Rates and sensitivity of knee cartilage thickness loss in specific central reading radiographic strata from the osteoarthritis initiative.

OBJECTIVE: To compare the rate and sensitivity to change of quantitative cartilage thickness change with magnetic resonance imaging (MRI) across specific radiographic strata of knee osteoarthritis (KOA) from central expert readings of the Osteoarthritis Initiative (OAI). Specifically, we explored whether Kellgren Lawrence grade (KLG) 2 knees with radiographic joint space narrowing (JSN) displayed greater cartilage loss than those without JSN, and whether knees with medial JSN grade2 had greater loss than those with grade1. METHODS: One-year femorotibial cartilage thickness change was obtained for 836 knees, 112 without, and 724 with definite radiographic KOA based on baseline site readings. The maximum subregional cartilage loss, and cartilage thickness change in the total femorotibial joint (FTJ) and medial femorotibial compartment (MFTC) were analyzed across different radiographic strata (central vs site readings). RESULTS: The maximum subregional rate of change was significantly greater in central_KLG2 knees with than in those without JSN (172 ± 152 vs 134 ± 100 µm; P = 0.03). In contrast, the rate did not differ significantly between central_KLG1 knees with and without JSN. MFTC cartilage loss in central_medial_grade2 JSN knees was substantially and significantly greater than in grade1 knees (-70 ± 159 vs -31 ± 126 µm; P = 0.02). For comparison, the loss in grade3 knees was -72 ± 122 µm. CONCLUSIONS: In KLG2 knees, presence of radiographic JSN was associated with significantly and substantially greater rates of subregional cartilage loss. Differentiating knees with mild vs moderate medial JSN, and definite radiographic OA knees with vs without JSN is important in predicting structural progression of KOA, and for planning clinical trials testing the efficacy of disease modifying drugs (DMOADs).

Lateral and medial joint space narrowing predict subsequent cartilage loss in the narrowed, but not in the non-narrowed femorotibial compartment--data from the Osteoarthritis Initiative.

OBJECTIVE: To determine the predictive value of unicompartimental joint space narrowing (JSN) for MRI-based cartilage thickness loss in the narrowed and the non-narrowed femorotibial compartment. METHODS: 922 knees from 922 Osteoarthritis Initiative (OAI) participants (62.2 ± 9.0 years, 61% females) with radiographic OA (158 without JSN [noJSN], 175 with lateral JSN [latJSN], 589 with medial JSN [medJSN]) were analyzed using 3 T MRI. One-year cartilage thickness change was determined in the lateral (LFTC) and medial femorotibial compartment (MFTC), and in femorotibial subregions. The probability of subsequent cartilage loss was calculated using predefined thresholds. The predictive value of JSN for the probability and magnitude of cartilage loss was compared between latJSN, medJSN and noJSN knees using Fisher's exact and Mann-Whitney-U tests. RESULTS: The probability of cartilage loss was greater in the narrowed compartment of latJSN/medJSN knees (34.9%/32.4%) than in noJSN knees (13.3%/12.7%, P ≤ 6.4 × 10(-6)) and so was the magnitude of cartilage thickness change (P ≤ 8.2 × 10(-6)). No significant differences were observed between the narrowed compartments of latJSN vs. medJSN knees (probability: P = 0.58, magnitude: P = 0.19) or between the non-narrowed compartment of latJSN/medJSN vs. noJSN knees (probability: P ≥ 0.35, magnitude: P = ≥0.23). These results were confirmed by the location-independent ordered value (OV) analyses of femorotibial subregions. CONCLUSION: The predictive value of latJSN for lateral compartment cartilage loss was comparable to that of medJSN for medial compartment cartilage loss, whereas cartilage loss in the non-narrowed compartment was similar to that in noJSN knees. These findings provide important clues to predicting progression of knee OA, and in tailoring inclusion criteria for clinical trials.

Imaging of cartilage and bone: promises and pitfalls in clinical trials of osteoarthritis.

Imaging in clinical trials is used to evaluate subject eligibility, and/or efficacy of intervention, supporting decision making in drug development by ascertaining treatment effects on joint structure. This review focusses on imaging of bone and cartilage in clinical trials of (knee) osteoarthritis. We narratively review the full-text literature on imaging of bone and cartilage, adding primary experience in the implementation of imaging methods in clinical trials. Aims and constraints of applying imaging in clinical trials are outlined. The specific uses of semi-quantitative and quantitative imaging biomarkers of bone and cartilage in osteoarthritis trials are summarized, focusing on radiography and magnetic resonance imaging (MRI). Studies having compared both imaging methodologies directly and those having established a relationship between imaging biomarkers and clinical outcomes are highlighted. To make this review of practical use, recommendations are provided as to which imaging protocols are ideal for capturing specific aspects of bone and cartilage tissue, and pitfalls in their usage are highlighted. Further, the longitudinal sensitivity to change, of different imaging methods is reported for various patient strata. From these power calculations can be accomplished, provided the strength of the treatment effect is known. In conclusion, current imaging methodologies provide powerful tools for scoring and measuring morphological and compositional aspects of most articular tissues, capturing longitudinal change with reasonable to excellent sensitivity. When employed properly, imaging has tremendous potential for ascertaining treatment effects on various joint structures, potentially over shorter time scales than required for demonstrating effects on clinical outcomes.

Differences between X-ray and MRI-determined knee cartilage thickness in weight-bearing and non-weight-bearing conditions.

OBJECTIVE: Determine the effect of loading upon MRI-based mean medial femorotibial cartilage thickness (mMFT_th) and radiograph-based minimum joint space width (mJSW), and determine loading's effect on the relationship between these measures. METHODS: MRI and radiographs were analyzed of 25 knees in weight-bearing and non-weight-bearing conditions. Eight subjects had a Kellgren-Lawrence (KL) grade of 0, indicating no evidence of radiographic OA. The rest were KL = 2 or KL = 3, indicating mild to moderate OA. The change from unloaded to loaded conditions was calculated. RESULTS: Joint space measures decreased from unloaded to loaded conditions for both radiographs (mJSW = 3.29 mm unloaded to 3.16 mm loaded, P < 0.05) and MRI (mMFT_th = 2.70 mm unloaded to 2.55 mm loaded P < 0.001). The mean absolute difference measured from radiographs was larger for the OA group than the control group, at -0.20 mm for OA vs +0.01 mm for control. Loaded X-ray and loaded MRI joint space values from our study were no better correlated to one another than loaded X-ray and unloaded MRI. CONCLUSION: Knee loading does not add a very significant value to the study of joint space on healthy knees, but loading may play a role in the study of OA knees. Unloaded MRI assessments of cartilage thickness are as correlated to loaded JSW as to loaded MRI measurements. More study is necessary to determine whether loaded MRI adds significant value to the study of OA progression.

Direct comparison of fixed flexion, radiography and MRI in knee osteoarthritis: responsiveness data from the Osteoarthritis Initiative.

OBJECTIVE: Minimum radiographic joint space width (mJSW) represents the Food and Drug Administration (FDA) standard for demonstrating structural therapeutic benefits for knee osteoarthritis (KOA), but only shows moderate responsiveness (sensitivity to change). We directly compare the responsiveness of magnetic resonance imaging (MRI)-based cartilage thickness and JSW measures from fixed-flexion radiography (FFR) and explore the correlation of region-matched changes between both methods. METHODS: Nine hundred and sixty-seven knees of Osteoarthritis Initiative participants with radiographic KOA were studied: 445 over 1 year with coronal FLASH MRI and FFR, and 375/522 over 1/2 years with sagittal DESS MRI and FFR. Standardized response means (SRM) of cartilage thickness and mJSW were compared using the sign-test. RESULTS: With FLASH MRI, SRM was -0.28 for medial femorotibial compartment (MFTC) cartilage loss vs -0.15 for mJSW, and -0.32 vs -0.22 for the most sensitive MRI subregion (central MFTC) vs the most sensitive fixed-location JSW(x = 0.25). With DESS MRI, 1-year SRM was -0.34 for MFTC vs -0.22 for mJSW and -0.44 vs -0.28 for central MFTC vs JSW(x = 0.225). Over 2 years, the SRM was significantly greater for MFTC than for mJSW (-0.43 vs -0.31, P = 0.017) and for central MFTC than for JSW(x = 0.225) (-0.51 vs -0.44, P < 0.001). Correlations between changes in spatially matched MRI subregions and fixed-location JSW were not consistently higher (r = 0.10-0.51) than those between non-matched locations (r = 0.15-0.50). CONCLUSIONS: MRI displays greater responsiveness in KOA than JSW FFR-based JSW, with the greatest SRM observed in the central medial femorotibial compartment. Fixed-location radiographic measures appear not capable of determining the spatial distribution of femorotibial cartilage loss.

Characterization of nitrotyrosine as a biomarker for arthritis and joint injury.

OBJECTIVES: To characterize the utility of nitrotyrosine (NT) as a biomarker for arthritis and joint injury. DESIGN: Synovial fluid, plasma, and urine from patients diagnosed with osteoarthritis (OA), rheumatoid arthritis (RA), anterior cruciate ligament (ACL) injury, meniscus injury and pseudogout, and knee-healthy volunteers were analyzed for concentrations of NT, nitrate and nitrite (NO(x)), matrix metalloproteinase (MMP)-3, MMP-1, MMP-9, more than 40 chemokines and cytokines. RESULTS: In OA, plasma and synovial fluid NT were increased versus healthy volunteers. Synovial fluid to plasma NT ratios were elevated in OA patients. Synovial fluid from patients with ACL and meniscus injury and pseudogout had increased levels of NT (P < 0.001). In these samples, NT levels significantly correlated with ARGS-aggrecan neoepitope generated by aggrecanase cleavage of aggrecan (P ≤ 0.001), cross-linked C-telopeptides of type II collagen (P < 0.001), MMP-1 (P = 0.008), and MMP-3 (P ≤ 0.001). In RA, plasma NT decreased following 6 months of anti-tumor necrosis factor (TNF) treatment. For every 1.1% change in log(10) NT, there was a 1.0% change in the log(10) disease activity scores (DAS28-3 CRP). Both predicted and observed DAS28-3 CRP showed a robust linear relationship with NT. RA plasma NT positively correlated with CRP, MMP-3 and interferon γ-induced protein 10. CONCLUSIONS: NT may serve as a useful biomarker for arthritis and joint injury. In RA, NT is highly correlated with several biomarkers and clinical correlates of disease activity and responds to anti-TNF therapy.

Using ordered values of subregional cartilage thickness change increases sensitivity in detecting risk factors for osteoarthritis progression.

OBJECTIVE: To examine whether ordered values of (sub)regional femorotibial cartilage thickness change are superior to region-based approaches in detecting risk factors for cartilage loss in osteoarthritis (OA). METHODS: 58 women with knee OA had 3 Tesla MR images acquired at baseline and 24 months. Changes in cartilage thickness (∆ThCtAB) were determined in eight medial femorotibial subregions. An ascending sort of individual ∆ThCtAB measurements was done to create "ordered values". Risk factors for cartilage loss considered were: age, BMI, anatomical knee axis (AAA), minimal (medial) joint space width (mJSW), and percent of medial tibial plateau covered by the meniscus (percent cover). All change metrics were tested for association with the risk factors using Kendall's τ and relative sensitivity of multiple tests of subregions and ordered values were compared with single metrics of change from plate and compartment summaries and the first ordered value. RESULTS: The associations between subregion ∆ThCtAB and AAA (P=0.0002), mJSW (P=0.016), and age (P=0.011) were significant, but only AAA (at α=0.05) and age (at α=0.1) remained significant after adjusting for multiple subregions. In contrast, cMFTC had P-values<0.05 for AAA (P=0.0001), mJSW (P=0.016), and meniscus subluxation (0.04). The first ordered value had significant associations with AAA (P=0.0004), mJSW (P=0.003), meniscus subluxation (P=0.02) and percent cover (P=0.031) all of which were significant at α=0.05 after adjusting for tests on multiple risk factors. CONCLUSION: Ordered values of ∆ThCtAB were more sensitive in detecting risk factors of cartilage loss than subregional ∆ThCtAB. Sensitivity was further enhanced by considering the minimum ordered value as a single test, thus not requiring adjustment for multiple tests. Using ordered values there was a significant association between ∆ThCtAB and baseline AAA, mJSW, meniscus subluxation and meniscus percent cover. This study provides an important step in validating ordered values of cartilage change.

Definition of osteoarthritis on MRI: results of a Delphi exercise.

OBJECTIVE: Despite a growing body of Magnetic Resonance Imaging (MRI) literature in osteoarthritis (OA), there is little uniformity in its diagnostic application. We envisage in the first instance the definition requiring further validation and testing in the research setting before considering implementation/feasibility testing in the clinical setting. The objective of our research was to develop an MRI definition of structural OA. METHODS: We undertook a multistage process consisting of a number of different steps. The intent was to develop testable definitions of OA (knee, hip and/or hand) on MRI. This was an evidence driven approach with results of a systematic review provided to the group prior to a Delphi exercise. Each participant of the steering group was allowed to submit independently up to five propositions related to key aspects in MRI diagnosis of knee OA. The steering group then participated in a Delphi exercise to reach consensus on which propositions we would recommend for a definition of structural OA on MRI. For each round of voting, ≥60% votes led to include and ≤20% votes led to exclude a proposition. After developing the proposition one of the definitions developed was tested for its validity against radiographic OA in an extant database. RESULTS: For the systematic review we identified 25 studies which met all of our inclusion criteria and contained relevant diagnostic measure and performance data. At the completion of the Delphi voting exercise 11 propositions were accepted for definition of structural OA on MRI. We assessed the diagnostic performance of the tibiofemoral MRI definition against a radiographic reference standard. The diagnostic performance for individual features was: osteophyte C statistic=0.61, for cartilage loss C statistic=0.73, for bone marrow lesions C statistic=0.72 and for meniscus tear in any region C statistic=0.78. The overall composite model for these four features was a C statistic=0.59. We detected good specificity (1) but less optimal sensitivity (0.46) likely due to detection of disease earlier on MRI. CONCLUSION: We have developed MRI definition of knee OA that requires further formal testing with regards their diagnostic performance (especially in datasets of persons with early disease), before they are more widely used. Our current analysis suggests that further testing should focus on comparisons other than the radiograph, that may capture later stage disease and thus nullify the potential for detecting early disease that MRI may afford. The propositions are not to detract from, nor to discourage the use of traditional means of diagnosing OA.

The effects of acute loading on T1rho and T2 relaxation times of tibiofemoral articular cartilage.

OBJECTIVE: To evaluate the effect of acute loading on healthy and osteoarthritic knee cartilage T(1ρ) and T(2) relaxation times. DESIGN: Twenty subjects with radiographic evidence of osteoarthritis (OA) and 10 age-matched controls were enrolled. Magnetic resonance imaging (MRI) acquisition, including T(1ρ) and T(2) map sequences were performed unloaded and loaded at 50% body mass. Cartilage masks were segmented semi-automatically on registered high-resolution spoiled gradient-echo (SPGR) images for each compartment (medial and lateral). Cartilage lesions were identified using a modified Whole Organ Magnetic Resonance Imaging Score (WORMS) score. Statistical differences were explored using separate two-way (group×loading condition) Analysis of Variance (ANOVA) using age as a covariate to evaluate the effects of loading on T(1ρ) and T(2) relaxation times. RESULTS: A significant decrease in T(1ρ) (44.5±3.8 vs 40.2±4.8ms for unloaded and loaded, respectively; P<0.001) and T(2) (31.8±3.8 vs 30.5±4.8ms for unloaded and loaded, respectively; P<0.001) relaxation times was observed in the medial compartment with loading while no differences were observed in the lateral compartment. This behavior occurred independent of WORMS score. Cartilage compartments with small focal lesions experienced greater T(1ρ) change scores with loading when compared to cartilage without lesions or cartilage with larger defects (P=0.05). CONCLUSIONS: Acute loading resulted in a significant decrease in T(1ρ) and T(2) relaxation times of the medial compartment, with greater change scores observed in cartilage regions with small focal lesions. These data suggest that changes of T(1ρ) values with loading may be related to cartilage biomechanical properties (i.e., tissue elasticity) and may be a valuable tool for the scientist and clinician at identifying early cartilage disease.

Sensitivity to change of cartilage morphometry using coronal FLASH, sagittal DESS, and coronal MPR DESS protocols--comparative data from the Osteoarthritis Initiative (OAI).

OBJECTIVE: The Osteoarthritis Initiative (OAI) is targeted at identifying sensitive biomarkers and risk factors of symptomatic knee osteoarthritis (OA) onset and progression. Quantitative cartilage imaging in the OAI relies on validated fast low angle shot (FLASH) sequences that suffer from relatively long acquisition times, and on a near-isotropic double echo steady-state (DESS) sequence. We therefore directly compared the sensitivity to cartilage thickness changes and the correlation of these protocols longitudinally. METHODS: Baseline (BL) and 12 month follow-up data of 80 knees were acquired using 1.5 mm coronal FLASH and 0.7 mm sagittal DESS (sagDESS) sequences. In these and in 1.5 mm coronal multi-planar reconstructions (MPR) of the DESS the medial femorotibial cartilage was segmented with blinding to acquisition order. In the weight-bearing femoral condyle, a 60% (distance between the trochlear notch and the posterior femur) and a 75% region of interest (ROI) were studied. RESULTS: The standardized response mean (SRM = mean change/standard deviation of change) in central medial femorotibial (cMFTC) cartilage thickness was -0.34 for coronal FLASH, -0.37 for coronal MPR DESS, -0.36 for sagDESS with the 60% ROI, and -0.38 for the 75% ROI. Using every second 0.7 mm sagittal slice (DESS) yielded similar SRMs in cMFTC for the 60% and 75% ROI from odd (-0.35/-0.36) and even slice numbers (-0.36/-0.39), respectively. BL cartilage thickness displayed high correlations (r > or = 0.94) between the three protocols; the correlations of longitudinal changes were > or = 0.79 (Pearson) and > or = 0.45 (Spearman). CONCLUSIONS: Cartilage morphometry with FLASH and DESS displays similar longitudinal sensitivity to change. Analysis of every second slice of the 0.7 mm DESS provides adequate sensitivity to change.

Femorotibial cartilage morphology: reproducibility of different metrics and femoral regions, and sensitivity to change in disease.

This study was designed to characterize the reproducibility and sensitivity to change of magnetic resonance imaging-based cartilage morphology metrics and femoral regions of interest (ROIs), in order to provide preferable outcome measures in longitudinal studies of cartilage morphology. Test-retest acquisitions were obtained at 3 tesla (T) in 33 subjects with and without radiographic signs of osteoarthritis (OA) (reproducibility study) as well as baseline and 2-year follow-up acquisitions in 28 subjects with radiographic signs of advanced OA (sensitivity study). Cartilage was segmented in the tibia and two distinct anatomical femoral ROIs, a 'long' ROI extending 60% from the trochlear notch to the posterior end of the condyles, and a 'short' ROI extending to the intercondylar bone bridge. Coefficients of variation (reproducibility study) and standardized response means (SRMs, sensitivity study) were obtained for different morphology metrics and anatomical regions. The subchondral bone area of the long ROI was 20% greater and less variable than that of the short ROI; cartilage morphology metrics were generally more reproducible in the long ROI. Normalized cartilage volume (VCtAB) and mean cartilage thickness (over the entire subchondral bone area; ThCtAB.Me) tended to be more reproducible and more sensitive to change (SRM up to -0.62) than cartilage volume (SRM up to -0.44), cartilage thickness over the cartilaginous area (ThCcAB; SRM up to -0.48) or maximum cartilage thickness (ThCtAB; SRM up to -0.35). The long femoral cartilage ROI provided more reproducible measurements than the short one. VCtAB and ThCtAB.Me may be preferable metrics in longitudinal studies of articular cartilage adaptation or OA.

Regional analysis of femorotibial cartilage loss in a subsample from the Osteoarthritis Initiative progression subcohort.

OBJECTIVE: The Osteoarthritis Initiative (OAI) is aimed at validating (imaging) biomarkers for monitoring progression of knee OA. Here we analyze regional femorotibial (FT) cartilage thickness changes over 1 year using 3 Tesla MRI. Specifically, we tested whether changes in central subregions exceed those in the total cartilage plates. METHODS: The right knees of a subsample of the OAI progression subcohort (n=156, age 60.9+/-9.9 years) were studied. Fifty-four participants had definite radiographic osteoarthritis (OA) (KLG 2 or 3) and a BMI>30. Mean and minimal cartilage thickness were determined in subregions of the medial/lateral tibia (MT/LT), and of the medial/lateral weight-bearing femoral condyle (cMF/cLF), after paired (baseline, follow up) segmentation of coronal FLASHwe images with blinding to the order of acquisition. RESULTS: The central aspect of cMF displayed a 5.8%/2.8% change in mean thickness in the group of 54/156 participants, respectively, with a standardized response mean (SRM) of -0.47/-0.31, whereas cartilage loss in the total cMF was 4.1%/1.9% (SRM -0.49/-0.30). In the central MT, the rate of change was -1.6%/-0.9% and the SRM -0.29/-0.20, whereas for the entire MT the rate was -1.0%/-0.5% and the SRM -0.21/-0.12. Minimal thickness displayed greater rates of change, but lower SRMs than mean thickness. CONCLUSIONS: This study shows that the rate of cartilage loss is greater in central subregions than in entire FT cartilage plates. The sensitivity to change in central subregions was higher than for the total cartilage plate in the MT and was similar to the total plate in the medial weight-bearing femur.

Relation of regional articular cartilage morphometry and meniscal position by MRI to joint space width in knee radiographs.

OBJECTIVE: To ascertain the contribution of articular cartilage morphometry and meniscal position on MRI to joint space width (JSW) measured in the Lyon schuss radiograph of the knee. DESIGN: 62 obese women with knee OA and 99 non-obese female controls (mean age 56.6 years) were imaged using 3T MRI and coronal water excitation spoiled gradient echo sequences. Segmentation of femorotibial cartilage morphology and regional morphometric analysis was performed using custom software. Meniscal position was measured quantitatively in sagittal and coronal planes. Minimum space width (mJSW) was measured in the Lyon Schuss knee radiograph; Kellgren and Lawrence grades (KLG) were assigned on standing anteroposterior knee films. The relative contribution of regional cartilage thickness and meniscal position to mJSW was assessed initially in univariate models and subsequently with multivariable modelling. RESULTS: 65% of the variation in mJSW was explained by regional cartilage thickness measures, different KLG and meniscal coverage. Of these measures the medial tibia cartilage thickness measures and central region of the central medial femur (ccMF) play a consistent role in variations in mJSW observed across all KLG. Further ccMF and the addition of percent meniscal coverage to this model explains the remaining differences in mean mJSW found between those subjects with definite joint space narrowing (KLG3) and those without OA. CONCLUSION: The variation in radiographic mJSW is best described by five regional cartilage thickness measures and percent meniscal coverage. The magnitude of each measures contribution differs according to radiographic severity with more variability explained by cartilage thickness of ccMF cartilage thickness and percent meniscal coverage with more severe disease.

OARSI-OMERACT definition of relevant radiological progression in hip/knee osteoarthritis.

BACKGROUND: Joint space width (JSW) evaluated in millimeters on plain X-rays is the currently optimal recognized technique to evaluate osteoarthritis (OA) structural progression. Data obtained can be presented at the group level (e.g., mean+/-standard deviation of the changes). Such presentation makes difficult the interpretation of the clinical relevance of the reported results. Therefore, a presentation at the individual level (e.g., % progressors) seems more attractive but requires to determining a cut-off. Several methodologies have been proposed to define cut-offs in JSW: arbitrary chosen cut-off, cut-off based on the validity to predict a relevant end-point such as the requirement of total articular replacement or cut-off based on the measurement error such as smallest detectable difference (SDD). OBJECTIVES: The objective of this OARSI-OMERACT initiative was to define a cut-off evaluated in millimeters on plain X-rays above which a change in JSW could be considered as relevant in patients with hip and knee OA. METHODS: The first step consisted in a systematic literature research performed using Medline database up to July 2007 to obtain all manuscripts published between 1990 and 2007 reporting a cut-off value in JSW evaluated in millimeters at either the knee or hip level. The second step consisted in a consensus based on the best knowledge of the 11 experts with the support of the available evidence. RESULTS: Among the 506 articles selected by the search, 47 articles reported cut-off of JSW in millimeters. There was a broad heterogeneity in cut-off values, whatever the methodologies or the OA localization considered (e.g., from 0.12 to 0.84 mm and from 0.22 to 0.78 mm for Knee (seven studies) and hip (seven studies), respectively when considering the data obtained based on the reliability). Based on the data extracted in the literature, the expert committee proposed a definition of relevant change in JSW based on plain X-rays, on an absolute change of JSW in millimeters and on the measurement error e.g., calculation of the SDD using the Bland and Altman technique. The results of the analysis of JSW should be expressed in terms of a dichotomous variable (e.g., progressors yes/no): a patient with a change in JSW during the study over such SDD will fulfill the definition of "progressor". Moreover, the pilot study aimed at evaluating the measurement error should be designed to reflect the different characteristics of the primary study in which the analysis of the radiological findings will be based on (patient's characteristics, centers characteristics, readers). CONCLUSION: This initiative based on both an Evidence Based Medicine (Systematic Literature Research) and Expert Opinion approach resulted in a proposal of definition of relevant radiological progression in OA to be used as end-point in clinical trials and also recommendations on the conduct of the reliability study allowing such definition.

Subregional femorotibial cartilage morphology in women--comparison between healthy controls and participants with different grades of radiographic knee osteoarthritis.

OBJECTIVE: To identify subregional differences in femorotibial cartilage morphology between healthy controls and women with different grades of radiographic knee osteoarthritis (OA). DESIGN: 158 women aged > or =40 years were studied. Weight-bearing extended anterior-posterior (AP) and Lyon schuss radiographs were obtained and the Kellgren Lawrence grade (KLG) determined. 97 women had a body mass index (BMI)< or =28, no symptoms, and were AP KLG0. 61 women had a BMI> or =30, symptoms in the target knee, and mild (KLG2=31) to moderate (KLG3=30) medial femorotibial radiographic OA in the AP views. Coronal spoiled gradient echo water excitation sequences were acquired at 3.0 Tesla. Total plate and regional measures of cartilage morphology of the weight-bearing femorotibial joint were quantified. RESULTS: KLG2 participants displayed, on average, thicker cartilage than healthy controls in the medial femorotibial compartment (particularly anterior subregion of the medial tibia (MT) and peripheral [external, internal] subregions of the medial femur), and in the lateral femur. KLG3 participants displayed significantly thinner cartilage than KLG0 participants in the medial weight-bearing femur (central subregion), in the external subregion of the MT, and in the internal subregion of the lateral tibia. These differences were generally unaffected when possible effects of demographic covariates were considered. CONCLUSIONS: The results indicate that in femorotibial OA regional cartilage thickening and thinning may occur, dependent on the (radiographic) disease status of the joint. These changes appear to display a heterogeneous spatial pattern, where certain subregions are more strongly affected than others.

Discovery and development of the N-terminal procollagen type II (NPII) biomarker: a tool for measuring collagen type II synthesis.

OBJECTIVE: Progression of joint damage in osteoarthritis (OA) is likely to result from an imbalance between cartilage degradation and synthesis processes. Markers reflecting these two components appear to be promising in predicting the rate of OA progression. Both N- and C-terminal propeptides of type II collagen reflect the rates of collagen type II synthesis. The ability to quantify the procollagen peptides in biological fluids would enable a better understanding of OA disease pathology and provide means for assessing the proof of mechanism of anabolic disease modifying OA drugs (DMOADs). METHODS: A polyclonal antibody that recognizes the sequence GPKGQKGEPGDIKDI in the propeptide region of rat, dog, and human type II collagen was raised in chicken and peptide-affinity purified. The immunoaffinity liquid chromatography mass spectrometry (LC-MS/MS) was used to extensively characterize N-terminal procollagen type II (NPII) peptides found in biological fluids. The novel competition enzyme-linked immunosorbent assay (ELISA) assay was developed to quantitatively measure the NPII peptides. RESULTS: Several peptides ranging from 17 to 41 amino acids with various modifications including hydroxylations on proline and lysine residues, oxidation of lysines to allysines, and attachments of glucose and galactose moieties to hydroxylysines were identified in a simple system such as ex vivo cultures of human articular cartilage (HAC) explants as well as in more complex biological fluids such as human urine and plasma. A competitive ELISA assay has been developed and applied to urine, plasma, and synovial fluid matrices in human, rat and dog samples. CONCLUSION: A novel NPII assay has been developed and applied to OA and normal human subjects to understand the changes in collagen type II synthesis related to the pathology of OA.

Performance of a non-fluoroscopically assisted substitute for the Lyon schuss knee radiograph: quality and reproducibility of positioning and sensitivity to joint space narrowing in osteoarthritic knees.

OBJECTIVE: This study evaluated the longitudinal performance of a modified Lyon schuss (LS) knee examination in the detection of radiographic joint space narrowing (JSN) in knees with osteoarthritis (OA). The modified LS exam entails two to four iterative acquisitions with empirically adjusted angulation of the X-ray beam to achieve superimposition of the anterior and posterior margins of the medial tibial plateau (MTP), a marker of parallel radioanatomic alignment that the original LS exam achieves with fluoroscopically guided beam angulation. METHODS: Seventy-four obese women with symptomatic knee OA underwent LS and fixed-flexion (FF, caudal 10 degrees beam angulation) X-ray exams at baseline and 1 year later. For 47 subjects, beam angulation for both LS exams was guided by fluoroscopy. For 27 subjects, the modified LS exam was performed at one or both times. Modified and original LS procedures were evaluated relative to concurrent FF radiographs with respect to the inter-margin distance (IMD) at the MTP midpoint (quality and reproducibility of alignment) and sensitivity to JSN. RESULTS: Compared to FF radiographs, modified LS radiographs afforded a smaller mean IMD at baseline (0.89 vs 2.06 mm, P=0.002), more reproducible IMD (mean change=0.49 vs 0.91 mm, P=0.007) and more rapid JSN (mean=0.25 vs 0.02 mm/yr, P=0.005). These differences paralleled those observed between original LS and FF procedures with respect to baseline alignment (0.96 vs 1.94 mm, P<0.001), reproducibility of alignment (0.49 vs 1.00 mm, P<0.001) and sensitivity to JSN (0.16 vs -0.01 mm/yr, P=0.007). CONCLUSION: In clinical centers where the absence of fluoroscopy equipment precludes use of the original LS protocol, a modified procedure employing iterative, empirical adjustment of the beam angle to achieve parallel radioanatomic alignment with the MTP affords a degree of superiority over the FF protocol with respect to quality and reproducibility of positioning and sensitivity to JSN in OA knees similar to that of the original.

Matrix metalloproteinase-13 expression in rabbit knee joint connective tissues: influence of maturation and response to injury.

The hypothesis of the present work was that expression of matrix metalloproteinase-13 (MMP-13, collagenase-3) would be induced during conditions involving important matrix remodeling such as ligament maturation, scar healing and joint instability. Therefore, MMP-13 expression in the medial collateral ligament (MCL) during the variable situations of tissue maturation and healing was assessed. MMP-13 expression in three intra-articular connective tissues of the knee (i.e. articular cartilage, menisci and synovium) following the transection of the anterior cruciate ligament of the knee was evaluated at 3 and 8 weeks post-injury. MMP-13 mRNA (semi-quantitative RT-PCR) and protein (immunohistochemistry and Western blotting) were detected in all of the tissues studied. Significantly higher MCL mRNA levels for MMP-13 were detected during the early phases of tissue maturation (i.e. 29 days in utero and 2-month-old rabbits) compared to later phases (5- and 12-month-old rabbits). This pattern of expression was recapitulated following MCL injury, with very high levels of expression in scar tissue at 3 weeks post-injury and then a decline to levels not significantly different from control values by 14 weeks. Elevated mRNA levels correlated with increased protein levels for MMP-13 in both menisci and synovium following the transection of the anterior cruciate ligament and during medial collateral ligament healing. These results indicate that MMP-13 expression is regulated by a number of variables and that high levels of expression occur in situations when connective tissue remodeling is very active.

Gene expression in menisci from the knees of skeletally immature and mature female rabbits.

This study, using the sensitive molecular technique of semiquantitative reverse transcription-polymerase chain reaction, evaluated mRNA levels for several molecules in medial and lateral menisci from the knees of skeletally mature and immature rabbits. Total RNA was extracted from the medial and lateral menisci of New Zealand White rabbits with the TRIspin method. Total RNA and DNA were similar in the two menisci of both immature and mature rabbits. The total RNA was reverse-transcribed and analyzed by semiquantitative polymerase chain reaction using rabbit-specific primer sets; levels of mRNA for a subset of molecules differed between the medial and lateral menisci. These variations in mRNA levels were also influenced by the degree of skeletal maturity of the rabbits. For most of the genes, mRNA levels were generally higher in the medial than in the lateral meniscus. The medial meniscus from immature and mature rabbits had significantly increased levels of mRNA for molecules such as transforming growth factor-beta, cyclooxygenase-2, and tissue inhibitor of metalloprotease-1. In contrast, compared with mRNA in the lateral meniscus, that for types II and III collagen, biglycan, insulin-like growth factor-2, plasminogen activator inhibitor-1, and matrix metalloprotease-1 was significantly increased in the medial meniscus of mature rabbits only and that for versican and type-I collagen was significantly increased in the medial meniscus of immature rabbits only. Levels of mRNA for inducible nitric oxide synthase and basic fibroblast growth factor were similar in both menisci for both age groups. The present study demonstrates that regulation of mRNA levels in medial and lateral menisci is tissue-specific and influenced by the skeletal maturity of the animals.

Phospholipase A2 activity in herniated lumbar discs. Clinical correlations and inhibition by piroxicam.

STUDY DESIGN: Prospective study of phospholipase A2 activity in the serum and intervertebral discs of patients undergoing surgery for sciatica due to disc herniation. OBJECTIVES: To determine correlations between herniated disc phospholipase A2 and clinical, radiographic, and anatomic signs of common sciatica; to evaluate serum phospholipase A2 activity as a marker of disc phospholipase A2; and to investigate the in vivo effect of piroxicam on disc phospholipase A2. SUMMARY OF BACKGROUND DATA: Several studies suggest disc inflammation as a mechanism of sciatica due to disc herniation, and phospholipase A2 emerges as a key enzyme of cartilage and disc tissues. METHODS: Phospholipase A2 activity was determined, using the degradation of a specific substrate, in the serum and discs of 31 patients (14 treated with acetaminophen and 17 treated with piroxicam) undergoing surgery for sciatica due to lumbar disc herniation. Visual analog scale for pain, Dallas Pain Questionnaire, Lasègue's sign, radiographic stage of degeneration of the herniated disc, volume of disc herniation shown by computed tomography, and surgical findings were recorded. RESULTS: Disc phospholipase A2 activity was independent of the patient's age or sex, the radiologic stage of disc degeneration, and the volume of the herniation, and showed no significant correlation with Lasègue's sign or pain measured on a visual analog scale. The correlation between disc phospholipase A2 and the Dallas category of items measuring the impact of pain on daily activities approached the level of significance (P = 0.07). Disc phospholipase A2 activity was significantly higher in cases of sequestrated discs than in other herniations. Disc phospholipase A2 was significantly correlated with serum phospholipase A2, and was significantly lower in patients treated with piroxicam than in those treated with acetaminophen. CONCLUSIONS: Disc phospholipase A2 is thought to participate in the physiopathology of sciatica and to bemodulated by nonsteroidal anti-inflammatory drug therapy. Serum phospholipase A2 is suggested as a biologic marker of disc inflammation in patients with sciatica.