Predictors of joint damage progression and stringent remission in patients with established rheumatoid arthritis in clinical remission.

OBJECTIVES: To study if clinical, radiographic and MRI markers can predict MRI and radiographic damage progression and achievement of stringent remission in patients with established RA in clinical remission followed by a targeted treatment strategy. METHODS: RA patients (DAS28-CRP <3.2, no swollen joints) receiving conventional synthetic DMARDs were randomized to conventional or MRI-targeted treat-to-target strategies with predefined algorithmic treatment escalations. Potentially predictive baseline variables were tested in multivariate logistic regression analyses. RESULTS: In the 171 patients included, baseline MRI osteitis independently predicted progression in MRI erosion [odds ratio (OR) 1.13 (95% CI 1.06, 1.22)], joint space narrowing [OR 1.15 (95% CI 1.07, 1.24)] and combined damage [OR 1.23 (95% CI 1.13, 1.37)], while tenosynovitis independently predicted MRI erosion progression [OR 1.13 (95% CI 1.03, 1.25)]. A predictor of radiographic erosion progression was age, while gender predicted progression in joint space narrowing. Following an MRI treat-to-target strategy predicted stringent remission across all remission definitions: Clinical Disease Activity Index remission OR 2.94 (95% CI 1.25, 7.52), Simplified Disease Activity Index remission OR 2.50 (95% CI 1.01, 6.66), ACR/EULAR Boolean remission OR 5.47 (95% CI 2.33, 14.13). Similarly, low tender joint count and low patient visual analogue scale pain and global independently predicted achievement of more stringent remission. CONCLUSION: Baseline MRI osteitis and tenosynovitis were independent predictors of 2 year MRI damage progression in RA patients in clinical remission, while independent predictors of radiographic damage progression were age and gender. Following an MRI treat-to-target strategy, low scores of patient-reported outcomes and low tender joint count predicted achievement of stringent remission. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT01656278.

Effect of Magnetic Resonance Imaging vs Conventional Treat-to-Target Strategies on Disease Activity Remission and Radiographic Progression in Rheumatoid Arthritis: The IMAGINE-RA Randomized Clinical Trial.

Importance: Whether using magnetic resonance imaging (MRI) to guide treatment in patients with rheumatoid arthritis (RA) improves disease activity and slows joint damage progression is unknown. Objective: To determine whether an MRI-guided treat-to-target strategy vs a conventional clinical treat-to-target strategy improves outcomes in patients with RA in clinical remission. Design, Setting, and Participants: Two-year, randomized, multicenter trial conducted at 9 hospitals in Denmark. Two hundred patients with RA in clinical remission (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] <3.2 and no swollen joints) were enrolled between April 2012 and June 2015. The final follow-up visit was April 2017. Interventions: Patients were randomly allocated (1:1) to an MRI-guided vs a conventional treat-to-target strategy. In the MRI-guided group, the treatment goal was absence of MRI bone marrow edema combined with clinical remission, defined as DAS28-CRP of 3.2 or less and no swollen joints. In the conventional group, the treatment goal was clinical remission. Main Outcomes and Measures: Co-primary outcomes were proportions of patients achieving DAS28-CRP remission (DAS28-CRP <2.6) and with no radiographic progression (no increase in total van der Heijde-modified Sharp score) at 24 months. Significance testing for the primary outcome was based on 1-sided testing. Secondary outcomes were clinical and MRI measures of disease activity, physical function, and quality of life. Results: Of 200 patients randomized (133 women [67%]; mean [SD] age, 61.6 [10.5] years; median baseline DAS28-CRP, 1.9 [interquartile range, 1.7-2.2]; van der Heijde-modified Sharp score, 18.0 [interquartile range, 7.0-42.5]), 76 patients (76%) in the MRI-guided group and 95 (95%) in the conventional group completed the study. Of these, 64 (85%) vs 83 (88%), respectively, reached the primary clinical end point (risk difference, -4.8% [1-sided 95% CI, -13.6% to + ∞; 1-sided P = .19]) and 49 (66%) vs 58 (62%), respectively, reached the primary radiographic end point (risk difference, 4.7% [1-sided 95% CI, -7.0% to + ∞; 1-sided P = .25). Of 10 key secondary end points, 8 were null and 2 showed statistically significant benefit for the MRI treat-to-target group. Seventeen patients (17%) in the MRI-guided treat-to-target group and 6 patients (6%) in the conventional treat-to-target group experienced serious adverse events. Conclusions and Relevance: Among patients with RA in clinical remission, an MRI-guided treat-to-target strategy compared with a conventional treat-to-target strategy did not result in improved disease activity remission rates or reduce radiographic progression. These findings do not support the use of an MRI-guided strategy for treating patients with RA. Trial Registration: ClinicalTrials.gov Identifier: NCT01656278.

Whole-body Magnetic Resonance Imaging Inflammation in Peripheral Joints and Entheses in Axial Spondyloarthritis: Distribution and Changes during Adalimumab Treatment.

OBJECTIVE: To investigate the distribution of whole-body magnetic resonance imaging (WB-MRI) inflammatory lesions of peripheral joints and entheses, and their response to adalimumab (ADA) treatment and agreement with clinical measures of disease activity in patients with axial spondyloarthritis (axSpA). METHODS: Explorative analysis of an investigator-initiated randomized controlled trial of ADA. WB-MRI was performed at weeks 0, 6, 24, and 48. Detailed analyses of WB-MRI lesions in peripheral joints and entheses were performed, including agreement with clinical measures of disease activity. RESULTS: WB-MRI inflammatory lesions were most frequently observed in the acromioclavicular, metatarsophalangeal, and wrist joints (> 10% of joints), and at the greater trochanter, calcaneal insertion of the Achilles tendon, and ischial tuberosity (> 15% of entheses). Inflammation resolved in ≥ 2/3 of involved sternoclavicular, metacarpophalangeal, first carpometacarpal, hip, and tarsometatarsal joints, and pubic symphyses and medial femoral condyles. In contrast, inflammation resolved in ≤ 1/6 of involved acromioclavicular joints, knee joints, and supraspinatus tendon insertions at humerus. Tenderness of joints and entheses agreed poorly with WB-MRI inflammation (κ < 0.40). Joint tenderness resolved more frequently in MRI-positive than MRI-negative joints (8/13, 62% vs 9/34, 26%) after 6 weeks of active treatment. CONCLUSION: Inflammatory lesions of peripheral joints and entheses in patients with predominantly axSpA, and changes therein, can be mapped using WB-MRI, and it may contribute to differentiate between inflammatory and noninflammatory joint tenderness. (Trial registration: ClinicalTrials NCT01029847).

Inflammatory and structural changes in vertebral bodies and posterior elements of the spine in axial spondyloarthritis: construct validity, responsiveness and discriminatory ability of the anatomy-based CANDEN scoring system in a randomised placebo-controlled trial.

BACKGROUND: The Canada-Denmark (CANDEN) definitions of spinal MRI lesions allow a detailed anatomy-based evaluation of inflammatory and structural lesions in vertebral bodies and posterior elements of the spine in patients with axial spondyloarthritis (axSpA). The objective was to examine the reliability, responsiveness and discrimination of scores for spinal inflammation, fat, bone erosion and new bone formation based on the CANDEN system and to describe patterns of inflammatory and structural lesions and their temporal development. METHODS: 49 patients with axSpA from an investigator-initiated, randomised, placebo-controlled trial of adalimumab underwent spinal MRI at weeks 0/6/24/48. MR images were scored according to the CANDEN system and the Spondyloarthritis Research Consortium of Canada (SPARCC) method. Total scores, and various subscores, were created by summing individual lesion scores. RESULTS: The CANDEN spine inflammation score had high responsiveness, similar to the SPARCC MRI spine index (Guyatt's responsiveness index 1.88 and 1.67, respectively), and discriminated between adalimumab and placebo treatment already at 6 weeks' follow-up (P=0.03). Anterior/posterior corner inflammation subscores showed similar responsiveness. Inter-reader reliability for the CANDEN spine inflammation and fat scores was good to very good for status and change scores (intraclass correlation coefficient (ICC)=0.71-0.92). Reliability for CANDEN new bone formation and erosion scores was good to very good for status scores (ICC=0.61-0.75) but, due to minimal progression, poor for change scores (ICC≤0.40). CONCLUSIONS: The CANDEN spine inflammation score showed good responsiveness, discrimination between active treatment and placebo and reliability. The CANDEN spine structural scores had good cross-sectional reliability, but longer studies are needed to investigate their sensitivity to change. TRIAL REGISTRATION NUMBER: NCT01029847; Results.

Whole-body Magnetic Resonance Imaging in Axial Spondyloarthritis: Reduction of Sacroiliac, Spinal, and Entheseal Inflammation in a Placebo-controlled Trial of Adalimumab.

OBJECTIVE: To investigate whether adalimumab (ADA) reduces whole-body (WB-) magnetic resonance imaging (MRI) indices for inflammation in the entheses, peripheral joints, sacroiliac joints, spine, and the entire body in patients with axial spondyloarthritis (axSpA). METHODS: An investigator-initiated, randomized, placebo-controlled, double-blinded 48-week followup trial included 49 patients with axSpA, who had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4.0 despite treatment with nonsteroidal antiinflammatory drugs and a clinical indication for tumor necrosis factor inhibitor treatment. Patients were randomized to subcutaneous ADA 40 mg or placebo every other week for 6 weeks; thereafter, all patients received ADA. Conventional MRI and WBMRI were performed at weeks 0, 6, 24, and 48. The primary WBMRI endpoint was the proportion of patients with an improvement in WBMRI total inflammation index above the smallest detectable change (SDC) at Week 6. RESULTS: The primary WBMRI endpoint (improvement of SDC > 2.3) was met in 11 (44%) patients in the ADA group and 3 (13%) patients in the placebo group (p = 0.025, Fisher's exact test). The primary conventional MRI endpoint, the minimally important change in Spondyloarthritis Research Consortium of Canada Spine MRI Inflammation Index at Week 6, was achieved by 9 (36%) patients in the ADA group and 4 (17%) patients in the placebo group (p = 0.20). The primary clinical endpoint, BASDAI reduction > 50% or 2.0 at Week 24, was attained by 32 (65%) patients. CONCLUSION: ADA provided significant reductions in WBMRI indices of peripheral, axial, and whole-body inflammation in patients with axSpA. WBMRI is promising for objective assessment and monitoring of peripheral and axial disease activity in future clinical trials.

Development and Validation of MRI Sacroiliac Joint Scoring Methods for the Semiaxial Scan Plane Corresponding to the Berlin and SPARCC MRI Scoring Methods, and of a New Global MRI Sacroiliac Joint Method.

OBJECTIVE: To develop semiaxial magnetic resonance imaging (MRI) scoring methods for assessment of sacroiliac joint (SIJ) bone marrow edema (BME) in patients with axial spondyloarthritis, and to compare the reliability with equivalent semicoronal scoring methods. METHODS: Two semiaxial SIJ MRI scoring methods were developed based on the principles of the semicoronal Berlin and Spondyloarthritis Research Consortium of Canada (SPARCC) methods. A global quadrant-based method was also developed. Baseline and 12-week MRI of the SIJ from 51 patients participating in a randomized double-blind placebo-controlled trial of adalimumab 40 mg every other week versus placebo were scored by the semiaxial and the corresponding semicoronal methods. Results were compared by linear regression analysis. The reproducibility and sensitivity were evaluated by intraclass correlation coefficients (ICC) and smallest detectable change [SDC, absolute values and percentage of the highest observed score (SDC-HOS)]. RESULTS: Interreader and intrareader ICC were moderate to very high for semiaxial scoring methods (baseline 0.83-0.88 and 0.85-0.97; change 0.33-0.78), while high to very high for semicoronal scoring methods (baseline 0.90-0.92 and 0.93-0.97; change 0.77-0.89). Association between semiaxial and semicoronal scores were high for both the Berlin and SPARCC method (baseline: R2 = 0.93 and 0.88; change: R2 = 0.82 and 0.87, respectively), while lower for the global method (baseline: R2 = 0.79; change: R2 = 0.54). The SDC-HOS were 9.8-18.6% and 5.9-10.7% for the semiaxial and semicoronal methods, respectively. CONCLUSION: Detection of SIJ BME in the semiaxial scan plane is feasible and reproducible. However, a slightly lower reliability of all 3 semiaxial methods supports the general practice of using the coronal scan-plane in therapeutic studies.

A prospective study comparing whole-body skeletal X-ray survey with 18F-FDG-PET/CT, 18F-NaF-PET/CT and whole-body MRI in the detection of bone lesions in multiple myeloma patients.

BACKGROUND: For decades, the most widely used imaging technique for myeloma bone lesions has been a whole-body skeletal X-ray survey (WBXR), but newer promising imaging techniques are evolving. PURPOSE: To compare WBXR with the advanced imaging techniques 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT), 18F-sodium fluoride (NaF) PET/CT and whole-body magnetic resonance imaging (WB-MRI) in the detection of myeloma bone lesions. MATERIAL AND METHODS: Fourteen patients with newly diagnosed multiple myeloma were prospectively enrolled. In addition to WBXR, all patients underwent FDG-PET/CT, NaF-PET/CT, and WB-MRI. Experienced specialists performed blinded readings based on predefined anatomical regions and diagnostic criteria. RESULTS: In a region-based analysis, a two-sided ANOVA test showed that the extent of detected skeletal disease depends on the scanning technique (P < 0.0001). Tukey's multiple comparison test revealed that WB-MRI on average detects significantly more affected regions than WBXR (P < 0.005), FDG-PET/CT (P < 0.0001), and NaF-PET/CT (P < 0.05). In a patient-based analysis, a Cochran's Q test showed that there are no significant differences in the proportion of patients with bone disease detected by the different scanning techniques (P = 0.23). Determination of intrareader variability resulted in Kappa coefficients corresponding to moderate (FDG-PET/CT) and substantial agreement (WB-MRI, WBXR, NaF-PET/CT). CONCLUSION: WB-MRI detects on average significantly more body regions indicative of myeloma bone disease compared to WBXR, FDG-PET/CT, and NaF-PET/CT. The lack of significance in the patient-based analysis is most likely due to the small number of study participants.

Course of Magnetic Resonance Imaging-Detected Inflammation and Structural Lesions in the Sacroiliac Joints of Patients in the Randomized, Double-Blind, Placebo-Controlled Danish Multicenter Study of Adalimumab in Spondyloarthritis, as Assessed by the Berlin and Spondyloarthritis Research Consortium of Canada Methods.

OBJECTIVE: To investigate changes in magnetic resonance imaging (MRI)-assessed inflammation and structural lesions in the sacroiliac (SI) joints during treatment with adalimumab versus placebo. METHODS: In a 48-week double-blind, placebo-controlled trial, 52 patients with spondyloarthritis were randomized to receive subcutaneous injections of either adalimumab 40 mg (n = 25) or placebo (n = 27) every other week for 12 weeks. Patients in the adalimumab group continued to receive and patients in the placebo group were switched to adalimumab 40 mg every other week for an additional 12 weeks. MRI of the SI joints was performed at weeks 0, 12, 24, and 48, and the images were assessed independently in a blinded manner using the modified Berlin and the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores for inflammation and structural lesions of the SI joints. RESULTS: At baseline, 56% of the adalimumab group and ∼72% of the placebo group had an MRI-assessed inflammation score of ≥1. Among the patients with inflammation at baseline, the mean percent reductions in MRI scores for inflammation from week 0 to 12 were greater in the adalimumab group compared with the placebo group (Berlin method, -62% versus -5%; SPARCC method, -58% versus -12% [both P < 0.04]). Furthermore, the mean SPARCC erosion score decreased (-0.6) and the SPARCC backfill score increased (+0.8) in the adalimumab group from week 0 to week 12. From week 12 to week 24, larger absolute reductions in the Berlin/SPARCC inflammation scores and the SPARCC erosion score and larger increases in the Berlin/SPARCC fatty lesion scores were seen in the placebo group compared with the adalimumab group. In univariate regression analyses (analysis of covariance) and multivariate stepwise regression analyses, treatment with adalimumab was independently associated with regression of the SPARCC erosion score from week 0 to 12 but not with changes in the other types of MRI lesions. CONCLUSION: Significant changes in the Berlin and SPARCC MRI-assessed inflammation scores and in the SPARCC MRI-assessed erosion scores occurred within 12 weeks after initiation of adalimumab. Tumor necrosis factor inhibitor treatment was associated with resolution of erosions and the development of backfill.