Pain Reduction With Oral Methotrexate in Knee Osteoarthritis : A Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: Treatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain. OBJECTIVE: To assess symptomatic benefits of methotrexate in knee OA (KOA). DESIGN: A multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41). SETTING: 15 secondary care musculoskeletal clinics in the United Kingdom. PARTICIPANTS: A total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion. INTERVENTION: Participants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia. MEASUREMENTS: The primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs). RESULTS: A total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren-Lawrence grade 3 to 4) were randomly assigned to methotrexate (n = 77) or placebo (n = 78). Follow-up was 86% (n = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51; P = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18]; P = 0.045) and function (5.01 points [CI, 1.29 to 8.74]; P = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2). LIMITATION: Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance. CONCLUSION: Oral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months. PRIMARY FUNDING SOURCE: Versus Arthritis.

Cohort profile: Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) - an international consortium of prospective cohort studies with individual participant data on hip osteoarthritis.

PURPOSE: Hip osteoarthritis (OA) is a major cause of pain and disability worldwide. Lack of effective therapies may reflect poor knowledge on its aetiology and risk factors, and result in the management of end-stage hip OA with costly joint replacement. The Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) consortium was established to pool and harmonise individual participant data from prospective cohort studies. The consortium aims to better understand determinants and risk factors for the development and progression of hip OA, to optimise and automate methods for (imaging) analysis, and to develop a personalised prediction model for hip OA. PARTICIPANTS: World COACH aimed to include participants of prospective cohort studies with ≥200 participants, that have hip imaging data available from at least 2 time points at least 4 years apart. All individual participant data, including clinical data, imaging (data), biochemical markers, questionnaires and genetic data, were collected and pooled into a single, individual-level database. FINDINGS TO DATE: World COACH currently consists of 9 cohorts, with 38 021 participants aged 18-80 years at baseline. Overall, 71% of the participants were women and mean baseline age was 65.3±8.6 years. Over 34 000 participants had baseline pelvic radiographs available, and over 22 000 had an additional pelvic radiograph after 8-12 years of follow-up. Even longer radiographic follow-up (15-25 years) is available for over 6000 of these participants. FUTURE PLANS: The World COACH consortium offers unique opportunities for studies on the relationship between determinants/risk factors and the development or progression of hip OA, by using harmonised data on clinical findings, imaging, biomarkers, genetics and lifestyle. This provides a unique opportunity to develop a personalised hip OA risk prediction model and to optimise methods for imaging analysis of the hip.

Variability in the prevalence of depression among adults with chronic pain: UK Biobank analysis through clinical prediction models.

BACKGROUND: The prevalence of depression among people with chronic pain remains unclear due to the heterogeneity of study samples and definitions of depression. We aimed to identify sources of variation in the prevalence of depression among people with chronic pain and generate clinical prediction models to estimate the probability of depression among individuals with chronic pain. METHODS: Participants were from the UK Biobank. The primary outcome was a "lifetime" history of depression. The model's performance was evaluated using discrimination (optimism-corrected C statistic) and calibration (calibration plot). RESULTS: Analyses included 24,405 patients with chronic pain (mean age 64.1 years). Among participants with chronic widespread pain, the prevalence of having a "lifetime" history of depression was 45.7% and varied (25.0-66.7%) depending on patient characteristics. The final clinical prediction model (optimism-corrected C statistic: 0.66; good calibration on the calibration plot) included age, BMI, smoking status, physical activity, socioeconomic status, gender, history of asthma, history of heart failure, and history of peripheral artery disease. Among participants with chronic regional pain, the prevalence of having a "lifetime" history of depression was 30.2% and varied (21.4-70.6%) depending on patient characteristics. The final clinical prediction model (optimism-corrected C statistic: 0.65; good calibration on the calibration plot) included age, gender, nature of pain, smoking status, regular opioid use, history of asthma, pain location that bothers you most, and BMI. CONCLUSIONS: There was substantial variability in the prevalence of depression among patients with chronic pain. Clinically relevant factors were selected to develop prediction models. Clinicians can use these models to assess patients' treatment needs. These predictors are convenient to collect during daily practice, making it easy for busy clinicians to use them.

Prevalence, incidence, and re-occurrence risk of musculoskeletal pain in older adults in the United Kingdom: a population-based study.

Background: Throughout the literature, pain burden has been assessed by asking different questions, often cross-sectionally, different populations of interest. We know little about pain re-occurrence and how to translate knowledge between pain questions within the population of interest. We aimed to estimate the burden of musculoskeletal pain by estimating prevalence, incidence rates, and re-occurrence risk of back, hand, hip, knee, and foot pain using different questions from UK population-based samples and predict the number of affected individuals in the UK in 2030. Methods: We used two UK population-representative studies, with two eight-year-apart follow-ups and two pain questions assessing recent pain episodes and often troubled pain when walking. We estimated prevalence, 8-year incidence rates, and 8-year pain re-occurrence risk for women and men aged 50 years and older and the relation between the two pain questions. Results: Among UK individuals older than 50 years, the prevalence of musculoskeletal pain episode was 20%-50%, and the incidence was 20-40/1,000 person-years, while the prevalence of pain when walking was 10%-25%, and the incidence was 6-12/1,000 person-years. The most prevalent musculoskeletal pain types were back and knee pain; of five women experiencing back or knee pain episodes, three are expected to be often troubled by pain. Hip and foot pain had similar estimates in both questions. Hand pain peaked in women aged 50-65 years. Women had higher prevalence and incidence rates, but men had higher 8-year re-occurrence risk of all types of musculoskeletal pain. Reporting a pain episode was associated with two times higher risk, but often troubled by pain when walking was associated with four to seven times times higher risk of the same pain in 8 years. Women and men with a body mass index (BMI) of ≥27 kg/m2 were twice as likely to experience musculoskeletal pain than those with BMI<27 kg/m2. In 2030, we expect 2-7 million people older than 50 years in the United Kingdom to seek site-specific musculoskeletal pain-focused healthcare. Conclusions: In individuals older than 50 years, the experience of musculoskeletal pain at least doubles the chance of experiencing it again. Women report musculoskeletal pain more often, but men report more persistent pain. Musculoskeletal pain presents a significant burden to public health.

Organizational risk profiling and education associated with reduction in professional pitching arm injuries: a natural experiment.

Background: Risk profiling and education are strategies implemented to help reduce injury risk; however, currently. there is little evidence on the effect of these interventions on injury incidence. The purpose of this study was to evaluate the influence of risk profiling and education on upper extremity injury incidence in minor league (MiLB) pitchers and to stratify by injury severity. Methods: A prospective natural experiment study was conducted from 2013 to 2019 on MiLB pitchers. Beginning in the 2015 season, pitchers were examined and risk profiled for upper extremity injury. Shoulder external, internal, total range of motion, horizontal adduction, and humeral torsion were measured. Organizational risk profiling and education was implemented starting in 2015, based on preseason assessments. Chi-squared test was performed to investigate potential differences between shoulder range of motion risk categories between 2013-2014 (pre) and 2015-2019 (post) seasons. Interrupted time series analyses were performed to assess the association between organizational risk profiling and education on arm injury in MiLB pitchers and were repeated for 7-27 and 28+ day injury severity. Results: 297 pitchers were included (pre: 119, post: 178). Upper extremity injury incidence was 1.5 injuries per 1000 athletic exposures. Pitchers in the 2015-2019 seasons demonstrated increased preseason shoulder injury risk for internal (P = .003) and external (P = .007), while the 2013-2014 seasons demonstrated greater horizontal adduction risk (P = .04). There were no differences between seasons for total range of motion risk (P =.76). Risk profiling and education resulted in an adjusted time loss upper extremity injury reduction for the 2015-2019 seasons (0.68 (95% CI: 0.47, 0.99)), which impacted 7-27 days (0.62 (95% CI: 0.42, 0.93)) but not for 28+ days (0.71 (95% CI: 0.47, 1.06)) time loss. There was no reduction in combined trunk and lower extremity injuries for the 2015-2019 seasons (1.55 (95% CI: 0.79, 3.01)). Conclusions: Organizational risk profiling and education appear to reduce professional pitching overall and 7-27-day upper extremity injury risk by 33%-38%. There was no difference in trunk and lower extremity injuries over the period, strengthening the reduction in upper extremity injury risk results. This suggests that while injury risk increased over time, organizational risk profiling mitigated the expected increase in upper extremity injury rates. Risk profiling and education can be used as a clinical screening and intervention tool to help decrease upper extremity injuries in professional baseball populations.

Relationship between shoulder abduction strength and rotator cuff tear in elderly women: a general population study.

OBJECTIVES: To investigate the effect of age-related rotator cuff tears on shoulder strength in a general population cohort. DESIGN: Cross sectional observational study. SETTING: This study was set in an outpatient clinic setting in Chingford, North East London, and was a component of the 20 year visit of the Chingford 1000 women cohort. PARTICIPANTS: Individuals were part of the Chingford 1000 women cohort, a 20-year-old longitudinal population study. This cohort has been extensively characterised as representative of the population of the UK. At the 20 year visit, 446 attended for shoulder assessment and were aged between 64 and 87. PRIMARY AND SECONDARY OUTCOME MEASURES: Isometric shoulder abduction strength measured using a Nottingham Mecmesin Myometer and the presence of rotator cuff pathology, determined via ultrasound examination (GE voluson i portable ultrasound machine with a 10-16MHz linear probe). Shoulders were classified into normal, abnormal tendon/partial tear, full-thickness tears (>0 and ≤2.5 cm) and full-thickness tears (>2.5 cm). Symptoms were defined using the Oxford Shoulder Score, where an abnormal score was defined as symptomatic. RESULTS: 446 women (891 shoulders) aged 71 (range 65-84) were included in the study. Age, the presence of pain and the non-dominant arm were demonstrated to reduce strength. Rotator cuff tears and pathology had no isolated effect on shoulder strength in those aged under 70. However, in the over 70s full-thickness tears>0 and ≤2.5 cm, and >2.5 cm had mean reductions of 6.3 and 12.7 N, respectively (p<0.001). CONCLUSION: Rotator cuff tears of all sizes in those aged under 70 were not associated with a loss of shoulder strength. In those aged over 70, strength was reduced by 30% with small and 40% with large full thickness tears. Loss in strength was associated a loss of ability to perform activities of daily living but only for large tears.

Description, Prediction, and Causation in Sport and Exercise Medicine Research: Resolving the Confusion to Improve Research Quality and Patient Outcomes.

SYNOPSIS: Researchers often assign a label (such as a risk factor or predictor) to a characteristic that is statistically associated with an outcome (such as future injury). Labeling signifies that the characteristic has an established clinical value. More often than not, these labels are assigned prematurely and haphazardly. The rampant practice conflates research goals, the ultimate clinical value of the findings, and many risk factors/predictors that may not warrant the label. To address these issues and improve injury prevention research, we (1) outline the problem; (2) clarify the key differences between the research goals of description, causation, and prediction/prognosis (along with labeling conventions); (3) differentiate the clinical implications for each label; and (4) frame an appropriate scientific process to follow before applying a label. J Orthop Sports Phys Ther 2023;53(7):1-7. Epub: 26 April 2023. doi:10.2519/jospt.2023.11773.

Improving Clinical Utility of Real-World Prediction Models: Updating Through Recalibration.

ABSTRACT: Bullock, GS, Shanley, E, Thigpen, CA, Arden, NK, Noonan, TK, Kissenberth, MJ, Wyland, DJ, and Collins, GS. Improving clinical utility of real-world prediction models: updating through recalibration. J Strength Cond Res 37(5): 1057-1063, 2023-Prediction models can aid clinicians in identifying at-risk athletes. However, sport and clinical practice patterns continue to change, causing predictive drift and potential suboptimal prediction model performance. Thus, there is a need to temporally recalibrate previously developed baseball arm injury models. The purpose of this study was to perform temporal recalibration on a previously developed injury prediction model and assess model performance in professional baseball pitchers. An arm injury prediction model was developed on data from a prospective cohort from 2009 to 2019 on minor league pitchers. Data for the 2015-2019 seasons were used for temporal recalibration and model performance assessment. Temporal recalibration constituted intercept-only and full model redevelopment. Model performance was investigated by assessing Nagelkerke's R-square, calibration in the large, calibration, and discrimination. Decision curves compared the original model, temporal recalibrated model, and current best evidence-based practice. One hundred seventy-eight pitchers participated in the 2015-2019 seasons with 1.63 arm injuries per 1,000 athlete exposures. The temporal recalibrated intercept model demonstrated the best discrimination (0.81 [95% confidence interval [CI]: 0.73, 0.88]) and R-square (0.32) compared with original model (0.74 [95% CI: 0.69, 0.80]; R-square: 0.32) and the redeveloped model (0.80 [95% CI: 0.73, 0.87]; R-square: 0.30). The temporal recalibrated intercept model demonstrated an improved net benefit of 0.34 compared with current best evidence-based practice. The temporal recalibrated intercept model demonstrated the best model performance and clinical utility. Updating prediction models can account for changes in sport training over time and improve professional baseball arm injury outcomes.

Return to work and employment retention after uni-compartmental and total knee replacement: findings from the Clinical Outcomes in Arthroplasty study.

BACKGROUND: Little is known about ability to work after unicompartmental knee replacement (UKR) and total knee replacement (TKR), especially in physically-demanding occupations. This study described rates of return-to-work (RTW) and ability to sustain work by job after arthroplasty. METHOD: Participants from The Clinical Outcomes in Arthroplasty Study (COASt) aged 18-65 were eligible if they underwent UKR or TKR and had at least 5 years' follow-up post-operation. We posted a survey asking about pre-operative occupation, post-operative occupations and associated physical demands, and whether they had quit a job post-surgery due to difficulties with the operated knee (knee-related job loss (KRJL)). We fitted Cox Proportional Hazard Models to investigate the role of demanding physical activities on KRJL. RESULTS: 251 people (143 UKR, 108 TKR) returned a questionnaire, of whom 101 UKR and 57 TKR worked post-operatively. Rates of RTW were highest amongst those in managerial and professional or technical roles, whichever operation they received. RTW was poorest amongst those in elementary occupations. In associate professional/technical occupations, RTW rates were better amongst UKR recipients. Amongst participants who returned to work, 17 reported KRJL (8.5% UKR and 16.7% TKR). Respondents were more likely to have KRJL if their job involved carrying/lifting ≥10 kg (HR:4.81, 95%CI 1.55-14.93) or climbing >30 flights of stairs (HR:4.03, 95%CI 1.36-11.98). CONCLUSIONS: Knee arthroplasty recipients working pre-operatively mostly RTW. RTW may be more difficult after TKR than UKR. Jobs which involve lifting and climbing stairs may be particularly challenging. Surgeons offering knee arthroplasty should counsel patients about workability as well as risk of revision.

The current state of the osteoarthritis drug development pipeline: a comprehensive narrative review of the present challenges and future opportunities.

In this narrative review article, we critically assess the current state of the osteoarthritis (OA) drug development pipeline. We discuss the current state-of-the-art in relation to the development and evaluation of candidate disease-modifying OA drugs (DMOADs) and the limitations associated with the tools and methodologies that are used to assess outcomes in OA clinical trials. We focus on the definition of DMOADs, highlight the need for an updated definition in the form of a consensus statement from all the major stakeholders, including academia, industry, regulatory agencies, and patient organizations, and provide a summary of the results of recent clinical trials of novel DMOAD candidates. We propose that DMOADs should be more appropriately targeted and investigated according to the emerging clinical phenotypes and molecular endotypes of OA. Based on the findings from recent clinical trials, we propose key topics and directions for the development of future DMOADs.