Robin Christensen

A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview

Background: We sought to compare the benefits and safety of 6 biologics (abatacept, adalimumab, anakinra, etanercept, infliximab and rituximab) in patients with rheumatoid arthritis. Methods: In this network meta-analysis, we included all completed and updated Cochrane reviews on biologics for rheumatoid arthritis. We included data from all placebo-controlled trials that used standard dosing regimens. The major outcomes were benefit (defined as a 50% improvement in patient- and physician-reported criteria of the American College of Rheumatology [ACR50]) and safety (determined by the number of withdrawals related to adverse events). We used mixed-effects logistic regression to carry out an indirect comparison of the treatment effects between biologics. Results: Compared with placebo, biologics were associated with a clinically important higher ACR50 rate (odds ratio [OR] 3.35, 95% confidence interval [CI] 2.62–4.29) and a number needed to treat for benefit of 4 (95% CI 4–6). However, biologics were associated with more withdrawals related to adverse events (OR 1.39, 95% CI 1.13–1.71), with a number needed to treat for harm of 52 (95% CI 29–152). Anakinra was less effective than all of the other biologics, although this difference was statistically significant only for the comparison with adalimumab (OR 0.45, 95% CI 0.21–0.99) and etanercept (OR 0.34, 95% CI 0.14–0.81). Adalimumab, anakinra and infliximab were more likely than etanercept to lead to withdrawals related to adverse events (adalimumab OR 1.89, 95% CI 1.18–3.04; anakinra OR 2.05, 95% CI 1.27–3.29; and infliximab OR 2.70, 95% CI 1.43–5.26). Interpretation: Given the limitations of indirect comparisons, anakinra was less effective than adalimumab and etanercept, and etanercept was safer than adalimumab, anakinra and infliximab. This summary of the evidence will help physicians and patients to make evidence-based choices about biologics for the treatment of rheumatoid arthritis.

Impact of Exercise Type and Dose on Pain and Disability in Knee Osteoarthritis: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials

To identify the optimal exercise program, characterized by type and intensity of exercise, length of program, duration of individual supervised sessions, and number of sessions per week, for reducing pain and patient‐reported disability in knee osteoarthritis (OA).

Treatment of Lateral Epicondylitis With Platelet-Rich Plasma, Glucocorticoid, or Saline A Randomized, Double-Blind, Placebo-Controlled Trial

Background: Lateral epicondylitis (LE) is a common musculoskeletal disorder for which an effective treatment strategy remains unknown. Purpose: To examine whether a single injection of platelet-rich plasma (PRP) is more effective than placebo (saline) or glucocorticoid in reducing pain in adults with LE after 3 months. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 60 patients with chronic LE were randomized (1:1:1) to receive either a blinded injection of PRP, saline, or glucocorticoid. The primary end point was a change in pain using the Patient-Rated Tennis Elbow Evaluation (PRTEE) questionnaire at 3 months. Secondary outcomes were ultrasonographic changes in tendon thickness and color Doppler activity. Results: Pain reduction at 3 months (primary end point) was observed in all 3 groups, with no statistically significant difference between the groups; mean differences were the following: glucocorticoid versus saline: −3.8 (95% CI, −9.9 to 2.4); PRP versus saline: −2.7 (95% CI, −8.8 to 3.5); and glucocorticoid versus PRP: −1.1 (95% CI, −7.2 to 5.0). At 1 month, however, glucocorticoid reduced pain more effectively than did both saline and PRP; mean differences were the following: glucocorticoid versus saline: −8.1 (95% CI, −14.3 to −1.9); and glucocorticoid versus PRP: −9.3 (95% CI, −15.4 to −3.2). Among the secondary outcomes, at 3 months, glucocorticoid was more effective than PRP and saline in reducing color Doppler activity and tendon thickness. For color Doppler activity, mean differences were the following: glucocorticoid versus PRP: −2.6 (95% CI, −3.1 to −2.2); and glucocorticoid versus saline: −2.0 (95% CI, −2.5 to −1.6). For tendon thickness, mean differences were the following: glucocorticoid versus PRP: −0.5 (95% CI, −0.8 to −0.2); and glucocorticoid versus saline: −0.8 (95% CI, −1.2 to −0.5). Conclusion: Neither injection of PRP nor glucocorticoid was superior to saline with regard to pain reduction in LE at the primary end point at 3 months. However, injection of glucocorticoid had a short-term pain-reducing effect at 1 month in contrast to the other therapies. Injection of glucocorticoid in LE reduces both color Doppler activity and tendon thickness compared with PRP and saline.

Consumption of industrial and ruminant trans fatty acids and risk of coronary heart disease: a systematic review and meta-analysis of cohort studies

The aim of this systematic review and meta-analysis was to summarize the evidence from observational studies assessing the association between intake of trans fatty acids (TFA) and the risk of coronary heart disease (CHD), with a specific emphasis on distinguishing between TFA of industrial and ruminant origin. By searching five bibliographic databases, analyses from six published and two unpublished prospective cohort studies, assessing the association of intake of TFA with fatal and/or non-fatal CHD, were identified. Four and three studies reported separate associations for intake of ruminant or industrial-TFA, respectively. The pooled relative risk estimates for comparison of extreme quintiles of total-TFA intake (corresponding to intake increments ranging from 2.8 to ∼10 g/day) were 1.22 (95% confidence interval: 1.08–1.38; P=0.002) for CHD events and 1.24 (1.07–1.43; P=0.003) for fatal CHD. Ruminant-TFA intake (increments ranging from 0.5 to 1.9 g/day) was not significantly associated with risk of CHD (risk ratio (RR)=0.92 (0.76–1.11); P=0.36), and neither was industrial-TFA intake, although there was a trend towards a positive association (RR=1.21 (0.97–1.50); P=0.09). In conclusion, our analysis suggests that industrial-TFA may be positively related to CHD, whereas ruminant-TFA is not, but the limited number of available studies prohibits any firm conclusions concerning whether the source of TFA is important. The null association of ruminant-TFA with CHD risk may be due to lower intake levels.

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.

Identifying core domains to assess flare in rheumatoid arthritis: an OMERACT international patient and provider combined Delphi consensus

Objective For rheumatoid arthritis (RA), there is no consensus on how to define and assess flare. Variability in flare definitions impairs understanding of findings across studies and limits ability to pool results. The OMERACT RA Flare Group sought to identify domains to define RA flares from patient and healthcare professional (HCP) perspectives. Methods Flare was described as a worsening of disease activity of sufficient intensity and duration to consider a change in therapy. International patients and HCPs participated in separate and combined rounds of Delphi exercises to rate candidate flare domains previously generated in patient focus groups. Core domains were defined as those with ≥70% ratings of being ‘essential’ according to the third/final Delphi exercise. Results The final Delphi included 125 RA patients from 10 countries and 108 HCPs from 23 countries who rated 14 domains. Patients had a mean (±SD) age of 56±12 years and disease duration of 18±12 years. HCPs included physicians from clinical practice/research and industry, allied health providers and researchers with 17±11 years experience. Core domains comprised: pain (93%), function (89%), swollen joints (84%), tender joints (81%), participation (81%), stiffness (79%), patient global assessment (76%) and self-management (75%). Fatigue (68%), which did not reach group consensus, will receive additional consideration. Conclusions As part of the process to develop a measure for RA flare, patients and HCPs agreed on eight core domains. Next steps include identifying items to assess domains and conducting studies to validate and refine a new measure.

Weight loss is effective for symptomatic relief in obese subjects with knee osteoarthritis independently of joint damage severity assessed by high-field MRI and radiography

OBJECTIVE With an increasing prevalence of older and obese citizens, the problems of knee osteoarthritis (KOA) will escalate. Weight loss is recommended for obese KOA patients and in a majority of cases this leads to symptomatic relief. We hypothesized that pre-treatment structural status of the knee joint, assessed by radiographs, 1.5 T magnetic resonance imaging (MRI) and knee-joint alignment, may influence the symptomatic changes following a significant weight reduction. DESIGN Patients were recruited from a Department of Rheumatology. Eligibility criteria were age above 50 years, body mass index ≥ 30 kg/m(2), primary KOA diagnosed according to the American College of Rheumatology (ACR) criteria and having verified structural damage. Patients underwent a 16 weeks dietary programme with formula products and counselling. MRI and radiographs of the most symptomatic knee were obtained at baseline and assessed for structural damage using the Boston-Leeds Osteoarthritis of the Knee Score, minimum joint space width and Kellgren-Lawrence score. Imaging variables, muscle strength and degree of alignment, were examined as predictors of changes in Knee Osteoarthritis Outcome Score (KOOS) and Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) - Osteoarthritis Research Society International (OARSI) Responder Criterion. RESULTS Structural damage at baseline assessed by imaging, muscle strength or knee-joint alignment showed no statistically significant association to changes in KOOS pain and function in daily living (r ≤ 0.13; P>0.05) or the OMERACT-OARSI Responder Criterion (OR 0.48-1.68; P-values ≥ 0.13). CONCLUSIONS Presence of joint damage did not preclude symptomatic relief following a clinically relevant weight loss in older obese patients with KOA. Neither muscle strength nor knee-joint alignment was associated with the degree of symptomatic relief.

Postoperative effects of neuromuscular exercise prior to hip or knee arthroplasty: a randomised controlled trial

Objective To investigate the postoperative efficacy of a supervised programme of neuromuscular exercise prior to hip or knee arthroplasty. Methods In this assessor-blinded randomised controlled trial, we included 165 patients scheduled for hip or knee arthroplasty due to severe osteoarthritis (OA). An 8-week preoperative neuromuscular supervised exercise programme was delivered twice a week for 1 h as adjunct treatment to the standard arthroplasty procedure and compared with the standard arthroplasty procedure alone. The primary outcome was self-reported physical function measured on the activities of daily living (ADL) subscale in the Hip disability and Osteoarthritis Outcome Score (HOOS) and the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaires for patients with hip and knee OA, respectively. Primary endpoint was 3 months after surgery. Results 165 patients randomised to the two groups were on average 67±8 years, 84 (51%) had hip OA and 92 (56%) were women. 153 patients (93%) underwent planned surgery and were evaluated postoperatively. There was no statistically significant difference in effects between hip or knee patients (p=0.7370). Three months postoperatively, no difference was found between groups for ADL (4.4, 95% CI −0.8 to 9.5) or pain (4.5, 95% CI −0.8 to 9.9). However, there was a statistically significant difference indicating an effect of exercise over the entire period (baseline to 3-months postoperatively) (p=0.0029). Conclusions Eight weeks of supervised neuromuscular exercise prior to total joint arthroplasty (TJA) of the hip or knee did not confer additional benefits 3 months postoperatively compared with TJA alone. However, the intervention group experienced a statistically significant short-term benefit in ADL and pain, suggesting an earlier onset of postoperative recovery. Trial registration ClinicalTrials NCT01003756.

Establishing a Core Domain Set to Measure Rheumatoid Arthritis Flares: Report of the OMERACT 11 RA Flare Workshop

Objective. The OMERACT Rheumatoid Arthritis (RA) Flare Group (FG) is developing a data-driven, patient-inclusive, consensus-based RA flare definition for use in clinical trials, longterm observational studies, and clinical practice. At OMERACT 11, we sought endorsement of a proposed core domain set to measure RA flare. Methods. Patient and healthcare professional (HCP) qualitative studies, focus groups, and literature review, followed by patient and HCP Delphi exercises including combined Delphi consensus at Outcome Measures in Rheumatology 10 (OMERACT 10), identified potential domains to measure flare. At OMERACT 11, breakout groups discussed key domains and instruments to measure them, and proposed a research agenda. Patients were active research partners in all focus groups and domain identification activities. Processes for domain selection and patient partner involvement were case studies for OMERACT Filter 2.0 methodology. Results. A pre-meeting combined Delphi exercise for defining flare identified 9 domains as important (> 70% consensus from patients or HCP). Four new patient-reported domains beyond those included in the RA disease activity core set were proposed for inclusion (fatigue, participation, stiffness, and self-management). The RA FG developed preliminary flare questions (PFQ) to measure domains. In combined plenary voting sessions, OMERACT 11 attendees endorsed the proposed RA core set to measure flare with ≥ 78% consensus and the addition of 3 additional domains to the research agenda for OMERACT 12. Conclusion. At OMERACT 11, a core domain set to measure RA flare was ratified and endorsed by attendees. Domain validation aligning with Filter 2.0 is ongoing in new randomized controlled clinical trials and longitudinal observational studies using existing and new instruments including a set of PFQ.

Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: a meta-analysis of randomized placebo-controlled trials

OBJECTIVE To estimate the efficacy and safety of diacerein as a pain-reducing agent in the treatment of osteoarthritis (OA), using meta-analysis of published randomized placebo-controlled trials (RCTs). METHODS Systematic searches of the bibliographic databases Medline, Embase, Cinahl, Chemical Abstracts, Cochrane and Web of Science for RCTs concerning diacerein treatment of OA. INCLUSION CRITERIA explicit statement about randomization to either diacerein or placebo, and co-primary outcomes being reduction in pain and improvement in function. Efficacy effect size (ES) was estimated using Hedgess standardized mean difference. Safety was measured via the risk ratio (RR) of patients having at least one episode of diarrhoea, or withdrawal due to adverse events. Trials were combined by using random-effects meta-analysis. Consistency was evaluated via the I-squared index. RESULTS Six trials (seven sub-studies; 1533 patients) contributed to the meta-analysis, revealing a large degree of inconsistency among the trials (I(2)=56%) in regard to pain reduction: the combined ES was -0.24 [95% confidence intervals (CI): -0.39 to -0.08, P=0.003], favouring diacerein. The statistically significant improvement in function (P=0.01) was based on a small amount of heterogeneity (I(2)=11%), but presented a questionable clinical effect size (ES=-0.14). Risk of publication bias could not be excluded, and trials with duration of more than 6 months did not favour diacerein. There was an increased risk of diarrhoea with diacerein (RR=3.51 [2.55-4.83], P<0.0001), and some withdrawal from therapy following adverse events (RR=1.58 [1.05-2.36], P=0.03). CONCLUSIONS Diacerein may be an alternative therapy for OA for patients who cannot take paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) because of adverse effects or lack of benefit. However, it is associated with increased risk of diarrhoea, and the symptomatic benefit after 6 months remains unknown.