Delayed gadolinium-enhanced magnetic resonance imaging of medial tibiofemoral cartilage and its relationship with meniscal pathology: a longitudinal study using 3.0T magnetic resonance imaging.

OBJECTIVE: To evaluate the relationship between medial meniscal pathology and cartilage matrix status using delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) in medial tibiofemoral cartilage in a sample of middle-aged women. METHODS: A total of 148 women ages ≥40 years were included, and 3.0T MRI of the knee was performed at baseline and at 1 year. T2-weighted, fat-suppressed and 3-dimensional inversion recovery-prepared spoiled gradient-recalled echo sequences were acquired 90 minutes after gadolinium injection. Baseline medial meniscal pathology was scored on a scale of 0-3, where 0 = normal, 1 = intrasubstance meniscal signal change, 2 = single tears, and 3 = complex tears/maceration. The central medial femur, the medial tibial plateau, and the posterior medial femur were subjected to dGEMRIC at baseline and at 1 year. Analysis of covariance was used to examine whether baseline and 1-year dGEMRIC indices in the same regions were related to the severity of meniscal damage at baseline, using normal medial menisci (grade 0) as the reference. RESULTS: Medial compartments with grade 3 lesions showed significantly lower dGEMRIC indices (less proteoglycan content) at the central medial femur region compared with compartments with normal menisci. Mean ± SEM differences in dGEMRIC indices between grade 3 and grade 0 menisci at the central medial femur were -119.1 ± 34.2 msec at baseline (P = 0.03) and -120.3 ± 35.2 msec at followup (P = 0.04). CONCLUSION: High-grade damage of the medial meniscus showed significant associations with lower dGEMRIC indices. The dGEMRIC technique may be a useful tool in detecting early degenerative changes of cartilage when meniscal function is lost.

Association of changes in delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) with changes in cartilage thickness in the medial tibiofemoral compartment of the knee: a 2†year follow-up study using 3.0†T MRI.

OBJECTIVE: To determine the association between changes in the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) index over 2 years as a measure of cartilage proteoglycan concentration, with changes in cartilage thickness in the medial tibiofemoral compartment of knees in middle-aged women. METHODS: One hundred and forty-eight women (one knee for each subject) aged ≥40 years were included. 3.0 T MR images of the knee were acquired at baseline, 1 year and 2 years. Three-dimensional (3D) spoiled gradient recalled echo (SPGR) sequences (for cartilage thickness) and 3D inversion recovery-prepared SPGR sequences after dGEMRIC were acquired. Segmentation was performed in the medial central (weight-bearing) femur and tibia to determine cartilage proteoglycan concentration and thickness. The association of change in the dGEMRIC indices between baseline and 1-year follow-up with (a) concomitant changes in cartilage thickness and (b) change in cartilage thickness between 1 and 2 years was assessed using linear regression. RESULTS: In the whole-sample model, a decrease in dGEMRIC indices over time at the central medial femur significantly predicted an increase in cartilage thickness at both the central medial femur (p=0.008) and the medial tibia (p=0.04). CONCLUSIONS: A decrease in dGEMRIC indices was associated with an increase in cartilage thickness in the medial compartment. Our results suggest that an increase in cartilage thickness may also be related to a decrease in proteoglycan concentration, which may represent swelling of cartilage in early stages of degeneration.

Considerations when designing a disease-modifying osteoarthritis drug (DMOAD) trial using radiography.

OBJECTIVE: Using placebo data from a recently completed disease-modifying osteoarthritis (OA) drug trial, we seek to inform study design of future radiographic studies. METHODS: Eligible patients aged ≥40 years, with body mass index (BMI) 25-40kg/m(2) and symptomatic knee OA diagnosed by modified Kellgren and Lawrence grade (KLG) 2 or 3 and pain/stiffness and/or use of medication for knee pain in the past year, were assessed by radiography using a modified Lyon-schuss (mL/S) protocol for joint space narrowing (JSN) (primary outcome variable) at baseline and weeks 48 and 96. Multifaceted quality control was conducted throughout. Repeat images were requested when the medial tibial plateau (MTP) was not aligned (inter-margin distance [IMD] >1.5mm) or for other quality issues. Data are given mean ± standard deviation. RESULTS: Patients (74.9% female; 61.3 ± 9.1 years) had BMI 31.6 ± 4.1kg/m(2) at baseline; 222 (173 females) had KLG2, 264 (191 female) KLG3. A significant loss in joint space width (JSW) from baseline to week 48 (-0.13 ± 0.36mm) and to week 96 (-0.22 ± 0.45mm) was observed for all randomised placebo patients (p < 0.001 for both), and at both time points when stratified by KLG2 or KLG3. Standard deviations were small relative to mean changes, providing standardised response means for all placebo patients of 0.35 (week 48) and 0.48 (week 96). CONCLUSIONS: Using a tightly controlled radiographic technique, JSN is a viable outcome variable for determining disease progression in mild-to-moderate knee OA. The mL/S protocol is a sensitive and feasible method for OA studies aiming to assess rate of JSN in the knee.

In normal knees, joint space width (JSW) is correlated with the intermargin distance (IMD), a measure of medial tibial plateau alignment. Variations in IMD explain variability in JSW in serial radiographs.

OBJECTIVE: To ascertain the importance of alignment of the medial tibial plateau (MTP), as determined by the distance between the anterior and posterior margins of the plateau (intermargin distance [IMD]), for measurements of joint space width (JSW) in radiographs of normal knees. METHODS: JSW and IMD were measured in paired baseline and 12-month knee films of 122 subjects from the osteoarthritis initiative (OAI). Relationships between JSW and IMD, and between the variation in JSW and variation in IMD, were evaluated. RESULTS: In cross-sectional analysis, a non-linear relationship existed between JSW and the concurrent IMD. With poor MTP alignment (IMD>1.7 mm), a 1.0-mm increase in IMD resulted in a 0.16-mm (95%CI: 0.11-0.21) increase in JSW (P<0.0001). In a longitudinal analysis, the effect of IMD variation on variation in JSW was also highly significant (P<0.0001). A variation of 1 mm between IMD(Baseline) and IMD(12month) was associated with a 0.10-mm (95% CI: 0.06-0.13) variation in JSW, with variations in JSW and IMD occurring in the same direction. An IMD variation less than or equal to 1.0mm was determined to be acceptable for accurate evaluation of JSW in serial radiographs. CONCLUSION: The error in measurement of JSW caused by variation in IMD in serial radiographs of normal knees can be as large, or larger, than the mean rate of 12-month joint space narrowing (JSN) in OA knees. MTP alignment and replication of alignment in serial knee films are required for accurate determination of JSN in OA knee.

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.

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.

In vivo measures of cartilage deformation: patterns in healthy and osteoarthritic female knees using 3T MR imaging.

OBJECTIVE: To explore and to compare the magnitude and spatial pattern of in vivo femorotibial cartilage deformation in healthy and in osteoarthritic (OA) knees. METHODS: One knee each in 30 women (age: 55 ± 6 years; BMI: 28 ± 2.4 kg/m(2); 11 healthy and 19 with radiographic femorotibial OA) was examined at 3Tesla using a coronal fat-suppressed gradient echo SPGR sequence. Regional and subregional femorotibial cartilage thickness was determined under unloaded and loaded conditions, with 50% body weight being applied to the knee in 20° knee flexion during imaging. RESULTS: Cartilage became significantly (p < 0.05) thinner during loading in the medial tibia (-2.7%), the weight-bearing medial femur (-4.1%) and in the lateral tibia (-1.8%), but not in the lateral femur (+0.1%). The magnitude of deformation in the medial tibia and femur tended to be greater in osteoarthritic knees than in healthy knees. The subregional pattern of cartilage deformation was similar for the different stages of radiographic OA. CONCLUSION: Osteoarthritic cartilage tended to display greater deformation upon loading than healthy cartilage, suggesting that knee OA affects the mechanical properties of cartilage. The pattern of in vivo deformation indicated that cartilage loss in OA progression is mechanically driven.

Radiographic grading and measurement of joint space width in osteoarthritis.

The progression of osteoarthritis is traditionally measured using radiographic joint space width (JSW). Numerous knee radiograph protocols have been developed with various levels of complexity and performance as it relates to detecting JSW loss (ie, joint space narrowing). Sensitivity to joint space narrowing is improved when radioanatomic alignment of the medial tibial plateau is achieved. Semiautomated software has been developed to improve the accuracy of JSW measurement over manual methods. JSW measurements include minimum JSW, mean JSW or joint space area, and JSW at fixed locations.

Radiographic-based grading methods and radiographic measurement of joint space width in osteoarthritis.

Accurate and highly reproducible measurements of the rate of progression of osteoarthritis is crucial to assessing structural change, and requires adherence to exacting standards of positioning, which include specifications for flexion and rotation of the joint, and angulation of the x-ray beam. The progression of osteoarthritis traditionally has been measured using radiographic joint space width (JSW). Over the past two decades, numerous knee radiographic protocols have been developed with various levels of complexity and performance as they relate to detecting JSW loss (ie, joint space narrowing). Semiautomated software has been developed to improve the accuracy of JSW measurement over manual methods. JSW measurements include minimum JSW, mean JSW or joint space area and JSW at fixed locations.

Positive association between increased popliteal artery vessel wall thickness and generalized osteoarthritis: is OA also part of the metabolic syndrome?

PURPOSE: The purpose of the study was to determine if a positive association exists between arterial vessel wall thickness and generalized osteoarthritis (OA). Our hypothesis is that generalized OA is another facet of the metabolic syndrome. MATERIALS AND METHODS: The medical ethical review board of our institution approved the study. Written informed consent was obtained from each patient prior to the study. Magnetic resonance (MR) images of the knee were obtained in 42 patients who had been diagnosed with generalized OA at multiple joint sites. Another 27 MR images of the knee were obtained from a matched normal (non-OA) reference population. Vessel wall thickness of the popliteal artery was quantitatively measured by dedicated software. Linear regression models were used to investigate the association between vessel wall thickness and generalized OA. Adjustments were made for age, sex, and body mass index (BMI). Confidence intervals (CI) were computed at the 95% level and a significance level of alpha = 0.05 was used. RESULTS: Patients in the generalized OA population had a significant higher average vessel wall thickness than persons from the normal reference population (p < or = alpha), even when correction was made for sex, age, and BMI. The average vessel wall thickness of the popliteal artery was 1.09 mm in patients with generalized OA, and 0.96 mm in the matched normal reference population. CONCLUSION: The association found between increased popliteal artery vessel wall thickness and generalized osteoarthritis suggests that generalized OA might be another facet of the metabolic syndrome.

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

INTRODUCTION: The 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. METHODS: An 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. RESULTS: Osteophyte 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. CONCLUSIONS: The 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.

Changes in outcome measures for impairment, activity limitation, and participation restriction over two years in osteoarthritis of the lower extremities.

OBJECTIVE: To describe changes in outcome measures in patients with knee and hip osteoarthritis (OA) over 2 years according to the International Classification of Functioning, Disability and Health, and to evaluate the sensitivity to change of available outcome instruments. METHODS: A total of 115 symptomatic knee or hip OA patients (mean age 60.0 years, 80% women) were followed for 2 years. Standardized knee and hip radiographs were scored for joint space narrowing (JSN) using the Osteoarthritis Research Society International Atlas. Pain intensity in knees and hips was graded during physical examination. Self-reported pain and functioning were assessed with the Western Ontario and McMaster Universities OA Index (WOMAC). Social functioning was assessed with social functioning scores of the RAND 36-item Health Survey. Standardized response means (SRMs) were calculated to evaluate sensitivity to change. RESULTS: Substantial increases in JSN and pain intensity total scores over 2 years were observed (SRMs 0.43 and 0.41, respectively). Twenty-three percent of patients had an increase of at least 1 point in JSN total scores. An increase in pain intensity total scores was present in 46% of patients, whereas a decrease was observed in 19.1.% of patients. WOMAC pain and function scores showed small increases (SRMs 0.15 and 0.18, respectively). No change was seen in social functioning scores (SRM 0.01). CONCLUSION: Objective instruments measuring impairment in body structures and function are more sensitive to change over 2 years in patients with OA than self-reported measurements of impairment in body function, activity limitation, and participation restriction. These findings encourage development of new instruments to improve measurement of disease outcome in OA.

Osteoarthritis of the knee: association between clinical features and MR imaging findings.

PURPOSE: To prospectively evaluate the association between clinical features and structural abnormalities found at magnetic resonance (MR) imaging in patients with osteoarthritis (OA) of the knee. MATERIALS AND METHODS: The study was approved by the institutional medical ethics review board. Written informed consent was obtained from each patient. MR images of the knee were obtained from 205 (42 [20%] men, 163 [80%] women; median age, 60 years; range, 43-77 years) patients in whom symptomatic OA at multiple joint sites was diagnosed. MR images were analyzed for various abnormalities of OA. All patients were interviewed concerning pain and stiffness in the knee that was imaged. Odds ratios (ORs) with 99% confidence intervals (CIs) were used to determine the association between the imaging findings and clinical features of OA. RESULTS: A large joint effusion was associated with pain (OR, 9.99; 99% CI: 1.28, 149) and stiffness (OR, 4.67; 99% CI: 1.26, 26.1). The presence of an osteophyte in the patellofemoral compartment (OR, 2.25; 99% CI: 1.06, 4.77) was associated with pain. All other imaging findings, including focal or diffuse cartilaginous abnormalities, subchondral cysts, bone marrow edema, subluxation of the meniscus, meniscal tears, or Baker cysts, were not associated with symptoms. CONCLUSION: Findings of this study indicate that only two associations exist between clinical symptoms and structural findings found on MR images in patients with OA of the knee.