Osteoarthritis Trials Research Articles

Association Between Participant Retention and the Proportion of Included Elderly People in Rheumatology Trials: Results From a Series of Exploratory Meta-Regression Analyses.

The elderly, a population defined by an age of ≥65 years, are underrepresented in rheumatology trials, possibly due to investigators' concerns of increased premature discontinuations in higher age groups. The present study was undertaken to evaluate whether the proportion of included elderly individuals (PE) is independently associated with participant retention in rheumatology trials. Medline was searched for randomized controlled trials (RCTs) in rheumatoid arthritis (RA) and osteoarthritis (OA) of any intervention (years 2016 and 2017). PE was either extracted from the research manuscript or estimated from an assumed (truncated) normal distribution. We used mixed-effects meta-regression models including several covariates to assess whether there is an independent association between PE and participant retention. Using sensitivity analyses, we evaluated whether associations were connected to attrition due to lack of efficacy (LoE) or adverse events (AE). In total, 243 RCTs comprising >48,000 participants were included. Pooled participant retention was 88%. PE was not associated with retention in the unadjusted (P = 0.97) or adjusted (all: P ≥ 0.14) models. Of all covariates, only study duration and type of intervention were associated with retention (both: P < 0.001). Post hoc analyses allowing for interaction revealed a small but statistically significant positive association between PE and retention in pharmacologic interventions and a negative association in physical/physiotherapeutic interventions (overall P for interaction = 0.05). No associations were found for PE and attrition due to LoE or AE. Participant retention in RA and OA trials is high and not associated with PE. These findings should motivate investigators to include more elderly participants in rheumatology trials.

Effect of daily 2000 IU versus 800 IU vitamin D on blood pressure among adults age 60 years and older: a randomized clinical trial

Observational studies report higher blood pressure (BP) among individuals with lower 25-hydroxyvitamin D concentration. Whether dosage of vitamin D supplementation has a differential effect on BP control remains unclear. The study aimed to determine if daily vitamin D supplementation with 2000 IU is more effective than 800 IU for BP control among older adults. This randomized, double-blind, ancillary trial of the Zurich Multiple Endpoint Vitamin D Trial in Knee Osteoarthritis enrolled adults aged ≥60 y who underwent elective surgery due to severe knee osteoarthritis. Participants were randomly assigned to receive high dose (2000 IU) or standard dose (800 IU) daily vitamin D3 for 24 mo. Outcomes included daytime and 24-h mean systolic BP. BP variability and serum 25-hydroxyvitamin D concentration were examined in a post hoc and observational analysis. Of the 273 participants randomly assigned, 250 participants completed a follow-up 24-h ambulatory BP monitoring (mean age: 70.4±6.4 y; 47.2% men). The difference in daytime mean systolic BP reduction between the 2000 IU (n=123) and 800 IU (n=127) groups was not statistically significant (-2.75 mm Hg vs. -3.94 mm Hg; difference: 1.18 mm Hg; 95% CI: -0.68, 3.05; P=0.21), consistent with 24-h mean systolic BP. However, systolic BP variability was significantly reduced with 2000 IU (average real variability: -0.37 mm Hg) compared to 800 IU vitamin D3 (0.11 mm Hg; difference: -0.48 mm Hg; 95% CI: -0.94, -0.01; P=0.045). Independent of group allocation, maximal reductions in mean BP were observed at 28.7 ng/mL of achieved serum 25-hydroxyvitamin D concentrations. While daily 2000 IU and 800 IU vitamin D3 reduced mean systolic BP over 2 y to a small and similar extent, 2000 IU reduced mean systolic BP variability significantly more compared with 800 IU. However, without a placebo control group we cannot ascertain whether vitamin D supplementation effectively reduces BP.This trial was registered at www.clinicaltrials.gov as NCT00599807.

Fibroblast growth factor signalling in osteoarthritis and cartilage repair.

Regulated fibroblast growth factor (FGF) signalling is a prerequisite for the correct development and homeostasis of articular cartilage, as evidenced by the fact that aberrant FGF signalling contributes to the maldevelopment of joints and to the onset and progression of osteoarthritis. Of the four FGF receptors (FGFRs 1-4), FGFR1 and FGFR3 are strongly implicated in osteoarthritis, and FGFR1 antagonists, as well as agonists of FGFR3, have shown therapeutic efficacy in mouse models of spontaneous and surgically induced osteoarthritis. FGF18, a high affinity ligand for FGFR3, is the only FGF-based drug currently in clinical trials for osteoarthritis. This Review covers the latest advances in our understanding of the molecular mechanisms that regulate FGF signalling during normal joint development and in the pathogenesis of osteoarthritis. Strategies for FGF signalling-based treatment of osteoarthritis and for cartilage repair in animal models and clinical trials are also introduced. An improved understanding of FGF signalling from a structural biology perspective, and of its roles in skeletal development and diseases, could unlock new avenues for discovery of modulators of FGF signalling that can slow or stop the progression of osteoarthritis.

Multimodal Interventions Including Rehabilitation Exercise for Older Adults With Chronic Musculoskeletal Pain: A Systematic Review and Meta-analyses of Randomized Controlled Trials.

Musculoskeletal disorders (MSKDs) are the most common causes of disabilities for older adults. The aim of this systematic review and meta-analysis is to assess the effectiveness of multimodal interventions including exercise rehabilitation for older adults with chronic MSKDs. A literature search was conducted up to February 2019 in 5 bibliographical databases to identify randomized controlled trials (RCTs) that compared multimodal interventions including exercise rehabilitation with usual medical care or no intervention. Randomized controlled trials were assessed with the Cochrane risk-of-bias tool. Meta-analyses were performed and pooled mean differences (MDs) or standardized mean differences (SMDs) were calculated. Sixteen RCTs (n = 2322 participants) were included. One RCT was considered at low risk of bias, 8 had some concerns of bias, and 7 had a high risk of bias. Participants suffered from hip or knee osteoarthritis (OA) (n = 12 RCTs), low back pain (LBP) (n = 2 RCTs) and generalized chronic pain (GCP) (n = 2 RCTs). Multimodal interventions were significantly more effective than usual care to decrease pain (visual analog scale, out of 10 points) in the short term, MD: -0.71 (95% confidence interval [CI] -1.08 to -0.34, n = 900), and in the long term: MD: -0.52 (95% CI -0.98 to -0.05, n = 575), but these differences are not considered clinically important. In terms of disabilities, multimodal interventions were also significantly more effective than usual care. The SMDs were -0.47 (95% CI -0.61 to -0.34, n = 903) and -0.29 (95% CI -0.46 to -0.13, n = 568) for OA trials in the short and long terms, respectively, and -0.47 (95% CI -0.81 to -0.12, n = 211) for LBP and GCP trials in the short term. The magnitude of these effects may be considered as small to moderate. Multimodal intervention including exercise rehabilitation combined with usual medical care is an efficacious therapeutic option to reduce disabilities in older adults with chronic MSKDs. A significant but not clinically important effect was observed for pain. The most beneficial component of the multimodal interventions in terms of education, exercises, or medication remains to be determined.

Microrna profile of mesenchymal stromal cells: a tool to predict their therapeutic efficasy in osteoarthritis

Background & Aim Osteoarthritis (OA) is a joint disease affecting > 5 million Canadians. Patients have limited palliative and joint-replacement surgical options, emphasizing the need for new curative therapies. Stromal cell therapy is emerging as a compelling treatment for OA. Our first-in-Canada Ph1/2 trial with bone marrow mesenchymal stromal cells (BM-MSCs) in OA patients showed significant improvements in patient outcomes. Although, MSCs showed beneficial effects in all the patients, we found variabilities in MSCs efficacy among participants. The goal of this study is to identify novel microRNAs (miRs) that correlate with therapeutic efficacy of MSCs in the context of OA. Methods, Results & Conclusion We have identified a panel of predictive anti-inflammatory markers (i.e. IL10, HGF, IL6, TSG6, PGE2) on MSCs that is strongly indicative of clinical efficacy in OA. To expend this panel, we conducted an unbiased miR sequencing on our clinical trial MSC samples. We are correlating differential miR expression with patient outcomes. We identified 25 miRs differentially expressed between MSCs from responder (5/5 on KOOS sub-scale responses are clinically significant) and mild responder (2-3/5 KOOS sub-scale responses are clinically significant) participants. Amongst these, 12 miRs showed higher expression in MSCs from responder participants and 13 miRs appeared to be expressed at lower level when compared to those levels in MSCs from mild responder participants. Interestingly, miR target and pathway analysis revealed that the identified miRs are associated with Toll like receptors, IL-4, IL-13, IL12, IL-1 and IL-10 cascades; as well as TGF-β, wnt and Smad signaling. Thus, contributing to immune response, fibrosis and consequently OA pathology. We have selected 10 miRs out of 25 differentially expressed miRs based on the relevance of their targets to OA pathology for further analysis. Currently, we are verifying these miRs by qPCR and their significance in OA pathology will be confirmed via knock down/overexpression experiments. This will help us to better understand and predict potent MSCs, and/or OA patients that are responders to MSC therapies. In conclusion, microRNA profile of MSCs contributes to therapeutic efficacy of MSCs. Understanding therapeutically relevant mechanism of action of MSCs will help to develop enhanced MSCs; and define potency criterion for screening effective MSCs in OA patients. This in turn will enable a successful MSC pivotal clinical trial in OA.

Biological Agents in OA - Hopes and Disappointments

Purpose: To review the trial in humans using biologics in osteoarthritis (OA) which can be can be categorized according to the main target: pain, structure or both. Methods: A literature review (Medline, Cochrane, Embase) of the most recent trials in OA using biologics Results: The analgesic effect of anti-nerve growth factor (NGF) was initially dramatic using high dose and intravenous route of administration, but emerging severe arthropathies (in the targeted knee but not only) have dampened down this enthusiasm. Most recent trials used anti NGF Mab, administered subcutaneously, with lower dose, shorter interval of administration and without concomitant use of NSAIDS. The effect on pain is still superior to placebo but with a much lesser magnitude. Unfortunately, long term follow-up in those trials still shows a concern in terms safety profile. Thus, Patients who will benefit of this anti NGF therapy should be strictly selected and followed up. Biologics agents targeting main cytokines (interleukines 1 and 6, tumor necrosis alpha) have been tested in knee OA and in hand OA. The first randomized controled trial in humans using a single local administration of the antagonist of IL-1, at 2 doses: 50 and 150 mg, failed to show an analgesic effect, except at day 3 with the highest dose. This negative result has been confirmed in trials using systemic administration of monoclonal antibodies directed against only IL1-β or against IL-1 α and Il-1 β in patients with knee OA and in patients with hand OA. However, in the CANTOR trial recruiting patients with cardiovascular disease treated with canakinumab, post hoc analysis indicated that the patients in the verum group, shows a dramatic decrease in the number of total joint replacement (hip and knee) (about 50%). This might open a door for a possible anti IL-1 strategy dedicated to patients with some part of systemic inflammation. Most of trial with anti TNF inhibitors have been performed in patients with erosive digital hand OA and all were negative on pain and on structure (measured by different parameters on magnetic resonance imaging). Finally the last cytokine that has been targeted is IL-6. Results of the RCP trial in hand OA are ongoing. Taking all together, biologics in OA are really disappointing, raising more questions than answers: choice of the targets, choice of selected phenotype of pain, selection of the route of administration, too short time of intra articular residence of the drug etc. News biologics targeting WNT, bradykinin or anti sense micro RNA are under development but so far, the preliminary results needs to be confirmed in large trials in humans. Finally, the last option is to try to stimulate the cartilage repair response which is naturally weak. Fibroblast growth factor 18 (sprifremin), an anabolic and mitogenic factor for the chondrocyte, has been tested against placebo in an ambitious trial over 5 years with 2 years of treatment and 3 years of follow-up. The drug was intra-articularly delivered every 6 months or every 12 months, with 2 different dosages. At the first end point, at year 2, with the highest dose of FGF-18, a statistically significant difference with the placebo was observed on the cartilage volume measured by MRI in the global, medial and lateral compartment on the involved knee. Unfortunately, there was no effect on pain in the ITT population, except in a sub group of patients with a minimum threshold of pain and an initial joint space width between 1.5mm and 3.5 mm (around one third of the population) show a significant effect on pain reduction compared to placebo. If results of this long term trial are confirmed in others trials, FGF-18 may constitute the first real disease modifying drug in OA. Conclusions Conclusion: The trials in humans using biologics are disappointing. We should keep in mind that blocking a single mediator will not stop the catabolic process in OA. Thus in the next future, we should probably adapt a drug owing to the evolution of the disease, to the profile of patient, to the radiological aspect of the disease and to the phenotype of pain. The story is just starting ⋯⋯

Microrna profile of mesenchymal stromal cells: A tool to predict their therapeutic efficacy in osteoarthritis

Purpose: Osteoarthritis (OA) is a joint disease affecting > 5 million Canadians. Patients have limited palliative and joint-replacement surgical options, emphasizing the need for new curative therapies. Stromal cell therapy is emerging as a compelling treatment for OA. Our first-in-Canada Ph1/2 trial with bone marrow mesenchymal stromal cells (BM-MSCs) in OA patients showed significant improvements in patient outcomes. Pro-inflammatory monocytes/macrophages were reduced in the synovial fluid (SF), suggestive of a clinical MSC anti-inflammatory action. Although, MSCs showed beneficial effects in all the patients, we found variabilities in MSCs efficacy among participants. The goal of this study is to identify novel microRNAs (miRs) that correlate with therapeutic efficacy of MSCs in the context of OA. Methods: We have identified a panel of predictive anti-inflammatory markers (i.e. IL10, HGF, IL6, TSG6, PGE2) on MSCs that is strongly indicative of clinical efficacy in OA. To expend this panel, we have conducted an unbiased miR sequencing on our clinical trial MSC samples exposed to pooled synovial fluid from eight OA patients in the same trial. We are correlating differential miR expression with patient outcomes. Results: We have identified 25 miRs differentially expressed between MSCs from responder (5/ out of 5 KOOS sub-scale responses are clinically significant) and mild responder (2-3/5 KOOS sub-scale responses are clinically significant) participants. Amongst these, 12 miRs showed higher expression in MSCs from responder participants and 13 miRs appeared to be expressed at lower level when compared to those levels in MSCs from mild responder participants. Interestingly, we found that the identified miRs are associated with immune response, fibrosis, OA pathology and three linage differentiation of MSCs. Currently, we are verifying the miRs and their targets by qPCR to better understand and predict potent MSCs, and/or OA patients that are responders to MSC therapies. Conclusions: microRNA profile of MSCs contributes to therapeutic efficacy of MSCs. Understanding therapeutically relevant mechanism of action of MSCs will help to develop enhanced MSCs; and define potency criterion for screening effective MSCs in OA patients. This in turn will enable a successful MSC pivotal clinical trial in OA.

Clinical trial data analysis of the placebo effect in osteoarthritis

Purpose: Despite an increasing awareness of the placebo effect in clinical trials in osteoarthritis (OA), there remains a need to better account for this effect in clinical trial analyses. The placebo effect is not a random process, but has been shown to be strongly influenced by quantifiable characteristics of the patient and the clinical context. We have analysed available placebo data in order to model a placebo response with consideration of the different types of therapy used in the clinical trials.

Objective performance tests assess aspects of function not captured by self-report in knee osteoarthritis

Purpose: Knee osteoarthritis (OA) may lead to substantial functional limitation, which can be assessed objectively with validated performance tests or using self-report data. The relationships between the findings of objective performance tests and self-report measures of functional status have received little investigation. We sought to determine whether the performance tests are independent of one another, whether they capture different information from self-report measures of function, and whether they are influenced by features of chronic pain including anxiety and depression, neuropathic pain, widespread pain, and pain catastrophizing. Methods: We used baseline data from participants enrolled in the ORBIT Registry (Osteoarthritis Registry of Biomarker and Imaging Trajectories). At study entry, participants were 40+ years old and had evidence of both symptomatic and radiographic knee OA (Kellgren-Lawrence grade 2-3) in at least one knee. Self-reported pain of the most bothersome knee (index knee) was ascertained using the Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain scale and functional status with the KOOS ADL scale (0-100, 100 best). Subjects completed the five-item Mental Health Index (MHI-5, a measure of anxiety and depressive symptoms), the Neuropathic Pain Scale (NPS), a widespread pain index (WPI; sum of 23 possible musculoskeletal pain locations), and the Pain Catastrophizing Scale (PCS). Performance testing included the 40-meter fast paced walk (40m Walk), Timed-Up-and-Go (TUG), timed single leg balance test (SLB), and 30-second sit-to-stand (30s STS) tests. We used Pearson correlation coefficients to examine linear associations among the four performance tests and the associations between each performance test and the self-report measures of pain, functional status and chronic pain features. We further investigated the associations between performance tests and self-reported knee pain and function with adjustment for MHI-5, WPI, PCS and NPS using partial correlations. Results: We assessed 78 subjects with mean age 63.1 (SD 10.0), mean body mass index (BMI) 30.2 (SD 5.4), 69% female. The mean (SD) values for the performance tests included: 40m Walk 27.9 (5.6) seconds, TUG 9.1 (2.2) seconds, SLB 21.8 (19.7) seconds, and 30s STS 11.7 (4.5) stands. The individual performance measures had modest correlations with one another (Pearson r ranging from 0.33 to 0.74). The highest correlation (r = 0.74) was between TUG and 40m Walk, indicating that just 50% of the variability in TUG was explained by variability in 40m Walk. ORBIT participants had an average KOOS ADL score of 66.1 (18.2) and KOOS Pain of 74.6 (19.8). The correlations between performance tests and KOOS Pain, KOOS ADL, PCS, NPS, WPI and MHI-5 are shown in the Table. None of the correlations exceeded 0.40. Correlations were weakest for the associations between widespread pain and MHI-5 scores and the performance tests (all ≤ 0.23). Partial correlations between KOOS ADL scores and the performance tests were 28-64% lower than the crude correlations, adjusting for PCS, NPS, widespread pain and MHI-5 (Table).Table 1Pearson correlation coefficients for associations between performance tests and self-report measures of pain, function and chronic pain features40 Meter WalkTimed Up and GoTimed Single Leg Balance30-Second Sit to StandKOOS Pain-0.25-0.260.290.40KOOS ADL-0.33-0.290.400.40Pain Catastrophizing0.340.26-0.19-0.24Neuropathic Pain Scale0.320.20-0.24-0.23Widespread Pain0.15-0.08-0.23-0.18Mental Health Index-0.10-0.050.170.03Partial correlations adjusting for pain catastrophizing, NPS, widespread pain, MHI-5KOOS Pain-0.15-0.240.280.30KOOS ADL-0.12-0.200.290.25 Open table in a new tab Conclusions: 40m Walk, TUG, SLB and 30s STS each assess different aspects of functional capacity in knee OA patients. Self-reported functional status in persons with knee OA has weak to modest correlations with objective measures of functional status, which are further attenuated with adjustment for pain catastrophizing, neuropathic symptoms, widespread pain and anxiety and depression. These data suggest that objective performance tests capture elements of physical functional status in persons with knee OA that are not assessed well by frequently used self-report measures of functional status. Objective performance tests are not influenced strongly by other features of chronic pain such as catastrophizing, neuropathic pain symptoms, widespread pain or depression and anxiety. These data point to the importance of adding objective measures to the assessment of functional status in OA trials.

The relation of MRI-based cartilage lesions to knee replacement and knee pain severity in the most study

Purpose: Historically, clinical trials of knee osteoarthritis (OA) have relied on radiographic joint-space width as the primary structural endpoint. Recently, the FDA has indicated that imaging biomarkers of relevance to clinically important outcomes may be considered with sufficiently supportive data, including MRI-based cartilage evaluations. Knee replacement (KR) is considered a clinically relevant endpoint for knee OA since it is typically performed for severe symptomatic knee OA that has failed other therapies and thus considered ‘end-stage’.

Is physical activity assessed with accelerometers more sensitive to knee pain than conventional functional performance tests? - data from the osteoarthritis initiative

Purpose: Functional performance measures (FPMs) represent important instruments in epidemiological and clinical trials of knee osteoarthritis, as they provide potentially more objective information than patient reported outcomes (PROs). We have shown previously that, amongst different FPMs, the Chair Stand Test (CST) is more sensitive to different levels of knee pain than the 20m and 400m walk test. Given the current interest in the use of wearables for functional evaluations in clinical trials and clinical practice, the aim of the current work was to analyze whether physical activity parameters obtained from accelerometry better discriminate between various knee pain strata than the CST.

Use of an activity tracker as a measurement tool in a knee osteoarthritis clinical trial (active-oa trial)

Purpose: In osteoarthritis (OA) clinical trials, reliable and responsive outcome measures to document improvements in function are limited. Current measures predominately rely on self-reported function tests, but they are poorly responsive, subject to misreporting and the placebo response. Functional measures such as observed timed-up-and-go test (TUG) and six-minute walk test (6MWT) are advocated, but their relevance may be limited in the context of a patient’s real-world functional capabilities. Using physical activity tracking devices/wearables as a way to measure improvements in function in day-to-day life is potentially an attractive and easily available alternative to conventional OA trial outcome measures. Consumer-level activity monitors have shown high validity for measurement of steps when compared with research-grade devices. The aim of this study is to assess if the use of an activity tracker in an OA clinical trial is a responsive measurement tool. Secondary objectives include the assessment of the feasibility of an activity tracker use and validity of an activity tracker in an OA clinical trial. Methods: This was a prospective cohort study nested in the Platelet-rich Plasma as a Symptom and Disease-Modifying Treatment for Knee Osteoarthritis - the RESTORE trial (ACTRN12617000853347). Consecutive participants recruited to the RESTORE trial were invited to join this study. Participants ≥ 50 years old with painful knee OA and Kellgren and Lawrence (KL) grade 2-3 were included. Participants were asked to wear an activity tracker (Fitbit Flex (2), Fitbit Inc, San Francisco, CA, USA) for seven consecutive days at the time of baseline assessment (week 0, before their injection therapies), and at the 2-month follow-up assessment. The primary outcome was mean steps per day calculated from a seven-day wear of an activity tracker. To determine the responsiveness of the activity tracker, the standardised response mean (SRM) was calculated for mean steps per day between baseline and 2 months; dividing the mean change scores by the standard deviation of the mean change scores. To investigate validity, correlation coefficient (r) was used to examine the relationship between change in the mean steps per day between baseline and 2 months and participant-perceived global ratings of change (global improvement in function) at 2 months. The relationship of change in mean steps per day and change in secondary outcomes between baseline and 2 months was examined: global improvement (pain and overall improvement), 6MWT, TUG, numeric rating scale (NRS) for pain, knee osteoarthritis outcome score (KOOS), and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC). Correlation coefficients were estimated for continuous variables. The activity tracker wear was deemed feasible if >70% of patients comply with wearing the trackers at least six out of seven days for each measurement period. Results: 65 participants were recruited (mean age = 61.3 years; 46% female; mean BMI 28.7 kg/m2; 41.5% KLG 2 and 58.5% KLG 3). 8 participants dropped out or had activity tracker misuse/failure at the 2-month follow-up. The SRM was -0.02 (95% CI -0.38 to 0.35) for mean steps per day between baseline and 2 months. The proportion of participants who wore the trackers for six out of seven days was 98% at baseline and 100% at 2-months follow-up. The correlation with change in mean steps per day at baseline and 2 months and outcome measures are detailed in table 1. Conclusions: The use of an activity tracker in a real-world OA clinical trial demonstrated small correlations between change in steps at baseline and 2 months follow-up with global improvement overall and WOMAC function. The use of a tracker is a feasible option with demonstration of good compliance amongst the trial participants. This study has not shown significant responsiveness or validity of the activity trackers in comparison with other regularly utilised outcome measures in OA clinical trials. However, the main challenge of this study is the lack of a gold standard outcome measure to validate against. Due to the complex nature of pain, perceived quality of life, and the interplay between these factors and measured function, a lack of correlation does not necessarily represent a failed validation in this context.

Comparative effectiveness of international osteoarthritis management program clinical cohorts: a project of the oarsi joint effort initiative in collaboration with the OA trial bank

Purpose: There is growing international interest in the implementation of structured osteoarthritis management programs (OAMPs) to deliver best evidence osteoarthritis (OA) care. A consortium of researchers, clinicians and consumers concerned with optimising implementation of OAMPs have established the ‘Joint Effort’ Initiative (the Initiative), endorsed by the Osteoarthritis Research Society International (OARSI) in 2018. A priority action of the Initiative is to evaluate the outcomes and implementation of existing OAMPs.

Self-reported adherence is not influenced by pain or functional outcomes in thumb base osteoarthritis trial

Self-reported adherence is not influenced by pain or functional outcomes in thumb base osteoarthritis trial

Current status of functional MRI of osteoarthritis for diagnosis and prognosis.

Osteoarthritis is a major source of disability, pain and socioeconomic cost worldwide. The epidemiology of the disorder is multifactorial including genetic, biological and biomechanical components, some of them detectable by MRI. This review provides the most recent update on MRI biomarkers which can provide functional information of the joint structures for diagnosis, prognosis and treatment response monitoring in osteoarthritis trials. Compositional or functional MRI can provide clinicians with valuable information on glycosaminoglycan content (chemical exchange saturation transfer, sodium MRI, T1ρ) and collagen organization (T2, T2, apparent diffusion coefficient, magnetization transfer) in joint structures. Other parameters may also provide useful information, such as volumetric measurements of joint structures or advanced image data postprocessing and analysis. Automated tools seem to have a great potential to be included in these efforts providing standardization and acceleration of the image data analysis process. Functional or compositional MRI has great potential to provide noninvasive imaging biomarkers for osteoarthritis. Osteoarthritis as a whole joint condition needs to be diagnosed in early stages to facilitate selection of patients into clinical trials and/or to measure treatment effectiveness. Advanced evaluation including machine learning, neural networks and multidimensional data analysis allow for wall-to-wall understanding of parameter interactions and their role in clinical evaluation of osteoarthritis.

Time-saving opportunities in knee osteoarthritis: T2 mapping and structural imaging of the knee using a single 5-min MRI scan

ObjectivesTo assess the discriminative power of a 5-min quantitative double-echo steady-state (qDESS) sequence for simultaneous T2 measurements of cartilage and meniscus, and structural knee osteoarthritis (OA) assessment, in a clinical OA population, using radiographic knee OA as reference standard.MethodsFifty-three subjects were included and divided over three groups based on radiographic and clinical knee OA: 20 subjects with no OA (Kellgren-Lawrence grade (KLG) 0), 18 with mild OA (KLG2), and 15 with moderate OA (KLG3). All patients underwent a 5-min qDESS scan. We measured T2 relaxation times in four cartilage and four meniscus regions of interest (ROIs) and performed structural OA evaluation with the MRI Osteoarthritis Knee Score (MOAKS) using qDESS with multiplanar reformatting. Between-group differences in T2 values and MOAKS were calculated using ANOVA. Correlations of the reference standard (i.e., radiographic knee OA) with T2 and MOAKS were assessed with correlation analyses for ordinal variables.ResultsIn cartilage, mean T2 values were 36.1 ± SD 4.3, 40.6 ± 5.9, and 47.1 ± 4.3 ms for no, mild, and moderate OA, respectively (p < 0.001). In menisci, mean T2 values were 15 ± 3.6, 17.5 ± 3.8, and 20.6 ± 4.7 ms for no, mild, and moderate OA, respectively (p < 0.001). Statistically significant correlations were found between radiographic OA and T2 and between radiographic OA and MOAKS in all ROIs (p < 0.05).ConclusionQuantitative T2 and structural assessment of cartilage and meniscus, using a single 5-min qDESS scan, can distinguish between different grades of radiographic OA, demonstrating the potential of qDESS as an efficient tool for OA imaging.Key Points• Quantitative T2values of cartilage and meniscus as well as structural assessment of the knee with a single 5-min quantitative double-echo steady-state (qDESS) scan can distinguish between different grades of knee osteoarthritis (OA).• Quantitative and structural qDESS-based measurements correlate significantly with the reference standard, radiographic degree of OA, for all cartilage and meniscus regions.• By providing quantitative measurements and diagnostic image quality in one rapid MRI scan, qDESS has great potential for application in large-scale clinical trials in knee OA.

Selective reporting bias due to discrepancies between registered and published outcomes in osteoarthritis trials.

Aim: Outcome reporting bias (ORB) occurs when outcomes planned in a study protocol are subsequently not reported or are partially reported. Our aim was to analyze ORB in randomized controlled trials (RCTs) about conservative interventions for osteoarthritis (OA) by comparing registered protocols and published manuscripts, as well as association between study funding type and intervention type, and ORB in those RCTs. Materials & methods: We analyzed RCTs that were published in a peer-review journal and analyzed any type of conservative intervention for treatment of OA in humans that reported in the manuscript registration in a public clinical trial registry and provided unique registration identifier. We extracted data indicating ORB by comparing outcomes in protocol and published article, and characteristics of trials. Results: In 190 (57%) of 334 included RCTs, it was indicated in the manuscript that a trial was registered. In 48% of trials we found discrepancies in number, type or time point of primary efficacy outcome between protocol and manuscript. Significantly less discrepancies in primary efficacy outcomes between protocols and published articles were found in trials funded by a commercial sponsor (p=0.0062) and trials of pharmacological interventions (p=0.0016). Conclusion: Trials about conservative therapies for OA have high prevalence of discrepancies between protocol and publication, and frequent ORB. This may mislead readers of published results because it has been shown that ORB can lead to both overestimation and underestimation of effects of interventions, depending on the intervention and outcome. Efforts to prevent nonregistration of protocols and selective reporting are needed.

Domains rated as important by patients with hand osteoarthritis.

No data exist on patient participation in the selection of core domains for clinical trials of hand osteoarthritis (HOA). We aim to explore HOA patients' perspectives in the relative importance of domains. Seven domains affecting patients' lives were derived from a prior qualitative study. We recruited consecutive patients with symptomatic HOA to rate on 11-point numeric rating scales for each domain, from 0 representing "not important at all" to 10 representing "most important", with consideration in two scenarios: (a) how important the domains are in affecting their current lives; and (b) how important the domains are when there are treatments for HOA (eg exercise or drugs). Forty-five patients (91% female; mean age±standard deviation 64.3±7.5years) with mild HOA symptoms were included. Of these, 31%-42% rated current impact of HOA in various domains as highly important. Seven domains with rated scores of ≥7/10 in importance were endorsed for clinical trials in the following order: pain and HOA symptoms (endorsed by 77.8% of patients), physical function (66.7%), ability to participate in social roles (64.4%), ability to participate in social activities (62.2%), work productivity (62.2%), emotional health (60%), and appearance of fingers (55.6%). The preliminary important domains as endorsed by patients with HOA for inclusion into clinical trials were explored. Apart from pain and physical function, further research is needed to refine other domains of impact, such as participation, emotional health and aesthetic concerns, as core domain sets for HOA.

Turmeric/curcumin

Curcumin is the primary curcuminoid present in the turmeric plant, Curcuma longa, and gives turmeric its orange-yellow color. The names “turmeric” and “curcumin” are often used interchangeably, especially for the spice used in cooking. Turmeric extracts and curcumin are used primarily for osteoarthritis (OA) and inflammatory conditions. They also may have activity in diabetes, obesity, and cardiovascular diseases. Curcumin has anti-inflammatory activity via inhibition of arachidonic acid, lipoxygenase, COX, nuclear factor-kappa B, tumor necrosis factor-alpha, and interleukins. In a study of knee OA, 30 mg of curcumin extract three times daily decreased COX-2 secretion into synovial fluid, similar to the effect of 25 mg of diclofenac three times daily. In another study of knee OA, serum levels of Coll2-1, a cartilage-specific biomarker, were significantly reduced. Clinical trials demonstrating benefit have used 1,000–1,500 mg per day in divided doses. The oral bioavailability of turmeric/curcumin may be low, so products that contain black pepper extracts or other compounds as absorption enhancers are preferred. The most common adverse effects are GI discomfort and nausea. Human studies have shown good tolerance even with higher dosages. Curcumin inhibits platelet aggregation in vitro and in vivo, so patients taking antithrombotic agents such as warfarin or clopidogrel should use this botanical cautiously. Multiple small studies have evaluated curcumin and related compounds for treatment of OA and rheumatoid arthritis (RA), alone or in combination with other natural products. Although some studies were placebo controlled, others compared curcumin with NSAIDs. An Iranian study of 40 participants with knee OA compared treatment with 1,500 mg of curcuminoids per day in three divided doses with placebo for 6 weeks. Treatment with curcuminoids resulted in greater improvements on standard OA assessment tools, including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne’s pain functional index, and visual analogue scale (VAS), with few adverse effects. Pain and physical function also improved, but not stiffness. An Indian trial1Amalraj A. et al.J Med Food. 2017; 20: 1022-1030Crossref PubMed Scopus (62) Google Scholar randomized 36 participants with RA into three groups to receive 250 mg or 500 mg of curcumin or placebo twice daily for 90 days. The active treatment groups had significant improvement in their clinical symptoms at study end. Favorable changes in disease markers also occurred, including the erythrocyte sedimentation rate, C-reactive protein levels, and rheumatoid factor values. A 2018 Indian study2Karlapudi V. et al.J Med Food. 2018; 21: 511-520Crossref PubMed Scopus (9) Google Scholar of 105 patients with OA evaluated a combination curcumin product versus placebo in a 90-day trial that demonstrated improvements in pain, physical function, and quality of life. A noninferiority trial of 367 participants with OA compared 1,500 mg of curcumin extract daily to 1,200 mg of ibuprofen daily for 4 weeks. The WOMAC total, pain, stiffness, and function scores were similar between the curcumin and ibuprofen groups, with about two-thirds of participants rating themselves as “improved” on the global assessment. Curcumin-treated patients had less abdominal pain. An OA trial of 120 participants evaluated several natural products. Patients were randomized to receive 500 mg of curcumin extract, 750 mg of glucosamine sulfate, curcumin extract/glucosamine sulfate, or placebo twice daily for 42 days. The VAS pain scores were reduced from baseline, with the greatest reduction in the curcumin extract group. The WOMAC scores were also improved in the curcumin extract group. Improvements from baseline were noted with glucosamine, but less than those with curcumin. Evidence for curcumin/turmeric is promising given its safety, and it may be an option for patients with mild OA symptoms. Inform patients that the curcumin formulations used in studies may not be widely available. Products containing compounds such as black pepper extract are recommended and should be taken with meals with fats or oils to enhance absorption.

Osteoartrozda yeni tedavi yöntemleri

Osteoartroz (OA) en yaygın artrit şeklidir. OA'da klinik çalışmaların sunduğu birçok zorluğa rağmen, hastalık patogenezi, hastalık süreci ve ağrının tedavisinin yanı sıra altta yatan hastalığın tedavisinde birçok yeni farmakolojik tedaviler ve klinik araştırmalar vardır. Yeni farmakolojik ajanlar ile klinikte OA'da semptomların ve hastalık sürecinin iyileştirilmesine yönelik fırsatlar ufukta görünmektedir.