Dieneke Schonenberg-Meinema

Pixel-by-pixel analysis of DCE-MRI curve shape patterns in knees of active and inactive juvenile idiopathic arthritis patients

AbstractObjectivesTo compare DCE-MRI parameters and the relative number of time–intensity curve (TIC) shapes as derived from pixel-by-pixel DCE-MRI TIC shape analysis between knees of clinically active and inactive juvenile idiopathic arthritis (JIA) patients.MethodsDCE-MRI data sets were prospectively obtained. Patients were classified into two clinical groups: active disease (n = 43) and inactive disease (n = 34). Parametric maps, showing seven different TIC shape types, were created per slice. Statistical measures of different TIC shapes, maximal enhancement (ME), maximal initial slope (MIS), initial area under the curve (iAUC), time-to-peak (TTP), enhancing volume (EV), volume transfer constant (Ktrans), extravascular space fractional volume (Ve) and reverse volume transfer constant (kep) of each voxel were calculated in a three-dimensional volume-of-interest of the synovial membrane.ResultsImaging findings from 77 JIA patients were analysed. Significantly higher numbers of TIC shape 4 (P = 0.008), median ME (P = 0.015), MIS (P = 0.001) and iAUC (P = 0.002) were observed in clinically active compared with inactive patients. TIC shape 5 showed higher presence in the clinically inactive patients (P = 0.036).ConclusionsThe pixel-by-pixel DCE-MRI TIC shape analysis method proved capable of differentiating clinically active from inactive JIA patients by the difference in the number of TIC shapes, as well as the descriptive parameters ME, MIS and iAUC.Key Points• The pixel-by-pixel TIC shape method differentiates clinically active and inactive JIA patients • Significantly higher numbers of TIC shape 4 were observed in clinically active patients • DCE-MRI parameters ME, MIS and iAUC differ between active and inactive patients • The pixel-by-pixel analysis method allows direct visualization of the heterogeneously distributed disease • The DCE-MRI TIC shape method may serve as a quantitative outcome measure

Dynamic contrast-enhanced magnetic resonance imaging of the wrist in children with juvenile idiopathic arthritis.

BackgroundDynamic contrast-enhanced MRI provides information on the heterogeneity of the synovium, the primary target of disease in children with juvenile idiopathic arthritis (JIA).ObjectiveTo evaluate the feasibility of dynamic contrast-enhanced MRI in the wrist of children with JIA using conventional descriptive measures and time-intensity-curve shape analysis. To explore the association between enhancement characteristics and clinical disease status.Materials and methodsThirty-two children with JIA and wrist involvement underwent dynamic contrast-enhanced MRI with movement-registration and were classified using validated criteria as clinically active (n = 27) or inactive (n = 5). Outcome measures included descriptive parameters and the classification into time-intensity-curve shapes, which represent the patterns of signal intensity change over time. Differences in dynamic contrast-enhanced MRI outcome measures between clinically active and clinically inactive disease were analyzed and correlation with the Juvenile Arthritis Disease Activity Score was determined.ResultsComprehensive evaluation of disease status was technically feasible and the quality of the dynamic dataset was improved by movement registration. The conventional descriptive measure maximum enhancement differed significantly between clinically active and inactive disease (P = 0.019), whereas time-intensity-curve shape analysis showed no differences. Juvenile Arthritis Disease Activity Score correlated moderately with enhancing volume (P = 0.484).ConclusionDynamic contrast-enhanced MRI is a promising biomarker for evaluating disease status in children with JIA and wrist involvement. Conventional descriptive dynamic contrast-enhanced MRI measures are better associated with clinically active disease than time-intensity-curve shape analysis.

Diffusion-weighted imaging for assessment of synovial inflammation in juvenile idiopathic arthritis: a promising imaging biomarker as an alternative to gadolinium-based contrast agents

AbstractObjectivesTo compare dynamic-contrast-enhanced MRI (DCE) and diffusion-weighted imaging (DWI) in quantifying synovial inflammation in juvenile idiopathic arthritis (JIA).MethodsRegions of interest (ROI) were drawn in the synovium of JIA patients on T1 DCE and T2 DWI, followed by extraction of the maximum enhancement (ME), maximum initial slope (MIS), time to peak (TTP), % of different time intensity curve shapes (TIC) and apparent diffusion coefficient (ADC) of the ROIs. Mann-Whitney-U test was used for comparing parameters between MRI-active and -inactive patients (defined by the juvenile arthritis MRI scoring system). Spearman’s rank was used to analyse the correlation between DCE and DWI.ResultsThirty-five JIA patients (18 MRI active and 17 MRI inactive) were included. Median age was 13.1 years and 71% were female. ME, MIS, TTP, % TIC 5 and ADC were significantly different in MRI-active versus MRI-inactive JIA with median ADC 1.49 × 10-3mm2/s in MRI-active and 1.25 × 10-3mm2/s in MRI-inactive JIA, p = 0.001, 95% confidence interval of difference in medians =0.11-0.53 × 10-3mm2/s. ADC correlated to ME, MIS and TIC 5 shapes (r = 0.62, r = 0.45, r = -0.51, respectively, all p < 0.05).ConclusionsSimilar to DCE parameters, DWI-derived ADC is significantly different in MRI-active JIA as compared to MRI-inactive JIA. The non-invasiveness of DWI combined with its possibility to detect synovial inflammation shows the potential of DWI.Key Points• MRI can quantify: dynamic contrast-enhanced and diffusion-weighted MRI can quantify synovitis • Both DWI and DCE can differentiate active from inactive JIA • The DWI-derived apparent diffusion coefficient (ADC) is higher in active JIA • DWI is non-invasive and thus safer and more patient-friendly • DWI is a potentially powerful and non-invasive imaging biomarker for JIA

Contrast-enhanced MRI findings of the knee in healthy children; establishing normal values

ObjectivesTo define normative standards for the knee in healthy children using contrast-enhanced MRI, focusing on normal synovial membrane thickness. Secondly, presence of joint fluid and bone marrow oedema was evaluated.MethodsFor this study, children without disorders potentially resulting in (accompanying) arthritis were included. Patients underwent clinical assessments, followed by contrast-enhanced MRI. MRI features were evaluated in consensus using the Juvenile Arthritis MRI Scoring (JAMRIS) system. Additionally, the presence of joint fluid was evaluated. No cartilage lesions or bone abnormalities were observed.ResultsWe included 57 healthy children. The overall mean thickness of the normal synovial membrane was 0.4 mm (min–max; 0.0–1.8mm). The synovium was thickest around the cruciate ligaments and retropatellar and suprapatellar regions. The mean overall diameter of the largest pocket of joint fluid was 2.8 mm (min–max; 0.9–8.0mm). Bone marrow changes were observed in three children (all in the apex patellae).ConclusionsThe normal synovial membrane was maximally 1.8 mm thick, indicating that the JAMRIS cut-off value of 2 mm can be considered a valid measure for evaluating synovial hypertrophy. Some joint fluid and bone marrow changes suggestive of bone marrow oedema in the apex patellae can be seen in healthy children.Key Points• Knowledge on the normal synovial appearance using contrast-enhanced MR is lacking.• In healthy children, normal synovial membrane is maximally 1.8 mm thick.• Normal synovium is thickest around the cruciate ligaments, retropatellar and suprapatellar.• Bone marrow oedema in the apex patellae is seen in healthy children.

Construct validity of pixel-by-pixel DCE-MRI: Correlation with conventional MRI scores in juvenile idiopathic arthritis

OBJECTIVES To assess the capability of the pixel-by-pixel DCE-MRI time intensity curve (TIC)-shape analysis method in the evaluation of juvenile idiopathic arthritis (JIA) disease activity by correlating DCE-MRI parameters with semi-quantitative conventional-MRI scores of synovitis. METHODS Clinical, laboratory, and (DCE)-MRI datasets of 85 JIA patients were prospectively obtained. TIC-shapes of each voxel were classified into one of seven predefined color-coded TIC shape categories. Spatial information on the relative amount of TIC-shapes, maximal enhancement (ME), maximal initial slope (MIS), initial area under the curve (iAUC), time-to-peak (TTP), enhancing volume (EV) was calculated of the synovial membrane. The grade of synovitis was scored on conventional MR images by two readers using the validated JAMRIS system. The Bonferroni method was used to correct for multiple testing, therefore, a P value of <0.0056 is considered significant (0.05/9=0.0056). RESULTS The semi-quantitative JAMRIS synovitis score correlated substantially with the ME, EV, and iAUC (Rs=0.658, P<0.001; Rs=0.618, P<0.001; Rs=0.639, P<0.001), and moderately with MIS (Rs=0.453, P<0.001). A poor correlation was observed between the relative number of TIC-shapes 2-5 and the JAMRIS synovitis score (Rs=0.209, P=0.054; Rs=0.328, P=0.002; Rs=0.241, P=0.023; Rs=-0.241, P=0.026). CONCLUSION In this explorative study, both TIC shape and semi-quantitative DCE-MRI analysis methods showed moderate to substantial correlations with conventional MRI scores of disease activity, indicating that this methods are feasible. Further research is warranted whether DCE-MRI holds potential to become an objective and quantitative method for the evaluation of disease activity in JIA.

Normal MRI findings of the knee in patients with clinically active juvenile idiopathic arthritis

OBJECTIVE In a number of patients with clinically active juvenile idiopathic arthritis (JIA), contrast-enhanced MRI shows no signs of synovitis. The objective of this study was to assess the frequency and the patient characteristics in clinically active JIA patients in which MRI showed no signs of synovitis. METHODS From our cohort of 313 patients in which contrast-enhanced MRI of the knee had been performed, we selected 72 JIA patients with clinically active disease involving the target joint. The validated Juvenile Arthritis MRI Scoring (JAMRIS) system was used to evaluate synovial thickening. Patients were divided into two groups based on MRI outcome: Group 1: thickened synovium on MRI (JAMRIS score ≥1) or Group 2: normal synovium on MRI (JAMRIS score 0). Patient characteristics and disease activity parameters were then compared. RESULTS In 35% (25/72) of these patients, MRI results contrasted with the clinical assessment (Group 2). In comparison to Group 1, the patients with discrepant findings were significantly older at the date of examination and JIA had been diagnosed at later age (median age of 13.2 vs. 10.9 and median age 10.0 vs. 8.0 respectively). In Group 2 there were significantly more patients with RF-negative polyarticular disease. CONCLUSION Patients with RF-negative polyarticular JIA who had been diagnosed at a later age and were older at the time of MRI were most likely to be considered clinically active while MRI showed no signs of synovitis. These particular JIA patients may benefit from monitoring of disease activity by MRI to prevent overtreatment.

Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial

Question Which is the best strategy to achieve (drug-free) inactive disease in juvenile idiopathic arthritis (JIA)? Methods In a randomised, single-blinded, study in disease-modifying anti-rheumatic drug (DMARD)-naive patients with JIA, three treatment-strategies were compared: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX +etanercept. Treatment-to-target entailed 3-monthly DMARD/biological adjustments in case of persistent disease activity, with drug tapering to nil in case of inactive disease. After 24 months, primary outcomes were time-to-inactive-disease and time-to-flare after DMARD discontinuation. Secondary outcomes were adapted ACRPedi30/50/70/90 scores, functional ability and adverse events. Results 94 children (67 % girls) aged median (IQR) 9.1 (4.6–12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. At baseline visual analogue scale (VAS) physician was mean 49 (SD 16) mm, VAS patient 53 (22) mm, erythrocyte sedimentation rate 12.8 (14.7), active joints median 8 (5–12), limited joints 2.5 (1–4.8) and Childhood Health Assessment Questionnaire score mean 1.0 (0.6). After 24 months, 71% (arm 1), 70% (arm 2) and 72% (arm 3) of patients had inactive disease and 45% (arm 1), 31% (arm 2) and 41% (arm 3) had drug-free inactive disease. Time-to-inactive-disease was median 9.0 (5.3–15.0) months in arm 1, 9.0 (6.0–12.8) months in arm 2 and 9.0 (6.0–12.0) months in arm 3 (p=0.30). Time-to-flare was not significantly different (overall 3.0 (3.0–6.8) months, p=0.7). Adapted ACR pedi-scores were comparably high between arms. Adverse events were similar. Conclusion Regardless of initial specific treatments, after 24 months of treatment-to-target aimed at drug-free inactive disease, 71% of recent-onset patients with JIA had inactive disease (median onset 9 months) and 39% were drug free. Tightly controlled treatment-to-target is feasible. Trial registration number 1574.

Protein array autoantibody profiles to determine diagnostic markers for neuropsychiatric systemic lupus erythematosus

Objective The aim was to investigate the association between autoantibodies (autoAbs) and neuropsychiatric (NP) involvement in patients with SLE and to evaluate whether any autoAb or a combination of these autoAbs could indicate the underlying pathogenic process. Methods Using a multiplexed protein array for 94 antigens, we compared the serum autoAb profiles of 69 NPSLE patients, 203 SLE patients without NP involvement (non-NPSLE) and 51 healthy controls. Furthermore, we compared the profiles of NPSLE patients with clinical inflammatory (n = 38) and ischaemic (n = 31) NP involvement. Results In total, 75 IgG and 47 IgM autoAbs were associated with SLE patients in comparison with healthy controls. Comparing NPSLE with non-NPSLE and healthy control sera, 9 IgG (amyloid, cardiolipin, glycoprotein 2, glycoprotein 210, heparin, heparan sulphate, histone H2A, prothrombin protein and vimentin) and 12 IgM (amyloid, cardiolipin, centromere protein A, collagen II, histones H2A and H2B, heparan sulphate, heparin, mitochondrial 2, nuclear Mi-2, nucleoporin 62 and vimentin) autoAbs were present at significantly different levels in NPSLE. The combination of IgG autoAbs against heparan sulphate, histone H2B and vimentin could differentiate NPSLE from non-NPSLE (area under the curve 0.845, 99.97% CI: 0.756, 0.933; P < 0.0001). Compared with non-NPSLE, four IgG and seven IgM autoAbs were significantly associated with inflammatory NPSLE. In ischaemic NPSLE, three IgG and three IgM autoAbs were significantly different from non-NPSLE patients. Conclusion In our cohort, the presence of high levels of anti-heparan sulphate and anti-histone H2B combined with low levels of anti-vimentin IgG autoAbs is highly suggestive of NPSLE. These results need to be validated in external cohorts.