In osteoarthritis (OA) treatment, although chondroitin sulfate (CS) was found in a number of studies using radiography to have a structure modifying effect, to date the question is still under debate. A clinical study using quantitative magnetic resonance imaging (qMRI) is therefore of the utmost importance.
Objectives
The present study has the objective to explore, as the first aim, in a two-year randomized, controlled double-blind clinical study using qMRI, the disease modifying effect of CS treatment versus celecoxib (CE) on cartilage volume loss (CVL) in knee OA. The second aim was to investigate and compare the effect of CS and CE on symptoms.
Methods
Symptomatic primary knee OA patients according to ACR criteria with Kellgren-Lawrence grades 2–3 and synovitis were included and treated with CS (1200 mg a day) or CE (200 mg once daily) for 24 months. Patients at high risk for cardiovascular and/or gastrointestinal disease were not included. MRI was performed at baseline, 12 and 24 months. CVL, bone marrow lesion (BML) size, and synovial membrane thickness were evaluated using qMRI, and presence of joint swelling and effusion clinically evaluated. Clinical symptoms were also assessed by validated questionnaires.
Results
In the intention-to-treat analysis (n=194), patients treated with CS had reduced CVL at 24 months in the medial compartment (p=0.026) and condyle (p=0.008) compared to celecoxib. In the completer analysis, CS reduced CVL in the medial compartment at 12 months (p=0.026) and medial compartment and condyle at 24 months (p=0.030, p=0.010). A trend toward a reduced (p=0.070) synovial thickness in the medial suprapatellar bursa was observed in CS patients. Both treatment groups experienced a marked reduction in incidence of patients with joint swelling/effusion and in symptoms (WOMAC total, pain, and function, and VAS pain) over time. Data showed similar good safety profiles for both drug treatments.
Conclusions
This trial demonstrated, for the first time, the superiority of CS over CE at reducing the long term progression of knee OA structural changes. Moreover, both drugs were found equally effective at reducing the symptoms of OA. These findings have important implications regarding the usefulness of CS for long term management of knee OA and its impact on disease outcome.
Disclosure of Interest
J. P. Pelletier Shareholder of: Arthrolab Inc., Grant/research support from: Bioiberica, Consultant for: Bioiberica, Speakers bureau: Bioiberica, J. P. Raynauld: None declared, A. Beaulieu: None declared, L. Bessette: None declared, F. Morin: None declared, A. J. Brum-Fernandes: None declared, F. Abram: None declared, M. Dorais: None declared, J. Martel-Pelletier Shareholder of: Arthrolab Inc., Grant/research support from: Bioiberica, Consultant for: Bioiberica
The guidelines from the regulatory agencies require that joint structure modification also translate into a significant clinical benefit for the patient before allowing the claim of DMOAD (1). To this end, the prevention of patient disability and of the need for joint replacement has been suggested as possible clinically relevant outcomes (2).
Objectives
To predict from clinical trial and MRI data the incidence of total knee replacement (TKR) during the long-term follow-up of knee osteoarthritis (OA) patients who formerly received chondroitin sulfate (CS) or placebo.
Methods
Symptomatic knee OA patients participating in a previous 6-month randomized, double-blind controlled trial evaluating the impact of CS (Condrosan®, Bioibérica S.A., Barcelona, Spain) (800 mg/day) vs. placebo, with subsequent 6-month extension with all patients on CS, were contacted to evaluate retrospectively the incidence of TKR of the study knee. A sub-group of patients (n=51) belonging to the according-to-protocol cohort were selected for this post-hoc retrospective analysis. The TKR incidence was assessed with a standardized phone interview.
Results
The patients' mean age was 62.9 years, 61% were female and the average body mass index was 30.6 kg$/$m2. A total of 13.7% TKRs were performed upon this sub-population in the time frame of 4 years after patient enrolment. More TKRs were performed within the placebo (71%) than the CS group (29%) (p=0.150, logistic regression). The baseline values of WOMAC pain (p=0.019, logistic regression), stiffness (p=0.013) and function (p=0.044), bone marrow lesions of the medial compartment (p=0.030), and C-reactive protein (CRP) levels (p=0.040) were strong predictors of TKR. Changes at 1 year in the medial cartilage volume (p=0.046) also predicted the occurrence of TKR.
Conclusions
In a knee OA clinical trial, it is possible to predict a "hard" outcome such as TKR using information from clinical and MRI data. The results also support the use of MRI as a surrogate for joint tissue damage upon which a DMOAD such as CS may act.
References
Guidance for the Industry. Clinical Development Programs for Drugs, Devices and Biological Products Intended for the Treatment Osteoarthritis. US Department of Health and Human Services. Food and Drug Administration, Center for Drug Evaluation and Research, July 1999. Altman RD et al. Osteoarthritis Cartilage 2005;13:13-9.
To conduct the first Canadian study of the comparative efficacy and safety of nabumetone and diclofenac SR in patients with primary osteoarthritis (OA) of the hip, knee and shoulder.Nabumetone 1000-1500 mg po daily was compared to diclofenac SR 100-150 mg po daily in a 6-month, double blind, randomized, controlled, multicenter, parallel trial. Initial starting doses were nabumetone 1000 mg daily and diclofenac SR 100 mg daily, with optional subsequent one-level dose titration permitted after 2 weeks on lower dose up to 1500 mg nabumetone and 150 mg diclofenac SR. The primary outcome measures were overall pain and disease activity as assessed by physician and patient. Secondary efficacy measures included tenderness, swelling, limitation of motion, duration of morning stiffness, acetaminophen consumption, physician and patient global assessment, and patient evaluation of efficacy and tolerability. Following an initial screening visit and a 2 to 7 day nonsteroidal antiinflammatory drug free washout period (i.e., randomization), patients were assessed at Weeks 2, 8, 14, 20, and 26.In all, 382 patients [nabumetone (n = 192), diclofenac SR (n = 190)] participated in the trial. Improvement in all efficacy variables was noted, but there was no statistically significant difference between drugs. Significantly fewer (p = 0.01) patients reported upper gastrointestinal (GI) adverse experiences in the nabumetone group. Significantly fewer (p < 0.04) patients withdrew from the study for adverse experiences in the nabumetone (14%) than the diclofenac SR (23%) group, particularly from upper abdominal pain (p < 0.04) and dyspepsia (p = 0.02). Three patients treated with diclofenac SR and none with nabumetone developed upper GI ulcers or bleeds. The number of patients experiencing clinically important elevations in transaminases (p < 0.04) or BUN/creatinine (p < 0.03) was significantly lower in the nabumetone group.Nabumetone is efficacious and well tolerated in patients with OA of the hip, knee or shoulder. In this group of patients it was similar in efficacy and superior in tolerability to diclofenac SR.
New agents with novel mechanisms of action are needed to treat the growing pool of patients with psoriatic arthritis (PsA) who do not respond to, lose response to, or do not tolerate biologics. Patients with PsA who fail one tumor necrosis factor inhibitor (TNFi) often demonstrate reduced treatment response to subsequent TNFi9s.
Objectives
To compare the long-term efficacy at weeks 12, 24, and 52 and safety of brodalumab in biologic-naïve vs. biologic-experienced patients with PsA.
Methods
Patients between 18 – 75 years with active PsA (Classification of Psoriatic Arthritis criteria with ≥3 tender and ≥3 swollen joints) for ≥6 months were randomly assigned (1:1:1) to receive double-blind placebo or brodalumab (140 or 280 mg Q2W); at week 12, patients could enter an open-label extension to receive 280 mg Q2W brodalumab. As observed American College of Rheumatology (ACR) response rates, and changes from baseline in Disease Activity Score (28 joint count C-reactive Protein [DAS28CRP]) and enthesitis and dactylitis counts were analyzed.
Results
A total of 168 patients were randomized (naïve N=82; experienced N=86); 156 entered the open-label phase. Patients were similar in baseline demographics, disease characteristics, and mean baseline doses of methotrexate (19 vs. 18 mg/wk), although PsA duration was slightly less in the naïve group (7 vs. 10 years). Approximately 97% of the experienced patients had used a TNFi; based on medication history, 54% were primary failures, 6% secondary failures, while the rest discontinued due to intolerance (10%) or other non-specified reasons (30%). ACR response rates were comparable between naïve and experienced patients at weeks 12, 24, and 52 (Table). The groups were also comparable in mean change from baseline in DAS28-CRP, enthesitis, and dactylitis. There was no difference in tolerability of brodalumab between the groups, with 91% (n/N=71/78) of both naïve and experienced patients reporting an adverse event, and 9% (n/N=7/78) and 4% (n/N=3/78) of patients experiencing a serious adverse event in the open-label phase.
Conclusions
Prior exposure to a biologic does not seem to affect the efficacy or tolerability of brodalumab over one year in the treatment of PsA.
The objective of this study was to evaluate the effects of dietary inclusion of hydrothermal, phytase, and organic acid pretreated canola meal (CM) on nutrient digestibility in swine. A basal diet barley, wheat, and CM based, was formulated. Four diets containing 30% hydrothermal pretreated CM with 50% moisture and 40°C, phytase (1000 FTU/kg activity), and either citric acid (CA), malic acid (MA), or lactic acid (LA), and a control containing pretreated CM without phytase or organic acid were fed to 12 ileal-cannulated finisher pigs (initial average BW 105.3 ± 2.7 kg) in a completely randomized design over two periods of 9 days per period. Nutrient composition and phytate content of the diets, ileal digesta, and feces were analyzed and apparent ileal and total tract digestibilities were determined. The inclusion of hydrothermal, phytase, and CA or MA pretreated CM in the diet decreased phytate P (by up to 38.6%) (p < 0.05), consequently increasing available P (by up to 55.6%). Apparent ileal digestibility (AID) was improved for P by 19.9 ‒ 35.1% units and apparent total tract digestibility of DM by 10.3 ‒ 14.8% units, of protein by 6.6 ‒ 12.1% units, and of gross energy by 12 ‒ 17% units across the treatments (p < 0.05), while AID of CP for MA treatment was up by 4.7% units (p < 0.05) relative to the control, indicating improved diet utilization, thus reduced excretion to the environment.
Four experiments were conducted to determine the nutritional value of flaxseed meal [FSM; 133 g of ether extract (EE) and 343 g of CP/kg of DM] for swine. In Exp. 1, apparent fecal digestibility (AD) of DM and EE, and the DE and NE contents were determined in growing pigs (n = 32; initial BW, 70 +/- 3 kg) and gestating sows (n = 24; parities, 2 to 4). Diets contained 0, 100, 200, or 300 g of FSM/kg at the expense of wheat, barley, and soybean meal. Fecal samples were collected for 3 d after a 9-d adaptation. The AD for DM and EE were 72.0 +/- 0.4% and 67.4 +/- 4.7%, respectively, for growing pigs and 68.0 +/- 0.5% and 48.9 +/- 1.9% for sows. The DE content was 3.51 and 3.54 Mcal/kg for growing pigs and gestating sows, and NE was estimated to be 2.43 and 2.44 Mcal/kg for growing pigs and sows, respectively. Five ileally cannulated barrows (initial BW, 38 +/- 3 kg) were fed semi-synthetic diets containing 400 g of FSM/kg for a 7-d period (4-d adaptation and 3-d collection) then 7 d of N-free diet to determine basal endogenous N losses in Exp. 2. Standardized ileal digestible AA contents were 29.6 +/- 1.0, 5.7 +/- 0.3, 12.1 +/- 0.8, 16.8 +/- 1.0, 10.3 +/- 0.4, 5.3 +/- 0.3, 14.0 +/- 0.7, 9.4 +/- 0.5, 2.9 +/- 0.2, and 13.8 +/- 0.8 g/kg of dry FSM for Arg, His, Ile, Leu, Lys, Met, Phe, Thr, Trp, and Val, respectively. In Exp. 3, the AD of P and the effects of phytase inclusion on P availability were determined. Five groups of 8 barrows (initial BW, 45 +/- 4 kg) were fed a 300 g of FSM/kg semi-synthetic diet with increasing concentrations of exogenous phytase [0, 575, 1,185, 2,400 and 2,570 phytase units (FTU)/kg]. The AD of P increased from 21 to 61% (P < 0.001). Broken-line analysis estimated the optimal phytase inclusion rate to be 1,415 FTU/kg of diet. Growth performance and carcass fatty acid (FA) profiles of pigs fed FSM were determined in Exp. 4. Two hundred pigs (100 barrows and 100 gilts; initial BW, 32 +/- 4 kg), blocked by sex, were housed in groups of 5 pigs per pen and fed 1 of 4 diets containing 0, 50, 100, or 150 g of FSM/kg. Six market pigs per diet were selected for carcass FA analysis. The ADG, ADFI, and G:F were not affected by dietary FSM (P > 0.05). Increasing FSM in the diet from 0 to 150 g of FSM/kg increased the alpha-linolenic acid content from 11.1 +/- 0.2 to 47.4 +/- 1.2 mg/g of backfat (P < 0.001) and from 5.0 +/- 0.1 to 10.1 +/- 0.6 mg/g of loin tissue (P < 0.001). Flaxseed meal despite its deficiency in lysine can be included up to 150 g/kg of diets for swine and will contribute to the enrichment of the carcass with n-3 fatty acids.
