MRI assessment of early response to certolizumab pegol in rheumatoid arthritis

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MRI assessment of early response to certolizumab pegol in rheumatoid arthritis
Key Take-Away: 

This is the first Magnetic Resonance image Verified early response on rheumatoid factor Positive arthritis (MARVELOUS) that helps to identify the first time point of an MRI-verified response to Certolizumab pegol in patients with Rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by the joint inflammation and damage. Early joint inflammation, including synovitis and bone edema (osteitis), is an important predictor of subsequent structural damage, and reliable tools are needed for its measurement. Magnetic resonance imaging (MRI) can detect early joint inflammation with high sensitivity and without the use of radiation and allows earlier identification of joint damage than would be possible using conventional radiographs. 

ABSTRACT: 
Background: 

Rheumatoid arthritis (RA) is characterized by the joint inflammation and damage. Early joint inflammation, including synovitis and bone edema (osteitis), is an important predictor of subsequent structural damage, and reliable tools are needed for its measurement. Magnetic resonance imaging (MRI) can detect early joint inflammation with high sensitivity and without the use of radiation and allows earlier identification of joint damage than would be possible using conventional radiographs.

Furthermore, MRI findings in RA are known to be strong predictors of subsequent radiographic progression. The Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA MRI scoring system (RAMRIS) is a validated scoring system for assessing synovitis, bone edema and bone erosion. Joint inflammation, damage in RA and changes in synovitis and bone edema at 12 weeks after initiation of anti-tumor necrosis factor (anti-TNF) therapy have been reported to be significant in several clinical trials. Certolizumab pegol (CZP), a Pegylated Fc-free anti-TNF, is an ideal agent to study the issue, as clinical response is observed as early as 1 week following initiation of CZP therapy.

Rationale behind research

  1. No previous study has yet looked for the earliest time point when an anti-TNF therapy effect on synovitis and other imaging signs of active joint inflammation can be documented
  2. This study was designed by performing MRIs before and after CZP treatment initiation.
  • Objective

To identify the first time point of an MRI verified response to certolizumab pegol (CZP) therapy in patients with rheumatoid arthritis (RA)

Methods: 

  • Study outcomes
    • Primary outcome: change in synovitis score in the CZP group
    • Secondary outcome: change in bone edema (osteitis) and erosion scores and clinical outcome measures.
  • Time-points
    • Efficacy
    • Primary outcome: Baseline and weeks 1, 2, 4, 8 and 16
    • Secondary outcome: Baseline and weeks 1, 2, 4, 8 and 16
Results: 

  • Baseline: At week 16, significant reduction from baseline in synovitis score was reported in the CZP group
  • The median decrease from baseline in synovitis score for CZP patients was numerically higher compared with placebo→CZP patients at weeks 1–16
  • Bone marrow edema score was significantly reduced from baseline at week 16 in CZP group
  • Mean changes (SD) in synovitis score from baseline in the CZP group/placebo→CZP group respectively were −0.6 (1.8)/+0.1 (1.0) at week 1, −0.4 (1.6)/+0.2 (1.4) at week 2, −0.4 (1.6)/+0.2 (1.2) at week 4, −0.7 (2.6)/+0.2 (1.5) at week 8 and −1.0 (2.3)/ −0.2 (1.6) at week 16
  • For all RAMRIS (rheumatoid arthritis MRI scoring system) parameters (synovitis, bone edema, bone erosion), very good intra reader reliability (intraclass correlations >0.90) was observed, supporting the reliability of the data
  • At week 16, 95.2% of CZP-treated patients achieved a moderate or good European League against Rheumatism (EULAR) response, and 86.4% achieved an American College of Rheumatology (ACR20) response, with a median Disease Activity Score (DAS28(CRP)) score of 2.48
Conclusion: 

The result indicates that the study with multiple MRIs following initiation of anti-TNF therapy showed reduced OMERACT RAMRIS synovitis and bone edema scores at week 16. This confirms, in agreement with previous MRI studies of anti-TNF therapies, the effect of CZP on objective measures of synovitis volume and extent of osteitis, that is, on reducing inflammation in synovium and bone. Hence, this study provides important information on optimal MRI timing for subsequent trials.

At week 16, when high ACR and EULAR response rates were seen, indicating good clinical response to CZP, significant reductions from baseline occurred in two of the inflammatory. OMERACT RAMRIS parameters: synovitis and bone edema. These results are consistent with other studies assessing the effect of scores on MRI scans of the wrist and metacarpophalangeal (MCP) joints were the strongest predictor of radiographic progression in the subsequent 2 years. Furthermore, in a recent randomized controlled trial, an early reduction in bone marrow edema was shown to predict radiographic damage up to 2 years after treatment initiation.

Ann Rheum Dis 2015 Jun ; 74:1156–1163
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