• Tomographic viewing perspective
  
  • Facilitates dimensional measurements by eliminating magnification and morphological distortion caused by projectional radiography
  • Increases sensitivity for detecting bone erosions by eliminating superimposition of overlapping structures, which can obscure abnormalities on radiographs
     
• Unparalleled tissue contrast
  
  • Allows direct visualization of marrow edema / inflammation, synovial tissue and effusion, articular cartilage, tendons and tendon sheaths, intra-articular and peri-articular ligaments, which cannot be seen with x-rays. This makes whole-organ assessment of the joint possible
  • Allows assessment of compositional (collagen, proteoglycan, water) and physiological (vascular perfusion) features in addition to morphology
     
• Digital image format
  
  • Compared to hard copy films, electronic images offer safer and more economical archival, rapid recovery and distribution to multiple readers, computer aided analysis and facilitated regulatory submission and auditing

These advantages can be leveraged in clinical trials of rheumatoid arthritis to extend the scope of structural assessments and increase discriminative power so as to reduce the number of patients and study sites, and shorten measurement intervals required to demonstrate efficacy. This can reduce uncertainty and cost in drug development dramatically, and also potentially accelerate market entry and revenues realized over the patent life of a new drug. With over 9,000 MRI systems available worldwide (over 4,000 systems in the U.S. alone), MR image acquisition is no longer restricted to specialized research facilities, and can be supported in large multi-center and multi-national clinical trials. Recent technological innovations in this area promise to markedly decrease the cost and increase the versatility and convenience of this remarkable technology for rheumatoid arthritis in the near future.

MRI is particularly useful for internal decision-making, as it can provide faster readouts in proof-of-concept, dose-selection and interval-selection studies than is possible with more conservative methods, which are required for pivotal therapeutic confirmatory studies seeking regulatory approval. Proper application of innovative methods in these early Phase II and III studies can shave several months off a drug development program.

MRI of Bone Erosion

MRI shows more than twice the sensitivity for bone erosion as conventional radiography. Increased sensitivity for bone erosion is particularly useful in:

• Active comparitor studies, in which differences in progression rates
  can be very small
• Internal decision-making
• proof of concept
• dose selection
• measurement interval selection
• interim evaluation
• Early rheumatoid arthritis (<1 year duration) when erosion is minimal
  

		MRI can reveal erosions that are invisible on X-ray. A. High quality radiograph of the hand of a patient with rheumatoid arthritis shows no erosions. B. MRI image of the same hand imaged with a small 0.2-Tesla dedicated extremity MRI system clearly delineates a radiographically occult erosion in the third metacarpal head.

Bone inflammation progresses to erosion. Spin-echo (upper panel) and fat-suppressed 3D gradient-echo (lower panel) images of a metacarpophalangeal joint at baseline, 3 months and 6 months. show no abnormalities at baseline, an ill-defined area of marrow inflammation at 3 months, and a sharply marginated bone erosion at 6 months.

SynaVu™ MRI Reading System

		Serial MRI reading. Four windows containing stacked coronal MRI images of the same hand from three time points in a study. The images in these windows are magnified to facilitate reading. The top left window contains a non-magnified image from one of the three data sets for anatomic reference.

The SynaVu™ system allows the reader to scroll back and forth through the anatomical slices to gain a 3D perspective of the joint destruction. The SynaVu™ reading system also provides numerous tools to aid in image analysis and measurement, and is capable of sophisticated multi-spectral and temporal data fusion to facilitate longitudinal assessements or quantify the volume of newly eroded bone. Validated electronic score sheets with reader sign-off and automatic databasing of the results are additional features of the system.

MRI data fusion and quantification. With multi-spectral and temporal data fusion, information from mages acquired with different MRI pulse sequences at multiple time points and at different imaging sites are fused together to generate a single image that maps tissues and changes over time in different colors. This can greatly facilitate longitudinal assessments and allow volumetric quantification of the tissue changes.

MRI of Synovitis

One of the most exciting features of MRI is its unique ability to detect and quantify pre-erosive changes, such as synovitis. Quantitative MRI markers of synovitis include the volume of synovial tissue and synovial fluid, and the rate of synovial enhancement following intravenous injection of contrast material. These can be used for:

•   Patient selection
   
  • Demonstration of synovitis can be a useful diagnostic aid in patients with very early rheumatoid arthritis (<6 months duration), in which bone erosions are scarce or absent.
  • The volume of synovitis at baseline predicts bone erosion on follow-up. This can help identify rapid progressors for proof-of-concept, dose-selection or other decision-making studies in which rapid results are the priority.
     
•  Rapid pharmacodynamic assessments
   
  • Since MRI markers of synovitis track vascular changes, therapeutic effects manifest extremely rapidly -often within only weeks of initiating therapy.
     

		Rapid therapeutic effect on synovitis. A. Transverse MR image of a wrist following iv Gd-DTPA shows extensive enhancing synovitis and distention of the synovial cavity. B. Repeat MRI with Gd-DTPA after 3 months of TNF-suppressive therapy shows marked reduction in the amount of enhancing tissue.

Imaging synovial enhancement rate. The graph depicts the rate of change in MR signal in synovial tissue in a patient with rheumatoid arthritis immediately prior to (closed circles) and 5 weeks following (open circles) initiation of treatment with methotrexate. Note the reduction in both the rate and maximum degree of enhancement following treatment.

MRI of Tendon Rupture

Tendon rupture is a serious complication of rheumatoid arthritis. Tendons get damaged in this disease by rubbing over jagged erosion margins or by direct tenosynovial invasion. Often, neither the patient nor the clinician are aware of the initial rupture. MRI is highly sensitive to the full spectrum of tendon pathology, and has been shown to identify tendonitis and rupture with greater accuracy than does clinical examination.

Flexor tendon rupture. Transverse spin-echo image of the metacarpophalangeal joints following i.v. injection of Gd-DTPA shows enlargement and deformity of the flexor tendon of the index finger, indicative of partial rupture. The other flexor tendons show mild tenosynovitis but are intact.

MRI of Ligament Damage

Ligament damage is an important cause of joint dysfunction in patients with rheumatoid arthritis. MRI can demonstrate inflammation and damage of inter-osseous ligaments in the hands and other joints of these patients. Bone erosions often develop at the entheseal insertions of these ligamentous. MRI can discriminate between active and inactive foci of enthesitis.

MRI identifies active enthesitis. Coronal T1-weighted (A) and fat-suppressed T2-weighted spin-echo (B) images of a metacarpophalangeal joint show enthesitis at the metacarpal insertion of the radial collateral ligament. A small sub-ligamentous erosion is forming at this site. In contrast, the ulnar collateral ligament of the same joint is intact and not inflamed.