Trainee, Andre Luquini; Best Abstract on Quality Care Initiatives in Rheumatology, Cheryl Barnabe and Ines Colmegna; Best Abstract on Research by Young Faculty, Bindee Kuriya; Practice Reflection Award, Gold, Jason Kur; Practice Reflection Award, Silver, May Choi. Lectures and other events included Keynote Lecture by Andre Picard: Quirky Past, Uncertain Future: The State of Medicare in Canada; Keynote Address by Diane Lacaille, Distinguished Investigator Awardee: Time to Re-Label Comorbidities in RA – Coexisting or Complications; State of the Art Lecture by Mark Roberts: Myositis and its Mimics; Dunlop-Dottridge Lecture by Gilles Boire: The 4-H of Biomarkers in Arthritis: A lot of Help, Potential Harm, Some Hype, Increasing Hope; and the Great Debate: Be it Resolved that Competency-based Medical Education will Result in Improved Quality of Care for Patients vs the “Old Way” of Training Rheumatologists. Arguing for: Mercedes Chan and Marie-Paule Morin, and against: Beth Hazel and Heather McDonald-Blumer. Topics including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren syndrome, psoriatic arthritis, spondyloarthritis, vasculitis, osteoarthritis, fibromyalgia, and their respective diagnoses, treatments, and outcomes are reflected in the abstracts, which we are pleased to publish in this issue of The Journal.

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.

To compare the symptoms and signs of dry eye disease (DED) in children with systemic lupus erythematosus (SLE) with those in healthy children using common diagnostic tools.Prospective, observational, single-center cohort study. Thirty-four subjects with SLE and 15 healthy subjects were recruited from the Hospital for Sick Children in Toronto, Canada. Subjects underwent subjective and objective dry eye assessments using the Canadian Dry Eye Assessment (CDEA) questionnaire, tear film osmolarity, slit lamp examination, tear film break-up time, corneal fluorescein staining, Schirmer test 1, and conjunctival lissamine green staining.No difference in symptoms was found between children with SLE and healthy children (CDEA score 6.4 ± 5.4 vs. 3.8 ± 3.2; P = 0.09). Corneal staining was more prevalent in children with SLE than in healthy children (58.8% vs. 20.0%; P = 0.01), and children with SLE had higher mean corneal fluorescein staining scores (1.7 ± 1.7 vs. 0.2 ± 0.4; P = 0.002). No statistically significant differences in tear osmolarity, inter-eye differences in tear osmolarity, tear film break-up time, Schirmer test 1, or lissamine green staining scores were observed between the 2 groups. In healthy children, CDEA scores weakly correlated with corneal fluorescein staining score (r = 0.53, P = 0.04). In children with SLE, no correlation between CDEA score and any of the diagnostic test outcomes was found.There is discordance between symptoms and signs of DED in children with SLE. Corneal fluorescein staining is essential for the diagnosis of DED in these children.

Objective.Currently there are 2 different classification criteria for systemic lupus erythematosus (SLE): American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC). The aim of this study was to compare the sensitivities of ACR and SLICC criteria in childhood-onset SLE (cSLE) using a large, multiethnic cohort.Methods.We conducted a retrospective study of 722 patients diagnosed with cSLE at The Hospital for Sick Children (SickKids). Prospectively collected data from SickKids’ Lupus Database were reviewed/validated against medical records prior to ACR and SLICC scoring based on cumulative symptoms up to the last visit. Sensitivities were compared using McNemar’s test. Descriptive statistics were used to identify SLE features unique to each set of criteria and autoantibodies not included in either.Results.ACR and SLICC sensitivities were as follows: 92.4% and 96.3% overall (p = 0.001); 82.5% and 91.3% (p = 0.01) in those scored ≤ 1 year from diagnosis; 92.7% and 97.9% (p = 0.02) in those scored 2–3 years from diagnosis. Forty-eight of 55 (87.3%) patients who did not meet ACR criteria met SLICC criteria through SLICC-specific criterion or renal biopsy. Twenty of 27 (74.1%) patients who did not meet SLICC criteria met ACR criteria as a result of photosensitivity (73.9%) and ACR lymphopenia criteria (26.1%). Six of 7 patients (85.7%) who were clinically diagnosed with cSLE but did not meet either SLICC or ACR criteria had anti-Ro antibodies.Conclusion.SLICC criteria were significantly more sensitive than ACR criteria in cSLE classification, especially early in the disease course. Because of the extreme rarity of primary Sjögren syndrome in children, one may consider adding anti-Ro antibodies to the classification criteria for cSLE because they are present in ∼40% of patents with cSLE.

ObjectiveTo evaluate the association between ethnicity and neonatal lupus erythematosus (NLE), as well as specific NLE manifestations in a large multiethnic population.MethodsWe conducted a cohort study of the children (≤ 1 yr of age) seen in the NLE clinic at The Hospital for Sick Children (SickKids), between January 2011 and April 2019. The cohort was divided into European, non-European, and mixed European–non-European groups according to parent-reported child’s ethnicity (Canada Census categories). Outcomes were NLE and specific NLE manifestations (cardiac, cutaneous, cytopenias, transaminitis, and macrocephaly). The frequency of NLE and specific manifestations were compared between ethnic groups (Fisher exact test). We tested the association between ethnicity and (1) NLE risk, and (2) specific NLE manifestations with logistic regression models, including covariates for child’s sex, maternal rheumatic disease status during pregnancy, and maternal use of antimalarials during pregnancy (multiple comparisons threshold P < 0.008).ResultsWe included 324 children born to 270 anti-Ro antibody–positive mothers. Median age at first visit was 1.8 (IQR 1.4–2.3) months, and median follow-up time was 12 (IQR 2–24) months. The majority was non-European (48%), with 34% European, and 18% mixed European–non-European. There was no significant association between non-European ethnicity (OR 1.18, 95% CI 0.71–1.94, P = 0.51), mixed European–non-European ethnicity (OR 1.13, 95% CI 0.59–2.16, P = 0.70), and NLE risk compared with European ethnicity. We also did not find an association between ethnicity and specific NLE manifestations in univariate or multivariable-adjusted models.ConclusionIn a large multiethnic cohort, there was no association between a child’s ethnicity and NLE risk or specific NLE manifestations.

Objective.Specific risk alleles for childhood-onset systemic lupus erythematosus SLE (cSLE) vs adult-onset SLE (aSLE) patients have not been identified. The aims of this study were to determine if there is an association (1) between non-HLA–related genetic risk score (GRS) and age of SLE diagnosis, and (2) between HLA-related GRS and age of SLE diagnosis.Methods.Genomic DNA was obtained from 2001 multiethnic patients and genotyped using the Immunochip. Following quality control, genetic risk counting (GRCS), weighted (GRWS), standardized counting (GRSCS), and standardized weighted (GRSWS) scores were calculated based on independent single-nucleotide polymorphisms from validated SLE loci. Scores were analyzed in a regression model and adjusted by sex and ancestral population.Results.The analyzed cohort consisted of 1540 patients: 1351 females and 189 males (675 cSLE and 865 aSLE). There were significant negative associations between all non-HLA GRS and age of SLE diagnosis: P = 0.011 and r2 = 0.175 for GRWS; P = 0.008 and r2 = 0.178 for GRSCS; P = 0.002 and r2 = 0.176 for GRSWS (higher GRS correlated with lower age of diagnosis.) All HLA GRS showed significant positive associations with age of diagnosis: P = 0.049 and r2 = 0.176 for GRCS; P = 0.022 and r2 = 0.176 for GRWS; P = 0.022 and r2 = 0.176 for GRSCS; P = 0.011 and r2 = 0.177 for GRSWS (higher GRS correlated with higher age of diagnosis).Conclusion.Our data suggest that there is a linear relationship between genetic risk and age of SLE diagnosis and that HLA and non-HLA GRS are associated with age of diagnosis in opposite directions.

ObjectiveMacrophage activation syndrome (MAS), a life-threatening inflammatory complication, is increasingly recognized in childhood-onset systemic lupus erythematosus (cSLE). It can be a challenge to differentiate active cSLE from MAS. We generated decision rules for discriminating MAS from active cSLE in newly diagnosed patients.MethodsWe conducted a retrospective cohort study of consecutive, newly diagnosed, active cSLE patients with fever, requiring hospital admission to The Hospital for Sick Children from January 2003 to December 2007 (cohort 1) and January 2008 to December 2013 (cohort 2). All patients met ≥ 4 American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria, and were steroid-naïve and infection-free. MAS was diagnosed based on expert opinion. Recursive partitioning was applied to each cohort to derive a decision rule based on clinical and laboratory features, distinguishing MAS from non-MAS cSLE. Each decision rule was applied to the alternate, independent cohort. Sensitivity and specificity of these decision rules were compared to existing criteria.ResultsCohort 1 (n = 34) and cohort 2 (n = 41) each had 10 patients with MAS. Recursive partitioning in cohort 1 identified ferritin ≥ 699 μg/L as the sole best discriminator between MAS and non-MAS patients (R2 = 0.48), and in cohort 2, ferritin ≥ 1107 μg/L was the best discriminator for MAS, followed by lymphocytes < 0.72 × 103/mm3 (R2 = 0.52). Cross-validation of our decision rules maintained 90–100% sensitivity and 65–85% specificity.ConclusionOur decision rule demonstrated improved performance compared to preliminary guidelines for MAS in cSLE from the Lupus Working Group of the Paediatric Rheumatology European Society and familial hemophagocytic lymphohistiocytosis diagnostic criteria. Validation in independent cohorts is required.

Objective.Persistent systemic lupus erythematosus (SLE) disease activity is associated with increased morbidity and mortality. In a multicenter cohort of patients with prevalent SLE, we described persistence, patterns, and predictors of change in disease activity over time.Methods.Based on SLE Disease Activity Index (SLEDAI)-2K scores at cohort entry, patients were classified into 4 groups: low (score < 4; LOW), moderate (4 to < 6; MOD), moderately high (6 to ≤ 10; MHIGH), and very high (> 10; VHIGH). Multivariable linear and longitudinal mixed linear regression models were used to identify predictors of change over time in SLEDAI-2K.Results.There were 2019 participants, with declining followup data over 5 years (1326, 580, 274, 186, and 148 patients, respectively). At cohort entry, mean (± SD) age was 42 (± 17) years, disease duration 11 (± 10) years, and 90% were female. The 4 groups included 44% LOW (n = 891), 20% MOD (n = 400), 22% MHIGH (n = 442), and 14% VHIGH (n = 286); therefore, 36% had clinically important SLE activity. The proportion of patients in the LOW group at entry who moved to a higher activity level varied from 30% (167/557) at 1 year, to 49% (41/83) at 3 years, and 54% (30/56) at 5 years. Among 181 patients with MOD to VHIGH entry activity and 3 years of followup, 116 (64.1%) remained active. In all analyses, only higher SLEDAI-2K at cohort entry remained a significant predictor of higher SLEDAI-2K in subsequent years.Conclusion.Higher SLEDAI-2K at study entry was the single major independent predictor of higher SLEDAI-2K over time, reflecting frequent persistence of active disease, even in patients with longstanding disease. This highlights gaps in the optimal treatment of SLE.

Purpose Genetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use. Methods We prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing. Results WGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24% P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A. Conclusion WGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Objective Although juvenile-onset proliferative lupus nephritis (PLN) leads to significant morbidity and mortality, there is no clinical trials–based evidence to support the treatment effectiveness of any therapy for juvenile-onset PLN. Marginal structural models enable us to estimate treatment effectiveness using observational data while accounting for confounding by indication. Methods We used prospectively collected data to examine the effect of mycophenolate mofetil (MMF), compared to the use of other therapies, on the long-term outcome of a juvenile-onset PLN cohort (age at PLN onset

Systemic lupus erythematosus (SLE) is a systemic, autoimmune, multisystem disease with a heterogeneous clinical phenotype. Genome-wide association studies have identified multiple susceptibility loci, but these explain a fraction of the estimated heritability. This is partly because within the broad spectrum of SLE are monogenic diseases that tend to cluster in patients with young age of onset, and in families. This article highlights insights into the pathogenesis of SLE provided by these monogenic diseases. It examines genetic causes of complement deficiency, abnormal interferon production, and abnormalities of tolerance, resulting in monogenic SLE with overlapping clinical features, autoantibodies, and shared inflammatory pathways.

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 associated with a decreased probability of developing cardiac but not non-cardiac neonatal lupus.

The 72nd Annual Meeting of The Canadian Rheumatology Association (CRA) was held at The Westin Ottawa, Ottawa, Ontario, Canada, February 8−11, 2017. The program consisted of presentations covering original research, symposia, awards, and lectures. Highlights of the meeting include the following 2017 award winners: Dr. Vinod Chandran, Young Investigator; Dr. Jacques P. Brown, Distinguished Investigator; Dr. David Robinson, Teacher-Educator; Dr. Michel Zummer, Distinguished Rheumatologist; Ms. Rebecca Gole, Best Abstract on SLE Research by a Trainee − Ian Watson Award; Ms. Bailey Russell, Best Abstract on Clinical or Epidemiology Research by a Trainee − Phil Rosen Award; Dr. Sahil Koppikar and Dr. Henry Averns, Practice Reflection Award; Dr. Shirine Usmani, Best Abstract on Basic Science Research by a Trainee; Ms. Carol Dou, Best Abstract for Research by an Undergraduate Student; Dr. Dania Basodan, Best Abstract on Research by a Rheumatology Resident; Dr. Claire Barber, Best Abstract on Adult Research by Young Faculty; Ms. Audrea Chen, Best Abstract by a Medical Student; Dr. Kun Huang, Best Abstract by a Post-Graduate Resident; and Dr. Ryan Lewinson, Best Abstract by a Post-Graduate Research Trainee. Lectures and other events included a Keynote Lecture by Jonathon Fowles: Exercise is Medicine: Is Exercise a Good or Bad Thing for People with Arthritis?; State of the Art Lecture by Matthew Warman: Insights into Bone Biology and Therapeutics Gleaned from the Sustained Investigation of Rare Diseases; Dunlop-Dottridge Lecture by Allen Steere: Lyme Disease: A New Problem for Rheumatologists in Canada; and the Great Debate: Be it Resolved that the Least Expensive Treatment Should be Chosen. Switch, Switch, Switch! Arguing for: Jonathan Chan and Antonio Avina, and against: Marinka Twilt and Glen Hazlewood. Topics such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren syndrome, psoriatic arthritis, spondyloarthritis, vasculitis, osteoarthritis, fibromyalgia, pediatric rheumatology, and their respective diagnoses, treatments, and outcomes are reflected in the abstracts, which we are pleased to publish in this issue of The Journal.

Background/aimsThere is a paucity of large trials investigating the effect of management strategies for paediatric non-infectious uveitis on complications requiring surgery. The purpose of our study is to investigate whether earlier initiation of systemic immunosuppression in paediatric non-infectious uveitis is associated with fewer ophthalmic surgeries.MethodsA retrospective review was conducted on 48 children with non-infectious uveitis assessed in 1998–2013. Patients were divided into uveitis diagnosed before December 2008 (group 1) and after January 2009 (group 2). Duration from uveitis onset to methotrexate initiation (U-MTX) and biological addition (U-Biologic) were reviewed. Follow-up visits with topical corticosteroids >3 times daily and active uveitis (≥1+ cells) during 3.5 years were documented. The main outcome measure was the need for ≥1 ophthalmic surgery at 3.5 years.ResultsIn group 1, 69.5% of patients required ≥1 ophthalmic surgery at 3.5 years versus 26.9% in group 2 (p=0.005). U-MTX was 28.9±11.8 weeks and 14.2±10.0 weeks for groups 1 and 2 (p=0.028). U-Biologic was 134.6±46.0 weeks and 82.3±43.3 weeks for groups 1 and 2 (p=0.0016). Corticosteroid use >3 times daily was 85.9±52.7 weeks and 14.6±11.1 weeks for groups 1 and 2. Multivariate regression showed methotrexate initiation within 6 months of uveitis onset lowered the likelihood of needing ophthalmic surgery at 3.5 years (OR=6.2, 95% CI 1.2 to 33.4; p=0.033). Univariate regression demonstrated biological addition within 18 months of uveitis onset reduced the likelihood of requiring ophthalmic surgery (OR 12.57, 95% CI 1.28 to 123.48; p=0.030).ConclusionEarlier control of uveitis by addition of immunosuppressive therapy reduced the need for ophthalmic surgery.

Background Fatigue is a common symptom of systemic autoimmune rheumatic disease (SARD). Patients with SARD have a protracted pre-clinical phase during which progressive immunologic derangements occur culminating in disease. In this study, we sought to determine when fatigue develops and whether its presence correlates with inflammatory factors or predicts disease progression. Methods Anti-nuclear antibody (ANA)-negative healthy controls (HCs) and ANA-positive participants with no criteria, at least one clinical criteria (undifferentiated connective tissue disease, UCTD), or meeting SARD classification criteria were recruited. Fatigue was assessed using a modified version of the FACIT-F questionnaire and the presence of fibromyalgia determined using a questionnaire based on the modified 2010 ACR criteria. Peripheral blood expression of five IFN-induced genes was quantified by NanoString and the levels of IL-1β, IL-6, or TNF-α by ELISA. Results Fatigue was as prevalent and severe in individuals lacking SARD criteria as it was in UCTD and SARD. Overall, ~ 1/3 of ANA+ subjects met fibromyalgia criteria, with no differences between sub-groups. Although fatigue was more severe in these individuals, those lacking fibromyalgia remained significantly more fatigued than ANA− HC. However, even in these subjects, fatigue correlated with the widespread pain index and symptom severity scores on the fibromyalgia questionnaire. Fatigue was not associated with elevated cytokine levels in any of the ANA+ sub-groups and did not predict imminent disease progression. Conclusions Fatigue is common in ANA+ individuals lacking sufficient criteria for a SARD diagnosis, correlates with fibromyalgia-related symptoms, and is not associated with inflammation or predictive of disease progression.

Background Neonatal Lupus (NL) is an acquired autoimmune disorder of newborns secondary to the transplacental passage of maternal anti-Ro and/or anti-La. Approximately 2% of children exposed to these antibodies develop NL. Prior studies have suggested that babies of non-European ancestry have a higher proportion of cardiac NL when compared to babies of European ancestry. This finding has not been consistently replicated. Objectives To examine the association between ethnicity and clinical manifestations of NL in our multi-ethnic population. Methods We conducted a cohort study of our large, multi-ethnic NL clinic population. The Neonatal Lupus clinic at the Hospital for Sick Children, Toronto, Canada was established in 1986. Children born to anti-Ro and/or anti-La antibody positive mothers are referred to the NL clinic. Antenatal testing is completed due to maternal rheumatologic diagnosis, a prior child born with NL and/or a history of symptoms that prompted physician testing for these antibodies. Beginning in 2011, families routinely reported ethnicity (Canadian census categories). We divided our NL patient cohort in European and non-European groups; the non-European group includes patients of African, Latin American, East Asian, South Asian and Mixed non-European ancestry (i.e. combination of two or more of non-European ethnicities). We included children assessed in the NL clinic ≤ 1 year of age between January 2011 to April 2018. There were 59 children censored for this analysis (7 missing ethnicity and 52 Mixed European-Non European ancestry). We analyzed prospectively collected data from our NL database, on specific NL manifestations: cardiac (heart block, myocarditis, endocardial fibroelastosis), dermatologic (typical rash of NL), hematologic (cytopenias), hepatic (transaminitis) and neurologic (macrocephaly). The frequency of NL clinical manifestations was compared among ethnicity groups (Fisher’s exact test). We tested the association between ethnicity and NL clinical manifestations in logistic models. Results Our study included 301 children, 149 (50%) female and 164 (55%) with NL (Table 1). The median follow-up period was 12.2 months (IQR: 4.8, 28.8 months). Ethnicity data was available for 294 (98%) of the children. The non-European group (40%) was comprised of East Asian (14%), South Asian (13%), African (10%), Latin American (2%) and Mixed Non-European ancestry (17%). We did not observe a difference between European and Non-European babies in the proportion with NL, nor any difference in the frequency of specific NL manifestations (p-values > 0.3). Conclusion In our multiethnic NL cohort of children born to mothers with positive anti-Ro and/or anti-La antibodies, there was no association between ethnicity and NL, nor specific NL manifestations. Future analyses will examine the effect of maternal ethnicity and rheumatic disease status on the risk of NL and specific NL manifestations. References [1] Neiman AR, Lee LA, Weston WL, Buyon JP. Cutaneous manifestations of neonatal lupus without heart block: Characteristics of mothers and children enrolled in a national registry. J Pediatr. 2000;137(5):674–80. [2] Izmirly PM, Saxena A, Kim MY, Wang D, Sahl SK, Llanos C, Friedman D, Buyon JP. Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro associated cardiac neonatal lupus. Circulation. 2011;124:1927–1935. Disclosure of Interests None declared

Background Lupus nephritis (LN) is one of the most common and severe manifestations of systemic lupus erythematosus (SLE). We tested the association of SLE-risk loci with LN risk in childhood- (cSLE) and adult-onset SLE (aSLE). Methods Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed 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 (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. Conclusions 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 directions will include incorporating SLE-risk SNPs specific to non-European ancestral groups and validating findings in an independent cohort. Funding Source(s): Dr. Hiraki: Canadian Institute of Health Research (CIHR) Project Scheme grant

Background Cutaneous eruptions in neonatal lupus erythematosus (NLE) are thought to be self-resolving. Limited literature suggests cutaneous changes may persist. Objective To characterize cutaneous residua in NLE and identify predictors for their development. Methods A retrospective cohort study of patients with cutaneous NLE born between January 1980 and May 2017 was performed. Primary outcome was the proportion of patients with cutaneous residua. Secondary outcomes included associations/predictors of sequelae. Results At the last follow-up, at a mean age of 4 years (range, 0.5-18.7 years), 34% of 106 patients had cutaneous sequelae, 13% had telangiectasia, 17% had dyspigmentation, and 9% had atrophic scarring. Scarring at the last follow-up was significantly associated with the presence of skin lesions at birth (P Limitations This study was limited by the retrospective design, short follow-up duration in a subset of patients, and small sample size. Conclusion Cutaneous NLE can exhibit long-term cutaneous residua. These findings underlie the importance of accurate diagnosis, long-term monitoring, and appropriate counseling.

ObjectiveLN 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).MethodsTwo Toronto-based tertiary care SLE cohorts included cSLE (diagnosed ResultsOf 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).ConclusionWe 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.

In 1979, it became recognized in the literature that what we call hemophagocytic lymphohistiocytosis (HLH), was a nonmalignant disease of histiocytes. Subsequently a familial form and a secondary form of HLH were differentiated. When HLH is secondary to an autoimmune disease rheumatologists refer to this entity as macrophage activation syndrome (MAS) to differentiate it from HLH itself. Although the first cases of MAS likely appeared in the literature in the 1970s, it was not until 1985 that the term activated macrophages was used to describe patients with systemic juvenile idiopathic arthritis (sJIA) complicated by MAS and the term macrophage activation syndrome first appeared in the title of a paper in 1993.

Objective To determine whether socioeconomic status assessed by education is associated with disease activity and the risk of organ damage in systemic lupus erythematosus (SLE). Methods Data from the 1000 Canadian Faces of Lupus, a multicenter database of adult SLE patients, was used to compare education as either low (did not complete high school) or high (completed high school or further) for disease activity and damage. Education was also studied as a continuous variable. The relationships between education and SLE outcomes (any organ damage defined as a Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI] score ≥1, serious organ damage [SDI score ≥3], and end-stage renal disease) were evaluated using logistic regression analyses adjusted for age, sex, race/ethnicity, and disease duration. Results A total of 562 SLE patients met inclusion criteria (mean age 47 years, 91% female, and mean disease duration of 10 years); 81% had high education. The low education group was twice as likely to be work disabled (30%; P

Objective.To determine cancer incidence in a large pediatric-onset systemic lupus erythematosus (SLE) population.Methods.Data were examined from 12 pediatric SLE registries in North America. Patients were linked to their regional cancer registries to detect cancers observed after cohort entry, defined as date first seen in the clinic. The expected number of malignancies was obtained by multiplying the person-years in the cohort (defined from cohort entry to end of followup) by the geographically matched age-, sex-, and calendar year–specific cancer rates. The standardized incidence ratio (SIR; ratio of cancers observed to expected) was generated, with 95% CI.Results.A total of 1168 patients were identified from the registries. The mean age at cohort entry was 13 years (SD 3.3), and 83.7% of the subjects were female. The mean duration of followup was 7.6 years, resulting in a total observation period of 8839 years spanning the calendar period 1974–2009. During followup, fourteen invasive cancers occurred (1.6 cancers per 1000 person-yrs, SIR 4.13, 95% CI 2.26–6.93). Three of these were hematologic (all lymphomas), resulting in an SIR for hematologic cancers of 4.68 (95% CI 0.96–13.67). SIR were increased for both male and female patients, and across age groups.Conclusion.Although cancer remains a relatively rare outcome in pediatric-onset SLE, our data do suggest an increase in cancer for patients followed an average of 7.6 years. About one-fifth of the cancers were hematologic. Longer followup, and study of drug effects and disease activity, is warranted.

A 16-year-old previously well girl presented with bilateral painful lower leg swelling and non-pruritic blanching rash across her torso and upper and lower limbs. These symptoms started after commencing amoxicillin for presumed tonsillitis. She was diagnosed with serum sickness-like illness and started on non-steroidal agents. The rash and painful leg swelling improved over the next 48 hours. However, she subsequently developed fevers, cough and new-onset haemoptysis.She continued to deteriorate with increasing amounts of haemoptysis, work of breathing and escalating respiratory support requirements. Serial chest radiographs showed worsening lung consolidation and enlarging pleural effusion. A CT chest revealed extensive bilateral lung consolidation, most likely pulmonary haemorrhage. Subsequent investigations showed positive classic antineutrophil cytoplasmic antibody, confirming the diagnosis of granulomatosis with polyangiitis.

Background Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD. Methods Healthy ANA− controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. Results A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA− healthy controls. Conclusions ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD. Electronic supplementary material The online version of this article (10.1186/s13075-018-1752-3) contains supplementary material, which is available to authorized users.

Background The diagnosis of Systemic Autoimmune Rheumatic Diseases (SARD), including Systemic Lupus Erythematosus (SLE), relies on the presence of ANAs, many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals most of whom will not develop SARD. A number of cellular immune changes are seen in SARD, and thus could constitute potential biomarkers/treatment targets for SARD, however it is not known at what point in disease progression these develop. Methods Healthy ANA- controls (n=32) and ANA+ (≥1:160 by immunofluorescence) participants with no (asymptomatic ANA+, n=61), at least one (UCTD, n=35), or meeting SARD classification criteria (n=59) were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry. Results Consistent with previous reports, SARD patients had increased proportions of activated B cells (CD86+ or CD95+) and in the SLE patient subset there were increased proportions of plasma cells/plasmablasts, as compared to ANA- controls. SARD patients also had reduced proportions of iNKT and IFN-γ producing cells, as well as, increased proportions of memory Tfh (CD4+CXCR5hiPD1hi) and T regulatory (Treg, CD4+FOXP3+HELIOS+) cells, especially in the SLE and Sjogren’s Disease patient subsets. In asymptomatic ANA+ individuals and UCTD patients, similar increases in the proportion of activated B cells, Tfh, and Treg cells, and decreases in the proportion of iNKT and IFN-γ producing cells were seen to those in SARD. In asymptomatic ANA+ individuals and SARD patients, the extent of serologic changes (number of specific ANAs detected by Bioplex® 2200 ANA screening system) positively correlated with activation in the switched memory B cell compartment and the proportion of Tfh cells, with the later being an independent predictor of serologic status in a multivariate analysis. However, significantly elevated levels of Tfh cells could still be seen in asymptomatic ANA+ individuals who lacked specific ANAs. Consistent with a role for Tfh cell in ANA production there was a strong correlation between the proportion of Tfh and plasma cells in asymptomatic ANA+ individuals. In preliminary studies, the majority of Tfh cells in asymptomatic ANA+ and UCTD patients were Tfh2 cells, with a trend to increased proportions of Tfh2 cells and decreased proportions Tfh17 cells as compared to active SLE patients. Conclusions Tfh cells appear to play an important role in the development of a positive ANA and in the epitope spreading that may accompany disease progression, and therefore constitute a promising target for treatment of early disease.

Background To develop GRADE-based recommendations for the diagnosis and monitoring of systemic lupus erythematosus patients in Canada. Methods Recommendations were developed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. The Canadian SLE Working Group (panel of Canadian rheumatologists and patient representative from CAPA (Canadian Arthritis Patient Alliance)) was created. A series of questions for recommendation development were identified based on the results of a survey of SLE practice patterns of members of the Canadian Rheumatology Association (CRA). Systematic literature reviews of randomized controlled trials and observational studies were conducted. Evidence to Recommendation Tables were prepared and presented to the panel at two face-to-face meetings for discussion and voting during and post-meeting online. Results There were a total of fourteen recommendations for assessing and monitoring lupus patients (table 1). Three recommendations focused on disease activity and damage assessment suggesting that a validated disease activity score per visit and annual damage score were important in evaluating the patient. One strong recommendation was made for cardiovascular risk assessment with conditional recommendations for osteoporosis (2) and osteonecrosis (1). Three conditional recommendations were made regarding peripartum assessments, one on cervical cancer screening and two on hepatitis B and C screening. A strong recommendation was made for annual influenza vaccination. Conclusions These are the first GRADE-based recommendations for the diagnosis and monitoring of SLE internationally. Evidence is largely of moderate to low quality resulting in more conditional versus strong recommendations. Further studies of higher quality and special attention to pediatric lupus populations are needed. Acknowledgements The authors are members of the Canadian SLE Working Group which was created to develop these recommendations.

Background There is strong evidence that genetics plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Genome wide association studies (GWAS) have identified >90 loci associated with SLE risk, which suggests SLE is a complex trait. Yet collectively these genes explain a small fraction of SLE heritability. Within the broad category of SLE, there are genetically distinct Mendelian/monogenic diseases, presenting with lupus features. Macrophage activation syndrome (MAS) is an increasing recognized complication of SLE. It shares similarities with familial hemophagocytic lymphohistiocytosis (HLH), a Mendelian disease. We hypothesize that whole exome (WES) and whole genome sequencing (WGS) of SLE patients suspected of carrying rare genetic variants with large effects, will identify variants and genes associated with SLE risk and MAS. This information has implication for therapy, screening as well as providing insights into the pathogenesis of SLE and MAS broadly. Methods WGS on 8 cSLE patients with one of: (i) age diagnosis Results WGS of cSLE patients revealed potential disease causing monogenic variants in known genes including SLC7A7 and DNASE1 . All MAS-SLE patients heterozygous for ≥1 rare variant in HLH gene, with 5/14 heterozygous for exonic non-synonymous variants in PRF1, LYST, ITK and AP3B1 . Conclusions We identified candidate variants leading to monogenic lupus and MAS in SLE. Additional validation studies are planned to confirm our findings and elucidate the precise pathogenic mechanism leading to disease. These variants have the potential for prognostication, secondary screening of family members and improved therapy for patients and families. Acknowledgements Childhood Arthritis and Rheumatology Research Alliance (CARRA) Small Grant, McLaughlin Centre, University of Toronto.

Background Systemic lupus erythematosus (SLE) is an autoimmune disease with genetic, hormonal, and environmental influences. In Western Europe and North America, individuals of West African descent have a 3–4 fold greater incidence of SLE than Caucasians. Paradoxically, West Africans in sub-Saharan Africa appear to have a low incidence of SLE, and some studies suggest a milder disease with less nephritis. In this study, we analyzed sera from African American female SLE patients and four other cohorts, one with SLE and others with varying degrees of risk for SLE in order to identify serologic factors that might correlate with risk of or protection against SLE. Methods Our cohorts included West African women with previous malaria infection assumed to be protected from development of SLE, clinically unaffected sisters of SLE patients with high risk of developing SLE, healthy African American women with intermediate risk, healthy Caucasian women with low risk of developing SLE, and women with a diagnosis of SLE. We developed a lupus risk index (LRI) based on titers of IgM and IgG anti-double stranded DNA antibodies and levels of C1q. Results The risk index was highest in SLE patients; second highest in unaffected sisters of SLE patients; third highest in healthy African-American women and lowest in healthy Caucasian women and malaria-exposed West African women. Conclusion This risk index may be useful in early interventions to prevent SLE. In addition, it suggests new therapeutic approaches for the treatment of SLE.

Background Anti-TNF (Tumor necrosis factor) therapy is effective in treating pediatric patients with refractory rheumatic disease. There is however a concern that anti-TNF usage may increase the risk of malignancy. Reports on specific types of malignancy in this patient population have been emerging over the past decade, but there is a need for additional malignancy reports, as these events are rare. Therefore, a retrospective chart review was performed on the biologic database of pediatric rheumatology patients at The Hospital for Sick Children (SickKids) from 1997 to 2013 for neoplasms, patient demographic information and rheumatologic treatment course. Findings 6/357 (1.68%) rheumatology patients treated with anti-TNF therapy between 1997 and 2013 developed neoplasms. One patient had two malignancies. One patient had a benign neoplasm. Cases were exposed to etanercept, infliximab or both. Neoplasms developed late after anti-TNF exposure (median 5.0 years) and infliximab treatment was associated with a shorter time to malignancy. The neoplasms identified were as follows: 2 renal clear cell carcinoma, 1 pilomatricoma, 1 nasopharyngeal carcinoma, 1 Ewing’s sarcoma, 1 hepatic T-cell lymphoma, 1 lymphoproliferative disease. Conclusions The malignancy rate at our centre is low, however more than half of the neoplasms identified were rare and unusual in the pediatric population. The 5-year malignancy-free probability for patients with juvenile idiopathic arthritis (JIA) treated with biologic therapy was 97% from our database. Long-term screening for rare neoplasms is important as part of the safety monitoring for any pediatric rheumatology patient receiving anti-TNF therapy.

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341.We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1. © The Author(s) 2018. Published by Oxford University Press. All rights reserved.

ObjectiveThis report aims to determine the safety, pharmacokinetics (PK) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis (polyJIA).MethodsIn this three-part randomised double-blinded placebo-controlled withdrawal trial, all patients received open-label golimumab (30 mg/m2 of body surface area; maximum: 50 mg/dose) every 4 weeks together with weekly methotrexate during Part 1 (weeks 0–16). Patients with at least 30% improvement per American College of Rheumatology Criteria for JIA (JIA ACR30) in Part 1 entered the double-blinded Part 2 (weeks 16–48) after 1:1 randomisation to continue golimumab or start placebo. In Part 3, golimumab was continued or could be restarted as in Part 1. The primary outcome was JIA flares in Part 2; secondary outcomes included JIA ACR50/70/90 responses, clinical remission, PK and safety.ResultsAmong 173 patients with polyJIA enrolled, 89.0% (154/173) had a JIA ACR30 response and 79.2%/65.9%/36.4% demonstrated JIA ACR50/70/90 responses in Part 1. At week 48, the primary endpoint was not met as treatment groups had comparable JIA flare rates (golimumab vs placebo: 32/78=41% vs 36/76=47%; p=0.41), and rates of clinical remission were comparable (golimumab vs placebo: 10/78=12.8% vs 9/76=11.8%). Adverse event and serious adverse event rates were similar in the treatment groups during Part 2. Injection site reactions occurred with ConclusionAlthough the primary endpoint was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyJIA. Golimumab was well tolerated, and no unexpected safety events occurred.Clinical Trial RegistrationNCT01230827; Results.

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

Objective.To examine the frequency and risk factors for symptomatic avascular necrosis (AVN) in childhood-onset systemic lupus erythematosus (cSLE).Methods.A single-center, nested, matched, case-control design was used. There were 617 patients with cSLE followed at the Hospital for Sick Children (SickKids) Lupus Clinic between July 1982 and June 2013 included in the study. The AVN cohort consisted of 37 patients identified with clinical findings of symptomatic AVN and diagnosis was confirmed by 1 or more imaging modalities. Three controls were matched to each patient with AVN by date and age at diagnosis. Baseline clinical, laboratory, and treatment characteristics were compared between patients with AVN and controls by univariable analyses and if statistically significant, were included in a multivariable logistic regression model.Results.A total of 37/617 patients (6%) developed symptomatic AVN in 91 joints during followup at SickKids. The mean duration to disease was 2.3 years. The hip was the most commonly involved joint (26/37, 70%). Compared with the matched non-AVN cohort, patients with AVN had a higher incidence of central nervous system (CNS) involvement and nephritis, required greater cumulative prednisone (PRED) from cSLE diagnosis to AVN, received a greater maximal daily PRED dose, and had more frequent use of pulse methylprednisolone therapy. Multivariable regression analysis confirmed major organ involvement (CNS disease and/or nephritis) and maximal daily PRED dose as significant predictors of symptomatic AVN development.Conclusion.Patients with cSLE with severe organ involvement including nephritis and CNS disease and higher maximal daily dose of PRED are more likely to develop symptomatic AVN.

Objective Systemic lupus erythematosus (SLE) is characterized by increased cardiovascular risk in adult-onset and childhood-onset SLE (cSLE). Type I interferons (IFNs) appear to play a prominent role in premature vascular damage in adult 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 if EPC dysfunction is present in cSLE in association with a type I IFN signature.

Background With modern treatments, the effect of juvenile idiopathic arthritis (JIA) on growth may be less than previously reported. Our objective was to describe height, weight and body mass index (BMI) development in a contemporary JIA inception cohort. Methods Canadian children newly-diagnosed with JIA 2005–2010 had weight and height measurements every 6 months for 2 years, then yearly up to 5 years. These measurements were used to calculate mean age- and sex-standardized Z-scores, and estimate prevalence and cumulative incidence of growth impairments, and the impact of disease activity and corticosteroids on growth. Results One thousand one hundred forty seven children were followed for median 35.5 months. Mean Z-scores, and the point prevalence of short stature (height 95th percentile, 15.8% to 16.4%) remained unchanged in the whole cohort. Thirty-three children (2.9%) developed new-onset short stature, while 27 (2.4%) developed tall stature (>97.5th percentile). Children with systemic arthritis (n = 77) had an estimated 3-year cumulative incidence of 9.3% (95%CI: 4.3–19.7) for new-onset short stature and 34.4% (23–49.4) for obesity. Most children (81.7%) received no systemic corticosteroids, but 1 mg/Kg/day prednisone-equivalent maintained for 6 months corresponded to a drop of 0.64 height Z-scores (0.56–0.82) and an increase of 0.74 BMI Z-scores (0.56–0.92). An increase of 1 in the 10-cm physician global assessment of disease activity maintained for 6 months corresponded to a drop of 0.01 height Z-scores (0–0.02). Conclusions Most children in this modern JIA cohort grew and gained weight as children in the general population. About 1 in 10 children who had systemic arthritis, uncontrolled disease and/or prolonged corticosteroid use, had increased risk of growth impairment. Electronic supplementary material The online version of this article (doi:10.1186/s12969-017-0196-7) contains supplementary material, which is available to authorized users.

The medical cycle of discovery from researcher to editor to reviewer to publisher to researcher and back again — often re-engaging the same players in different roles — is a model for vetting and sharing medical information that inspired longtime Journal Editor Duncan Gordon1 (Figure 1). Figure 1. The medical discovery cycle; adapted with permission1. Little did anyone know at that time — not Duncan Gordon, the associate editors, reviewers, and authors — to what extent the discovery process would speed up and multiply itself, in particular with the emergence of electronic resource networks on the Internet. Today, electronic resources are apparent … Address reprint requests to Dr. E.D. Silverman; e-mail: jrheum{at}jrheum.com

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P, Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong ethnic and gender bias. In a transancestral genetic association study, Langefeld et al. identify 24 novel regions associated with risk to lupus and propose a cumulative hits hypothesis for loci conferring risk to SLE.

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. 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.

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 a lack of rigor of study designs. This study aimed to systematically assess the methodologic 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% of studies for confounders, 57% 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. Conclusion 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 methodologic rigor.

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.

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.

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.

Objective To examine the association between smoking and cutaneous involvement in systemic lupus erythematosus (SLE). Methods We analyzed data from a multicenter Canadian SLE cohort. Mucocutaneous involvement was recorded at the most recent visit using the Systemic Lupus Erythematosus Disease Activity Index 2000 Update (rash, alopecia, and oral ulcers), Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (alopecia, extensive scarring, and skin ulceration), and the ACR revised criteria for SLE (malar rash, discoid rash, photosensitivity, and mucosal involvement). Multivariate logistic regression models were used to estimate the independent association between mucocutaneous involvement and cigarette smoking, age, sex, ethnicity, lupus duration, medications, and laboratory data. Results In our cohort of 1,346 patients (91.0% women), the mean ± SD age was 47.1 ± 14.3 years and the mean ± SD disease duration was 13.2 ± 10.0 years. In total, 41.2% of patients were ever smokers, 14.0% current smokers, and 27.1% past smokers. Active mucocutaneous manifestations occurred in 28.4% of patients; cutaneous damage occurred in 15.4%. Regarding the ACR criteria, malar rash was noted in 59.5%, discoid rash in 16.9%, and photosensitivity in 55.7% of patients. In the multivariate analysis, current smoking was associated with active SLE rash (odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.07, 2.48]). Having ever smoked was associated with ACR discoid rash (OR 2.36 [95% CI 1.69, 3.29]) and photosensitivity (OR 1.47 [95% CI 1.11, 1.95]), and with the ACR total cutaneous score (OR 1.50 [95% CI 1.22, 1.85]). We did not detect any associations between previous smoking and active cutaneous manifestations. No association was found between smoking and cutaneous damage or mucosal ulcers. No interaction was seen between smoking and antimalarials. Conclusion Current smoking is associated with active SLE rash, and ever smoking with the ACR total cutaneous score. This provides additional motivation for smoking cessation in SLE.

ObjectiveParticipants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy.MethodsSubgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score ≥4 as post-pubertal or ResultsSignificant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures.ConclusionsPubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy.ClinicalTrials.gov identifier:NCT00065806.

Systemic lupus erythematosus (SLE) is a multisystem disease with significant morbidity and even mortality. Cytomegalovirus (CMV) is a ubiquitous herpesvirus that, similar to SLE, can also lead to significant morbidity and mortality in the immunocompromised host. The relationship between SLE and CMV is complex, with observations suggesting that CMV induces the autoimmunity of SLE in addition to occurring in the immunocompromised host with known SLE. In this article, we first consider CMV infection in the immunocompetent host, and further examine how this infection differs in the patient with SLE. We focus on disease mechanisms, CMV detection and treatment. We review the differences between CMV infection, syndrome and disease, as identifying the correct state will determine the appropriate treatment. We propose guidelines for the screening and management of CMV infection in childhood-onset SLE, and recognize that further study in this population is required to increase our understanding of the interplay between these disease entities.

Review the epidemiology, pathogenesis, and clinical-histological features of lupus nephritis.