When Is Osteonecrosis Not Osteonecrosis?: Adjudication of Reported Serious Adverse Joint Events in the Tanezumab Clinical Development Program.

OBJECTIVE: Tanezumab, a monoclonal antibody against nerve growth factor, has demonstrated efficacy in clinical trials of chronic pain in osteoarthritis (OA) and chronic low back pain. Unexpected adverse events (AEs) described as osteonecrosis (ON) occurred during tanezumab development, leading the US Food and Drug Administration to impose a partial clinical hold for all indications except cancer pain. A blinded Adjudication Committee (AC) including orthopedic surgeons, rheumatologists, and an orthopedic pathologist reviewed and adjudicated joint-related AEs in the tanezumab clinical program. METHODS: The AC adjudicated all reported cases of ON as well as cases of total joint replacements (TJRs) not reported as ON for which radiographs obtained within 9 months of the surgery were available. The AC prespecified categories for joint safety events including primary ON, worsening OA (rapid progression of OA [RPOA], normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA), other, or insufficient information to distinguish between primary ON and worsening OA or another diagnosis. RESULTS: The AC reviewed events in 249 of 386 patients with an investigator-reported AE of ON and/or a TJR. Two events were adjudicated as primary ON, 200 events were adjudicated as worsening OA (68 of which were classified as RPOA), 29 events had another diagnosis, 11 had insufficient information to distinguish primary ON from worsening OA, and 7 did not have committee member consensus. CONCLUSION: Despite initial reports, tanezumab treatment was not associated with an increase in ON but was associated with an increase in RPOA. Higher doses of tanezumab, tanezumab administered with nonsteroidal antiinflammatory drugs, and preexisting subchondral insufficiency fractures were risk factors for RPOA in this cohort.

Considerations when designing a disease-modifying osteoarthritis drug (DMOAD) trial using radiography.

OBJECTIVE: Using placebo data from a recently completed disease-modifying osteoarthritis (OA) drug trial, we seek to inform study design of future radiographic studies. METHODS: Eligible patients aged ≥40 years, with body mass index (BMI) 25-40kg/m(2) and symptomatic knee OA diagnosed by modified Kellgren and Lawrence grade (KLG) 2 or 3 and pain/stiffness and/or use of medication for knee pain in the past year, were assessed by radiography using a modified Lyon-schuss (mL/S) protocol for joint space narrowing (JSN) (primary outcome variable) at baseline and weeks 48 and 96. Multifaceted quality control was conducted throughout. Repeat images were requested when the medial tibial plateau (MTP) was not aligned (inter-margin distance [IMD] >1.5mm) or for other quality issues. Data are given mean ± standard deviation. RESULTS: Patients (74.9% female; 61.3 ± 9.1 years) had BMI 31.6 ± 4.1kg/m(2) at baseline; 222 (173 females) had KLG2, 264 (191 female) KLG3. A significant loss in joint space width (JSW) from baseline to week 48 (-0.13 ± 0.36mm) and to week 96 (-0.22 ± 0.45mm) was observed for all randomised placebo patients (p < 0.001 for both), and at both time points when stratified by KLG2 or KLG3. Standard deviations were small relative to mean changes, providing standardised response means for all placebo patients of 0.35 (week 48) and 0.48 (week 96). CONCLUSIONS: Using a tightly controlled radiographic technique, JSN is a viable outcome variable for determining disease progression in mild-to-moderate knee OA. The mL/S protocol is a sensitive and feasible method for OA studies aiming to assess rate of JSN in the knee.

In normal knees, joint space width (JSW) is correlated with the intermargin distance (IMD), a measure of medial tibial plateau alignment. Variations in IMD explain variability in JSW in serial radiographs.

OBJECTIVE: To ascertain the importance of alignment of the medial tibial plateau (MTP), as determined by the distance between the anterior and posterior margins of the plateau (intermargin distance [IMD]), for measurements of joint space width (JSW) in radiographs of normal knees. METHODS: JSW and IMD were measured in paired baseline and 12-month knee films of 122 subjects from the osteoarthritis initiative (OAI). Relationships between JSW and IMD, and between the variation in JSW and variation in IMD, were evaluated. RESULTS: In cross-sectional analysis, a non-linear relationship existed between JSW and the concurrent IMD. With poor MTP alignment (IMD>1.7 mm), a 1.0-mm increase in IMD resulted in a 0.16-mm (95%CI: 0.11-0.21) increase in JSW (P<0.0001). In a longitudinal analysis, the effect of IMD variation on variation in JSW was also highly significant (P<0.0001). A variation of 1 mm between IMD(Baseline) and IMD(12month) was associated with a 0.10-mm (95% CI: 0.06-0.13) variation in JSW, with variations in JSW and IMD occurring in the same direction. An IMD variation less than or equal to 1.0mm was determined to be acceptable for accurate evaluation of JSW in serial radiographs. CONCLUSION: The error in measurement of JSW caused by variation in IMD in serial radiographs of normal knees can be as large, or larger, than the mean rate of 12-month joint space narrowing (JSN) in OA knees. MTP alignment and replication of alignment in serial knee films are required for accurate determination of JSN in OA knee.

A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee.

OBJECTIVE: To determine if inhibition of inducible nitric oxide synthase (iNOS) with cindunistat hydrochloride maleate slows progression of osteoarthritis (OA) METHODS: This 2-year, multinational, double-blind, placebo-controlled trial enrolled patients with symptomatic knee OA (Kellgren and Lawrence Grade (KLG) 2 or 3). Standard OA therapies were permitted throughout. Patients were randomly assigned to cindunistat (50 or 200 mg/day) or placebo. Randomisation was stratified by KLG. Radiographs to assess joint space narrowing (JSN) were acquired using the modified Lyon-schuss protocol at baseline, week 48 and 96. RESULTS: Of 1457 patients (50 mg/day, n=485; 200 mg/day, n=486; placebo, n=486), 1048 (71.9%) completed the study. Patients were predominantly women; 56% had KLG3. The primary analysis did not demonstrate superiority of cindunistat versus placebo for rate of change in JSN. In KLG2 patients, JSN after 48 weeks was lower with cindunistat 50 mg/day versus placebo (p=0.032). Least-squares mean±SE JSN with cindunistat 50 mg/day ( -0.048±0.028 mm) and 200 mg/day (-0.062±0.028 mm) were 59.9% (95% CI 6.8% to 106.9%) and 48.7% (95% CI -8.4% to 93.9%) of placebo, improvement was not maintained at 96 weeks. No improvement was observed for KLG3 patients at either time-point. Cindunistat did not improve joint pain or function, but was generally well tolerated. CONCLUSIONS: Cindunistat (50 or 200 mg/day) did not slow the rate of JSN versus placebo. After 48-weeks, KLG2 patients showed less JSN; however, the improvement was not sustained at 96-weeks. iNOS inhibition did not slow OA progression in KLG3 patients. CLINICAL TRIAL LISTING: NCT00565812.

Differences in the osteoarthritic synovial fluid composition and rheology between patients with or without flare: a pilot study.

OBJECTIVES: To study the influence of the inflammatory status (flare or not) on hyaluronic acid (HA) and protein composition and on the intrinsic viscosity of the synoviol fluid (SF) from patients with knee osteoarthritis (KOA). METHODS: Patients with KOA were classified as having flare (F+) when they fulfilled the 4 following clinical criteria: 1) sudden aggravation of knee pain, 2) whose beginning was identifiable, 3) causing nocturnal awakenings 4) with clinical evidence of knee effusion. Patients were classified F- (no flare) if they do not fulfill any of the 3 first criteria. Forty-four SF were obtained by arthrocentesis and assayed using steric exclusion chromatography, which allows HA to be separated from the proteins and to determine both molecular weight (Mw) and concentration (C) of both HA and proteins. SF rheology was determined using a rheometer at 25°C using a cone and plate geometry. Steady-state viscosity was determined in Pa.s, as a function of the shear rate at 1s-1. Correlations between ( Pa.s) and HA and Pr (Mw, C and Mw x C) were calculated. RESULTS: Among the 44 assayed SF, 25 were classified F- and 19 F+. There were statistically significant differences between F- and F+ for most of the studied variables: HA concentration and Mw (p=0.01 and 0.001 respectively), protein concentration and Mw (p=0.02 and 0.001 respectively), product Mw x C of the proteins (p<0.0001) and viscosity ή (p=0.0005). The product [(Mw xC) HA x (MwxC) proteins] was highly discriminating between F+ and F- (p<0.0001). The steady state viscosity was highly related to HA concentration (p= 0.0002) and HA Mw (p=0.01) and was negatively correlated with (Mw x C) proteins (p=0.0005), protein concentration (p=0.0007) and protein Mw (p=0.03). CONCLUSIONS: This pilot study shows significant differences of SF composition in patients having a flare-up compared to that of patients who do not have flare. These differences relate to both protein and HA composition and suggest that SF analysis makes possible to distinguish patients with and without flare-up.

Early effect of hyaluronic acid intra-articular injections on serum and urine biomarkers in patients with knee osteoarthritis: An open-label observational prospective study.

The aim of the study was to investigate the effect of hyaluronic acid (HA) intra articular injections (IA) on osteoarthritis (OA) biomarkers in patients with knee OA. Prospective open label study. Fifty-one patients with unilateral symptomatic K-OA received IA injections of 2mL of HA on days (D) 1, 7, 14 and were followed 3 months. At D-15 patients were examined and X-rays performed, to exclude patients with bilateral K-OA, or those with more than three symptomatic OA joints. From 15 days (D-15) before the first injection to D90 concomitant therapies were unchanged. Walking pain (WP) on VAS was obtained at each visit. Urine (U) and serum (S) samples were obtained at D-15, D1, D30, and D90. S-C2C, S-Cartilage oligomeric matrix protein, S-HA, S-CS 846 epitope, S-type II collagen propeptide, and U-type II collagen C telopeptide (U-CTX II/creatinin) were assayed. Predictive factors of response were analyzed using logistic regression. Correlations between variables were obtained using Spearman test. Forty-five patients were analyzed. Between D-15 and D1 there was no difference for any biomarkers At D1, WP (SD) was correlated with U-CTX II/creat (p = 0.006). Between D1 and D90: U-CTX II/creat decreased significantly. After adjustment for confounding variables there was a significant correlation between clinical response and U-CTX II/creat variation. U-CTX II and S-HA at baseline were independently predictive of clinical response. This study showed that 90 days after HA IA injections, U-CTX II levels significantly decrease compared to baseline, suggesting a slowdown of type II collagen degradation.

Osteoarthritis of the knee at 3.0 T: comparison of a quantitative and a semi-quantitative score for the assessment of the extent of cartilage lesion and bone marrow edema pattern in a 24-month longitudinal study.

OBJECTIVE: To compare a semi-quantitative and a quantitative morphological score for assessment of early osteoarthritis (OA) evolution. MATERIALS AND METHODS: 3.0 T MRI of the knee was performed in 60 women, 30 with early OA (each 15 with Kellgren-Lawrence grade 2 and 3) and 30 age-matched controls at baseline and at 12 and 24 months. Pathological condition was assessed with the whole-organ magnetic resonance imaging score (WORMS). Cartilage abnormalities and bone marrow edema pattern (BMEP) were also quantified using a previously introduced morphological quantitative score. These data were correlated with changes in clinical parameters and joint space width using generalized estimation equations (GEE). RESULTS: At baseline, OA patients had significantly (p < 0.05) more and larger cartilage lesions and BMEP. During follow-up, cartilage lesions increased significantly (p < 0.05) in the patients compared with controls: WORMS showed progression only at the lateral patella, whereas the quantitative score revealed progression additionally at the trochlea and at the medial compartment. Both scores showed a significant (p < 0.05) increase in BMEP at the lateral femur in OA patients. In addition, quantitative scores of BMEP of the whole knee decreased significantly (p < 0.05) after 12 months and increased after 24 months in the patients, but showed an increase in controls at all follow-up examinations. Only weak correlations between structural imaging findings and clinical parameters were observed. CONCLUSION: Quantitative assessment of cartilage lesions and BMEP is more sensitive to changes during the course of the disease than semi-quantitative scoring. However, structural imaging findings do not correlate well with the clinical progression of OA.

Factors predicting patient satisfaction 2 years after total knee arthroplasty for osteoarthritis.

OBJECTIVE: To identify factors predicting patient satisfaction 2 years after total knee arthroplasty (TKA) for osteoarthritis. METHODS: Prospective multicenter study of patients followed up for 2 years after TKA for osteoarthritis. We evaluated pain and function (Lequesne index and WOMAC) at baseline and after 2 years. After 2 years, the patients rated their satisfaction as a percentage, with values greater than 50% defining good satisfaction. Factors associated with good satisfaction were identified by univariate analyses followed by multivariate analysis. RESULTS: Of 299 patients, 264 completed the study (26 were lost to follow-up, six died, and three refused the 2-year evaluation), including 237 (89.8%) with satisfaction scores greater than 50%. Highly significant improvements were found after 2 years versus baseline in the Lequesne index (7.9 vs. 14.5, P<0.0001) and WOMAC index (26.3 vs. 51.3, P<0.0001). There were 26 (9.8%) complications. Factors significantly associated with good satisfaction in the multivariate model were absence of complications (P=0.004), body mass index less than 27 kg/m² (P=0.015), high radiological joint narrowing score (P=0.038), age greater or equal to 70 years (P=0.038), and absence of depression at the 2-year evaluation (P=0.002). CONCLUSION: We report the first prospective multicenter study done in France to assess pain and function in a large number of patients treated with TKA for osteoarthritis. Our results indicate a high success rate. We identified three factors that predict patient satisfaction and can be assessed before surgery (age greater than 70 years, absence of obesity, and severe joint space narrowing).

Management recommendations for knee osteoarthritis: how usable are they?

OBJECTIVES: Despite the availability of practice guidelines for the management of knee osteoarthritis, inadequacies in practices of clinicians and patients have been found, leading to suboptimal outcomes. Literature has shown that simply disseminating management recommendations does not lead to adherence. Research suggests that barriers to use should be identified and addressed to improve adherence. The objective of this study was to identify barriers to use of conservative management recommendations for knee osteoarthritis by patients, general practitioners and physiotherapists. METHODS: Following systematic reviews of evidence and guidelines, 12 key management recommendations were elaborated on four themes: medication, exercise, self-management and occupation. Focus groups were separately done with patients with knee osteoarthritis, general practitioners and physiotherapists to assess barriers to the use of recommendations. RESULTS: Patients and general practitioners appeared generally fatalistic with regards to knee osteoarthritis, with physiotherapists being more positive regarding long-term improvement of knee osteoarthritis. For medication, discrepancies were found between recommendations and views of clinicians. Both patients and general practitioners appeared ambivalent towards exercise and activity, recognizing its usefulness but identifying it at the same time as a cause of knee osteoarthritis. Patients and general practitioners appeared to consider weight loss particularly difficult. DISCUSSION/CONCLUSIONS: Barriers specific to each knee osteoarthritis management recommendation and stakeholder group were identified. Recommendations to address these barriers were elaborated. Results of this study can be used to develop implementation strategies to overcome identified barriers, with the goal of facilitating the use of guideline recommendations and improving outcomes.

Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry.

OBJECTIVE: A number of open-label studies have suggested the potential benefit of rituximab (RTX) in systemic lupus erythematosus (SLE). However, in 2 recent randomized controlled trials (RCTs) of RTX, the primary end points were not met. We undertook this study to evaluate the safety and efficacy of RTX in off-trial patients with SLE seen in regular clinical practice. METHODS: We analyzed prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with RTX. RESULTS: One hundred thirty-six patients received treatment for SLE. The mean +/- SD score on the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) was 11.3 +/- 8.9 at baseline. Severe infections were noted in 12 patients (9%), corresponding to a rate of 6.6/100 patient-years. Most severe infections occurred within the first 3 months after the last RTX infusion. Five patients died, due to severe infection (n = 3) or refractory autoimmune disease (n = 2). Overall response was observed in 80 of 113 patients (71%) by the SELENA-SLEDAI assessment. Efficacy did not differ significantly between patients receiving RTX monotherapy and those receiving concomitant immunosuppressive agents (who had higher baseline disease activity). Articular, cutaneous, renal, and hematologic improvements were noted in 72%, 70%, 74%, and 88% of patients, respectively. Among responders, 41% experienced a relapse of disease, with a response in 91% after retreatment with RTX. CONCLUSION: Data from the AIR registry show a satisfactory tolerance profile and clinical efficacy of RTX in patients with SLE. The contrasting results with those from recent RCTs leave open the question of the therapeutic use of RTX in SLE. Additional controlled studies with new designs are needed to define the place of RTX in the therapeutic arsenal for SLE.

Radiographic assessment of the femorotibial joint of the CCLT rabbit experimental model of osteoarthritis.

BACKGROUND: The purposes of the study were to determine the relevance and validity of in vivo non-invasive radiographic assessment of the CCLT (Cranial Cruciate Ligament Transection) rabbit model of osteoarthritis (OA) and to estimate the pertinence, reliability and reproducibility of a radiographic OA (ROA) grading scale and associated radiographic atlas. METHODS: In vivo non-invasive extended non weight-bearing radiography of the rabbit femorotibial joint was standardized. Two hundred and fifty radiographs from control and CCLT rabbits up to five months after surgery were reviewed by three readers. They subsequently constructed an original semi-quantitative grading scale as well as an illustrative atlas of individual ROA feature for the medial compartment. To measure agreements, five readers independently scored the same radiographic sample using this atlas and three of them performed a second reading. To evaluate the pertinence of the ROA grading scale, ROA results were compared with gross examination in forty operated and ten control rabbits. RESULTS: Radiographic osteophytes of medial femoral condyles and medial tibial condyles were scored on a four point scale and dichotomously for osteophytes of medial fabella. Medial joint space width was scored as normal, reduced or absent. Each ROA features was well correlated with gross examination (p < 0.001). ICCs of each ROA features demonstrated excellent agreement between readers and within reading. Global ROA score gave the highest ICCs value for between (ICC 0.93; CI 0.90-0.96) and within (ICC ranged from 0.94 to 0.96) observer agreements. Among all individual ROA features, medial joint space width scoring gave the highest overall reliability and reproducibility and was correlated with both meniscal and cartilage macroscopic lesions (rs = 0.68 and rs = 0.58, p < 0.001 respectively). Radiographic osteophytes of the medial femoral condyle gave the lowest agreements while being well correlated with the macroscopic osteophytes (rs = 0.64, p < 0.001). CONCLUSION: Non-invasive in vivo radiography of the rabbit femorotibial joint is feasible, relevant and allows a reproducible grading of experimentally induced OA lesion. The radiographic grading scale and atlas presented could be used as a template for in vivo non invasive grading of ROA in preclinical studies and could allow future comparisons between studies.

Rheologic behavior of osteoarthritic synovial fluid after addition of hyaluronic acid: a pilot study.

Viscosupplementation is a symptomatic treatment of osteoarthritis (OA) intended to restore rheologic homeostasis of the synovial fluid by injecting hyaluronic acid intraarticularly. Despite the long history of this therapy, little is known about its mechanisms of action and differences between commercial preparations. We investigated the rheologic behavior of OA synovial fluid with time, when stored at 4 degrees C, before and after the addition of two hyaluronic acid commercial preparations (linear and cross-linked). Thirteen OA synovial fluids were stored at 4 degrees C and assayed using steric exclusion chromatography, which allows hyaluronic acid to be separated from the remaining pool of proteins and its molecular weight and concentration to be determined without any pretreatment and calibration. The synovial fluid rheology also was studied in vitro, before and after addition of two viscosupplements, over 6 weeks. The non-Newtonian behavior of synovial fluid throughout followup appears to be the result of loose interactions between proteins and hyaluronic acid. When mixed with the linear hyaluronic acid, synovial fluid becomes less non-Newtonian whereas the non-Newtonian behavior was reinforced when mixed with the cross-linked hyaluronic acid. The rheology was nearly unchanged for all synovial fluids over 6 weeks. Our preliminary trial shows it is possible to study synovial fluid, stored at 4 degrees C, over a long time and suggests the enzymatic degradation of hyaluronic acid is negligible under these experimental conditions.

Validation of the KOFUS (Knee Osteoarthritis Flare-Ups Score).

OBJECTIVE: To develop a diagnostic score for knee osteoarthritis flare-ups and to evaluate its sensitivity and specificity. METHODS: We used two epidemiological databases built using the same methodology. One database was from a general-practice study and served to develop the score, whereas the other was from a rheumatology study and served to validate the score. Physicians determined the flare-up status of each patient. The rheumatologist diagnosis was the reference standard. Logistic regression was performed to identify factors significantly associated with having a flare-up. RESULTS: Of the 6085 patients in the general-practice database, 52.3% had a knee osteoarthritis flare-up. The score was built by assigning points to features that were present, with a weighting system based on the odds ratio of each feature for having a flare-up (0, feature absent; 1, morning stiffness for longer than 20 min; 2, pain causing nocturnal awakenings and knee effusion; 3, limping, joint swelling, and increased warmth over the knee). The score could range from 0 to 14. The receiver-operating characteristic curve showed that 7 was the best cutoff for diagnosing a flare-up. In the rheumatologist database, the numbers of patients having a flare-up were 274 (46.4%) based on the score and 270 (45.7%) based on the rheumatologist diagnosis. Sensitivity of the score was 87.0%, specificity 87.9%, positive predictive value 85.8%, and negative predictive value 89.0%. The Youden index was 0.75. CONCLUSION: A score equal to or greater than 7 points correlated well with a rheumatologist diagnosis of flare-up. Our score may constitute a valid objective criterion for standardizing the diagnosis of knee osteoarthritis flare-up, most notably when screening patients for inclusion in therapeutic trials.

Safety, efficacy and predictive factors of efficacy of a single intra-articular injection of non-animal-stabilized-hyaluronic-acid in the hip joint: results of a standardized follow-up of patients treated for hip osteoarthritis in daily practice.

AIM: To evaluate, in daily clinical practice, the efficacy and tolerability of a single intra-articular injection of non-animal-stabilized hyaluronic acid (NASHA) in patients treated for symptomatic hip OA (HOA). METHODS: Standardized follow-up (FU). PATIENTS: forty patients suffering from HOA treated by a single intra-articular injection of NASHA in the painful hip under fluoroscopy. EVALUATION: patient global assessment (PGA) and walking pain (WP) on a 100 mm visual analogue scale, WOMAC index, Lequesne index at each visit. STATISTICS: last observation carried forward. Treatment efficacy was assessed using OMERACT-OARSI response criteria, minimal clinically important improvement (MCII), patient acceptable symptom state (PASS) obtained from PGA, WOMAC and WP. Predictive factors of efficacy were also studied. RESULTS: Efficacy evaluation: 34 patients were assessable (mean FU 159 days). All clinical variables (WP, PGA, WOMAC, Lequesne index) decreased significantly between baseline and last evaluation. Twenty-two patients (71%) were classified OMERACT-OARSI responders, 25 subjects (75.8%) were classified PASS+, and 19 (61.3%) fulfilled criteria for MCII. Out of clinical and radiological variables only Lequesne index (p = 0.04) and WOMAC (p = 0.04) at baseline were found to be predictive of treatment efficacy. Safety evaluation: the treatment was well tolerated. There were no severe adverse events related to the treatment or to the procedure. However 15 of the 28 assessable patients experienced transient increase of pain in the target hip during the first week after injection. CONCLUSION: Viscosupplementation of the hip with NASHA is easily feasible in daily clinical practice, safe and well tolerated despite a frequent increase of pain the days following injection. Prospective controlled trials are needed to confirm these data and to evaluate both safety and efficacy of a second course of treatment.

A critical appraisal of guidelines for the management of knee osteoarthritis using Appraisal of Guidelines Research and Evaluation criteria.

Clinical practice guidelines have been elaborated to summarize evidence related to the management of knee osteoarthritis and to facilitate uptake of evidence-based knowledge by clinicians. The objectives of the present review were summarizing the recommendations of existing guidelines on knee osteoarthritis, and assessing the quality of the guidelines using a standardized and validated instrument--the Appraisal of Guidelines Research and Evaluation (AGREE) tool. Internet medical literature databases from 2001 to 2006 were searched for guidelines, with six guidelines being identified. Thirteen clinician researchers participated in the review. Each reviewer was trained in the AGREE instrument. The guidelines were distributed to four groups of three or four reviewers, each group reviewing one guideline with the exception of one group that reviewed two guidelines. One independent evaluator reviewed all guidelines. All guidelines effectively addressed only a minority of AGREE domains. Clarity/presentation was effectively addressed in three out of six guidelines, scope/purpose and rigour of development in two guidelines, editorial independence in one guideline, and stakeholder involvement and applicability in none. The clinical management recommendation tended to be similar among guidelines, although interventions addressed varied. Acetaminophen was recommended for initial pain treatment, combined with exercise and education. Nonsteroidal anti-inflammatory drugs were recommended if acetaminophen failed to control pain, but cautiously because of gastrointestinal risks. Surgery was recommended in the presence of persistent pain and disability. Education and activity management interventions were superficially addressed in most guidelines. Guideline creators should use the AGREE criteria when developing guidelines. Innovative and effective methods of knowledge translation to health professionals are needed.

Cross-sectional study of pain and disability at knee replacement surgery for osteoarthritis in 299 patients.

OBJECTIVE: To evaluate pain and disability at the time of knee replacement surgery for osteoarthritis. METHODS: In this multicenter cross-sectional study, 299 patients at 12 orthopedic surgery centers in Lyon, France were evaluated on the day before knee replacement surgery. Pain severity was assessed on a visual analog scale (VAS) and function using the Lequesne index and the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: There were 207 women and 92 men with a mean age of 73 years. Mean (+/-SD) VAS pain score upon walking was 55.8+/-24mm. Compared to patients with very severe disability (Lequesne index>12), those with mild-to-severe disability (Lequesne index27kg/m(2) (OR, 2.2; 95%CI, 1.3-3.3) and to engage in sporting activities (OR, 3.3; 95%CI, 1.4-10). CONCLUSION: Patients about to undergo knee replacement surgery had high levels of pain and disability, with little variation across centers. Nevertheless, the severity of pain and disability may depend in part on age, gender, body mass index, and sporting activities, which probably influence the decision to perform knee replacement surgery.

Retroperitoneal fibrosis: a rare vascular and immune entity disclosed by chronic lombalgia.

Retroperitoneal fibrosis is a rare inflammatory and fibrotic process in the retroperitoneal peri-aortic tissues, associated with ureters and other abdominal organs' entrapment. Here we report an original observation of a 55-year-old patient presenting with chronic lombalgia disclosing idiopathic retroperitoneal fibrosis. After one-year follow-up, treatment with corticosteroids led to a complete clinical, biological, and radiological response. Pathogenesis and therapeutic options in idiopathic retroperitoneal fibrosis are discussed.

Clinical response to intra-articular injections of hylan G-F 20 in symptomatic hip osteoarthritis: the OMERACT-OARSI criteria applied to the results of a pilot study.

OBJECTIVE: To assess, using the OMERACT-OARSI criteria, the clinical response of patients presenting with symptomatic hip osteoarthritis (OA) to one intra-articular injection of hylan G-F 20. METHODS: Open-label, multi-centre, prospective, pilot study. Fifty-six patients presenting with primary hip OA, Kellgren-Lawrence grade II-III, age > or =40, with walking pain measuring 50-90 mm on a 100 mm visual analogue scale (VAS). Intra-articular injection of a single 2 ml dose of hylan G-F 20 into the hip joint under fluoroscopic guidance. A second injection could be administered at day (D) 30, 60 or 90 if pain was unchanged or returned to baseline levels. EFFICACY CRITERIA: The outcome of the first injection in the intent-to-treat (ITT) population was analysed 90 days after the injection in those patients that received a single injection, and on the day of the second injection in those patients that required two injections, using OMERACT-OARSI responder criteria (obtained from WOMAC A and C indices and the patient's global evaluation) and variation in walking pain on VAS. RESULTS: The percentage of responders according to the OMERACT-OARSI response criteria was 53.6%. An inverse correlation was observed between reduction in pain and joint space narrowing score (P=0.03). CONCLUSION: In the absence of a control group, the efficacy of the treatment cannot be determined conclusively. Nevertheless these data suggest that hylan G-F 20 is a symptomatic treatment of hip OA, particularly in less severe radiological cases. A double-blind, controlled study is required to confirm these data.

Osteoarthritis of the knee and hip and activity: a systematic international review and synthesis (OASIS).

UNLABELLED: The goal of this study was to determine which activities in four domains, daily life, exercises, sports and occupational activities, should be recommended, in favor or against, for the patient suffering from knee or hip OA. METHODS: Scientific literature was searched in Medline, Embase and Cochrane databases for articles in French or English, reporting original data. The articles were evaluated with standardized epidemiological criteria. Seventy-two articles were retained. Recommendations were graded according to the level of scientific evidence (A high, B moderate, C clinical consensus) and were formulated for primary care. CONCLUSIONS AND RECOMMENDATIONS: For activity of daily life (ADL), the OASIS group states with a moderate level of scientific evidence, that ADL are a risk factor for knee OA and that risk increases with intensity and duration of activity. The group concludes that healthy subjects as well as OA patients in general can pursue a high level of physical activity, provided the activity is not painful and does not predispose to trauma (grade B). Radiographic or clinical OA is not a contraindication to promoting activity in patients who have a sedentary lifestyle (grade C). For exercises and other structured activities pursued with a goal of health improvement, the group states with a high level of scientific evidence that they have a favourable effect on pain and function in the sedentary knee OA patient. The OASIS group recommends the practice of exercises and other structured activities for the sedentary patient with knee OA (grade A). Static exercises are not favored over dynamic exercises, availability, preference and tolerance being the criteria for the choice of an exercise (grade A). As results deteriorate when exercises are stopped, they should be performed at a frequency of between one and three times per week (grade B). Professional assistance can be useful in improving initial compliance and perseverance (grade B). There is no scientific argument to support halting exercise in case of an OA flare-up (grade C). For sports and recreational activity, the group states with a high degree of scientific evidence, that these activities are a risk factor for knee and hip OA and that the risk correlates with intensity and duration of exposure. The group also states, with a high degree of scientific evidence, that the risk of OA associated with sport is lesser than that associated with a history of trauma and overweight. No firm conclusion could be drawn about the possible protective role of sports such as cycling, swimming or golf. The OASIS group recommends that athletes should be informed that joint trauma is a greater risk factor than the practice of sport (Grade A). The high level athlete should be informed that the risk of OA is associated with the duration and intensity of exposure (Grade B). The OA patient can continue to engage regularly in recreational sports as long as the activity does not cause pain (Grade C). The OA patient who practices a sport at risk for joint trauma should be encouraged to change sport (Grade C). For occupational activity, the OASIS group states with a high level of scientific evidence that there is a relationship between occupational activity and OA of the knee and hip. The precise nature of biomechanical stresses leading to OA remains unclear but factors such as high loads on the joint, unnatural body position, heavy lifting, climbing and jumping may contribute to knee and hip OA. The group recommends that taking an occupational history should always be part of managing the OA patient (Grade B). In the knee or hip OA patient, work-related activity that produces or maintains pain should be avoided (Grade B). Physicians should be alerted by the early knee and hip signs and symptoms in workers exposed to stresses that are known or supposed to favour knee or hip OA (Grade C).

Reproducibility and sensitivity to change of various methods to measure joint space width in osteoarthritis of the hip: a double reading of three different radiographic views taken with a three-year interval.

Joint space width (JSW) and narrowing (JSN) measurements on radiographs are currently the best way to assess disease severity or progression in hip osteoarthritis, yet we lack data regarding the most accurate and sensitive measurement technique. This study was conducted to determine the optimal radiograph and number of readers for measuring JSW and JSN. Fifty pairs of radiographs taken three years apart were obtained from patients included in a structure modification trial in hip osteoarthritis. Three radiographs were taken with the patient standing: pelvis, target hip anteroposterior (AP) and oblique views. Two trained readers, blinded to each other's findings, time sequence and treatment, each read the six radiographs gathered for each patient twice (time interval > or = 15 days), using a 0.1 mm graduated magnifying glass. Radiographs were randomly coded for each reading. The interobserver and intraobserver cross-sectional (M0 and M36) and longitudinal (M0-M36) reproducibilities were assessed using the intraclass coefficient (ICC) and Bland-Altman method for readers 1 and 2 and their mean. Sensitivity to change was estimated using the standardized response mean (SRM = change/standard deviation of change) for M0-M36 changes. For interobserver reliability on M0-M36 changes, the ICCs (95% confidence interval [CI]) were 0.79 (0.65-0.88) for pelvic view, 0.87 (0.78-0.93) for hip AP view and 0.86 (0.76-0.92) for oblique view. Intraobserver reliability ICCs were 0.81 (0.69-0.89) for observer 1 and 0.97 (0.95-0.98) for observer 2 for the pelvic view; 0.87 (0.78-0.92) and 0.97 (0.96-0.99) for the hip AP view; and 0.73 (0.57-0.84) and 0.93 (0.88-0.96) for the oblique view. SRMs were 0.61 (observer 1) and 0.82 (observer 2) for pelvic view; 0.64 and 0.75 for hip AP view; and 0.77 and 0.70 for oblique view. All three views yielded accurate JSW and JSN. According to the best reader, the pelvic view performed slightly better. Both readers exhibited high precision, with SRMs of 0.6 or greater for assessing JSN over three years. Selecting a single reader was the most accurate method, with 0.3 mm precision. Using this cutoff, 50% of patients were classified as 'progressors'.