Both dynamic contrast-enhanced MRI (DCE-MRI) and RA MRI Score (RAMRIS) measures were equally sensitive to treatment effects with Infliximab.

With the technology advancements over the past decade, the treatment options for rheumatoid arthritis (RA) have expanded markedly. However, the acceptable duration for placebo control has also shortened, with rescue therapy typically offered within 14–16 weeks.

As per the evidences MRI has been more sensitive technique than radiography for detecting joint destruction in RA patients. A method developed by OMERACT (Outcome Measures in Rheumatology) known as RAMRIS is the widely used method for monitoring bone erosion, osteitis and synovitis with MRI in RA.  The 9-point cartilage score (CARLOS) is the another most commonly used MRI method for evaluating cartilage loss in RA. Dynamic contrast-enhanced MRI (DCE-MRI) is a quantitative method for assessing synovitis. It is based on the rate and magnitude of enhancement of synovial tissue by intravenously administered gadolinium-based contrast agents (GBCAs). However, it is more difficult to perform than the conventional contrast-enhanced MRI.

The present study by Chan Beals et al. have overcome these challenges by designing a DCE-MRI technique that simultaneously imaged the entire wrist and MCP joints. They compared the short-term discriminative power and sensitivity to change of the volume transfer rate of GBCA from the blood plasma in synovium (Ktrans) with those of RAMRIS-synovitis in a randomized, controlled, multicenter trial of infliximab plus methotrexate (MTX) versus placebo plus MTX in patients with active RA. Both imaging methods similarly discriminated infliximab treatment from placebo on measures related to synovial inflammation yet remained stable during placebo treatment. The RAMRIS and CARLOS methods had additional utility of identifying damage to bone and cartilage that could be prevented by infliximab. Appropriate MRI techniques, along with clinical measures of RA activity, should improve the characterization of drug effects on inflammation and structural damage in RA.

Rationale behind the research:

There are many technical challenges associated with performing DCE-MRI reproducibly across multiple time points and multiple clinical sites.

Therefore, the present study was performed to overcome these challenges by designing a DCE-MRI technique that simultaneously scans the entire wrist and MCP joints.  

Objective:

To compare the scope and the discriminative power of DCE-MRI with those of semiquantitative MRI scoring for evaluating treatments for RA in multicenter randomized clinical trials (RCTs). 

Study outcome measures:

Primary endpoint: DAS28(CRP) which is a composite score of the number of tender joints (28 joint count), the number of swollen joints (28 joint count), patient global assessment of disease (GADP) on a 100 mm visual analog scale (VAS), and CRP (mg/dL).

Time period: Week 0, 2, 6, and 14

Study Outcomes:

Clinical outcomes:

• After only two weeks of treatment, infliximab significantly reduced DAS28(CRP) disease activity compared with placebo (Figure 2A). At 14 weeks, infliximab-treated patients had a least squares (LS) mean DAS28(CRP) (90% CI) that was 1.0 (0.62, 1.43) units lower than that of placebo treated patients.

• There were significant treatment effects of infliximab over placebo at 14 weeks in each of the components of DAS28(CRP) except VAS(GADP). At 14 weeks, ACR 20 was 32.3% for placebo treated patients and 56.7% for infliximab treated patients (p<0.05 by Fisher’s exact test). At 14 weeks ACR 50 was 0% for placebo treated patients and 20% for infliximab treated patients (p<0.05 by Fisher’s exact test). 

Figure 2: 2(A) Mean changes from baseline (SE) in DAS28(CRP). 2(B) Mean changes from baseline in Dynamic Contrast Enhanced assessments of the wrist. 2(C) and 2(D) Mean changes from baseline in Dyamic Contrast Enhanced assessments of the metacarpophalengeal joint (MCP) and Enhancing tissue 

MRI outcomes:

• Out of 6325 bones only 20 (0.32%) were examined for erosion and 1 (0.02%) for osteitis. While only 6 (0.20%) of 3,050 joints examined for cartilage loss. All MCP and wrist joints were evaluable for assessing synovitis with RAMRIS and DCE-MRI. Inter-reader agreement was high: baseline ICCs for RAMRIS erosion, osteitis and synovitis and for CARLOS were 0.93, 0.92, 0.89 and 0.97, respectively. Sensitivity to change at the individual patient level was also high: SDCs were 1.52, 2.31, 2.24 and 1.25 units, respectively.
• Representative DCE-MRI images are shown in Figure 3. Mean Ktrans of synovium in the wrist and the MCPs each showed a significant treatment effect as early as 2 weeks following initiation of infliximab. This treatment effect was observed at each subsequent time point as well (Figure 2B and 2C). Placebo treatment resulted in no change in Ktrans of wrist or MCP synovium. Mean Ktrans of total enhancing tissue (synovitis and osteitis) in the wrist and MCPs similarly showed significant improvement at 2 weeks, 4 weeks and 14 weeks following treatment with infliximab but not placebo (Figure 2D).

Figure 3: Baseline vs Week 14 DCE-MRI

• Infliximab significantly reduced the RAMRIS scores for both synovitis and osteitis in the wrist and MCPs as early as 2 weeks, and maintained reduction through 14 weeks (p<0.001) (Figure 4 and Table 2). Both erosions and cartilage loss progressed in the placebo group, as expected for these measures of accumulating joint damage. The rates of progression were consistent with those reported from other RCT. Change from baseline in RAMRIS erosion scores became significantly different between infliximab and placebo groups by 14 weeks. Cartilage loss was evaluated at baseline and 14 weeks only (due to project resource limitations); infliximab significantly reduced progression of cartilage loss at 14 weeks (Table 2, p= 0.025). Cumulative probability plots showed no outliers in any of the change data (Figure 5).

Figure 4: 4(a) Mean changes from baseline (SE) in Rheumatoid Arthritis MRI Score (RAMRIS) of synovitis at the wrist. 4(b) Mean changes from baseline (SE) in Rheumatoid Arthritis MRI Score (RAMRIS) of metacarpophalangeal joint (MCP)

Figure 5: Cumulative probability of change from baseline in RAMRIS synovitis

Comparison among RA measures:

• At baseline, DAS28(CRP) correlated significantly with synovial K_trans in the wrist (Pearson correlation coefficient (90% CI) = 0.39 (0.19–0.55)) and MCPs (0.36 (0.16–0.53)) and with RAMRIS-synovitis in the wrist (0.29 (0.08–0.47)) and MCPs (0.54 (0.37–0.67)). Baseline DAS28(CRP) also correlated with baseline RAMRIS-osteitis in the MCPs (0.33 (0.13–0.51)), with baseline RAMRIS-erosion in the MCPs (0.43 (0.24–0.59)), and with baseline CARLOS (0.27 (0.04; 0.48)).
• Change in DAS28(CRP) after 14 weeks of infliximab treatment correlated with change in synovial K_trans in the MCPs (0.33 (0.03; 058) but not the wrist and similarly with change in RAMRIS-synovitis in the MCPs (0.39 (0.10–0.62)) but not the wrist.
• Synovial K_trans correlated with RAMRIS-synovitis scores at baseline in the wrist (0.53 (0.36–0.67)) and MCPs (0.61 (0.45–0.73)) and for change at 2 weeks, 4 weeks, and 14 weeks in the MCPs (0.34 (0.03–0.58), 0.39 (0.10–0.63) and 0.46 (0.18–0.67), respectively). Similarly, synovial K_trans correlated with RAMRIS-osteitis scores at baseline in the wrist (0.40 (0.21–0.57)) and MCPs (0.37 (0.17–0.54)) and in the MCPs for change at 2 weeks and 4 weeks (0.48 (0.21–0.69), and 0.54 (0.27–0.72), respectively), though not at 14 weeks. Synovial K_trans also correlated with RAMRIS-erosion scores at baseline in the MCPs (0.26 (0.05–0.45)) but not for change, and with CARLOS at baseline in the MCPs (0.28 (0.05–0.48)) but not for change.
• The effect size of DAS28(CRP) (90% CI) was 1.08 (0.63, 1.53), whereas those of K_trans-wrist and K_trans -MCP were 1.00 (0.55–1.45) and 0.87 (0.43–1.31), respectively. The effect sizes of other MRI measures were close to 1 (Fig 6).

Figure 6: Effect sizes of treatment responses for various measures of rheumatoid arthritis for infliximab 3 mg/kg vs placebo

Safety and tolerability:

• There were no serious adverse events or discontinuations reported for any reason. 

In the regulatory guidance, the unresponsive RA patients recover within 14-16 weeks. With the modern trend towards slowing structural progression rates, discriminating efficacy reliably with radiography would be challenging. In many of the RCTs, MRI has been shown to distinguish suppression of joint damage and inflammation in ≤12 weeks. In the current study, RAMRIS and CARLOS demonstrated that the bone erosion and cartilage loss were suppressed with infliximab within 14 weeks.

The results indicate that synovitis and osteitis are the underlying processes that drive bone erosions and cartilage loss in RA, which in turn lead to constant pain and physical impairment. In numerous multi-center RCTs, RAMRIS and CARLOS measures have been used successfully to demonstrate treatment efficacy. However, none of the studies reported the successful use of DCE-MRI in a multi-center RCTs. The present study successfully performed this technique in a multicenter clinical trial using a knee coil to image both the wrist and MCPs simultaneously. The correlations demonstrated in this study support the validity of these MRI endpoints as measures of clinical outcomes in RA. This study suggests that RAMRIS and K_trans have similar abilities to discriminate anti-inflammatory treatments. Since RAMRIS and CARLOS have the broader scope than DCE-MRI and are easier to implement in multicenter clinical trials, no advantage to recommend the use of DCE-MRI as applied in this study was reported.

DCE-MRI can be interpreted in a model-free fashion, by measuring the early-enhancement rate and maximal enhancement of the enhancement curves. These empirical measurements are reliable and have been correlated with cellular infiltration and vessel density in the rheumatoid synovium and are responsive to treatment. While somewhat easier to measure, these measurements depend on pulse sequence and machine parameters, rendering comparisons among centers difficult. Because of our interest in methodologies to support clinical testing of RA therapies, we used a compartment model to interpret DCE-MRI. The simple compartment model has one vascular compartment, and one tissue compartment and the measured signal is used to derive the constant of proportionality in the leak of GBCA from capillaries to tissue, K_trans. K_trans has been shown to discriminate among patient groups with early arthritis and change with treatment.

In Conclusion, it was demonstrated that both DCE-MRI and RAMRIS measures of RA inflammation are as sensitive to treatment effects with infliximab as is the standard clinical measure of RA activity. DAS28(CRP) identifying impacts as soon as 2 weeks in small numbers of patients. Furthermore, MRI measures of joint damage (RAMRIS-erosion and CARLOS) can discriminate treatment effects as early as 14 weeks. In contrast to clinical tests, however, MRI measures are not vulnerable to placebo effects. Appropriate MRI techniques, along with clinical measures of RA activity, should improve the discrimination of drug effects in reducing inflammation and structural damage in RA.