E. Maheu

Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: A prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect

OBJECTIVE To assess the efficacy and safety of avocado/soybean unsaponifiables (ASU) in the treatment of patients with symptomatic osteoarthritis (OA) of the knee or hip, as well as the potential residual effects of ASU after stopping treatment, to determine whether ASU might be a symptomatic slow-acting drug for the treatment of OA. METHODS One hundred sixty-four patients with regular, painful, primary OA of the knee (n = 114) or hip (n = 50) entered a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial with a 6-month treatment period and a 2-month posttreatment followup. A 15-day washout period for nonsteroidal antiinflammatory drugs (NSAIDs) preceded the study. Efficacy was judged according to 1) Lequesnes functional index (LFI) and 2) pain on Huskissons visual analog scale (VAS; 100-mm scale), intake of NSAIDs/analgesics, and overall disability score (by 100-mm VAS). RESULTS Eighty-five patients received ASU; 79 received placebo. One hundred forty-four patients were evaluable at month 6 (75 taking ASU; 69 taking placebo). The mean +/- SEM LFI score decreased from 9.7 +/- 0.3 to 6.8 +/- 0.4 in the ASU group and from 9.4 +/- 0.3 to 8.9 +/- 0.4 in the placebo group (P < 0.001 for intergroup difference at month 6). Pain decreased from 56.1 +/- 1.6 mm to 35.3 +/- 2.3 in the ASU group and from 56.1 +/- 1.8 mm to 45.7 +/- 2.6 in the placebo group (P = 0.003 at month 6). NSAID consumption was slightly lower in the ASU group. Fewer patients in the ASU group required NSAIDs (48%, versus 63% in the placebo group; P = 0.054). The success rate was 39% in the ASU group and 18% in the placebo group. Overall functional disability was significantly reduced in the ASU group. Improvement appeared more marked in patients with hip OA. A residual effect was observed at month 8. Tolerance was good to excellent for most patients. CONCLUSION ASU treatment showed significant symptomatic efficacy over placebo in the treatment of OA, acting from month 2 and showing a persistent effect after the end of treatment.

A randomised, double-blind, controlled trial comparing two intra-articular hyaluronic acid preparations differing by their molecular weight in symptomatic knee osteoarthritis

Objectives To compare the effects of an intermediate molecular weight (MW) intra-articular hyaluronic acid (HA) with a low MW product on knee osteoarthritis (OA) symptoms. Methods Patients with symptomatic knee OA were enrolled inarandomised, controlled, double-blind, parallel-group, non-inferiority trial with the possibility to shift to superiority. Patients were randomised to GO-ON(MW 800–1500 kD, 25 mg/2.5 ml) or Hyalgan(MW 500–730 kD, 20 mg/2 ml) injected at 3-weekly intervals. The primary outcome was 6-month change in the WOMAC pain subscale (0–100 mm). Sample size was calculated on a non-inferiority margin of 9 mm, lower than the minimum perceptible clinical improvement. Secondary endpoints included OARSI-OMERACT responder rates Results The intention-to-treat (ITT) and per-protocol (PP) populations consisted of 217 and 209 patients and 171 and 172 patients in the GO-ON and Hyalgan groups, respectively. ITT WOMAC pain of 47.5±1.0(SE) and 48.8±1.0 mm decreased by 22.9±1.4 mm with GO-ON and 18.4±1.5 mm with Hyalgan after 6 months. The primary analysis was conducted in the PP population followed by the ITT population.Mean (95% CI) differences in WOMAC pain change were 5.2 (0.9 to 9.6)mm and 4.5 (0.5 to 8.5)mm, respectively,favouring GO-ON, satisfying the claim for non-inferiority (lower limit>−9 mm) and for statistical superiority (95% CI all>0, p=0.021). Ahigher proportion of OARSI/OMERACT responders was observed with GO-ONthan with Hyalgan (73.3% vs58.4%, p=0.001). Both preparations were well tolerated. Conclusions Treatment with 3-weekly injections of intermediate MW HA may be superior to low MW HA on knee OA symptoms over 6 months, with similar safety.

OARSI Clinical Trials Recommendations: Hand imaging in clinical trials in osteoarthritis

Tremendous advances have occurred in our understanding of the pathogenesis of hand osteoarthritis (OA) and these are beginning to be applied to trials targeted at modification of the disease course. The purpose of this expert opinion, consensus driven exercise is to provide detail on how one might use and apply hand imaging assessments in disease modifying clinical trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for MRI); commonly encountered problems (including positioning, hardware and coil failures, sequences artifacts); quality assurance/control procedures; measurement methods; measurement performance (reliability, responsiveness, validity); recommendations for trials; and research recommendations.

Reproducibility and sensitivity to change of four scoring methods for the radiological assessment of osteoarthritis of the hand

Background: Osteoarthritis (OA) of the hand could be a relevant model to study the progression of OA in structure-modification trials. Various methods are proposed to assess hand OA and its progression radiologically. Objective: To compare intra-reader and inter-reader precision and sensitivity to change of four radiological scoring methods proposed in hand OA. Methods: 2 trained readers scored separately 105 pairs of radiographs (baseline; year 1), selected from patients enrolled in a randomised controlled trial, for inter-reader reliability and sensitivity to change. They scored twice 60 pairs among the 105 for cross-sectional and longitudinal intra-reader reliability. Radiological hand OA assessment used: global, Kellgren–Lawrence (KL), Kallman and Verbruggen scoring methods. Inter- and intra-reader reliabilities were studied using intraclass coefficient (ICC) and the Bland–Altman method. Sensitivity to change was compared by calculating the standardised response means. Results: Transversal intra-reader reproducibility ICCs ranged from 0.922 to 0.999. Verbruggen ranked the highest, followed by the KL and Kallman methods. Inter-rater reliability was higher for the Verbruggen scores, followed by the KL, global and Kallman scores (ICC 0.706–0.999). Longitudinal intra-reader reliability (baseline; year 1) was better using the Kallman and KL (ICC 0.986 and 0.990), followed by the Verbruggen (0.941) or global methods (0.939). Standardised response means ranged from 0.24 (KL) to 0.29 (Kallman). Conclusion: All four methods compared well with respect to reliabilities. However, the Verbruggen and Kallman methods performed better. The method most sensitive to change was the Kallman method, followed by Verbruggen and global scores. This study also suggests that structural changes could be detected in hand OA over a 1-year period.

Randomised, controlled trial of avocado–soybean unsaponifiable (Piascledine) effect on structure modification in hip osteoarthritis: the ERADIAS study

Objective To assess the ability of avocado–soybean unsaponifiable—Expanscience (ASU-E) to slow radiographic progression in symptomatic hip osteoarthritis (OA). Methods Prospective, randomised, double blind, parallel group, placebo controlled 3 year trial. Patients with symptomatic (painful ≥1 year, Lequesne Index between 3 and 10) hip OA (American College of Rheumatology criteria) and a minimum joint space width (JSW) of the target hip between 1 and 4 mm on a pelvic radiograph were randomly assigned to 300 mg/day ASU-E or placebo. Standing pelvis, target hip anteroposterior (AP) and oblique views were taken annually. The primary outcome was JSW change at year 3, measured at the narrowest point on pelvic or target hip AP view (manual measure using a 0.1 mm graduated magnifying glass). The full analysis dataset (FAS) included all patients having at least two successive radiographs. An analysis of covariance Mixed Model for Repeated Measurements with Missing at Random (for missing data) was performed to compare adjusted 3 year JSW changes (primary outcome) and the percentages of ‘progressors’ (JSW loss≥0.5 mm) between groups. Results 399 patients were randomised (345 kept in the FAS), aged 62 (35–84) years, 54% women, mean body mass index 27 (SD 4) kg/m2, mean symptom duration 4 (SD 5) years, 0–100 normalised Lequesne Index 30 (SD 9) and global pain visual analogue scale 37 (SD 23) mm. Mean baseline JSW was 2.8 (0.9) mm. There was no significant difference on mean JSW loss (−0.638 mm vs −0.672 mm, p=0.72, in the ASU-E and placebo groups, respectively) but there were 20% less progressors in the ASU-E than in the placebo group (40% vs 50%, respectively, p=0.040). No difference was observed on clinical outcomes. Safety was excellent. Conclusions 3 year treatment with ASU-E reduces the percentage of JSW progressors, indicating a potential structure modifying effect in hip OA to be confirmed, and the clinical relevance requires further assessment. Trial registration number on ClinicalTrial.gov NCT01062737

Clinical and radiological evaluation of hip, knee and hand osteoarthritis

Evaluation of hip, knee and hand osteoarthritis (OA) involves clinical and radiological outcome measures. Clinical, mainly visual analog scale (VAS) for pain, algofunctional or Lequesne’s indices for hip and knee OA, Western Ontario and Mac Master Universities OA Index (WOMAC) for hip and knee OA, Dreiser’s functional index for hand OA and some quality-of-life (QoL) indices are presented and discussed. Their utility is considered according to various uses: assessment of OA severity and course in therapeutic trials, in daily practice, as a help for surgical decision, and with regard to QoL as instruments for establishing the place of OA among differing chronic rheumatic conditions. Radiological assessment methods, especially for potential structure-modifying drug trials, mainly involve either manual measurement of joint space narrowing on radiographs over a period of several years, or measurement on X-ray digitized images. Last but not least, to conclude this review, we propose a selection of the most rapid and practical instruments allowing OA assessment in daily practice, with appropriate comments.

Efficacy and safety of hyaluronic acid in the management of osteoarthritis: Evidence from real-life setting trials and surveys

The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm recommends intra-articular (IA) hyaluronic acid (HA) for management of knee osteoarthritis (OA) as second-line treatment in patients who remain symptomatic despite use of non-steroidal anti-inflammatory drugs (NSAIDs). This recommendation is based upon accumulating evidence that IA HA provides a significant benefit in knee OA. There is good evidence that IA HA injections reduce pain and increase function in knee OA, and the benefits are long-lasting as compared with IA corticosteroids. Evidence from real-life studies of repeat courses of IA HA demonstrates an improvement in pain or function lasting up to 40 months (12 months after the last injection cycle), a reduction in use of concomitant analgesia by up to 50%, and suggests that there may be a delay in the need for total knee replacement (TKR) of around 2 years. The clinical benefit of IA HA on knee OA may be 2-fold: (i) mechanical viscosupplementation of the joint (allowing lubrication and shock absorption) and (ii) the re-establishment of joint homeostasis through induction of endogenous HA production, which continues long after the exogenous injection has left the joint. The magnitude of the clinical effect may be different for different HA products, but this has not been proven so far and requires further investigation. IA HA injections are generally considered to be safe, although a slightly higher number of cases of local reactions and post-injection non-septic arthritis has been reported with high molecular weight cross-linked HAs. The use of IA HA in knee OA patients with mild-moderate disease, and for more severe patients wishing to delay TKR surgery, is recommended by the ESCEO task force. Further investigation into the OA patient types most likely to benefit from IA HA is warranted. Viscosupplementation with IA HA is a safe and effective component of the multi-modal management of knee OA.

Recommendations for an update of the 2010 European regulatory guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis and reflections about related clinically relevant outcomes: expert consensus statement.

OBJECTIVE The European Society on Clinical and Economic aspects of Osteoporosis and Osteoarthritis (ESCEO) organised a working group to evaluate the need for updating the current European guideline on clinical investigation of drugs used in the treatment of osteoarthritis (OA). DESIGN Areas of potential attention were identified and the need for modifications, update or clarification was examined. Proposals were then developed based on literature reviews and through a consensus process. RESULTS It was agreed that the current guideline overall still reflects the current knowledge in OA, although two possible modifications were identified. The first relates to the number and timing of measurements required as primary endpoints during clinical trials of symptom-relieving drugs, either drugs with rapid onset of action or slow acting drugs. The suggested modifications are intended to take into consideration the time related clinical need and expected time response to these drugs - i.e., a more early effect for the first category in addition to the maintenance of effect, a more continuous benefit over the long-term for the latter - in the timing of assessments. Secondly, values above which a benefit over placebo should be considered clinically relevant were considered. Based on literature reviews, the most consensual values were determined for primary endpoints of both symptom-relieving drugs (i.e., pain intensity on a visual analogue scale (VAS)) and disease-modifying drugs (i.e., radiographic joint-space narrowing). CONCLUSIONS This working document might be considered by the European regulatory authorities in a future update of the guideline for the registration of drugs in OA.

OARSI Clinical Trials Recommendations for Hip Imaging in Osteoarthritis

Imaging of hip in osteoarthritis (OA) has seen considerable progress in the past decade, with the introduction of new techniques that may be more sensitive to structural disease changes. The purpose of this expert opinion, consensus driven recommendation is to provide detail on how to apply hip imaging in disease modifying clinical trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, artifacts associated with various MRI sequences); quality assurance/control procedures; measurement methods; measurement performance (reliability, responsiveness, and validity); recommendations for trials; and research recommendations.

Assessment and determinants of aesthetic discomfort in hand osteoarthritis

Background Dissatisfaction with hand appearance is frequently the presenting complaint of patients with hand osteoarthritis (HOA), yet no tool exists for its measurement and few studies have examined aesthetic discomfort. Objectives The aims of this study were to measure the extent and to explore the associations of aesthetic concerns in HOA. Methods 172 patients with HOA were assessed with tender joint and node count, global and pain scores, Functional Index for Hand Osteoarthritis, Short Form-12, Hospital Anxiety and Depression Scale and posterior–anterior hand radiographs. Patients scored the aesthetic impact of the disease on a Visual Analogue Scale of 0–100 mm and were classifi ed into low, intermediate and high aesthetic concern (HAC) based on this score. Results Of 172 patients (155 women), the majority (92%) had nodes and 46% had erosive disease. The mean aesthetic score was 44.8 mm (SD 35.9), and 59 (34.3%) patients scored their aesthetic discomfort ≥66 mm. Factors associated with HAC were female gender, a high number of tender joints and nodes, high global and pain scores, high radiological damage scores, the presence of erosions and high depression and anxiety levels. The multivariate analysis identifi ed two independent factors associated with HAC: patient’s global assessment (p=0.0005) and radiographic erosions (p=0.03). Conclusions Aesthetic discomfort is a major concern for a signifi cant number of patients with HOA, particularly women, those with a high burden of HOA disease and those with erosive osteoarthritis, and is also associated with depression, anxiety and poor health-related quality of life.