Individual patient data meta-analysis of trials investigating the effectiveness of intra-articular glucocorticoid injections in patients with knee or hip osteoarthritis:an OA Trial Bank protocol for a systematic review

BACKGROUND: Based on small to moderate effect sizes for the wide range of symptomatic treatments in osteoarthritis (OA), and on the heterogeneity of OA patients, treatment guidelines for OA have stressed the need for research on clinical predictors of response to different treatments. A meta-analysis to quantify the effect modified by the predictors using individual patient data (IPD) is suggested. The initiative to collect and analyze IPD in OA research is commenced by the OA Trial Bank. The study aims are therefore: to evaluate the efficacy of intra-articular glucocorticoids for knee or hip OA in specific subgroups of patients with severe pain and (mild) inflammatory signs, over both short-term and long-term follow-up, using IPD from existing studies; to reach consensus on the rules for cooperation in a consortium; and to develop and explore the methodological issues of meta-analysis with individual OA patient data. METHODS/DESIGN: For the current IPD analysis we will collect and synthesize IPD from randomized trials studying the effect of intra-articular glucocorticoid injections in patients with hip or knee OA. Subgroup analyses will be performed for the primary outcome of pain at both short-term and long-term follow-up, in the subgroups of patients with and without severe pain and with and without inflammatory signs. DISCUSSION: This study protocol includes the first study of the OA Trial Bank, an international collaboration that initiates meta-analyses on predefined subgroups of OA patients from existing literature. This approach ensures a widely supported initiative and is therefore likely to be successful in data collection of existing trials. The collaboration developed (that is, the OA Trial Bank) may also lead to future IPD analyses on subgroups of patients with several intervention strategies applied in OA patients

The placebo effect and its determinants in fibromyalgia: meta-analysis of randomized controlled trials

The aims of this study were to determine whether placebo treatment in randomised controlled trials (RCTs) is effective for fibromyalgia and to identify possible determinants of the magnitude of any such placebo effect. A systematic literature search was undertaken for RCTs in people with fibromyalgia that included a placebo and/or a no-treatment (observation only or waiting list) control group. Placebo effect size (ES) for pain and other outcomes was measured as the improvement of each outcome from baseline divided by the standard deviation of the change from baseline. This effect was compared with changes in the no-treatment control groups. Meta-analysis was undertaken to combine data from different studies. Subgroup analysis was conducted to identify possible determinants of the placebo ES. A total of 3912 studies were identified from the literature search. After scrutiny, 229 trials met the inclusion criteria. Participants who received placebo in the RCTs experienced significantly better improvements in pain, fatigue, sleep quality, physical function, and other main outcomes than those receiving no treatment. The ES of placebo for pain relief was clinically moderate (0.53, 95%CI 0.48 to 0.57). The ES increased with increasing strength of the active treatment, increasing participant age and higher baseline pain severity, but decreased in RCTS with more women and with longer duration of fibromyalgia. In addition, placebo treatment in RCTs is effective in fibromyalgia. A number of factors (expected strength of treatment, age, gender, disease duration) appear to influence the magnitude of the placebo effect in this condition

Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs49654

Surgery for Dupuytren's contracture of the fingers.

Dupuytren's disease is a benign fibroproliferative disorder that causes the fingers to be drawn into the palm via formation of new tissue under the glabrous skin of the hand. This disorder causes functional limitations, but it can be treated through a variety of surgical techniques. As a chronic condition, it tends to recur. Objectives:To assess the benefits and harms of different surgical procedures for treatment of Dupuytren's contracture of the index, middle, ring and little fingers

Intra-articular Injection Administration in UK Ex-professional Footballers During Their Playing Careers and the Association with Post-career Knee Osteoarthritis

© 2020, The Author(s). Background: The long-term risk from knee intra-articular (KIA) injections in professional athletes such as ex-footballers remains unknown. The use of KIA injections is controversial and remains anecdotally prolific as it is perceived as being safe/beneficial. The aim of this study was to determine the number, type and frequency KIA injections administered to retired professional footballers during their playing careers and the associations with post-career knee osteoarthritis (KOA). Methods: This is a cross-sectional study involving a postal questionnaire (n = 1207) and subsequent knee radiographs in a random sample of questionnaire responders (n = 470). Footballers self-reported in the questionnaire whether they had received KIA injections and the estimated total number over the course of their playing career. Participant characteristics and football career-related details were also recorded. KOA was measured as self-reported knee pain (KP), total knee replacement (TKR) and radiographic KOA (RKOA). Results: 44.5% of footballers had received at least one KIA injection (mean: 7.5; SD ± 11.2) during their professional career. 71% of knee injections were cortisone/corticosteroid based. Multivariate logistic regression, adjusting for age, body mass index (BMI) and significant knee injury identified that footballers with injections weretwo times more likely to have KP (OR 1.81, 95% CI 1.40–2.34) and TKR (OR 2.21, 95% CI 1.43–3.42) than those without injections. However, there was no association with RKOA (OR 1.30, 95% CI 0.85–2.01). Given, the association with KP and TKR, we found a significant dose–response relationship as the more injections a player received (by dose–response groups), the greater the risk of KP and TKR outcomes after adjustment for knee injury and other confounders (p for trend < 0.01). Conclusion: On average, 8 KIA injections were given to the ex-footballers during their professional career. The most commonly administered injections were cortisone based. These injections associated with KP and TKR after they retired. The associations are independent of knee injuries and are dose dependent. The study suggests that there may have been excessive use of KIA injections to expedite return to play and this contributed to detrimental long-term outcomes such as KP and TKR post-retirement from professional football

Depressive symptoms and the general health of retired professional footballers compared with the general population in the UK:a case-control study

Objectives To determine the prevalence of depressive symptoms and general health of male ex-professional footballers compared with general population controls.Methods 572 retired professional footballers and 500 general population controls in the UK were assessed by postal questionnaire. Anxiety and depressive symptoms were assessed using the Hospital Anxiety and Depression Scale and a threshold score of ≥11 was used to indicate probable caseness. General health was ascertained using the Short Form-12 Health Survey Questionnaire quality of life (QoL) tool; self-reported comorbidities, analgesic usage and body pain; and Index of Multiple Deprivation based on postcode data. Mood was assessed using the Positive and Negative Affect Scale and sleep using the Medical Outcome Survey. Linear regression analysis was used to determine adjusted relative risk with 95% CI and adjusted for age, body mass index, comorbidities, body pain and medication usage.Results The prevalence of depressive symptoms in retired professional footballers was 5.66% compared with 5.76% in the general population and anxiety prevalence was also comparable (12.01% vs 10.29%; all p&gt;0.05). However, footballers had lower physical and mental component scores compared with controls (p&lt;0.01). They also reported significantly more sleep problems, more negative mood profiles and more widespread body pain (adjusted relative risk (aRR) 1.88, 95% CI 1.15 to 3.09). They also reported greater pain medication usage compared with controls (aRR 1.54, 95% CI 1.26 to 1.89). However, compared with controls, they were 26% (95% CI 15% to 37%) less likely to report comorbidities, especially heart attacks (aRR 57%, 95% CI 27% to 74%) and diabetes (aRR 61%, 95% CI 37% to 76%).Conclusions The prevalence of depressive symptoms and anxiety symptoms and probable caseness in ex-professional footballers is comparable with general population controls. However, ex-footballers reported lower health-related QoL, more widespread body pain and higher analgesic usage. Conversely, lower reporting of diabetes and heart attacks indicates potential long-term physical health benefits of professional football

Risk Factors for Knee Osteoarthritis in Retired Professional Footballers: A Cross-Sectional Study

Objective: To determine risk factors for three knee osteoarthritis (KOA) outcomes, knee pain (KP), radiographic KOA (RKOA) and total knee replacement (TKR), in professional footballers.Design: This was a cross-sectional study involving a postal questionnaire, followed by radiographic assessment in a sub-cohort of responders. Settings and Participants: 4775 questionnaires were sent to retired professional footballers, who had played in the English football league, and 1207 responded. Of these, 470 underwent knee radiographs. Assessment of Risk Factors: Potential factors include age, BMI, knee alignment, a history of football-related knee injury, and training hours (during career) were collected via the questionnaire.Main Outcome Measures: KOA outcomes were current KP (pain for most days of the previous month), TKR (self-reported) and RKOA (observed via radiographs). Results: Football-related injury was the strongest risk factor for KP [aOR 4.22, 95%CI 3.26-5.48], RKOA [aOR 2.88, 95%CI 1.81-4.59] and TKR [aOR 4.83, 95%CI 2.87-8.13]. Footballers had a 7% increased risk of RKOA for every 1000 hours trained. While age and gout were associated with all three KOA outcomes, BMI, nodal OA, a family history of OA, knee malalignment and 2D:4D ratio were associated with one or another of these three KOA outcomes.Conclusion: This study is the first to examine KOA risk factors in retired professional footballers. The study has identified several risk factors, both specific (for example, knee injury and training dose), and non-specific (for example, age and gout) to footballers. This may be used to develop prevention strategies to reduce the risk of KOA in professional footballers following retirement

Predictors of placebo response to local (intra-articular) therapy in osteoarthritis: an individual patient data meta-analysis protocol

Abstract Introduction Osteoarthritis (OA) is a highly prevalent and disabling condition with limited safe and effective treatment options. Intra-articular therapies are increasingly being used, however whether the effect of these agents is due to active treatment or placebo remains unclear. As the placebo response can be attributed to multiple factors, assessment of the placebo response using individual patient data (IPD) meta-analysis will give insight into the different modifiers of response to placebo. The aim of this IPD meta-analysis is to investigate the predictors of placebo response in intra-articular injection trials in OA. IPD meta-analysis is considered to be superior to conventional meta-analysis, as it combines multiple trial data, facilitates the standardisation of analyses across different studies and allows measuring derivation of the desired information. Method and analysis A systematic literature search will be conducted for randomised clinical trials comparing corticosteroid and viscosupplementation/hyaluronic acid intra-articular injections with placebo for knee and hip OA. Pubmed (Medline), EMBASE, Web of Science, Cochrane Central and SCOPUS will be searched from inception to September 2018. Corresponding authors of the original trials will be contacted to obtain IPD. Risk of bias will be assessed using the Cochrane Collaboration’s tool. The primary outcome will be change in pain from baseline. Secondary outcomes will be change in function and patient’s global assessment. Potential predictors of placebo response assessed will include patient’s characteristics, pain mechanism characteristics, radiographic severity, pain severity, intervention characteristics and trial design characteristics. A multilevel logistic regression analyses will be applied. Results will be reported using the Preferred Reporting Items for Systematic review and Meta-Analysis -IPD guidelines. Ethics and dissemination This study does not include identifiable data and ethical approval was obtained by the original investigators. Results of the IPD meta-analysis will be disseminated for publication in peer-reviewed journals and conference presentations

Foot and ankle Osteoarthritis and Cognitive impairment in retired UK Soccer players (FOCUS): protocol for a cross-sectional comparative study with general population controls

INTRODUCTION: Professional footballers commonly experience sports-related injury and repetitive microtrauma to the foot and ankle, placing them at risk of subsequent chronic pain and osteoarthritis (OA) of the foot and ankle. Similarly, repeated heading of the ball, head/neck injuries and concussion have been implicated in later development of neurodegenerative diseases such as dementia. A recent retrospective study found that death from neurodegenerative diseases was higher among former professional soccer players compared with age matched controls. However, well-designed lifetime studies are still needed to provide evidence regarding the prevalence of these conditions and their associated risk factors in retired professional football players compared with the general male population. OBJECTIVES: To determine whether former professional male footballers have a higher prevalence than the general male population of: (1) foot/ankle pain and radiographic OA; and (2) cognitive and motor impairments associated with dementia and Parkinson's disease. Secondary objectives are to identify specific football-related risk factors such as head impact/concussion for neurodegenerative conditions and foot/ankle injuries for chronic foot/ankle pain and OA. METHODS AND ANALYSIS: This is a cross-sectional, comparative study involving a questionnaire survey with subsamples of responders being assessed for cognitive function by telephone assessment, and foot/ankle OA by radiographic examination. A sample of 900 adult, male, ex professional footballers will be recruited and compared with a control group of 1100 age-matched general population men between 40 and 100 years old. Prevalence will be estimated per group. Poisson regression will be performed to determine prevalence ratio between the populations and logistic regression will be used to examine risk factors associated with each condition in footballers. ETHICS AND DISSEMINATION: This study was approved by the East Midlands-Leicester Central Research Ethics Committee on 23 January 2020 (REC ref: 19/EM/0354). The study results will be disseminated at national and international meetings and submitted for peer-review publication

The development and validation of prognostic model for leflunomide discontinuation with abnormal blood-tests during long-term treatment: a cohort study using data from Clinical Practice Research Datalink Gold and Aurum

Objective: To develop and validate a prognostic model for leflunomide discontinuation with abnormal blood-test results. Methods: Data from CPRD Gold and Aurum were used for model development and external validation respectively. Participants prescribed leflunomide between 01/01/2007 and 31/12/2019 were followed-up from six-months after first GP prescription to the earliest of date of outcome, death, 5-year follow-up or 31/12/2019. Candidate prognostic factors were ascertained using theory and data driven approaches. Penalised Cox regression was performed to develop the risk equation, followed by internal validation using 500-bootstraps to correct for optimism. Multiple imputation was applied to handle missing data. Model performance was assessed in terms of calibration and discrimination. Results: Data for 1,487 and 2,329 participants contributing 3,140 and 5,246 person years follow-up were included in the development and validation cohorts respectively. Thirteen candidate predictors were included in the model. Epilepsy, and either cytopenia or elevated liver enzymes during first six months of shared-care leflunomide prescription were strong predictors of drug discontinuation with hazard ratio (95%CI) 4.39 (1.74 -11.06) and 3.06 (2.15 - 4.35) respectively. The unadjusted and optimism adjusted calibration slope in development data was 1.00 (95% CI 0.75-1.25) and 0.72 (95% CI 0.47-0.97) respectively. The calibration slope in validation data was 0.91 (95% CI 0.74-1.07). The model showed prognostic separation with optimism adjusted Royston D statistic of 0.73 (95% CI 0.44-1.02). 3 Conclusion: We have developed and externally validated an easy-to-use prognostic model that may be used to risk-stratify monitoring for leflunomide toxicity and to make informed choices about risks when choosing treatment