Evaluation of disease activity assessments in patients with rheumatoid arthritis and an inadequate response to anti-TNF therapy: analyses of abatacept clinical trial data.

OBJECTIVES: To assess the ability of efficacy measures that incorporate onset or sustainability to detect treatment effect or reflect patient satisfaction, using exploratory analyses of data from the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate Responders) trial. METHODS: 218 abatacept- and 99 placebo-treated patients were evaluated. Reporting methods included time to onset (first American College of Rheumatology [ACR] 50 response/Low Disease Activity State [LDAS; DAS28 < or =3.2]) and sustainability of ACR50/LDAS, both assessed according to discriminatory capacity (number of patients needed to study [NNS]) and patient satisfaction with treatment. RESULTS: Efficacy measures incorporating elements of sustainability or onset decreased discriminatory capacity, while sustainability, but not onset of action, was important in reflecting patient satisfaction. CONCLUSIONS: Optimal assessment methods depend on whether the outcome of interest is ability to detect treatment effects or to reflect patient satisfaction. Sustainability of response (and possibly, at a lower magnitude, fast onset of action) may be important when evaluating patient satisfaction with RA therapies in patients who have previously failed anti-TNF therapy.

Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3-year, prospective EULAR study.

OBJECTIVES: To determine clinical and ultrasonographic predictors of joint replacement surgery across Europe in primary osteoarthritis (OA) of the knee. METHODS: This was a 3-year prospective study of a painful OA knee cohort (from a EULAR-sponsored, multicentre study). All subjects had clinical evaluation, radiographs and ultrasonography (US) at study entry. The rate of knee replacement surgery over the 3-year follow-up period was determined using Kaplan-Meier survival data analyses. Predictive factors for joint replacement were identified by univariate log-rank test then multivariate analysis using a Cox proportional-hazards regression model. Potential baseline predictors included demographic, clinical, radiographic and US features. RESULTS: Of the 600 original patients, 531 (88.5%), mean age 67+/-10 years, mean disease duration 6.1+/-6.9 years, had follow-up data and were analysed. During follow-up (median 3 years; range 0-4 years), knee replacement was done or required for 94 patients (estimated event rate of 17.7%). In the multivariate analysis, predictors of joint replacement were as follows: Kellgren and Lawrence radiographic grade (grade > or =III vs or =4 mm vs <4 mm) (HR = 2.63 (95% CI 1.70 to 4.06), p<0.0001); knee pain intensity on a 0-100 mm visual analogue scale (> or =60 vs <60) (HR = 1.81 (95% CI 1.15 to 2.83), p=0.01) and disease duration (> or =5 years vs <5 years) (HR=1.63 (95% CI 1.08 to 2.47), p=0.02). Clinically detected effusion and US synovitis were not associated with joint replacement in the univariate analysis. CONCLUSION: Longitudinal evaluation of this OA cohort demonstrated significant progression to joint replacement. In addition to severity of radiographic damage and pain, US-detected effusion was a predictor of subsequent joint replacement.

Evaluation of different methods used to assess disease activity in rheumatoid arthritis: analyses of abatacept clinical trial data.

OBJECTIVES: To evaluate different methods of reporting response to treatment or disease status for their ability to discriminate between active therapy and placebo, or to reflect structural progression or patient satisfaction with treatment using an exploratory analysis of the Abatacept in Inadequate Responders to Methotrexate (AIM) trial. METHODS: 424 active (abatacept approximately 10 mg/kg) and 214 placebo-treated patients with rheumatoid arthritis (RA) were evaluated. METHOD: of reporting included: (1) response (American College of Rheumatology (ACR) criteria) versus state (disease activity score in 28 joints (DAS28) criteria); (2) stringency (ACR20 vs 50 vs 70; moderate disease activity state (MDAS; DAS28 <5.1) vs low disease activity state (LDAS; DAS28 or=2). More stringent criteria (at least ACR50/LDAS), faster onset (3 visits) of ACR50/LDAS best reflected patient satisfaction (positive LR >10). CONCLUSIONS: The optimal method for reporting a measure of disease activity may differ depending on the outcome of interest. Time to onset and sustainability can be important factors when evaluating treatment response and disease status in patients with RA.

Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy.

OBJECTIVE: To evaluate the safety and efficacy of abatacept during 2 years of the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) trial in patients with rheumatoid arthritis. METHODS: Patients completing the 6-month, double-blind period were eligible to enter the long-term extension; patients received abatacept approximately 10 mg/kg, plus disease-modifying antirheumatic drugs. Safety and efficacy (American College of Rheumatology (ACR) criteria responses, DAS28 (C-reactive protein), HAQ-DI, SF-36, Medical Outcomes Study Sleep Problems Index, fatigue VAS) were assessed through 2 years. RESULTS: 317 patients (218 from the abatacept and 99 from the placebo group) entered and 222 (70%) completed 18 months of long-term extension treatment. The incidence and type of adverse events were consistent between the double-blind and cumulative (double-blind plus long-term extension) periods. Rates of serious adverse events were 25.6 and 23.4 per 100 patient-years in the double-blind versus cumulative period. At 6 months and 2 years, using non-responder analyses, ACR responses in abatacept-treated patients were: ACR 20, 59.4% and 56.2%; ACR 50, 23.5% and 33.2%; ACR 70, 11.5% and 16.1%; HAQ-DI responses were 54.4% and 47.9%. At 6 months and 2 years, using post-hoc as-observed analyses, the percentage of patients (95% confidence interval) achieving DAS28 (C-reactive protein) low disease activity score (< or = 3.2) and DAS28 (C-reactive protein)-defined remission (< 2.6) increased from 18.3% (13.0, 23.5) to 32.0% (24.6, 39.4) and 11.1% (6.8, 15.3) to 20.3% (13.9, 26.6). Clinically meaningful improvements in SF-36, pain, fatigue and sleep problems were also maintained throughout the 2 years of abatacept treatment. CONCLUSION: No unique safety observations were reported during open-label exposure. Improvements in the signs and symptoms of rheumatoid arthritis, physical function and health-related quality of life observed after 6 months, were maintained throughout the 2 years in this population with difficult-to-treat disease. TRIAL REGISTRATION NUMBER: NCT00124982.

EULAR report on the use of ultrasonography in painful knee osteoarthritis. Part 2: exploring decision rules for clinical utility.

BACKGROUND: Synovial inflammation (as defined by hypertrophy and effusion) is common in osteoarthritis (OA) and may be important in both pain and structural progression. OBJECTIVE: To determine if decision rules can be devised from clinical findings and ultrasonography (US) to allow recognition of synovial inflammation in patients with painful knee OA. METHODS: A EULAR-ESCISIT cross sectional, multicentre study enrolled subjects with painful OA knee who had clinical, radiographic, and US evaluations. A classification and regression tree (CART) analysis was performed to find combinations of predictor variables that would provide high sensitivity and specificity for clinically detecting synovitis and effusion in individual subjects. A range of definitions for the two key US variables, synovitis and effusion (using different combinations of synovial thickness, depth, and appearance), were also included in exploratory analyses. RESULTS: 600 patients with knee OA were included in the analysis. For both knee synovitis and joint effusion, the sensitivity and specificity were poor, yielding unsatisfactory likelihood ratios (75% sensitivity, 45% specificity, and positive LR of 1.36 for knee synovitis; 71.6% sensitivity, 43.2% specificity, and positive LR of 1.26 for joint effusion). The exploratory analyses did not improve the sensitivity and specificity (demonstrating positive LRs of between 1.26 and 1.57). CONCLUSION: Although it is possible to determine clinical and radiological predictors of OA inflammation in populations, CART analysis could not be used to devise useful clinical decision rules for an individual subject. Thus sensitive imaging techniques such as US remain the most useful tool for demonstrating synovial inflammation of the knee at the individual level.

EULAR report on the use of ultrasonography in painful knee osteoarthritis. Part 1: prevalence of inflammation in osteoarthritis.

OBJECTIVES: To assess the prevalence of inflammation in subjects with chronic painful knee osteoarthritis (OA), as determined by the presence of synovitis or joint effusion at ultrasonography (US); and to evaluate the correlation between synovitis, effusion, and clinical parameters. METHODS: A cross sectional, multicentre, European study was conducted under the umbrella of EULAR-ESCISIT. SUBJECTS: had primary chronic knee OA (ACR criteria) with pain during physical activity >or=30 mm for at least 48 hours. Clinical parameters were collected by a rheumatologist and an US examination of the painful knee was performed by a radiologist or rheumatologist within 72 hours of the clinical examination. Ultrasonographic synovitis was defined as synovial thickness >or=4 mm and diffuse or nodular appearance, and a joint effusion was defined as effusion depth >or=4 mm. RESULTS: 600 patients with painful knee OA were analysed. At US 16 (2.7%) had synovitis alone, 85 (14.2%) had both synovitis and effusion, 177 (29.5%) had joint effusion alone, and 322 (53.7%) had no inflammation according to the definitions employed. Multivariate analysis showed that inflammation seen by US correlated statistically with advanced radiographic disease (Kellgren-Lawrence grade >or=3; odds ratio (OR)=2.20 and 1.91 for synovitis and joint effusion, respectively), and with clinical signs and symptoms suggestive of an inflammatory "flare", such as joint effusion on clinical examination (OR=1.97 and 2.70 for synovitis and joint effusion, respectively) or sudden aggravation of knee pain (OR=1.77 for joint effusion). CONCLUSION: US can detect synovial inflammation and effusion in painful knee OA, which correlate significantly with knee synovitis, effusion, and clinical parameters suggestive of an inflammatory "flare".

Paracetamol in osteoarthritis of the knee.

BACKGROUND: Paracetamol is a recommended symptomatic treatment of osteoarthritis (OA), but in clinical trials sample sizes have been relatively small and variable daily doses of paracetamol have been used. OBJECTIVES: To determine the therapeutic efficacy of paracetamol in OA of the knee and identify predictive factors of clinical response to treatment. METHODS: A double blind, parallel group, placebo controlled trial of analgesic efficacy and safety of paracetamol versus placebo including 779 patients with OA of the knee. Patients were randomly assigned to receive paracetamol 4 g/day (n = 405) or placebo (n = 374) for 6 weeks. Symptomatic OA of the knee was required at inclusion with global pain intensity of the knee during physical activities for the past 24 hours of >or=30 mm on a 100 mm visual analogue scale. The primary end point was a 30% decrease of global pain intensity of the knee. Intention to treat analyses were performed. RESULTS: The percentage of responders did not differ significantly between groups: 52.6% and 51.9% in paracetamol and placebo groups, respectively (p = 0.840). In a subgroup of patients with chronic mechanical knee pain without signs of inflammation (n = 123), the mean change in pain intensity from baseline was 25.2 mm v 15.2 mm, in the paracetamol (n = 63) and placebo (n = 60) groups, respectively-mean difference 10.0 mm; 95% CI 1.0 to 19.0; p = 0.0294. No serious adverse events were attributable to treatment. CONCLUSION: A statistically significant symptomatic effect of oral paracetamol 4 g/day over placebo was not found, suggesting that paracetamol use in symptomatic OA of the knee should be further explored. The tolerability and safety of paracetamol, at the recommended maximum dose of 4 g/day, was confirmed over 6 weeks.

[Liver and renal tolerance to paracetamol: 3 g or 4 g per day?]. / Tolérances hépatique et rénale du paracétamol: 3 g ou 4 g par jour?

OBJECTIVES: To compare the hepatic and renal safety profiles of two daily dosage regimens of paracetamol (acetaminophen) (3 g versus 4 g) in patients with painful chronic rheumatoid diseases. METHODS: Medical files of outpatients in the United Kingdom were investigated using an automated database. Two acetaminophen groups (3 g and 4 g) were compared with regard to demographic variables, treatments, associated diseases and occurrence of hepatorenal adverse events. Variables collected from the files for selected patients were also analyzed using the decision tree method to identify the specific variables best explaining the occurrence of hepatorenal adverse events. RESULTS: A total of 1.5 million medical files were investigated. Of the 7781 patients identified with paracetamol prescriptions for chronic rheumatoid disorders, 1868 (24%) were treated with 3 g/day and 5913 (76%) with 4 g/day. The mean overall duration of paracetamol exposure was 277 and 201 days respectively. No difference between the two acetaminophen groups was found with the numbers of patients with hepatorenal adverse events potentially related to acetaminophen intake (0.86%: group 3 g versus 0.68% group 4 g). Using the decision tree method, daily dosage of paracetamol (3 g or 4 g) was never identified as a discriminating variable capable of explaining the occurrence of hepatorenal adverse events. CONCLUSION: When risk factors are taken into account, such as concomitant chronic diseases, both daily dosages of paracetamol (3 g and 4 g) have a comparable hepatorenal safety profiles in rheumatology, even in elderly patients.