Marie-Pierre Hellio Le Graverand

Change in cartilage morphometry: a sample of the progression cohort of the Osteoarthritis Initiative

Objective: The performance characteristics of hyaline articular cartilage measurement on magnetic resonance imaging (MRI) need to be accurately delineated before widespread application of this technology. Our objective was to assess the rate of natural disease progression of cartilage morphometry measures from baseline to 1 year in knees with osteoarthritis (OA) from a subset of participants from the Osteoarthritis Initiative (OAI). Methods: Subjects included for this exploratory analysis are a subset of the approximately 4700 participants in the OAI Study. Bilateral radiographs and 3T MRI (Siemans Trio) of the knees and clinical data were obtained at baseline and annually in all participants. 160 subjects from the OAI Progression subcohort all of whom had both frequent symptoms and, in the same knee, radiographic OA based on a screening reading done at the OAI clinics were eligible for this exploratory analysis. One knee from each subject was selected for analysis. 150 participants were included. Using sagittal 3D DESSwe (double echo, steady-state sequence with water excitation) MR images from the baseline and 12 follow-up month visit, a segmentation algorithm was applied to the cartilage plates of the index knee to compute the cartilage volume, normalised cartilage volume (volume normalised to bone surface interface area), and percentage denuded area (total cartilage bone interface area denuded of cartilage). Results: Summary statistics of the changes (absolute and percentage) from baseline at 1 year and the standardised response mean (SRM), ie, mean change divided by the SD change were calculated. On average the subjects were 60.9 years of age and obese, with a mean body mass index of 30.3 kg/m2. The SRMs for cartilage volume of various locations are: central medial tibia −0.096; central medial femur −0.394; and patella −0.198. The SRMs for normalised cartilage volume of the various locations are central medial tibia −0.044, central medial femur −0.338 and patella −0.193. The majority of participants had a denuded area at baseline in the central medial femur (62%) and central medial tibia (60%). In general, the SRMs were small. Conclusions : These descriptive results of cartilage morphometry and its change at the 1-year time point from the first substantive MRI data release from the OAI Progression subcohort indicate that the annualised rates of change are small with the central medial femur showing the greatest consistent change.

Change in regional cartilage morphology and joint space width in osteoarthritis participants versus healthy controls: a multicentre study using 3.0 Tesla MRI and Lyon–Schuss radiography

Objective: Cartilage morphology displays sensitivity to change in osteoarthritis (OA) with quantitative MRI (qMRI). However, (sub)regional cartilage thickness change at 3.0 Tesla (T) has not been directly compared with radiographic progression of joint space narrowing in OA participants and non-arthritic controls. Methods: A total of 145 women were imaged at 7 clinical centres: 86 were non-obese and asymptomatic without radiographic OA and 55 were obese with symptomatic and radiographic OA (27 Kellgren–Lawrence grade (KLG)2 and 28 KLG3). Lyon–Schuss (LS) and fixed flexion (FF) radiographs were obtained at baseline, 12 and 24 months, and coronal spoiled gradient echo MRI sequences at 3.0 T at baseline, 6, 12 and 24 months. (Sub)regional, femorotibial cartilage thickness and minimum joint space width (mJSW) in the medial femorotibial compartment were measured and the standardised response means (SRMs) determined. Results: At 6 months, qMRI demonstrated a −3.7% “annualised” change in cartilage thickness (SRM −0.33) in the central medial femorotibial compartment (cMFTC) of KLG3 subjects, but no change in KLG2 subjects. The SRM for mJSW in 12-month LS/FF radiographs of KLG3 participants was −0.68/−0.13 and at 24 months was −0.62/−0.20. The SRM for cMFTC changes measured with qMRI was −0.32 (12 months; −2.0%) and −0.48 (24 months; −2.2%), respectively. Conclusions: qMRI and LS radiography detected significant change in KLG3 participants at high risk of progression, but not in KLG2 participants, and only small changes in controls. At 12 and 24 months, LS displayed greater, and FF less, sensitivity to change in KLG3 participants than qMRI.

Comparison of radiographic joint space width with magnetic resonance imaging cartilage morphometry: analysis of longitudinal data from the Osteoarthritis Initiative.

Magnetic resonance imaging (MRI) and radiography are established imaging modalities for the assessment of knee osteoarthritis (OA). The objective of our study was to compare the responsiveness of radiographic joint space width (JSW) with MRI‐derived measures of cartilage morphometry for OA progression in participants from the Osteoarthritis Initiative (OAI).

A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee

Objective To determine if inhibition of inducible nitric oxide synthase (iNOS) with cindunistat hydrochloride maleate slows progression of osteoarthritis (OA) Methods This 2-year, multinational, double-blind, placebo-controlled trial enrolled patients with symptomatic knee OA (Kellgren and Lawrence Grade (KLG) 2 or 3). Standard OA therapies were permitted throughout. Patients were randomly assigned to cindunistat (50 or 200 mg/day) or placebo. Randomisation was stratified by KLG. Radiographs to assess joint space narrowing (JSN) were acquired using the modified Lyon-schuss protocol at baseline, week 48 and 96. Results Of 1457 patients (50 mg/day, n=485; 200 mg/day, n=486; placebo, n=486), 1048 (71.9%) completed the study. Patients were predominantly women; 56% had KLG3. The primary analysis did not demonstrate superiority of cindunistat versus placebo for rate of change in JSN. In KLG2 patients, JSN after 48 weeks was lower with cindunistat 50 mg/day versus placebo (p=0.032). Least-squares mean±SE JSN with cindunistat 50 mg/day ( −0.048±0.028 mm) and 200 mg/day (−0.062±0.028 mm) were 59.9% (95% CI 6.8% to 106.9%) and 48.7% (95% CI -8.4% to 93.9%) of placebo, improvement was not maintained at 96 weeks. No improvement was observed for KLG3 patients at either time-point. Cindunistat did not improve joint pain or function, but was generally well tolerated. Conclusions Cindunistat (50 or 200 mg/day) did not slow the rate of JSN versus placebo. After 48-weeks, KLG2 patients showed less JSN; however, the improvement was not sustained at 96-weeks. iNOS inhibition did not slow OA progression in KLG3 patients. Clinical trial listing NCT00565812

Relationship of compartment-specific structural knee status at baseline with change in cartilage morphology: a prospective observational study using data from the osteoarthritis initiative.

IntroductionThe aim was to investigate the relationship of cartilage loss (change in medial femorotibial cartilage thickness measured with magnetic resonance imaging (MRI)) with compartment-specific baseline radiographic findings and MRI cartilage morphometry features, and to identify which baseline features can be used for stratification of fast progressors.MethodsAn age and gender stratified subsample of the osteoarthritis (OA) initiative progression subcohort (79 women; 77 men; age 60.9 ± 9.9 years; body mass index (BMI) 30.3 ± 4.7) with symptomatic, radiographic OA in at least one knee was studied. Baseline fixed flexion radiographs were read centrally and adjudicated, and cartilage morphometry was performed at baseline and at one year follow-up from coronal FLASH 3 Tesla MR images of the right knee.ResultsOsteophyte status at baseline was not associated with medial cartilage loss. Knees with medial joint space narrowing tended to show higher rates of change than those without, but the relationship was not statistically significant. Knees with medial femoral subchondral bone sclerosis (radiography), medial denuded subchondral bone areas (MRI), and low cartilage thickness (MRI) at baseline displayed significantly higher cartilage loss than those without, both with and without adjusting for age, sex, and BMI. Participants with denuded subchondral bone showed a standardized response mean of up to -0.64 versus -0.33 for the entire subcohort.ConclusionsThe results indicate that radiographic and MRI cartilage morphometry features suggestive of advanced disease appear to be associated with greater cartilage loss. These features may be suited for selecting patients with a higher likelihood of fast progression in studies that attempt to demonstrate the cartilage-preserving effect of disease-modifying osteoarthritis drugs.

Rates of change and sensitivity to change in cartilage morphology in healthy knees and in knees with mild, moderate, and end-stage radiographic osteoarthritis: results from 831 participants from the Osteoarthritis Initiative.

To study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (OA), specifically healthy knees and knees with end‐stage radiographic OA.

Radiologic markers of osteoarthritis progression.

Purpose of reviewTo review radiographic and MRI developments in measuring osteoarthritis progression in the tibiofemoral compartment of the knee. Recent findingsStandardized techniques for measuring joint space width in the medial tibiofemoral compartment, using standardized radiographic protocols, have become accepted for quantifying changes in tibiofemoral in knee osteoarthritis. In addition, there is a significant body of supporting data on the longitudinal change in MRI-derived cartilage morphology (thickness, volume) as an end point to reflect osteoarthritis progression/cartilage loss. SummaryThis review appraises the current methods of measurement of osteoarthritis progression and limitations with regards their interpretation and further development.

Does the use of ordered values of subregional change in cartilage thickness improve the detection of disease progression in longitudinal studies of osteoarthritis

OBJECTIVE To propose a novel strategy for more efficiently measuring changes in cartilage thickness in osteoarthritis (OA) using magnetic resonance imaging, and to hypothesize that determining the magnitude of thickness change independent of the anatomic location provides improved discrimination between healthy subjects and OA participants longitudinally. METHODS A total of 148 women were imaged; 90 were Kellgren/Lawrence (K/L) grade 0, 30 were K/L grade 2, and 28 were K/L grade 3. Magnetic resonance images (3T) were acquired at baseline and at 24 months. Changes in femorotibial cartilage thickness were determined in 5 tibial and 3 femoral medial and lateral subregions, respectively (conventional approach). The new strategy provided ordered values of subregional change in each compartment, ranked according to the direction and magnitude of change. RESULTS Using the new ordered values approach, the minimal P value for the differences in 2-year change in medial cartilage thickness of K/L grade 3 and K/L grade 0 participants was 0.001 (Wilcoxon test), with 4 ordered medial subregions differing significantly between both groups. With the conventional approach, only 1 medial subregion differed significantly between K/L grade 3 and K/L grade 0 (P = 0.037). Cartilage thickening was significantly greater in K/L grade 2 versus K/L grade 0 participants in 1 medial subregion using the conventional approach (P = 0.016), and in 2 medial subregions (minimal P = 0.007) using the ordered values approach. CONCLUSION The novel ordered values approach is more sensitive in detecting cartilage thinning in K/L grade 3 and cartilage thickening in K/L grade 2 versus K/L grade 0 participants. The new method may be particularly useful in the context of other comparisons, e.g., a group treated with a disease-modifying OA drug versus one treated with a placebo.

Loading of the knee during 3.0T MRI is associated with significantly increased medial meniscus extrusion in mild and moderate osteoarthritis.

PURPOSE Standard knee MRI is performed under unloading (ULC) conditions and not much is known about changes of the meniscus, ligaments or cartilage under loading conditions (LC). The aim is to study the influence of loading of different knee structures at 3Tesla (T) in subjects with osteoarthritis (OA) and normal controls. MATERIALS AND METHODS 30 subjects, 10 healthy and 20 with radiographic evidence of OA (10 mild and 10 moderate) underwent 3T MRI under ULC and LC at 50% body weight. All images were analyzed by two musculoskeletal radiologists identifying and grading cartilage, meniscal, ligamentous abnormalities. The changes between ULC and LC were assessed. For meniscus, cartilage and ligaments the changes of lesions, signal and shape were evaluated. In addition, for the meniscus changes in extrusion were examined. A multivariate regression model was used for correlations to correct the data for the impact of age, gender, BMI. A paired T-Test was performed to calculate the differences in meniscus extrusion. RESULTS Subjects with degenerative knee abnormalities demonstrated significantly increased meniscus extrusion under LC when compared to normal subjects (p=0.0008-0.0027). Subjects with knee abnormalities and higher KL scores showed significantly more changes in lesion, signal and shape of the meniscus (80% (16/20) vs. 20% (2/10); p=0.0025), ligaments and cartilage during LC. CONCLUSION The study demonstrates that axial loading has an effect on articular cartilage, ligament, and meniscus morphology, which is more significant in subjects with degenerative disease and may serve as an additional diagnostic tool for disease diagnosis and assessing progression in subjects with knee OA.

A three-dimensional quantitative method to measure meniscus shape, position, and signal intensity using MR images: A pilot study and preliminary results in knee osteoarthritis

This pilot study presents a technique for three‐dimensional and quantitative analysis of meniscus shape, position, and signal intensity and compares results in knees with (n = 20) and without (n = 11) radiographic osteoarthritis. 3‐T MR images with 2mm section thickness were acquired using a proton density–weighted, fat‐suppressed, coronal, fast spin‐echo sequence. Segmentation of the tibial, femoral, and external surface of the medial meniscus and the tibial joint surface was performed. Three‐dimensional parameters were computed to describe the shape, position, and signal intensity of the entire meniscus and three subregions (body, anterior, and posterior horn). Key results included a greater size (i.e., volume, surface areas, and thickness), increased medial extrusion (i.e., greater extrusion distance, greater meniscal area uncovered by tibial surface), and elevated signal intensity of the medial meniscus in osteoarthritis than in nonosteoarthritis knees, particularly in the meniscus body. These results need to be confirmed in larger cohorts, preferably under weight‐bearing conditions. Magn Reson Med 63:1162–1171, 2010.