Henning Bliddal

Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials

BACKGROUND Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. We did a meta-analysis of all published randomised controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent rimonabant. METHODS We searched The Cochrane database and Controlled Trials Register, Medline via Pubmed, Embase via WebSpirs, Web of Science, Scopus, and reference lists up to July, 2007. We collected data from four double-blind, randomised controlled trials (including 4105 participants) that compared 20 mg per day rimonabant with placebo. FINDINGS Patients given rimonabant had a 4.7 kg (95% CI 4.1-5.3 kg; p<0.0001) greater weight reduction after 1 year than did those given placebo. Rimonabant caused significantly more adverse events than did placebo (OR=1.4; p=0.0007; number needed to harm=25 individuals [95% CI 17-58]), and 1.4 times more serious adverse events (OR=1.4; p=0.03; number needed to harm=59 [27-830]). Patients given rimonabant were 2.5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo (OR=2.5; p=0.01; number needed to harm=49 [19-316]). Furthermore, anxiety caused more patients to discontinue treatment in rimonabant groups than in placebo groups (OR=3.0; p=0.03; number needed to harm=166 [47-3716]). INTERPRETATION Our findings suggest that 20 mg per day rimonabant increases the risk of psychiatric adverse events--ie, depressed mood disorders and anxiety-despite depressed mood being an exclusion criterion in these trials. Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with rimonabant, we recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions.

EULAR evidence-based recommendations for the management of fibromyalgia syndrome

Objective: To develop evidence-based recommendations for the management of fibromyalgia syndrome. Methods: A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords “fibromyalgia”, “treatment or management” and “trial”. Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. Results: 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and “other pharmacological” and exercise, cognitive behavioural therapy, education, dietary interventions and “other non-pharmacological”. In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. Conclusions: Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.

Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis

This review aims to assess by meta-analysis of randomised controlled trials (RCTs) changes in pain and function when overweight patients with knee osteoarthritis (OA) achieve a weight loss. Systematic searches were performed and reference lists from the retrieved trials were searched. RCTs were enclosed in the systematic review if they explicitly stated diagnosis of knee OA and reported a weight change as the only difference in intervention from the control group. Outcome Measures for Arthritis Clinical Trials III outcome variables were considered for analysis. Effect size (ES) was calculated using RevMan, and meta-regression analyses were performed using weighted estimates from the random effects analyses. Among 35 potential trials identified, four RCTs including five intervention/control groups met our inclusion criteria and provided data from 454 patients. Pooled ES for pain and physical disability were 0.20 (95% CI 0 to 0.39) and 0.23 (0.04 to 0.42) at a weight reduction of 6.1 kg (4.7 to 7.6 kg). Meta-regression analysis showed that disability could be significantly improved when weight was reduced over 5.1%, or at the rate of >0.24% reduction per week. Clinical efficacy on pain reduction was present, although not predictable after weight loss. Meta-regression analysis indicated that physical disability of patients with knee OA and overweight diminished after a moderate weight reduction regime. The analysis supported that a weight loss of >5% should be achieved within a 20-week period—that is, 0.25% per week.

Test-retest reliability of trunk accelerometric gait analysis.

The purpose of this study was to determine the test-retest reliability of a trunk accelerometric gait analysis in healthy subjects. Accelerations were measured during walking using a triaxial accelerometer mounted on the lumbar spine of the subjects. Six men and 14 women (mean age 35.2; range 18-57) underwent the same protocol on 2 consecutive days. The raw acceleration signals from six self-selected walking speeds were transformed into a horizontal-vertical coordinate system to remove unwanted variability caused by gravity. Acceleration root mean square values, cadences, step and stride lengths were then computed and interpolated using quadratic curve fits and point estimates were calculated at a standardised walking speed of 1.35 m/s. Relative reliability was determined using two models of intraclass correlation coefficients (ICC(1,1) and ICC(3,1)) to assess any systematic shifts and absolute reliability was determined using measurement error (ME). The results of the study showed high ICC values (0.77-0.96) and ME values of 0.007-0.01 g for mean acceleration; 0.009 m for step lengths; 0.022 m for stride length and 1.644 step/min for cadences. In conclusion, the method was found to be reliable and may have a definite potential in clinical gait analysis.

Inhibition of maximal voluntary contraction force by experimental muscle pain: A centrally mediated mechanism

Muscle weakness frequently accompanies conditions with musculoskeletal pain. It is not clear if this attenuation of force is due to peripheral or central processes. The effect of experimental muscle pain on maximal voluntary contraction torque and peripheral contractile properties was therefore assessed. Experimental muscle pain reduced the torque produced by isometric knee extension, but the contractile properties assessed by twitch interpolation were not affected. This indicates that force inhibition by muscle pain is centrally mediated. This has clinical implications for rehabilitation and training of patients with musculoskeletal pain.

A RANDOMIZED CONTROLLED TRIAL OF AQUATIC AND LAND-BASED EXERCISE IN PATIENTS WITH KNEE OSTEOARTHRITIS*

OBJECTIVE To compare the efficacy of aquatic exercise and a land-based exercise programme vs control in patients with knee osteoarthritis. METHODS Primary outcome was change in pain, and in addition Knee Injury and Osteoarthritis Outcome Score questionnaire (KOOS). Standing balance and strength was also measured after and at 3-month follow-up. Seventy-nine patients (62 women), with a mean age of 68 years (age range 40-89 years) were randomized to aquatic exercise (n = 27), land-based exercise (n = 25) or control (n = 27). RESULTS No effect was observed immediately after exercise cessation (8 weeks). At 3-month follow-up a reduction in pain was observed only in the land-based exercise group compared with control (-8.1 mm, (95% confidence interval -15.4 to -0.4; p = 0.039), but no differences between groups were observed for KOOS; and no improvement following aquatic exercise. Eleven patients reported adverse events (i.e. discomfort) in land-based exercise, while only 3 reported adverse events in the aquatic exercise. CONCLUSION Only land-based exercise showed some improvement in pain and muscle strength compared with the control group, while no clinical benefits were detectable after aquatic exercise compared with the control group. However, aquatic exercise has significantly less adverse effects compared with a land-based programme.

Comparative Effectiveness of Injection Therapies in Lateral Epicondylitis A Systematic Review and Network Meta-analysis of Randomized Controlled Trials

Background: Injection therapy with glucocorticoids has been used since the 1950s as a treatment strategy for lateral epicondylitis (tennis elbow). Lately, several novel injection therapies have become available. Purpose: To assess the comparative effectiveness and safety of injection therapies in patients with lateral epicondylitis. Study Design: Systematic review and meta-analysis. Methods: Randomized controlled trials comparing different injection therapies for lateral epicondylitis were included provided they contained data for change in pain intensity (primary outcome). Trials were assessed using the Cochrane risk of bias tool. Network (random effects) meta-analysis was applied to combine direct and indirect evidence within and across trial data using the final end point reported in the trials, and results for the arm-based network analyses are reported as standardized mean differences (SMDs). Results: Seventeen trials (1381 participants; 3 [18%] at low risk of bias) assessing injection with 8 different treatments—glucocorticoid (10 trials), botulinum toxin (4 trials), autologous blood (3 trials), platelet-rich plasma (2 trials), and polidocanol, glycosaminoglycan, prolotherapy, and hyaluronic acid (1 trial each)—were included. Pooled results (SMD [95% confidence interval]) showed that beyond 8 weeks, glucocorticoid injection was no more effective than placebo (−0.04 [−0.45 to 0.35]), but only 1 trial (which did not include a placebo arm) was at low risk of bias. Although botulinum toxin showed marginal benefit (−0.50 [−0.91 to −0.08]), it caused temporary paresis of finger extension, and all trials were at high risk of bias. Both autologous blood (−1.43 [−2.15 to −0.71]) and platelet-rich plasma (−1.13 [−1.77 to −0.49]) were also statistically superior to placebo, but only 1 trial was at low risk of bias. Prolotherapy (−2.71 [−4.60 to −0.82]) and hyaluronic acid (−5.58 [−6.35 to −4.82]) were both more efficacious than placebo, whereas polidocanol (0.39 [−0.42 to 1.20]) and glycosaminoglycan (−0.32 [−1.02 to 0.38]) showed no effect compared with placebo. The criteria for low risk of bias were only met by the prolotherapy and polidocanol trials. Conclusion: This systematic review and network meta-analysis of randomized controlled trials found a paucity of evidence from unbiased trials on which to base treatment recommendations regarding injection therapies for lateral epicondylitis.

Effect of whole body vibration exercise on muscle strength and proprioception in females with knee osteoarthritis

The purpose of this study was to assess the effect of whole body vibration (WBV) exercise on muscle strength and proprioception in female patients with osteoarthritis in the knee (knee-OA). A single blinded, randomised, controlled trial was performed in an outpatient clinic on 52 female patients diagnosed with knee-OA (mean age 60.4 years+/-9.6). They were randomly assigned to one of 3 groups: 1. WBV-exercise on a stable platform (VibM; n=17 (mean age, 61.5+/-9.2)), WBV-exercise on a balance board (VibF; n=18 (mean age, 58.7+/-11.0)), or control group (Con; n=18 (mean age, 61.1+/-8.5)). The WBV groups trained twice a week for 8 weeks, with a progressively increasing intensity. The WBV groups performed unloaded static WBV exercise. The following were measured: knee muscle strength (extension/flexion) and proprioception (threshold for detection of passive movement (TDPM)). Self-reported disease status was measured using WOMAC. It was found that muscle strength increased significantly (p<0.001) in VibM compared to Con. Isometric knee-extension significantly increased (p=0.021) in VibM compared to Con. TDPM was significantly improved (p=0.033) in VibF compared to Con, while there was a tendency (p=0.051) for VibM to perform better compared to Con. There were no effects in the self-reported disease status measures. This study showed that the WBV-exercise regime on a stable platform (VibM) yielded increased muscle strength, while the WBV-exercise on a balance board (VibF) showed improved TDPM. The WBV-exercise is a time-saving and safe method for rehabilitation of women with knee-OA.

Learning effect of isokinetic measurements in healthy subjects, and reliability and comparability of Biodex and Lido dynamometers

The aim of this study was to examine the learning effect during a set of isokinetic measurements, to evaluate the reliability of the Biodex System 3 PRO dynamometer, and to compare the Biodex System 3 PRO and the Lido Active dynamometers on both extension and flexion over the elbow and the knee at 60° s−1. Thirteen (nine women, four men) healthy participants were measured five times using the Biodex and once using the Lido dynamometer. The intervals between the first four tests were 20 min, and 1 week between tests 4 and 5. Between Biodex and Lido measurements there was a 20 min time interval. When comparing the first five measurements (Biodex), no systematic effect over time and an excellent reliability were found with respect to elbow and knee flexion and extension. No difference in muscle strength (Nm) between the Biodex and Lido was observed for knee flexion (P = 0·59), knee extension (P = 0·18) and elbow extension (P = 0·63). However, elbow flexion showed a 14·8% (95% CI: 11·2–18·4%; P = 0·0001) higher peak torque on Biodex. In conclusion, no learning effect was observed and the Biodex proved to be a highly reliable isokinetic dynamometer. A difference was observed when comparing Biodex and Lido on elbow flexion, but the difference did not outrange the expected variation found with a typical isokinetic measurement, which is why both sets of equipment seem applicable in clinical practice.

Chronic widespread pain in the spectrum of rheumatological diseases.

Fibromyalgia (FM) is a rheumatic disease characterised by musculoskeletal pain, chronic diffuse tension and/or stiffness in joints and muscles, fatigue, sleep and emotional disturbances and pressure pain sensitivity in at least 11 of 18 tender points. There are currently no instrumental tests or specific diagnostic markers, and the characteristic symptoms of the disease overlap those of many other conditions classified in a different manner. FM is often associated with other diseases that act as confounding and aggravating factors, including primary Sjögrens syndrome (pSS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). It has been reported to coexist in 25% of patients with RA, 30% of patients with SLE and 50% of patients with pSS. Its clinical diagnosis is not easy because FM-like symptoms are frequent, and its differential diagnosis with other causes of chronic diffuse pain is difficult. This is even more true in the case of patients who are positive for antinuclear antibodies (ANAs) because, although sensitive, ANA positivity is not specific for SLE or connective tissue diseases, and can also be found in 10-15% of FM patients. Furthermore, composite indices such as the disease activity score (DAS)-28, which are widely used in everyday clinical practice and clinical trials, may be insufficient to evaluate real inflammatory activity in patients with RA associated with chronic pain syndromes such as FM, and can lead to an overestimate of disease activity in RA. The presence of diffuse pain in autoimmune rheumatic diseases compromises the quality of life of the patients, although overall mortality is not increased. A misdiagnosis harms the patients and the community. Rheumatologists should be able to recognise and distinguish primary and secondary FM, and need new guidelines and instruments to avoid making mistakes.