Double inversion recovery MRI versus contrast-enhanced MRI for evaluation of knee synovitis in juvenile idiopathic arthritis

The current study is part of the Amsterdam Juvenile Arthritis Cohort Studies, a multicenter study designed to investigate the value of imaging markers as well as immunological markers for assessment of JIA disease activity. The three participating pediatric rheumatology centers were: Amsterdam University Medical Centers (location: Academic Medical Centre), Reade and Onze Lieve Vrouwe Gasthuis, all in Amsterdam, the Netherlands. Clinical data were obtained in the three centers. In order to optimize uniformity in imaging acquisition, MRI scanning was performed in one center (i.e., Amsterdam University Medical Centers [location: Academic Medical Centre]).

Study participants

From January 2018 until January 2021, all consecutive children diagnosed with JIA who underwent knee MRI were prospectively included. A study participant flow diagram is shown in Fig. 1. The diagnosis of JIA was made by one of four pediatric rheumatologists (A.N., D.S., J.M.v.d.B., and K.M.D.: range of years’ experience = 5–17) according to the International League of Associations for Rheumatology (ILAR) criteria [23]. The decision to perform MRI examination was based on clinical indication. Exclusion criteria were: (1) intra-articular corticosteroid injection within the last six months and (2) need for anesthesia-assisted MRI. A waiver of informed consent was granted by the local ethics committee for this specific study.

Fig. 1figure 1

Study participant flow diagram

Clinical assessment

Prior to MRI examination, all children underwent clinical evaluation. Physical examination included a joint-specific assessment of tenderness, swelling, and joint mobility for 71 joints in total. Physician’s global assessment of overall disease activity was measured on a 100 mm visual analogue scale [24]. Laboratory examination included erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).

Reference standard for presence of knee arthritis

Based on the consensus statement by a multidisciplinary expert group [25], the included children with JIA were subdivided into two subgroups: ‘presence of knee arthritis’ and ‘absence of knee arthritis.’ The panel consisted of pediatric rheumatologists, a pediatric rheumatology nurse, and radiologists. During bimonthly multidisciplinary team sessions, the expert group discussed the clinical data (i.e., age, sex, medical history, JIA subtype, disease course, treatment effect, physical examination findings, and laboratory results) and imaging results (i.e., ultrasound, conventional radiography, and/or pre- and post-contrast MRI) of each child and subsequently determined whether knee arthritis was present or not. DIR images were not available during the meetings. Participant categorization preceded study image analysis.

MRI protocol

Images were obtained using a 3.0-T Ingenia MRI scanner (Philips Medical Systems) equipped with a dedicated knee coil. Participants were situated in a supine position with the knee placed centrally in the magnetic field. Standard knee MRI scanning protocol included three-dimensional fat-saturated T1- and T2-weighted scans before contrast administration and three-dimensional post-contrast fat-saturated T1-weighted scans. The post-contrast fat-saturated T1-weighted scans, obtained < 5 min after intravenous gadolinium injection (0.1 mg/kg body weight; gadobutrol; Schering AG), were used for image analysis (scanning parameters are presented in Table 1).

Table 1 Parameters of the MRI sequences used for image analysis

For the purpose of this study, an axial DIR pulse sequence was added to the routine scanning protocol and applied prior to contrast administration. Standard DIR sequence settings, embedded in the MRI Scanner software, were adjusted in accordance with the protocol presented by Jahng et al. [20] and Son et al. [21] (Table 1). To acquire adequate delineation of the synovium by simultaneous suppression of fat tissue and synovial effusion, we used the inversion times reported by Son et al. [21] (i.e., first inversion time = 2830 ms; second inversion time = 254 ms). Total scan duration of the DIR sequence was 2 min and 14 s.

Image analysis

To avoid any bias, the MRI dataset was anonymized and randomized. The following study parameters were assessed in the axial plane: (1) confidence in visual identification of the synovial lining, (2) overlap of the synovial distribution patterns, and (3) maximal synovial thickness. In accordance with the validated Juvenile Arthritis MRI Scoring (JAMRIS) system for the knee, parameters were evaluated at the following 6 anatomical locations: patellofemoral, suprapatellar recesses, infrapatellar fat pad, cruciate ligaments, medial posterior condyle, and lateral posterior condyle [26]. Study variables were evaluated by radiologists (R.H., a musculoskeletal radiologist with 11 years of experience; K.F.v.D., a musculoskeletal radiologist with 22 years of experience; E.E.D., a pediatric radiologist with 13 years of experience; and M.M., a musculoskeletal radiologist with 22 years of experience), from two institutions, blinded to clinical data. Study measurements were carried out consecutively during one scoring session, unless otherwise stated.

To assess whether the DIR pulse sequence delineates the synovium in the knee in children with JIA, we assessed reader’s confidence (readers: R.H. and M.M.; [endpoint: consensus score]) in visual identification of the synovium on DIR MRI and compared it to conventional CE-MRI. Confidence to depict the synovial lining was rated on a visual analogue scale from 0 (no confidence) to 100 (maximal confidence) [25, 27]. To reduce potential effects of reader preferences, this specific study parameter was assessed on separate occasions (i.e., session 1 = DIR MRI; session 2 = CE-MRI), with a 4-week interval in between and MRI dataset re-randomization before start of the second scoring session. Pairing DIR scans with post-contrast images was prohibited.

To assess whether the area covered by the synovium on DIR MRI corresponds with the synovial signature on CE-MRI, the synovial distribution patterns on both imaging techniques were compared (readers: R.H. and M.M.; [endpoint: consensus score]) using aligned DIR/post-contrast image pairs [21]. DIR images were always presented on the left side of the screen. The degree of correspondence was evaluated as the estimated percentage of overlap of the synovial distribution patterns (i.e., ≤ 25%; 26–50%; 51–75%; > 75%).

Measurement of maximal synovial thickness using CE-MRI is still the only validated MRI tool for assessment of synovitis in the knee in children with JIA [26]. To evaluate if similar results can be obtained using DIR MRI, maximal synovial thickness was evaluated on DIR MRI and compared to corresponding findings acquired using CE-MRI. This specific study parameter was evaluated by 4 individual readers (R.H., K.F.v.D., E.E.D., and M.M.). To test intra-reader reliability for evaluation of the maximal synovial thickness on DIR MRI, measurements were repeated by the 4 readers after 3 weeks, to minimize recall bias, in all study participants.

To assess whether the value of DIR-derived maximal synovial thickness per child for detection of arthritis corresponds with CE-MRI, we compared the findings between the children with knee arthritis and those without knee arthritis.

Statistical analysis

Sample size selection (i.e., at least 12 participants per group of interest) was based on the data provided by a feasibility study using DIR MRI for evaluation of the synovium in a small cohort of adults [21], and recommendations for studies with a pilot nature [28]. Subgroup comparisons were performed by using the Student's t test, Mann–Whitney U test, Kruskal–Wallis test, Chi-square test, and Fisher's exact test. The Wilcoxon signed-rank test and Friedman test were carried out to evaluate differences between paired data. Spearman’s rank-order correlation coefficients [29] were computed to assess the relationship between DIR MRI and CE-MRI regarding maximal synovial thickness measurements. Intraclass correlation coefficient’s (ICC’s), based on single-measurement, absolute-agreement, two-way random effects model, were used to evaluate inter-reader reliability regarding measurement of the maximal synovial thickness. To evaluate intra-reader reliability, we used Bland–Altman plots and ICC’s [30], based on a single-measurement, absolute-agreement, two-way mixed effects model. Two-sided p values were used for all statistical assessments and a p value < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics for Windows version 26.0 (IBM) and GraphPad Prism 8.0 (GraphPad Software).

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