Synovitis in Knee Osteoarthritis Assessed by Contrast-enhanced Magnetic Resonance Imaging (MRI) is Associated with Radiographic Tibiofemoral Osteoarthritis and MRI-detected Widespread Cartilage Damage: The MOST Study

Study design and subjects

Subjects were participants in the Multicenter Osteoarthritis Study (MOST), a prospective study of 3026 persons aged 50–79 years with a goal of identifying risk factors for incident and progressive knee OA in a sample either with OA or at high risk of developing the disease. Those considered at high risk included persons who were overweight or obese, those with knee pain, aching, or stiffness on most of the previous 30 days, a history of knee injury that made it difficult to walk for at least 1 week, or previous knee surgery. Subjects were recruited from 2 US communities, Birmingham, Alabama, and Iowa City, Iowa. Details of subject inclusion, exclusion, and recruitment have been described^3,10. Subjects were excluded from MOST if they screened positive for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, reactive arthritis (previously known as Reiter syndrome), had renal insufficiency that required hemo- or peritoneal dialysis, a history of cancer (except for non-melanoma skin cancer), had or planned to have bilateral knee replacement surgery, were unable to walk without assistance, or were planning to move out of the area in the next 3 years. The study protocol was approved by the institutional review boards at the University of Iowa; University of Alabama, Birmingham; University of California, San Francisco; and Boston University Medical Campus; and written informed consent was obtained from all participants.

For our present study, we examined a subset of MOST subjects who volunteered to undergo a 1.5T CEMRI of 1 knee at the 30-month followup clinic visit. CEMRI were obtained on 1 knee only. To choose the knee to image, radiographs were read and the knee with the lower Kellgren-Lawrence (KL) grade was selected to avoid knees with severe OA and likely co-occurrence in these knees of structural features associated with pain. While assessment of pain was not part of our study, it was part of the ancillary study of MOST using CEMRI, from which our data were derived, and therefore the same selection criteria were applied. If the grade was the same for both knees, the dominant leg (which was defined as the leg with which the subject preferred to kick a ball) was chosen. CEMRI was performed on the same day or within 30 days of non-CEMRI obtained in all MRI eligible subjects in the parent study. For subjects with renal disease, diabetes, or those over the age of 65, serum creatinine was determined and the glomerular filtration rate (GFR) calculated before intravenous gadolinium administration. Those subjects with renal insufficiency (GFR < 30 ml/min) were excluded from the study. No adverse events following contrast administration were reported in any subjects. Figure 1 shows the flow chart of the subject selection process.

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Figure 1.

Flow chart showing subject inclusion and exclusion for the current study. CEMRI: contrast-enhanced magnetic resonance imaging; OA: osteoarthritis.

Radiographs

All subjects underwent weight-bearing posteroanterior fixed flexion knee radiographs using the protocol by Peterfy, et al, and an acrylic positioning frame (SynaFlexer)¹¹ at 30-month followup. A musculoskeletal radiologist (a non-author) and a rheumatologist (DTF) blinded to clinical data graded radiographs according to the KL grade¹², followed by an adjudication process (by 2 non-authors and DTF). The weighted kappa coefficient of interobserver reliability for the KL readings of the radiograph was 0.79.

MRI acquisition

In the MOST parent study, MR imaging without contrast enhancement was performed using a 1.0T extremity-based OrthOne scanner (GE Healthcare). Images were acquired using a circumferential extremity coil with fat-suppressed, fast spin echo, proton density-weighted sequence in 2 planes, sagittal [TR 4800 ms, TE 35 ms, 3.0 mm slice thickness, 0 mm interslice gap, field of view (FOV) 14 × 14 cm, matrix 288 × 192, NEX2]; and axial (TR 4700 ms, TE 13.2 ms, 3.0 mm slice thickness, 0 mm interslice gap, FOV 14 cm, matrix 288 × 192, NEX2) and a short-tau inversion recovery sequence in the coronal plane (TR 7820 ms, TE 14 ms, TI 100 ms, 3.0 mm slice thickness, 0 mm interslice gap, FOV 14 cm, matrix 256 × 256, NEX2).

For the purpose of our study, CEMRI were obtained with 1.5 T system (Siemens Symphony) with a circumferential extremity coil. Axial and sagittal fat-suppressed T1-weighted CE sequences were acquired (TR 600 ms, TE 13 ms, 3.0 mm slice thickness, 0.3 mm interslice gap, FOV 16 × 16 cm, matrix 512 × 512, ETL 1). Intravenous gadolinium [Magnevist (gadopentetate dimeglumine); Bayer Schering Pharma AG] or Omniscan (gadodiamide; GE Healthcare) was administered at a dose of 0.2 ml (0.1 mmol)/kg body weight. Two minutes after completing the injection of the gadolinium, sagittal sequences were obtained, immediately followed by the axial sequences. The timing of scanning (2 min postinjection) was chosen so that we could visualize the maximal synovial enhancement, and also to be able to complete acquisition of images before blurring of synovitis/effusion borderline occurred, caused by effusion enhancement from the periphery¹³. The CEMRI was performed on the same day or within 30 days of non-CEMRI scans obtained in all MRI-eligible subjects.

MRI interpretation

MRI readings were performed independently by 2 musculoskeletal radiologists (AG, FWR), with 11 and 9 years of experience, respectively, in semiquantitative MR assessment of knee OA, after an initial session of training and calibration with 20 test cases that were randomly selected. Axial and sagittal CEMRI sequences were used only for the purpose of synovitis assessment. Non-CEMRI was used for scoring of cartilage damage and meniscal damage. MR images were assessed using eFilm software (Version 2.0.0, Merge Healthcare).

We used a published scoring method for synovitis by Guermazi and colleagues⁷ based on CEMRI. Using this scoring method, synovitis was defined as enhancing thickened synovium (≥ 2 mm) and was evaluated at 11 sites of the joint, i.e., the medial and lateral parapatellar recess, suprapatellar, infrapatellar, intercondylar, medial and lateral perimeniscal, and adjacent to the anterior and posterior cruciate ligaments in all subjects. If knees presented with Baker’s cysts or loose bodies, those 2 sites were scored in addition. Synovial thickness was scored semiquantitatively based on the maximal thickness in any slice at each site as follows: grade 0 if < 2 mm, grade 1 if 2–4 mm, and grade 2 if > 4 mm⁷.

Cartilage damage was semiquantitatively assessed using the Whole Organ Magnetic Resonance Imaging Score (WORMS)¹⁴. In each of the 14 articular-surface subregions defined by WORMS, cartilage was scored using an 8-point scale: 0 = normal thickness and signal; 1 = normal thickness but increased signal on fat-suppressed proton density-weighted images; 2 = partial-thickness focal defect < 1 cm in greatest width; 2.5 = full-thickness focal defect < 1 cm in greatest width; 3 = multiple areas of partial-thickness (grade 2) defects intermixed with areas of normal thickness; 4 = diffuse (≥ 75% of the region) partial-thickness loss; 5 = multiple areas of full-thickness loss (grade 2.5) or a grade 2.5 lesion wider than 1 cm but < 75% of the region; 6 = diffuse (≥ 75% of the region) full-thickness loss. The number of subregions with a score of 2 or above was noted for each knee, and knees with 4 or more subregions with cartilage score of 2 or above were considered to have widespread cartilage damage. However, there is no definitive definition of “widespread cartilage damage” and the change in the threshold may produce different results. Thus, we also used an alternative definition for “widespread” cartilage damage as having cartilage score of 2 or above in 6 or more subregions.

Meniscal damage was also assessed using the WORMS system. The anterior, middle, and posterior thirds of each meniscus were scored for tears and degeneration using the following 5-point scale: 0 = normal; 1 = minimal radial or parrot beak tear; 2 = non-displaced tear or surgical repair; 3 = displaced tear or partial maceration or partial resection; 4 = complete maceration or total resection. The maximum score of all subregions in each meniscus was recorded and used for analyses.

Statistical analysis

For the CEMRI-based assessment of synovitis, we used the maximum synovitis score (1 or above in any location) from each knee as the definition of the presence of whole-knee synovitis. Interobserver and intraobserver reliability for each individual site was calculated using weighted kappa statistics on a set of 50 randomly selected MR examinations, which were re-read with an interval > 1 month between readings. The intraobserver reliability (weighted kappa) for the individual sites were 0.67–1.00 for reader 1 and 0.63–1.00 for reader 2. Interobserver reliability for the individual sites ranged 0.67–0.92⁷.

Logistic regression with the proportional odds model was used to assess the possible association of the presence of definite synovitis (defined by the summed synovitis score of 5 or above, as described) and the maximum synovitis score with the presence of radiographic OA (KL grade 2 or above), widespread cartilage damage (2 definitions, as defined), meniscal status (maximum WORMS score of 1 or above in any subregion), adjusting for age, sex, and body mass index (BMI).

We excluded the following subjects from these analyses: (1) those who had chondrocalcinosis on radiography, which may suggest the presence of calcium pyrophosphate deposition disease, an important concomitant condition in OA that may lead to synovitis as well as secondary OA, and (2) those who were taking antiinflammatory medication, which might have affected the severity of synovitis. All analyses were performed using SAS 9.1 (SAS Institute).