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.

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.

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.

Children treated for developmental dysplasia of the hip at birth and with normal acetabular index at 1 year: How many had residual dysplasia at 5 years?

Purpose: The purpose of the study was to assess the effect of further follow-up for children treated for developmental dysplasia of the hip, with normal clinical and radiological findings at 1-year time point. The effect was quantified by the number of hips with a pathologic deterioration up to 5 years. Methods: Among 47,289 children born in Sør-Trøndelag county in Norway between 2003 and 2015, 265 children had developmental dysplasia of the hip. Of these, 164 children (239 hips) treated for developmental dysplasia of the hip with normal clinical findings and normal acetabular index at the 1-year time point were included in the study. The number of hips with pathologic acetabular index at the 5-year time point were reported. The diagnostic uncertainty related to radiological measurements was quantified together with the effect of introducing a second radiographic measurement, the center edge angle. Results: A total of 239 treated hips were normal at the 1-year time point. At 5-year time point, 10 (4.2%) hips had a pathologic acetabular index measurement and none classified to have developmental dysplasia of the hip caused by measurement inaccuracy. Eight (3.3%) hips had pathologic center edge angle measurement. Four hips had both pathologic acetabular index and center edge angle measurements, with three later treated with surgery. The intra- and interobserver repeatability coefficients were within 3.1°-6.6°. Conclusion: The repeatability coefficient of the acetabular index measurements was high and no hips could be classified to have developmental dysplasia of the hip at the 5-year time point when taking this repeatability into account. Hips classified as pathologic combining acetabular index and center edge angle measurements were likely to be treated with surgery for residual dysplasia. We recommend further follow-up for these children. Level of evidence: level II.

Observer agreement of imaging measurements used for evaluation of dentofacial deformity in juvenile idiopathic arthritis.

OBJECTIVES: To examine the precision of imaging measures commonly used to assess mandibular morphology in children and adolescents with juvenile idiopathic arthritis (JIA). Secondly, to compare cone-beam computed tomography (CBCT) and magnetic resonance imaging (MRI) in the measurement of condylar height. METHODS: Those included were children diagnosed with JIA during 2015-18 who had had an MRI, a CBCT of the temporomandibular joints (TMJs) and a lateral cephalogram (ceph) of the head within one month of each other. Agreement within and between observers and methods was examined using Bland-Altman mean-difference plots and 95% limits of agreement (LOA). A 95% LOA within 15% of the sample mean was considered acceptable. Minimal detectable change (MDC) within and between observers was estimated. RESULTS: 90 patients (33 males) were included, with a mean age of 12.8 years. For MRI, intra- and interobserver 95% LOA were relatively narrow for total mandibular length: 9.6% of the sample mean. For CBCT, condylar height, both intra- and interobserver 95% LOA were wide: 16.0 and 28.4% of the sample mean, respectively. For ceph, both intra- and interobserver 95% LOA were narrow for the SNA-angle and gonion angle: 5.9 and 8% of the sample mean, and 6.2 and 6.8%, respectively. CONCLUSIONS: We have identified a set of precise measurements for facial morphology assessments in JIA, including one MRI-based (total mandibular length), one CBCT-based (condylar height), and three ceph-based. Condylar height was higher for MRI than for CBCT; however, the measurement was too imprecise for clinical use. MDC was also determined for a series of measurements.

MRI in the Assessment of TMJ-Arthritis in Children with JIA; Repeatability of a Newly Devised Scoring System.

RATIONALE AND OBJECTIVES: The temporomandibular joint (TMJ) is commonly involved in children with juvenile idiopathic arthritis. The diagnosis and evaluation of the disease progression is dependent on medical imaging. The precision of this imaging is under debate. Several scoring systems have been proposed but transparent testing of the precision of the constituents of the scoring systems is lacking. The present study aims to test the precision of 25 imaging features based on magnetic resonance imaging (MRI). MATERIALS AND METHODS: Clinical data and imaging were obtained from the Norwegian juvenile idiopathic arthritis study, The NorJIA study. Twenty-five imaging features of the TMJ in MRI datasets from 86 study participants were evaluated by two experienced radiologists for inter- and intraobserver agreement. Agreement of ordinal variables was measured with Cohen´s linear or weighted Kappa as appropriate. Agreement of continuous measurements was assessed with 95% limit of agreement according to Bland-Altman. RESULTS: In the osteochondral domain, the ordinal imaging variables "loss of condylar volume," "condylar shape," "condylar irregularities," "shape of the eminence/fossa," "disk abnormalities," and "condylar inclination" showed inter- and intraobserver agreement above Kappa 0.5. In the inflammatory domain, the ordinal imaging variables "joint fluid," "overall impression of inflammation," "synovial enhancement" and "bone marrow oedema" showed inter- and intraobserver agreement above Kappa 0.5. Continuous measurements performed poorly with wide limits of agreement. CONCLUSION: A precise MRI-based scoring system for assessment of TMJ in JIA is proposed consisting of seven variables in the osteochondral domain and four variables in the inflammatory domain. Further testing of the clinical validity of the variables is needed.

Effects of motion correction, sampling rate and parametric modelling in dynamic contrast enhanced MRI of the temporomandibular joint in children affected with juvenile idiopathic arthritis.

The temporomandibular joint (TMJ) is typically involved in 45-87% of children with Juvenile Idiopathic Arthritis (JIA). Accurate diagnosis of JIA is difficult as various clinical tests, including MRI, disagree. The purpose of this study is to optimize the methodological aspects of Dynamic Contrast Enhanced (DCE) MRI of the TMJ in children. In this cross-sectional study, including data from 73 JIA affected children, aged 6-15 years, effects of motion correction, sampling rate and parametric modelling on DCE-MRI data is investigated. Consensus among three radiologists determined the regions of interest. Quantitative perfusion parameters were estimated using four perfusion models; the Adiabatic Approximation to Tissue Homogeneity (AATH), Distributed Capillary Adiabatic Tissue Homogeneity (DCATH), Gamma Capillary Transit Time (GCTT) and Two Compartment Exchange (2CXM) models. Effects of motion correction were evaluated by a sum of least squares between corrected raw data and the GCTT model. The effect of systematically down sampling the raw data was tested. The sum of least squares was computed across all pharmacokinetic models. Relative difference perfusion parameters between the left and right TMJ were used for an unsupervised k-means based stratification of the data based on a principal component analysis, as well as for a supervised random forest classification. Diagnostic sensitivity and specificity were computed relative to structural image scorings. Paired sample t-tests, as well as ANOVA tests, were used (significant threshold: p < 0.05) with Tukeys post hoc test. High-level elastic motion correction provides the best least square fit to the GCTT model (percental improvement: 72-84%). A 4 s sampling rate captures more of the potentially disease relevant signal variations. The various parametric models all leave comparable residues (relative standard deviation: 3.4%). In further evaluation of DCE-MRI as a potential diagnostic tool for JIA a high-level elastic motion correction scheme should be adopted, with a sampling rate of at least 4 s. Results suggest that DCE-MRI data can be a valuable part in JIA diagnostics in the TMJ.

Revisiting the radiographic assessment of osteoporosis-Osteopenia in children 0-2 years of age. A systematic review.

BACKGROUND: Imaging for osteoporosis has two major aims, first, to identify the presence of low bone mass (osteopenia), and second, to quantify bone mass using semiquantitative (conventional radiography) or quantitative (densitometry) methods. In young children, densitometry is hampered by the lack of reference values, and high-quality radiographs still play a role although the evaluation of osteopenia as a marker for osteoporosis is subjective and based on personal experience. Medical experts questioned in court over child abuse, often refer to the literature and state that 20-40% loss of bone mass is warranted before osteopenia becomes evident on radiographs. In our systematic review, we aimed at identifying evidence underpinning this statement. A secondary outcome was identifying normal references for cortical thickness of the skeleton in infants born term, < 2 years of age. METHODS: We undertook systematic searches in Medline, Embase and Svemed+, covering 1946-2020. Unpublished material was searched in Clinical trials and International Clinical Trials Registry Platform (ICTRP). Both relevant subject headings and free text words were used for the following concepts: osteoporosis or osteopenia, radiography, children up to 6 years. RESULTS: A total 5592 publications were identified, of which none met the inclusion criteria for the primary outcome; the degree of bone loss warranted before osteopenia becomes visible radiographically. As for the secondary outcome, 21 studies were identified. None of the studies was true population based and none covered the pre-defined age range from 0-2 years. However, four studies of which three having a crossectional and one a longitudinal design, included newborns while one study included children 0-2 years. CONCLUSIONS: Despite an extensive literature search, we did not find any studies supporting the assumption that a 20-40% bone loss is required before osteopenia becomes visible on radiographs. Reference values for cortical thickness were sparse. Further studies addressing this important topic are warranted.

Normal magnetic resonance appearances of the temporomandibular joints in children and young adults aged 2-18 years.

BACKGROUND: Knowledge of normal appearances of the temporomandibular joint (TMJ) is paramount when assessing the joint for disease in juvenile idiopathic arthritis. Reliable features defining normal TMJs in children are limited. OBJECTIVE: To establish reliable normal standards for the TMJ at magnetic resonance imaging (MRI). MATERIALS AND METHODS: We included children and young adults aged 2-18 years undergoing a head MRI for reasons not believed to affect the TMJs. We assessed TMJ anatomy and contrast enhancement using a high-resolution 3-D T1-weighted sequence. We noted joint fluid and bone marrow oedema based on a T2-weighted sequence. Three experienced radiologists read all examinations twice in consensus and defined intraobserver consensus agreement. RESULTS: We evaluated the TMJs in 101 children and young adults (45 female), mean age 10.7 years (range 2-18 years). The intraobserver consensus agreement for the assessment of anterior condylar inclination in the sagittal/oblique plane was moderate to good (Cohen κ=0.7 for the right side). Cohen κ for intraobserver consensus agreement for condylar shape in the coronal plane on a 0-2 scale was 0.4 for the right and 0.6 for the left. Intraobserver agreement for measurement of joint space height and assessment of bone marrow oedema was poor. There was a statistically significant increase in anterior inclination by age in the sagittal plane on a 0-2 scale (P<0.0001). Eighty percent of the condyles showed a rounded shape in the coronal plane while 20% showed mild flattening. Thirty-five of 36 right TMJs showed contrast enhancement (mild enhancement in 32 joints, moderate in 3 joints). CONCLUSION: Subjective assessment of the anterior condylar inclination in the sagittal/oblique plane and condylar flattening in the coronal plane can be considered precise features for describing TMJ anatomy in healthy children. There is an increasing anterior inclination by age. Mild contrast enhancement of the TMJs should be considered a normal finding.