Marc Dorais

Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis patients starting as early as 6 months after initiation of therapy: a randomised, double-blind, placebo-controlled pilot study using MRI

Objective To determine the effect of chondroitin sulphate (CS) treatment on cartilage volume loss, subchondral bone marrow lesions (BML), synovitis and disease symptoms in patients with knee osteoarthritis (OA). Methods In this pilot multicentre, randomised, double-blind, controlled trial in primary knee OA, 69 patients with clinical signs of synovitis were randomised to receive CS 800 mg or placebo once daily for 6 months followed by an open-label phase of 6 months in which patients in both groups received CS 800 mg once daily. Cartilage volume and BML were assessed by MRI at baseline and at 6 and 12 months; synovial membrane thickness was assessed at baseline and at 6 months. Results The CS group showed significantly less cartilage volume loss than the placebo group as early as 6 months for the global knee (p=0.030), lateral compartment (p=0.015) and tibial plateaus (p=0.002), with significance persisting at 12 months. Significantly lower BML scores were found for the CS group at 12 months in the lateral compartment (p=0.035) and the lateral femoral condyle (p=0.044). Disease symptoms were similar between the two groups. Conclusion CS treatment significantly reduced the cartilage volume loss in knee OA starting at 6 months of treatment, and BML at 12 months. These findings suggest a joint structure protective effect of CS and provide new in vivo information on its mode of action in knee OA.

Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI

Objective: In a multicentre study to explore the effects of licofelone as a disease-modifying osteoarthritis drug in comparison with naproxen in patients with knee osteoarthritis (OA), using MRI and x-ray examination. Methods: Patients with knee OA (n = 355) were randomised to receive either licofelone (200 mg twice a day) or naproxen (500 mg twice a day). MRI and x-ray examinations were performed at baseline, 6 months (MRI only), 12 and 24 months. MRI was used to assess quantitatively changes in cartilage volume, and x-ray examinations (Lyon–Schuss) to measure changes in the mean and minimum joint space width (JSW) in the medial compartment. Questionnaires probing symptoms were completed. Data were presented as intention to treat (ITT) and according to protocol (ATP). Results: Cartilage volume loss in the global joint and medial and lateral compartments was significantly less in the licofelone than in the naproxen group for ITT at 12 and 24 months and for ATP at all times except in the medial compartment. Patients with medial meniscal extrusion had a greater loss of cartilage volume. In these patients, licofelone markedly reduced the cartilage loss for both ITT and ATP at 12 and 24 months. Although licofelone showed less reduction in the JSW than naproxen, this did not reach significance. All clinical variables were improved at 24 months (p<0.001) for both groups, with a good safety profile. Conclusion: Licofelone and naproxen were equally effective in reducing OA symptoms; however, licofelone significantly reduced cartilage volume loss over time, thus having a protective effect in patients with knee OA. This study proves the superiority of quantitative MRI over x-ray examinations in a multicentre clinical trial.

Risk factors predictive of joint replacement in a 2-year multicentre clinical trial in knee osteoarthritis using MRI: results from over 6 years of observation

Objective To identify predictive factors for total knee replacement (TKR) using data from MRI of knee osteoarthritis patients in a phase III multicentre disease-modifying osteoarthritis drug (DMOAD) study. Methods Knee osteoarthritis patients from a 2-year clinical trial evaluating licofelone versus naproxen were investigated for the incidence of TKR of the study knee. Patients (n=161) who completed the study according to protocol were selected. Incidence of TKR was assessed blindly to the treatment following telephone interviews (n=123). Results 18 TKR (14.6%) were performed in 4–7 years following enrolment in the original study. More TKR were performed within the naproxen than the licofelone group (61% vs 39%, p=0.232). Baseline score of bone marrow lesions (BML) in the medial compartment (p=0.0001), medial joint space width (JSW) as assessed by standardised radiographs (p=0.0008), presence of severe medial meniscal tear (p=0.004), medial meniscal extrusion (p=0.013), and C-reactive protein level (p=0.049) were strong predictors of TKR. Changes at the end of the study also yielded strong predictors: change in cartilage volume of the medial compartment (p=0.005) and of the global knee (p=0.034), reduction in the JSW of greater than 7% (p=0.009), and WOMAC pain (p=0.009) and function (p=0.023) scores. Multivariate analysis showed that baseline severe medial meniscal tear (p=0.023) and presence of medial BML (p=0.025) were the strongest independent long-term predictors of TKR. Conclusion This study shows that in the context of osteoarthritis trials, clinical data and structural changes identified by MRI allow prediction of a ‘hard’ outcome such as TKR. The findings support the usefulness and predictive value of MRI in defining study outcome in DMOAD trials.

Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis

Objectives To explore the impact of disease-modifying osteoarthritis drug (DMOAD) treatment on biomarker levels and their correlation with cartilage volume loss and disease symptoms in a 2-year phase III clinical trial in patients with knee OA. Methods 161 patients with knee OA (according-to-protocol population) were selected from a 2-year DMOAD trial studying the effect of licofelone (200 mg twice daily) versus naproxen (500 mg twice daily). Clinical evaluation of patients was carried out using the Western Ontario and McMaster Universities (WOMAC) questionnaire. Biomarker measurements of matrix metalloproteinase (MMP)-1, MMP-3, interleukin (IL)-6, C reactive protein (CRP), cartilage oligomeric matrix protein (COMP) and type I collagen C-terminal telopeptide (CTX-I) in serum, type II collagen C-terminal telopeptide (CTX-II) in urine, and knee MRI were performed at baseline and 2 years. Results Over time an increase occurred in all biomarker levels with the exception of IL-6, CRP and CTX-II which decreased. The increase in MMP-1 and MMP-3 was significantly less (p=0.05; p<0.01, respectively) in the licofelone group. The baseline MMP-1 level was significantly but inversely predictive of cartilage volume loss for the medial compartment in both univariate (p=0.04) and multivariate (p≤0.04) regression analyses, and COMP, a predictor for the lateral compartment, in both univariate and multivariate models (p<0.01). Baseline levels of IL-6 and CRP also showed a significant relationship with volume loss for the medial compartment (univariate analysis, p=0.04 and p=0.01, respectively; multivariate analysis, p=0.03, p=0.01). A significant association (univariate) was observed between the change in the levels of MMP-1 (p=0.03) and MMP-3 (p=0.02) and cartilage volume loss (lateral compartment) over 2 years. Baseline levels of CTX-I correlated (p=0.02) with an increase in the size of the bone marrow lesion in the medial compartment. The baseline CRP levels correlated with worsening of symptoms: WOMAC total index (p<0.01), pain (p<0.01) and function (p<0.01). Conclusion Higher baseline values of IL-6, CRP and COMP are predictive of greater risk of cartilage loss in OA. However, over time a reduction in MMP-1 and MMP-3 levels correlated best with reduction in cartilage volume loss and the effect of drug treatment. Baseline CRP was found to be a good predictor of the symptomatic response to treatment.

Disease-modifying effect of strontium ranelate in a subset of patients from the Phase III knee osteoarthritis study SEKOIA using quantitative MRI: reduction in bone marrow lesions protects against cartilage loss

Objective To explore, using MRI, the disease-modifying effect of strontium ranelate (SrRan) treatment on cartilage volume loss (CVL) and bone marrow lesions (BMLs) in a subset of patients from a Phase III clinical trial in knee osteoarthritis (OA) (SrRan Efficacy in Knee OsteoarthrItis triAl (SEKOIA)). Material and methods Patients with primary symptomatic knee OA were randomised to receive either SrRan 1 g/day or 2 g/day or placebo (SEKOIA study). A subset of these patients had MRIs at baseline, 12, 24 and 36 months to assess the knee cartilage volume and BMLs. Missing values were imputed and the analyses were adjusted according to Bonferroni. Results In this MRI subset, the distribution of patients (modified intention-to-treat; n=330) was 113, 105 and 112 for SrRan 1 g/day, 2 g/day and placebo, respectively. The groups were fairly balanced at baseline regarding demographics, clinical symptoms or imaging characteristics. Treatment with SrRan 2 g/day significantly decreased CVL on the plateaus at 12 (p=0.002) and 36 (p=0.003) months compared with placebo. Of note, in the medial femur and plateau, SrRan 1 g/day, but not SrRan 2 g/day, had more CVL than placebo. In patients with BML in the medial compartment at baseline, the BML score at 36 months was decreased in both treatment groups compared with the placebo group (SrRan 1 g/day, p=0.002 and SrRan 2 g/day p=0.001, respectively), and CVL significantly decreased with SrRan 2 g/day (p=0.023) in the plateau compared with placebo. Conclusions In knee OA patients, treatment with SrRan 2 g/day was found to have beneficial effects on structural changes by significantly reducing CVL in the plateau and BML progression in the medial compartment.

First-line analysis of the effects of treatment on progression of structural changes in knee osteoarthritis over 24 months: data from the osteoarthritis initiative progression cohort

OBJECTIVE To determine, using data from participants enrolled in the progression cohort of the OAI, the effects of conventional osteoarthritis (OA) pharmacological treatment and those of the combination of glucosamine and chondroitin sulfate (Glu/CS) on knee structural changes. METHODS Six hundred patients with knee OA were stratified based on whether or not they received for 24 consecutive months the OA conventional pharmacological treatment and/or Glu/CS. The main outcomes were knee structural changes, including the loss of joint space width (JSW) and of cartilage volume measured by quantitative MRI. RESULTS Participants reported taking (+) (n=300) or not taking (-) (n=300) OA treatment (analgesic/NSAIDs). The +analgesic/NSAIDs participants had higher Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores (p<0.001) and smaller JSW (p=0.01), reflecting more severe disease at baseline. In the -analgesic/NSAIDs group, participants taking Glu/CS had significantly reduced loss of cartilage volume at 24 months in the medial central plateau (p=0.007). Further subdivision revealed that this effect of Glu/CS occurred in participants with a higher severity of the disease (JSW≤median). In the +analgesic/NSAIDs group, those taking Glu/CS had significantly reduced loss of cartilage volume in the global plateau at 12 months (p=0.05), and in the central plateau at 24 months (p=0.05). These effects occurred in participants with less disease severity (JSW>median). By contrast, no significant reduction in JSW was found between all groups. CONCLUSIONS In +analgesic/NSAIDs groups and -analgesic/NSAIDs groups, participants who took Glu/CS had reduced loss of cartilage volume over 24 months in subregions when assessed with qMRI, arguing for a disease-modifying effect of Glu/CS which could not be identified by X-rays.

Relationship between bone marrow lesions, cartilage loss and pain in knee osteoarthritis: results from a randomised controlled clinical trial using MRI

Objective To assess in a multicentre randomised double-blind phase III clinical trial evaluating the effect of licofelone in comparison with naproxen on knee osteoarthritis (OA) the presence of, and change in, bone marrow lesions (BML) over time, their relationship to cartilage volume loss, meniscal extrusion and pain. Methods Patients with knee OA were selected from the dataset of a recently published randomised controlled trial. MRI was performed at baseline, 6, 12 and 24 months to assess BML score (modified Whole-Organ MRI Score) and cartilage volume changes over time. Pain levels were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. Results One hundred and sixty-one patients completed the study according to protocol. The global knee and all subregions showed increased BML scores over time (p <0.001, 24 months) except for the medial tibial plateau in the licofelone group. In multivariate regression analysis, licofelone treatment predicted reduction in BML score in the medial tibial plateau (β= −0.280, p = 0.026). BML scores at baseline correlated with cartilage volume over time; however, correlation was limited to 12 months. No positive correlation was found between BML and WOMAC scores. Conclusions BML scores were found to increase over time, probably owing to accumulation of chronic structural changes. Correlation between BML and cartilage volume was strong at baseline but not over time, probably due to the study drug. Licofelone reduced the BML score in the medial tibial plateau. In contrast to previous reports, no positive relationship was found between BML score (baseline or change over time) and pain, probably an effect of the selected population.

Analysis of the precision and sensitivity to change of different approaches to assess cartilage loss by quantitative MRI in a longitudinal multicentre clinical trial in patients with knee osteoarthritis

IntroductionCartilage thickness and volume loss measurements using quantitative magnetic resonance imaging (qMRI) are suggested to detect significant cartilage changes over short time intervals. We aimed to compare these two different approaches looking at the global knee and subregions, using data from an osteoarthritis (OA) multicentre randomised clinical trial.MethodsThree hundred and fifty-five patients with symptomatic knee OA were recruited for a two-year, double-blind, randomised clinical trial evaluating the effect of 200 mg licofelone twice daily and 500 mg naproxen twice daily on cartilage loss, and 301 patients had baseline MRI. MRIs were performed at baseline, 6, 12 and 24 months. Cartilage volume and thickness in the global joint, medial and lateral compartments, and central weight-bearing subregions of the medial and lateral femoral condyles and tibial plateaus were analysed. Data were analysed for the mean value imputed for intent-to-treat (ITT-MVI) and statistical analyses were performed using two-sample Students t-test.ResultsCartilage mean thickness loss in the global joint, lateral and medial compartments, as well as in medial compartments stratified according to patients with or without meniscal extrusion, was significantly less in the licofelone compared with the naproxen group at 12 and 24 months. Interestingly, these data were similar to those found when using cartilage volume loss as an outcome. Although greater cartilage volume and mean thickness loss was seen in central weight-bearing subregions of the medial and lateral compartments compared with the whole compartment and also in patients with meniscal lesions/extrusion, suggesting good sensitivity to change, its high standard deviation precluded for the condyles a high statistical power and abrogated statistically significant differences between the treatment groups.ConclusionsThese data demonstrate that both the measurement of cartilage thickness and that of cartilage volume provide the same level of sensitivity to estimate cartilage loss in a clinical trial. However, the potential of gaining statistical power with the use of thickness/volume change in knee subregions as an outcome seems negated by high inter-patient variability. Moreover, there is no superiority in statistical power by selecting patients with meniscal extrusion.

Treatment persistence with leukotriene receptor antagonists and inhaled corticosteroids

Background. Leukotriene receptor antagonists (LTRAs) and inhaled corticosteroids (ICSs) must be taken continuously to control persistent asthma. We compared the use of LTRAs and ICSs in patients with similar level of asthma control at treatment initiation with particular attention to treatment persistence. Methods. Two cohorts of 15 to 45 year old patients with asthma were selected from the Quebec Health Insurance Plan Database between January 1, 1998, and December 31, 2000. We first identified new users of LTRAs and from the remaining patients, we selected new users of ICSs. The ICS patients were then one-to-one matched to LTRA patients on the use of short-acting β2-agonists and oral corticosteroids in the year prior to the date of the first LTRA or ICS dispensation (index date). We compared compliance to initial therapies using Cox proportional hazards models. Results. Each of the LTRA and ICS cohorts included 2200 patients. Multivariate model showed that compliance was significantly better for LTRAs than for ICSs [adjusted rate ratio of treatment discontinuation (aRR), 0.46; 95% confidence interval (CI), 0.42–0.49]. If in both groups all medications filled were taken at the prescribed dose, the annual percent of days on therapy for LTRA users would have been twice that for ICS users (38% vs. 19%; p < 0.0001). Conclusion. The findings of this observational study indicate a far from optimal persistence to LTRAs and ICSs in asthmatic patients. The superior persistence to LTRAs might result in better effectiveness.

Telephone contact to improve adherence to dual antiplatelet therapy after drug-eluting stent implantation

Background Many patients delay or interrupt dual antiplatelet therapy (DAT) after drug-eluting stent (DES) implantation, which increases the risk of stent thrombosis and death. Objective To test the hypothesis that simple telephone contact made by nurses would improve adherence to and persistence of DAT. Design Randomised controlled trial. Patients and intervention A total of 300 patients (mean±SD 64±10 years, 73% male) were recruited immediately after DES implantation performed between June 2009 and June 2010. The last patient recruited reached the 1-year follow-up time point in June 2011. Patients were randomised to one of two groups: intervention, with four telephone follow-ups, versus a control group. In the intervention group, phone calls were made within 7 days of the DES implantation and at 1, 6 and 9 months to support drug adherence. Control patients were followed as per usual clinical practice. Pharmacy data were collected to assess drug prescription filling and refill. Setting Tertiary care university cardiovascular centre and community. Main outcome measures The primary end point was the proportion of days covered with aspirin and clopidogrel over the year after discharge as assessed by pharmacy refill data. Secondary outcome measures included persistence of aspirin and clopidogrel treatment, defined as no gaps longer than 14 days during follow-up. Results Most patients (73%) underwent DES implantation in the context of an acute coronary syndrome. All patients had drug insurance cover, either from the public plan (59%) or through private plans (41%). Complete pharmacy follow-up data were available for 96% of the cohort. At 12 months, median scores (25th–75th centile) for adherence to aspirin and clopidogrel were 99.2% (97.5–100%) and 99.3% (97.5–100%), respectively, in the intervention group compared with 90.2% (84.2–95.4%) and 91.5% (85.1–96.0%), respectively, in the control group (p<0.0001 for aspirin and clopidogrel). Patients in the intervention group were significantly more persistent in the aspirin and clopidogrel treatment than those in the control group. For clopidogrel, 87.2% of patients in the intervention group were still persistent at 12 months compared with only 43.1% in the control group (p<0.0001). Conclusions A simple approach of four telephone calls to patients after DES implantation significantly improved 1-year drug adherence to near-perfect scores. Persistence of DAT was also significantly improved by the intervention.