Search

Objective: To evaluate the efficacy and safety of the anti-catabolic ADAMTS-5 inhibitor S201086/GLPG1972 for the treatment of symptomatic knee osteoarthritis., Design: ROCCELLA (NCT03595618) was a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 trial in adults (aged 40-75 years) with knee osteoarthritis. Participants had moderate-to-severe pain in the target knee, Kellgren-Lawrence grade 2 or 3 and Osteoarthritis Research Society International joint space narrowing (grade 1 or 2). Participants were randomized 1:1:1:1 to once-daily oral S201086/GLPG1972 75, 150 or 300 mg, or placebo for 52 weeks. The primary endpoint was change from baseline to week 52 in central medial femorotibial compartment (cMFTC) cartilage thickness assessed quantitatively by magnetic resonance imaging. Secondary endpoints included change from baseline to week 52 in radiographic joint space width, Western Ontario and McMaster Universities Osteoarthritis Index total and subscores, and pain (visual analogue scale). Treatment-emergent adverse events (TEAEs) were also recorded., Results: Overall, 932 participants were enrolled. No significant differences in cMFTC cartilage loss were observed between placebo and S201086/GLPG1972 therapeutic groups: placebo vs 75 mg, P = 0.165; vs 150 mg, P = 0.939; vs 300 mg, P = 0.682. No significant differences in any of the secondary endpoints were observed between placebo and treatment groups. Similar proportions of participants across treatment groups experienced TEAEs., Conclusions: Despite enrolment of participants who experienced substantial cartilage loss over 52 weeks, during the same time period, S201086/GLPG1972 did not significantly reduce rates of cartilage loss or modify symptoms in adults with symptomatic knee osteoarthritis., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Osteoarthritis (OA) is the most common form of arthritis, with the knee being the joint most frequently affected, and symptomatic knee OA affecting around one quarter of the general population. For patients who do not respond to non-pharmacologic or pharmacologic treatment, surgery is a recommended option. The objectives of this study were to compare the willingness of patients with knee OA to undergo surgery, together with reasons for delaying surgery, and factors affecting successful outcomes., Methods: A point-in-time survey was conducted in 729 primary care physicians, rheumatologists, orthopedic surgeons, and 2,316 patients with knee OA across three geographical regions: Japan, the United States (US), and Europe (EUR: France, Spain, Italy, Germany, and the United Kingdom), in order to garner their perceptions of knee surgery. Regression models were used to identify factors that might affect patients' and physicians' perceptions of surgery, including severity of OA (mild/moderate/severe), number of affected joints, surgery status, and willingness to undergo or delay surgery., Results: Baseline demographics were similar between US and EUR, although patients in Japan were more likely to be female, older, and only 7% in fulltime employment. We found that few patients with end-stage knee OA, across all regions, but particularly Japan, were willing to undergo surgery (Japan 17%, US 32%, EUR 38%), either through fear, or the lack of awareness of the risk/benefits. Moreover, surgeons are prepared to delay surgery in elderly or unwilling patients, due to their dissatisfaction with the outcome, and may defer surgery in younger patients due to the need for future revision. We also identified a disconnect between physicians, of whom over 80% consider improved functioning to be the most important outcome of surgery, and patients, who seek pain relief (Japan 60%, US 35%, EUR 14%). Since physicians across all regions considered pain reduction to be an indication of surgery success (Japan 27%, US 47%, EUR 43%), this may indicate a need for improved communication to patients on the potential benefits of surgery., Conclusion: Managing the expectations of patients undergoing surgery remains an important goal in the treatment of knee OA and may help guide physician choice., (© 2022. The Author(s).)

Objective: We conducted a systematic review in order to understand the relationship between imaging-visualised meniscus pathologies, hyaline cartilage, joint replacement and pain in knee osteoarthritis (OA)., Design: A search of the Medline, Excerpta Medica database (EMBASE) and Cochrane library databases was performed for original publications reporting association between imaging-detected meniscal pathology (extrusion or tear/damage) and longitudinal and cross-sectional assessments of hyaline articular cartilage loss [assessed on magnetic resonance imaging (MRI)], incident joint replacement and pain (longitudinal and cross-sectional) in knee OA. Each association was qualitatively characterised by a synthesis of data from each analysis, based upon study design and quality scoring (including risk of bias assessment and adequacy of covariate adjustment using Cochrane recommended methodology)., Results: In total 4,878 abstracts were screened and 82 publications were included (comprising 72 longitudinal analyses and 49 cross-sectional). Using high quality, well-adjusted data, meniscal extrusion and meniscal tear/damage were associated with longitudinal progression of cartilage loss, cross-sectional cartilage loss severity and joint replacement, independently of age, sex and body mass index (BMI). Medial and lateral meniscal tears were associated with cartilage loss when they occurred in the body and posterior horns, but not the anterior horns. There was a lack of high quality, well-adjusted meniscal pathology and pain publications and no clear independent association between meniscal extrusion or tear/damage with pain severity, progression in pain or incident frequent knee symptoms., Conclusion: Meniscal features have strong associations with cartilage loss and joint replacement in knee OA, but weak associations with knee pain. Systematic review PROSPERO registration number: CRD 42020210910., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Sprifermin is under investigation as a potential disease-modifying osteoarthritis drug. Previously, 2-year results from the FORWARD study showed significant dose-dependent modification of cartilage thickness in the total femorotibial joint (TFTJ), medial and lateral femorotibial compartments (MFTC, LFTC), and central medial and lateral TFTJ subregions, by quantitative magnetic resonance imaging (qMRI) using manual segmentation., Objective: To determine whether qMRI findings from FORWARD could be reproduced by an independent method of automated segmentation using an identical dataset and similar anatomical regions in a post-hoc analysis., Method: Cartilage thickness was assessed at baseline and 6, 12, 18 and 24 months, using automated cartilage segmentation with active appearance models, a supervised machine learning method. Images were blinded for treatment and timepoint. Treatment effect was assessed by observed and adjusted changes using a linear mixed model for repeated measures., Results: Based on automated segmentation, statistically significant, dose-dependent structural modification of cartilage thickness was observed over 2 years with sprifermin vs placebo for TFTJ (overall treatment effect and dose response, both P < 0.001), MFTC (P = 0.004 and P = 0.044), and LFTC (both P < 0.001) regions. For highest dose, in the central medial tibial (P = 0.008), central lateral tibial (P < 0.001) and central lateral femoral (P < 0.001) regions., Conclusions: Cartilage thickness assessed by automated segmentation provided a consistent dose response in structural modification compared with manual segmentation. This is the first time that two independent quantification methods of image analysis have reached the same conclusions in an interventional trial, strengthening the conclusions that sprifermin modifies structural progression in knee osteoarthritis., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Osteoarthritis (OA) is the most common joint condition and, with a burgeoning ageing population, is due to increase in prevalence. Beyond conventional medical and surgical interventions, there are an increasing number of 'alternative' therapies. These alternative therapies may have a limited evidence base and, for this reason, are often only afforded brief reference (or completely excluded) from current OA guidelines. Thus, the aim of this review was to synthesize the current evidence regarding autologous chondrocyte implantation (ACI), mesenchymal stem cell (MSC) therapy, platelet-rich plasma (PRP), vitamin D and other alternative therapies. The majority of studies were in knee OA or chondral defects. Matrix-assisted ACI has demonstrated exceedingly limited, symptomatic improvements in the treatment of cartilage defects of the knee and is not supported for the treatment of knee OA. There is some evidence to suggest symptomatic improvement with MSC injection in knee OA, with the suggestion of minimal structural improvement demonstrated on MRI and there are positive signals that PRP may also lead to symptomatic improvement, though variation in preparation makes inter-study comparison difficult. There is variability in findings with vitamin D supplementation in OA, and the only recommendation which can be made, at this time, is for replacement when vitamin D is deplete. Other alternative therapies reviewed have some evidence (though from small, poor-quality studies) to support improvement in symptoms and again there is often a wide variation in dosage and regimens. For all these therapeutic modalities, although controlled studies have been undertaken to evaluate effectiveness in OA, these have often been of small size, limited statistical power, uncertain blindness and using various methodologies. These deficiencies must leave the question as to whether they have been validated as effective therapies in OA (or chondral defects). The conclusions of this review are that all alternative interventions definitely require clinical trials with robust methodology, to assess their efficacy and safety in the treatment of OA beyond contextual and placebo effects.

Objective: To evaluate the structural effects of weight loss on hip or knee osteoarthritis (OA) and to summarize which structural joint pathologies have been examined and the evidence for the outcome measurement instruments applied., Design: Based on a pre-specified protocol (available: PROSPERO CRD42017065263), we conducted a systematic search of the bibliographic databases, Medline, Embase and Web of Science identifying longitudinal articles reporting the effects of weight loss on structural imaging outcomes in OA of the hip or knee in people who are overweight or obese., Results: From 1625 potentially eligible records, 14 articles (from 6 cohorts) were included. 2 cohorts were derived from RCTs. Evaluated pathologies were: articular cartilage (n = 7), joint space width (n = 3), bone marrow lesions (n = 5), synovitis (n = 2), effusion (n = 1), meniscus (n = 3), bone marrow density (n = 1) and infrapatellar fat pad (IPFP; n = 2). Cartilage showed conflicting results when evaluating cartilage thickness by direct thickness measurements. Compositional dGEMRIC and T2 mapping measures in early knee OA showed trends towards reduced cartilage degeneration. Joint space width on conventional radiographs showed no change. Weight loss reduced the size of the IPFP. Synovitis and effusion were not affected. Following weight loss DXA showed bone loss at the hip., Conclusion: We did not find consistent evidence of the effects of weight loss on OA structural pathology in people who are overweight or obese. There is a need to achieve consensus on which structural pathologies and measurements to apply in weight loss and OA research., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: To investigate changes in knee 3D bone shape over the first 5 years after acute anterior cruciate ligament (ACL) injury in participants of the randomized controlled KANON-trial., Methods: Serial MR images over 5 years from 121 young (32 women, mean age 26.1 years) adults with an acute ACL tear in a previously un-injured knee were analyzed using statistical shape models for bone. A matched reference cohort of 176 individuals was selected from the Osteoarthritis Initiative (OAI). Primary endpoint was change in bone area of the medial femoral condyle; exploratory analyses compared results by treatment and examined other knee regions. Comparisons were made using repeated measures mixed model ANOVA with adjustment for age, sex and body mass index (BMI)., Results: Mean medial femur bone area increased 3.2% (78.0 [95% CI 70.2 to 86.4] mm 2 ) over 5 years after ACL injury and most prominently in knees treated with ACL reconstruction (ACLR). A higher rate of increase occurred over the first 2 years compared to the latter 3-years (66.2 [59.3 to 73.2] vs 17.6 [12.2 to 23.0] mm 2 ) and was 6.7 times faster than in the reference cohort. The pattern and location of shape change in the extrapolated KANON data was very similar to that observed in another knee-osteoarthritis cohort., Conclusion: 3D shape modelling after acute ACL injury revealed rapid bone shape changes, already evident at 3 months. The bone-change pattern after ACL injury demonstrated flattening and bone growth on the outer margins of the condyles similar to that reported in established knee osteoarthritis., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: There are few guidelines for clinical trials of interventions for prevention of post-traumatic osteoarthritis (PTOA), reflecting challenges in this area. An international multi-disciplinary expert group including patients was convened to generate points to consider for the design and conduct of interventional studies following acute knee injury., Design: An evidence review on acute knee injury interventional studies to prevent PTOA was presented to the group, alongside overviews of challenges in this area, including potential targets, biomarkers and imaging. Working groups considered pre-identified key areas: eligibility criteria and outcomes, biomarkers, injury definition and intervention timing including multi-modality interventions. Consensus agreement within the group on points to consider was generated and is reported here after iterative review by all contributors., Results: The evidence review identified 37 studies. Study duration and outcomes varied widely and 70% examined surgical interventions. Considerations were grouped into three areas: justification of inclusion criteria including the classification of injury and participant age (as people over 35 may have pre-existing OA); careful consideration in the selection and timing of outcomes or biomarkers; definition of the intervention(s)/comparator(s) and the appropriate time-window for intervention (considerations may be particular to intervention type). Areas for further research included demonstrating the utility of patient-reported outcomes, biomarkers and imaging outcomes from ancillary/cohort studies in this area, and development of surrogate clinical trial endpoints that shorten the duration of clinical trials and are acceptable to regulatory agencies., Conclusions: These considerations represent the first international consensus on the conduct of interventional studies following acute knee joint trauma., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Bone shape and bone marrow lesions (BMLs) represent different features of Magnetic resonance imaging (MRI)-detected subchondral pathology in osteoarthritis (OA). The aim of this study was to determine how these features are related and how they change in OA progression., Methods: 600 participants from the Osteoarthritis Initiative (OAI) FNIH Biomarkers Initiative were included, having Kellgren-Lawrence grade 1-3, at baseline and MRI data at baseline and 24 months. The associations between 3D quantitative bone shape vectors and presence of (MRI Osteoarthritis Knee Score) MOAKS semi-quantitative BMLs (total BML size ≥1) were analysed for femurs and tibias using linear regression. Responsiveness over 24 months was calculated for both features in four pre-defined progression groups and reported as standardised response means (SRMs). Multilevel models investigated the longitudinal relationship between change in BML size and change in bone shape., Results: Mean age was 61.5, 59% female and mean body mass index (BMI) 30.7. Correlation between baseline femur vector and BML was r = 0.28, P < 0.001. The presence of BMLs was associated with higher bone shape vector; coefficient (95% CI) 0.75 (0.54, 0.96) and 0.57 (0.38, 0.77) for femur and tibia respectively, both P < 0.001. After covariate adjustment, only the femur remained significant [coefficient 0.49, (95% CI 0.30, 0.68)]. Longitudinally bone vector demonstrated more responsiveness to change than BMLs (SRM 0.89 vs 0.13) while multilevel models revealed that increase in BML size was related to a more positive bone shape vector (representing worsening OA)., Conclusion: There is a relationship between bone shape and BMLs, with prevalence of BMLs associated with increasing OA bone shape. Bone shape demonstrated greater responsiveness than semi-quantitative BMLs., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine factors associated with orthopaedic surgeons' decision to recommend total joint replacement (TJR) in people with knee and hip osteoarthritis (OA)., Design: Cross-sectional study in eleven countries. For consecutive outpatients with definite hip or knee OA consulting an orthopaedic surgeon, the surgeon's indication of TJR was collected, as well as patients' characteristics including comorbidities and social situation, OA symptom duration, pain, stiffness and function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), joint-specific quality of life, Osteoarthritis Research Society International (OARSI) joint space narrowing (JSN) radiographic grade (0-4), and surgeons' characteristics. Univariable and multivariable logistic regressions were performed to identify factors associated with the indication of TJR, adjusted by country., Results: In total, 1905 patients were included: mean age was 66.5 (standard deviation [SD], 10.8) years, 1082 (58.0%) were women, mean OA symptom duration was 5.0 (SD 7.0) years. TJR was recommended in 561/1127 (49.8%) knee OA and 542/778 (69.7%) hip OA patients. In multivariable analysis on 516 patients with complete data, the variables associated with TJR indication were radiographic grade (Odds Ratio, OR for one grade increase, for knee and hip OA, respectively: 2.90, 95% confidence interval [1.69-4.97] and 3.30 [2.17-5.03]) and WOMAC total score (OR for 10 points increase: 1.65 [1.32-2.06] and 1.38 [1.15-1.66], respectively). After excluding radiographic grade from the analyses, on 1265 patients, greater WOMAC total score was the main predictor for knee and hip OA; older age was also significant for knee OA., Conclusion: Radiographic severity and patient-reported pain and function play a major role in surgeons' recommendation for TJR., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Population-based osteoarthritis (OA) cohorts provide vital data on risk factors and outcomes of OA, however the methods to define OA vary between cohorts. We aimed to provide recommendations for combining knee and hip OA data in extant and future population cohort studies, in order to facilitate informative individual participant level analyses., Method: International OA experts met to make recommendations on: 1) defining OA by X-ray and/or pain; 2) compare The National Health and Nutrition Examination Survey (NHANES)-type OA pain questions; 3) the comparability of the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) scale to NHANES-type OA pain questions; 4) the best radiographic scoring method; 5) the usefulness of other OA outcome measures. Key issues were explored using new analyses in two population-based OA cohorts (Multicenter Osteoarthritis Study; MOST and Osteoarthritis Initiative OAI)., Results: OA should be defined by both symptoms and radiographs, with symptoms alone as a secondary definition. Kellgren and Lawrence (K/L) grade ≥2 should be used to define radiographic OA (ROA). The variable wording of pain questions can result in varying prevalence between 41.0% and 75.4%, however questions where the time anchor is similar have high sensitivity and specificity (91.2% and 89.9% respectively). A threshold of 3 on a 0-20 scale (95% CI 2.1, 3.9) in the WOMAC pain subscale demonstrated equivalence with the preferred NHANES-type question., Conclusion: This research provides recommendations, based on expert agreement, for harmonising and combining OA data in existing and future population-based cohorts., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: To determine the association between bisphosphonate treatment with the change of periarticular bone area and three-dimensional (3D) shape in participants of the Osteoarthritis Initiative (OAI) study., Design: Using propensity score (PS) matching method in females, 48 bisphosphonate users and 105 non-users, who were matched for osteoarthritis (OA) and osteoporosis (OP) related factors were included. Baseline and 24-month magnetic resonance imaging (MRI)-based periarticular bone area and 3D shape measurements were used. The association between bisphosphonate intake and 24-month interval changes of the periarticular bone area and 3D shape were evaluated using paired Wilcoxon signed rank test. We used conditional logistic regression models for determining the association between bisphosphonate intake and periarticular bone change, defined using the standard deviation of difference (SDD) and reliable change index (RCI) methods. P-values have been adjusted for multiple comparisons using Benjamini & Hochberg procedure and false discovery rate (FDR)-adjusted P-values were reported., Results: The 24-month interval increases in the periarticular bone area in medial side of tibia were significantly greater in non-users than users (FDR-adjusted P-value: 0.002). There was an approaching significance trend for lower medial tibial periarticular bone area expansion in bisphosphonate users in comparison with non-users (For 1SDD change, odds ratio 95% confidence interval (OR (95% CI)): 0.514 (0.271-0.975), FDR-adjusted P-value: 0.085) (For 1.96RCI change, OR (95% CI): 0.552 (0.309-0.986), FDR-adjusted P-value: 0.085)., Conclusions: Bisphosphonate intake was associated with a reduction in the odds (approaching but not achieving significance) of expansion periarticular bone area, specifically in the medial tibial sub-region., (Published by Elsevier Ltd.)

Objective: Intra-articular (IA) corticosteroids relieve osteoarthritis (OA) pain, but rapid absorption into systemic circulation may limit efficacy and produce untoward effects. We compared the pharmacokinetics (PK) of IA triamcinolone acetonide (TA) delivered as an extended-release, microsphere-based formulation (FX006) vs a crystalline suspension (TAcs) in knee OA patients., Method: This Phase 2 open-label study sequentially enrolled 81 patients who received a single IA injection of FX006 (5 mL, 32 mg delivered dose, N = 63) or TAcs (1 mL, 40 mg, N = 18). Synovial fluid (SF) aspiration was attempted in each patient at baseline and one post-IA-injection visit (FX006: Week 1, Week 6, Week 12, Week 16 or Week 20; TAcs: Week 6). Blood was collected at baseline and multiple post-injection times. TA concentrations (validated LC-MS/MS, geometric means (GMs)), PK (non-compartmental analysis models), and adverse events (AEs) were assessed., Results: SF TA concentrations following FX006 were quantifiable through Week 12 (pg/mL: 231,328.9 at Week 1; 3590.0 at Week 6; 290.6 at Week 12); post-TAcs, only two of eight patients had quantifiable SF TA at Week 6 (7.7 pg/mL). Following FX006, plasma TA gradually increased to peak (836.4 pg/mL) over 24 h and slowly declined to <110 pg/mL over Weeks 12-20; following TAcs, plasma TA peaked at 4 h (9628.8 pg/mL), decreased to 4991.1 pg/mL at 24 h, and was 149.4 pg/mL at Week 6, the last post-treatment time point assessed. AEs were similar between groups., Conclusion: In knee OA patients, microsphere-based TA delivery via a single IA injection prolonged SF joint residency, diminished peak plasma levels, and thus reduced systemic TA exposure relative to TAcs., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Meniscal pathology is integral to knee osteoarthritis (OA) and its progression; it provides a progression biomarker and a potential treatment target. Magnetic resonance imaging (MRI) demonstrates large heterogeneity in meniscal damage; this structural complexity means measurement is difficult. The aim of this study was to apply novel 3D image analysis to determine which meniscal pathologies demonstrated most change during OA progression., Methods: Knee images were selected from the progression cohort of the Osteoarthritis Initiative choosing participants with risk factors for medial OA progression. Medial and lateral menisci were manually segmented then analysed using a statistical shape model of the tibia as a reference surface. Responsiveness was assessed at 1 year using standardised response means (SRMs) for four constructs: meniscal volume, extrusion volume, thickness and tibial coverage; anatomical sub-regions of these constructs were also explored., Results: Paired images from 86 participants (median age 61.5, 49% female, 56% obese) were included. Reliability of the novel meniscal measurements was very good intraclass correlation coefficients (ICCs all > 0.98). Meniscal volume and extrusion demonstrated no significant change. Moderate responsiveness was observed for medial meniscus thickness (SRM -0.35) and medial tibial coverage (SRM -0.36). No substantial change was seen for the lateral meniscus measures. Sub-region analysis did not improve responsiveness; while greater change was seen in the posterior medial compartment, it was associated with increased variance of the change., Conclusions: The location of meniscal damage was consistently in the posterior medial region, and two measurements (thickness and tibial coverage) were most responsive. Meniscal measures should add to discriminatory power in OA progression assessment., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Radiographic measures of osteoarthritis (OA) are based upon two dimensional projection images. Active appearance modelling (AAM) of knee magnetic resonance imaging (MRI) enables accurate, 3D quantification of joint structures in large cohorts. This cross-sectional study explored the relationship between clinical characteristics, radiographic measures of OA and 3D bone area (tAB)., Methods: Clinical data and baseline paired radiographic and MRI data, from the medial compartment of one knee of 2588 participants were obtained from the NIH Osteoarthritis Initiative (OAI). The medial femur (MF) and tibia (MT) tAB were calculated using AAM. 'OA-attributable' tAB (OA-tAB) was calculated using data from regression models of tAB of knees without OA. Associations between OA-tAB and radiographic measures of OA were investigated using linear regression., Results: In univariable analyses, height, weight, and age in female knees without OA explained 43.1%, 32.1% and 0.1% of the MF tAB variance individually and 54.4% when included simultaneously in a multivariable model. Joint space width (JSW), osteophytes and sclerosis explained just 5.3%, 14.9% and 10.1% of the variance of MF OA-tAB individually and 17.4% when combined. Kellgren Lawrence (KL) grade explained approximately 20% of MF OA-tAB individually. Similar results were seen for MT OA-tAB., Conclusion: Height explained the majority of variance in tAB, confirming an allometric relationship between body and joint size. Radiographic measures of OA, derived from a single radiographic projection, accounted for only a small amount of variation in 3D knee OA-tAB. The additional structural information provided by 3D bone area may explain the lack of a substantive relationship with these radiographic OA measures., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Sensitive biomarkers are needed to understand synovial response to therapy in osteoarthritis (OA). Dynamic, contrast-enhanced magnetic resonance imaging (DCE MRI) provides quantitative, novel measures of synovial inflammation. This exploratory study examined DCE-assessed synovial response to intra-articular corticosteroid (IACS)., Methods: People with ACR clinical criteria OA knee underwent 3 T MRI pre- and 2 weeks post-IACS. Five MRI variables were assessed blindly: total synovial volume (semi-automated computer program), early enhancement rate (EER) and late enhancement ratio of the entire knee, synovial volume × late enhancement and a semi-quantitative (SQ) score (six sites scored 0-3). Clinical symptoms were assessed using pain visual analogue score (VAS) and WOMAC., Results: 13 participants (5 male, mean age 63, mean pain VAS 66 mm mean body mass index (BMI) 31.3 kg/m(2)) were included. The majority of MRIs demonstrated no change in SQ score although the DCE variables changed to some extent in all. There was generally a reduction in synovial volume ((Wilcoxon test) median (interquartile range (IQR)) reduction 14 cm(3) (-1, 29)), EER (0.2% (-0.3, 0.6)) and late enhancement ratio (8% (-0.5, 41)). Synovial volume × late enhancement ratio demonstrated a substantive reduction (2250 (-930, 5630)) as well as the largest effect size, r = 0.45. There was a median 26% reduction in EER in participants with good symptomatic response to IACS, contrasting with a 23% increase in those who responded poorly., Conclusions: DCE MRI may be more sensitive than a SQ score at detecting post-therapy synovial changes. The association between EER and symptomatic response to IACS may reflect a closer relation of this biomarker to synovial inflammation than with volumetric assessment., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objectives: To review and synthesize the existing literature on the experience of living with a diagnosis of hip and/or knee osteoarthritis (OA)., Method: A systematic review was undertaken using meta-ethnography. A search of both published (AMED, CINAHL, EMBASE, PsychINFO, SportsDisc, MEDLINE, Cochrane Clinical Trials Registry, PubMed) and unpublished/trial registry databases [World Health Organization (WHO) International Clinical Trials Registry Platform, Current Controlled Trials, the United States National Institute of Health Trials Registry, National Institute for Health Research (NIHR) Clinical Research Portfolio Database] was undertaken from their inception to 5 June 2013., Results: Thirty-two studies formed the meta-ethnography of the lived experiences of people with OA. In total, 1643 people with OA were sampled, the majority diagnosed with knee OA. The evidence base was weak to moderate in quality. The majority of studies indicated that people viewed living with OA negatively. Four key factors influenced their attitudes to the condition: the severity of their symptoms; the impact of these symptoms on their functional capability; their attitude towards understanding their disease; and their perceptions of other people's beliefs towards their disease., Conclusions: The current literature suggests that greater knowledge of the pathology of OA, management of symptoms, promotion of functional activity for patients and their family/friends networks, and understanding to better inform OA patient's role in society are all important elements that affect a person's attitude to OA. By better understanding these factors during future consultations, clinicians may forge stronger relationships with their patients to more effectively manage this long-term disabling condition.

Knee osteoarthritis is associated with structural changes in the joint. Despite its many drawbacks, radiography is the current standard for evaluating joint structure in trials of potential disease-modifying osteoarthritis drugs. MRI is a non-invasive alternative that provides comprehensive imaging of the whole joint. Frequently used MRI measurements in knee osteoarthritis are cartilage volume and thickness; others include synovitis, synovial fluid effusions, bone marrow lesions (BML) and meniscal damage. Joint replacement is considered a clinically relevant outcome in knee osteoarthritis; however, its utility in clinical trials is limited. An alternative is virtual knee replacement on the basis of symptoms and structural damage. MRI may prove to be a good alternative to radiography in definitions of knee replacement. One of the MRI parameters that predicts knee replacement is medial compartment cartilage volume/thickness, which correlates with radiographic joint space width, is sensitive to change, and predicts outcomes in a continuous manner. Other MRI parameters include BML and meniscal lesions. MRI appears to be a viable alternative to radiography for the evaluation of structural changes in knee osteoarthritis and prediction of joint replacement.

Objective: Low-dose transdermal opioids offer a new therapeutic option for osteoarthritis (OA). This study compared symptom relief obtained with buprenorphine patches plus oral paracetamol with that obtained with an oral codeine-paracetamol combination tablet (co-codamol) in older adults with OA., Method: Two hundred and twenty people (aged ≥60 years) with OA hip and/or knee pain were randomised to treatment with 7-day buprenorphine patches plus oral paracetamol (5-25 μg/h buprenorphine patches plus 1000 mg oral paracetamol q.i.d. (4 times daily); n=110) or co-codamol tablets (two 8/500-two 30/500 mg tablets q.i.d.; n=110). They entered a titration period of up to 10 weeks, during which their dose of study medication was adjusted until they reached optimum pain control. Patients who achieved optimum pain control entered a 12-week assessment period. The primary outcome was average daily pain scores recorded using the box scale-11 (BS-11) pain scale., Results: Both treatments significantly reduced patient pain scores. The estimated treatment difference [95% confidence interval (CI)] was -0.02 (-0.64, 0.60) for the per protocol (PP) population. The results were similar for the full analysis population. Patients receiving 7-day buprenorphine patches plus oral paracetamol needed significantly less escape medication (ibuprofen) than those receiving co-codamol tablets (P=0.002; PP population). Less than 10% of patients in the 7-day buprenorphine patches plus oral paracetamol group were receiving the highest dose level at the end of the study, compared with 34% in the co-codamol group. Withdrawal rates were high in both groups. The incidence of adverse events (AEs) was comparable between the groups (86.4% of patients in the 7-day buprenorphine patches plus oral paracetamol group; 81.7% in the co-codamol group). Six serious AEs were reported in three patients (2.7%) in the 7-day buprenorphine patches plus oral paracetamol group and one (0.9%) in the co-codamol group., Conclusions: 7-day buprenorphine patches plus oral paracetamol were non-inferior to co-codamol tablets with respect to analgesic efficacy in older adults with OA pain in the hip/knee., (Copyright © 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: In an effort to evolve semi-quantitative scoring methods based upon limitations identified in existing tools, integrating expert readers' experience with all available scoring tools and the published data comparing the different scoring systems, we iteratively developed the magnetic resonance imaging (MRI) Osteoarthritis Knee Score (MOAKS). The purpose of this report is to describe the instrument and its reliability., Methods: The MOAKS instrument refines the scoring of bone marrow lesions (BMLs) (providing regional delineation and scoring across regions), cartilage (sub-regional assessment), and refines the elements of meniscal morphology (adding meniscal hypertrophy, partial maceration and progressive partial maceration) scoring. After a training and calibration session two expert readers read MRIs of 20 knees separately. In addition, one reader re-read the same 20 MRIs 4 weeks later presented in random order to assess intra-rater reliability. The analyses presented here are for both intra- and inter-rater reliability (calculated using the linear weighted kappa and overall percent agreement)., Results: With the exception of inter-rater reliability for tibial cartilage area (kappa=0.36) and tibial osteophytes (kappa=0.49); and intra-rater reliability for tibial BML number of lesions (kappa=0.54), Hoffa-synovitis (kappa=0.42) all measures of reliability using kappa statistics were very good (0.61-0.8) or reached near-perfect agreement (0.81-1.0). Only intra-rater reliability for Hoffa-synovitis, and inter-rater reliability for tibial and patellar osteophytes showed overall percent agreement <75%., Conclusion: MOAKS scoring shows very good to excellent reliability for the large majority of features assessed. Further iterative development and research will include assessment of its validation and responsiveness., (Copyright © 2011 Osteoarthritis Research Society International. All rights reserved.)

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., (Copyright © 2011 Osteoarthritis Research Society International. All rights reserved.)

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., (Copyright © 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the pain and functional disability levels corresponding to an indication for total joint replacement (TJR) in hip and knee osteoarthritis (OA)., Design: International cross-sectional study in 10 countries., Patients: Consecutive outpatients with definite hip or knee OA attending an orthopaedic outpatient clinic. Gold standard measure for recommendation for TJR: Surgeon's decision that TJR is justified., Outcome Measures: Pain (ICOAP: intermittent and constant osteoarthritis pain, 0-100) and functional impairment (HOOS-PS/KOOS-PS: Hip/Knee injury and Osteoarthritis Outcome Score Physical function Short-form, 0-100)., Analyses: Comparison of patients with vs without surgeons' indication for TJR. Receiver Operating Characteristic (ROC) curve analyses and logistic regression were applied to determine cut points of pain and disability defining recommendation for TJR., Results: In all, 1909 patients were included (1130 knee/779 hip OA). Mean age was 66.4 [standard deviation (SD) 10.9] years, 58.1% were women; 628/1130 (55.6%) knee OA and 574/779 (73.7%) hip OA patients were recommended for TJR. Although patients recommended for TJR (yes vs no) had worse symptom levels [pain, 55.5 (95% confidence interval 54.2, 56.8) vs. 44.9 (43.2, 46.6), and functional impairment, 59.8 (58.7, 60.9) vs. 50.9 (49.3, 52.4), respectively, both P<0.0001], there was substantial overlap in symptom levels between groups, even when adjusting for radiographic joint status. Thus, it was not possible to determine cut points for pain and function defining 'requirement for TJR'., Conclusion: Although symptom levels were higher in patients recommended for TJR, pain and functional disability alone did not discriminate between those who were and were not considered to need TJR by the orthopaedic surgeon., (Copyright © 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objectives: To determine clinical and ultrasonographic predictors of joint replacement surgery across Europe in primary osteoarthritis (OA) of the knee., Methods: This was a 3-year prospective study of a painful OA knee cohort (from a EULAR-sponsored, multicentre study). All subjects had clinical evaluation, radiographs and ultrasonography (US) at study entry. The rate of knee replacement surgery over the 3-year follow-up period was determined using Kaplan-Meier survival data analyses. Predictive factors for joint replacement were identified by univariate log-rank test then multivariate analysis using a Cox proportional-hazards regression model. Potential baseline predictors included demographic, clinical, radiographic and US features., Results: Of the 600 original patients, 531 (88.5%), mean age 67+/-10 years, mean disease duration 6.1+/-6.9 years, had follow-up data and were analysed. During follow-up (median 3 years; range 0-4 years), knee replacement was done or required for 94 patients (estimated event rate of 17.7%). In the multivariate analysis, predictors of joint replacement were as follows: Kellgren and Lawrence radiographic grade (grade > or =III vs or =4 mm vs <4 mm) (HR = 2.63 (95% CI 1.70 to 4.06), p<0.0001); knee pain intensity on a 0-100 mm visual analogue scale (> or =60 vs <60) (HR = 1.81 (95% CI 1.15 to 2.83), p=0.01) and disease duration (> or =5 years vs <5 years) (HR=1.63 (95% CI 1.08 to 2.47), p=0.02). Clinically detected effusion and US synovitis were not associated with joint replacement in the univariate analysis., Conclusion: Longitudinal evaluation of this OA cohort demonstrated significant progression to joint replacement. In addition to severity of radiographic damage and pain, US-detected effusion was a predictor of subsequent joint replacement.

Conventional radiography is still the first and most important imaging examination in a clinical setting when evaluating a patient with a known or suspected diagnosis of osteoarthritis (OA). In research and clinical trials, it still is a valuable tool for stratifying patients who have OA into different categories for inclusion criteria and eligibility. MRI has become crucial in understanding the natural history of the disease and in guiding future therapies because of its ability to image the knee as a whole organ and to assess cartilage morphology and composition directly and in a three-dimensional manner. The other modalities discussed in this article are valuable additional techniques indicated on a case-by-case basis.

Objective: To investigate whether early changes in biochemical markers of bone (NTX-I) and cartilage (CTX-II [C-terminal crosslinking telopeptide of type II collagen]) degradation are associated with radiological progression in patients with knee osteoarthritis (OA) receiving risedronate., Design: Two thousand four hundred and eighty three patients with medial compartment knee OA were randomized in two 24-month studies in North America (NA) and European Union (EU). Studies evaluated risedronate 5 mg/day, 35 mg/week (EU), 50 mg/week (NA), and 15 mg/day (NA and EU), compared to placebo in reducing signs and symptoms and in slowing radiographic progression. One thousand eight hundred and eighty five patients from the pooled EU and NA studies with available NTX-I/CTX-II at both baseline and 6 months and radiographs at baseline and at 24 months were analyzed., Results: Risedronate produced a dose-dependent reduction of NTX-I and CTX-II observed at 6 months which continued up to 24 months. Patients who had CTX-II levels returned to low levels (<150 ng/mmol creatinine) at 6 months had a lower risk of radiographic progression at 24 months than patients whose CTX-II levels were increased both at baseline and 6 months [odds-ratio (95% confidence interval): 0.57 (0.39-0.85) after adjustment for demographics and joint space width]. The lowest risk of progression was observed in patients who had low CTX-II levels both at baseline and at 6 months [odds-ratio 0.36 (0.21-0.63)]. No significant association between NTX-I levels and radiological progression was observed., Conclusion: CTX-II decreased with risedronate in patients with knee OA and levels reached after 6 months were associated with radiological progression at 24 months. Monitoring a marker of cartilage degradation 6 months after initiating treatment may be instructive in identifying patients with low progression.

Objective: To develop a short measure of physical function for knee osteoarthritis (OA) using multi-national data from individuals with varying degrees of severity of knee OA., Methods: Rasch analysis, based on the partial credit model, was conducted on Knee injury and Osteoarthritis Outcome Score and Western Ontario McMaster Universities' Osteoarthritis Index data from individuals with knee OA, ranging from community to pre-total knee replacement samples from five countries. Fit of the data to the Rasch model was evaluated by overall model fit and item-level fit statistics (chi(2), size of residual, F-test). Invariance across age, gender and country was evaluated. Unidimensionality was evaluated by factor analysis of residuals. The derived short measure was further tested for fit through re-analyses in individual sub-samples. A nomogram converting raw summed scores to Rasch-derived interval scores was developed., Results: Thirteen data sets were included (n=2145), with an age range of 26-95 years, and a male/female ratio of 1:1.4. The final model included seven of the original 22 items. From easiest to most difficult, the items (logit) were as follows: rising from bed (1.366), putting on socks/stockings (1.109), rising from sitting (0.537), bending to the floor (0.433), twisting/pivoting on injured knee (-0.861), kneeling (-1.292) and squatting (-1.292). Sub-sample analyses confirmed findings., Conclusion: Based on the use of accepted Rasch-based measurement methods and the compliment of countries, languages and OA severity represented in this study, our seven item short measure of physical function for knee OA is likely generalizable and widely applicable. This measure has potential for use as the function component in an OA severity scoring system.

Aim: MRI provides unparalleled visualisation of all the anatomical structures involved in the osteoarthritis (OA) process. There is a need for reliable methods of quantifying abnormalities of these structures. The aim of this work was to assess the reliability of a novel MRI scoring system for evaluating OA of the knee and explore the validity of the bone marrow lesion (BML) scoring component of this new tool., Methods: After review of the relevant literature, a collaborative group of rheumatologists and radiologists from centres in the UK and USA established preliminary anatomical divisions, items (necessarily broadly inclusive) and scaling for a novel semi-quantitative knee score. A series of iterative reliability exercises were performed to reduce the initial items, and the reliability of the resultant Boston-Leeds Osteoarthritis Knee Score (BLOKS) was examined. A further sample had both the BLOKS and WORMS (Whole Organ MRI Score) bone marrow lesion (BML) score performed to assess the construct validity (relation to knee pain) and longitudinal validity (prediction of cartilage loss) of each scoring method., Results: The BLOKS scoring method assesses nine intra-articular regions and contains eight items, including features of bone marrow lesions, cartilage, osteophytes, synovitis, effusions and ligaments. The scaling for each feature ranges from 0-3. The inter-reader reliability for the final BLOKS items ranged from 0.51 for meniscal extrusion up to 0.79 for meniscal tear. The reliability for other key features was 0.72 for BML grade, 0.72 for cartilage morphology, and 0.62 for synovitis. Maximal BML size on the BLOKS scale had a positive linear relation with visual analogue scale (VAS) pain, however the WORMS scale did not. Baseline BML was associated with cartilage loss on both BLOKS and WORMS scale. This association was stronger for BLOKS than WORMS., Conclusion: We have designed a novel scoring system for MRI OA knee, BLOKS, that demonstrates good reliability. Preliminary inspection of the validity of one of the components of this new tool supports the validity of the BLOKS BML scoring method over an existing instrument. Further iterative development will include validation for use in both clinical trials and epidemiological studies.

Objective: To examine the relationship between longitudinal fluctuations in synovitis with change in pain and cartilage in knee osteoarthritis., Methods: Study subjects were patients 45 years of age and older with symptomatic knee osteoarthritis from the Boston Osteoarthritis of the Knee Study. Baseline and follow-up assessments at 15 and 30 months included knee magnetic resonance imaging (MRI), BMI and pain assessment (VAS) over the last week. Synovitis was scored at 3 locations (infrapatellar fat pad, suprapatellar and intercondylar regions) using a semiquantitative scale (0-3) at all 3 time points on MRI. Scores at each site were added to give a summary synovitis score (0-9)., Results: We assessed 270 subjects whose mean (SD) age was 66.7 (9.2) years, BMI 31.5 (5.7) kg/m(2); 42% were female. There was no correlation of baseline synovitis with baseline pain score (r = 0.09, p = 0.17). The change in summary synovitis score was correlated with the change in pain (r = 0.21, p = 0.0003). An increase of one unit in summary synovitis score resulted in a 3.15-mm increase in VAS pain score (0-100 scale). Effusion change was not associated with pain change. Of the 3 locations for synovitis, changes in the infrapatellar fat pad were most strongly related to pain change. Despite cartilage loss occurring in over 50% of knees, synovitis was not associated with cartilage loss in either tibiofemoral or patellofemoral compartment., Conclusions: Change in synovitis was correlated with change in knee pain, but not loss of cartilage. Treatment of pain in knee osteoarthritis (OA) needs to consider treatment of synovitis.

Objective: Five double-blind, randomized, saline-controlled trials (RCTs) were included in the United States marketing application for an intra-articular hyaluronan (IA-HA) product for the treatment of osteoarthritis (OA) of the knee. We report an integrated analysis of the primary Case Report Form (CRF) data from these trials., Method: Trials were similar in design, patient population and outcome measures - all included the Lequèsne Algofunctional Index (LI), a validated composite index of pain and function, evaluating treatment over 3 months. Individual patient data were pooled; a repeated measures analysis of covariance was performed in the intent-to-treat (ITT) population. Analyses utilized both fixed and random effects models. Safety data from the five RCTs were summarized., Results: A total of 1155 patients with radiologically confirmed knee OA were enrolled: 619 received three or five IA-HA injections; 536 received "placebo" saline injections. In the active and control groups, mean ages were 61.8 and 61.4 years; 62.4% and 58.8% were women; baseline total Lequèsne scores 11.03 and 11.30, respectively. Integrated analysis of the pooled data set found a statistically significant reduction (P < 0.001) in total Lequèsne score with hyaluronan (HA) (-2.68) vs placebo (-2.00); estimated difference -0.68 (95% CI: -0.56 to -0.79), effect size 0.20. Additional modeling approaches confirmed robustness of the analyses., Conclusions: This integrated analysis demonstrates that multiple design factors influence the results of RCTs assessing efficacy of intra-articular (IA) therapies, and that integrated analyses based on primary data differ from meta-analyses using transformed data.

Magnetic resonance imaging (MRI) provides a sensitive tool for examining all the structures involved in the osteoarthritis (OA) process. While much of the MRI literature previously focussed on cartilage, there is increasing research on whole-organ evaluation and including features such as synovitis, bone marrow edema, and meniscal and ligamentous pathology. The aim of this session at the Outcome Measures in Rheumatology Clinical Trials (OMERACT)-Osteoarthritis Research Society International (OARSI) Workshop for Consensus in Osteoarthritis Imaging was to describe the current MRI methods for identifying and quantifying non-cartilaginous structures and review their associations with both OA symptoms and structural progression. Although there is much experience in measuring synovitis (derived from the rheumatoid arthritis literature), only one study has reported an association of MRI-detected synovitis and effusions with OA pain. Bone marrow edema lesions, which may represent areas of trabecular remodelling, have been associated with pain and compartment-specific structural deterioration. MRI studies have confirmed the frequency and importance of meniscal damage in progressive cartilage loss, but not related such damage to symptoms. Osteophytes have been associated with cartilage loss and malalignment to the side of the osteophyte. Ligament damage, including anterior cruciate ligament tears, has been found more commonly than expected in painful OA knees. Improvements in quantitative and semi-quantitative assessments of non-cartilage features will greatly assist understanding of the OA process and its response to therapy.

Objective: The aim of this study was to determine the responsiveness, effect size (ES) and smallest detectable difference (SDD) of two Magnetic Resonance Imaging (MRI) measures for osteoarthritis (OA) of the knee: a whole-organ semiquantitative evaluation and cartilage volume., Design: This analysis was performed on a dataset from a randomized, double-blind trial (Roche NI-15713) conducted in 1998 of a novel therapy in subjects with mild-moderate knee OA, with MRI at baseline and 6-month follow-up. The trial measurements included (1) cartilage volume measured using a proprietary software method; and (2) semiquantitative scoring of other parameters important for "whole organ" evaluation of OA knee joint pathology, using the Whole-Organ MRI Score (WORMS). The analysis initially examined the distributional characteristics of WORMS items, such as cartilage morphology. Standardized response mean (SRM), ES, and SDD between baseline and 6-month follow-up were then calculated in the whole group and the placebo group alone., Results: In general, the differences were small and this was reflected in the small ESs and SRMs. There was also a suggestion of a treatment effect with reduction in differences between baseline and follow-up in the treatment group., Conclusion: Of the MRI semiquantitative measures, cartilage morphology, synovitis and osteophytes appeared to be responsive to change and the focus of repeat measures should highlight these articular features. In general, the ESs and SRMs were small.

Objective: The ability to reliably quantify all the structural abnormalities in osteoarthritis (OA) of the knee is a long-standing goal of OA research. On December 5 and 6, 2002, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society, International held a Workshop for Consensus on Osteoarthritis Imaging in Bethesda, MD, with the aim of providing a state-of-the-art review of imaging outcome measures for OA of the knee. As part of the Workshop, data from previous clinical trials and epidemiological studies of OA were analysed with respect to the metrological properties of the measurement methods used. The following report outlines the results of analyses aimed at evaluating the internal construct validity of a whole-organ, ordinal (semi-quantitative) magnetic resonance imaging score (WORMS) using Rasch analysis. The fit of data to the Rasch model offers a measure of the validity of summing different items into a subscale score and the degree to which this score behaves as a unidimensional, interval level measurement tool., Methods: The Rasch model was applied in two OA studies. The first was a clinical cohort comprising OA knee subjects entering a clinical trial; study entry criteria included patients with at least moderate pain, radiographic osteophytes and a minimum of 1.5mm tibiofemoral joint-space width. The second cohort was from the Boston Osteoarthritis Knee Study, an observational cohort of subjects with symptomatic knee OA with pain on most days and a definite osteophyte in either the tibiofemoral or patellofemoral joints. Baseline WORMS scores from both studies were used for the Rasch analysis, performed with RUMM 2020 software., Results: There was a substantial proportion of subjects in both study populations with zero scores in several of the subscales of WORMS. Few of the subscales met the requirements of the Rasch measurement model when summated across all sites, and summations of some postulated compartmentally based sites also failed to fit the Rasch model. The existing scoring categories also required rescoring at many sites., Conclusion: There remain important issues in constructing outcome measurements that summate different features across multiple anatomical sites. The whole-organ scoring system evaluated here is no exception. Resolving these issues will improve the ability of imaging studies to assess complex pathological structural change.

Objective: Recent studies using various standardized radiographic acquisition techniques have demonstrated the necessity of reproducible radioanatomic alignment of the knee to assure precise measurements of medial tibiofemoral joint space width (JSW). The objective of the present study was to characterize the longitudinal performance of several acquisition techniques with respect to long-term reproducibility of positioning of the knee, and the impact of changes in positioning on the rate and variability of joint space narrowing (JSN)., Methods: Eighty subjects were randomly selected from each of three cohorts followed in recent studies of the radiographic progression of knee osteoarthritis (OA): the Health ABC study (paired fixed-flexion [FF] radiographs taken at a 36-month interval); the Glucosamine Arthritis Intervention Trial (GAIT) (paired metatarsophalangeal [MTP] radiographs obtained at a 12-month interval), and a randomized clinical trial of doxycycline (fluoroscopically assisted semiflexed anteroposterior (AP) radiographs taken at a 16-month interval). Manual measurements were obtained from each radiograph to represent markers of radioanatomic positioning of the knee (alignment of the medial tibial plateau and X-ray beam, knee rotation, femorotibial angle) and to evaluate minimum JSW (mJSW) in the medial tibiofemoral compartment. The effects on the mean annualized rate of JSN and on the variability of that rate of highly reproduced vs variable positioning of the knee in serial radiographs were evaluated., Results: Parallel or near-parallel alignment was achieved significantly more frequently with the fluoroscopically guided positioning used in the semiflexed AP protocol than with either the non-fluoroscopic FF or MTP protocol (68% vs 14% for both FF and MTP protocols when measured at the midpoint of the medial compartment; 75% vs 26% and 34% for the FF and MTP protocols, respectively, when measured at the site of mJSW; P<0.001 for each). Knee rotation was reproduced more frequently in semiflexed AP radiographs than in FF radiographs (66% vs 45%, P<0.01). In contrast, the FF technique yielded a greater proportion of paired radiographs in which the femorotibial angle was accurately reproduced than the semiflexed AP or MTP protocol (78% vs 59% and 56%, respectively, P<0.01 for each). Notably, only paired radiographs with parallel or near-parallel alignment exhibited a mean rate of JSN (+/-SD) in the OA knee that was more rapid and less variable than that measured in all knees (0.186+/-0.274 mm/year, standardized response to mean [SRM]=0.68 vs 0.128+/-0.291 mm/year, SRM=0.44)., Conclusion: This study confirms the importance of parallel radioanatomic alignment of the anterior and posterior margins of the medial tibial plateau in detecting JSN in subjects with knee OA. The use of radiographic methods that assure parallel alignment during serial X-ray examinations will permit the design of more efficient studies of biomarkers of OA progression and of structure modification in knee OA.

Background: Synovial inflammation (as defined by hypertrophy and effusion) is common in osteoarthritis (OA) and may be important in both pain and structural progression., Objective: To determine if decision rules can be devised from clinical findings and ultrasonography (US) to allow recognition of synovial inflammation in patients with painful knee OA., Methods: A EULAR-ESCISIT cross sectional, multicentre study enrolled subjects with painful OA knee who had clinical, radiographic, and US evaluations. A classification and regression tree (CART) analysis was performed to find combinations of predictor variables that would provide high sensitivity and specificity for clinically detecting synovitis and effusion in individual subjects. A range of definitions for the two key US variables, synovitis and effusion (using different combinations of synovial thickness, depth, and appearance), were also included in exploratory analyses., Results: 600 patients with knee OA were included in the analysis. For both knee synovitis and joint effusion, the sensitivity and specificity were poor, yielding unsatisfactory likelihood ratios (75% sensitivity, 45% specificity, and positive LR of 1.36 for knee synovitis; 71.6% sensitivity, 43.2% specificity, and positive LR of 1.26 for joint effusion). The exploratory analyses did not improve the sensitivity and specificity (demonstrating positive LRs of between 1.26 and 1.57)., Conclusion: Although it is possible to determine clinical and radiological predictors of OA inflammation in populations, CART analysis could not be used to devise useful clinical decision rules for an individual subject. Thus sensitive imaging techniques such as US remain the most useful tool for demonstrating synovial inflammation of the knee at the individual level.

Objectives: Synovitis is common in osteoarthritis (OA) of the knee. In order to evaluate its importance, valid and reliable quantification methods are required. The aim of this study was to compare simple, semiquantitative synovitis scores with detailed volume assessments in subjects with knee OA using magnetic resonance imaging (MRI) as the investigative tool., Methods: Thirty-five subjects with clinically diagnosed OA of the knee were assessed for synovitis using gadolinium-enhanced MRI. The volume measurement of synovitis was assessed at four sites (medial and lateral parapatellar recesses, intercondylar notch and suprapatellar pouch). The semiquantitative scoring of synovitis was scored on a 0-3 scale. Establishment of a correlative relationship was undertaken using Spearman's rho for the individual site-specific measurements. Ordinal regression modelling was undertaken in order to establish the capacity of the synovitis scoring to predict the volume measurement., Results: A total of 140 sites were assessed. There were good correlations between the semiquantitative scores and the volume measurements, ranging from rho = 0.86 (P < 0.00) for the medial parapatellar recess to rho = 0.71 (P < 0.00) for the lateral parapatellar recess. The ordinal regression suggested that, while the synovitis scores predicted between 50 and 70% (R2 = 0.53, P < 0.00 to R2 = 0.71, P < 0.00) of the volume measurements, there was some minor overlap, particularly in the mid-range synovitis scores., Conclusions: These results suggest that semiquantitative synovitis scores are valid and will enable feasible evaluation of the synovium in OA cohorts.

Aim: To assess whether simple, limited section analysis can replace detailed volumetric assessment of synovitis in patients with osteoarthritis (OA) of the knee using contrast-enhanced magnetic resonance imaging (MRI)., Materials and Methods: Thirty-five patients with clinical and radiographic OA of the knee were assessed for synovitis using gadolinium-enhanced MRI. The volume of enhancing synovium was quantitatively assessed in four anatomical sites (the medial and lateral parapatellar recesses, the intercondylar notch and the suprapatellar pouch) by summing the volumes of synovitis in consecutive sections. Four different combinations of section analysis were evaluated for their ability to predict total synovial volume., Results: A total of 114 intra-articular sites were assessed. Simple linear regression demonstrated that the best predictor of total synovial volume was the analysis containing the inferior, mid and superior sections of each of the intra-articular sites, which predicted between 40-80% (r(2) = 0.396, p < 0.001 for notch; r(2) = 0.818, p < 0.001 for medial parapatellar recess) of the total volume assessment., Conclusions: The results suggest that a three-section analysis on axial post-gadolinium sequences provides a simple surrogate measure of synovial volume in OA knees.

Objectives: To assess the prevalence of inflammation in subjects with chronic painful knee osteoarthritis (OA), as determined by the presence of synovitis or joint effusion at ultrasonography (US); and to evaluate the correlation between synovitis, effusion, and clinical parameters., Methods: A cross sectional, multicentre, European study was conducted under the umbrella of EULAR-ESCISIT., Subjects: had primary chronic knee OA (ACR criteria) with pain during physical activity >or=30 mm for at least 48 hours. Clinical parameters were collected by a rheumatologist and an US examination of the painful knee was performed by a radiologist or rheumatologist within 72 hours of the clinical examination. Ultrasonographic synovitis was defined as synovial thickness >or=4 mm and diffuse or nodular appearance, and a joint effusion was defined as effusion depth >or=4 mm., Results: 600 patients with painful knee OA were analysed. At US 16 (2.7%) had synovitis alone, 85 (14.2%) had both synovitis and effusion, 177 (29.5%) had joint effusion alone, and 322 (53.7%) had no inflammation according to the definitions employed. Multivariate analysis showed that inflammation seen by US correlated statistically with advanced radiographic disease (Kellgren-Lawrence grade >or=3; odds ratio (OR)=2.20 and 1.91 for synovitis and joint effusion, respectively), and with clinical signs and symptoms suggestive of an inflammatory "flare", such as joint effusion on clinical examination (OR=1.97 and 2.70 for synovitis and joint effusion, respectively) or sudden aggravation of knee pain (OR=1.77 for joint effusion)., Conclusion: US can detect synovial inflammation and effusion in painful knee OA, which correlate significantly with knee synovitis, effusion, and clinical parameters suggestive of an inflammatory "flare".

Background: Qualitative differences in synovitis between the cartilage-pannus junction (CPJ) region and the adjoining suprapatellar pouch (SPP) have been reported in rheumatoid arthritis and the spondyloarthropathies., Objective: To determine if the distribution of synovitis is the same in osteoarthritis (OA) using sensitive measures of inflammation derived from dynamic, contrast enhanced magnetic resonance imaging (DEMRI)., Methods: 20 subjects with established OA of the knee were recruited. Conventional MR images together with the DEMRI measurements were obtained. Areas of synovitis at the CPJ region and at a distant site in the SPP were calculated; differences in CPJ and SPP synovitis were determined using DEMRI parameters: the initial rate of contrast enhancement (IRE) and maximal enhancement (ME)., Results: The area of synovitis was significantly greater adjacent to the CPJ than in the SPP. IRE and ME measures were greater at the CPJ than the SPP., Conclusions: The magnitude of synovitis at the CPJ is not disease-specific and applies across the spectrum of degenerative disease as well as inflammatory diseases.

Objective: To determine the localisation and level of expression of human type IIa secretory phospholipase A2 (sPLA2) in the synovium of rheumatoid arthritis (RA), osteoarthritis (OA), and non-arthritic (NA) patients and to examine the relation between sPLA2 and histological features of inflammation., Methods: Immunoperoxidase staining using the anti-sPLA2 monoclonal antibody 9C1 was performed on frozen sections of knee synovium of 10 RA, 10 OA, and 10 NA patients. sPLA2 positive cells were scored on a scale of 0-3 in 10 fields of a representative tissue section from each case. Double labelling immunofluorescence confocal microscopy with antibodies to CD14 or CD45 and 9C1 was used to determine cell type specificity. Inflammation was assessed by semiquantitative scoring of lining layer thickness and mononuclear cell infiltrates (MC) and a cumulative inflammation score, generated by summing the two parameters. Scores in each group were compared using non-parametric statistical analysis., Results: sPLA2 was localised to endothelium (EC), vascular smooth muscle (VSM), and mast cells (M) in all tissue sections. In RA and OA sections, staining was seen in both macrophage-like and fibroblast-like cells in the synovial lining layer (LL) and subsynovial lining layer (SLL). Perineural cells stained positively. Subintimal lymphoid aggregates (LA) were negative in all sections. The RA group showed significantly greater staining in extravascular synovial tissue (median 3.6, range 1.5-6.0) than the OA (median 1.95, range 0-5.3) or NA (median 0, range 0-5.9) groups (p < 0.05). LL staining was significantly higher in RA than both OA and NA sections (p < 0.05). The OA group showed a trend to higher staining scores than the NA group that did not reach significance. There was a significant correlation between the sPLA2 staining score and inflammation score within the RA patient group (p < 0.05)., Conclusions: The synovium is a site of increased expression of sPLA2 antigen in both RA and OA relative to NA. Its presence in both fibroblast and macrophage-like cells in the LL and SLL of synovial tissue in RA and OA, but not NA, indicates that the enzyme is specifically induced in these regions in both conditions with expression in the LL being particularly characteristic of RA. The widespread expression of sPLA2 in synovium suggests it is likely to play a significant part in synovial pathology.