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Background and Objectives: Neurological involvement associated with SARS-CoV-2 infection is increasingly recognized. However, the specific characteristics and prevalence in pediatric patients remain unclear. The objective of this study was to describe the neurological involvement in a multinational cohort of hospitalized pediatric patients with SARS-CoV-2. Methods: This was a multicenter observational study of children Results: One-hundred forty-seven (21%) of 697 hospitalized children with SARS-CoV-2 infection had neurological signs/symptoms. Headache (n = 103), encephalopathy (n = 28), and seizures (n = 30) were the most reported. Neurological signs/symptoms were significantly associated with ICU admission (OR: 1.71, 95% CI: 1.15–2.55; p = 0.008), satisfaction of MIS-C criteria (OR: 3.71, 95% CI: 2.46–5.59; p < 0.001), fever during hospitalization (OR: 2.15, 95% CI: 1.46–3.15; p < 0.001), and gastrointestinal involvement (OR: 2.31, 95% CI: 1.58–3.40; p < 0.001). Non-headache neurological manifestations were significantly associated with ICU admission (OR: 1.92, 95% CI: 1.08–3.42; p = 0.026), underlying neurological disorders (OR: 2.98, 95% CI: 1.49–5.97, p = 0.002), and a history of fever prior to hospital admission (OR: 2.76, 95% CI: 1.58–4.82; p < 0.001). Discussion: In this study, approximately 21% of hospitalized children with SARS-CoV-2 infection had neurological signs/symptoms. Future studies should focus on pathogenesis and long-term outcomes in these children.

Objective The aim of this study was to develop and validate a brief disability screen for children with JIA, the Kids Disability Screen (KDS). Methods A total of 216 children enrolled in the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) Registry in 2017–2018 formed a development cohort, and 220 children enrolled in 2019–2020 formed a validation cohort. At every clinic visit, parents answered two questions derived from the Childhood Health Assessment Questionnaire (CHAQ): ‘Is it hard for your child to run and play BECAUSE OF ARTHRITIS?’ (‘Hard’ 0–10), and ‘Does your child usually need help from you or another person BECAUSE OF ARTHRITIS?’ (‘Help’, 0–10). We used 36-fold cross-validation and tested nine different mathematical methods to combine the answers and optimize psychometric properties. The results were confirmed in the validation cohort. Results Expressed as the mean of the two answers, KDS best balanced ease of use and psychometric properties, while a LASSO regression model combining the two answers with other patient characteristics [estimated CHAQ [eCHAQ]) had the highest responsiveness. In the validation cohort, 22.7%, 25.9% and 28.6% of patients had a score of 0 at enrolment for the KDS, eCHAQ and CHAQ, respectively. Responsiveness was 0.67, 0.74 and 0.62, respectively. Sensitivity to detect a CHAQ > 0 was 0.90 and specificity 0.56, KDS detecting some disability in 44% of children with a CHAQ = 0. Conclusion This simple KDS has psychometric properties comparable with those of a full CHAQ and may be used at every clinic visit to identify those children who need a full disability assessment.

SARS-CoV-2 infection can lead to multisystem inflammatory syndrome in children (MIS-C). We sought to investigate risk factors for admission to the intensive care unit (ICU) and explored changes in disease severity over time.We obtained data from chart reviews of children younger than 18 years with confirmed or probable MIS-C who were admitted to 15 hospitals in Canada, Iran and Costa Rica between Mar. 1, 2020, and Mar. 7, 2021. Using multivariable analyses, we evaluated whether admission date and other characteristics were associated with ICU admission or cardiac involvement.Of 232 children with MIS-C (median age 5.8 yr), 130 (56.0%) were male and 50 (21.6%) had comorbidities. Seventy-three (31.5%) patients were admitted to the ICU but none died. We observed an increased risk of ICU admission among children aged 13-17 years (adjusted risk difference 27.7%, 95% confidence interval [CI] 8.3% to 47.2%), those aged 6-12 years (adjusted risk difference 25.2%, 95% CI 13.6% to 36.9%) or those with initial ferritin levels greater than 500 μg/L (adjusted risk difference 18.4%, 95% CI 5.6% to 31.3%). Children admitted to hospital after Oct. 31, 2020, had numerically higher rates of ICU admission (adjusted risk difference 12.3%, 95% CI -0.3% to 25.0%) and significantly higher rates of cardiac involvement (adjusted risk difference 30.9%, 95% CI 17.3% to 44.4%). At Canadian sites, the risk of ICU admission was significantly higher for children admitted to hospital between December 2020 and March 2021 than those admitted between March and May 2020 (adjusted risk difference 25.3%, 95% CI 6.5% to 44.0%).We observed that age and higher ferritin levels were associated with more severe MIS-C. We observed greater severity of MIS-C later in the study period. Whether emerging SARS-CoV-2 variants pose different risks of severe MIS-C needs to be determined.

Objective The COVID-19 pandemic has disrupted healthcare delivery and clinical research worldwide, with data from areas most affected demonstrating an impact on rheumatology care. This study aimed to characterize the impact of the pandemic on the initial presentation of JIA and JIA-related research in Canada. Methods Data collected from the Canadian Alliance of Pediatric Rheumatology Investigators JIA Registry from the year pre-pandemic (11 March 2019 to 10 March 2020) was compared with data collected during the first year of the pandemic (11 March 2020 to 10 March 2021). Outcomes included time from symptom onset to first assessment, disease severity at presentation and registry recruitment. Proportions and medians were used to describe categorical and continuous variables, respectively. Results The median time from symptom onset to first assessment was 138 (IQR 64–365) days pre-pandemic vs 146 (IQR 83–359) days during the pandemic. The JIA category frequencies remained overall stable (44% oligoarticular JIA pre-pandemic, 46.8% pandemic), except for systemic JIA (12 cases pre-pandemic, 1 pandemic). Clinical features, disease activity (cJADAS10), disability (CHAQ) and quality of life (JAQQ) scores were similar between the two cohorts. Pre-pandemic, 225 patients were enrolled, compared with 111 in the pandemic year, with the greatest decrease from March to June 2020. Conclusions We did not observe the anticipated delay in time to presentation or increased severity at presentation, suggesting that, within Canada, care adapted well to provide support to new patient consults without negative impacts. The COVID-19 pandemic was associated with an initial 50% decrease in registry enrolment but has since improved.

A number of studies have demonstrated that patients with autoimmune disease have lower levels of vitamin D prompting speculation that vitamin D might suppress inflammation and immune responses in children with juvenile idiopathic arthritis (JIA). The objective of this study was to compare vitamin D levels in children with JIA at disease onset with healthy children. We hypothesized that children and adolescents with JIA have lower vitamin D levels than healthy children and adolescents. Data from a Canadian cohort of children with new-onset JIA (n= 164, data collection 2007-2012) were compared to Canadian Health Measures Survey (CHMS) data (n=4027, data collection 2007-2011). We compared 25-hydroxy vitamin D (25(OH)D) concentrations with measures of inflammation, vitamin D supplement use, milk intake, and season of birth. Mean 25(OH)D level was significantly higher in patients with JIA (79 ± 3.1 nmol/L) than in healthy controls (68 ± 1.8 nmol/L P.05). Patients with JIA more often used vitamin D containing supplements (50% vs. 7%; P.05). The prevalence of 25(OH)D deficiency (30 nmol/L) was 6% for both groups. Children with JIA with 25(OH)D deficiency or insufficiency (50 nmol/L) had higher C-reactive protein levels. Children with JIA were more often born in the fall and winter compared to healthy children. In contrast to earlier studies, we found vitamin D levels in Canadian children with JIA were higher compared to healthy children and associated with more frequent use of vitamin D supplements. Among children with JIA, low vitamin D levels were associated with indicators of greater inflammation.

Objective Guidelines for methotrexate (MTX) use in rheumatic disease may not be feasible for physicians practicing in the least developed countries. We aimed to understand the experiences of MTX prescribers relating to MTX use for rheumatic disease in African countries to inform the development of culturally and geographically appropriate recommendations. Methods African physicians who self‐identified as MTX prescribers from countries classified as having a low versus a medium or high Human Development Index (L‐HDI versus MH‐HDI) participated in semistructured interviews between August 2016 and September 2017. Interviews were transcribed verbatim, coded thematically, and stratified by HDI. Results Physicians (23 rheumatologists; six internists) from 29 African countries were interviewed (15 L‐HDI; 14 MH‐HDI). Identified barriers to MTX use included inconsistent MTX supply (reported by 87% L‐HDI versus 43% MH‐HDI), compounded by financial restrictions (reported by 93% L‐HDI versus 64% MH‐HDI), patient hesitancy based partly on cultural beliefs and societal roles (reported by 71%), few prescribers (reported by 33%), prevalent infections (especially viral hepatitis, tuberculosis, and human immunodeficiency virus), and both availability and cost of monitoring tests. MTX pretreatment evaluation and starting and maximal doses were similar between L‐HDI countries and MH‐HDI countries. Conclusion The challenges of treating rheumatic disease in African countries include unreliable drug availability and cost, limited subspecialists, and patient beliefs. Adapting recommendations for MTX use in the context of prevalent endemic infections; ensuring safe but feasible MTX monitoring strategies, enhanced access to stable drug supply, and specialized rheumatology care; and improving patient education are key to reducing the burden of rheumatic diseases in L‐HDI countries.

This report presents 2 pediatric cases of multisystem inflammatory syndrome in children and adults (MIS-C/A) post severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination (MIS-V). Both children presented with MIS-V within 6 weeks of receiving their first and only dose of Pfizer-BioNTech’s SARS-CoV-2 vaccine. The first patient had symptoms of MIS-C/A with peri-myocarditis and shock, and the second 1 had classic Kawasaki disease features. Both responded well to intravenous immunoglobulins and/or systemic corticosteroids. Both children were positive only for SARS-2-CoV antispike (S) (and not for antinucleocapsid [NC]) antibodies consistent with a postvaccine, and not a postinfection, event. Surveillance for rare adverse events following immunization should continue, especially now that SARS-CoV-2 vaccination is approved in the 5 to 11 year age group that has had the highest risk of developing MIS-C post SARS-CoV-2 infection. Our patients did not receive any further SARS-CoV-2 vaccines. Our report highlights the importance of measuring differentiating antibodies (anti-S and anti-NC) that can be used within a specific timeframe to help determine if a patient has MIS-V post vaccine (only anti-S present), or MIS-C/A post SARS-CoV-2 infection (both anti-S and anti-NC present).

Coagulopathy and thrombosis associated with SARS-CoV-2 infection are well defined in hospitalized adults and leads to adverse outcomes. Pediatric studies are limited.An international multicentered (n = 15) retrospective registry collected information on the clinical manifestations of SARS-CoV-2 and multisystem inflammatory syndrome (MIS-C) in hospitalized children from February 1, 2020 through May 31, 2021. This sub-study focused on coagulopathy. Study variables included patient demographics, comorbidities, clinical presentation, hospital course, laboratory parameters, management, and outcomes.Nine hundred eighty-five children were enrolled, of which 915 (93%) had clinical information available; 385 (42%) had symptomatic SARS-CoV-2 infection, 288 had MIS-C (31.4%), and 242 (26.4%) had SARS-CoV-2 identified incidentally. Ten children (1%) experienced thrombosis, 16 (1.7%) experienced hemorrhage, and two (0.2%) experienced both thrombosis and hemorrhage. Significantly prevalent prothrombotic comorbidities included congenital heart disease (p-value .007), respiratory support (p-value .006), central venous catheter (CVC) (p = .04) in children with primary SARS-CoV-2 and in those with MIS-C included respiratory support (p-value .03), obesity (p-value .002), and cytokine storm (p = .012). Comorbidities prevalent in children with hemorrhage included age10 years (p = .04), CVC (p = .03) in children with primary SARS-CoV-2 infection and in those with MIS-C encompassed thrombocytopenia (p = .001) and cytokine storm (p = .02). Eleven patients died (1.2%), with no deaths attributed to thrombosis or hemorrhage.Thrombosis and hemorrhage are uncommon events in children with SARS-CoV-2; largely experienced by those with pre-existing comorbidities. Understanding the complete spectrum of coagulopathy in children with SARS-CoV-2 infection requires ongoing research.

BackgroundPaediatric inflammatory multisystem syndrome (PIMS) is a rare but serious condition temporally associated with SARS-CoV-2 infection. Using the Canadian Paediatric Surveillance Program (CPSP), a national surveillance system, we aimed to 1) study the impact of SARS-CoV-2 linkage on clinical and laboratory characteristics, and outcomes in hospitalized children with PIMS across Canada 2) identify risk factors for ICU admission, and 3) establish the minimum national incidence of hospitalizations due to PIMS and compare it to acute COVID-19.MethodsWeekly online case reporting was distributed to the CPSP network of more than 2800 pediatricians, from March 2020 to May 2021. Comparisons were made between cases with respect to SARS-CoV-2 linkage. Multivariable modified Poisson regression was used to identify risk factors for ICU admission and Minimum incidence proportions were calculated.FindingsIn total, 406 PIMS cases were analyzed, of whom 202 (49· 8%) had a positive SARS-CoV-2 linkage, 106 (26· 1%) had a negative linkage, and 98 (24· 1%) had an unknown linkage. The median age was 5· 4 years (IQR 2· 5–9· 8), 60% were male, and 83% had no identified comorbidities. Compared to cases with a negative SARS-CoV-2 linkage, children with a positive SARS-CoV-2 linkage were older (8· 1 years [IQR 4· 2–11· 9] vs. 4· 1 years [IQR 1· 7–7· 7]; pInterpretationWhile PIMS is rare, almost 1 in 3 hospitalized children required ICU admission and respiratory/hemodynamic support, particularly those ≥ 6 years and with a positive SARS-CoV-2 linkage.FundingFinancial support for the CPSP was received from the Public Health Agency of Canada.

Vertebral fractures are clinically important sequelae of a wide array of pediatric diseases. In this study, we examined the accuracy of case-finding strategies for detecting incident vertebral fractures (IVF) over 2 years in glucocorticoid-treated children (n = 343) with leukemia, rheumatic disorders, or nephrotic syndrome. Two clinical situations were addressed: the prevalent vertebral fracture (PVF) scenario (when baseline PVF status was known), which assessed the utility of PVF and low lumbar spine bone mineral density (LS BMD; Z-score-1.4), and the non-PVF scenario (when PVF status was unknown), which evaluated low LS BMD and back pain. LS BMD was measured by dual-energy X-ray absorptiometry, vertebral fractures were quantified on spine radiographs using the modified Genant semiquantitative method, and back pain was assessed by patient report. Forty-four patients (12.8%) had IVF. In the PVF scenario, both low LS BMD and PVF were significant predictors of IVF. Using PVF to determine which patients should have radiographs, 11% would undergo radiography (95% confidence interval [CI] 8-15) with 46% of IVF (95% CI 30-61) detected. Sensitivity would be higher with a strategy of PVF or low LS BMD at baseline (73%; 95% CI 57-85) but would require radiographs in 37% of children (95% CI 32-42). In the non-PVF scenario, the strategy of low LS BMD and back pain produced the highest specificity of any non-PVF model at 87% (95% CI 83-91), the greatest overall accuracy at 82% (95% CI 78-86), and the lowest radiography rate at 17% (95% CI 14-22). Low LS BMD or back pain in the non-PVF scenario produced the highest sensitivity at 82% (95% CI 67-92), but required radiographs in 65% (95% CI 60-70). These results provide guidance for targeting spine radiography in children at risk for IVF. © 2021 American Society for Bone and Mineral Research (ASBMR).

Most recommendations for the use of methotrexate (MTX) in rheumatoid arthritis (RA) are issued by developed countries. It is unknown whether they are relevant globally. We reviewed existing recommendations on the use of MTX for the treatment of RA and summarized areas of agreement that could be relevant for least developed countries (LDCs).Electronic databases and registries were searched for recommendations on MTX use in RA, duplicates were eliminated, and the most updated version adopted when there were several versions on the same recommendation. Reviewers used the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument for study quality assessment. Similarities and discrepancies of recommendations are reported.After deduplication, 1693 unique citations were found; 25 full texts were screened and 12 included in the narrative synthesis. Average scores for the AGREE II domains ranged from 33.3 to 83.3%. Recommendations targeted rheumatologists and health care providers involved in RA care. Most covered some but not all of the following areas: baseline "pre-MTX" assessment (7/12;58%), prescription of MTX (10/12;83.3%), management of MTX side effects (6/12;50%), and special considerations (e.g., peri-operative management) (8/12; 66.7%). Recommendations agreed on baseline tests prior to starting MTX, monitoring, and need for folic acid supplementation. These aspects can serve as the foundation for the development of MTX recommendations relevant to LDCs. Recommendations disagreed on the MTX starting dose, optimal route, titration, and intervals to monitor toxicity.Existing recommendations do not uniformly address all aspects related to the use of MTX and disagree in relevant aspects of MTX use. Adaptations to these recommendations are needed to facilitate their implementation in LDCs. Key Points • This paper summarizes current recommendations on the use of methotrexate for the treatment of rheumatoid arthritis. • Areas of agreement between recommendations include the following: pre-methotrexate patient assessment, need for folic acid supplementation, and toxicity monitoring. • Areas of disagreement relate to methotrexate starting and maximal dose, titration, and frequency of assessments.

OBJECTIVE Undervaluing the effectiveness of conventional treatments may lead to overtreatment with biologic medications in children with juvenile idiopathic arthritis (JIA). Using data from a nationwide inception cohort and strict methods to control bias, the aim of our study was to estimate the real-world effectiveness of simple JIA treatment strategies recommended in current guidelines. METHODS Children with JIA who were recruited at 16 Canadian centers from 2005 to 2010 were followed for up to 5 years. For each child, all observed treatment changes over time were assessed by independent physicians using prospectively collected data and published response criteria. Success was defined as attainment of inactive disease or maintenance of this state when stepping down treatment; minimally active disease was deemed acceptable for children with polyarticular JIA. Success rates were calculated for treatments tried ≥25 times, and logistic regression analysis identified features associated with success. RESULTS A total of 4,429 treatment episodes were observed in 1,352 children. Nonsteroidal antiinflammatory drug (NSAID) monotherapy was attempted 697 times, mostly as initial treatment when

Introduction: Hematologic complications of SARS-CoV-2 infection are well described in hospitalized adults with correlation to adverse outcomes. Information published in children has been limited. Methods: An international multi-centered retrospective registry was established to collect data on the clinical manifestations of SARS-CoV-2 or multisystem inflammatory syndrome (MIS-C) in hospitalized children between February 1, 2020 – May 31, 2021. This sub-study focused on hematologic manifestations. Study variables included patient demographics, comorbidities, clinical presentation, course, laboratory parameters, management, and outcomes. Results: Nine hundred and eighty-five children were enrolled and 915 (93%) had clinical information available; 385 (42%) had symptomatic SARS-CoV-2 infection upon admission, 288 had MIS-C (31.4%) and 242 (26.4%) had alternate diagnosis with SARS-CoV-2 identified incidentally. During hospitalization, 10 children (1%) experienced a thrombotic event, 16 (1.7%) had hemorrhage and 2 (0.2%) had both thrombotic and hemorrhagic episodes. Significant prothrombotic comorbidities included congenital heart disease (p-value = 0.007), central venous catheter (p = 0.04) in children with primary SARS-CoV-2 infection; and obesity (p-value= 0.002), cytokine storm (p= 0.012) in those with MIS-C. Significant pro- hemorrhagic conditions included age > 10 years (p = 0.04), CVC (p= 0.03) in children with primary SARS-CoV-2infection; and thrombocytopenia (0.001), cytokine storm (0.02) in those with MIS-C. Eleven patients died (1.2 %) with no deaths attributed to thrombosis or hemorrhage Conclusion: Thrombotic and hemorrhagic complications are uncommon in children with SARS-CoV-2 infection and observed with underlying co-morbid conditions. Understanding the complete spectrum of hematologic complications in children with SARS-CoV-2 infection or MIS-C requires ongoing multi-center studies.

Due to concerns about cumulative radiation exposure in the pediatric population, it is not standard practice to perform spine radiographs in most conditions that predispose to vertebral fracture (VF). In this study we examined the accuracy of two clinical predictors, back pain and lumbar spine bone mineral density (LS BMD), to derive four case-finding paradigms for detection of prevalent VF (PVF). Subjects were 400 children at risk for PVF (leukemia 186, rheumatic disorders 135, nephrotic syndrome 79). Back pain was assessed by patient report, LS BMD was measured by dual-energy X-ray absorptiometry, and PVF were quantified on spine radiographs using the modified Genant semiquantitative method. Forty-four patients (11.0%) had PVF. Logistic regression analysis between LS BMD and PVF produced an odds ratio (OR) of 1.9 (95% confidence interval [CI], 1.5 to 2.5) per reduction in Z-score unit, an area under the receiver operating characteristic curve of 0.70 (95% CI, 0.60 to 0.79), and an optimal BMD Z-score cutoff of -1.6. Case identification using either low BMD alone (Z-score < -1.6) or back pain alone gave similar results for sensitivity (55%, 52%, respectively), specificity (78%, 81%, respectively), positive predictive value (PPV; 24%, 25%, respectively), and negative predictive value (NPV; 93%, 93%, respectively). The paradigm using low BMD plus back pain produced lower sensitivity (32%), higher specificity (96%), higher PPV (47%), and similar NPV (92%). The approach using low BMD or back pain had the highest sensitivity (75%), lowest specificity (64%), lowest PPV (20%), and highest NPV (95%). All paradigms had increased sensitivities for higher fracture grades. Our results show that BMD and back pain history can be used to identify children with the highest risk of PVF so that radiography can be used judiciously. The specific paradigm to be applied will depend on the expected PVF rate and the clinical approach to the use of radiography. © 2019 American Society for Bone and Mineral Research.

ImportanceChildren are less likely than adults to have severe outcomes from SARS-CoV-2 infection and the corresponding risk factors are not well established.ObjectiveTo identify risk factors for severe disease in symptomatic children hospitalized for PCR-positive SARS-CoV-2 infection.DesignCohort study, enrollment from February 1, 2020 until May 31, 2021Setting15 children’s hospitals in Canada, Iran, and Costa RicaParticipantsPatients ExposuresVariables assessed for their association with disease severity included patient demographics, presence of comorbidities, clinical manifestations, laboratory parameters and chest imaging findings.Main Outcomes and MeasuresThe primary outcome was severe disease defined as a WHO COVID-19 clinical progression scale of ≥6, i.e., requirement of non-invasive ventilation, high flow nasal cannula, mechanical ventilation, vasopressors, or death. Multivariable logistic regression was used to evaluate factors associated with severe disease.ResultsWe identified 403 hospitalizations. Median age was 3.78 years (IQR 0.53-10.77). At least one comorbidity was present in 46.4% (187/403) and multiple comorbidities in 18.6% (75/403). Severe disease occurred in 33.8% (102/403). In multivariable analyses, presence of multiple comorbidities (adjusted odds ratio 2.24, 95% confidence interval 1.04-4.81), obesity (2.87, 1.19-6.93), neurological disorder (3.22, 1.37-7.56), anemia, and/or hemoglobinopathy (5.88, 1.30-26.46), shortness of breath (4.37, 2.08-9.16), bacterial and/or viral coinfections (2.26, 1.08-4.73), chest imaging compatible with COVID-19 (2.99, 1.51-5.92), neutrophilia (2.60, 1.35-5.02), and MIS-C diagnosis (3.86, 1.56-9.51) were independent risk factors for severity. Comorbidities, especially obesity (40.9% vs 3.9%, pConclusions and RelevancePediatric risk factors for severe SARS-CoV-2 infection vary according to age and can potentially guide vaccination programs and treatment approaches in children.Key pointsQuestionWhat are the risk factors for severe disease in children hospitalized for PCR-positive SARS-CoV-2 infection?FindingsIn this multinational cohort study of 403 children, multiple comorbidities, obesity, neurological disorder, anemia, and/or hemoglobinopathy, shortness of breath, bacterial and/or viral coinfections, chest imaging compatible with COVID-19, neutrophilia, and MIS-C diagnosis were independent risk factors for severity. The risk profile and presence of comorbidities differed between pediatric age groups, but age itself was not associated with severe outcomes.MeaningThese results can inform targeted treatment approaches and vaccine programs that focus on patient groups with the highest risk of severe outcomes.

ObjectiveTo identify risk factors for severe disease in children hospitalised for SARS-CoV-2 infection.DesignMulticentre retrospective cohort study.Setting18 hospitals in Canada, Iran and Costa Rica from 1 February 2020 to 31 May 2021.PatientsChildrenMain outcome measureSeverity on the WHO COVID-19 Clinical Progression Scale was used for ordinal logistic regression analyses.ResultsWe identified 403 hospitalisations. Median age was 3.78 years (IQR 0.53–10.77). At least one comorbidity was present in 46.4% (187/403) and multiple comorbidities in 18.6% (75/403). Eighty-one children (20.1%) met WHO criteria for PCR-positive MIS-C. Progression to WHO clinical scale score ≥6 occurred in 25.3% (102/403). In multivariable ordinal logistic regression analyses adjusted for age, chest imaging findings, laboratory-confirmed bacterial and/or viral coinfection, and MIS-C diagnosis, presence of a single (adjusted OR (aOR) 1.90, 95% CI 1.13 to 3.20) or multiple chronic comorbidities (aOR 2.12, 95% CI 1.19 to 3.79), obesity (aOR 3.42, 95% CI 1.76 to 6.66) and chromosomal disorders (aOR 4.47, 95% CI 1.25 to 16.01) were independent risk factors for severity. Age was not an independent risk factor, but different age-specific comorbidities were associated with more severe disease in age-stratified adjusted analyses: cardiac (aOR 2.90, 95% CI 1.11 to 7.56) and non-asthma pulmonary disorders (aOR 3.07, 95% CI 1.26 to 7.49) in childrenConclusionWe identified risk factors for disease severity among children hospitalised for PCR-positive SARS-CoV-2 infection. Comorbidities predisposing children to more severe disease may vary by age. These findings can potentially guide vaccination programmes and treatment approaches in children.

ObjectiveTo develop guidance on the use of coronavirus disease 2019 (COVID-19) vaccines in patients with autoimmune rheumatic diseases (ARD).MethodsThe Canadian Rheumatology Association (CRA) formed a multidisciplinary panel including rheumatologists, researchers, methodologists, vaccine experts, and patients. The panel used the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Outcomes were prioritized according to their importance for patients and clinicians. Evidence from the COVID-19 clinical trials was summarized. Indirect evidence for non–COVID-19 vaccines in ARD was also considered. The GRADE evidence-to-decision (EtD) framework was used to develop a recommendation for the use of the 4 COVID-19 vaccines approved in Canada as of March 25, 2021 (BNT162b2, mRNA-1273, ChAdOx1, and Ad26.COV2.S), over 4 virtual panel meetings.ResultsThe CRA guideline panel suggests using COVID-19 vaccination in persons with ARD. The panel unanimously agreed that for the majority of patients, the potential health benefits of vaccination outweigh the potential harms in people with ARDs. The recommendation was graded as conditional because of low or very low certainty of the evidence on the effects in the population of interest, primarily due to indirectness and imprecise effect estimates. The panel felt strongly that persons with autoimmune rheumatic diseases who meet local eligibility should not be required to take additional steps compared to people without ARDs to obtain their vaccination. Guidance on medications, implementation, monitoring of vaccine uptake, and research priorities are also provided.ConclusionThis recommendation will be updated over time as new evidence emerges, with the latest recommendation, evidence summaries, and EtD available on the CRA website.

Objective To identify discrete clusters comprising clinical features and inflammatory biomarkers in children with JIA and to determine cluster alignment with JIA categories. Methods A Canadian prospective inception cohort comprising 150 children with JIA was evaluated at baseline (visit 1) and after six months (visit 2). Data included clinical manifestations and inflammation-related biomarkers. Probabilistic principal component analysis identified sets of composite variables, or principal components, from 191 original variables. To discern new clinical-biomarker clusters (clusters), Gaussian mixture models were fit to the data. Newly-defined clusters and JIA categories were compared. Agreement between the two was assessed using Kruskal–Wallis analyses and contingency plots. Results Three principal components recovered 35% (three clusters) and 40% (five clusters) of the variance in patient profiles in visits 1 and 2, respectively. None of the clusters aligned precisely with any of the seven JIA categories but rather spanned multiple categories. Results demonstrated that the newly defined clinical-biomarker lustres are more homogeneous than JIA categories. Conclusion Applying unsupervised data mining to clinical and inflammatory biomarker data discerns discrete clusters that intersect multiple JIA categories. Results suggest that certain groups of patients within different JIA categories are more aligned pathobiologically than their separate clinical categorizations suggest. Applying data mining analyses to complex datasets can generate insights into JIA pathogenesis and could contribute to biologically based refinements in JIA classification.

Chronic pediatric musculoskeletal (MSK) conditions are a major cause of morbidity. The burden of pediatric rheumatic diseases in East Africa is largely unknown. The purposes of this study were to estimate frequencies and assess the spectrum of MSK-related diagnoses using ICD-10 diagnostic codes among outpatients at a pediatric hospital in Kenya and to evaluate the accuracy of the assigned codes used for the 'arthropathies' category. All pediatric outpatient diagnoses classified under the ICD-10 codes for 'diseases of the MSK system and connective tissue' (M00-M99) recorded between January and December 2011 were extracted from the electronic medical record system at Gertrude's Children's Hospital (GCH). For each of the ten MSK disease categories, frequencies were calculated. The assigned ICD10 code for cases in the 'arthropathies' (M00-M25) category was assessed by two rheumatologists. MSK diagnoses (n = 1078) accounted for 0.5% of all GCH outpatient consults available for analysis. 'Soft tissue disorders' were the most frequent MSK diagnoses (n = 614, 57%), followed by 'arthropathies' (n = 332, 30.8%), 'dorsopathies' (n = 81, 7.5%), 'osteopathies and chondropathies' (n = 39, 3.6%), and 'other' disorders (n = 12, 1.1%). No patients were classified in the category of 'systemic connective tissue disorders'. In cases classified as 'arthropathies', there was poor agreement (Kappa 0.136) between the ICD10 code assigned by the treating physicians and that assigned by the rheumatologists. However, when the rheumatologists' classification was loosened, agreement was moderate (Kappa 0.533). This study provides estimates of the frequency of outpatient MSK diagnoses at a pediatric hospital in Kenya in 2011. MSK diagnoses were not rare. Despite limitations of administrative databases to estimate frequencies of specific diagnoses, they provide a snapshot of the overall burden and spectrum of MSK conditions.

Context Osteoporotic fractures are an important cause of morbidity in children with glucocorticoid-treated rheumatic disorders. Objective This work aims to evaluate the incidence and predictors of osteoporotic fractures and potential for recovery over six years following glucocorticoid (GC) initiation in children with rheumatic disorders. Methods Children with GC-treated rheumatic disorders were evaluated through a prospective inception cohort study led by the Canadian STeroid-induced Osteoporosis in the Pediatric Population (STOPP) Consortium. Clinical outcomes included lumbar spine bone mineral density (LS BMD), vertebral fractures (VF), non-VF, and vertebral body reshaping. Results A total of 136 children with GC-treated rheumatic disorders were enrolled (mean age 9.9 years, SD 4.4). The 6-year cumulative fracture incidence was 16.3% for VF, and 10.1% for non-VF. GC exposure was highest in the first 6 months, and 24 of 38 VF (63%) occurred in the first 2 years. Following VF, 16 of 19 children (84%) had complete vertebral body reshaping. Increases in disease activity and body mass index z scores in the first year and declines in LS BMD z scores in the first 6 months predicted incident VF over the 6 years, while higher average daily GC doses predicted both incident VF and non-VF. LS BMD z scores were lowest at 6 months (mean –0.9, SD 1.2) and remained low by 6 years even when adjusted for height z scores (–0.6, SD 0.9). Conclusion VF occurred early and were more common than non-VF in children with GC-treated rheumatic disorders. Eighty-four percent of children with VF underwent complete vertebral body reshaping, whereas vertebral deformity persisted in the remainder of children. On average, LS BMD z scores remained low at 6 years, consistent with incomplete recovery.

ObjectivesThis study aimed to expand knowledge about soluble low-density lipoprotein receptor-related protein 1 (sLRP1) in juvenile idiopathic arthritis (JIA) by determining associations of sLRP1 levels in nonsystemic JIA patients with clinical and inflammatory biomarker indicators of disease activity.MethodsPlasma sLRP1 and 44 inflammation-related biomarkers were measured at enrollment and 6 months later in a cohort of 96 newly diagnosed Canadian patients with nonsystemic JIA. Relationships between sLRP1 levels and indicators of disease activity and biomarker levels were analyzed at both visits.ResultsAt enrollment, sLRP1 levels correlated negatively with age and active joint counts. Children showed significantly higher levels of sLRP1 than adolescents (mean ranks: 55.4 and 41.9, respectively; P = 0.02). Participants with 4 or fewer active joints, compared to those with 5 or more active joints, had significantly higher sLRP1 levels (mean ranks: 56.2 and 40.7, respectively; P = 0.006). At enrollment, considering the entire cohort, sLRP1 correlated negatively with the number of active joints (r = –0.235, P = 0.017). In the entire cohort, sLRP1 levels at enrollment and 6 months later correlated with 13 and 6 pro- and antiinflammatory biomarkers, respectively. In JIA categories, sLRP1 correlations with inflammatory markers were significant in rheumatoid factor–negative polyarticular JIA, oligoarticular JIA, enthesitis-related arthritis, and psoriatic arthritis at enrollment. Higher sLRP1 levels at enrollment increased the likelihood of absence of active joints 6 months later.ConclusionPlasma sLRP1 levels correlate with clinical and biomarker indicators of short-term improvement in JIA disease activity, supporting sLRP1 as an upstream biomarker of potential utility for assessing JIA disease activity and outcome prediction.

Two antimalarial agents, chloroquine (CQ) and hydroxychloroquine (HCQ), have been trusted treatments for a range of rheumatic diseases over the past 70 years1. These agents have attracted intense media attention in the past few weeks with suggestions that this category of drugs may have potential in the management of the coronavirus (SARS-CoV2)–associated disease called COVID-192,3.

Objective To identify early predictors of disease activity at 18 months in JIA using clinical and biomarker profiling. Methods Clinical and biomarker data were collected at JIA diagnosis in a prospective longitudinal inception cohort of 82 children with non-systemic JIA, and their ability to predict an active joint count of 0, a physician global assessment of disease activity of ≤1 cm, and inactive disease by Wallace 2004 criteria 18 months later was assessed. Correlation-based feature selection and ReliefF were used to shortlist predictors and random forest models were trained to predict outcomes. Results From the original 112 features, 13 effectively predicted 18-month outcomes. They included age, number of active/effused joints, wrist, ankle and/or knee involvement, ESR, ANA positivity and plasma levels of five inflammatory biomarkers (IL-10, IL-17, IL-12p70, soluble low-density lipoprotein receptor-related protein 1 and vitamin D), at enrolment. The clinical plus biomarker panel predicted active joint count = 0, physician global assessment ≤ 1, and inactive disease after 18 months with 0.79, 0.80 and 0.83 accuracy and 0.84, 0.83, 0.88 area under the curve, respectively. Using clinical features alone resulted in 0.75, 0.72 and 0.80 accuracy, and area under the curve values of 0.81, 0.78 and 0.83, respectively. Conclusion A panel of five plasma biomarkers combined with clinical features at the time of diagnosis more accurately predicted short-term disease activity in JIA than clinical characteristics alone. If validated in external cohorts, such a panel may guide more rationally conceived, biologically based, personalized treatment strategies in early JIA.

We studied children enrolled within 90 days of juvenile idiopathic arthritis diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) prospective inception cohort to identify longitudinal trajectories of pain severity and features that may predict pain trajectory at diagnosis. A total of 1062 participants were followed a median of 24.3 months (interquartile range = 16.0-37.1 months). Latent trajectory analysis of pain severity, measured in a 100-mm visual analogue scale, identified 5 distinct trajectories: (1) mild-decreasing pain (56.2% of the cohort); (2) moderate-decreasing pain (28.6%); (3) chronically moderate pain (7.4%); (4) minimal pain (4.0%); and (5) mild-increasing pain (3.7%). Mean disability and quality of life scores roughly paralleled the pain severity trajectories. At baseline, children with chronically moderate pain, compared to those with moderate-decreasing pain, were older (mean 10.0 vs 8.5 years, P = 0.01) and had higher active joint counts (mean 10.0 vs 7.2 joints, P = 0.06). Children with mild-increasing pain had lower joint counts than children with mild-decreasing pain (2.3 vs 5.2 joints, P < 0.001). Although most children with juvenile idiopathic arthritis in this cohort had mild or moderate initial levels of pain that decreased quickly, about 1 in 10 children had concerning pain trajectories (chronically moderate pain and mild-increasing pain). Systematic periodic assessment of pain severity in the months after diagnosis may help identify these concerning pain trajectories early and lay out appropriate pain management plans. Focused research into the factors leading to these concerning trajectories may help prevent them.

Rheumatologic disease patients receiving immunomodulating drugs such as methotrexate (MTX) have increased infection rates. Strongyloides, a global endemic intestinal parasite, can cause significant or fatal disease in immunocompromised patients. The risk of serious Strongyloides infection with MTX dosed for rheumatologic disease is unknown.We performed a systematic literature review searching EMBASE, Medline and Web of Science databases. All studies reporting humans exposed to MTX and tested for Strongyloides were reviewed. Exclusion criteria were bone marrow transplantation, intrathecal route and MTX exposure completed1 year prior to clinically apparent Strongyloides disease.After excluding duplicates, 294 articles were reviewed. Of these, 29 cases were described in 27 papers. Twenty cases (69%) had an underlying rheumatologic or dermatologic disease, the rest had a haematologic disease. Hyperinfection or dissemination was found in 59% of cases (52% low-dose MTX; 75% high-dose MTX). Death occurred in 34% of cases (19% low-dose MTX; 75% high-dose MTX, P 0.01). All eight patients on high-dose MTX received other immunosuppressants. Corticosteroids were taken in 18/21 patients on low-dose MTX. One of the three patients on MTX monotherapy had hyperinfection syndrome. None had disseminated Strongyloides.Serious Strongyloides infection can occur with low-dose MTX particularly when given with other immunosuppression. Global travel and greater awareness of rheumatologic conditions in low- to middle-income countries will increase the exposure of individuals prescribed MTX (with or without corticosteroids) to Strongyloides. Strongyloides screening and treatment should be considered for individuals receiving low-dose MTX therapy, particularly if combined with additional immunosuppression.Les patients atteints de maladies rhumatologiques recevant des médicaments immunomodulateurs tels que le méthotrexate (MTX) présentent des taux d'infection plus élevés. Strongyloides, un parasite intestinal endémique mondial, peut causer une maladie grave ou fatale chez les patients immunodéprimés. Le risque d'infection sévère à Strongyloides sous administration de MTX pour le traitement de la maladie rhumatologique est inconnu. MÉTHODES: Nous avons effectué une revue systématique de la littérature en recherchant les bases de données EMBASE, Medline et Web of Science. Toutes les études rapportant sur des humains exposés au MTX et testés pour Strongyloides ont été passées en revue. Les critères d'exclusion étaient la greffe de moelle osseuse, la voie intrathécale et l'exposition au MTX complétée plus d'un an avant l'apparition de la maladie à Strongyloides cliniquement apparente. RÉSULTATS: Après exclusion des doublons, 294 articles ont été analysés. Parmi ceux-ci, 29 cas ont été décrits dans 27 articles. Vingt cas (69%) avaient une maladie rhumatologique ou dermatologique sous-jacente, les autres avaient une maladie hématologique. Une hyperinfection ou dissémination a été constatée dans 59% des cas (52% sous MTX à faible dose; 75% sous MTX à forte dose). La mort est survenue dans 34% des cas (19% des cas sous MTX à faible dose; 75% des cas sous MTX à forte dose, p0,01). Tous les huit patients ayant reçu une dose élevée de MTX avaient reçu d'autres immunosuppresseurs. Des corticostéroïdes ont été administrés à 18 patients sur 21 sous MTX à faible dose. Un des trois patients sous MTX en monothérapie avait un syndrome d'hyperinfection. Aucun n'avait une infection disséminée à Strongyloides.Une infection sévère à Strongyloides peut survenir avec le MTX à faible dose, en particulier lorsqu'administré avec une autre immunosuppression. Les voyages à travers le monde et une plus grande sensibilisation aux conditions rhumatologiques dans les pays à revenu faible et intermédiaire augmenteront l'exposition à Strongyloides chez les individus chez qui le MTX (avec ou sans corticostéroïdes) est prescrit. Le dépistage et le traitement de Strongyloides devraient être envisagés chez les personnes recevant un traitement au MTX à faible dose, en particulier lorsqu'associé à une immunosuppression supplémentaire.

Background Treatment of recent onset Rheumatoid Arthritis (RA) is key to preventing deformities. Initial treatment with methotrexate (MTX) is standard of care. RA treatment in resource-limited countries is complicated by competing health priorities and a lack of rheumatologists. The sole public adult rheumatology clinic in Ethiopia, is at Tikur Anbessa Specialty hospital (TASH) (Addis Ababa). Due to the lack of rheumatologists, care is provided by internists with limited rheumatology training. Objectives To evaluate changes in RA management practice patterns following a series of educational activities provided by visiting rheumatologists. Methods With local faculty support, visiting rheumatologists conducted educational activities at TASH between July 2016 and December 2018 (2 continuing medical education workshops; 4 clinical preceptorships lasting 2-4 weeks each). Clinical charts of a convenience sample of RA patients seen in the TASH rheumatology clinic were reviewed in September 2016 (n=48) by a team of rheumatologists and a second set in December 2018 (n=78) by an internist. Socio-demographics, arthritis features, treatment patterns and drug safety monitoring were recorded when documented. Practice patterns were compared between 2016 and 2018 using univariate statistics. Results The patients were mainly female (90%) with a mean (standard deviation) age of 36(13) years, resided in Addis Ababa (61%) and received government funded health care (57%). When documented, (95/117; 81%) had polyarthritis and (42/55; 76%) clinical joint deformity (2016 vs 2018 p=NS). More patients were seropositive in 2016 compared to 2018 (32/43 vs 14/75 p Conclusion An educational program conducted with support from the local medical community has potential to improve management of rheumatic disease in resource limited regions without adequate rheumatology capacity. However, interventions must be maintained over time and changes in practice measured to ensure that appropriate diagnosis and safe prescribing practices continue until local rheumatology expertise and capacity is available. Acknowledgement Study funding by ILAR Disclosure of Interests CArol Hitchon Grant/research support from: Pfizer, UCB (unrelated studies), Becky Abdissa Adugna: None declared, Birhanu Demelash: None declared, Rosie Scuccimarri: None declared, Ines Colmegna: None declared, Frehiywot Kifle : None declared, Paul Caldron: None declared, Addisu Melkie: None declared, Michele Meltzer: None declared, Yewondwossen Mengistu: None declared

Background:Increased awareness of the efficacy of MTX in rheumatic disease is leading to more MTX use in patients from HIV endemic areas. While HIV related immunosuppression may contribute to improvement of some rheumatic diseases, immune reconstitution from highly active antiretroviral therapy (HAART) may lead to exacerbation or presentation of autoimmune disorders for which MTX therapy may be warranted. Most management guidelines for rheumatic disease do not address MTX use in the context of HIV.Objectives:To systematically review the published literature on the safety of using MTX ≤30 mg per week in HIV.Methods:We searched CINAHL, Embase, Global, MEDLINE and World of Science databases (Jan 1990 to May 2018) for terms including ‘methotrexate’ and ‘human immunodeficiency virus’. We also searched citations from review articles. Titles, abstracts or full manuscripts were screened independently by 2 reviewers to identify studies reporting HIV in patients taking MTX. Study quality was assessed using the McGill Mixed Methods Appraisal Tool (MMAT). Data was extracted on MTX and HIV adverse events (MTX toxicity, HIV viral load, CD4 count). Descriptive summaries are presented for studies providing outcomes in patients taking MTX ≤30 mg per week.Results:After removing duplicates and studies not meeting criteria or not providing sufficient information, 42 of the 2714 identified reports were included (1 clinical trial, 2 cohort, 1 cross-sectional study, 38 case reports/case series). Most reports (81%) originated from USA or Europe. Study quality was generally good with most studies fulfilling 50-100% of MMAT criteria. The randomized controlled trial (USA) assessing MTX on atherosclerotic disease in HIV showed that adverse events were more common in MTX versus placebo (12.8% vs 5.6%, p non-inferiority Conclusion:There remains limited data on the safety of low dose MTX in HIV. Surveillance for HIV is warranted for individuals on MTX who are at risk for acquiring HIV. Caution and careful monitoring for MTX toxicity, opportunistic infections and HIV state is suggested if MTX is used in the setting of HIV particularly if combined with other immunosuppression.References:[1] Clin Infectious Disease 2019:68[2] J Rheumatology 2014:41[3] Arthritis and Rheumatism 2003:49[4] Medicine 2017:96Acknowledgments :Funding from International League Against RheumatismMcGill University Global Health Scholar AwardsDisclosure of Interests:Alize Gunay: None declared, Anna Davidson: None declared, Ines Colmegna: None declared, Diane Lacaille: None declared, Hal Loewen: None declared, Michele Meltzer: None declared, Yewondwossen Mengistu: None declared, Rosie Scuccimarri: None declared, Zenebe Yirsaw: None declared, Sasha Bernatsky: None declared, Carol Hitchon Grant/research support from: UCB Canada; Pfizer Canada

Background:Increased awareness of the importance of MTX in rheumatic disease is leading to more MTX use in patients from TB-endemic areas. Current management guidelines for rheumatic disease address TB in the context of biologics but not MTX use.Objectives:To systematically review the published literature on TB rates with MTX ≤30 mg per week.Methods:We searched CINAHL, Embase, Global, MEDLINE and World of Science databases (Jan 1990 to May 2018) for terms including ‘methotrexate’ and ‘tuberculosis’. We also searched citations from review articles. Titles, abstracts or full manuscripts of the 4707 reports identified were screened independently by 2 reviewers to identify studies reporting TB in patients taking MTX. Study quality was assessed using the McGill Mixed Methods Appraisal Tool (MMAT). Data was extracted on TB incidence (new TB diagnosis vs reactivation of latent TB), and outcomes (pulmonary, dissemination, death) and safety of isoniazid, INH. Descriptive summaries are presented on studies providing outcomes in patients taking MTX ≤30 mg per week.Results:After removing duplicates and studies not meeting criteria or providing sufficient information, 31 studies were included (8 cohort, 7 case-control, 1 clinical trial, 15 case reports/case series). Only 27% of articles reported data from low to moderate human development index countries. Studies were of moderate quality. Seven case control studies were heterogeneous but most demonstrated a modest increased risk of TB with MTX (Table). Five cohort studies reported TB incidence rates in rheumatic disease (treated with MTX +/- biologics) ranging from 102-367.9/100,000 patient-years. These rates were generally higher than comparator general population rates. Two cohort studies of MTX in RA (without biologic) reported cumulative TB incidence in Maldova (12 TB cases in 44 RA patients, 27%) and in China (9/114, 7.9%). Other cohort studies generated rates of overt infection (143/100,000 patient years in Spain, higher if co-prescribed with corticosteroids and other immunosuppressants in South Africa), and latent TB rates detection (16/922 RA screened, 1.7%, in Canada). When reported, rates of extra-pulmonary TB were higher than comparator general population rates. One clinical trial (China), 2 cohorts (Japan, USA) and 2 case-series (Belgium, USA) evaluated safety of INH and MTX. Isoniazid-related hepatotoxicity and neutropenia were generally more common when taken with MTX, but were usually reversible.Conclusion:Despite a paucity of high-quality data, this review confirms that TB screening and clinical surveillance are needed in patients from TB-endemic areas who are prescribed MTX, particularly with co-administration of corticosteroids or other immunosuppressants. Isoniazid, if monitored, appears safe and prevents TB reactivation.References:Table .Case control studiesRegion (Year)DiagnosisTB with MTXTB without MTXOdds RatioMexico(1999)Mixed (4 RA)1/65/752.76Japan(2004)RA3/4717/1540.56Canada(2009)RA29/48321/10463.12Brazil(2010)Lupus2/31/57112Taiwan(2012)Psoriasis33/144464/23411.2Taiwan(2015)JIA4/3574/10262.90South Africa (2017)RA0/1340/18NAJIA=juvenile idiopathic arthritisAcknowledgments:Funded by the International League Against Rheumatism and McGill University Global Health Scholar AwardsDisclosure of Interests:Anna Davidson: None declared, Alize Gunay: None declared, Ines Colmegna: None declared, Diane Lacaille: None declared, Hal Loewen: None declared, Michele Meltzer: None declared, Rosie Scuccimarri: None declared, Yewondwossen Mengistu: None declared, Sasha Bernatsky: None declared, Carol Hitchon Grant/research support from: UCB Canada; Pfizer Canada

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.

Objective.To date, there are no standardized disease activity tools for systemic juvenile idiopathic arthritis (sJIA). We developed a core set of disease activity measures for sJIA.Methods.We conducted a validation study in patients with sJIA recruited from 3 Canadian institutions. Disease activity scores were based on questionnaires, clinical factors, and laboratory measures. The physician’s global assessment was our criterion standard. We determined the strength of association of each item with the criterion standard. We then surveyed international experts to determine the top 10 items. Finally, we used the experts’ responses to generate a proposed core set of disease activity measures.Results.We enrolled 57 subjects — 26 with moderately or severely active disease, and 31 with mildly active or inactive disease. Items that most strongly correlated with the criterion standard were number of active joints (r = 0.79), parent’s global assessment of disease activity (r = 0.53), erythrocyte sedimentation rate (ESR; r = 0.62), and C-reactive protein (CRP; r = 0.61). The response rate from international experts was 82% (154/187). Items with the most votes, in descending order, were number of active joints, number of days with fever in the preceding 2 weeks, patient’s and parent’s global assessments of disease activity, sJIA rash, ESR, CRP, and hemoglobin level.Conclusion.We propose a core set of items for measuring disease activity in sJIA. Future research should be aimed at further validation of this core set in the international context.

BACKGROUND:Acetylsalicylic acid (ASA) is part of the recommended treatment of Kawasaki disease (KD). Controversies remain regarding the optimal dose of ASA to be used. We aimed to evaluate the noninferiority of ASA at an antiplatelet dose in acute KD in preventing coronary artery (CA) abnormalities.METHODS:This is a multicenter, retrospective, nonrandomized cohort study including children 0 to 10 years of age with acute KD between 2004 and 2015 from 5 institutions, of which 2 routinely use low-dose ASA (3–5 mg/kg per day) and 3 use high-dose ASA (80 mg/kg per day). Outcomes were CA abnormalities defined as a CA diameter with a z score ≥2.5. We assessed the risk difference of CA abnormalities according to ASA dose. All subjects received ASA and intravenous immunoglobulin within 10 days of fever onset.RESULTS:There were 1213 subjects included, 848 in the high-dose and 365 in the low-dose ASA group. There was no difference in the risk of CA abnormalities in the low-dose compared with the high-dose ASA group (22.2% vs 20.5%). The risk difference adjusted for potential confounders was 0.3% (95% confidence interval [CI]: −4.5% to 5.0%). The adjusted risk difference for CA abnormalities persisting at the 6-week follow-up was −1.9% (95% CI: −5.3% to 1.5%). The 95% CI of the risk difference of CA abnormalities adjusted for confounders was within the prespecified 5% margin considered to be noninferior.CONCLUSIONS:In conjunction with intravenous immunoglobulin, low-dose ASA in acute KD is not inferior to high-dose ASA for reducing the risk of CA abnormalities.

Objective To describe the prevalence, associated characteristics, and course of enthesitis in a juvenile idiopathic arthritis (JIA) inception cohort. Methods Canadian children newly diagnosed with JIA between 2005 and 2010 were categorized using International League of Associations for Rheumatology criteria at the 6-month visit and followed in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) cohort for up to 5 years. The presence of entheseal tenderness on examination at 33 sites shown on a homunculus was recorded at 0, 6, 12, 18, 24, 36, 48, and 60 months after enrollment. Enthesitis was defined as entheseal tenderness at more than 1 site or on more than 1 occasion. Analyses consisted of descriptive statistics and linear mixed models for longitudinal data. Results Of 1,406 patients, 219 (16%) had enthesitis and, of those with enthesitis, 141 (64%) were classified as having enthesitis-related arthritis (ERA). Children with enthesitis were more often older (10.7 versus 7.5 years), male (57% versus 31%), and with polyarthritis (57% versus 41%) and sacroiliac involvement (30% versus 4%). Entheseal tenderness was most frequent at the calcaneal plantar fascial insertion (39%), Achilles tendon insertion (31%), and tibial tuberosity (30%). The mean number of tender entheseal sites decreased in parallel with active joint counts. There was no difference in active joint counts over time in children with or without enthesitis (P = 0.73). Conclusion Enthesitis was observed in 16% of patients with JIA, but only two thirds were categorized as having ERA. Contrary to expectations, most children with enthesitis had polyarticular involvement. The course of enthesitis paralleled the course of active joint counts.

Background Pediatric rheumatic diseases are chronic illnesses that can cause considerable disease burden to children and their families. There is limited epidemiologic data on these diseases in East Africa. The aim of this study was to assess the spectrum of pediatric rheumatic diagnoses in an in-patient setting and determine the accuracy of ICD-10 codes in identifying these conditions. Methods Medical records from Gertrude’s Children’s Hospital in Kenya were reviewed for patients diagnosed with “diseases of the musculoskeletal system and connective tissue” as per ICD-10 diagnostic codes assigned at discharge between January and December 2011. Cases were classified as “rheumatic” or “non-rheumatic”. Accuracy of the assigned ICD-10 code was ascertained. Death records were reviewed. Longitudinal follow-up of “rheumatic” cases was done by chart review up to March 2014. Results Twenty six patients were classified as having a “rheumatic” condition accounting for 0.32% of patients admitted. Of these, 11 (42.3%) had an acute inflammatory arthropathy, 6 (23.1%) had septic arthritis, 4 (15.4%) had Kawasaki disease, 2 (7.7%) had pyomyositis, and there was one case each of septic bursitis, rheumatic fever, and a non-specific soft tissue disorder. No cases of juvenile idiopathic arthritis (JIA) were identified. One case of systemic lupus erythematosus was documented by death records. The agreement between the treating physician’s discharge diagnosis and medical records ICD-10 code assignment was good (Kappa: 0.769). On follow-up, one child had recurrent knee swelling that was suspicious for JIA. Conclusions Pediatric rheumatic conditions represented 0.32% of admissions at a pediatric hospital in Kenya. Acute inflammatory arthropathies, septic arthritis and Kawasaki disease were the most frequent in-patient rheumatic diagnoses. Chronic pediatric rheumatic diseases were rare amongst this in-patient population. Despite limitations associated with the use of administrative diagnostic codes, they can be a first step in evaluating the spectrum of pediatric rheumatic conditions in Kenya and other countries in East Africa.

ObjectiveTo describe probabilities and characteristics of disease flares in children with juvenile idiopathic arthritis (JIA) and to identify clinical features associated with an increased risk of flare.MethodsWe studied children in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) prospective inception cohort. A flare was defined as a recurrence of disease manifestations after attaining inactive disease and was called significant if it required intensification of treatment. Probability of first flare was calculated with Kaplan–Meier methods, and associated features were identified using Cox regression.Results1146 children were followed up a median of 24 months after attaining inactive disease. We observed 627 first flares (54.7% of patients) with median active joint count of 1, physician global assessment (PGA) of 12 mm and duration of 27 weeks. Within a year after attaining inactive disease, the probability of flare was 42.5% (95% CI 39% to 46%) for any flare and 26.6% (24% to 30%) for a significant flare. Within a year after stopping treatment, it was 31.7% (28% to 36%) and 25.0% (21% to 29%), respectively. A maximum PGA >30 mm, maximum active joint count >4, rheumatoid factor (RF)-positive polyarthritis, antinuclear antibodies (ANA) and receiving disease-modifying antirheumatic drugs (DMARDs) or biological agents before attaining inactive disease were associated with increased risk of flare. Systemic JIA was associated with the lowest risk of flare.ConclusionsIn this real-practice JIA cohort, flares were frequent, usually involved a few swollen joints for an average of 6 months and 60% led to treatment intensification. Children with a severe disease course had an increased risk of flare.

Objective.To compare access to biologic therapies for children with juvenile idiopathic arthritis (JIA) across Canada, and to identify differences in provincial regulations and criteria for access.Methods.Between June and August 2010, we compiled the provincial guidelines for reimbursement of biologic drugs for children with JIA and conducted a multicenter Canada-wide survey of pediatric rheumatologists to determine their experience with accessing biologic therapies for their patients.Results.There were significant difficulties accessing biologic treatments other than etanercept and abatacept for children. There were large discrepancies in the access criteria and coverage of biologic agents across provinces, notably with age restrictions for younger children.Conclusion.Canadian children with JIA may not receive optimal internationally recognized “standard” care because pediatric coverage for biologic drugs through provincial formularies is limited and inconsistent across the country. There is urgent need for public policy to improve access to biologic therapies for these children to ensure optimal short-term and longterm health outcomes.

Objective.There are a number of different approaches to the initial treatment of juvenile dermatomyositis (JDM). We assessed the therapeutic approaches of North American pediatric rheumatologists to inform future studies of therapy in JDM.Methods.A survey describing clinical cases of JDM was sent to pediatric rheumatologists. The cases described children with varying severity of typical disease, disease with atypical features, or refractory disease. Three open-ended questions were asked following each case: (1) What additional investigations would you order; (2) What medicine(s) would you start (dose, route, frequency, adjustment over time); and (3) What nonmedication treatment(s) would you start.Results.The response rate was 84% (141/167). For typical cases of JDM, regardless of severity, almost all respondents used corticosteroids and another medication, methotrexate (MTX) being the most commonly used. The route and pattern of corticosteroid administration was variable. Intravenous immunoglobulin (IVIG) was used more frequently for more severe disease, for refractory disease, and for prominent cutaneous disease. Hydroxychloroquine was often used in milder cases and cases principally characterized by rash. Cyclophosphamide was reserved for ulcerative disease and JDM complicated by lung disease.Conclusion.For the majority of North American pediatric rheumatologists, corticosteroids and MTX appear to be the standard of care for typical cases of JDM. There is variability, however, in the route of administration of corticosteroids and use of IVIG and hydroxychloroquine.

Objective To compare the criteria for Wegener's granulomatosis (WG) of the American College of Rheumatology (ACR) with those of the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PRES) in a cohort of children with WG and other antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAVs), and to describe the interval to diagnosis, presenting features, and initial treatment for WG. Methods Eligible patients had been diagnosed by site rheumatologists (termed the “MD diagnosis”) since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients. Results MD diagnoses of 117 patients (82 of whom were female) were WG (n = 76), microscopic polyangiitis (n = 17), ANCA-positive pauci-immune glomerulonephritis (n = 5), Churg-Strauss syndrome (n = 2), and unclassified vasculitis (n = 17). The sensitivities of the ACR and EULAR/PRES classification criteria for WG among the spectrum of AAVs were 68.4% and 73.6%, respectively, and the specificities were 68.3% and 73.2%, respectively. Two more children were identified as having WG by the EULAR/PRES criteria than by the ACR criteria. For the 65 ACR-classified WG patients, the median age at diagnosis was 14.2 years (range 4–17 years), and the median interval from symptom onset to diagnosis was 2.7 months (range 0–49 months). The most frequent presenting features by organ system were constitutional (89.2%), pulmonary (80.0%), ear, nose, and throat (80.0%), and renal (75.4%). Fifty-four patients (83.1%) commenced treatment with the combination of corticosteroids and cyclophosphamide, with widely varying regimens; the remainder received methotrexate alone (n = 1), corticosteroids alone (n = 4), or a combination (n = 6). Conclusion The EULAR/PRES criteria minimally improved diagnostic sensitivity and specificity for WG among a narrow spectrum of children with AAVs. Diagnostic delays may result from poor characterization of childhood WG. Initial therapy varied considerably among participating centers.

Objective To determine early predictors of 6-month outcomes in a prospective cohort of patients with juvenile idiopathic arthritis (JIA). Methods Patients selected were those enrolled in an inception cohort study of JIA, the Research in Arthritis in Canadian Children Emphasizing Outcomes Study, within 6 months after diagnosis. The juvenile rheumatoid arthritis core criteria set and quality of life measures were collected at enrollment and 6 months later. Outcomes evaluated included inactive disease, Juvenile Arthritis Quality of Life Questionnaire (JAQQ) scores, and Childhood Health Assessment Questionnaire (C-HAQ) scores at 6 months. Results Thirty-three percent of patients had inactive disease at 6 months. Onset subtype and most baseline core criteria set measures correlated with all 3 outcomes. Relative to oligoarticular JIA, the risks of inactive disease were lower for enthesitis-related arthritis, polyarthritis rheumatoid factor (RF)–negative JIA, and polyarthritis RF-positive JIA, and were similar for psoriatic arthritis. In multiple regression analyses, the baseline JAQQ score was an independent predictor of all 3 outcomes. Other independent baseline predictors included polyarthritis RF-negative and systemic JIA for inactive disease; C-HAQ score and polyarthritis RF-positive JIA for the 6-month C-HAQ score; and active joint count, pain, and time to diagnosis for the 6-month JAQQ score. Conclusion Clinical measures soon after diagnosis predict short-term outcomes for patients with JIA. The JAQQ is a predictor of multiple outcomes. Time to diagnosis affects quality of life in the short term.

To determine the prevalence of and the risk factors for vertebral fractures in a cohort of children with chronic rheumatic diseases considered at risk for osteopenia.We conducted a cross-sectional study of patients with chronic rheumatic diseases at the Montreal Children's Hospital.Of the 90 study participants (22 boys, 68 girls), 10 boys and 7 girls (19%) were found to have vertebral fractures. These 17 children had a total of 50 fractures, an average of 2.9 per affected child. Fractures in the upper thoracic region (T5-8) accounted for 55%. Only 56% of all fractures were symptomatic. With multivariate regression, we identified male sex (P.01), body mass index z-score (P.02), and cumulative glucocorticoid dose (P.01) as significant predictors of the number of vertebral fractures.Our study examined the prevalence of vertebral fractures in a high-risk pediatric population. Nineteen percent of our cohort had vertebral fractures. Significant risk factors for the development of vertebral fractures include male sex and cumulative glucocorticoid dose. Better understanding of the extent of the problem in this population will allow us to further refine screening guidelines and treatment in these patients.

Vertebral fractures are an important yet underrecognized manifestation of osteoporosis in children with chronic, glucocorticoid-treated illnesses. Our goal was to determine the incidence and clinical predictors of vertebral fractures in the 3 years following glucocorticoid initiation among pediatric patients with rheumatic disorders. Incident vertebral fractures were evaluated according to the Genant semiquantitative method on lateral radiographs at baseline and then annually in the 3 years following glucocorticoid initiation. Extended Cox models were used to assess the association between vertebral fractures and clinical risk predictors. A total of 134 children with rheumatic disorders were enrolled in the study (mean ± standard deviation (SD) age 9.9 ± 4.4 years; 65% girls). The unadjusted vertebral fracture incidence rate was 4.4 per 100 person-years, with a 3-year incidence proportion of 12.4%. The highest annual incidence occurred in the first year (6.0%; 95% confidence interval (CI) 2.9% to 11.7%). Almost one-half of the patients with fractures were asymptomatic. Every 0.5 mg/kg increase in average daily glucocorticoid (prednisone equivalents) dose was associated with a twofold increased fracture risk (hazard ratio (HR) 2.0; 95% CI 1.1 to 3.5). Other predictors of increased vertebral fracture risk included: (1) increases in disease severity scores between baseline and 12 months; (2) increases in body mass index Z-scores in the first 6 months of each 12-month period preceding the annual fracture assessment; and (3) decreases in lumbar spine bone mineral density Z-scores in the first 6 months of glucocorticoid therapy. As such, we observed that a clinically significant number of children with rheumatic disorders developed incident vertebral fractures in the 3 years following glucocorticoid initiation. Almost one-half of the children were asymptomatic and thereby would have been undiagnosed in the absence of radiographic monitoring. In addition, discrete clinical predictors of incident vertebral fractures were evident early in the course of glucocorticoid therapy.

A six-month-old Caucasian boy presents with a three-day history of fever. The parents report that he had red eyes without pus two days previously. On examination, otitis media is noted as well as a nonexudative pharyngitis. Amoxicillin is prescribed. They return on the sixth day of illness and report that the child is still febrile, not responding to antipyretics and has a rash. The rash appears urticarial and the otitis media persists. A different antibiotic is prescribed. The family presents to the emergency room on the eighth day of fever. The child is irritable and difficult to console. He is noted to have red, cracked lips and a nonexudative pharyngitis. He has bilateral otitis media, no lymphadenopathy or conjunctivitis, and has a maculopapular rash on his trunk and extremities. Swelling of the hands and feet or palmar/plantar erythema is not noted. Other than tachycardia, the cardiovascular examination is unremarkable, as is the rest of the examination. Investigations reveal a white blood cell count of 22×109/L (normal range 6×109/L to 17.5×109/L) with a left shift, hemoglobin level of 90 g/L (normal range 95 g/L to 135 g/L) and platelet count of 425×109/L (normal range 140×109/L to 450×109/L). His erythrocyte sedimentation rate is 65 mm/h (normal range 3 mm/h to 13 mm/h) and C-reactive protein level is 188 mg/L (normal range 0 mg/L to 5 mg/L). His liver enzyme levels are mildly elevated and albumin level is low. No pyuria is noted. The diagnosis of incomplete Kawasaki disease (KD) is suspected and the child is admitted. He is given intravenous immunoglobulin (IVIG) and acetylsalicylic acid (ASA). Echocardiography reveals a small coronary artery aneurysm. LEARNING POINTS KD is a systemic vasculitis and the leading cause of acquired heart disease in Canadian children. It can affect children of all ages, but mainly occurs in those