Systematic review of the concurrent and predictive validity of MRI biomarkers in OA.

OBJECTIVE: To summarize literature on the concurrent and predictive validity of MRI-based measures of osteoarthritis (OA) structural change. METHODS: An online literature search was conducted of the OVID, EMBASE, CINAHL, PsychInfo and Cochrane databases of articles published up to the time of the search, April 2009. 1338 abstracts obtained with this search were preliminarily screened for relevance by two reviewers. Of these, 243 were selected for data extraction for this analysis on validity as well as separate reviews on discriminate validity and diagnostic performance. Of these 142 manuscripts included data pertinent to concurrent validity and 61 manuscripts for the predictive validity review. For this analysis we extracted data on criterion (concurrent and predictive) validity from both longitudinal and cross-sectional studies for all synovial joint tissues as it relates to MRI measurement in OA. RESULTS: Concurrent validity of MRI in OA has been examined compared to symptoms, radiography, histology/pathology, arthroscopy, CT, and alignment. The relation of bone marrow lesions, synovitis and effusion to pain was moderate to strong. There was a weak or no relation of cartilage morphology or meniscal tears to pain. The relation of cartilage morphology to radiographic OA and radiographic joint space was inconsistent. There was a higher frequency of meniscal tears, synovitis and other features in persons with radiographic OA. The relation of cartilage to other constructs including histology and arthroscopy was stronger. Predictive validity of MRI in OA has been examined for ability to predict total knee replacement (TKR), change in symptoms, radiographic progression as well as MRI progression. Quantitative cartilage volume change and presence of cartilage defects or bone marrow lesions are potential predictors of TKR. CONCLUSION: MRI has inherent strengths and unique advantages in its ability to visualize multiple individual tissue pathologies relating to pain and also predict clinical outcome. The complex disease of OA which involves an array of tissue abnormalities is best imaged using this imaging tool.

Responsiveness and reliability of MRI in knee osteoarthritis: a meta-analysis of published evidence.

OBJECTIVE: To summarize literature on the responsiveness and reliability of MRI-based measures of knee osteoarthritis (OA) structural change. METHODS: A literature search was conducted using articles published up to the time of the search, April 2009. 1338 abstracts obtained with this search were preliminarily screened for relevance and of these, 243 were selected for data extraction. For this analysis we extracted data on reliability and responsiveness for every reported synovial joint tissue as it relates to MRI measurement in knee OA. Reliability was defined by inter- and intra-reader intra-class correlation (ICC), or coefficient of variation, or kappa statistics. Responsiveness was defined as standardized response mean (SRM) - ratio of mean of change over time divided by standard deviation of change. Random-effects models were used to pool data from multiple studies. RESULTS: The reliability analysis included data from 84 manuscripts. The inter-reader and intra-reader ICC were excellent (range 0.8-0.94) and the inter-reader and intra-reader kappa values for quantitative and semi-quantitative measures were all moderate to excellent (range 0.52-0.88). The lowest value (kappa=0.52) corresponded to semi-quantitative synovial scoring intra-reader reliability and the highest value (ICC=0.94) for semi-quantitative cartilage morphology. The responsiveness analysis included data from 42 manuscripts. The pooled SRM for quantitative measures of cartilage morphometry for the medial tibiofemoral joint was -0.86 (95% confidence intervals (CI) -1.26 to -0.46). The pooled SRM for the semi-quantitative measurement of cartilage morphology for the medial tibiofemoral joint was 0.55 (95% CI 0.47-0.64). For the quantitative analysis, SRMs are negative because the quantitative value, indicating a loss of cartilage, goes down. For the semi-quantitative analysis, SRMs indicating a loss in cartilage are positive (increase in score). CONCLUSION: MRI has evolved substantially over the last decade and its strengths include the ability to visualize individual tissue pathologies, which can be measured reliably and with good responsiveness using both quantitative and semi-quantitative techniques.

Summary and recommendations of the OARSI FDA osteoarthritis Assessment of Structural Change Working Group.

OBJECTIVE: The Osteoarthritis Research Society International initiated a number of working groups to address a call from the US Food and Drug Administration (FDA) on updating draft guidance on conduct of osteoarthritis (OA) clinical trials. The development of disease-modifying osteoarthritis drugs (DMOADs) remains challenging. The Assessment of Structural Change (ASC) Working Group aimed to provide a state-of-the-art critical update on imaging tools for OA clinical trials. METHODS: The Group focussed on the performance metrics of conventional radiographs (CR) and magnetic resonance imaging (MRI), performing systematic literature reviews for these modalities. After acquiring these reviews, summary and research recommendations were developed through a consensus process. RESULTS: For CR, there is some evidence for construct and predictive validity, with good evidence for reliability and responsiveness of metric measurement of joint space width (JSW). Trials off at least 1 and probably 2 years duration will be required. Although there is much less evidence for hip JSW, it may provide greater responsiveness than knee JSW. For MRI cartilage morphometry in knee OA, there is some evidence for construct and predictive validity, with good evidence for reliability and responsiveness. The responsiveness of semi-quantitative MRI assessment of cartilage morphology, bone marrow lesions and synovitis was also good in knee OA. CONCLUSIONS: Radiographic JSW is still a recommended option for trials of structure modification, with the understanding that the construct represents a number of pathologies and trial duration may be long. MRI is now recommended for clinical trials in terms of cartilage morphology assessment. It is important to study all the joint tissues of the OA joint and the literature is growing on MRI quantification (and its responsiveness) of non-cartilage features. The research recommendations provided will focus researchers on important issues such as determining how structural change within the relatively short duration of a trial reflects long-term change in patient-centred outcomes.

Validity and responsiveness of radiographic joint space width metric measurement in hip osteoarthritis: a systematic review.

AIM: To perform a systematic review of the literature on the concurrent validity, predictive validity and responsiveness of radiographic metric measurement of femoro-acetabular joint space width (JSW) in hip osteoarthritis (OA). ELIGIBILITY CRITERIA: studies reporting any data on (1) JSW on X-rays in hip OA patients and (2) concurrent validity (correlations with clinical symptoms), predictive validity (correlations with future symptomatic state, joint space loss or joint replacement), and/or responsiveness (JSW change over time evaluated using the standardized response mean (SRM)). SEARCH STRATEGY: Medline PUBMED and Embase databases. STATISTICAL ANALYSIS: Random-effects models were constructed to obtain pooled SRMs. RESULTS: Of 448 articles, 79 met the abstract inclusion criteria and were read for further screening. Of these, 15 reported measures of validity and 11 reported measures of responsiveness. Concurrent validity: Five studies suggested an association between JSW and symptoms in the general population. Two evaluated the correlations between JSW and symptoms in hip OA patients, with conflicting results. Five demonstrated that JSW is predictive of future hip joint replacement. Responsiveness was moderate (SRM=0.66; 95% confidential interval (95%CI): 0.41, 0.91), but tended to be lower in randomized clinical trials than in cohort studies (0.35 vs 0.83), using an intention to treat rather than a completer analysis (0.30 vs 0.80), and using manual rather than computer-based measurement (0.47 vs 1.12). CONCLUSION: There is evidence of a weak association between JSW and symptoms, of predictive validity for subsequent joint replacement, and of moderate responsiveness of metric measurement of JSW.

Responsiveness to change and reliability of measurement of radiographic joint space width in osteoarthritis of the knee: a systematic review.

OBJECTIVE: The goal of this systematic review was to report the responsiveness to change and reliability of conventional radiographic joint space width (JSW) measurement. METHOD: We searched the PubMed and Embase databases using the following search criteria: [osteoarthritis (OA) (MeSH)] AND (knee) AND (X-ray OR radiography OR diagnostic imaging OR radiology OR disease progression) AND (joint space OR JSW or disease progression). We assessed responsiveness by calculating the standardized response mean (SRM). We assessed reliability using intra- and inter-reader intra-class correlation (ICC) and coefficient of variation (CV). Random-effects models were used to pool results from multiple studies. Results were stratified by study duration, design, techniques of obtaining radiographs, and measurement method. RESULTS: We identified 998 articles using the search terms. Of these, 32 articles (43 estimates) reported data on responsiveness of JSW measurement and 24 (50 estimates) articles reported data on measures of reliability. The overall pooled SRM was 0.33 [95% confidence interval (CI): 0.26, 0.41]. Responsiveness of change in JSW measurement was improved substantially in studies of greater than 2 years duration (0.57). Further stratifying this result in studies of greater than 2 years duration, radiographs obtained with the knee in a flexed position yielded an SRM of 0.71. Pooled intra-reader ICC was estimated at 0.97 (95% CI: 0.92, 1.00) and the intra-reader CV estimated at 3.0 (95% CI: 2.0, 4.0). Pooled inter-reader ICC was estimated at 0.93 (95% CI: 0.86, 0.99) and the inter-reader CV estimated at 3.4% (95% CI: 1.3%, 5.5%). CONCLUSIONS: Measurement of JSW obtained from radiographs in persons with knee is reliable. These data will be useful to clinicians who are planning RCTs where the change in minimum JSW is the outcome of interest.

Forecasting the burden of advanced knee osteoarthritis over a 10-year period in a cohort of 60-64 year-old US adults.

OBJECTIVE: To forecast the burden of symptomatic knee osteoarthritis (OA) in the elderly US population over a 10-year horizon. DESIGN: Using a computer simulation model of the natural history and management of knee OA combined with population-based data from the 2008 US Census we projected the 10-year burden of knee OA among persons 60-64 years of age. Knee OA incidence and progression rates were derived from national cohorts and calibrated to published literature. RESULTS: Using national data we estimated that 13% of 14,338,292 adults 60-64 years old have prevalent symptomatic, radiographic knee OA. Among persons surviving the next decade, 20% will have symptomatic advanced (Kellgren-Lawrence [K-L] grade 3) or end-stage (K-L 4) knee OA. Prevalence of advanced knee OA will range from 10% among non-obese to 35% among obese persons. Our estimates show that a more sensitive imaging tool, such as magnetic resonance imaging (MRI), may increase the number of OA cases diagnosed by up to 94% assuming that 50% of all 'pre-radiographic knee OA' (K-L 1) has some evidence of cartilage degeneration seen on MRI. CONCLUSIONS: Projecting new and advanced cases of knee OA among persons aged 60-64 years over the next decade creates a benchmark that can be used to evaluate population-based benefits of future disease-modifying OA drugs that are currently undergoing testing at various stages.

Joint space narrowing and Kellgren-Lawrence progression in knee osteoarthritis: an analytic literature synthesis.

OBJECTIVE: While the interpretation of cartilage findings on magnetic resonance imaging (MRI) evolves, plain radiography remains the standard method for assessing progression of knee osteoarthritis (OA). We sought to describe factors that explain variability in published estimates of radiographic progression in knee OA. DESIGN: We searched PubMed between January 1985 and October 2006 to identify studies that assessed radiographic progression using either joint space narrowing (JSN) or the Kellgren-Lawrence (K-L) scale. We extracted cohort characteristics [age, gender, and body mass index (BMI)] and technical and other study factors (radiographic approach, study design, OA-related cohort composition). We performed meta-regression analyses of the effects of these variables on both JSN and K-L progression. RESULTS: Of 239 manuscripts identified, 34 met inclusion criteria. The mean estimated annual JSN rate was 0.13 +/- 0.15 mm/year. While we found no significant association between JSN and radiographic approach among observational studies, full extension was associated with greater estimated JSN among randomized control trials (RCTs). Overall, observational studies that used the semi-flexed approach reported greater JSN than RCTs that used the same approach. The overall mean risk of K-L progression by at least one grade was 5.6 +/- 4.9%, with higher risk associated with shorter study duration, OA definition (K-L > or = 2 vs K-L > or = 1) and cohorts composed of subjects with both incident and prevalent OA. CONCLUSION: While radiographic approach and study design were associated with JSN, OA definition, cohort composition and study duration were associated with risk of K-L progression. These findings may inform the design of disease modifying osteoarthritis drug (DMOAD) trials and assist clinicians in optimal timing of OA treatments.