Olivier Benichou

A Phase II Randomized Study of Subcutaneous Ixekizumab, an Anti–Interleukin‐17 Monoclonal Antibody, in Rheumatoid Arthritis Patients Who Were Naive to Biologic Agents or Had an Inadequate Response to Tumor Necrosis Factor Inhibitors

To evaluate ixekizumab, an anti–interleukin‐17A (anti–IL‐17A) monoclonal antibody, in 2 populations of rheumatoid arthritis (RA) patients: biologics‐naive patients and patients with an inadequate response to tumor necrosis factor (TNF) inhibitors.

Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial

BACKGROUND Myostatin inhibits skeletal muscle growth. The humanised monoclonal antibody LY2495655 (LY) binds and neutralises myostatin. We aimed to test whether LY increases appendicular lean body mass (aLBM) and improves physical performance in older individuals who have had recent falls and low muscle strength and power. METHODS In this proof-of-concept, randomised, placebo-controlled, double-blind, parallel, multicentre, phase 2 study, we recruited patients aged 75 years or older who had fallen in the past year from 21 investigator sites across Argentina, Australia, France, Germany, Sweden, and the USA. Eligible patients had low performance on hand grip strength and chair rise tests, tested with the procedure described by Guralnik and colleagues. Participants were stratified by country, age, hand grip strength, and performance on the chair rise test, and were randomly assigned (1:1) by a computer-generated random sequence to receive subcutaneous injections of placebo or 315 mg LY at weeks 0 (randomisation visit), 4, 8, 12, 16, and 20, followed by 16 weeks observation. The primary outcome was change in aLBM from baseline to 24 weeks. We measured physical performance as secondary outcomes (four-step stair climbing time, usual gait speed, and time to rise five times from a chair without arms, or with arms for participants unable to do it without arms) and exploratory outcomes (12-step stair climbing test, 6-min walking distance, fast gait speed, hand grip strength, and isometric leg extension strength). Efficacy analyses included all randomly assigned patients who received at least one dose and had a baseline and at least one subsequent measure. The primary analysis and all other tests of treatment effect (except physical performance tests) were done at a two-sided alpha level of 0·05. Tests of treatment effect on physical performance tests were done at a pre-specified two-sided alpha level of 0·1. This trial is registered with ClinicalTrials.gov, number NCT01604408. FINDINGS Between June 19, 2012, and Dec 12, 2013, we screened 365 patients. 99 were randomly assigned to receive placebo and 102 to receive LY. Treatment was completed in 85 (86%) of patients given placebo and in 82 (80%) given LY. At 24 weeks, the least-squares mean change in aLBM was -0·123 kg (95% CI -0·287 to 0·040) in the placebo group and 0·303 kg (0·135 to 0·470) in the LY group, a difference of 0·43 kg (95% CI 0·192 to 0·660; p<0·0001). Stair climbing time (four-step and 12-step tests), chair rise with arms, and fast gait speed improved significantly from baseline to week 24 with differences between LY and placebo of respectively -0·46 s (p=0·093), -1·28 s (p=0·011), -4·15 s (p=0·054), and 0·05 m/s (p=0·088). No effect was detected for other performance-based measures. Injection site reactions were recorded in nine (9%) patients given placebo and in 31 (30%) patients given LY (p<0·0001), and were generally mild, and led to treatment discontinuation in two patients given LY. INTERPRETATION Our findings show LY treatment increases lean mass and might improve functional measures of muscle power. Although additional studies are needed to confirm these results, our data suggest LY should be tested for its potential ability to reduce the risk of falls or physical dependency in older weak fallers. FUNDING Eli Lilly and Company.

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

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

Magnetic resonance imaging-based cartilage loss in painful contralateral knees with and without radiographic joint space narrowing: Data from the osteoarthritis initiative

OBJECTIVE To determine by magnetic resonance imaging (MRI), whether knees with advanced radiographic disease (medial joint space narrowing [mJSN]) encounter greater longitudinal cartilage loss than contralateral knees with earlier disease (no or less mJSN). METHODS Participants were selected from 2,678 cases in the Osteoarthritis Initiative, based on exhibition of bilateral pain, body mass index >25 (kg/m(2)), mJSN in 1 knee, no or less mJSN in the contralateral knee, and no lateral JSN in both knees. Eighty participants (mean +/- SD age 60.6 +/- 9.1 years) fulfilled these criteria. Medial tibial and femoral cartilage morphology was analyzed from the baseline and the 1-year followup MRI (sagittal double echo at steady state by 3.0T) of both knees by experienced readers blinded to the time point and mJSN status. RESULTS Knees with more radiographic mJSN displayed greater medial cartilage loss (-80 mum) assessed by MRI than contralateral knees with less mJSN (-57 mum). The difference reached statistical significance in participants with an mJSN grade of 2 or 3 (P = 0.005-0.08), but not in participants with an mJSN grade of 1 (P = 0.28-0.98). In knees with more mJSN, cartilage loss increased with higher grades of mJSN (P = 0.003 in the medial femur). Knees with an mJSN grade of 2 or 3 displayed greater cartilage loss in the weight-bearing medial femur than in the posterior femur or in the medial tibia (P = 0.048). CONCLUSION Knees with advanced mJSN displayed greater cartilage loss than contralateral knees with less mJSN. These data suggest that radiography can be used to stratify fast structural progressors, and that MRI cartilage thickness loss is more pronounced at advanced radiographic disease stage.

Tabalumab, an anti-BAFF monoclonal antibody, in patients with active rheumatoid arthritis with an inadequate response to TNF inhibitors

Objective To evaluate the efficacy and safety of tabalumab, a monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with active rheumatoid arthritis (RA) who showed inadequate response to tumour necrosis factor (TNF) inhibitors. Methods Patients on stable methotrexate and with inadequate response to one or more TNF inhibitors were randomised to placebo (n=35), 30 mg tabalumab (n=35) or 80 mg tabalumab (n=30) given intravenously at 0, 3 and 6 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology 50% response (ACR50) at week 16 (all tabalumab-treated patients vs placebo). Results At week 16, no significant differences were observed in the combined tabalumab group versus placebo in ACR50 (12.7% vs 2.9%, p=0.101) or ACR20 response rates (27.0% vs 17.1%, p=0.198). However, significant differences between the combined tabalumab group and placebo were observed at earlier time points for ACR20, ACR50 and Disease Activity Score in 28 joints (DAS28)-C-reactive protein (CRP) reduction. Treatment-emergent adverse events (AEs) were similar with 30 mg tabalumab (65.7%), 80 mg tabalumab (76.7%) and placebo (71.4%), although certain events occurred more often with tabalumab than placebo (eg, infection, anaemia and gastrointestinal events). Serious AEs occurred in two (6.7%) patients receiving 80 mg tabalumab and three (8.6%) receiving placebo, with one serious infection in the placebo group. Initial increases in total and mature B cells were followed by progressive decreases, despite declines in serum tabalumab. Conclusions At week 16, the primary end point was not achieved, but an indication of efficacy was observed at earlier time points. Safety findings for tabalumab were consistent with other biological RA therapies. Clinical trial registration number NCT00689728.

Rates of change and sensitivity to change in cartilage morphology in healthy knees and in knees with mild, moderate, and end-stage radiographic osteoarthritis: results from 831 participants from the Osteoarthritis Initiative.

To study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (OA), specifically healthy knees and knees with end‐stage radiographic OA.

Magnitude and regional distribution of cartilage loss associated with grades of joint space narrowing in radiographic osteoarthritis – data from the Osteoarthritis Initiative (OAI)

OBJECTIVE Clinically, radiographic joint space narrowing (JSN) is regarded a surrogate of cartilage loss in osteoarthritis (OA). Using magnetic resonance imaging (MRI), we explored the magnitude and regional distribution of differences in cartilage thickness and subchondral bone area associated with specific Osteoarthritis Research Society International (OARSI) JSN grades. METHOD Seventy-three participants with unilateral medial JSN were selected from the first half (2678 cases) of the OA Initiative cohort (45, 21, and 7 with OARSI JSN grades 1, 2, and 3, respectively, no medial JSN in the contra-lateral knee). Bilateral sagittal baseline DESSwe MRIs were segmented by experienced operators. Intra-person between-knee differences in cartilage thickness and subchondral bone areas were determined in medial femorotibial subregions. RESULTS Knees with medial OARSI JSN grades 1, 2, and 3 displayed a 190 microm (5.2%), 630 microm (18%), and 1560 microm (44%) smaller cartilage thickness in weight-bearing medial femorotibial compartments compared to knees without JSN, respectively. The weight-bearing femoral condyle displayed relatively greater differences than the posterior femoral condyle or the medial tibia (MT). The central subregion within the weight-bearing medial femur (cMF) of the femoral condyle (30-75 degrees ), and the external and central subregions within the tibia displayed relatively greater JSN-associated differences compared to other medial femorotibial subregions. Knees with higher JSN grades also displayed larger than contra-lateral femorotibial subchondral bone areas. CONCLUSIONS This study provides quantitative estimates of JSN-related cartilage loss, with the central part of the weight-bearing femoral condyle being most strongly affected. Knees with higher JSN grades displayed larger subchondral bone areas, suggesting that an increase in subchondral bone area occurs in advanced OA.

Different thresholds for detecting osteophytes and joint space narrowing exist between the site investigators and the centralized reader in a multicenter knee osteoarthritis study—data from the Osteoarthritis Initiative

ObjectiveTo evaluate how the reading of knee radiographs by site investigators differs from that by an expert musculoskeletal radiologist who trained and validated them in a multicenter knee osteoarthritis (OA) study.Materials and methodsA subset of participants from the Osteoarthritis Initiative progression cohort was studied. Osteophytes and joint space narrowing (JSN) were evaluated using Kellgren-Lawrence (KL) and Osteoarthritis Research Society International (OARSI) grading. Radiographs were read by site investigators, who received training and validation of their competence by an expert musculoskeletal radiologist. Radiographs were re-read by this radiologist, who acted as a central reader. For KL and OARSI grading of osteophytes, discrepancies between two readings were adjudicated by another expert reader.ResultsRadiographs from 96 subjects (49 women) and 192 knees (138 KL grade ≥ 2) were included. The site reading showed moderate agreement for KL grading overall (kappa = 0.52) and for KL ≥ 2 (i.e., radiographic diagnosis of “definite OA”; kappa = 0.41). For OARSI grading, the site reading showed substantial agreement for lateral and medial JSN (kappa = 0.65 and 0.71), but only fair agreement for osteophytes (kappa = 0.37). For KL grading, the adjudicator’s reading showed substantial agreement with the centralized reading (kappa = 0.62), but only slight agreement with the site reading (kappa = 0.10).ConclusionSite investigators over-graded osteophytes compared to the central reader and the adjudicator. Different thresholds for scoring of JSN exist even between experts. Our results suggest that research studies using radiographic grading of OA should use a centralized reader for all grading.

A phase 2 dose-ranging study of subcutaneous tabalumab for the treatment of patients with active rheumatoid arthritis and an inadequate response to methotrexate

Objectives To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX). Methods In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ≥50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified α=0.10). Results At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50–69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only. Conclusions A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. Clinical Trial # NCT00785928.

Femorotibial subchondral bone area and regional cartilage thickness: a cross-sectional description in healthy reference cases and various radiographic stages of osteoarthritis in 1,003 knees from the Osteoarthritis Initiative.

To identify structural differences in total subchondral bone area (tAB) and cartilage thickness between healthy reference knees and knees with radiographic osteoarthritis (OA).