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Summary Objective To examine if relationships between knee osteoarthritis (OA) progression with knee moments and muscle activation during gait vary between patients with non-traumatic and post-traumatic knee OA. Design This longitudinal study included participants with non-traumatic (n = 17) and post-traumatic (n = 18) knee OA; the latter group had a previous anterior cruciate ligament rupture. Motion capture cameras, force plates, and surface electromyography measured knee moments and lower extremity muscle activation during gait. Cartilage volume change were determined over 2 years using magnetic resonance imaging in four regions: medial and lateral plateau and condyle. Linear regression analysis examined relationships between cartilage change with gait metrics (moments, muscle activation), group, and their interaction. Results Measures from knee adduction and rotation moments were related to lateral condyle cartilage loss in both groups, and knee adduction moment to lateral plateau cartilage loss in the non-traumatic group only [β = −1.336, 95% confidence intervals (CI) = -2.653 to −0.019]. Generally, lower levels of stance phase muscle activation were related to greater cartilage loss. The relationship between cartilage loss in some regions with muscle activation characteristics varied between non-traumatic and post-traumatic groups including for: lateral hamstring (lateral condyle β = 0.128, 95%CI = 0.003 to 0.253; medial plateau β = 0.199, 95%CI = 0.059 to 0.339), rectus femoris (medial condyle β = −0.267, 95%CI = −0.460 to −0.073), and medial hamstrings (medial plateau; β = −0.146, 95%CI = −0.244 to −0.048). Conclusion Findings indicate that gait risk factors for OA progression may vary between patients with non-traumatic and post-traumatic knee OA. These OA subtypes should be considered in studies that investigate gait metrics as risk factors for OA progression.

OBJECTIVE By using machine learning, our study aimed to build a model to predict risk and time to total knee replacement (TKR) of an osteoarthritic knee. METHODS Features were from the Osteoarthritis Initiative (OAI) cohort at baseline. Using the lasso method for variable selection in the Cox regression model, we identified the 10 most important characteristics among 1,107 features. The prognostic power of the selected features was assessed by the Kaplan-Meier method and applied to 7 machine learning methods: Cox, DeepSurv, random forests algorithm, linear/kernel support vector machine (SVM), and linear/neural multi-task logistic regression models. As some of the 10 first-found features included similar radiographic measurements, we further looked at using the least number of features without compromising the accuracy of the model. Prediction performance was assessed by the concordance index, Brier score, and time-dependent area under the curve (AUC). RESULTS Ten features were identified and included radiographs, bone marrow lesions of the medial condyle on magnetic resonance imaging, hyaluronic acid injection, performance measure, medical history, and knee-related symptoms. The methodologies Cox, DeepSurv, and linear SVM demonstrated the highest accuracy (concordance index scores of 0.85, Brier score of 0.02, and an AUC of 0.87). DeepSurv was chosen to build the prediction model to estimate the time to TKR for a given knee. Moreover, we were able to decrease the features to only 3 and maintain the high accuracy (concordance index of 0.85, Brier score of 0.02, and AUC of 0.86), which included bone marrow lesions, Kellgren/Lawrence grade, and knee-related symptoms, to predict risk and time of a TKR event. CONCLUSION For the first time, we developed a model using the OAI cohort to predict with high accuracy if a given osteoarthritic knee would require TKR, when a TKR would be required, and who would likely progress fast toward this event.

Objective. The infrapatellar fat pad (IPFP) has been associated with knee osteoarthritis onset and progression. This study uses machine learning (ML) approaches to predict serum levels of some adipokines/related inflammatory factors and their ratios on knee IPFP volume of osteoarthritis patients.Methods. Serum and MRI were from the OAI at baseline. Variables comprised the 3 main osteoarthritis risk factors (age, gender, BMI), 6 adipokines, 3 inflammatory factors, and their 36 ratios. IPFP volume was assessed on MRI with a ML methodology. The best variables and models were identified in Total-cohort (n = 678), High-BMI (n = 341) and Low-BMI (n = 337), using a selection approach based on ML methods. Results. The best model for each group included three risk factors and adipsin/C-reactive protein combined for Total-cohort, adipsin/chemerin; High-BMI, chemerin/adiponectin HMW; and Low-BMI, interleukin-8. Gender separation improved the prediction (13–16%) compared to the BMI-based models. Reproducibility with osteoarthritis patients from a clinical trial was excellent (R: female 0.83, male 0.95). Pseudocodes based on gender were generated.Conclusion. This study demonstrates for the first time that the combination of the serum levels of adipokines/inflammatory factors and the three main risk factors of osteoarthritis could predict IPFP volume with high reproducibility, with the superior performance of the model accounting for gender separation.

OBJECTIVE To examine whether joint line tenderness and patellofemoral grind from physical examination were associated with cartilage volume loss, worsening of radiographic osteoarthritis, and the risk of total knee replacement. METHODS This study examined 4,353 Osteoarthritis Initiative participants. For each measurement of joint line tenderness and patellofemoral grind, the patterns were defined as no (none at baseline and at 1 year), fluctuating (present at either time point), and persistent (present at both time points). Cartilage volume loss and worsening of radiographic osteoarthritis over 4 years were assessed using magnetic resonance imaging and radiographs, and total knee replacement over 6 years was assessed. RESULTS A total of 35.0% of participants had joint line tenderness, and 15.8% had patellofemoral grind. Baseline patellofemoral grind, but not joint line tenderness, was associated with increased cartilage volume loss (1.08% per year versus 0.96% per year; P = 0.02) and an increased risk of total knee replacement (odds ratio [OR] 1.55 [95% confidence interval (95% CI) 1.11-2.17]; P = 0.01). While the patterns of joint line tenderness were not significantly associated with joint outcomes, participants with persistent patellofemoral grind had an increased rate of cartilage volume loss (1.30% per year versus 0.90% per year; P < 0.001) and an increased risk of total knee replacement (OR 2.10 [95% CI 1.30-3.38]; P = 0.002) compared with those participants without patellofemoral grind. CONCLUSION Patellofemoral grind, but not joint line tenderness, may represent a clinical marker associated with accelerated cartilage volume loss over 4 years and an increased risk of total knee replacement over 6 years. This simple clinical examination may provide clinicians with an inexpensive way to identify those at higher risk of disease progression who should be targeted for surveillance and management.

Summary Objective To compare cartilage thickness between patients with non-traumatic and post-traumatic knee osteoarthritis (OA) and healthy controls and to determine if disease severity and alignment impact these differences. Design Participants with non-traumatic (n = 22) and post-traumatic (n = 19) knee OA, and healthy controls (n = 22) were recruited for this cross-sectional study. Participants underwent 3T magnetic resonance imaging (T1-weighted, 3D sagittal gradient echo sequence) and cartilage thickness was determined in four regions: medial and lateral condyle, and medial and lateral plateau. Lower extremity alignment (mechanical axis angle) and disease severity (Kellgren–Lawrence scores) were measured from full length radiographs. Statistical analysis included one-way analysis of variance (ANOVA) and modified Bonferroni test adjusting for multiple pairwise comparisons. Linear regression analyses examined the relationship between cartilage thickness and knee OA group after controlling for disease severity, meniscal status, and alignment. Results In participants with predominantly medial compartment knee OA, compared to healthy controls, those with non-traumatic knee OA had diminished cartilage thickness in the medial plateau (p = 0.035) and those with post-traumatic knee OA had greater cartilage thickness in the lateral condyle (p = 0.044). In the lateral condyle, data revealed that alignment accounted for the variance in cartilage thickness (p = 0.035), in which a stronger relationship was found in the non-traumatic (r = −0.61) than the post-traumatic (r = −0.12) OA group. Conclusions Emerging data demonstrated that participants with non-traumatic knee OA have a stronger relationship between alignment and cartilage thickness than those with post-traumatic knee OA. This indicates that factors involved in knee OA initiation and progression may differ between these OA subtypes.

Vastus medialis intramuscular fat has been proposed to be a modifiable determinant of knee cartilage loss in patients with knee osteoarthritis. The objective was to determine whether vastus medialis intramuscular fat relates to osteoarthritis severity and quadriceps muscle strength in patients with non-traumatic and post-traumatic knee osteoarthritis.For this cross-sectional study, participants with knee osteoarthritis were classified into two groups: non-traumatic (n = 22; mean age = 60 years) and post-traumatic (n = 19; mean age = 56 years). Healthy adults were included (n = 22; mean age = 59 years). A 3-Tesla magnetic resonance imaging was used to measure vastus medialis cross-sectional area and intramuscular fat. Isometric knee extensor muscle torque was assessed using an isokinetic dynamometer and normalized to body mass (Nm/kg). Knee osteoarthritis severity was assessed using standing antero-posterior radiographs (Kellgren-Lawrence scores). Regression analyses examined relationships between 1) vastus medialis intramuscular fat with knee osteoarthritis severity and osteoarthritis group, after accounting for sex and body mass index, and 2) knee extensor muscle torque with vastus medialis intramuscular fat, after accounting for sex and vastus medialis cross-sectional area.Vastus medialis intramuscular fat was positively associated with body mass index (B = 0.321, P 0.001), but not with osteoarthritis severity or group (P 0.05). Higher vastus medialis intramuscular fat was associated with reduced knee extensor muscle torque (B = -0.040, P = 0.018).Greater vastus medialis intramuscular fat was associated with lower quadriceps muscle strength in patients with knee OA. It is unclear whether this is due to the accumulation of vastus medialis intramuscular fat or other potential factors, such as diet and physical inactivity.

Aim: In osteoarthritis (OA) there is a need for automated screening systems for early detection of structural progressors. We built a comprehensive machine learning (ML) model that bridges major OA risk factors and serum levels of adipokines/related inflammatory factors at baseline for early prediction of at-risk knee OA patient structural progressors over time. Methods: The patient- and gender-based model development used baseline serum levels of six adipokines, three related inflammatory factors and their ratios (36), as well as major OA risk factors [age and bone mass index (BMI)]. Subjects (677) were selected from the Osteoarthritis Initiative (OAI) progression subcohort. The probability values of being structural progressors (PVBSP) were generated using our previously published prediction model, including five baseline structural features of the knee, i.e. two X-rays and three magnetic resonance imaging variables. To identify the most important variables amongst the 47 studied in relation to PVBSP, we employed the ML feature classification methodology. Among five supervised ML algorithms, the support vector machine (SVM) demonstrated the best accuracy and use for gender-based classifiers development. Performance and sensitivity of the models were assessed. A reproducibility analysis was performed with clinical trial OA patients. Results: Feature selections revealed that the combination of age, BMI, and the ratios CRP/MCP-1 and leptin/CRP are the most important variables in predicting OA structural progressors in both genders. Classification accuracies for both genders in the testing stage (OAI) were >80%, with the highest sensitivity of CRP/MCP-1. Reproducibility analysis showed an accuracy ⩾92%; the ratio CRP/MCP-1 demonstrated the highest sensitivity in women and leptin/CRP in men. Conclusion: This is the first time that such a framework was built for predicting knee OA structural progressors. Using this automated ML patient- and gender-based model, early prediction of knee structural OA progression can be performed with high accuracy using only three baseline serum biomarkers and two risk factors. Plain language summary Machine learning model for early knee osteoarthritis structural progression Knee osteoarthritis is a well-known debilitating disease leading to reduced mobility and quality of life – the main causes of chronic invalidity. Disease evolution can be slow and span many years; however, for some individuals, the progression/evolution can be fast. Current treatments are only symptomatic and conventional diagnosis of osteoarthritis is not very effective in early identification of patients who will progress rapidly. To improve therapeutic approaches, we need a robust prediction model to stratify osteoarthritis patients at an early stage according to risk of joint structure disease progression. We hypothesize that a prediction model using a machine learning system would enable such an early identification of individuals for whom osteoarthritis knee structure will degrade rapidly. Data were from the Osteoarthritis Initiative, a National Institute of Health (United States) databank, and the robustness and generalizability of the developed model was further evaluated using osteoarthritis patients from an external cohort. Using the supervised machine learning system (support vector machine), we developed an automated patient- and gender-based model enabling an early clinical prognosis for individuals at high risk of structural progressive osteoarthritis. In brief, this model employed at baseline (when the subject sees a physician) easily obtained features consisting of the two main osteoarthritis risk factors, age and bone mass index (BMI), in addition to the serum levels of three molecules. Two of these molecules belong to a family of factors names adipokines and one to a related inflammatory factor. In brief, the model comprising a combination of age, BMI, and the ratios CRP/MCP-1 and leptin/CRP were found very robust for both genders, and the high accuracy persists when tested with an external cohort conferring the gender-based model generalizability. This study offers a new automated system for identifying early knee osteoarthritis structural progressors, which will significantly improve clinical prognosis with real time patient monitoring.

Although intra-articular corticosteroid injections (IACI) are commonly used for the treatment of knee osteoarthritis (OA), there is controversy regarding possible deleterious effects on joint structure. In this line, this study investigates the effects of IACI on the evolution of knee OA structural changes and pain. Participants for this nested case–control study were from the Osteoarthritis Initiative. Knees of participants who had received an IACI and had magnetic resonance images (MRI) were named cases (n = 93), and each matched with one control (n = 93). Features assessed at the yearly visits and their changes within the follow-up period were from MRI (cartilage volume, meniscal thickness, bone marrow lesions, bone curvature, and synovial effusion size), X-ray (joint space width), and clinical (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain score) data. Participants who received IACI experienced a transient and significantly greater rate of loss of the meniscal thickness (p = 0.006) and joint space width (p = 0.011) in the knee medial compartment in the year they received the injection, compared to controls. No significant effect of the IACI was found on the rate of cartilage loss nor on any other knee structural changes or WOMAC pain post-treatment. In conclusion, a single IACI in knee OA was shown to be safe with no negative impact on structural changes, but there was a transient meniscal thickness reduction, a phenomenon for which the clinical relevance is at present unknown.

Whether meniscal extrusion and bone marrow lesions (BMLs) are independently associated with the risk of knee osteoarthritis (OA) is unknown.Data was extracted from the Osteoarthritis Initiative (OAI) cohort. Participants were grouped according to the absence (Kellgren-Lawrence (KL) grade ≤ 1, n = 2120) or presence (KL ≥ 2, n = 2249) of radiographic OA (ROA). Baseline meniscal extrusion and tibial BMLs were assessed. Tibial plateau cartilage volume was assessed at baseline and 72 months, while radiographic disease was assessed at baseline and 48 months. Total knee replacement (TKR) was assessed at 72 months.In those with ROA, the presence of a baseline meniscal extrusion (independent of BMLs) was associated with accelerated cartilage volume loss (medial tibia: -2.1%/annum vs -1.5%; lateral: -2.6%/annum vs -1.6%; both P 0.001), progressive ROA and TKR (Odds ratio (OR) range 1.4-1.8; 95% CI range 1.1-2.9). The presence of a baseline BML was associated with accelerated cartilage volume loss (medial tibia: -2.1%/annum vs -1.6%; lateral: -1.9%/annum vs -1.6%; P ≤ 0.02), progressive ROA and joint replacement (OR range 1.5-2.4; 95% CI range 1.1-3.4). In those with no ROA, a baseline medial meniscal extrusion was associated with accelerated cartilage volume loss (medial tibia: -2.1%/annum vs -1.2%, P 0.001), and a baseline medial BML with incident ROA (OR 1.7, 95% CI 1.1 to 2.9).The presence of baseline meniscal extrusion and BMLs are associated with incident and progressive knee of each other (OA) and represent important structural targets for the treatment and prevention of knee OA.

Knee alignment and anterior cruciate ligament (ACL) injury are risk factors for knee osteoarthritis (OA). The objective was to examine interactions between knee alignment and ACL status on cartilage volume loss in participants with or at risk of knee OA.Participants were from the Osteoarthritis Initiative, a longitudinal cohort study. Data were from baseline and 24- and 72-month follow-up visits. Participants with knee OA (progression subcohort) or at risk of knee OA (incidence subcohort) that had partial or full ACL tears (OA-ACL group; n=66) or an intact ACL (OA-only group, n=367) were selected. Femur-tibia angles from radiographs quantified knee alignment. Changes in tibial and femoral cartilage volumes were measured using magnetic resonance imaging. Hierarchical linear models examined if knee alignment, presence of ACL, and their interaction were related to cartilage volume loss after accounting for other variables.Interactions between alignment and ACL status were significantly related to cartilage volume loss in the lateral plateau (β=-20.19, 95% confidence interval [CI]=-34.65 to -5.73) and lateral condyle (β=-23.64, 95%CI=-43.06 to -4.23). Valgus alignment was related to lateral compartment cartilage loss in the OA-ACL group, but not in the OA-only group. Varus alignment was related to cartilage loss in the medial plateau (β=7.49, 95%CI=0.17 to 14.80) and medial condyle (β=19.70, 95%CI=5.96 to 33.44) in both groups.The impact of knee alignment on knee OA initiation and progression varies based on ACL status. Initial lateral compartment damage or changes in joint kinematics after ACL rupture might account for these findings.Key Points• The relationship between knee alignment and lateral compartment cartilage loss depended on the status of the anterior cruciate ligament in participants with knee osteoarthritis or at risk for knee osteoarthritis.• Valgus alignment was related to lateral compartment cartilage loss in participants with a deficient anterior cruciate ligament.• Varus alignment was related to medial compartment cartilage loss regardless of the status of the anterior cruciate ligament.

Objective To examine the long-term (6-year) effect of combined glucosamine (Glu) and chondroitin sulfate (CS) treatment on cartilage volume in knee osteoarthritis (OA). Methods Participants were from the Osteoarthritis Initiative progression and incidence subcohorts, had magnetic resonance imaging (MRI) of the target knee at baseline and 6 years, joint space width >1 mm, and data available on Glu/CS consumption (n = 1,593). They were stratified into 2 main groups based on whether or not they had medial meniscal extrusion at baseline. The group with meniscal extrusion (n = 429) was further stratified into subgroups based on exposure or no exposure to Glu/CS as follows: not exposed, 1 year, 2–3 years, and 4–6 years. Cartilage volume was assessed using fully automated quantitative MRI technology. Results The Jonckheere-Terpstra trend test indicated that treatment with Glu/CS significantly reduced the cartilage volume loss in the global knee, associated with the lateral compartment. Multivariate analysis further demonstrated that the extent of the treatment's positive effect was related to exposure time to treatment, the protective effect at 6 years being significant in participants exposed to ≥2 years of treatment. Conclusion These findings provide future support for the long-term protective structure-modifying effects of Glu/CS treatment in knee OA subjects.

Background:One of the hurdles in osteoarthritis (OA) drug discovery and the improvement of therapeutic approaches is the early identification of patients who will progress. It is therefore crucial to find efficient and reliable means of screening OA progressors. Although the main risk factors, age, gender and body mass index (BMI), are important, they alone are poor predictors. However, serum factors could be potential biomarkers for early prediction of knee OA progression.Objectives:In a first step toward finding early reliable predictors of OA progressors, this study aimed to determine, in OA individuals, the optimum combination of serum levels of adipokines/related inflammatory factors, their ratios, and the three main OA risk factors for predicting knee OA infrapatellar fat pad (IPFP) volume, as this tissue has been associated with knee OA onset and progression.Methods:Serum and magnetic resonance images (MRI) were from the Osteoarthritis Initiative at baseline. Variables (48) comprised the 3 main OA risk factors (age, gender, BMI), 6 adipokines, 3 inflammatory factors, and their 36 ratios. IPFP volume was assessed on MRI with a neural network methodology. The best variables and models were identified in Total cohort (n=678), High-BMI (n=341) and Low-BMI (n=337), using an artificial intelligence selection approach: the adaptive neuro-fuzzy inference system embedded with fuzzy c-means clustering (ANFIS-FCM). Performance was validated using uncertainty analyses and statistical indices. Reproducibility was done using 80 OA patients from a clinical trial (female, n=57; male, n=23).Results:For the three groups, 8.44E+14 sub-variables were investigated and 48 models were selected. The best model for each group included five variables: the three risk factors and adipsin/C-reactive protein combined for Total cohort, adipsin/chemerin; High-BMI, chemerin/adiponectin high molecular weight; and Low-BMI, interleukin-8. Data also revealed that the main form of the ratio used for the model was justified, as the use of the inverse form slightly decreased the performance of the model in both training and testing stages. Further investigation indicated that gender improved (13-16%) the prediction results compared to the BMI-based models. For each gender, we then generated a pseudocode (an evolutionary computation equation) with the 5 variables for predicting IPFP volume. Reproducibility experiments were excellent (correlation coefficient: female 0.83, male 0.95).Conclusion:This study demonstrates, for the first time, that the combination of the serum levels of adipokines/inflammatory factors and the three main risk factors of OA could predict IPFP volume with high reproducibility, and superior performance with gender separation. By using the models for each gender and the pseudocodes for OA patients provided in this study, the next step will be to develop a predictive model for OA progressors.Acknowledgments:This work was funded by the Chair in Osteoarthritis of the University of Montreal, the Osteoarthritis Research Unit of the University of Montreal Hospital Research Centre, the Groupe de recherches des maladies rhumatismales du Québec and by ArthroLab Inc., all from Montreal, Quebec, Canada.Disclosure of Interests:Hossein Bonakdari: None declared, Ginette Tardif: None declared, François Abram Employee of: ArthroLab Inc., Jean-Pierre Pelletier Shareholder of: ArthroLab Inc., Grant/research support from: TRB Chemedica, Speakers bureau: TRB Chemedica and Mylan, Johanne Martel-Pelletier Shareholder of: ArthroLab Inc., Grant/research support from: TRB Chemedica

Background:Intra-articular corticosteroid injections (IACI) are commonly used for the treatment of symptomatic knee osteoarthritis (OA) and therapeutic guidelines have recommended their use. However, their safety regarding the evolution of structural changes remains unknown.Objectives:This study explored the effects of IACI on the evolution of knee OA structural changes assessed by magnetic resonance imaging (MRI).Methods:Participants were selected from the Osteoarthritis Initiative database. In this nested case-control design study, participants who received one treatment with IACI and had MRI exams available at the yearly follow-up visits before (pre-treatment), during (treatment), and after (post-treatment) were defined as “cases”. Each case was matched with one control for age, gender, body mass index (BMI), height, joint space width (JSW), cartilage volume, bone marrow lesion (BML), meniscal extrusion, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain at baseline. Ninety-three (93) participants fulfilling the inclusion criteria were selected and matched to controls (n=93). The study structural variables were MRI (cartilage volume, meniscal thickness, bone marrow lesion (BML), bone curvature), X-rays (JSW), and symptoms (WOMAC pain), assessed at the yearly consecutive visits and changes measured within the follow-up periods.Results:At baseline, the control and treatment groups were balanced. In the pre-treatment period, the cartilage volume loss in the medial compartment was significantly greater in the IACI (p=0.006) compared to the control group, with a numerical trend (p=0.071) in the lateral compartment. In the treatment period, the cartilage loss was not different between groups, with the exception of a significantly greater loss in the lateral compartment in the IACI group (p=0.041). In the post-treatment period there was no difference in the cartilage loss between the groups in both compartments. For the meniscal thickness loss in the pre-treatment period, no difference was found between groups; however, there was a significantly greater loss (p=0.007) during the treatment period in the IACI. In the post-treatment period, the loss of the medial meniscus was similar in both groups. For the lateral meniscus, there was no significant difference at any time between the two groups. The loss in JSW in the pre- and post-treatment periods was not different between groups, but was significantly greater (p=0.011) in the IACI group in the treatment period. The changes in the BML sizes over time were small and similar between groups. For the bone curvature, IACI group showed a smaller change compared to the control (p=0.037) at the treatment period. The WOMAC pain changes in both groups were small and unlikely to be clinically relevant.Conclusion:This study provides evidence that in knee OA, IACI were not associated with the occurrence of any deleterious effect on knee structures post-treatment, including cartilage volume and loss. The increase in the rate loss of medial meniscal thickness, which was associated with a loss of JSW, was a transient phenomenon and its clinical relevance unknown at that time.Acknowledgments:This initiative was funded by a grant from La Chaire en arthrose de l’Université de Montréal, and by ArthroLab Inc. (both in Montreal, Quebec, Canada).Disclosure of Interests:Jean-Pierre Pelletier Shareholder of: ArthroLab Inc., Grant/research support from: TRB Chemedica, Speakers bureau: TRB Chemedica and Mylan, Jean-Pierre Raynauld Consultant of: ArthroLab Inc., François Abram Employee of: ArthroLab Inc., Marc Dorais Consultant of: ArthroLab Inc., Patrice Paiement Employee of: ArthroLab Inc., Johanne Martel-Pelletier Shareholder of: ArthroLab Inc., Grant/research support from: TRB Chemedica

Background:Knee osteoarthritis (OA), a leading cause of disability worldwide, can be difficult to define as its development is often insidious and involves different subgroups. We still lack robust prediction models that are able to guide clinical decisions and stratify OA patients according to risk of disease progression.Objectives:This study aimed at identifying the most important features of knee OA progressors. To this end, we used machine learning (ML) algorithms on a large set of subjects and features to develop advanced prediction models that provide high classification and prediction performance.Methods:Participants, features and outcomes were from the Osteoarthritis Initiative. Features were from baseline (1107), including articular knee tissues (135) assessed by quantitative MRI. OA progressors were ascertained by four outcomes: cartilage volume loss in medial plateau at 48 and 96 months (Prop_CV_48M, 96M); Kellgren-Lawrence (KL) grade ≥2; and medial joint space narrowing (JSN) ≥1 at 48 months. Subjects’ numbers were as follows: 1598 for the outcome Prop_CV_96M, 1044 for the Prop_CV_48M, and 1468 for each KL grade ≥2 at 48 months and JSN ≥1 at 48 months. Six feature selection models were used to identify the common features in each outcome. Six classification methods were applied to measure the accuracy of the selected features in classifying the subjects into progressors and non-progressors. Classification of the best features was done using auto-ML interface and the area under the curve (AUC). To prioritize the top features, Sparse Partial Least Square (sPLS) method was used.Results:For the classification of the best common features in each outcome, Multi-Layer Perceptron (MLP) achieved the highest AUC in Prop_CV_96M, KL, and JSN (0.80, 0.88, 0.95), and Gradient Boosting Machine (GBM) for Prop_CV_48M (0.70). sPLS revealed that the baseline top five features to predict knee OA progressors are the joint space width (JSW), mean cartilage thickness of peripheral, medial, and central tibial plateau, and JSN.Conclusion:This is the first time that such a comprehensive study was performed for identifying the best features and classification methods for knee OA progressors. Data revealed that early prediction of knee OA progression can be done with high accuracy and based on only a few features. This study identifies the baseline X-ray and MRI-based features as the most important for predicting knee OA progressors. These results could be used for the development of a tool enabling prediction of knee OA progressors.Acknowledgments:This work was supported in part by the Osteoarthritis Research Unit of the University of Montreal Hospital Research Centre; the Chair in Osteoarthritis, University of Montreal, (both from Montreal, Quebec, Canada); and the Computational Biology Laboratory, Laval University Hospital Research Center, (Québec, Quebec, Canada). A Jamshidi received a bursary from the Canada First Research Excellence Fund through TransMedTech Institute, (Montreal, Quebec, Canada).Disclosure of Interests:Afshin Jamshidi: None declared, Mickaël Leclercq: None declared, Aurelie Labbe: None declared, Jean-Pierre Pelletier Shareholder of: ArthroLab Inc., Grant/research support from: TRB Chemedica, Speakers bureau: TRB Chemedica and Mylan, François Abram Employee of: ArthroLab Inc., Arnaud Droit: None declared, Johanne Martel-Pelletier Shareholder of: ArthroLab Inc., Grant/research support from: TRB Chemedica

Objective To examine whether metformin use was associated with knee cartilage volume loss over 4 years and risk of total knee replacement over 6 years in obese individuals with knee osteoarthritis. Methods This study analysed the Osteoarthritis Initiative participants with radiographic knee osteoarthritis (Kellgren-Lawrence grade ≥ 2) who were obese (body mass index [BMI] ≥ 30 kg/m2). Participants were classified as metformin users if they self-reported regular metformin use at baseline, 1-year and 2-year follow-up (n = 56). Non-users of metformin were defined as participants who did not report the use of metformin at any visit from baseline to 4-year follow-up (n = 762). Medial and lateral cartilage volume (femoral condyle and tibial plateau) were assessed using magnetic resonance imaging at baseline and 4 years. Total knee replacement over 6 years was assessed. General linear model and binary logistic regression were used for statistical analyses. Results The rate of medial cartilage volume loss was lower in metformin users compared with non-users (0.71% vs. 1.57% per annum), with a difference of − 0.86% per annum (95% CI − 1.58% to − 0.15%, p = 0.02), after adjustment for age, gender, BMI, pain score, Kellgren-Lawrence grade, self-reported diabetes, and weight change over 4 years. Metformin use was associated with a trend towards a significant reduction in risk of total knee replacement over 6 years (odds ratio 0.30, 95% CI 0.07–1.30, p = 0.11), after adjustment for age, gender, BMI, Kellgren-Lawrence grade, pain score, and self-reported diabetes. Conclusions These data suggest that metformin use may have a beneficial effect on long-term knee joint outcomes in those with knee osteoarthritis and obesity. Randomised controlled trials are needed to confirm these findings and determine whether metformin would be a potential disease-modifying drug for knee osteoarthritis with the obese phenotype.

Background There is evidence that knee pain not only is a consequence of structural deterioration in osteoarthritis (OA) but also contributes to structural progression. Clarifying this is important because targeting the factors related to knee pain may offer a clinical approach for slowing the progression of knee OA. The aim of this study was to examine whether knee pain over 1 year predicted cartilage volume loss, incidence and progression of radiographic osteoarthritis (ROA) over 4 years. Methods Osteoarthritis Initiative participants with no ROA (Kellgren-Lawrence grade ≤ 1) (n = 2120) and with ROA (Kellgren-Lawrence grade > 2) (n = 2249) were examined. Knee pain was assessed at baseline and 1 year using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Knee pain patterns were categorised as no pain (WOMAC pain 5 at either time point) and persistent pain (WOMAC pain > 5 at both time points). Cartilage volume, incidence and progression of ROA were assessed using magnetic resonance imaging and x-rays at baseline and 4-years. Results In both non-ROA and ROA, greater baseline WOMAC knee pain score was associated with increased medial and lateral cartilage volume loss (p ≤ 0.001), incidence (OR 1.07, 95% CI 1.01–1.13) and progression (OR 1.07, 95% CI 1.03–1.10) of ROA. Non-ROA and ROA participants with fluctuating and persistent knee pain had increased cartilage volume loss compared with those with no pain (p for trend ≤ 0.01). Non-ROA participants with fluctuating knee pain had increased risk of incident ROA (OR 1.62, 95% CI 1.04–2.54), corresponding to a number needed to harm of 19.5. In ROA the risk of progressive ROA increased in participants with persistent knee pain (OR 1.82, 95% CI 1.28–2.60), corresponding to a number needed to harm of 9.6. Conclusions Knee pain over 1 year predicted accelerated cartilage volume loss and increased risk of incident and progressive ROA. Early management of knee pain and controlling knee pain over time by targeting the underlying mechanisms may be important for preserving knee structure and reducing the burden of knee OA. Electronic supplementary material The online version of this article (10.1186/s13075-018-1751-4) contains supplementary material, which is available to authorized users.

Summary Objective There is a need to identify reliable biomarkers that can predict knee osteoarthritis (OA) progression. We investigated a panel of adipokines and some related inflammatory factors alone and their ratios for their associative value at assessing cartilage volume loss over time and symptoms in obese [High body mass index (BMI)] and non-obese (Low BMI) OA subjects. Design Human OA serum was from the Osteoarthritis Initiative Progression subcohort. Baseline levels of adiponectin (high and low molecular weight forms), adipsin, chemerin, leptin, visfatin, C-reactive protein (CRP), interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) were evaluated with specific assays. Cartilage volume was assessed at baseline and 48 months by quantitative magnetic resonance imaging (MRI), and symptoms using baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. Data were analysed by linear regression with confounding factors at baseline, followed by multiple comparison adjustment. Results The levels of the nine biomarkers and their ratios (36) were studied. Among High BMI subjects, only the ratio adipsin/MCP-1 was associated with cartilage volume loss over time in the lateral compartment [β, −2.95; 95% confidence interval (CI), −4.42, −1.49; P = 0.010], whereas MCP-1 was associated with WOMAC pain (−1.74; −2.75, −0.73; P = 0.030) and the ratio CRP/MCP-1 with WOMAC pain (0.76; 0.37, 1.14; P = 0.023), function (2.43; 1.20, 3.67; P = 0.020) and total (3.29; 1.58, 5.00; P = 0.027). No associations were found for biomarkers or ratios in Low BMI OA. Conclusion In this study, the ratio adipsin/MCP-1 was found to be associated with the knee structural changes and that of CRP/MCP-1 with symptoms in obese OA subjects. Our data further underline the relevance of ratios as biomarkers to a stronger association to OA progression and symptoms.

Objective: To examine whether baseline knee joint effusion volume and the change in effusion volume over 1 year are associated with cartilage volume loss, progression of radiographic OA (ROA) over 4 years and risk of total knee replacement over 6 years. Methods: This study included 4115 Osteoarthritis Initiative participants with knee joint effusion volume quantified by MRI at baseline. The change in effusion volume over 1 year was assessed. Cartilage volume loss and progression of ROA over 4 years were assessed using MRI and X-ray and total knee replacement over 6 years was assessed. Multiple linear regression and binary logistic regression were used for data analyses. Results: Baseline knee effusion volume (per 5 ml) was positively associated with a loss of medial and lateral cartilage volume [regression coefficient 0.13%/year (95% CI 0.10, 0.17) and 0.13%/year (95% CI 0.10, 0.16), respectively, both P < 0.001], progression of ROA [odds ratio (OR) 1.28 (95% CI 1.20, 1.37), P < 0.001], and risk of knee replacement [OR 1.12 (95% CI 1.05, 1.20), P = 0.001]. A 5 ml increase in knee effusion volume over 1 year was positively associated with medial cartilage volume loss [regression coefficient 0.09%/year (95% CI 0.04, 0.15), P = 0.001], progression of ROA [OR 1.21 (95% CI 1.11, 1.33), P < 0.001] and risk of knee replacement [OR 1.24 (95% CI 1.12, 1.37), P < 0.001]. Conclusions: Knee joint effusion volume assessed from MRI provides a continuous and sensitive measure that was associated with cartilage volume loss, progression of ROA and risk of total knee replacement. It may provide a method to identify individuals with an inflammatory OA phenotype who are at higher risk of disease progression.

Objective In the perspective of personalized management of osteoarthritis (OA), a clinically relevant concern is the impact of meniscal extrusion (Ext) on response to treatment. This study aimed at determining the effects of conventional OA pharmacological treatments and those of the combination of glucosamine and chondroitin sulfate (Glu/CS) on knee structural changes in the presence or absence of Ext, using data from the progression cohort of the Osteoarthritis Initiative. Methods In this longitudinal study, knee OA participants were stratified based on whether (+) or not (−) they received analgesics/NSAIDs (+ and −analgesics/NSAIDs) and/or Glu/CS (+ and −Glu/CS) for 24 consecutive months and on the presence (Ext+) or absence (Ext−) of medial meniscal extrusion at baseline. The main outcomes were knee structural changes including the loss of joint space width (JSW) and cartilage volume loss measured by quantitative MRI. Results In both − and +analgesics/NSAIDs groups ( n = 300 each), the Ext+ participants had more-advanced disease at baseline (T0) and more JSW loss and cartilage volume loss in the medial compartment ( p ≤ 0.003, univariate; p ≤ 0.049, multivariate analyses) at both 12 (T12) and 24 (T24) months compared to Ext− participants. In the −analgesics/NSAIDs group, Ext+ participants taking Glu/CS had significantly less cartilage volume loss in the medial plateau at T24 ( p ≤ 0.010, univariate and multivariate analyses). In the +analgesics/NSAIDs group at T24, Ext− participants taking Glu/CS had less cartilage volume loss in the global ( p ≤ 0.002, univariate and multivariate analyses) and medial and lateral plateaus ( p = 0.034 and p = 0.013, respectively, multivariate analysis). No significant difference in JSW loss was found between the groups. Conclusion This study is the first to demonstrate, using qMRI, that meniscal extrusion can modify the response to Glu/CS treatment in knee OA patients, depending on the severity of the disease.

Objective Studies have proposed vastus medialis (VM) muscle cross-sectional area change as a variable associated with cartilage volume loss in knee osteoarthritis (OA). However, the VM also includes fat (%Fat), which may influence knee function. This study analyzed the VM area and %Fat data, separately and in combination, to predict symptoms, cartilage volume loss, and bone marrow lesion (BML) change in knee OA. Methods This study included the according-to-protocol population (n = 143) of a 2-year knee OA randomized clinical trial having magnetic resonance imaging at baseline and 2 years. Correlations used multivariate analyses. Results Greater baseline value for VM area and %Fat were significantly associated with sex (male, area; female, %Fat), higher body mass index (BMI), and Western Ontario and McMaster Universities Osteoarthritis Index stiffness, function, and total scores (better, high area; worse, high %Fat). Moreover, a VM %Fat increase of 1% at 2 years was associated with worsening of cartilage volume loss in the global knee (P = 0.015) and some subregions (P ≤ 0.030), and with an increment of BML global score change (P < 0.001). A 1% decrease in VM area at 2 years was associated with worsening of knee pain score (P = 0.048). Importantly, the concurrent presence of low VM area, high VM %Fat, and high BMI identified a subgroup of patients with greater cartilage volume loss in the medial femur (P = 0.028) than the rest of the cohort. Conclusion These data demonstrated, for the first time, that VM fat content is a strong predictor of cartilage volume loss and the occurrence and progression of BML. Importantly, the combined data of VM area, VM %Fat, and BMI identified patients at higher risk for OA progression.

To determine, using data from participants enrolled in the progression cohort of the OAI, the effects of conventional osteoarthritis (OA) pharmacological treatment and those of the combination of glucosamine and chondroitin sulfate (Glu/CS) on knee structural changes.Six hundred patients with knee OA were stratified based on whether or not they received for 24 consecutive months the OA conventional pharmacological treatment and/or Glu/CS. The main outcomes were knee structural changes, including the loss of joint space width (JSW) and of cartilage volume measured by quantitative MRI.Participants reported taking (+) (n=300) or not taking (-) (n=300) OA treatment (analgesic/NSAIDs). The +analgesic/NSAIDs participants had higher Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores (p0.001) and smaller JSW (p=0.01), reflecting more severe disease at baseline. In the -analgesic/NSAIDs group, participants taking Glu/CS had significantly reduced loss of cartilage volume at 24 months in the medial central plateau (p=0.007). Further subdivision revealed that this effect of Glu/CS occurred in participants with a higher severity of the disease (JSW≤median). In the +analgesic/NSAIDs group, those taking Glu/CS had significantly reduced loss of cartilage volume in the global plateau at 12 months (p=0.05), and in the central plateau at 24 months (p=0.05). These effects occurred in participants with less disease severity (JSWmedian). By contrast, no significant reduction in JSW was found between all groups.In +analgesic/NSAIDs groups and -analgesic/NSAIDs groups, participants who took Glu/CS had reduced loss of cartilage volume over 24 months in subregions when assessed with qMRI, arguing for a disease-modifying effect of Glu/CS which could not be identified by X-rays.

Objective To evaluate the impact of 2 magnetic resonance imaging (MRI) sequences on cartilage defect assessment in knee osteoarthritis (OA) patients and the sensitivity to change over time comparing cartilage defect (semiquantitative) with cartilage volume loss (quantitative) methods. Methods Gradient-echo (GRE) and intermediate-weighted fast spin-echo (IW-FSE) sequences were compared. Knee OA MRIs were from two 2-year studies (cohort 1, n = 55; cohort 2, n = 143). For both cohorts, a GRE sequence was used and patients in cohort 1 underwent an additional IW-FSE sequence. Cohort 2 included patients from a previous trial. Cartilage defects and cartilage volume were evaluated. Results The cartilage defect assessment provided consistently significantly higher scores in IW-FSE than in GRE sequences at baseline and 2 years. However, there was no difference in the change at 2 years between the sequences. The standardized response mean (SRM) for change did not show a difference between the 2 sequences, but was consistently higher (2–2.5-fold) for the quantitative method. The cartilage defect score change between the 2 treatment groups revealed a trend toward significance only in the medial tibial plateau, whereas the change in cartilage volume loss demonstrated a significant difference in the global knee, global femur, lateral femur, and lateral compartment. The SRMs for the treatment groups combined were markedly higher for cartilage volume loss than for the defect scoring by 4.3- to 6.0-fold. Conclusion The direct comparison between GRE and IW-FSE sequences did not suggest superior sensitivity to cartilage defect change over time of one sequence over the other. Interestingly, the quantitative cartilage volume assessment was more sensitive than the semiquantitative scoring in the detection of treatment effect on OA cartilage changes.

Objective To predict, using clinical and qMRI data, the incidence of total knee replacement (TKR) during the long-term follow-up of knee osteoarthritis (OA) patients who formerly received chondroitin sulfate (CS) or placebo treatment. Design A post hoc intention-to-treat analysis to evaluate the incidence of TKR was done on knee OA patients who had participated in a 12-month trial evaluating the impact of CS (800 mg/d) versus placebo for 6 months, followed by a 6-month open-phase in which all patients received CS. Additionally, the clinical and qMRI predictors of TKR were determined. Results Thirteen TKRs were performed in the population after a 4-year follow-up. More TKRs were performed in the placebo group than in the CS group (69% vs. 31%, P = 0.150, logistic regression). The statistically significant predictors of TKRs were, at baseline, higher WOMAC pain and function scores, presence of bone marrow lesions (BMLs), and higher C-reactive protein levels. Loss of medial cartilage volume and increase in WOMAC pain and function at one-year were also predictors of TKR. Multivariate analyses revealed that baseline presence of BML and higher WOMAC pain score were independent predictors. Time to occurrence of the TKR also favored the CS group versus placebo (log-rank, P = 0.094). Conclusion Symptoms such as knee pain and function, presence of BML, and cartilage volume loss predict the long-term occurrence of a “hard” outcome such as TKR.

Background: Bone marrow lesions (BMLs) are associated with osteoarthritis (OA). We assessed the performance of two commonly used MRI sequences, IW-TSE and DESS, for reliability in the detection of BMLs and sensitivity to estimate change over time. We suggested that the IW-TSE would demonstrate higher sensitivity to change than DESS in the assessment of BML prevalence and change over time. This study was performed using a subset of the Osteoarthritis Initiative (OAI) cohort. Methods: A sub-group of 144 patients was selected from the OAI progression cohort who all had IW-TSE and DESS MRI acquisitions at baseline and 24 months. BMLs were assessed using a semi-quantitative scale in the global knee, medial and lateral compartments, and subregions. Intra-reader reliability was assessed on a subset of 51 patients. Results: Intra-reader reliability was substantial for the global knee ≥ 0.64, medial ≥ 0.70, and lateral ≥ 0.63 compartments for IW-TSE and DESS. The prevalence of BML detected at baseline was only slightly greater for IW-TSE compared to DESS. The mean BML score at baseline was significantly higher (p ≤ 0.006) for the IW-TSE than the DESS. However, mean change at 24 months was similar for both sequences for all regions except the medial compartment (p = 0.034) and medial femur (p = 0.015) where they were significantly higher for DESS than IW-TSE. Moreover, the prevalence of BML change at 24 months was similar in all regions except the global knee (p = 0.047) and the lateral tibial plateau (p = 0.031). Conclusion: This study does not suggest superior sensitivity to change of one sequence over the other for almost all the regions. The only difference is a higher BML mean change over time detected by the DESS sequence in the medial compartment and femur. These data bring into perspective that both sequences seem equivalent regarding their use for the assessment of BML in clinical trials.

Background In osteoarthritis (OA) treatment, although chondroitin sulfate (CS) was found in a number of studies using radiography to have a structure-modifying effect, to date CS use is still under debate. A clinical study using quantitative magnetic resonance imaging (qMRI) is therefore of the utmost importance. Here we report data from a 24-month, randomised, double-blind, double-dummy, controlled, comparative exploratory study of knee OA. The primary endpoint was to determine the effect of CS 1200 mg/day versus celecoxib 200 mg/day on cartilage volume loss (CVL) in the lateral compartment over time as measured by qMRI. Secondary endpoints included assessment of the OA structural changes and signs and symptoms of OA. Methods qMRI was performed at baseline and at 12 and 24 months. CVL, bone marrow lesion size, and synovial thickness were evaluated using qMRI. The primary statistical analysis was carried out on the modified intention-to-treat (mITT) population (n = 138) using chi-squared, Fisher’s exact, Wilcoxon Mann–Whitney, and Student’s t tests and analysis of covariance. Analyses were also conducted on the according-to-protocol (ATP; n = 120) population. Results In the adjusted mITT analysis, compared with celecoxib treatment, patients treated with CS had a significant reduced CVL at 24 months in the medial compartment (celecoxib –8.1 % ± 4.2, CS –6.3 % ± 3.2; p = 0.018) and medial condyle (–7.7 % ± 4.7, –5.5 % ± 3.9; p = 0.008); no significant effect was seen in the lateral compartment. In the ATP population, CS reduced CVL in the medial compartment at 12 months (celecoxib –5.6 % ± 3.0, CS –4.5 % ± 2.6; p = 0.049) and 24 months (celecoxib –8.4 % ± 4.2, CS –6.6 % ± 3.3; p = 0.021), and in the medial condyle at 24 months (celocoxib –8.1 % ± 4.7, CS –5.7 % ± 4.0; p = 0.010). A trend towards a statistically reduced synovial thickness (celecoxib +17.96 ± 33.73 mm, CS –0.66 ± 22.72 mm; p = 0.076) in the medial suprapatellar bursa was observed in CS patients. Both groups experienced a marked reduction in the incidence of patients with joint swelling/effusion and in symptoms over time. Data showed similar good safety profiles including cardiovascular adverse events for both drugs. Conclusion This study demonstrated, for the first time in a 2-year randomised controlled trial using qMRI, the superiority of CS over celecoxib at reducing CVL in knee OA patients. Trial registration ClinicalTrials.gov NCT01354145. Registered 13 May 2011. Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-1149-0) contains supplementary material, which is available to authorized users.

Objectives Knee bone curvature assessed by MRI was associated with OA cartilage loss. A recent knee OA trial demonstrated the superiority of chondroitin sulfate over celecoxib (comparator) at reducing cartilage volume loss (CVL) in the medial compartment (condyle). The main objectives were to identify which baseline bone curvature regions of interest (BCROI) best associated with CVL and investigate whether baseline BCROI and 2-year change are correlated with the protective effect of chondroitin sulphate on CVL. Methods This post hoc analysis of a clinical trial used the according-to-protocol population (chondroitin sulphate, n = 57; celecoxib, n = 63) baseline and 2-year MRI to assess bone curvature and CVL. Global optimum search identified the BCROI in the medial condyle using celecoxib as reference. Statistical analyses were performed with Pearson's correlation, Mann-Whitney U -test, Student's t -test and analysis of covariance. Results The BCROI including the medial posterior condyle and lateral central condyle was found to correlate best with medial condyle CVL at 2 years ( r = 0.33, P = 0.008). In patients with a baseline BCROI value less than the median (more flattened bone), chondroitin sulphate demonstrated a protective effect on CVL compared with celecoxib in the medial compartment (P = 0.037). In patients with 2-year BCROI changes greater than the median (greater severity of bone flattening), chondroitin sulphate protected against CVL in the medial compartment, condyle and central plateau (P ⩽ 0.030). Conclusion This study is the first to demonstrate the feasibility and usefulness of bone curvature measurements to predict effectiveness of OA treatment on CVL. The results identify bone curvature as a potential novel biomarker for knee OA clinical trials.

SummaryObjectiveSex 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.DesignCross-sectional study of 489 women aged 50–80years. 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.ResultsParity was associated with a deficit in total knee cartilage volume [adjusted β=−0.69ml, 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

Objective To identify predictive factors for total knee replacement (TKR) using data from MRI of knee osteoarthritis patients in a phase III multicentre diseasemodifying 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 identifi ed by MRI allow prediction of a ‘hard’ outcome such as TKR. The fi ndings support the usefulness and predictive value of MRI in defi ning study outcome in DMOAD trials.

ObjectiveTo 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).MethodsIn this pilot multicentre, randomised, double-blind, 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.ResultsThe 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.ConclusionCS 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.

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.

ObjectiveTo 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.MethodsPatients 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.ResultsOne hundred and sixty-one patients completed the study according to protocol. The global knee and all subregions showed increased BML scores over time (p ConclusionsBML 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.

ObjectivesTo 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.Methods161 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.ResultsOver 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; pConclusionHigher 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.

SummaryObjectiveTo assess the evolution of bone marrow lesions (BMLs) in a canine model of knee osteoarthritis (OA) using three different magnetic resonance imaging (MRI) sequences.DesignThree MRI sequences [coronal, T1-weighted three-dimensional fast gradient recalled echo (T1-GRE), sagittal fat-suppressed 3D spoiled gradient echo at a steady state (SPGR), and sagittal T2-weighted fast spin echo with fat saturation (T2-FS)] were performed at baseline, and at week 4, 8 and 26 in five dogs following transection of the anterior cruciate ligament. The same reader scored (0–3) subchondral BMLs twice, in blinded conditions, according to their extent in nine joint subregions, for all imaging sessions, and independently on the three MRI sequences. Correlation coefficients and Bland–Altman plots evaluated intra-reader repeatability. Readings scores were averaged and the nine subregions were summed to generate global BML scores.ResultsBMLs were most prevalent in the central and medial portions of the tibial plateau. Intra-reader repeatability was good to excellent for each sequence (rs=0.87–0.97; P