Prediction of unfavorable outcome in Juvenile Idiopathic Arthritis (JIA) and assessment of the long-term outcomes in JIA-associated uveitis – A prospective Nordic multicenter study of JIA from childhood to adulthood

Juvenile idiopathic arthritis (JIA) is a chronic childhood disease with joint inflammation as the main feature. The course and outcomes are heterogeneous with a large span in disease severity. There is increasing evidence that early aggressive treatment may modify the disease course in JIA. Precise determination of disease prognosis is therefore sought to guide early decisions on which children need disease modifying anti-rheumatic drugs (DMARDs) and biologics. We aimed to develop and validate clinically applicable models for the prediction of unfavorable outcomes in JIA. The goal was to improve JIA outcomes by providing a practical application to support clinicians in treatment decisions. We collaborated with Canadian researchers who separately had developed a model for predicting severe disease course. We developed a multivariable logistic regression model with eight clinical variables in the Nordic JIA cohort. The model performed well in predicting non-achievement of remission (the Nordic outcome), both in internal validation and in external validation in the Canadian cohort. We externally validated the Canadian model in the Nordic cohort yielding an excellent predictive ability. The Nordic model performed almost equally as well without blood tests and also performed well in predicting severe disease course (the Canadian outcome). The Canadian model did not attain an acceptable prediction of the Nordic outcome. Uveitis is the most common extraarticular manifestation of JIA and may lead to severe sight-threatening complications. We found a high cumulative incidence of uveitis in 96 of 434 children (22%) in the Nordic cohort. Ocular complications, mainly cataract and glaucoma, were present in 39% of the young adults with uveitis at follow-up 18 years after onset of JIA. Predictors associated with development of ocular complications were uveitis before JIA, short interval between JIA and uveitis, and ANA positivity. Our results strongly suggest early and tight eye screening programs and close collaboration between ophthalmologists and pediatric rheumatologists for optimal treatment to minimize long-term complications

Efficacy and safety of intraarticular corticosteroid injections in adolescents with juvenile idiopathic arthritis in the temporomandibular joint: a Norwegian 2-year prospective multicenter pilot study

Background Intraarticular corticosteroids (IACs) have been used to treat temporomandibular joint (TMJ) arthritis. However, prospective clinical studies with magnetic resonance imaging (MRI) scoring are lacking. The aim of this study was to examine efficacy and safety of a single IAC in the TMJ in adolescents with juvenile idiopathic arthritis (JIA) in a clinical setting. Methods In this Norwegian prospective multicenter pilot study 15 patients with JIA (mostly persistent oligoarthritis or RF negative polyarthritis categories) and a clinically and MRI-verified diagnosis of TMJ arthritis were treated with IACs and followed for 2 years. Demographics, systemic medication, general disease activity and outcome measures were recorded including a pain-index score and maximal incisal opening (MIO). Inflammation and bone damage scores were assessed, using two recently published MRI scoring systems with masked radiological evaluation. Results Among the 15 patients, 13 received a single IAC (5 bilateral), and 2 repeated IACs once unilaterally. Thus, the total number of IACs was 22. Median age was 15 years and the majority had an age not thought of as critical regarding mandibular growth retardation due to steroid injection. During the 2-year observation period systemic medication with disease modifying antirheumatic drugs (DMARDs) including biologics was initiated or adjusted in 10/15 (67%) patients. At the 2-months study visit after injection we observed a minimal improvement in MIO from median 44 (1st, 3rd quartiles; 36, 48) mm to 45 (43, 47) mm, p = 0.045 and decreased MRI mean additive inflammatory score from 4.4 ± 1.8 standard deviations (SD) to 3.4 ± 2.0, p = 0.040. From baseline to the 2-months follow-up pain improved in 6/11 patients but pain scores were not significantly improved. MRI-assessed damage increased in two patients with repeated IACs, and decreased in 3 patients but most of the patients were stable over the 2-year follow-up. Intra-rater repeatability of the MRI scoring system domains varied from poor to excellent. Conclusions In this pilot study of predominately single IACs to the TMJ in combination with systemic treatment we observed improvement in MRI-assessed inflammation, mostly stable condylar bone conditions and minimal clinical improvement in adolescents with JIA and TMJ arthritis. No severe side effects were seen.publishedVersio

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  Results - The same OHRQoL questionnaire was completed both at first visit and two-year follow-up in 101 children  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

Salivary Oral Microbiome of Children With Juvenile Idiopathic Arthritis: A Norwegian Cross-Sectional Study

Background: The oral microbiota has been connected to the pathogenesis of rheumatoid arthritis through activation of mucosal immunity. The objective of this study was to characterize the salivary oral microbiome associated with juvenile idiopathic arthritis (JIA), and correlate it with the disease activity including gingival inflammation. Methods: Fifty-nine patients with JIA (mean age, 12.6 ± 2.7 years) and 34 healthy controls (HC; mean age 12.3 ± 3.0 years) were consecutively recruited in this Norwegian cross-sectional study. Information about demographics, disease activity, medication history, frequency of tooth brushing and a modified version of the gingival bleeding index (GBI) and the simplified oral hygiene index (OHI-S) was obtained. Microbiome profiling of saliva samples was performed by sequencing of the V1-V3 region of the 16S rRNA gene, coupled with a species-level taxonomy assignment algorithm; QIIME, LEfSe and R-package for Spearman correlation matrix were used for downstream analysis. Results: There were no significant differences between JIA and HC in alpha- and beta-diversity. However, differential abundance analysis revealed several taxa to be associated with JIA: TM7-G1, Solobacterium and Mogibacterium at the genus level; and Leptotrichia oral taxon 417, TM7-G1 oral taxon 352 and Capnocytophaga oral taxon 864 among others, at the species level. Haemophilus species, Leptotrichia oral taxon 223, and Bacillus subtilis, were associated with healthy controls. Gemella morbillorum, Leptotrichia sp. oral taxon 498 and Alloprevotella oral taxon 914 correlated positively with the composite juvenile arthritis 10-joint disease activity score (JADAS10), while Campylobacter oral taxon 44 among others, correlated with the number of active joints. Of all microbial markers identified, only Bacillus subtilis and Campylobacter oral taxon 44 maintained false discovery rate (FDR) Conclusions: In this exploratory study of salivary oral microbiome we found similar alpha- and beta-diversity among children with JIA and healthy. Several taxa associated with chronic inflammation were found to be associated with JIA and disease activity, which warrants further investigation

Prediction of unfavorable outcome in Juvenile Idiopathic Arthritis (JIA) and assessment of the long-term outcomes in JIA-associated uveitis – A prospective Nordic multicenter study of JIA from childhood to adulthood

Juvenile idiopathic arthritis (JIA) is a chronic childhood disease with joint inflammation as the main feature. The course and outcomes are heterogeneous with a large span in disease severity. There is increasing evidence that early aggressive treatment may modify the disease course in JIA. Precise determination of disease prognosis is therefore sought to guide early decisions on which children need disease modifying anti-rheumatic drugs (DMARDs) and biologics. We aimed to develop and validate clinically applicable models for the prediction of unfavorable outcomes in JIA. The goal was to improve JIA outcomes by providing a practical application to support clinicians in treatment decisions. We collaborated with Canadian researchers who separately had developed a model for predicting severe disease course. We developed a multivariable logistic regression model with eight clinical variables in the Nordic JIA cohort. The model performed well in predicting non-achievement of remission (the Nordic outcome), both in internal validation and in external validation in the Canadian cohort. We externally validated the Canadian model in the Nordic cohort yielding an excellent predictive ability. The Nordic model performed almost equally as well without blood tests and also performed well in predicting severe disease course (the Canadian outcome). The Canadian model did not attain an acceptable prediction of the Nordic outcome. Uveitis is the most common extraarticular manifestation of JIA and may lead to severe sight-threatening complications. We found a high cumulative incidence of uveitis in 96 of 434 children (22%) in the Nordic cohort. Ocular complications, mainly cataract and glaucoma, were present in 39% of the young adults with uveitis at follow-up 18 years after onset of JIA. Predictors associated with development of ocular complications were uveitis before JIA, short interval between JIA and uveitis, and ANA positivity. Our results strongly suggest early and tight eye screening programs and close collaboration between ophthalmologists and pediatric rheumatologists for optimal treatment to minimize long-term complications

Kardioproteksjon: Er proteksjon med adenosin, nicorandil og isofluran additiv? :en studie av isolerte perfunderte rottehjerter

Adenosin, nicorandil og isofluran har hver for seg vist å ha kardioprotektive egenskaper. I denne studien ønsker vi å finne ut om adenosin, nicorandil og isofluran gitt sammen gir en additiv effekt. Vi skal på bakgrunn av dette kombinere de ulike medikamentene for å finne ut om de potenserer hverandre og sammen gir en større beskyttelse av rottehjertet enn hva de ville gjort hver for seg. Metode: Eksperimentene ble gjennomført etter Langendorff-metoden og var i regi av avdeling for medisinsk fysiologi og kirurgisk avdeling på UiT. Forsøkene fordelte seg over en periode på ett år; sommer 2007, høst 2007 og sommer 2008. Det ble brukt totalt 94 rotter. Hoveddelen av forsøkene ble utført på Wistar-rotter med gjennomsnittlig vekt på 279 gram (SD ± 31,5g). Anestesi ble administrert intraperitonealt i form av pentobarbital 50mg/kg og tromboseprofylakse med heparin 1000 IE/kg. Rottene ble randomisert til tre ulike protokoller. Hver protokoll bestod av en stabiliseringsfase etterfulgt av global ischemi og reperfusjon. Varigheten av periodene var avhengig av protokoll. Farmakologisk postkondisjonering med nicorandil og adenosin (pilotstudie): Kontroller (n=8 hannrotter, n=6 hunnrotter), adenosin og nicorandil (n=7 hannrotter, n=7 hunnrotter). Farmakologisk prekondisjonering med nicorandil og adenosin: Kontroller (n=12), nicorandil og adenosin (n=9), nicorandil (n=8), adenosin (n=8), og en gruppe postkondisjonering nicorandil og adenosin (n=4). Farmakologisk prekondisjonering med isofluran, nicorandil og adenosin: Kontroller (n=6), nicorandil, isofluran og adenosin (n=6), nicorandil (n=6) og isofluran (n=7). Nicorandil og adenosin ble administrert i Krebs og Henseleit- buffer i konsentrasjoner på henholdsvis 0,1mmol/l og 1,2 mmol/l . Isoflurandosering: 4% med en air-flow på 700ml/min som innledningsdose. Vedlikeholdsdosen var på 2,5% med en air-flow på rundt 450ml/min og ble tilført i 30 minutter. Konklusjon: Infarktstørrelse: Studien farmakologisk prekondisjonering med nicorandil og adenosin: Nicorandil og adenosin 7,4% infarkt mot kontroller 24,1% ( p-verdi= 1,0*10-5, korrigert= 4,0*10-5). Adenosin 10,5% infarkt (p-verdi= 0,001, korrigert= 0,004) og nicorandil 14,3% ( p-verdi= 0,002, korrigert= 0,008). Studien farmakologisk prekondisjonering med isofluran, nicorandil og adenosin: Isofluran, nicorandil og adenosin hadde 8,8% infarkt (p-verdi 0,005) mot kontroller 31,2%. Nicorandil 19,2% infarkt (p-verdi= 0,06). Isofluran 21,2% infarkt (p-verdi=0,10). Vi har vist at det i rottehjerter er en additiv effekt av å tilsette nicorandil og adenosin til isofluran ved bruk av infarktstørrelse som endepunkt

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

Clustering and climate associations of Kawasaki Disease in San Diego County suggest environmental triggers

Kawasaki Disease (KD) is the most common cause of pediatric acquired heart disease, but its etiology remains unknown. We examined 1164 cases of KD treated at a regional children’s hospital in San Diego over a period of 15 years and uncovered novel structure to disease incidence. KD cases showed a well-defined seasonal variability, but also clustered temporally at much shorter time scales (days to weeks), and spatiotemporally on time scales of up to 10 days and spatial scales of 10–100 km. Temporal clusters of KD cases were associated with strongly significant regional-scale air temperature anomalies and consistent larger-scale atmospheric circulation patterns. Gene expression analysis further revealed a natural partitioning of KD patients into distinct groups based on their gene expression pattern, and that the different groups were associated with certain clinical characteristics that also exhibit temporal autocorrelation. Our data suggest that one or more environmental triggers exist, and that episodic exposures are modulated at least in part by regional weather conditions. We propose that characterization of the environmental factors that trigger KD in genetically susceptible children should focus on aerosols inhaled by patients who share common disease characteristics

Predicting unfavorable long-term outcome in juvenile idiopathic arthritis: Results from the Nordic cohort study

Background The aim was to develop prediction rules that may guide early treatment decisions based on baseline clinical predictors of long-term unfavorable outcome in juvenile idiopathic arthritis (JIA). Methods In the Nordic JIA cohort, we assessed baseline disease characteristics as predictors of the following outcomes 8 years after disease onset. Non-achievement of remission off medication according to the preliminary Wallace criteria, functional disability assessed by Childhood Health Assessment Questionnaire (CHAQ) and Physical Summary Score (PhS) of the Child Health Questionnaire, and articular damage assessed by the Juvenile Arthritis Damage Index-Articular (JADI-A). Multivariable models were constructed, and cross-validations were performed by repeated partitioning of the cohort into training sets for developing prediction models and validation sets to test predictive ability. Results The total cohort constituted 423 children. Remission status was available in 410 children: 244 (59.5%) of these did not achieve remission off medication at the final study visit. Functional disability was present in 111/340 (32.7%) children assessed by CHAQ and 40/199 (20.1%) by PhS, and joint damage was found in 29/216 (13.4%). Model performance was acceptable for making predictions of long-term outcome. In validation sets, the area under the curves (AUCs) in the receiver operating characteristic (ROC) curves were 0.78 (IQR 0.72–0.82) for non-achievement of remission off medication, 0.73 (IQR 0.67–0.76) for functional disability assessed by CHAQ, 0.74 (IQR 0.65–0.80) for functional disability assessed by PhS, and 0.73 (IQR 0.63–0.76) for joint damage using JADI-A. Conclusion The feasibility of making long-term predictions of JIA outcome based on early clinical assessment is demonstrated. The prediction models have acceptable precision and require only readily available baseline variables. Further testing in other cohorts is warranted

Validation of prediction models of severe disease course and non-achievement of remission in juvenile idiopathic arthritis: part 1-results of the Canadian model in the Nordic cohort.

Background Models to predict disease course and long-term outcome based on clinical characteristics at disease onset may guide early treatment strategies in juvenile idiopathic arthritis (JIA). Before a prediction model can be recommended for use in clinical practice, it needs to be validated in a different cohort than the one used for building the model. The aim of the current study was to validate the predictive performance of the Canadian prediction model developed by Guzman et al. and the Nordic model derived from Rypdal et al. to predict severe disease course and non-achievement of remission in Nordic patients with JIA. Methods The Canadian and Nordic multivariable logistic regression models were evaluated in the Nordic JIA cohort for prediction of non-achievement of remission, and the data-driven outcome denoted severe disease course. A total of 440 patients in the Nordic cohort with a baseline visit and an 8-year visit were included. The Canadian prediction model was first externally validated exactly as published. Both the Nordic and Canadian models were subsequently evaluated with repeated fine-tuning of model coefficients in training sets and testing in disjoint validation sets. The predictive performances of the models were assessed with receiver operating characteristic curves and C-indices. A model with a C-index above 0.7 was considered useful for clinical prediction. Results The Canadian prediction model had excellent predictive ability and was comparable in performance to the Nordic model in predicting severe disease course in the Nordic JIA cohort. The Canadian model yielded a C-index of 0.85 (IQR 0.83–0.87) for prediction of severe disease course and a C-index of 0.66 (0.63–0.68) for prediction of non-achievement of remission when applied directly. The median C-indices after fine-tuning were 0.85 (0.80–0.89) and 0.69 (0.65–0.73), respectively. Internal validation of the Nordic model for prediction of severe disease course resulted in a median C-index of 0.90 (0.86–0.92). Conclusions External validation of the Canadian model and internal validation of the Nordic model with severe disease course as outcome confirm their predictive abilities. Our findings suggest that predicting long-term remission is more challenging than predicting severe disease course