Inflammatory Biomarkers Can Differentiate Acute Lymphoblastic Leukemia with Arthropathy from Juvenile Idiopathic Arthritis Better Than Standard Blood Tests.

OBJECTIVE: To evaluate the predictive value of biomarkers of inflammation like phagocyte-related S100 proteins and a panel of inflammatory cytokines in order to differentiate the child with acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA). STUDY DESIGN: In this cross-sectional study, we measured S100A9, S100A12, and 14 cytokines in serum from children with ALL (n = 150, including 27 with arthropathy) and JIA (n = 236). We constructed predictive models computing areas under the curve (AUC) as well as predicted probabilities in order to differentiate ALL from JIA. Logistic regression was used for predictions of ALL risk, considering the markers as the respective exposures. We performed internal validation using repeated 10-fold cross-validation and recalibration, adjusted for age. RESULTS: In ALL, the levels of S100A9, S100A12, interleukin (IL)-1 beta, IL-4, IL-13, IL-17, matrix metalloproteinase-3, and myeloperoxidase were low compared with JIA (P < .001). IL-13 had an AUC of 100% (95% CI 100%-100%) due to no overlap between the serum levels in the 2 groups. Further, IL-4 and S100A9 had high predictive performance with AUCs of 99% (95% CI 97%-100%) and 98% (95% CI 94%-99%), respectively, exceeding both hemoglobin, platelets, C-reactive protein, and erythrocyte sedimentation rate. CONCLUSIONS: The biomarkers S100A9, IL-4, and IL-13 might be valuable markers to differentiate ALL from JIA.

Cone beam computed tomography in the assessment of TMJ deformity in children with JIA: repeatability of a novel scoring system.

BACKGROUND: The temporomandibular joint (TMJ) is frequently involved in juvenile idiopathic arthritis (JIA). Diagnostic imaging is necessary to correctly diagnose and evaluate TMJ involvement, however, hitherto little has been published on the accuracy of the applied scoring systems and measurements. The present study aims to investigate the precision of 20 imaging features and five measurements based on cone beam computed tomography (CBCT). METHODS: Imaging and clinical data from 84 participants in the Norwegian study on juvenile idiopathic arthritis, the NorJIA study, were collected. Altogether 20 imaging features and five measurements were evaluated independently by three experienced radiologists for intra- and interobserver agreement. Agreement of categorical variables was assessed by Fleiss', Cohen's simple or weighted Kappa as appropriate. Agreement of continuous variables was assessed with 95% limits of agreement as advised by Bland and Altman. RESULTS: "Overall impression of TMJ deformity" showed almost perfect intraobserver agreement with a kappa coefficient of 0.81 (95% CI 0.69-0.92), and substantial interobserver agreement (Fleiss' kappa 0.70 (0.61-0.78)). Moreover, both "flattening" and "irregularities" of the eminence/fossa and condyle performed well, with intra- and interobserver agreements of 0.66-0.82 and 0.55-0.76, respectively. "Reduced condylar volume" and "continuity" of the fossa/eminence had moderate intra- and interobserver Kappa values, whereas continuity of the condyle had Kappa values above 0.55. Measurements of distances and angles had limits of agreement of more than 15% of the sample mean. CONCLUSIONS: We propose a CBCT-based scoring system of nine precise imaging features suggestive of TMJ deformity in JIA. Their clinical validity must be tested.

Oral health-related quality of life, impaired physical health and orofacial pain in children and adolescents with juvenile idiopathic arthritis - a prospective multicenter cohort study.

BACKGROUND: Knowledge on oral health-related quality of life (OHRQoL) in children and adolescents with juvenile idiopathic arthritis (JIA) is limited, and longitudinal studies are lacking. We aimed to describe OHRQoL in children and adolescents with JIA compared to controls, and to explore the validity and internal consistency of the Early Childhood Oral Health Impact Scale (ECOHIS) and the Child Oral Impact on Daily Performance (Child-OIDP). Furthermore, we wanted to investigate associations between OHRQoL and orofacial pain, physical health, disease activity, and temporomandibular joint (TMJ) involvement in JIA. METHODS: The Norwegian prospective, multicenter cohort study recruited participants with JIA between 4 and 16 years of age and corresponding controls from three pediatric university hospital departments and public dental health services. In the present study, we analyzed OHRQoL in all children < 12 years with the ECOHIS and adolescents ≥ 12 years with the Child-OIDP at the first visit and the two-year follow-up. Associations between OHRQoL and JIA characteristics, collected in clinical exam and questionnaires, were analyzed in logistic regressions. RESULTS: The same OHRQoL questionnaire was completed both at first visit and two-year follow-up in 101 children < 12 years (47 JIA, 54 controls) and 213 adolescents ≥ 12 years (111 JIA, 102 controls). The frequency of OHRQoL impacts in children was similar at the first visit and the two-year follow-up (ECOHIS > 0: JIA group 81% and 85%, p = 0.791; control group 65% and 69%, p = 0.815), while adolescents with JIA reported fewer impacts at the two-year follow-up (Child OIDP > 0: JIA group 27% and 15%, p = 0.004; control group 21% and 14%, p = 0.230). The internal consistency of the OHRQoL instruments was overall acceptable and the criterion validity indicated that the instruments were valid at both visits. Orofacial pain was more frequent in children and adolescents with JIA than in controls. We found associations between OHRQoL impacts and orofacial pain, impaired physical health, disease activity, and TMJ involvement. CONCLUSIONS: Children and adolescents with orofacial pain or impaired physical health were more likely to report impacts on daily life activities than those without. Pediatric rheumatologists and dentists should be aware of impaired OHRQoL in individuals with JIA with active disease or temporomandibular joint involvement. TRIAL REGISTRATION: Registered on clinicaltrials.gov (NCT03904459, 05/04/2019).

Increased incidence of inflammatory bowel disease on etanercept in juvenile idiopathic arthritis regardless of concomitant methotrexate use.

OBJECTIVE: To describe risk factors for IBD development in a cohort of children with JIA. METHODS: JIA patients who developed IBD were identified from the international Pharmachild register. Characteristics were compared between IBD and non-IBD patients and predictors of IBD were determined using multivariable logistic regression analysis. Incidence rates of IBD events on different DMARDs were calculated, and differences between therapies were expressed as relative risks (RR). RESULTS: Out of 8942 patients, 48 (0.54% ) developed IBD. These were more often male (47.9% vs 32.0%) and HLA-B27 positive (38.2% vs 21.0%) and older at JIA onset (median 8.94 vs 5.33 years) than patients without IBD development. They also had more often a family history of autoimmune disease (42.6% vs 24.4%) and enthesitis-related arthritis (39.6% vs 10.8%). The strongest predictors of IBD on multivariable analysis were enthesitis-related arthritis [odds ratio (OR): 3.68, 95% CI: 1.41, 9.40] and a family history of autoimmune disease (OR: 2.27, 95% CI: 1.12, 4.54). Compared with methotrexate monotherapy, the incidence of IBD on etanercept monotherapy (RR: 7.69, 95% CI: 1.99, 29.74), etanercept with methotrexate (RR: 5.70, 95% CI: 1.42, 22.77) and infliximab (RR: 7.61, 95% CI: 1.27, 45.57) therapy was significantly higher. Incidence on adalimumab was not significantly different (RR: 1.45, 95% CI: 0.15, 13.89). CONCLUSION: IBD in JIA was associated with enthesitis-related arthritis and a family history of autoimmune disease. An increased IBD incidence was observed for etanercept therapy regardless of concomitant methotrexate use.

Vitamin D, oral health, and disease characteristics in juvenile idiopathic arthritis: a multicenter cross-sectional study.

BACKGROUND: Vitamin D deficiency has been associated with autoimmune diseases and oral health. Knowledge about the association between vitamin D status and oral conditions in JIA is limited. We aimed to investigate vitamin D status in a cohort of Norwegian children and adolescents with JIA and possible associations between serum vitamin D levels, clinical indicators of oral health, and JIA disease characteristics. METHODS: This multi-center, cross-sectional study, included individuals with JIA aged 4-16 years from three geographically spread regions in Norway. Demographic data, age at disease onset, disease duration, JIA category, disease status, medication, and vitamin D intake were registered. One blood sample per individual was analyzed for 25(OH) vitamin D, and the level of insufficiency was defined as < 50 nmol/L. A clinical oral examination was performed applying commonly used indices in epidemiological studies of dental caries, dental erosion, enamel defects, gingival bleeding, and oral hygiene. Serum vitamin D was used as exposure variable in multivariable regression analyses to estimate the associations between insufficient vitamin D level, JIA disease status, and oral conditions, with adjustments for age, sex, geographical region, BMI, seasonal blood sampling, and parental education. RESULTS: Among the 223 participants with JIA, 97.3% were Caucasians, 59.2% were girls, and median age was 12.6 years. Median disease duration was 4.6 years, and 44.4% had oligoarticular JIA. Mean serum vitamin D level was 61.4 nmol/L and 29.6% had insufficient levels. Vitamin D levels did not differ between sexes, but between regions, iso-BMI categories, age groups, and seasons for blood sampling. Insufficient vitamin D levels were associated with dentin caries (adjusted OR 2.89, 95% CI 1.43-5.86) and gingival bleeding (adjusted OR 2.36, 95% CI 1.10-5.01). No associations were found with active JIA disease or more severe disease characteristics. CONCLUSION: In our study, nearly 30% had vitamin D insufficiency, with a particularly high prevalence among adolescents. Vitamin D insufficiency was associated with dentin caries and gingival bleeding, but not with JIA disease activity. These results point to the need for a multidisciplinary approach in the follow-up of children with JIA, including an increased focus on vitamin D status and oral health.

Uveitis in Juvenile Idiopathic Arthritis: 18-Year Outcome in the Population-based Nordic Cohort Study.

PURPOSE: To assess the long-term outcome of uveitis in juvenile idiopathic arthritis (JIA). DESIGN: Population-based, multicenter, prospective JIA cohort, with a cross-sectional assessment of JIA-associated uveitis (JIA-U) 18 years after the onset of JIA. PARTICIPANTS: A total of 434 patients with JIA, of whom 96 had uveitis, from defined geographic areas of Denmark, Finland, Norway, and Sweden. METHODS: Patients with onset of JIA between January 1997 and June 2000 were prospectively followed for 18 years. Pediatric rheumatologists and ophthalmologists collected clinical and laboratory data. MAIN OUTCOME MEASURES: Cumulative incidence of uveitis and clinical characteristics, JIA and uveitis disease activity, ocular complications, visual outcome, and risk factors associated with the development of uveitis-related complications. RESULTS: Uveitis developed in 96 (22.1%) of 434 patients with JIA. In 12 patients (2.8%), uveitis was diagnosed between 8 and 18 years of follow-up. Systemic immunosuppressive medication was more common among patients with uveitis (47/96 [49.0%]) compared with patients without uveitis (78/338 [23.1%]). Active uveitis was present in 19 of 78 patients (24.4%) at the 18-year visit. Ocular complications occurred in 31 of 80 patients (38.8%). Short duration between the onset of JIA and the diagnosis of uveitis was a risk factor for developing ocular complications (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.8). Patients with a diagnosis of uveitis before the onset of JIA all developed cataract and had an OR for development of glaucoma of 31.5 (95% CI, 3.6-274). Presence of antinuclear antibodies (ANAs) was also a risk factor for developing 1 or more ocular complications (OR, 3.0; 95% CI, 1.2-7.7). Decreased visual acuity (VA) <6/12 was found in 12 of 135 eyes (8.9%) with uveitis, and 4 of 80 patients (5.0%) with JIA-U had binocular decreased VA <6/12. CONCLUSIONS: Our results suggest that uveitis screening should start immediately when the diagnosis of JIA is suspected or confirmed and be continued for more than 8 years after the diagnosis of JIA. Timely systemic immunosuppressive treatment in patients with a high risk of developing ocular complications must be considered early in the disease course to gain rapid control of ocular inflammation.

The Norwegian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Norwegian language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic and clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 301 JIA patients (3.3% systemic, 41.2% oligoarticular, 25.9% RF negative polyarthritis, and 29.6% other categories) and 74 healthy children were enrolled in three centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Norwegian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Long-term outcome in juvenile-onset mixed connective tissue disease: a nationwide Norwegian study.

OBJECTIVES: To describe the characteristics, outcome and predictive factors of juvenile mixed connective tissue disease (JMCTD) in a nationwide cohort of patients. METHODS: We examined 55 patients with JMCTD after a mean disease duration of 16.2 years (SD 10.0). Patients were registered according to Kasukawa's criteria. Remission criteria were defined according to those for juvenile idiopathic arthritis, plus absence of cytopenia, myositis, progressive sclerodactyly, lung and oesophageal manifestations. Organ damage was assessed with the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index and the Juvenile Arthritis Damage Index (JADI). Medical records were reviewed for early predictors for outcome, which were assessed by multivariate logistic regression analyses. RESULTS: Three patients developed systemic lupus erythematosus (SLE). Fifty-two patients had continuous JMCTD; the most common manifestations were: Raynaud (100%), arthritis (94%), puffy hands (77%) and pulmonary manifestations (58%). SLE-like, systemic sclerosis (SSc)-like and polymyositis (PM)-like findings were found in 98%, 77% and 48%, respectively. Over time, SLE-like and PM-like manifestations decreased, and SSc-like findings increased. At follow-up, 35 patients (67%) had active disease and 17 (33%) were in remission. In 34 patients (65%), SLICC or JADI≥1 assessments indicated organ damage. Active disease was associated with higher anti-ribonucleoprotein antibody titres at follow-up and positive rheumatoid factor (RF) at diagnosis and follow-up. CONCLUSIONS: Most patients with JMCTD had active disease and organ damage after a mean follow-up of 16.2 years. Active disease was associated with higher anti-ribonucleoprotein antibody levels and positive RF. The presence of RF at diagnosis predicted persistent disease activity.

High-sensitive CRP as a predictive marker of long-term outcome in juvenile idiopathic arthritis.

To evaluate whether C-reactive protein (CRP), including variation within the normal range, is predictive of long-term disease outcome in Juvenile Idiopathic Arthritis (JIA). Consecutive patients with newly diagnosed JIA were included prospectively from defined geographic areas of the Nordic countries from 1997 to 2000. Inclusion criteria were availability of a baseline serum sample within 12 months after disease onset and 8-year clinical assessment data. Systemic onset JIA was not included. CRP was measured by high-sensitive ELISA (detection limit of 0.2 mg/l). One hundred and thirty participants with a median follow-up time of 97 months (range 95-100) were included. At follow-up, 38% of the patients were in remission off medication. Absence of remission was associated with elevated level of CRP at baseline (odds ratio (OR) 1.33, confidence interval (CI) 1.08-1.63, p = 0.007). By applying a cutoff at the normal upper limit (>10 mg/l), the risk of not achieving remission was increased to an OR of 8.60 (CI 2.98-24.81, p < 0.001). Variations of CRP within the normal range had no predictive impact on disease activity at follow-up. Baseline levels of ESR were available in 80 patients (61%) and elevated ESR was associated with absence of remission in a multivariable logistic regression analysis (OR 2.32, CI 1.35-4.00, p = 0.002). This results of this study indicate that baseline CRP concentrations above 10 mg/l are predictive of a poor outcome at 8-year follow-up. We could not demonstrate any predictive value of CRP variations within the normal range.

Bronchiolitis should not be treated with glucocorticoids or antibiotics. / Bronkiolitt skal ikke behandles med glukokortikoider eller antibiotika.

We are in the midst of a hectic season for viral respiratory infections. Respiratory syncytial virus is the most common cause of bronchiolitis in children. The guidelines from the Norwegian Society of Pediatricians are clear that oral glucocorticoids have no place in the treatment of bronchiolitis, and antibiotics are rarely needed.

Ankle arthritis predicts polyarticular disease course and unfavourable outcome in children with juvenile idiopathic arthritis.

OBJECTIVES: To evaluate the occurrence, clinical characteristics and prognostic factors associated with ankle arthritis in children with juvenile idiopathic arthritis (JIA). METHODS: 440 children with JIA were followed for eight years in a prospective Nordic population-based cohort study. Data on remission was available for 427 of these children. Occurrence of clinically assessed ankle arthritis was analysed in relation to JIA category, clinical characteristics and remission data eight years after disease onset. RESULTS: In 440 children with JIA, 251 (57%) experienced ankle arthritis during the first eight years of disease. Ankle arthritis was least common in the persistent oligoarticular category (25%) and most common in children with extended oligoarticular (83%) and polyarticular RF-negative (85%) JIA. Children who developed ankle arthritis during the first year of disease were younger at disease onset (median age 4.9 (IQR 2.1-8.8) vs. 6.6 (IQR 2.8-10.1) years, p<0.003) and had more cumulative affected joints at 8-year follow-up (median involved joints 10 (IQR 6-16) vs. 3 (IQR 2-9), p<0.001). The odds ratio for not achieving remission eight years after disease onset, if the ankle joint was involved during the first year of disease was 2.0 (95 % CI:1.3-3.0, p<0.001). Hind-, mid- and forefoot involvements were more common compared to patients without ankle arthritis. CONCLUSIONS: In this Nordic population-based 8-year follow-up study, occurrence of ankle arthritis during the first year was associated with an unfavourable disease outcome. We suggest that ankle arthritis should be recognised in the assessment of prognosis and choice of treatment strategy in JIA.

Disease activity trajectories from childhood to adulthood in the population-based Nordic juvenile idiopathic arthritis cohort.

OBJECTIVES: To identify long-term disease activity trajectories from childhood to adulthood by using the clinical Juvenile Arthritis Disease Activity Score (cJADAS10) in juvenile idiopathic arthritis (JIA). Second, to evaluate the contribution of the cJADAS10 components and explore characteristics associated with active disease at the 18-year follow-up. METHODS: Patients with onset of JIA in 1997-2000 were followed for 18 years in the population-based Nordic JIA cohort. We used a discrete mixture model for longitudinal clustering of the cJADAS10 and its components. We assessed factors potentially associated with higher scores on the patient's global assessment of well-being (PaGA) by hierarchical clustering and correlation analysis. RESULTS: Four disease activity trajectories were identified based on the cJADAS10 components among 427 patients. In trajectory-group 2, the PaGA and the physician's global assessment of disease activity (PhGA) increased significantly during the course, but not the active joint count. The increase in the PaGA was significantly higher than the increases in the PhGA and the active joint count (p<0.0001). A similar pattern was found among all the patients with active disease in the total cohort. Patients with higher PaGA scores had unfavourable scores on several other patient-reported outcomes. CONCLUSIONS: We have identified groups of patients based on long-term disease activity trajectories. In our study the PaGA was the most important driver of disease activity into adulthood assessed by cJADAS10. We need to better understand how our patients interpret global well-being and implement strategies to achieve inactive disease perceived both by the patient and the physician.

Body mass index is associated with health-related quality of life and disease characteristics in young adults with juvenile idiopathic arthritis.

BACKGROUND: There is a growing interest concerning the relationship between obesity and several medical conditions and inflammation. Nevertheless, there is a lack of studies regarding body mass index (BMI) among patients with juvenile idiopathic arthritis (JIA). Our aim was to investigate the impact of BMI on health-related quality of life (HRQoL) measured with a 36-Item Short Form Survey (SF-36), disease activity, and disability in young adults with JIA. METHODS: This study is a part of the population-based Nordic JIA cohort study. All newly diagnosed patients with JIA were recruited consecutively between 1997-2000 in specific regions in the Nordic countries. Patients in this sub-study were enrolled from 434 patients who attended their 18-year follow-up visit. Patients were classified according to the World Health Organization (WHO) into four groups based on their BMI. HRQoL, disease characteristics, disability, fatigue, sleep quality, physical activity, pain, comorbidities, and social status were assessed. RESULTS: Three hundred fifty-five patients from the original study cohort were enrolled in this study and 72% of them were female. Mean age was 23.9 (± SD 4.4) years. A significant relationship was found between the JIA categories and BMI groups (p = 0.014). A significant relationship was also found between BMI and disease activity scores (DAS28) (p = 0.028), disability (p < 0.001), pain (p = 0.013), fatigue (p = 0.035), and sleep quality (p = 0.044). Moreover, a significant relationship between BMI and HRQoL regarding bodily pain (p = 0.010) and general health (p = 0.048) was revealed when adjusted for sex, age, and JIA subtype. CONCLUSION: We discovered that BMI was significantly related to HRQoL, disease activity, and disability. BMI deserves more attention considering the treatment options and outcome of JIA in young adults.

Serum and salivary inflammatory biomarkers in juvenile idiopathic arthritis-an explorative cross-sectional study.

BACKGROUND: Biomarkers may be useful in monitoring disease activity in juvenile idiopathic arthritis (JIA). With new treatment options and treatment goals in JIA, there is an urgent need for more sensitive and responsive biomarkers. OBJECTIVE: We aimed to investigate the patterns of 92 inflammation-related biomarkers in serum and saliva in a group of Norwegian children and adolescents with JIA and controls and in active and inactive JIA. In addition, we explored whether treatment with tumor necrosis factor inhibitors (TNFi) affected the biomarker levels. METHODS: This explorative, cross-sectional study comprised a subset of children and adolescents with non-systemic JIA and matched controls from the Norwegian juvenile idiopathic arthritis study (NorJIA Study). The JIA group included individuals with clinically active or inactive JIA. Serum and unstimulated saliva were analyzed using a multiplex assay of 92 inflammation-related biomarkers. Welch's t-test and Mann-Whitney U-test were used to analyze the differences in biomarker levels between JIA and controls and between active and inactive disease. RESULTS: We included 42 participants with JIA and 30 controls, predominantly females, with a median age of 14 years. Of the 92 biomarkers, 87 were detected in serum, 73 in saliva, and 71 in both biofluids. A pronounced difference between serum and salivary biomarker patterns was found. Most biomarkers had higher levels in serum and lower levels in saliva in JIA versus controls, and in active versus inactive disease. In serum, TNF and S100A12 levels were notably higher in JIA and active disease. The TNF increase was less pronounced when excluding TNFi-treated individuals. In saliva, several biomarkers from the chemokine family were distinctly lower in the JIA group, and levels were even lower in active disease. CONCLUSION: In this explorative study, the serum and salivary biomarker patterns differed markedly, suggesting that saliva may not be a suitable substitute for serum when assessing systemic inflammation in JIA. Increased TNF levels in serum may not be a reliable biomarker for inflammatory activity in TNFi-treated children and adolescents with JIA. The lower levels of chemokines in saliva in JIA compared to controls and in active compared to inactive disease, warrant further investigation.

A practical approach to uveitis screening in children with juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA)-associated uveitis typically presents as a silent chronic anterior uveitis and can lead to blindness. Adherence to current screening guidelines is hampered by complex protocols which rely on the knowledge of specific JIA characteristics. The Multinational Interdisciplinary Working Group for Uveitis in Childhood identified the need to simplify screening to enable local eye care professionals (ECPs), who carry the main burden, to screen children with JIA appropriately and with confidence. METHODS: A consensus meeting took place in January 2023 in Barcelona, Spain, with an expert panel of 10 paediatric rheumatologists and 5 ophthalmologists with expertise in paediatric uveitis. A summary of the current evidence for JIA screening was presented. A nominal group technique was used to reach consensus. RESULTS: The need for a practical but safe approach that allows early uveitis detection was identified by the panel. Three screening recommendations were proposed and approved by the voting members. They represent a standardised approach to JIA screening taking into account the patient's age at the onset of JIA to determine the screening interval until adulthood. CONCLUSION: By removing the need for the knowledge of JIA categories, antinuclear antibody positivity or treatment status, the recommendations can be more easily implemented by local ECP, where limited information is available. It would improve the standard of care on the local level significantly. The proposed protocol is less tailored to the individual than the 'gold standard' ones it references and does not aim to substitute those where they are being used with confidence.

A novel serum calprotectin (MRP8/14) particle-enhanced immuno-turbidimetric assay (sCAL turbo) helps to differentiate systemic juvenile idiopathic arthritis from other diseases in routine clinical laboratory settings.

BACKGROUND: Differential diagnosis in children with signs of unprovoked inflammation can be challenging. In particular, differentiating systemic juvenile idiopathic arthritis (SJIA) from other diagnoses is difficult. We have recently validated the complex of myeloid-related proteins 8/14 (MRP8/14, also known as S100A8/A9 complex or serum calprotectin) as a helpful biomarker supporting the diagnosis of SJIA. The results were subsequently confirmed with a commercial ELISA. However, further optimization of the analytical technology is important to ensure its feasibility for large-scale use in routine laboratory settings. METHODS: To evaluate the accuracy in identifying children with SJIA, the performance of a particle-enhanced immuno-turbidimetric assay for serum calprotectin (sCAL turbo) on an automated laboratory instrument was analyzed. Samples from 615 children were available with the diagnoses SJIA (n = 99), non-systemic JIA (n = 169), infections (n = 51), other inflammatory diseases (n = 126), and acute lymphoblastic leukemia (ALL, n = 147). In addition, samples from 23 healthy controls were included. RESULTS: The sCAL turbo assay correlated well with the MRP8/14 ELISA used in previous validation studies (r = 0.99, p < 0.001). It could reliably differentiate SJIA from all other diagnoses with significant accuracy (cutoff at 10,500 ng/ml, sensitivity 84%, specificity 94%, ROC area under curve 0.960, p < 0.001). CONCLUSIONS: Serum calprotectin analyses are a helpful tool supporting the diagnosis of SJIA in children with prolonged fever or inflammatory disease. Here, we show that an immuno-turbidimetric assay for detection of serum calprotectin on an automated laboratory instrument can be implemented in clinical laboratory settings to facilitate its use as a diagnostic routine test in clinical practice.

Identification of a regulatory pathway governing TRAF1 via an arthritis-associated non-coding variant.

TRAF1/C5 was among the first loci shown to confer risk for inflammatory arthritis in the absence of an associated coding variant, but its genetic mechanism remains undefined. Using Immunochip data from 3,939 patients with juvenile idiopathic arthritis (JIA) and 14,412 control individuals, we identified 132 plausible common non-coding variants, reduced serially by single-nucleotide polymorphism sequencing (SNP-seq), electrophoretic mobility shift, and luciferase studies to the single variant rs7034653 in the third intron of TRAF1. Genetically manipulated experimental cells and primary monocytes from genotyped donors establish that the risk G allele reduces binding of Fos-related antigen 2 (FRA2), encoded by FOSL2, resulting in reduced TRAF1 expression and enhanced tumor necrosis factor (TNF) production. Conditioning on this JIA variant eliminated attributable risk for rheumatoid arthritis, implicating a mechanism shared across the arthritis spectrum. These findings reveal that rs7034653, FRA2, and TRAF1 mediate a pathway through which a non-coding functional variant drives risk of inflammatory arthritis in children and adults.

Management of Orofacial Manifestations of Juvenile Idiopathic Arthritis: Interdisciplinary Consensus-Based Recommendations.

Involvement of the temporomandibular joint (TMJ) is common in juvenile idiopathic arthritis (JIA). TMJ arthritis can lead to orofacial symptoms, orofacial dysfunction, and dentofacial deformity with negative impact on quality of life. Management involves interdisciplinary collaboration. No current recommendations exist to guide clinical management. We undertook this study to develop consensus-based interdisciplinary recommendations for management of orofacial manifestations of JIA, and to create a future research agenda related to management of TMJ arthritis in children with JIA. Recommendations were developed using online surveying of relevant stakeholders, systematic literature review, evidence-informed generation of recommendations during 2 consensus meetings, and Delphi study iterations involving external experts. The process included disciplines involved in the care of orofacial manifestations of JIA: pediatric rheumatology, radiology, orthodontics, oral and maxillofacial surgery, orofacial pain specialists, and pediatric dentistry. Recommendations were accepted if agreement was >80% during a final Delphi study. Three overarching management principles and 12 recommendations for interdisciplinary management of orofacial manifestations of JIA were outlined. The 12 recommendations pertained to diagnosis (n = 4), treatment of TMJ arthritis (active TMJ inflammation) (n = 2), treatment of TMJ dysfunction and symptoms (n = 3), treatment of arthritis-related dentofacial deformity (n = 2), and other aspects related to JIA (n = 1). Additionally, a future interdisciplinary research agenda was developed. These are the first interdisciplinary recommendations to guide clinical management of TMJ JIA. The 3 overarching principles and 12 recommendations fill an important gap in current clinical practice. They emphasize the importance of an interdisciplinary approach to diagnosis and management of orofacial manifestations of JIA.

Ongoing disease activity and changing categories in a long-term nordic cohort study of juvenile idiopathic arthritis.

OBJECTIVE: To describe the disease characteristics, long-term course, and outcome of patients with juvenile idiopathic arthritis (JIA) in a population-based setting. METHODS: Consecutive cases of JIA from defined geographic areas of Denmark, Finland, Sweden, and Norway in whom disease onset occurred in 1997-2000 were included in a prospective, multicenter cohort study. The study was designed to be as close to a population-based study as possible, with centers participating only if they were able to include in their catchment area all children in whom JIA was diagnosed. RESULTS: Of 500 children included, 440 (88.0%) had repeated visits, with the last visit occurring at least 7 years after disease onset (median 98 months, range 84-147 months). Changes in the International League of Associations for Rheumatology category were observed in 10.8% of the children, and, in addition, extended oligoarthritis developed in 34.7% of the group with oligoarticular JIA. During the observation period, 58.0% of the children were treated with disease-modifying antirheumatic drugs, including biologic medications. Ongoing disease activity was mostly mild, but some JIA-related damage developed in 22.9% of the children. At the last followup visit, remission off medication was observed in 42.4% of the children, 8.9% were in remission on medication, and 48.7% were not in remission. The highest rates of remission were observed in patients with persistent oligoarticular JIA and in those with systemic JIA. CONCLUSION: In this long-term prospective study of JIA in a population-based Nordic setting, ongoing disease was evident in a majority of the children. The present results underline the need to identify early predictors of outcome, to further improve therapy, and to continue long-term followup of patients with JIA.

Therapeutic approaches in the treatment of juvenile dermatomyositis in patients with recent-onset disease and in those experiencing disease flare: an international multicenter PRINTO study.

OBJECTIVE: To evaluate response to therapy over a 24-month period in a large prospective international cohort of patients with juvenile dermatomyositis (DM). METHODS: The study included 145 patients with recent-onset juvenile DM and 130 juvenile DM patients experiencing disease flare, all of whom were <18 years old. Disease activity parameters and therapeutic approaches in 4 geographic areas were analyzed at baseline and at 6, 12, and 24 months. Response was assessed according to the Pediatric Rheumatology International Trials Organization (PRINTO) juvenile DM response criteria, and data were reported "as observed" and in the intent-to-treat (ITT) population. RESULTS: Patients with recent-onset juvenile DM at baseline had higher baseline disease activity and greater improvement over 24 months when compared to juvenile DM patients experiencing disease flare at baseline. Methotrexate (MTX) or high-dose corticosteroids were administered more frequently to patients with recent-onset juvenile DM, compared to juvenile DM patients experiencing disease flare, who were more likely to receive cyclosporine. Compared to patients from Western and Eastern Europe, a higher proportion of patients from South and Central America and North America received pulse steroids, and the average steroid dosage was higher in the North American and South and Central American patients. The use of MTX was similar in all 4 regions, while cyclosporin A was more frequently used in Western Europe. In the "as observed" analysis, 57.9% of the patients with recent-onset juvenile DM and 36.4% of the patients experiencing disease flare (P<0.001) reached at least a 70% response by PRINTO criteria at 6 months; these proportions had increased at month 24 to 78.4% and 51.2%, respectively (P<0.001). Corresponding results of the ITT analysis were much lower, with only one-third of the patients able to maintain the initial assigned therapy over 24 months. CONCLUSION: Patients with recent-onset juvenile DM are more likely to achieve significant clinical improvement over 24 months, when compared to patients experiencing flares of juvenile DM. Internationally, various therapeutic approaches are used to treat this disease.