MRI assessment of suppression of structural damage in patients with rheumatoid arthritis receiving rituximab: results from the randomised, placebo-controlled, double-blind RA-SCORE study.

OBJECTIVE: To evaluate changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in a Phase 3 study of patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) who were naive to biological therapy. METHODS: Patients were randomised to receive two infusions of placebo (n=63), rituximab 500 mg (n=62), or rituximab 1000 mg (n=60) intravenously on days 1 and 15. MRI scans and radiographs of the most inflamed hand and wrist were acquired at baseline, weeks 12 (MRI only), 24 and 52. The primary end point was the change in MRI erosion score from baseline at week 24. RESULTS: Patients treated with rituximab demonstrated significantly less progression in the mean MRI erosion score compared with those treated with placebo at weeks 24 (0.47, 0.18 and 1.60, respectively, p=0.003 and p=0.001 for the two rituximab doses vs placebo) and 52 (-0.30, 0.11 and 3.02, respectively; p<0.001 and p<0.001). Cartilage loss at 52 weeks was significantly reduced in the rituximab group compared with the placebo group. Other secondary end points of synovitis and osteitis improved significantly with rituximab compared with placebo as early as 12 weeks and improved further at weeks 24 and 52. CONCLUSIONS: This study demonstrated that rituximab significantly reduced erosion and cartilage loss at week 24 and week 52 in MTX-inadequate responder patients with active RA, suggesting that MRI is a valuable tool for assessing inflammatory and structural damage in patients with established RA receiving rituximab. TRIAL REGISTRATION NUMBER: NCT00578305.

Evaluating joint-space narrowing and cartilage loss in rheumatoid arthritis by using MRI.

INTRODUCTION: Magnetic resonance imaging (MRI) has been shown to be superior to radiography (XR) for assessing synovitis, osteitis, and bone erosion in rheumatoid arthritis (RA), particularly in clinical trials. However, relatively little has been reported on the ability of MRI to evaluate articular cartilage loss, or joint-space narrowing (JSN), in the hands and wrists. In a previous study, we adapted the nine-point Genant-modified Sharp XR-JSN score for use with MRI (MRI-JSN). In this study, we compare MRI-JSN with XR-JSN by using images from two multicenter clinical trials. METHODS: Baseline XR and 1.5-Tesla MR images of one hand and wrist from each of 47 subjects with RA enrolled in one of two multicenter clinical trials were evaluated by using the XR-JSN and MRI-JSN methods by a single radiologist experienced in the two methods. Radiographs and MR images were read independently on different occasions. RESULTS: In total, 575 of 611 joints were compared (one metacarpophalangeal joint of the thumb and 35 proximal interphalangeal joints were outside the MRI field of view and could not be assessed). The 22 (47%) subjects showed JSN with both XR and MRI, and 25 (53%) subjects showed no JSN with either method. No subject showed JSN with only one or the other method. MRI showed high agreement with XR (intraclass correlation coefficient = 0.83). Sensitivity of MRI for JSN, by using XR as the gold standard, was 0.94; specificity was 0.91; accuracy was 0.91; positive predictive value was 0.64; and negative predictive value was 0.99. CONCLUSIONS: This validation exercise suggests that MRI JSN scoring may offer a viable alternative to XR JSN scoring in multicenter clinical trials of RA. However, the relative longitudinal sensitivity of MRI to change and the ability to discriminate therapeutic effect on JSN were not evaluated in this study.

Magnetic resonance imaging in rheumatoid arthritis clinical trials: emerging patterns based on recent experience.

OBJECTIVE: The current validated magnetic resonance imaging (MRI) scoring method for rheumatoid arthritis (RA) in clinical trials, RA MRI Score (RAMRIS), incorporates all metacarpophalangeal (MCP) and wrist joints except MCP-1. The experience with radiographic scoring, however, was that excluding certain bones in the wrist improved the discriminative power for changes over time. In this study, we pool MRI data from randomized controlled clinical trails (RCT) to determine which combination of MCP and wrist joints are most sensitive and discriminative for structural changes over time. METHODS: MR images from 4 multicenter RCT, including 522 RA patients, were read by 2 radiologists, using the RAMRIS scoring system for erosion, osteitis, and synovitis. In one RCT, joint-space narrowing (JSN) was assessed cross-sectionally by one radiologist using a previously validated method. Baseline frequencies of erosion, JSN, osteitis, and synovitis of different bones and joints in the hand and wrist were compared. Intraclass correlation coefficients between readers were determined for each location. Finally, 7 different combinations of bone/joint locations were compared for their ability to discriminate subjects showing increases or decreases from baseline greater than or equal to smallest detectable changes (SDC) at Weeks 12 or 24. RESULTS: Frequency of involvement and reliability for assessing change varied by location. As in earlier analyses, excluding certain wrist bones increased the percentage of subjects showing changes greater than or equal to SDC. CONCLUSION: These findings suggest that excluding wrist bones that do not frequently or reliably demonstrate structural changes improves the discriminative power of the RAMRIS scoring system.

High circulating vascular endothelial growth factor (VEGF) is related to a better systolic function in diabetic hypertensive patients.

BACKGROUND: VEGF seems to have a protective role on cardiac microcirculation, but no data are available on its action on cardiac function and morphology in diabetic patients. We sought to test the hypothesis that circulating VEGF levels could influence the cardiac performance in type 2 diabetic hypertensive patients. METHODS: We studied 30 patients with type 2 diabetes and hypertension, without severe cardiac, retinal, renal and peripheral vascular damage. Ten non-diabetic hypertensive patients represented the control group. VEGF plasma levels (ELISA) and echocardiographic parameters were evaluated. RESULTS: Diabetic patients had VEGF plasma levels higher than hypertensive non-diabetic subjects [median 82 (IQR 12-190) vs 50.5 (IQR 28-77) pg/mL, p=0.05]. Simple linear regression analysis showed that VEGF levels are related to relative wall thickness (RWT) and both endocardial and midwall systolic parameters in the diabetic patients. Multiple linear regression analysis showed that RWT and ejection fraction (EF) were the only independent correlates of VEGF (r2=0.274, p=0.03, p=0.05; respectively). CONCLUSIONS: Our data showed that high VEGF plasma levels are associated to a better systolic function in diabetic hypertensive patients with cardiac remodeling. VEGF may play a role in the improvement of cardiac performance in diabetes.

Pre-perceptual pain sensory responses (N1 component) in type 1 diabetes mellitus.

We investigated the integrity of the ascending pathways for pain sensitivity in the early stage of type 1 diabetes mellitus, by measuring the N1 component and the conventional N2/P2 vertex potentials of laser evoked potentials (LEPs). Brain responses to laser stimuli were obtained in 21 healthy volunteers and 21 type 1 diabetic patients, without either clinical neuropathy or electrophysiological evidence of large-fiber damage. In diabetic patients N1 and P2 latencies were prolonged and the N1 and N2/P2 amplitudes were decreased after foot stimulation. A significant reduction of the conduction velocity of Adelta fibers in the lower limbs was also observed. LEPs reveal an early, subclinical and selective damage of pain sensation in diabetic patients. N1 and P2 potentials are delayed and decreased in parallel giving evidence that LEP abnormalities are not secondary to a cognitive dysfunction and mostly reflect a small-fiber dysfunction.