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Wildi L.M.,University of Montréal | Raynauld J.-P.,University of Montréal | Martel-Pelletier J.,University of Montréal | Beaulieu A.,Laval University | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objective To determine the effect of chondroitin sulphate (CS) treatment on cartilage volume loss, subchondral bone marrow lesions (BML), synovitis and disease symptoms in patients with knee osteoarthritis (OA). Methods In this pilot multicentre, randomised, doubleblind, controlled trial in primary knee OA, 69 patients with clinical signs of synovitis were randomised to receive CS 800 mg or placebo once daily for 6 months followed by an open-label phase of 6 months in which patients in both groups received CS 800 mg once daily. Cartilage volume and BML were assessed by MRI at baseline and at 6 and 12 months; synovial membrane thickness was assessed at baseline and at 6 months. Results The CS group showed significantly less cartilage volume loss than the placebo group as early as 6 months for the global knee (p=0.030), lateral compartment (p=0.015) and tibial plateaus (p=0.002), with significance persisting at 12 months. Significantly lower BML scores were found for the CS group at 12 months in the lateral compartment (p=0.035) and the lateral femoral condyle (p=0.044). Disease symptoms were similar between the two groups. Conclusion CS treatment significantly reduced the cartilage volume loss in knee OA starting at 6 months of treatment, and BML at 12 months. These findings suggest a joint structure protective effect of CS and provide new in vivo information on its mode of action in knee OA.


Raynauld J.-P.,University of Montréal | Martel-Pelletier J.,University of Montréal | Beaulieu A.,Laval University | Bessette L.,Groupe de Recherche en Rhumatologie et Maladies Osseuses | And 4 more authors.
Seminars in Arthritis and Rheumatism | Year: 2010

Objectives: The aim of the study was to evaluate by quantitative magnetic resonance imaging the effect of celecoxib 200 mg daily on cartilage volume loss over 12 months in knee osteoarthritis. Methods: The primary outcome of this study was to evaluate cartilage volume loss in the medial compartment of the knee (femoral condyle and tibial plateau) assessed by quantitative magnetic resonance imaging on subjects receiving continuous treatment with celecoxib 200 mg daily for 12 months compared with a modelized historical control cohort, as expressed by the percentage loss from baseline. Safety of the medication was also assessed. Comparison of the observed volume loss to the expected loss was evaluated by a multivariate linear regression model based on a historical cohort. Results: For the primary outcome, the 95% confidence intervals for the mean observed celecoxib cohort joint medial compartment cartilage volume loss (6.81% [6.01; 7.60]) and mean predicted loss (modelized historical cohort) (5.65% [5.10; 6.19]) overlap, indicating no significant difference and hence no effect of celecoxib on the medial compartment cartilage volume loss. Similar findings were demonstrated for the lateral compartment cartilage loss. The safety data reported several minor adverse events similar to those typically seen in a 1-year clinical trial. Conclusions: Although celecoxib was demonstrated to be safe for knee osteoarthritis at a 200 mg daily dose, it did not provide a protective effect on knee cartilage loss. Cohort modelization is an efficient and unbiased way to provide a comparator group for the assessment of novel treatments when classic head-to-head randomized controlled trials are not feasible. © 2010 Elsevier Inc.


Tanamas S.K.,Monash University | Wluka A.E.,Monash University | Pelletier J.-P.,University of Montréal | Pelletier J.M.,University of Montréal | And 5 more authors.
Rheumatology | Year: 2010

Objectives: The presence of bone marrow lesions (BMLs) has been linked to pain and progression of knee OA. The aim of this study was to determine the relationship between BMLs and longitudinal change in tibial cartilage volume and risk of knee joint replacement in subjects with knee OA. Methods: One hundred and nine men and women with symptomatic knee OA were recruited. The same knee was imaged using MRI at baseline and ∼2 years later. Tibial cartilage volume and BMLs were measured. Knee joint replacement over 4 years was determined. Results: The mean age of the subjects at baseline was 63.2 (s.d. 10.3) years. BMLs were present in 66% of the subjects. Cross-sectionally, BMLs were negatively associated with both medial (regression coefficient -121.4; 95% CI -183.8, -859.1; P < 0.001) and lateral (regression coefficient -142.1; 95% CI -241.8, -42.4; P = 0.01) tibial cartilage volume data. Longitudinally, for every 1-score increase in baseline BML severity (range 0-4), the annual total tibial cartilage loss was increased by 1.14% (95% CI 0.29%, 1.87%; P = 0.01). The risk of knee joint replacement over 4 years increased with increasing BML score (odds ratio 1.57; 95% CI 1.04, 2.35; P = 0.03). Conclusion. The prevalence and severity of BMLs are associated with less tibial cartilage volume and greater cartilage loss over 2 years. Moreover, severity of BMLs was positively associated with risk of knee joint replacement over 4 years. This provides further support for the importance of BMLs in identifying those with OA most likely to progress. Identifying factors that prevent or reduce the severity of BMLs may provide an important target in the prevention of disease progression and treatment of OA, and the subsequent need for arthroplasty. © The Author 2010. All rights reserved.


Wei S.,Menzies Research Institute | Venn A.,Menzies Research Institute | Ding C.,Menzies Research Institute | Martel-Pelletier J.,University of Montréal | And 4 more authors.
Osteoarthritis and Cartilage | Year: 2011

Objective: Sex hormones and reproductive factors may be important for osteoarthritis (OA). The aim of this study was to describe the associations of parity, use of hormone replacement therapy (HRT) and oral contraceptives (OCs) with cartilage volume, cartilage defects and radiographic OA in a population-based sample of older women. Design: Cross-sectional study of 489 women aged 50-80. years. Parity, use of HRT and OC was assessed by questionnaire; knee cartilage volume and defects by magnetic resonance imaging and knee joint space narrowing (JSN) and osteophytes by X-ray. Results: Parity was associated with a deficit in total knee cartilage volume [adjusted β= -0.69. ml, 95% confidence interval (CI) -1.34, -0.04]. Increasing parity was associated with decreasing cartilage volume in both the tibial compartment and total knee (both P trend <0.05). Parity was also associated with greater cartilage defects in the patella compartment [adjusted odds ratio (OR) = 2.87, 95% CI = 1.39, 5.93] but not other sites. There was a consistent but non-significant increase in knee JSN (OR = 2.78, 95% CI = 0.75, 10.31) and osteophytes (OR = 1.69, 95% CI = 0.59, 4.82) for parous women. Use of HRT and/or OC was not associated with cartilage volume, cartilage defects or radiographic change. Conclusions: Parity (but not use of HRT or OC) is independently associated with lower cartilage volume primarily in the tibial compartment and higher cartilage defects in the patella compartment in this population-based sample of older women. © 2011 Osteoarthritis Research Society International.


Raynauld J.-P.,University of Montréal | Martel-Pelletier J.,University of Montréal | Haraoui B.,University of Montréal | Choquette D.,University of Montréal | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objective: To identify predictive factors for total knee replacement (TKR) using data from MRI of knee osteoarthritis patients in a phase III multicentre disease-modifying osteoarthritis drug (DMOAD) study. Methods: Knee osteoarthritis patients from a 2-year clinical trial evaluating licofelone versus naproxen were investigated for the incidence of TKR of the study knee. Patients (n=161) who completed the study according to protocol were selected. Incidence of TKR was assessed blindly to the treatment following telephone interviews (n=123). Results: 18 TKR (14.6%) were performed in 4-7 years following enrolment in the original study. More TKR were performed within the naproxen than the licofelone group (61% vs 39%, p=0.232). Baseline score of bone marrow lesions (BML) in the medial compartment (p=0.0001), medial joint space width (JSW) as assessed by standardised radiographs (p=0.0008), presence of severe medial meniscal tear (p=0.004), medial meniscal extrusion (p=0.013), and C-reactive protein level (p=0.049) were strong predictors of TKR. Changes at the end of the study also yielded strong predictors: change in cartilage volume of the medial compartment (p=0.005) and of the global knee (p=0.034), reduction in the JSW of greater than 7% (p=0.009), and WOMAC pain (p=0.009) and function (p=0.023) scores. Multivariate analysis showed that baseline severe medial meniscal tear (p=0.023) and presence of medial BML (p=0.025) were the strongest independent long-term predictors of TKR. Conclusion: This study shows that in the context of osteoarthritis trials, clinical data and structural changes identified by MRI allow prediction of a 'hard' outcome such as TKR. The findings support the usefulness and predictive value of MRI in defining study outcome in DMOAD trials.


Li W.,ArthroVision Inc. | Abram F.,ArthroVision Inc. | Pelletier J.-P.,University of Montréal | Raynauld J.-P.,University of Montréal | And 3 more authors.
Arthritis Research and Therapy | Year: 2010

Introduction: Joint effusion is frequently associated with osteoarthritis (OA) flare-up and is an important marker of therapeutic response. This study aimed at developing and validating a fully automated system based on magnetic resonance imaging (MRI) for the quantification of joint effusion volume in knee OA patients.Methods: MRI examinations consisted of two axial sequences: a T2-weighted true fast imaging with steady-state precession and a T1-weighted gradient echo. An automated joint effusion volume quantification system using MRI was developed and validated (a) with calibrated phantoms (cylinder and sphere) and effusion from knee OA patients; (b) with assessment by manual quantification; and (c) by direct aspiration. Twenty-five knee OA patients with joint effusion were included in the study.Results: The automated joint effusion volume quantification was developed as a four stage sequencing process: bone segmentation, filtering of unrelated structures, segmentation of joint effusion, and subvoxel volume calculation. Validation experiments revealed excellent coefficients of variation with the calibrated cylinder (1.4%) and sphere (0.8%) phantoms. Comparison of the OA knee joint effusion volume assessed by the developed automated system and by manual quantification was also excellent (r = 0.98; P < 0.0001), as was the comparison with direct aspiration (r = 0.88; P = 0.0008).Conclusions: The newly developed fully automated MRI-based system provided precise quantification of OA knee joint effusion volume with excellent correlation with data from phantoms, a manual system, and joint aspiration. Such an automated system will be instrumental in improving the reproducibility/reliability of the evaluation of this marker in clinical application. © 2010 Martel-Pelletier et al.; licensee BioMed Central Ltd.


Pelletier J.-P.,University of Montréal | Raynauld J.-P.,University of Montréal | Caron J.,University of Montréal | Mineau F.,University of Montréal | And 5 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Objectives: To explore the impact of disease-modifying osteoarthritis drug (DMOAD) treatment on biomarker levels and their correlation with cartilage volume loss and disease symptoms in a 2-year phase III clinical trial in patients with knee OA. Methods: 161 patients with knee OA (according-to-protocol population) were selected from a 2-year DMOAD trial studying the effect of licofelone (200 mg twice daily) versus naproxen (500 mg twice daily). Clinical evaluation of patients was carried out using the Western Ontario and McMaster Universities (WOMAC) questionnaire. Biomarker measurements of matrix metalloproteinase (MMP)-1, MMP-3, interleukin (IL)-6, C reactive protein (CRP), cartilage oligomeric matrix protein (COMP) and type I collagen C-terminal telopeptide (CTX-I) in serum, type II collagen C-terminal telopeptide (CTX-II) in urine, and knee MRI were performed at baseline and 2 years. Results: Over time an increase occurred in all biomarker levels with the exception of IL-6, CRP and CTX-II which decreased. The increase in MMP-1 and MMP-3 was significantly less (p=0.05; p<0.01, respectively) in the licofelone group. The baseline MMP-1 level was significantly but inversely predictive of cartilage volume loss for the medial compartment in both univariate (p=0.04) and multivariate (p≤0.04) regression analyses, and COMP, a predictor for the lateral compartment, in both univariate and multivariate models (p<0.01). Baseline levels of IL-6 and CRP also showed a significant relationship with volume loss for the medial compartment (univariate analysis, p=0.04 and p=0.01, respectively; multivariate analysis, p=0.03, p=0.01). A significant association (univariate) was observed between the change in the levels of MMP-1 (p=0.03) and MMP-3 (p=0.02) and cartilage volume loss (lateral compartment) over 2 years. Baseline levels of CTX-I correlated (p=0.02) with an increase in the size of the bone marrow lesion in the medial compartment. The baseline CRP levels correlated with worsening of symptoms: WOMAC total index (p<0.01), pain (p<0.01) and function (p<0.01). Conclusion: Higher baseline values of IL-6, CRP and COMP are predictive of greater risk of cartilage loss in OA. However, over time a reduction in MMP-1 and MMP-3 levels correlated best with reduction in cartilage volume loss and the effect of drug treatment. Baseline CRP was found to be a good predictor of the symptomatic response to treatment.


Dodin P.,ArthroVision Inc. | Pelletier J.-P.,University of Montréal | Martel-Pelletier J.,University of Montréal | Abram F.,ArthroVision Inc.
IEEE Transactions on Biomedical Engineering | Year: 2010

This study aimed at developing a new automatic segmentation algorithm for human knee cartilage volume quantification from MRI. Imaging was performed using a 3T scanner and a knee coil, and the exam consisted of a double echo steady state (DESS) sequence, which contrasts cartilage and soft tissues including the synovial fluid. The algorithm was developed on MRI 3-D images in which the bonecartilage interface for the femur and tibia was segmented by an independent segmentation process, giving a parametric surface of the interface. First, the MR images are resampled in the neighborhood of the bone surface. Second, by using texture-analysis techniques optimized by filtering, the cartilage is discriminated as a bright and homogeneous tissue. This process of excluding soft tissues enables the detection of the external boundary of the cartilage. Third, a technology based on a Bayesian decision criterion enables the automatic separation of the cartilage and synovial fluid. Finally, the cartilage volume and changes in volume for an individual between visits was assessed using the developed technology. Validation included first, for nine knee osteoarthritis patients, a comparison of the cartilage volume and changes over time between the developed automatic system and a validated semi-automatic cartilage volume system, and second, for five knee osteoarthritis patients, a testretest procedure. Data revealed excellent Pearson correlations and Dice similarity coefficients (DSC) for the global knee (r = 0.96, p < 0.0001, and median DSC = 0.84), for the femur (r = 0.95, p < 0.0001, and median DSC = 0.85), and the tibia (r = 0.83, p < 0.0001, and median DSC = 0.84). Very good similarity between the automatic and semi-automatic methods in regard to cartilage loss was also found for the global knee (r = 0.76 and p = 0.016) as well as for the femur (r = 0.79 and p = 0.011). The testretest revealed an excellent measurement error of -0.3 ± 1.6% for the global knee and 0.14 ± 1.7% for the femur. In conclusion, the newly developed fully automatic method described herein provides accurate and precise quantification of knee cartilage volume and will be a valuable tool for clinical follow-up studies. © 2010 IEEE.


Wildi L.M.,University of Montréal | Raynauld J.-P.,University of Montréal | Martel-Pelletier J.,University of Montréal | Abram F.,ArthroVision Inc. | And 2 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Objective: To assess in a multicentre randomised double-blind phase III clinical trial evaluating the effect of licofelone in comparison with naproxen on knee osteoarthritis (OA) the presence of, and change in, bone marrow lesions (BML) over time, their relationship to cartilage volume loss, meniscal extrusion and pain. Methods: Patients with knee OA were selected from the dataset of a recently published randomised controlled trial. MRI was performed at baseline, 6, 12 and 24 months to assess BML score (modified Whole-Organ MRI Score) and cartilage volume changes over time. Pain levels were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. Results: One hundred and sixty-one patients completed the study according to protocol. The global knee and all subregions showed increased BML scores over time (p <0.001, 24 months) except for the medial tibial plateau in the licofelone group. In multivariate regression analysis, licofelone treatment predicted reduction in BML score in the medial tibial plateau (β= -0.280, p = 0.026). BML scores at baseline correlated with cartilage volume over time; however, correlation was limited to 12 months. No positive correlation was found between BML and WOMAC scores. Conclusions: BML scores were found to increase over time, probably owing to accumulation of chronic structural changes. Correlation between BML and cartilage volume was strong at baseline but not over time, probably due to the study drug. Licofelone reduced the BML score in the medial tibial plateau. In contrast to previous reports, no positive relationship was found between BML score (baseline or change over time) and pain, probably an effect of the selected population.


Dodin P.,ArthroVision Inc. | Martel-Pelletier J.,University of Montréal | Pelletier J.-P.,University of Montréal | Abram F.,ArthroVision Inc.
Medical and Biological Engineering and Computing | Year: 2011

This study aimed at developing a fully automated bone segmentation method for the human knee (femur and tibia) from magnetic resonance (MR) images. MR imaging was acquired on a whole body 1.5T scanner with a gradient echo fat suppressed sequence using an extremity coil. The method was based on the Ray Casting technique which relies on the decomposition of the MR images into multiple surface layers to localize the boundaries of the bones and several partial segmentation objects being automatically merged to obtain the final complete segmentation of the bones. Validation analyses were performed on 161 MR images from knee osteoarthritis patients, comparing the developed fully automated to a validated semi-automated segmentation method, using the average surface distance (ASD), volume correlation coefficient, and Dice similarity coefficient (DSC). For both femur and tibia, respectively, data showed excellent bone surface ASD (0.50 ± 0.12 mm; 0.37 ± 0.09 mm), average oriented distance between bone surfaces within the cartilage domain (0.02 ± 0.07 mm; -0.05 ± 0.10 mm), and bone volume DSC (0.94 ± 0.05; 0.92 ± 0.07). This newly developed fully automated bone segmentation method will enable large scale studies to be conducted within shorter time durations, as well as increase stability in the reading of pathological bone. © 2011 International Federation for Medical and Biological Engineering.

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