Report of similar placebo response in one internet versus onsite randomised controlled trials from the literature.

Objective: The aim of this study was to compare the magnitude and the predictors of the placebo response in an internet versus onsite randomised controlled trials (RCTs) in people with hand osteoarthritis (HOA). Method: This study is a post-hoc analysis based on one internet RCT (RADIANT) and previously published onsite RCTs for HOA identified through a rigorous searching and selection strategy. The magnitude of the placebo response in the two different types of RCTs were compared using heterogeneity statistics and forest plots visualisation. Classic placebo predictors as well as a combined model, defined with data from onsite RCTs, were tested to predict the placebo response. Results: We analysed the dataset from RADIANT and fourteen previously published onsite RCTs. None of the analyses showed a significant difference between the placebo response for the internet versus onsite RCTs. The "classic" placebo predictors combined in a multivariate predictive model correlated significantly with the placebo response measured in RADIANT study. Conclusion: Despite the absence of face-to-face interactions with the study personnel, there is no evidence that either the magnitude or the predictors of the placebo response of this internet RCT differ from those of onsite RCTs. This analysis is considered as a first step towards evaluating the difference between these designs and strengthens the argument that internet RCTs remain an acceptable alternative way to assess the efficacy of an active treatment in comparison to a placebo.

Association of biochemical markers with bone marrow lesion changes on imaging-data from the Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium.

BACKGROUND: To assess the prognostic value of short-term change in biochemical markers as it relates to bone marrow lesions (BMLs) on MRI in knee osteoarthritis (OA) over 24 months and, furthermore, to assess the relationship between biochemical markers involved with tissue turnover and inflammation and BMLs on MRI. METHODS: Data from the Foundation for the National Institutes of Health OA Biomarkers Consortium within the Osteoarthritis Initiative (n = 600) was analyzed. BMLs were measured according to the MRI Osteoarthritis Knee Score (MOAKS) system (0-3), in 15 knee subregions. Serum and urinary biochemical markers assessed were as follows: serum C-terminal crosslinked telopeptide of type I collagen (CTX-I), serum crosslinked N-telopeptide of type I collagen (NTX-I), urinary CTX-Iα and CTX-Iß, urinary NTX-I, urinary C-terminal cross-linked telopeptide of type II collagen (CTX-II), serum matrix metalloproteinase (MMP)-degraded type I, II, and III collagen (C1M, C2M, C3M), serum high sensitivity propeptide of type IIb collagen (hsPRO-C2), and matrix metalloproteinase-generated neoepitope of C-reactive protein (CRPM). The association between change in biochemical markers over 12 months and BMLs over 24 months was examined using regression models adjusted for covariates. The relationship between C1M, C2M, C3M, hsPRO-C2, and CRPM and BMLs at baseline and over 24 months was examined. RESULTS: Increases in serum CTX-I and urinary CTX-Iß over 12 months were associated with increased odds of changes in the number of subregions affected by any BML at 24 months. Increase in hsPRO-C2 was associated with decreased odds of worsening in the number of subregions affected by any BML over 24 months. C1M and C3M were associated with BMLs affected at baseline. CONCLUSIONS: Short-term changes in serum CTX-I, hsPRO-C2, and urinary CTX-Iß hold the potential to be prognostic of BML progression on MRI. The association of C1M and C3M with baseline BMLs on MRI warrants further investigation.

Predictors of Placebo Response to Local (Intra-Articular) Therapy In Osteoarthritis: An Individual Participant Data Meta-Analysis.

OBJECTIVE: We undertook this study to evaluate potential predictors of placebo response with intra-articular (IA) injections for knee/hip osteoarthritis (OA) using individual participant data (IPD) from existing trials. METHODS: Randomized placebo-controlled trials evaluating IA glucocorticoid or hyaluronic acid published to September 2018 were selected. IPD for disease characteristics and outcome measures were acquired. Potential predictors of placebo response included participant characteristics, pain severity, intervention, and trial design. Placebo response was defined as at least a 20% reduction in baseline pain. Logistic regression models and odds ratios were computed as effect measures to evaluate patient and pain mechanisms and then pooled using a random effects model. Generalized mixed-effect models were applied to intervention and trial characteristics. RESULTS: Of 56 eligible trials, 6 shared data, and these were combined with the existing 4 OA Trial Bank studies, yielding 10 studies with IPD of 621 placebo participants for analysis. In the total placebo population, at short-term follow-up, the use of local anesthetic and ultrasound guidance were associated with reduced odds of placebo response. At midterm follow-up, mid- to long-term trial duration was associated with increased odds of placebo response, and worse baseline function scores were associated with reduced odds of a placebo response. CONCLUSION: The administration of local anesthetics or ultrasound guidance may reduce IA placebo response at short-term follow-up. At midterm follow-up, participants with worse baseline function scores may be less likely to respond to IA placebo, and mid- to long-term trial duration may enhance the placebo response. Further studies are required to corroborate these potential predictors of IA placebo response.

Assessment of Pain in Osteoarthritis of the Knee.

Knee osteoarthritis (KOA) pain is a subjective and personal experience, making it challenging to characterise patients' experiences and assess their pain. In addition, there is no global standard for the assessment of pain in KOA. Therefore, this article examines the possible methods of assessing and characterising pain in patients with KOA using clinical symptoms, pain assessment tools, and imaging. We examine the current methods of assessment of pain in KOA and their application in clinical practice and clinical trials. Furthermore, we explore the possibility of creating individualised pain management plans to focus on different pain characteristics. With better evaluation and standardisation of pain assessment in these patients, it is hoped that patients would benefit from improved quality of life. At the same time, improvement in pain assessment would enable better data collection regarding symptom response in clinical trials for the treatment of osteoarthritis.

Investigation of a family affected by early-onset osteoarthritis - proposal of a clinical pathway and bioinformatics pipeline for the investigation of cases of familial OA.

BACKGROUND: Familial cases of early-onset osteoarthritis (OA) are rare although the exact prevalence is unknown. Early recognition of underlying OA-associated disorders is vital for targeted treatment, when available, and genetic counselling, in case of skeletal dysplasias. Currently, there is no clear guidance on how best to investigate families affected by early-onset OA. METHODS: We investigated a family with multiple members affected by early-onset OA (age at onset ≤ 40 years). Clinical and demographic characteristics were collected, followed by laboratory investigations screening for a range of potential OA-associated disorders, and whole genome sequencing in selected individuals. RESULTS: Seventeen members of the family were included (7 affected and 10 non-affected). There was an even split between the two sexes and two participants were under 18 years old. No pattern of abnormality was seen in the laboratory investigation that could explain the OA phenotype in the family. Whole-genome sequencing was perfomed in one participant and analysed for likely pathogenic variants in genes known to be associated with skeletal dysplasias. A heterozygous variant in the COL2A1 gene was identified (p.Arg519Cys). Confirmatory tests were performed in five additional participants (four affected and one unaffected). CONCLUSION: The methodology used in this study, including the clinical pathway and bioinformatics pipeline, could be applied to other families affected by early-onset OA.

The OA Trial Bank: Update of individual patient data meta-analysis of intra-articular glucocorticoids in persons with knee and hip osteoarthritis.

Objective: To evaluate the efficacy of intra--articular (IA) glucocorticoid for knee or hip osteoarthritis (OA) in specific subgroups of patients according to the baseline severity of pain and inflammatory signs using individual patient data (IPD) from existing trials. Furthermore, this study aims to assess if a baseline pain cut-off was associated with clinically important effectiveness of IA glucocorticoid. This is an update of an IA glucocorticoid IPD meta-analysis by the OA Trial Bank. Method: Randomized trials evaluating one or more IA glucocorticoid preparations in hip and knee OA, published to May 2018 were selected. IPD of patient and disease characteristics and outcome measures were acquired. The primary outcome was pain severity at short-term follow-up (up to 4 weeks). Potential interaction effect of severe pain (≥70 points, 0-100 scale) and signs of inflammation at baseline were studied using a two-stage approach with general liner model followed by random effects model. Analysis of trend was conducted, assessing if a baseline pain cut-off was associated with the threshold for clinically important treatment effect of IA glucocorticoid compared to placebo. Results: Four out of 16 eligible randomized clinical trials (n â€‹= â€‹641) were combined with the existing OA Trial Bank studies (n â€‹= â€‹620), yielding 1261 participants from eleven studies. Participants with severe baseline pain compared to those with less severe pain had greater pain reduction at mid-term (around 12 weeks) (mean reduction: -6.90 (95%CI -10.91; -2.90)), but not at short- and long-term. No interaction effects were found between inflammatory signs and IA glucocorticoid injections compared to placebo at all follow-up time-points. Analysis of trend demonstrated treatment response to IA glucocorticoid from baseline pain levels >50 (0-100 scale) and above. Conclusion: This updated IPD meta-analysis demonstrated that participants with severe pain compared to those with less severe pain at baseline experienced significantly more pain relief with IA glucocorticoid compared with placebo at mid-term.

Baseline knee osteoarthritis radiographic severity as a predictor of symptom response to diet and exercise program: A secondary analysis.

OBJECTIVE: To investigate whether baseline joint space narrowing (JSN) predicted disease remission, knee pain, and physical function changes in persons with knee osteoarthritis (OA). METHODS: This study is a secondary analysis of a two-armed randomized controlled trial. Participants were aged ≥50 years (n = 171) with a body mass index ≥28 kg/m2 and radiographic medial tibiofemoral OA. Participants in the intervention group received diet and exercise programs and special treatment (cognitive behavioral therapy, knee brace, and muscle strengthening exercises) according to the disease remission. Remission of pain and remission of patient global assessment of disease activity and/or functional impairment were used to define the disease remission. The control group were provided with an education pamphlet. The primary outcome was disease remission at 32 weeks, and the secondary outcomes were the changes in knee pain and physical function at 20 and 32 weeks. Baseline JSN was scored from 0 to 3, and the association between baseline JSN and outcomes was assessed using multiple regression. RESULTS: There was no association of baseline JSN with disease remission at 32 weeks when the disease remission has been achieved. The baseline JSN grade 3 was associated with changes in knee pain at 20 weeks (p < .05). There was no association between baseline JSN and physical function. CONCLUSION: Baseline JSN severity predicted changes in knee pain but not the disease remission or changes in physical functions. Identification of baseline radiographic severity may be helpful in identifying differences in response to diet and exercise programs in knee OA.

Sexual activity satisfaction in symptomatic hip osteoarthritis patients: A cross-sectional, national web-based study.

AIM: Despite high-interest rates in sex in people with hip osteoarthritis (OA), clinicians tend not to address sexual issues, especially in older adults. The objective of this study is to evaluate sexual activity and factors associated with sexual activity satisfaction in people with symptomatic hip OA. METHODS: A cross-sectional study was conducted among 252 participants with symptomatic hip OA in Australia. Quality of sex life was assessed using the online composite of sexual activities and positions questionnaires. A Poisson model with robust variance was used to calculate the prevalence ratio (PR). Factors that showed a univariate association with sexual satisfaction were then included in a multivariable model. PR with corresponding 95% confidence intervals (CI) are reported. RESULTS: Among the 282 participants registered on the study website, 252 met the inclusion criteria, and 60.3% (152/252) completed the sexual activity questionnaires. Hip OA interfered with sexual activity in 70.0% of the participants. High confidence in completing sexual activity (PR: 0.53, 95% CI: 0.36 to 0.77) was associated with an increased prevalence ratio of sexual satisfaction. High anxiety, depression or stress during sexual activity (PR: 1.33, 95% CI: 1.10 to 1.60) was associated with an increased prevalence ratio of sexual dissatisfaction after adjusting for hip pain level and perceived partner's orgasm. CONCLUSION: Although a large proportion of people with hip OA remain sexually active, a substantial proportion of persons are dissatisfied with their sexual activity. Hip OA interfered with sexual activity in most participants. Psychological factors were found to be associated with sexual activity satisfaction.

Biomarkers in osteoarthritis: current status and outlook - the FNIH Biomarkers Consortium PROGRESS OA study.

Currently, no disease-modifying therapies are approved for osteoarthritis (OA) use. One obstacle to trial success in this field has been our existing endpoints' limited validity and responsiveness. To overcome this impasse, the Foundation for the NIH OA Biomarkers Consortium is focused on investigating biomarkers for a prognostic context of use for subsequent qualification through regulatory agencies. This narrative review describes this activity and the work underway, focusing on the PROGRESS OA study.

Pain, function, and radiographic disease in trapeziometacarpal osteoarthritis.

INTRODUCTION: Trapeziometacarpal joint osteoarthritis (OA) produces significant functional impairment due to pain and loss of strength in both power and precision grips, but few studies have related radiographic scores to functional and pain-based measures. PURPOSE: To investigate the association between markers of radiographic disease and outcomes for symptomatic and functional disease. STUDY DESIGN: This study in an exploratory analysis of baseline data from the first 100 participants in a clinical trial evaluating the efficacy of combined conservative therapies for base of thumb OA (COMBO). METHODS: Functional Index for Hand Osteoarthritis (FIHOA) scores and Visual Analogue Scale (VAS) scores for pain were recorded for the index hand. Bilateral isometric grip and tip-pinch strength measurements were taken, as well as posteroanterior and Eaton stress-view hand radiographs. Generalized estimating equations (GEEs), univariate, and multivariate analyses were used according to whether the data were bilateral or unilateral. RESULTS: A total of 79 females and 21 males were included, with a median Kellgren-Lawrence (KL) grade of 3 in the index hand. Higher KL and Eaton grades were associated with lower grip strength in the GEE analysis (B-coefficients of -1.25 and -1.16, and P-values of .002 and .010, respectively). Higher KL grade was also associated with poorer function and higher pain levels in the multivariable analysis (B-coefficients of 1.029 and 3.681, and P-values of .021 and .047, respectively). Lower radial subluxation ratios were associated with lower grip strength in the GEE analysis, and higher pain scores in the multivariable analysis (B-coefficients of 2.06 and -42.1, and P-values of .006 and .031, respectively). Greater pain scores were also associated with poorer function (B-coefficient 0.082, P-value .001). CONCLUSION: More advanced radiographic trapeziometacarpal OA severity is associated with lower grip strength and poorer self-reported functional outcomes. Lower subluxation ratios were associated with higher pain scores and lower grip strength.

Determinants of quality of life and hand function among people with hand osteoarthritis.

OBJECTIVE: The objectives of this study are to ascertain the determinants of quality of life (QoL) and hand function among persons with hand osteoarthritis (OA) and to assess the influence of hand function on QoL among persons with OA. METHODOLOGY: Two hundred and four participants in a clinical trial completed the baseline assessment. Demographic, socioeconomic, QoL (AqoL-4D), hand function (Functional Index for Hand Osteoarthritis, FIHOA), pain assessment, radiographic and clinical characteristics of participants were measured using standard methods. Univariate and multivariate analyses were performed to evaluate potential associations. RESULTS: We studied 204 participants (76% female, age 65.63 ± 8.13 years, body mass index 28.7 ± 6.5 kg/m2 ) with hand OA. The mean pain score of the participants on a visual analog scale was 57.8 (SD ±13.6). There was a significant, negative moderate correlation between hand function and QoL scores except for the sense domain score. Global assessment, household income and serious illness were associated with QoL (P < .001) and explained 18% of the variance of the QoL. Pain scale, Patient Global Assessment, Mental Health Score, grip strength and cyst index were associated with hand function score and explained 26% of the variance of hand function. CONCLUSION: The results indicate increasing impairment in hand function decreases the QoL of persons with hand OA. Some determinants were significantly associated with hand function and QoL. Determinants related to hand functions may be modifiable. In future, appropriate intervention strategies should be implemented, and further studies should be conducted to identify the effectiveness of those interventions.

Phenotypes in Osteoarthritis: Why Do We Need Them and Where Are We At?

This article is part of the Osteoarthritis issue for the Clinics in Geriatric Medicine journal. It covers the main aspects related to research and clinical practice of osteoarthritis phenotyping, including the concepts, the rationale for studies of OA phenotypes and their history, the approaches to OA phenotyping, recent advances in this area, and future directions.

Short-term pain trajectories in patients with knee osteoarthritis.

AIM: It is unknown if pain in knee osteoarthritis (KOA) follows distinct patterns over the short term. Therefore, the aim of this study was to identify whether persons with a previous history of KOA pain fluctuations have distinct trajectories of pain over 90 days and to examine associations between baseline characteristics and pain trajectories. METHOD: People with a previous history of KOA were selected from a web-based longitudinal study. Baseline variables were sex, age, being obese/overweight, years of KOA, knee injury, knee buckling, satisfactory Lubben Social Support Score, pain and stress scales, Intermittent Constant Osteoarthritis Pain Score (ICOAP), medication use, and physical activity. Participants completed a Knee Injury and Osteoarthritis Outcomes Score (KOOS) pain subscale (KOOS-p, rated 0 = extreme to 100 = no knee problems) at 10-day intervals for 90 days. Short-term KOOS-p trajectories were identified using latent growth mixture modeling and the baseline risk factors for these pain trajectories were examined. RESULTS: Participants (n = 313) had a mean age of 62.2 (SD ± 8.1) years and and a body mass index of 29.8 (SD ± 6.6) kg/m2 . The three-class latent growth mixture modeling quadratic model with best fit indices was chosen (based on lowest sample-size-adjusted Bayesian Information Criterion, high probability of belonging, interpretability). Three distinct pain trajectory clusters (over 90 days) were identified: low-moderate pain at baseline with large improvement (n = 11), minimal change in pain over 90 days (n = 248), and moderate-high pain with worsening (n = 46). Higher ICOAP (intermittent scale), perceived stress, negative affect score, and knee buckling at baseline were associated with a worse knee pain trajectory (P < 0.05). CONCLUSIONS: Persons with KOA showed unique short-term pain trajectories over 90 days, with distinct characteristics at baseline associated with each trajectory.

Multivariable Modeling of Biomarker Data From the Phase I Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium.

OBJECTIVE: To determine the optimal combination of imaging and biochemical biomarkers for use in the prediction of knee osteoarthritis (OA) progression. METHODS: The present study was a nested case-control trial from the Foundation of the National Institutes of Health OA Biomarkers Consortium that assessed study participants with a Kellgren/Lawrence grade of 1-3 who had complete biomarker data available (n = 539 to 550). Cases were participants' knees that had radiographic and pain progression between 24 and 48 months compared to baseline. Radiographic progression only was assessed in secondary analyses. Biomarkers (baseline and 24-month changes) that had a P value of <0.10 in univariate analysis were selected, including quantitative cartilage thickness and volume on magnetic resonance imaging (MRI), semiquantitative MRI markers, bone shape and area, quantitative meniscal volume, radiographic progression (trabecular bone texture [TBT]), and serum and/or urine biochemical markers. Multivariable logistic regression models were built using 3 different stepwise selection methods (complex models versus parsimonious models). RESULTS: Among baseline biomarkers, the number of locations affected by osteophytes (semiquantitative), quantitative central medial femoral and central lateral femoral cartilage thickness, patellar bone shape, and semiquantitative Hoffa-synovitis predicted OA progression in most models (C statistic 0.641-0.671). In most models, 24-month changes in semiquantitative MRI markers (effusion-synovitis, meniscal morphologic changes, and cartilage damage), quantitative central medial femoral cartilage thickness, quantitative medial tibial cartilage volume, quantitative lateral patellofemoral bone area, horizontal TBT (intercept term), and urine N-telopeptide of type I collagen predicted OA progression (C statistic 0.680-0.724). A different combination of imaging and biochemical biomarkers (baseline and 24-month change) predicted radiographic progression only, which had a higher C statistic of 0.716-0.832. CONCLUSION: The present study highlights the combination of biomarkers with potential prognostic utility in OA disease-modifying trials. Properly qualified, these biomarkers could be used to enrich future trials with participants likely to experience progression of knee OA.

High baseline pain is associated with treatment adherence in persons diagnosed with thumb base osteoarthritis: An observational study.

BACKGROUND: Thumb osteoarthritis (OA) is a common and disabling condition. Adherence to prescribed conservative interventions may affect outcomes of thumb OA trials. PURPOSE: The aim of the study was to determine whether baseline pain and hand function is associated with treatment adherence over 12 weeks in participants with thumb base OA. STUDY DESIGN: Observational cohort study nested within a randomized-controlled trial. METHODS: Ninety-four participants from the intervention group were included in the analysis. Baseline pain and function were assessed using a 100 mm Visual Analogue Scale and the Functional Index for Hand Osteoarthritis questionnaire (0-30), respectively. Participants received a combination of treatments including education, orthosis, hand exercises, and topical anti-inflammatory gel. Adherence was measured using a daily self-reported diary. Participants were classified as non-adherent, partially adherent or fully adherent if they completed none, 1 and/or 2 or all 3 of the interventions as prescribed. Ordinal logistic regression modelling was performed. RESULTS: At 12-week follow-up, half of the participants were fully adherent to the treatments (n = 46, 48.9%), 30.9% of participants were partially adherent (n = 29) and 20.2% were non-adherent (n = 19, 20.2%). High baseline pain was a significantly associated with better adherence in the unadjusted model [OR = 3.15, 95% CI (1.18, 8.42)] and adjusted model [OR = 3.20, 95% CI (1.13, 8.20)]. Baseline function was not associated with adherence [OR = 1.03, 95% CI (0.47, 2.23)]. CONCLUSION: High baseline pain was associated with better adherence in participants with thumb base OA. Higher baseline functional impairment was not associated with better adherence.

Associations between radiographic features, clinical features and ultrasound of thumb-base osteoarthritis: A secondary analysis of the COMBO study.

AIM: To investigate the associations of ultrasound and radiographic features of thumb-base osteoarthritis (OA) with thumb-base pain and hand function at baseline and 12 weeks. METHOD: Data from a randomized controlled trial conducted in participants with symptomatic radiographic thumb-base OA were analyzed. Participants who finished follow up were included in this secondary analysis. Pain and hand function were assessed using self-reported measures. All participants underwent ultrasound examinations for synovitis, power Doppler signal (PDS), and osteophytes, and underwent radiography for osteophytes, joint space narrowing (JSN), and subchondral bone sclerosis at baseline. Hand pain and function were reassessed after the 12-week follow up. The associations of ultrasound and radiographic findings with clinical features were further evaluated, using linear regression analyses, after adjustment for relevant confounding factors. RESULTS: A total of 166 participants (average age 66.2 years; 76.5% female) were included. At baseline, radiographic JSN and subchondral bone sclerosis were associated with hand function. There was a significant association between ultrasound-detected PDS and patient's global assessment (PGA) at baseline. Baseline radiographic JSN was significantly associated with the changes in stiffness and PGA from baseline to 12 weeks. There was no association between ultrasound features and changes in the clinical outcomes over 12 weeks. CONCLUSION: This study indicates that radiographic features significantly correlate with hand function, and ultrasound PDS is closely related to the PGA at baseline in thumb-base OA. Radiographic JSN may be a predictor for stiffness and PGA in thumb-base OA.

Reliability and Convergent Construct Validity of Quantitative Ultrasound for Synovitis, Meniscal Extrusion, and Osteophyte in Knee Osteoarthritis With MRI.

AIMS: To determine: 1) inter-rater reliability of quantitative measurements of ultrasound-detected synovitis, meniscal extrusion, and osteophytes; and 2) construct (convergent) validity via correlations and absolute agreements between ultrasound- and gold-standard magnetic resonance imaging (MRI)-outcomes in knee osteoarthritis. METHODS: Dynamic ultrasound images for supra-patellar synovitis, meniscal extrusion, and osteophytes were acquired and quantified by a physician operator, musculoskeletal ultrasonographer, and medical student independently. On the same day, 3T MRI images were acquired. Effusion-synovitis, meniscal extrusion, and osteophytes were quantified on sagittal or coronal proton-density-weighted fat-suppressed noncontrast TSE sequences, respectively. Intra-class correlation coefficients (ICCs), Pearson's correlations (r), and Bland-Altman plots were used to analyze inter-rater reliability, and correlations, and agreements between the two imaging modalities. RESULTS: Eighty-nine participants [48 females (53.9%)] with mean (standard deviation) age of 61.5 ± 6.9 years were included. The inter-rater reliability was excellent for osteophytes (ICC range = 0.90-0.96), meniscal extrusion (ICC range = 0.90-0.93), and synovitis (ICC range = 0.86-0.88). The correlations between ultrasound pathologies and their MRI counterparts were very strong (ICC range = 0.85-0.98) except for lateral meniscal extrusion [0.66 (95% CI, 0.52-0.76)]. Bland-Altman plots showed 0.01, 0.05, 0.10, 0.53, and 0.60 mm larger size in ultrasound medial tibial and medial femoral osteophytes, medial meniscal extrusions, synovitis, and lateral meniscal extrusions with 95% limits of agreements [±0.39, ±0.44, ±0.85, ±0.70, and ±0.90 (SDs)] than MRI measures, respectively. The lines of equality were within 95% CI of the mean differences (bias) only for medial osteophytes and medial meniscal extrusion. CONCLUSION: The quantitative assessment of synovitis, meniscal extrusion, and osteophytes generally showed excellent inter-rater reliability and strong correlations with MRI-based measurements. Absolute agreement was strong for medial tibiofemoral pathologies.

Efficacy and cost-effectiveness of Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis: protocol for a randomised placebo-controlled trial (the SCUlpTOR trial).

INTRODUCTION: Knee osteoarthritis (KOA) is a highly prevalent disabling joint disease. Intra-articular stem cell therapy is increasingly being used for treating KOA with little high-quality evidence to support its use. The aim of this study is to investigate the efficacy, safety and cost-effectiveness of allogeneic mesenchymal stem cells (Cymerus MSCs) for treating symptomatic tibiofemoral KOA and improving knee structure over 24 months. METHODS AND ANALYSIS: The Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis study is a phase III, multi-centre, parallel, superiority, randomised, double-blind, placebo-controlled trial, which will be conducted in Sydney and Hobart, Australia. 440 participants (220 per arm) aged over 40 years with painful KOA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) with medial minimum joint space width between 1 and 4 mm in the study knee will be recruited from the community and randomly allocated to receive either intra-articular MSCs or saline at baseline, week 3 and week 52. The coprimary outcomes will be the proportion of participants achieving patient-acceptable symptom state for knee pain at 24 months and quantitative central medial femorotibial compartment cartilage thickness change from baseline to 24 months. Main secondary outcomes include change in knee pain, Patient Global Assessment, physical function, quality of life and other structural changes. Additional data for cost-effectiveness analysis will also be recorded. Adverse events will be monitored throughout the study. The primary analysis will be conducted using modified intention-to-treat. ETHICS AND DISSEMINATION: This protocol has been approved by The University of Sydney (USYD) Human Research Ethics Committee (HREC) #: 2020/119 and The University of Tasmania (UTAS) HREC #: H0021868. All participants will be required to provide informed consent. Dissemination will occur through conferences, social media, and scientific publications. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trials Registry (ACTRN12620000870954); U1111-1234-4897.