Bo Ejbjerg

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 ⩾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.

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 mm3 (median 10; range 0 to 248) and 30 mm3 (18; 1 to 163) on MRI. Total erosion volumes (per patient/control) were 97 mm3 (29; 0 to 485) on CT and 90 mm3 (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.

Synovitis and osteitis are very frequent in rheumatoid arthritis clinical remission: results from an MRI study of 294 patients in clinical remission or low disease activity state.

Objective. In rheumatoid arthritis (RA), radiographic progression may occur despite clinical remission. This may be explained by subclinical inflammation. Magnetic resonance imaging (MRI) provides a greater sensitivity than clinical examination and radiography for assessing disease activity. Our objective was to determine the MRI characteristics of RA patients in clinical remission or low disease activity (LDA) state. Methods. Databases from 6 cohorts were collected from 5 international centers. RA patients in clinical remission according to Disease Activity Score28-C-reactive protein (DAS28-CRP < 2.6; n = 213) or LDA-state (2.6 ≤ DAS28-CRP < 3.2; n = 81) with available MRI data were included. MRI were assessed according to the OMERACT RA MRI scoring system (RAMRIS). Results. Patient characteristics: 70% women, median age 55 (interquartile range, IQR 43–63) years, disease duration 2.3 (IQR 0.7–5.1) years, DAS28-CRP 2.2 (IQR 1.8–2.6), Simplified Disease Activity Index, SDAI, 3.9 (IQR 1.9–6.5), Clinical Disease Activity Index, CDAI, 3.1 (IQR 1.5– 5.8), rheumatoid factor/anti-cyclic citrullinated peptide positivity 57%/54%, presence of radiographic erosions: 66%. Wrist and metacarpophalangeal MRI (MCP-MRI) data were available for 287 and 241 patients, respectively. MRI inflammatory activity in wrist and/or MCP joints was observed in the majority [synovitis: 95%, bone edema (osteitis): 35%] of patients. The median (IQR) RAMRIS score was 6 (3–9) for synovitis and 0 (0–2) for osteitis. Synovitis and osteitis were not less frequent in DAS28 clinical remission (synovitis/osteitis 96%/35%) than LDA (91/36). A trend towards lower frequencies of osteitis in patients in SDAI and CDAI remission was observed. Conclusion. Subclinical inflammation was identified by MRI in the majority of RA patients in clinical remission or LDA state. This may explain structural progression in such patients. Further work is required to understand the place of modern imaging in future remission criteria.

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

Bone edema on magnetic resonance imaging is an independent predictor of rheumatoid arthritis development in patients with early undifferentiated arthritis

OBJECTIVE To study magnetic resonance imaging (MRI) as a tool for early diagnosis of rheumatoid arthritis (RA) in patients with early undifferentiated arthritis (UA). METHODS Patients (n = 116) without a specific rheumatologic diagnosis, but with ≥2 tender joints and/or ≥2 swollen joints among the metacarpophalangeal, proximal interphalangeal, wrist, or metatarsophalangeal (MTP) joints for >6 weeks but <24 months, underwent clinical, biochemical, conventional radiographic, and MRI examinations and were followed up for >12 months for the final diagnosis of RA or non-RA. Based on univariate analyses, clinical, biochemical, and imaging parameters were selected for inclusion as explanatory variables in multiple logistic regression analysis, with development of RA as the dependent variable. A prediction model was developed, and its performance was tested and compared with that of a previous model developed by van der Helm-van Mil et al (the vdHvM model). RESULTS Of the 116 patients with early UA, 27 (23.3%) developed RA. When the prediction model was applied, which included as explanatory variables presence of hand arthritis, positivity for rheumatoid factor (RF), morning stiffness lasting >1 hour, and the Outcome Measures in Rheumatology Clinical Trials MRI summary score for bone edema in the MTP and wrist joints, the outcome of RA or non-RA was correctly identified in 82% of the patients (sensitivity 81%, specificity 82%). Another cutoff value for the prediction index in the model would allow a higher specificity (98%) and higher accuracy (83%), but lower sensitivity (36%). With the vdHvM model, RA/non-RA was predicted in 60.2% of the population. CONCLUSION MRI evidence of bone edema in the MTP and wrist joints is an independent predictor of future RA in patients with early UA. A prediction model that includes the variables clinical hand arthritis, morning stiffness, positivity for RF, and bone edema on MRI in the MTP and wrist joints correctly identified the development or lack of development of RA in 82% of patients.

Determining a Magnetic Resonance Imaging Inflammatory Activity Acceptable State Without Subsequent Radiographic Progression in Rheumatoid Arthritis: Results from a Followup MRI Study of 254 Patients in Clinical Remission or Low Disease Activity

Objective. To assess the predictive value of magnetic resonance imaging (MRI)-detected subclinical inflammation for subsequent radiographic progression in a longitudinal study of patients with rheumatoid arthritis (RA) in clinical remission or low disease activity (LDA), and to determine cutoffs for an MRI inflammatory activity acceptable state in RA in which radiographic progression rarely occurs. Methods. Patients with RA in clinical remission [28-joint Disease Activity Score-C-reactive protein (DAS28-CRP) < 2.6, n = 185] or LDA state (2.6 ≤ DAS28-CRP < 3.2, n = 69) with longitudinal MRI and radiographic data were included from 5 cohorts (4 international centers). MRI were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI scoring system (RAMRIS). Statistical analyses included an underlying conditional logistic regression model stratified per cohort, with radiographic progression as dependent variable. Results. A total of 254 patients were included in the multivariate analyses. At baseline, synovitis was observed in 95% and osteitis in 49% of patients. Radiographic progression was observed in 60 patients (24%). RAMRIS synovitis was the only independent predictive factor in multivariate analysis. ROC analysis identified a cutoff value for baseline RAMRIS synovitis score of 5 (maximum possible score 21). Rheumatoid factor (RF) status yielded a significant interaction with synovitis (p value = 0.044). RF-positive patients with a RAMRIS synovitis score of > 5 vs ≤ 5, had an OR of 4.4 (95% CI 1.72–11.4) for radiographic progression. Conclusion. High MRI synovitis score predicts radiographic progression in patients in clinical remission/LDA. A cutoff point for determining an MRI inflammatory activity acceptable state based on the RAMRIS synovitis score was established. Incorporating MRI in future remission criteria should be considered.

Magnetic resonance imaging for accelerated assessment of drug effect and prediction of subsequent radiographic progression in rheumatoid arthritis : a study of patients receiving combined anakinra and methotrexate treatment

Objectives: By MRI to assess the efficacy of addition of anakinra for controlling synovitis and stopping erosive progression in patients with clinically active RA despite receiving methotrexate, and to determine the predictive value of MRI for subsequent radiographic erosive progression. Methods: 100 mg anakinra subcutaneously/day was added to the treatment of 17 patients with clinically active RA despite methotrexate. MRI of the non-dominant wrist and 2nd-5th MCP joints (OMERACT evaluation) was performed at weeks 0, 12, and 36, and radiography of both hands and wrists (modified Sharp evaluation) at weeks 0 and 36. Results: MRI synovitis scores were not significantly changed. Radiography of both hands and wrists after 36 weeks showed erosive progression in 11 patients, and MRI after 12 weeks in 10 patients. Nine of 10 patients with MRI progression at 12 weeks had radiographic progression at 36 weeks. Baseline MRI synovitis and erosion scores, but no clinical/biochemical parameters, correlated significantly with subsequent erosive progression. Conclusion: Addition of anakinra did not significantly reduce MRI signs of synovitis, and most patients had progressive joint destruction. Baseline MRI findings predicted subsequent radiographic erosive progression. Unilateral wrist and MCP joint MRI after 12 weeks had a similar sensitivity for detection of erosive progression as bilateral hand and wrist radiography after 36 weeks.

Short- and long-term efficacy of intra-articular injections with betamethasone as part of a treat-to-target strategy in early rheumatoid arthritis: impact of joint area, repeated injections, MRI findings, anti-CCP, IgM-RF and CRP

Objective To investigate the short-term and long-term efficacy of intra-articular betamethasone injections, and the impact of joint area, repeated injections, MRI pathology, anticyclic citrullinated peptide (CCP) and immunoglobulin M rheumatoid factor (IgM-RF) status in patients with early rheumatoid arthritis (RA). Methods During 2 years of follow-up in the CIMESTRA trial, 160 patients received intra-articular betamethasone in up to four swollen joints/visit in combination with disease-modifying antirheumatic drugs. Short-term efficacy was assessed by EULAR good response. Long-term efficacy by Kaplan–Meier plots of the joint injection survival (ie, the time between injection and renewed flare). Potential predictors of joint injection survival were tested. Results 1373 Unique joints (ankles, elbows, knees, metacarpophalangeal (MCP), metatarsophalangeal, proximal interphalangeal (PIP), shoulders, wrists) were injected during 2 years. 531 Joints received a second injection, and 262 a third. At baseline, the median numbers of injections (dose of betamethasone) was 4 (28 mg), declining to 0 (0 mg) at subsequent visits. At weeks 2, 4 and 6, 50.0%, 58.1% and 61.7% had achieved a EULAR good response. After 1 and 2 years, respectively, 62.3% (95% CI 58.1% to 66.9%) and 55.5% (51.1% to 60.3%) of the joints injected at baseline had not relapsed. All joint areas had good 2-year joint injection survival, longest for the PIP joints: 73.7% (79.4% to 95.3%). 2-Year joint injection survival was higher for first injections: 56.6% (53.7% to 59.8%) than for the second: 43.4% (38.4% to 49.0%) and the third: 31.3% (25.0% to 39.3%). Adverse events were mild and transient. A high MRI synovitis score of MCP joints and anti-CCP-negativity were associated with poorer joint injection survival, whereas IgM-RF and C-reactive protein were not. Conclusion In early RA, intra-articular injections of betamethasone in small and large peripheral joints resulted in rapid, effective and longlasting inflammatory control. The cumulative dose of betamethasone was low, and the injections were well tolerated.

Conventional radiography requires a MRI-estimated bone volume loss of 20% to 30% to allow certain detection of bone erosions in rheumatoid arthritis metacarpophalangeal joints

The aim of this study was to demonstrate the ability of conventional radiography to detect bone erosions of different sizes in metacarpophalangeal (MCP) joints of rheumatoid arthritis (RA) patients using magnetic resonance imaging (MRI) as the standard reference. A 0.2 T Esaote dedicated extremity MRI unit was used to obtain axial and coronal T1-weighted gradient echo images of the dominant 2nd to 5th MCP joints of 69 RA patients. MR images were obtained and evaluated for bone erosions according to the OMERACT recommendations. Conventional radiographs of the 2nd to 5th MCP joints were obtained in posterior-anterior projection and evaluated for bone erosions. The MRI and radiography readers were blinded to each others assessments. Grade 1 MRI erosions (1% to 10% of bone volume eroded) were detected by radiography in 20%, 4%, 7% and 13% in the 2nd, 3rd, 4th and 5th MCP joint, respectively. Corresponding results for grade 2 erosions (11% to 20% of bone volume eroded) were 42%, 10%, 60% and 24%, and for grade 3 erosions (21% to 30% of bone volume eroded) 75%, 67%, 75% and 100%. All grade 4 (and above) erosions were detected on radiographs. Conventional radiography required a MRI-estimated bone erosion volume of 20% to 30% to allow a certain detection, indicating that MRI is a better method for detection and grading of minor erosive changes in RA MCP joints.

Does low-field dedicated extremity MRI (E-MRI) reliably detect bone erosions in rheumatoid arthritis? A comparison of two different E-MRI units and conventional radiography with high-resolution CT scanning

Objectives: To compare the ability of two different E-MRI units and conventional radiography (CR) to identify bone erosions in rheumatoid arthritis (RA) metacarpophalangeal (MCP) and wrist joints with CT scanning as the standard reference method. Methods: 20 patients with RA and 5 controls underwent CR, CT and two E-MRI examinations (Esaote Biomedica Artoscan and MagneVu MV1000) of one hand during a 2-week period. In all modalities, each bone of the wrist and MCP joints was blindly evaluated for erosions. MagneVu images were also assessed for the proportion of each bone being visualised. Results: 550 bones were examined. CT, Artoscan, MagneVu and CR detected 188, 116, 55 and 45 bones with erosions, respectively. The majority were located in the carpal bones. The sensitivity of the Artoscan for detecting erosions was higher than that of the MagneVu and CR (MCP joints: 0.68, 0.54 and 0.57, respectively; wrists: 0.50, 0.23 and 0.29). Corresponding specificities for detecting erosions were 0.94, 0.93 and 0.99, respectively, in the MCP joints and 0.92, 0.98 and 0.98 in the wrist. The MagneVu allowed visualisation of 1.5 cm of the ventral-dorsal diameter of the bone. In the wrist, 31.6% of bones were visualised entirely and 37.9% of bones were 67–99% visualised. In MCP joints, 84.2% of bones were visualised entirely and 15.8% of bones were 67–99% visualised. Conclusion: With CT as the reference method for detecting erosions in RA hands, the Artoscan showed higher sensitivity than the MagneVu and CR. All imaging modalities had high specificities. The better performance of the Artoscan should be considered when selecting an imaging method in RA.