Validity and Responsiveness of Combined Inflammation and Combined Joint Damage Scores Based on the OMERACT Rheumatoid Arthritis MRI Scoring System (RAMRIS).

OBJECTIVE: The RAMRIS [Outcome Measures in Rheumatology rheumatoid arthritis (RA) magnetic resonance imaging (MRI) Scoring system] is used in clinical RA trials. We have investigated methods to combine the RAMRIS features into valid and responsive scores for inflammation and joint damage. METHODS: We used data from 3 large randomized early RA trials to assess 5 methods to develop a combined score for inflammation based on RAMRIS bone marrow edema, synovitis, and tenosynovitis scores, and a combined joint damage score based on erosions and joint space narrowing. Methods included unweighted summation, normalized summation, and 3 different variants of weighted summation of the RAMRIS features. We used a derivation cohort to calculate summation weights to maximize the responsiveness of the combined score. Construct validity of the combined scores was examined by assessing correlations to imaging, clinical, and biochemical measures. Responsiveness was tested by calculating the standardized response mean (SRM) and the relative efficiency of each score in a validation cohort. RESULTS: Patient characteristics, as well as baseline and followup RAMRIS scores, were comparable between cohorts. All combined scores were significantly correlated to other imaging, clinical, and biochemical measures. Inflammation scores combined by normalized and weighted summation had significantly higher responsiveness in comparison to unweighted summation, with SRM (95% CI) for unweighted summation 0.62 (0.51-0.73), normalized summation 0.73 (0.63-0.83), and weighted summation 0.74 (0.64-0.84). For the damage score, there was a trend toward higher responsiveness for weighted summation. CONCLUSION: Combined MRI scores calculated by normalized or weighted summation of individual MRI pathologies were valid and responsive.

Magnetic resonance imaging assessed inflammation in the wrist is associated with patient-reported physical impairment, global assessment of disease activity and pain in early rheumatoid arthritis: longitudinal results from two randomised controlled trials.

OBJECTIVES: To examine whether MRI assessed inflammation and damage in the wrist of patients with early rheumatoid arthritis (RA) are associated with patient-reported outcomes (PROs). METHODS: Wrist and hand MRIs of 210 patients with early RA from two investigator-initiated, randomised controlled studies (CIMESTRA/OPERA) were assessed according to the Outcome Measures in Rheumatology RA MRI score (RAMRIS) for synovitis, tenosynovitis, osteitis, bone erosions and joint space narrowing (JSN) at baseline, 1 and 5 years follow-up. These features, and changes therein, were assessed for associations with health assessment questionnaires (HAQ), patient global visual analogue scales (VAS-PtGlobal) and VAS-pain using Spearman's correlations, generalised estimating equations and univariate/multivariable linear regression analyses. MRI features were further tested for trends against specific hand-related HAQ items using Jonckheere trend tests. RESULTS: MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS-pain for status and change scores, independently of C reactive protein and swollen joint count. MRI-assessed synovitis was most consistently associated with PROs, particularly VAS-PtGlobal and VAS-pain. MRI-assessed synovitis and tenosynovitis mean scores were positively associated with patient-reported difficulty to cut meat and open a milk carton (p<0.01), and similar patterns were seen for other hand-related HAQ items. Incorporating metacarpophalangeal joints in the analyses did not strengthen the associations between MRI pathology and PROs. CONCLUSIONS: MRI-assessed inflammation, but not damage, in early RA wrists is associated with patient-reported physical impairment, global assessment of disease activity and pain and influences the physical function in the hand. TRIAL REGISTRATION NUMBER: NCT00660647.

MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial.

OBJECTIVES: To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). METHODS: Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. RESULTS: Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. CONCLUSIONS: MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01023256.

Radiographic progression and remission rates in early rheumatoid arthritis - MRI bone oedema and anti-CCP predicted radiographic progression in the 5-year extension of the double-blind randomised CIMESTRA trial.

OBJECTIVE: At 5 years' follow-up of early (<6 months) rheumatoid arthritis patients to (1) investigate whether initial combination therapy with methotrexate (MTX) and ciclosporin (CSA) (n=80) is superior to initial monotherapy with MTX (n=80) with respect to prevention of radiographic progression, (2) investigate whether the favourable clinical and radiographic response reported at 2 years in the CIMESTRA trial can be maintained and (3) identify predictors of radiographic outcome. METHODS: 139 patients completed 5 years' follow-up with maintained double-blinding and a strict synovitis suppressive treatment strategy with intra-articular betamethasone injections (intra-articular glucocorticosteroid (GC)) and escalation of disease-modifying anti-rheumatic drug treatment. Disease activity, total Sharp-van der Heijde Score (TSS) of hands, wrists and forefeet were assessed at baseline and after 3, 4 and 5 years. MRI of the wrist and anti-cyclic citrullinated peptide (anti-CCP) were assessed at baseline. RESULTS: At 5 years, TSS progression rate was <1 unit/year and 47% had not progressed radiographically since baseline. 78% were in Disease Activity Score remission, 56% in American College of Rheumatology remission and 17% withdrawn from treatment due to remission. There were no differences between initial treatment groups. MRI-bone marrow oedema, TSS and anti-CCP predicted radiographic progression at 5 years. CONCLUSION: Early and strict synovitis suppressive treatment with MTX and intra-articular GC lead to high remission rates and halting of erosive progression at 5 years. No additional effect of initial combination therapy with CSA was found. The results parallel those reported for tumour necrosis factor α antagonists. Baseline MRI-bone oedema, TSS and anti-CCP predicted radiographic progression.

Detection of bone erosions in rheumatoid arthritis wrist joints with magnetic resonance imaging, computed tomography and radiography.

BACKGROUND: The objectives of the present study were, with multidetector computed tomography (CT) as the reference method, to determine the performance of magnetic resonance imaging (MRI) and radiography for the detection of bone erosions in rheumatoid arthritis wrist bones, and to test whether measuring volumes of erosions on CT and MRI is reproducible and correlated to semiquantitative assessments (scores) of erosions on CT, MRI and radiography. METHODS: Seventeen patients with rheumatoid arthritis and four healthy control individuals underwent CT, MRI and radiography of one wrist, performed on the same day. CT was performed on a Philips Mx8000IDT unit (voxel size 0.4 mm x 0.4 mm x 1 mm) and MRI was performed on a Philips Panorama 0.6T unit (voxel size 0.4 mm x 0.4 mm x 0.4 mm). Images were evaluated separately for erosions in all wrist bones and were scored according to the principles of the Outcome Measures in Rheumatology Rheumatoid Arthritis MRI Scoring System (CT and MRI) and the Sharp/van der Heijde (radiographs) scoring methods. Measurements of erosion volumes of all erosions were performed twice with a 1-week interval. RESULTS: With CT as the reference method, the overall sensitivity, specificity and accuracy (concordance) of MRI for detecting erosions were 61%, 93% and 77%, respectively, while the respective values were 24%, 99% and 63% for radiography. The intramodality agreements when measuring erosion volumes were high for both CT and MRI (Spearman correlation coefficients 0.92 and 0.90 (both P < 0.01), respectively). Correlations between volumes and scores of individual erosions were 0.96 for CT and 0.99 for MRI, while they were 0.83 (CT) and 0.80 (MRI) for persons' total erosion volume and total score (all P < 0.01). CONCLUSION: With CT as the reference method, MRI showed moderate sensitivity and good specificity and accuracy for detection of erosions in rheumatoid arthritis and healthy wrist bones, while radiography showed very low sensitivity. The tested volumetric method was highly reproducible and correlated to scores of erosions.

Rheumatoid arthritis bone erosion volumes on CT and MRI: reliability and correlations with erosion scores on CT, MRI and radiography.

OBJECTIVES: To investigate intramodality and intermodality agreements of CT and MRI erosion volumes in metacarpophalangeal (MCP) joints in rheumatoid arthritis (RA), and to compare the volumes with erosion scores for CT, MRI and radiography. METHODS: In total, 17 patients with RA and four healthy controls underwent unilateral CT, MRI and radiography of second to fifth MCP joints in one hand. Erosion volumes (using OSIRIS software) and scores were determined from CT, MRI and radiography (scores only). RESULTS: CT, MRI and radiography detected 77, 62 and 12 erosions, respectively. On CT, the mean erosion volume was 26 mm(3) (median 10; range 0 to 248) and 30 mm(3) (18; 1 to 163) on MRI. Total erosion volumes (per patient/control) were 97 mm(3) (29; 0 to 485) on CT and 90 mm(3) (46; 0 to 389) on MRI. For volumes, Spearman correlation coefficients were 0.96 to 0.99 (CT vs CT), 0.95 to 0.98 (MRI vs MRI) and 0.64 to 0.89 (CT vs MRI), all p<0.01. MRI erosion volumes correlated with the Outcome Measures in Rheumatology Clinical Trials/Rheumatoid Arthritis Magnetic Resonance Imaging Score (OMERACT RAMRIS) erosion scores (0.91 to 0.99; p<0.01) and the Sharp/van der Heijde erosion score (0.49 to 0.63; p<0.01). CONCLUSION: Very high intramodality and high intermodality agreements of CT and MRI erosion volumes were found, encouraging further testing in longitudinal studies. A close correlation with CT and MRI erosion volumes supports the OMERACT RAMRIS erosion score as a valid measure of joint destruction in RA.

Introduction of a novel magnetic resonance imaging tenosynovitis score for rheumatoid arthritis: reliability in a multireader longitudinal study.

OBJECTIVES: To describe a novel scoring system for the assessment of tenosynovitis by magnetic resonance imaging (MRI) in patients with rheumatoid arthritis, and assess its intra- and inter-reader reliability in a multireader, longitudinal setting. METHODS: Flexor and extensor tenosynovitis were evaluated at the level of the wrist in 10 different anatomical areas, graded semi-quantitatively from grade 0 to 3 (total score 0-30), based on the maximum width of post-contrast enhancement within each anatomical area on axial T1-weighted MR images. Ten sets of baseline and 1-year follow-up MR images of the wrists of patients with rheumatoid arthritis with early and established disease were scored independently by four readers twice on 2 consecutive days. Intra- and inter-reader agreements were evaluated. RESULTS: The intrareader intraclass correlation coefficients (ICCs) were high for status scores (median ICCs 0.84-0.88) and slightly lower for change score (0.74). The smallest detectable difference (SDD) in % of the maximum score was 11.2-11.5% for status scores and 13.3% for change scores. Inter-reader single-measure ICCs were acceptable for both status scores (median 0.73-0.74) and change scores (0.67), while average-measures ICCs were very high for both status and change score (all > or =0.94). The median scoring time per patient (baseline and follow-up images) was 7 min (range 3-10). CONCLUSIONS: The introduced tenosynovitis scoring system demonstrates a high degree of multireader reliability, is feasible, and may be used as an adjuvant to the existing OMERACT RAMRIS score, allowing improved quantification of inflammatory soft tissue changes in patients with rheumatoid arthritis.

Ultrasonography and magnetic resonance imaging in early rheumatoid arthritis: recent advances.

Efficient methods for diagnosis, monitoring, and prognostication are essential in early rheumatoid arthritis. Data on the value of ultrasonography and MRI are accumulating rapidly, fueling their increasing use in early rheumatoid arthritis. This review focuses on recent advances in the clinical applications of these imaging modalities.

Are bone erosions detected by magnetic resonance imaging and ultrasonography true erosions? A comparison with computed tomography in rheumatoid arthritis metacarpophalangeal joints.

The objective of the study was, with multidetector computed tomography (CT) as the reference method, to determine whether bone erosions in rheumatoid arthritis (RA) metacarpophalangeal (MCP) joints detected with magnetic resonance imaging (MRI) and ultrasonography (US), but not with radiography, represent true erosive changes. We included 17 RA patients with at least one, previously detected, radiographically invisible MCP joint MRI erosion, and four healthy control individuals. They all underwent CT, MRI, US and radiography of the 2nd to 5th MCP joints of one hand on the same day. Each imaging modality was evaluated for the presence of bone erosions in each MCP joint quadrant. In total, 336 quadrants were examined. The sensitivity, specificity and accuracy, respectively, for detecting bone erosions (with CT as the reference method) were 19%, 100% and 81% for radiography; 68%, 96% and 89% for MRI; and 42%, 91% and 80% for US. When the 16 quadrants with radiographic erosions were excluded from the analysis, similar values for MRI (65%, 96% and 90%) and US (30%, 92% and 80%) were obtained. CT and MRI detected at least one erosion in all patients but none in control individuals. US detected at least one erosion in 15 patients, however, erosion-like changes were seen on US in all control individuals. Nine patients had no erosions on radiography. In conclusion, with CT as the reference method, MRI and US exhibited high specificities (96% and 91%, respectively) in detecting bone erosions in RA MCP joints, even in the radiographically non-erosive joints (96% and 92%). The moderate sensitivities indicate that even more erosions than are seen on MRI and, particularly, US are present. Radiography exhibited high specificity (100%) but low sensitivity (19%). The present study strongly indicates that bone erosions, detected with MRI and US in RA patients, represent a loss of calcified tissue with cortical destruction, and therefore can be considered true bone erosions.

Reliability and sensitivity to change of the OMERACT rheumatoid arthritis magnetic resonance imaging score in a multireader, longitudinal setting.

OBJECTIVE: To assess the intra- and interreader reliability and the sensitivity to change of the Outcome Measures in Rheumatology Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) system on digital images of the wrist joints of patients with early or established rheumatoid arthritis (RA). METHODS: Ten sets of baseline and 1-year followup MR images of the wrists of patients with progressive changes on conventional hand radiographs were scored independently by 4 readers on 2 consecutive days, preceded by reader training and calibration. The MR images were acquired and scored according to the recommendations from the OMERACT MRI group. The intra- and interreader agreement (evaluated by intraclass correlation coefficients [ICCs]) and the sensitivity to change (evaluated by the smallest detectable difference [SDD]) were determined for scores of synovitis, erosion, and bone marrow edema status and for change scores. RESULTS: Intrareader ICCs were generally very high, both for status scores (median baseline and followup 0.89 and 0.90 for synovitis, 0.91 and 0.90 for erosion, and 0.90 and 0.98 for edema) and for change scores (median 0.80 for synovitis, 0.96 for erosion, and 0.97 for edema). The SDDs were generally low, suggesting a high potential to detect changes. Interreader single-measure ICCs were high for status scores (mean baseline and followup 0.69 and 0.78 for synovitis, 0.83 and 0.73 for erosion, and 0.79 and 0.95 for edema) and for change scores (mean 0.74 for synovitis, 0.67 for erosion, and 0.95 for edema). The average-measure ICCs were > or =0.94 for all components of both the status scores and change scores. CONCLUSION: The RAMRIS showed very good intrareader reliability, good interreader reliability, and a high level of sensitivity to change. The results suggest that the RAMRIS may be a suitable system for use in monitoring joint inflammation and destruction in RA.