Gain-of-function mutations in a member of the Src family kinases cause autoinflammatory bone disease in mice and humans.

Autoinflammatory syndromes are characterized by dysregulation of the innate immune response with subsequent episodes of acute spontaneous inflammation. Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder that presents with bone pain and localized swelling. Ali18 mice, isolated from a mutagenesis screen, exhibit a spontaneous inflammatory paw phenotype that includes sterile osteomyelitis and systemic reduced bone mineral density. To elucidate the molecular basis of the disease, positional cloning of the causative gene for Ali18 was attempted. Using a candidate gene approach, a missense mutation in the C-terminal region of Fgr, a member of Src family tyrosine kinases (SFKs), was identified. For functional confirmation, additional mutations at the N terminus of Fgr were introduced in Ali18 mice by CRISPR/Cas9-mediated genome editing. N-terminal deleterious mutations of Fgr abolished the inflammatory phenotype in Ali18 mice, but in-frame and missense mutations in the same region continue to exhibit the phenotype. The fact that Fgr null mutant mice are morphologically normal suggests that the inflammation in this model depends on Fgr products. Furthermore, the levels of C-terminal negative regulatory phosphorylation of Fgr Ali18 are distinctly reduced compared with that of wild-type Fgr. In addition, whole-exome sequencing of 99 CRMO patients including 88 trios (proband and parents) identified 13 patients with heterozygous coding sequence variants in FGR, including two missense mutant proteins that affect kinase activity. Our results strongly indicate that gain-of-function mutations in Fgr are involved in sterile osteomyelitis, and thus targeting SFKs using specific inhibitors may allow for efficient treatment of the disease.

Causal pathways to health-related quality of life in children with juvenile idiopathic arthritis: results from the ReACCh-Out cohort.

OBJECTIVE: Structural equation modelling was applied to data from the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort to help elucidate causal pathways to decreased health-related quality of life (HRQoL) in children with JIA. METHODS: Based on published literature and clinical plausibility, a priori models were constructed with explicit root causes (disease activity, treatment intensity) and mediators (pain, disease symptoms, functional impairments) leading to HRQoL [measured by the Quality of my Life (QoML) scale and the Juvenile Arthritis Quality of Life Questionnaire (JAQQ)] at five disease stages: (i) diagnosis, (ii) 3-9 months after diagnosis, (iii) flare, (iv) remission on medications, (v) remission off medications. Following structural equation modelling, a posteriori models were selected based on data fit and clinical plausibility. RESULTS: We included 561, 887, 137, 186 and 182 patients at each stage, respectively. In a posteriori models for active disease stages, paths from disease activity led through pain, functional impairments, and disease symptoms, directly or through restrictions in participation, to decreased QoML scores. Treatment intensity had detrimental effects through psychosocial domains; while treatment side effects had a lesser role. Pathways were similar for QoML and JAQQ, but JAQQ models provided greater specificity. Models for remission stages were not supported by the data. CONCLUSION: Our findings support disease activity and treatment intensity as being root causes of decreased HRQoL in children with JIA, with pain, functional impairments, and participation restrictions being mediators for disease activity; they support psychosocial effects and side effects as being mediators for treatment intensity.

Associations of clinical and inflammatory biomarker clusters with juvenile idiopathic arthritis categories.

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.

Clinical and associated inflammatory biomarker features predictive of short-term outcomes in non-systemic juvenile idiopathic arthritis.

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.

Teens Taking Charge: A Randomized Controlled Trial of a Web-Based Self-Management Program With Telephone Support for Adolescents With Juvenile Idiopathic Arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a serious and potentially debilitating pediatric illness. Improved disease self-management may help to improve health outcomes. OBJECTIVE: This study aimed to evaluate the effectiveness of the Teens Taking Charge Web-based self-management intervention in reducing symptoms and improving health-related quality of life (HRQL) in adolescents with JIA compared with a Web-based education control condition. METHODS: Adolescents with JIA aged 12 to 18 years were recruited from 11 Canadian pediatric rheumatology centers. Caregivers were invited to participate along with their child. In addition to standard medical care, participants were randomized to receive either (1) the Teens Taking Charge self-management intervention or (2) a Web-based education control condition for a period of 12 weeks. Adolescents in the intervention group completed website modules addressing cognitive behavioral coping skills, stress management, and other self-management topics, while also receiving monthly telephone calls from a trained health coach. Adolescents in the education control group were instructed to view a series of preselected public JIA educational websites and received monthly calls from a coach who asked about their own best efforts at managing JIA. Caregivers in the intervention group completed website modules related to promoting independence and disease self-management in their child. Caregivers in the education control group were instructed to view a series of preselected public JIA educational websites. Outcome assessment occurred at baseline, 12 weeks (posttreatment), and at 6 and 12 months postrandomization. The primary outcomes were pain intensity, pain interference, and HRQL. Secondary outcomes were emotional symptoms, adherence, coping, knowledge, and self-efficacy. RESULTS: In total, 333 adolescents and 306 caregivers were enrolled. Significant overall reductions in pain intensity (P=.02) and pain interference (P=.007) were observed for intervention group participants compared with those in the education control group, after adjusting for baseline levels. There was a significant overall improvement in HRQL related to problems with pain (P=.02) and problems with daily activities (P=.01). There was also a significant difference in the intervention group over time (P=.008) for HRQL related to treatment problems, with the intervention group participants demonstrating improved HRQL by 12 months compared with education control group participants. Both groups showed nonsignificant improvements compared with baseline in other primary outcomes. There were no significant differences between the groups in any secondary outcomes or caregiver-reported outcomes. CONCLUSIONS: The results of this randomized trial suggest that the Teens Taking Charge Web-based intervention is effective at reducing both pain intensity and pain interference, as well as improving HRQL in adolescents with JIA, compared with education control. These effects are sustained for up to 12 months following program completion. The Teens Taking Charge program is now publicly available at no cost. TRIAL REGISTRATION: ClinicalTrials.gov NCT01572896; https://clinicaltrials.gov/ct2/show/NCT01572896.

Diagnostic Accuracy of MRI-Based Sacroiliitis Scoring Systems: A Systematic Review.

OBJECTIVE. Accurate and reproducible MRI assessment of the sacroiliac joint (SIJ) is challenging. Numerous scoring systems have been proposed to facilitate consistent SIJ assessment. The purpose of this article is to evaluate the diagnostic accuracy and reliability of existing MRI-based SIJ scoring systems for the evaluation of spondyloarthropathy. CONCLUSION. Among existing methods, there is fair (grade B) evidence to recommend the Spondyloarthropathy Research Consortium of Canada scoring systems as tools for MRI evaluation of the SIJ. However, limited data on criterion validity limit assessment of scoring system accuracy.

Recurrent oral ulcerations following heart transplant in a pediatric patient: A diagnostic dilemma.

Oral ulceration is a non-specific clinical finding with many potential causes. The persistence of oral ulcers in the context of a patient post-SOT is concerning for PTLD. There is growing evidence that SOT recipients may also be at higher risk of autoimmune diseases. This case report describes a pediatric patient with persistent oral ulcers after heart transplant, who underwent an extensive workup for PTLD, including repeat investigations, with a subsequent diagnosis of Behçet's disease.

The risk and nature of flares in juvenile idiopathic arthritis: results from the ReACCh-Out cohort.

OBJECTIVE: To 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. METHODS: We 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. RESULTS: 1146 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. CONCLUSIONS: In 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.

The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort.

OBJECTIVE: To describe clinical outcomes of juvenile idiopathic arthritis (JIA) in a prospective inception cohort of children managed with contemporary treatments. METHODS: Children newly diagnosed with JIA at 16 Canadian paediatric rheumatology centres from 2005 to 2010 were included. Kaplan-Meier survival curves for each JIA category were used to estimate probability of ever attaining an active joint count of 0, inactive disease (no active joints, no extraarticular manifestations and a physician global assessment of disease activity <10 mm), disease remission (inactive disease >12 months after discontinuing treatment) and of receiving specific treatments. RESULTS: In a cohort of 1104 children, the probabilities of attaining an active joint count of 0 exceeded 78% within 2 years in all JIA categories. The probability of attaining inactive disease exceeded 70% within 2 years in all categories, except for RF-positive polyarthritis (48%). The probability of discontinuing treatment at least once was 67% within 5 years. The probability of attaining remission within 5 years was 46-57% across JIA categories except for polyarthritis (0% RF-positive, 14% RF-negative). Initial treatment included joint injections and non-steroidal anti-inflammatory drugs for oligoarthritis, disease-modifying antirheumatic drugs (DMARDs) for polyarthritis and systemic corticosteroids for systemic JIA. CONCLUSIONS: Most children with JIA managed with contemporary treatments attain inactive disease within 2 years of diagnosis and many are able to discontinue treatment. The probability of attaining remission within 5 years of diagnosis is about 50%, except for children with polyarthritis.

Whole-body MRI of juvenile spondyloarthritis: protocols and pictorial review of characteristic patterns.

Spondyloarthritides are a group of inflammatory rheumatological diseases that cause arthritis with a predilection for spinal or sacroiliac involvement in addition to a high association with HLA-B27. Juvenile spondyloarthritis is distinct from adult spondyloarthritis and manifests more frequently as peripheral arthritis and enthesitis. Consequently juvenile spondyloarthritis is often referred to as enthesitis-related arthritis (ERA) subtype under the juvenile idiopathic arthritis (JIA) classification criteria. The American College of Rheumatology Treatment Recommendations for JIA, including ERA, are based on the following clinical parameters: current treatment, disease activity and the presence of poor prognostic features. The MRI features of juvenile spondyloarthritis include marrow edema, peri-enthesal soft-tissue swelling and edema, synovitis and joint or bursal fluid. Marrow edema is nonspecific and can be seen with other pathologies as well as in healthy subjects, and this is an important pitfall to consider. With further longitudinal study and validation, however, whole-body MRI with dedicated images of the more commonly affected areas such as the spine, sacroiliac joints, hips, knees, ankles and feet can serve as a more objective tool compared to clinical exam for early detection and monitoring of disease activity and ultimately direct therapeutic management.

Reliability assessment of the OMERACT whole-body magnetic resonance imaging scoring system for juvenile idiopathic arthritis.

Inter-reader reliability of a new scoring system for evaluating joint inflammation and enthesitis in whole body MRI (WBMRI) in juvenile idiopathic arthritis was tested. The scoring system grades 732 item-region combinations of bone marrow and soft tissue changes for commonly involved joints and entheseal sites. Five radiologists rated 17 WBMRI scans through an online rating platform. Item-wise reliability was calculated for 117 items with non-zero scores in >10 % of readings. Interquartile ranges of the five-reader Kappa reliability coefficients were 0.58-0.73 (range: 0.36-0.88) for the joints, 0.65-0.81 (range: 0.39-0.95) for the entheses, and 0.62-0.75 (range: 0.60-0.76) for chronic nonbacterial osteomyelitis-like lesions.

Classification Criteria for Axial Disease in Youth with Juvenile Spondyloarthritis.

OBJECTIVES: To develop and validate classification criteria for axial disease in youth with juvenile spondyloarthritis (SpA; AxJSpA). METHODS: This international initiative consisted of four phases: 1) Item generation; 2) Item reduction; 3) Criteria development; and 4) Validation of the AxJSpA criteria by an independent team of experts in an internationally representative Validation cohort. RESULTS: These criteria are intended to be used on youth with a physician diagnosis of juvenile SpA and for whom axial disease is suspected. Item generation consisted of a systematic literature review and a free-listing exercise using input from international physicians and collectively resulted in 108 items. After the item reduction exercise and expert panel input, 37 items remained for further consideration. The final AxJSpA criteria domains included: imaging: active inflammation, imaging: structural lesions, pain chronicity, pain pattern, pain location, stiffness, and genetics. The most heavily weighted domains were active inflammation and structural lesions on imaging. Imaging typical of sacroiliitis was deemed necessary, but not sufficient, to classify a youth with AxJSpA. The threshold for classification of AxJSpA was a score of ≥55 (out of 100). When tested in the validation data set, the final criteria had a specificity of 97.5% (95% CI: 91.4-99.7), sensitivity of 64.3% (95% CI: 54.9-73.1) and Area Under the Receiver Operating Characteristic (AUROC) curve of 0.81 (95% CI: 0.76-0.86). CONCLUSIONS: The new AxJSpA classification criteria require an entry criterion, physician diagnosis of juvenile SpA, and include seven weighted domains. The AxJSpA classification criteria are validated and designed to identify participants for research studies.

Later-onset rheumatoid factor negative polyarticular juvenile idiopathic arthritis (JIA): a unique patient group?

OBJECTIVES: To determine the two-year outcome of patients with later-onset polyarticular rheumatoid factor (RF) negative (-) juvenile idiopathic arthritis (JIA), and predictors of outcome. METHODS: All patients ages 10 to16 years diagnosed and followed in the Rheumatology Clinic at SickKids Hospital with the diagnosis of polyarticular RF- JIA were eligible for study. A retrospective chart analysis was performed and number of active joints, medications, laboratory information and childhood health assessment questionnaire scores were recorded at diagnosis, and 6, 12, and 24 months following diagnosis. RESULTS: As early as 6 months after diagnosis the mean number of active joints decreased from 16 to < 10, with 50% of the patients having < 5 active joints. The predominant joints affected were the wrist, knee, and small joints of the hand. The only predictor of active joint count at the 2-year follow-up was initial presenting active joint count as classified as mild, moderate, or severe. Sex, age, and laboratory results at presentation did not show any correlation with active joint count at 2 years. Majority of patients were treated with non-steroidal anti-inflammatory drugs (98%) and at least one disease-modifying anti-rheumatic drug (56%). CONCLUSIONS: The two-year outcome of patients with late-onset RF- polyarticular JIA was very good with the majority of patients having minimally active disease at last follow-up. Presence of significant polyarthritis at presentation was the only feature associated with long-term joint activity. Sex and lab results did not show any correlation with active joint in this cohort of RF-JIA patients.

Determination of Relative Weightings for Sacroiliac Joint Pathologies in the OMERACT Juvenile Arthritis Magnetic Resonance Imaging Sacroiliac Joint Score.

This study aims to determine the relative weights (point value) of items of the juvenile idiopathic arthritis magnetic resonance imaging-sacroiliac joint scoring system (JAMRIS-SIJ). An adaptive multicriteria decision analysis was performed using the 1000Minds web application to determine the relative weights of the items in the JAMRIS-SIJ inflammation and damage domains. Experts in imaging and rheumatology independently completed a conjoint analysis survey (CAS) to determine the point value of the measurement items of the JAMRIS-SIJ. Each CAS survey question asked the expert to compare two hypothetical patient profiles, which were otherwise similar but different at two items at a time, and to select which item showed a more severe stage of inflammation or osteochondral damage. In addition, experts ranked 14 JAMRIS-SIJ grade only or image + grade patient vignettes while blinded to the CAS-derived weights. The validity of the weighted JAMRIS-SIJ was tested by comparing the expert CAS-weighted score and the image + grade ranking method. Seventeen experts completed the CAS (11 radiologists and 6 rheumatologists). Considering the point value for inflammation domain items, osteitis (24.7%) and bone marrow edema (24.3%) had higher group-averaged percentage weights compared to inflammation in erosion cavity (16.9%), joint space enhancement (13.1%), joint space fluid (9.1%), capsulitis (7.3%), and enthesitis (4.6%). Similarly, concerning the damage domain, ankylosis (41.3%) and erosion (25.1%) showed higher group-averaged weights compared to backfill (13.9%), sclerosis (10.7%), and fat metaplasia lesion (9.1%). The Spearman correlation coefficients of the CAS-weighted vignette order and unweighted JAMRIS-SIJ grade only order vignettes for all experts were 0.79 for inflammation and 0.80 for damage. The correlations of image vignettes among imaging experts to CAS were 0.75 for inflammation and 0.90 for damage. The multicriteria decision analysis identified differences in relative weights among the JAMRIS-SIJ measurement items. The determination of the relative weights provided expert-driven score scaling and face validity for the JAMRIS-SIJ, enabling the future evaluation of its longitudinal construct validity.

Sleep and fatigue and the relationship to pain, disease activity and quality of life in juvenile idiopathic arthritis and juvenile dermatomyositis.

OBJECTIVES: To determine and compare the prevalence of disturbed sleep in JIA and JDM and the relationship of sleep disturbance to pain, function, disease activity and medications. METHODS: One hundred fifty-five patients (115 JIA, 40 JDM) were randomly sampled and were mailed questionnaires. Sleep disturbance was assessed by the sleep self-report (SSR) and the children's sleep habits questionnaire (CSHQ). Fatigue, pain and function were assessed by the paediatric quality of life inventory (PedsQL) and disease activity by visual analogue scales (VASs). Joint counts were self-reported. RESULTS: Eighty-one per cent responded, of whom 44% reported disturbed sleep (CSHQ > 41); there were no differences between disease groups. Poor reported sleep (SSR) was highly correlated with PedsQL fatigue (r = 0.56, P < 0.0001). Fatigue was highly negatively correlated with quality of life (r = -0.77, P < 0.0001). The worst pain intensity in the last week was correlated to sleep disturbance (r = 0.32, P = 0.0005). Fatigue was associated with prednisone and DMARD use. CONCLUSIONS: Sleep disturbance and fatigue are prevalent among children with different rheumatic diseases. Sleep disturbance and fatigue are strongly associated with increased pain and decreased quality of life. Strategies aimed at improving sleep and reducing fatigue should be studied as possible ways of improving quality of life for children with rheumatic illness.

Whole-body MRI Quantification for Assessment of Bone Lesions in Chronic Nonbacterial Osteomyelitis Patients Treated With Pamidronate: A Prevalence, Reproducibility, and Responsiveness Study.

OBJECTIVE: The purpose of this study was (1) to assess the interreader reliability in detecting and scoring the inflammatory bone lesions in pediatric patients with chronic nonbacterial osteomyelitis (CNO) by using whole-body magnetic resonance imaging (WB-MRI), and (2) to evaluate the responsiveness of the MRI-detected CNO lesions to pamidronate therapy. METHODS: Eighty-eight WB-MRI examinations were independently reviewed and scored by 2 radiologists blinded to clinical details in 32 retrospectively enrolled pediatric patients with CNO. Inflammatory bone lesions, soft tissue abnormality, and bony structural changes were scored before and after pamidronate therapy. Lesion responsiveness was calculated by using standardized response mean and interreader reliability was assessed by k statistics. RESULTS: There was good to excellent interreader agreement for the detection and quantification of bone lesions. After the first cycle of pamidronate in all 32 patients, 96 of the 279 lesions (34%; after excluding 108 lesions of hand and feet) resolved, whereas in a subset of 11 patients with 2 or more cycles, 76% of lesions resolved after the second cycle. Twenty-one (7.5%) lesions worsened and 46 (16.4%) new lesions developed after 1 cycle in all 32 patients. In these 11 patients, the number of worsened lesions reduced to 2 (2%) and new lesions to 14 (14.9%) after the second cycle as detected on MRI. Vertebral lesions had the highest response to treatment. CONCLUSION: WB-MRI is a reliable tool for objective quantification and assessment of response to treatment of pediatric CNO bone lesions and could be used to monitor disease activity for clinical and research purposes.

Toward Developing a Semiquantitative Whole Body-MRI Scoring for Juvenile Idiopathic Arthritis: Critical Appraisal of the State of the Art, Challenges, and Opportunities.

With powerful new therapies available for management of juvenile idiopathic arthritis (JIA), early diagnosis leading to appropriate treatment may prevent long-term structural joint damage. Although magnetic resonance imaging (MRI) is typically used to assess individual body parts, indications for whole body (WB) MRI are increasing. Its utility as a diagnostic and monitoring tool has already been widely investigated in adult rheumatology patients, but less so in pediatric rheumatologic patients. This paper is a comprehensive review of scoring systems and a proposal for the conceptual development of a WB-MRI scoring system for the evaluation of JIA. In this review we identify, summarize, and critically appraise the available literature on the use of WB-MRI in inflammatory arthritis, addressing relevant considerations on components of a classification system that can lead to the development of a future pediatric WB-MRI scoring system for use in children with JIA. We also discuss advantages and challenges of developing such a WB-MRI scoring system for assessment of JIA and outline next steps toward the conceptual development of this scoring system.

Consensus-driven conceptual development of a standardized whole body-MRI scoring system for assessment of disease activity in juvenile idiopathic arthritis: MRI in JIA OMERACT working group.

OBJECTIVES: Whole body-MRI is helpful in directing diagnostic and treatment approaches, and as a research outcome measure. We describe our initial consensus-driven phase towards developing a whole body-MRI scoring system for juvenile idiopathic arthritis. METHODS: An iterative approach using three rounds of anonymous Delphi surveys followed by a consensus meeting was used to draft the structure of the whole body-MRI scoring system, including the relevant anatomic joints and entheses for assessment, diagnostic item selection, definition and grading, and selection of appropriate MRI planes and sequences. The surveys were completed independently by an international expert group consisting of pediatric radiologists and rheumatologists. RESULTS: Twenty-two experts participated in at least one of three rounds of Delphi surveys and a concluding consensus meeting. A first iteration scoring system was developed which ultimately included the assessment of 100 peripheral, 23 chest, and 76 axial joints, and 64 entheses, with 2-4 diagnostic items graded in each of the items, using binary (presence/absence) and 2-3-level ordinal scores. Recommendations on anatomic MRI planes and sequences were specified as the minimally necessary imaging protocol for the scoring system. CONCLUSION: A novel whole body-MRI scoring system for juvenile idiopathic arthritis was developed by consensus among members of MRI in JIA OMERACT working group. Further iterative refinements, reliability testing, and responsiveness are warranted in upcoming studies.

Higher concentrations of vitamin D in Canadian children with juvenile idiopathic arthritis compared to healthy controls are associated with more frequent use of vitamin D supplements and season of birth.

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.

Soluble Low-density Lipoprotein Receptor-related Protein 1 in Juvenile Idiopathic Arthritis.

OBJECTIVES: This 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. METHODS: Plasma 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. RESULTS: At 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. CONCLUSION: Plasma 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.