Kawasaki Disease and Systemic Juvenile Idiopathic Arthritis - Two Ends of the Same Spectrum.

Kawasaki disease (KD) and systemic juvenile idiopathic arthritis (sJIA) are two distinct systemic inflammatory diseases of childhood. Each diagnosis is based on criteria, but numerous clinical features are overlapping. As no specific diagnostic tests are available, differentiation between both disease entities can be challenging. Here, we describe the disease course of patients with co-diagnosis of both KD and sJIA (KD/sJIA). All our KD (n = 1765) and sJIA (n = 112) cases were critically reviewed for co-diagnosis of KD/sJIA. Eight KD/sJIA cases were identified and their clinical presentation, treatment regimens, coronary artery outcome and complications are herein described. Each KD/sJIA patient fulfilled diagnostic criteria for KD and for sJIA. Ongoing fever, rash and arthritis were present in each patient. The KD/sJIA patients had recalcitrant KD requiring multiple doses of intravenous immunoglobulin and steroids. Five patients had coronary artery dilatation at KD diagnosis, which resolved in all by 6 weeks. Pericardial effusion was present in 5 patients. One KD/sJIA patient developed macrophage activation syndrome. In conclusion, a small proportion (0.5%) of our KD patients evolved into sJIA, and 7% of our sJIA population presented initially as KD. KD/sJIA patients were characterized by a recalcitrant KD course and a high prevalence of coronary artery dilatation. Patients with co-diagnoses may provide a clue to potentially shared immunopathology in KD and sJIA, leading us to posit that both entities may be part of the same clinical spectrum.

Patterns of joint involvement in juvenile idiopathic arthritis and prediction of disease course: A prospective study with multilayer non-negative matrix factorization.

BACKGROUND: Joint inflammation is the common feature underlying juvenile idiopathic arthritis (JIA). Clinicians recognize patterns of joint involvement currently not part of the International League of Associations for Rheumatology (ILAR) classification. Using unsupervised machine learning, we sought to uncover data-driven joint patterns that predict clinical phenotype and disease trajectories. METHODS AND FINDINGS: We analyzed prospectively collected clinical data, including joint involvement using a standard 71-joint homunculus, for 640 discovery patients with newly diagnosed JIA enrolled in a Canada-wide study who were followed serially for five years, treatment-naïve except for nonsteroidal anti-inflammatory drugs (NSAIDs) and diagnosed within one year of symptom onset. Twenty-one patients had systemic arthritis, 300 oligoarthritis, 125 rheumatoid factor (RF)-negative polyarthritis, 16 RF-positive polyarthritis, 37 psoriatic arthritis, 78 enthesitis-related arthritis (ERA), and 63 undifferentiated arthritis. At diagnosis, we observed global hierarchical groups of co-involved joints. To characterize these patterns, we developed sparse multilayer non-negative matrix factorization (NMF). Model selection by internal bi-cross-validation identified seven joint patterns at presentation, to which all 640 discovery patients were assigned: pelvic girdle (57 patients), fingers (25), wrists (114), toes (48), ankles (106), knees (283), and indistinct (7). Patterns were distinct from clinical subtypes (P < 0.001 by χ2 test) and reproducible through external data set validation on a 119-patient, prospectively collected independent validation cohort (reconstruction accuracy Q2 = 0.55 for patterns; 0.35 for groups). Some patients matched multiple patterns. To determine whether their disease outcomes differed, we further subdivided the 640 discovery patients into three subgroups by degree of localization-the percentage of their active joints aligning with their assigned pattern: localized (≥90%; 359 patients), partially localized (60%-90%; 124), or extended (<60%; 157). Localized patients more often maintained their baseline patterns (P < 0.05 for five groups by permutation test) than nonlocalized patients (P < 0.05 for three groups by permutation test) over a five-year follow-up period. We modelled time to zero joints in the discovery cohort using a multivariate Cox proportional hazards model considering joint pattern, degree of localization, and ILAR subtype. Despite receiving more intense treatment, 50% of nonlocalized patients had zero joints at one year compared to six months for localized patients. Overall, localized patients required less time to reach zero joints (partial: P = 0.0018 versus localized by log-rank test; extended: P = 0.0057). Potential limitations include the requirement for patients to be treatment naïve (except NSAIDs), which may skew the patient cohorts towards milder disease, and the validation cohort size precluded multivariate analyses of disease trajectories. CONCLUSIONS: Multilayer NMF identified patterns of joint involvement that predicted disease trajectory in children with arthritis. Our hierarchical unsupervised approach identified a new clinical feature, degree of localization, which predicted outcomes in both cohorts. Detailed assessment of every joint is already part of every musculoskeletal exam for children with arthritis. Our study supports both the continued collection of detailed joint involvement and the inclusion of patterns and degrees of localization to stratify patients and inform treatment decisions. This will advance pediatric rheumatology from counting joints to realizing the potential of using data available from uncovering patterns of joint involvement.

Contrast-enhanced MRI compared with the physical examination in the evaluation of disease activity in juvenile idiopathic arthritis.

OBJECTIVES: To assess the value of magnetic resonance imaging (MRI) in discriminating between active and inactive juvenile idiopathic arthritis (JIA) patients and to compare physical examination outcomes with MRI outcomes in the assessment of disease status in JIA patients. METHODS: Consecutive JIA patients with knee involvement were prospectively studied using an open-bore MRI. Imaging findings from 146 JIA patients were analysed (59.6% female; mean age, 12.9 years). Patients were classified as clinically active or inactive. MRI features were evaluated using the JAMRIS system, comprising validated scores for synovial hypertrophy, bone marrow oedema, cartilage lesions and bone erosions. RESULTS: Inter-reader reliability was good for all MRI features (intra-class correlation coefficient [ICC] = 0.87-0.94). No differences were found between the two groups regarding MRI scores of bone marrow oedema, cartilage lesions or bone erosions. Synovial hypertrophy scores differed significantly between groups (P = 0.016). Nonetheless, synovial hypertrophy was also present in 14 JIA patients (35.9%) with clinically inactive disease. Of JIA patients considered clinically active, 48.6% showed no signs of MRI-based synovitis. CONCLUSIONS: MRI can discriminate between clinically active and inactive JIA patients. However, physical examination is neither very sensitive nor specific in evaluating JIA disease activity compared with MRI. Subclinical synovitis was present in >35% of presumed clinically inactive patients. KEY POINTS: • MRI is sensitive for evaluating juvenile idiopathic arthritis (JIA) disease activity. • Contrast-enhanced MRI can distinguish clinically active and inactive JIA patients. • Subclinical synovitis is present in 35.9 % of presumed clinically inactive patients. • Physical examination is neither sensitive nor specific in evaluating JIA disease activity.

One-year followup study on clinical findings and changes in magnetic resonance imaging-based disease activity scores in juvenile idiopathic arthritis.

OBJECTIVE: To evaluate whether clinical disease activity findings during 1-year followup of patients with juvenile idiopathic arthritis (JIA) is associated with changes of magnetic resonance imaging (MRI)-based disease activity scores. METHODS: Patients with JIA who had active knee involvement were studied using an open-bore MRI. After followup of a median of 1.3 years, patients were re-evaluated and classified as improved or unimproved according to the American College of Rheumatology Pediatric-50 (ACR-Ped50) criteria. Baseline and followup MRI features were scored by 2 readers using the Juvenile Arthritis MRI Scoring (JAMRIS) system, comprising validated scores for synovial hypertrophy, bone marrow changes, cartilage lesions, and bone erosions. RESULTS: Data of 40 patients were analyzed (62.5% female, mean age 12.2 yrs). After followup, 27 patients (67.5%) were classified as clinically improved, whereas 13 patients (32.5%) showed no clinical improvement. The clinically improved patients showed a significant reduction in synovial hypertrophy scores during followup (p < 0.001), with substantial effects (standardized response mean -0.70). No such changes were observed for any of the other MRI features. Significant differences were detected regarding a change in synovial hypertrophy scores comparing clinically improved and unimproved patients (p = 0.004), without statistically significant differences for changes in scores for bone marrow changes (p = 0.079), cartilage lesions (p = 0.165), and bone erosions (p = 0.078). CONCLUSION: This is one of the first studies to provide evidence for MRI-based improvement upon followup in JIA patients with knee involvement. There is a strong association with clinical improvement according to the ACR-Ped50 criteria and changes in MRI-based synovial hypertrophy scores, supporting the role of MRI as a responsive outcome measure to evaluate disease activity with antiinflammatory treatment strategies.

The diagnostic accuracy of unenhanced MRI in the assessment of joint abnormalities in juvenile idiopathic arthritis.

OBJECTIVES: To assess the diagnostic accuracy and reliability of MRI without contrast enhancement in the evaluation of JIA knee joint abnormalities. METHODS: JIA patients with clinically active knee involvement were prospectively studied using an 1-T open-bore magnet. MRI features were independently evaluated by two readers using the JAMRIS system. The first reading included unenhanced images, whereas complete image sets were available for the second reading. RESULTS: Imaging findings from 73 patients were analysed. Agreement between Gd-enhanced (+Gd) and Gd-unenhanced (-Gd) MRI scores of bone marrow changes, cartilage lesions and bone erosions was good concerning sensitivity, specificity, negative predictive value and positive predictive value. Inter-observer agreement was good for both -Gd and +Gd scores (ICC = 0.91-1.00, 0.93-1.00, respectively). Regarding the assessment of synovial hypertrophy, specificity of -Gd was high (0.97), but the sensitivity of unenhanced MRI was only 0.62. Inter-reader agreement for +Gd MRI was ICC = 0.94; however, omitting post-Gd acquisitions increased inter-reader variation (ICC = 0.86). CONCLUSIONS: If Gd-enhanced MRI is the reference standard, omitting Gd contrast medium is irrelevant for the assessment of bone marrow changes, cartilage lesions and bone erosions as joint abnormalities in JIA. Omitting intravenous Gd in the MRI assessment of joints in JIA is inadvisable, because it decreases the reliability of detecting synovial disease. KEY POINTS: • Magnetic resonance imaging is increasingly used to assess juvenile idiopathic arthritis. • Synovial hypertrophy, a marker of JIA activity, is well shown by MRI. • Omitting intravenous contrast medium decreases the reliability of synovial hypertrophy scores. • Bone marrow, cartilage and erosions can be reliably evaluated without contrast enhancement. • In the evaluation of JIA disease activity, unenhanced MRI is inadvisable.

Effectiveness of a web-based application to monitor health-related quality of life.

BACKGROUND AND OBJECTIVE: Monitoring health-related quality of life (HRQoL) by using electronic patient-reported outcomes (ePROs) has been only minimally evaluated in pediatrics. Children with juvenile idiopathic arthritis (JIA) are at risk for HRQoL problems. The aim of this study was to investigate the effectiveness of ePROs in clinical pediatric rheumatology care. METHODS: All children (aged 0-18 years) with JIA visiting any of the 4 pediatric rheumatology clinics in Amsterdam between February 2009 and February 2010 were eligible for this sequential cohort intervention study. Before an outpatient consultation, children (aged 8-18 years) or parents (of children aged 0-7 years) completed web-based questionnaires. The resulting ePROfile was provided to the pediatric rheumatologist (PR). The study was divided into a control period in which the ePROfile was not discussed during consultation, and an intervention period in which the ePROfile was provided and discussed during consultation. Effectiveness was evaluated in terms of communication about different HRQoL topics, referral to a psychologist, and satisfaction with the consultations. RESULTS: Out of the eligible JIA patients, 176 (65%) participated in the study. Use of the ePROfile increased discussion of psychosocial topics (P < .01), as well as the PR's satisfaction with provided care during consultation (P < .01). The use of ePROfiles did not affect referrals to a psychologist or parental satisfaction. Parents and PRs evaluated the use of the ePROfile as positive in 80% to 100% of the consultations. CONCLUSIONS: Our web-based application to systemically monitor HRQoL problems in pediatric rheumatology contributed significantly to communication about psychosocial issues in a positive way. We recommend implementation of ePROs in pediatric clinical practice.

Reliability and responsiveness of the Juvenile Arthritis MRI Scoring (JAMRIS) system for the knee.

OBJECTIVES: To assess the reliability and responsiveness of a new Juvenile Arthritis MRI Scoring (JAMRIS) system for evaluating disease activity of the knee. METHODS: Twenty-five juvenile idiopathic arthritis (JIA) patients with clinical knee involvement were studied using open-bore 1-T MRI. MRI features of synovial hypertrophy, bone marrow changes, cartilage lesions and bone erosions were independently scored by five readers using the JAMRIS system. In addition, the JAMRIS system was determined to be a follow-up parameter by two readers to evaluate the response to therapy in 15 consecutive JIA patients. RESULTS: Inter-reader (ICCs 0.86-0.95) and intra-reader reliability (ICCs 0.92-1.00) for the scoring of JAMRIS features was good. Reliability of the actual scores and changes in scores over time was good for all items: ICCs 0.89-1.00, 0.87-1.00, respectively. Concerning therapy response, the mean synovial hypertrophy scores decreased significantly (mean 1.1 point; P < 0.001, SRM = -0.65). No change was observed with respect to bone marrow change, cartilage lesion and bone erosion scores. CONCLUSIONS: The JAMRIS proved to be a simple and highly reliable assessment score in the evaluation of JIA disease activity of the knee. The JAMRIS system may serve as an objective and accurate outcome measure in future research and clinical trials.

Two-year outcome of juvenile idiopathic arthritis in current daily practice: what can we tell our patients?

OBJECTIVES: This paper aims to evaluate disease course and outcome of patients in the first 2 years after diagnosis of juvenile idiopathic arthritis (JIA) when treated according to local standard of clinical care, focusing on achievement of inactive disease, functional ability and radiological joint damage. METHODS: A retrospective inception cohort study of children with JIA, diagnosed between January 2003 and June 2007 and treated in referral centres in Amsterdam, was carried out. Disease status was determined for every outpatient-clinic visit. Data regarding medication, functional outcome and radiography were recorded. RESULTS: One hundred and forty-nine consecutive newly diagnosed JIA patients were included. Median age at diagnosis was 11.8 years; median follow-up was 33 months. Synthetic DMARDs (sDMARDs) were used by 95% of patients, including methotrexate in 85%, sulfasalazine in 41% and biologics in 20%. sDMARDs were started within median 1 month after diagnosis. During follow-up, 77% of patients achieved a total of 244 episodes of inactive disease (ID). ID was reached after median 10 months. No baseline predictive factors for achievement of ID could be identified. After 2 years a median CHAQ score of 0.6 was reported. Radiological joint damage occurred at some point in 18 patients (12%); 10 of these patients developed erosions within median 20 months after their first clinic visit. CONCLUSIONS: With current management strategies in daily clinical practice, 77% of newly diagnosed JIA patients achieved a first episode of inactive disease within a median of 10 months. After 2 years, patients reported moderate functional disability and more than 10% showed radiological evidence of joint damage.

Increasing feasibility and patient comfort of MRI in children with juvenile idiopathic arthritis.

BACKGROUND: MRI is the most sensitive imaging modality in juvenile idiopathic arthritis (JIA), but has practical limitations. Optimizing the scanning protocol is, therefore, necessary to increase feasibility and patient comfort. OBJECTIVE: To determine the feasibility of bilateral non-contrast-enhanced open-bore MRI of knees and to assess the presence of literature-based MRI features in unsedated children with JIA. MATERIALS AND METHODS: Children were classified into two clinical subgroups: active arthritis (group 1; n = 29) and inactive disease (group 2; n = 18). MRI features were evaluated using a literature-based score, comprising synovial hypertrophy, cartilage lesions, bone erosions, bone marrow changes, infrapatellar fat pad heterogeneity, effusion, tendinopathy and popliteal lymphadenopathy. RESULTS: The MRI examination was successfully completed in all 47 children. No scan was excluded due to poor image quality. Synovial hypertrophy was more frequent in group 1 (36.2%), but was also seen in 19.4% of the knees in group 2. Infrapatellar fat pad heterogeneity was more prevalent in group 2 (86.1%; P = 0.008). Reproducibility of the score was good (Cohen kappa, 0.49-0.96). CONCLUSION: Bilateral non-contrast-enhanced open-bore knee MRI is feasible in the assessment of disease activity in unsedated children with JIA. Signs differing among children with active and inactive disease include infrapatellar fat pad heterogeneity and synovial hypertrophy.