Purpose (the aim of the study): The Osteoarthritis Research Society International (OARSI) has launched an initiative to develop classification criteria for early-stage symptomatic knee osteoarthritis (EsSKOA). The goal is to establish a standardized way to identify and enrol individuals with symptomatic knee OA but without established or later-stage knee OA into clinical studies, i.e., at an earlier stage of symptomatic disease. The classification criteria must accurately discriminate individuals with EsSKOA both from individuals with other causes for their knee symptoms and individuals with established or later-stage knee OA.

ObjectiveTo determine i) pain phenotypes (PP) in people with early-stage knee osteoarthritis (EKOA); ii) the longitudinal association between the phenotypes and pain worsening at two years.DesignWe studied participants with EKOA from the Multicenter Osteoarthritis Study defined as pain intensity ≤3/10, Kellgren and Lawrence grade ≤2, intermittent pain none to sometimes, and no constant pain. Two models of PP were explored. Model A included pressure pain thresholds, temporal summation, conditioned pain modulation, pain catastrophizing, sleep quality, depression, and widespread pain (WSP). In Model B, gait characteristics, quadriceps strength, comorbidities, and magnetic resonance imaging features were added to Model A. Latent Class Analysis was used to create phenotypes, and logistic regression was used to determine their association with pain worsening.Results750 individuals (60% females), mean age [standard deviation (SD)]: 60.3 (9.4) were included in Model A and 333 individuals (60% females), mean age (SD): 59.4 (8.1) in Model B. 3-class and 4-class solutions were chosen for Model A and Model B. In Model A, the most "severe" phenotype was dominated by psychosocial factors, WSP, and measures of nervous system sensitization. Similarly in Model B, the Model A phenotype plus gait variables, quadriceps strength, and comorbidities were dominant. Surprisingly, none of the phenotypes in either model had a significant relationship with pain worsening.ConclusionPhenotypes based upon various factors thought to be important for the pain experience were identified in those with EKOA but were not significantly related to pain worsening. These phenotypes require validation with clinically relevant endpoints.

BackgroundCytokines such as tumor necrosis factor (TNFα) have been shown to elicit inflammatory and catabolic events in the joints of patients with osteoarthritis. Recent RCTs demonstrated that TNFα inhibition has no effect on pain and MRI-detected synovitis or bone marrow lesions in patients with erosive hand OA1-3. However, the progression of bone erosions was reduced in a subgroup of patients with more clinically swollen distal interphalangeal joints in one RCT1. Consequently, it remains possible that TNFα inhibition may have beneficial effects in specific subgroups of patients with a high inflammatory component.ObjectivesWe aimed to evaluate the efficacy and safety of a TNFα inhibitor, adalimumab (ADA), in a proof-of-concept study in patients with inflammatory OA of the knee.MethodsOKINADA was a 52-week, randomized, double-blind, placebo-controlled, parallel-group study done at 11 sites in Canada (NCT02471118). Eligible participants were adults (aged ≥18 years) with a diagnosis of OA of the index knee and classified according to American College of Rheumatology criteria, including radiological evidence of OA (Kellgren-Lawrence grades 2 or 3) with clinical signs of knee effusion. Subjects had persistent knee pain of ≥ one month duration with a pain score of ≥ 4 (0-10 NRS) in the index knee at screening and baseline despite conventional treatment with maximum tolerated acetaminophen and/or non-steroidal anti-inflammatory drug. Patients were randomly assigned (1:1) to receive subcutaneous 40 mg ADA every 2 weeks or placebo (PBO). Primary endpoint was the Outcome Measures in Rheumatology and Osteoarthritis Research Society International set of responder criteria (OMERACT-OARSI) at week 16 defined as: (1) improvement in pain or function ≥50% and an absolute change ≥20 mm; or (2) improvement of ≥20% with an absolute change ≥10 mm in at least two of the following three categories: pain, function, and patient’s global assessment. Secondary endpoints included: the Knee Injury and Osteoarthritis Outcome Score (KOOS) for the domains of pain, activities of daily living (ADL), OA symptoms, sport and recreation function (SRF), and knee-related quality of life (QoL), patient’s global assessment of disease status (PGAD), investigator global assessment of disease status (IGAD), and expanded Target Joint Assessment (TJA) score.ResultsA total of 59 patients were randomized (29 to PBO, 30 to ADA). The primary endpoint was not met: OMERACT-OARSI combined (ADA: 9 [30.0%] vs PBO: 7 [24.1%], p=0.62). For KOOS pain, ≥20% improvement was noted in 11 (36.7%) ADA vs 7 (24.1%) PBO patients (p=0.30), and ≥50% improvement in 5 (16.7%) ADA vs 6 (20.7%) PBO patients (p=0.69). There were no significant treatment-group differences in baseline to 16-week change in continuous secondary endpoints (ADA vs PBO: KOOS ADL 6.5 vs 8.4 (p=0.71), KOOS QoL 10.1 vs 7.4 (p=0.66), KOOS symptoms 7.8 vs 11.5 (p=0.42), KOOS SRF 5.8 vs 7.7 (p=0.76), PGAD -1.0 vs 0.1 (p=0.10), IGAD -1.5 vs -2.1 (p=0.30), TJA -2.4 vs -2.2 (p=0.87) or in lab markers (ESR, CRP). There were 11 withdrawals (4 ADA, 7 PBO) of which 2 were for adverse events (1 ADA, 1 PBO) and 2 for increasing knee pain (1 ADA, 1 PBO). No new safety signals were identified and there were no serious adverse events.ConclusionAlthough the treatment was safe, short-term treatment with anti-TNFα therapy does not appear to provide clinically meaningful improvements in OA symptoms in patients with established radiographic knee OA. Analyses of structural endpoints will be reported when results are available.References[1]Verbruggen G, et al. Ann Rheum Dis 2012; 71: 891-8.[2]Chevalier X, et al. Ann Rheum Dis 2015; 74: 1697-705.[3]Aitken D, et al. Osteoarthritis Cartilage 2018; 26: 880-7.AcknowledgementsAbbvie supported this investigator-initiated studyDisclosure of InterestsWalter P Maksymowych Speakers bureau: Abbvie, Janssen, Novartis, Pfizer, UCB, Consultant of: Abbvie, Boehringer Ingelheim, Celgene, Eli-Lilly, Galapagos, Novartis, Pfizer, UCB, Grant/research support from: Abbvie, Novartis, Pfizer, UCB, Louis Bessette Speakers bureau: Amgen, BMS, Janssen, Roche, UCB, Abbvie, Pfizer, Merck, Lilly, Novartis, Sanofi, TEVA, Fresenius Kabi, Sandoz, Consultant of: Amgen, BMS, Janssen, Roche, UCB, Abbvie, Pfizer, Celgene, Lilly, Novartis, Sanofi, Gilead, TEVA, Fresenius Kabi, Sandoz, Grant/research support from: Amgen, BMS, Janssen, Roche, UCB, Abbvie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Gilead, Robert G Lambert Paid instructor for: Novartis, Amanda Carapellucci: None declared, C. Thomas Appleton Speakers bureau: Abbvie, Amgen, Bristol Myers Squibb, Celgene, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Organon, Pfizer, Hoffman LaRoche, Sandoz, Sanofi-Genzyme, UCB, Consultant of: Abbvie, Amgen, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Organon, Pfizer, Hoffman LaRoche, Sandoz, Sanofi-Genzyme, UCB, Grant/research support from: Abbvie, Fresenius Kabi, Novartis, Pfizer

Background Health outcomes of Indigenous patients are impacted by culturally unsafe specialty care environments. The ‘Educating for Equity (E4E)’ program is a continuing professional development (CPD) intervention which incorporates skill-based teaching to improve Indigenous patient experiences and outcomes in healthcare interactions. Methods The E4E program was delivered to rheumatologists in two phases, each delivered as experiential learning workshops where participants engaged with and applied course content within an interactive format focusing on real-time feedback. The phase 1 workshop focused on skill development of E4E Framework concepts and principles. Phase 2 concentrated on building capacity for teaching of E4E content. Evaluation of the program’s effectiveness was through longitudinal responses to the Social Cultural Confidence in Care Survey (SCCCS), self-reported strategies employed to address social issues and improve therapeutic relationships, engagement with teaching others, and satisfaction with the program. Results Two cohorts of participants have participated in the program ( n = 24 Phase 1, n = 10 Phase 2). For participants completing both phases of training, statistically significant improvements were observed in exploring social factors with patients, gaining knowledge and skills related to cultural aspects of care, improved communication and relationship building, and reflections on held stereotypes. Strategies to address social issues and build therapeutic relationships remained consistent throughout participation, while the training enhanced exploration and confidence to ask about cultural and traditional practices, and stronger communication strategies for exploring beliefs, expectations, social barriers, and residential school impacts on health. Participants reported feeling prepared to teach Indigenous health concepts to others and subsequently lead teaching with residents, fellows, and allied health professionals. Satisfaction with the delivery and content of the workshops was high, and participants valued interactions with peers in learning. Conclusions This CPD intervention had a beneficial impact on self-reported confidence and enhanced practice strategies to engage with Indigenous patients.

Osteoarthritis (OA) is the most common chronic health condition and a leading cause of disability and pain in the United States and Canada. Current methods for monitoring the development of knee OA (KOA) involve x-ray radiography and magnetic resonance imaging (MRI) to assess femoral articular cartilage (FAC) degradation and synovial membrane inflammation. However, x-ray radiography cannot be used to quantify FAC loss or synovial membrane inflammation due to a lack of soft tissue contrast, and MRI is associated with high costs, long waitlists, long scan times, and is inaccessible to many patients. We have developed a counterbalanced point-of-care (POC) system to track multiple three-dimensional (3D) ultrasound (US) acquisitions and register them for visualizing the entire suprapatellar synovium. This work aims to validate the tracking accuracy of the POC system against an external optical tracking system. Validation was conducted using optical tracking as a reference by mounting a custom optical tracking stylus in place of the 3D US scanner on the POC system. The stylus was manipulated in 3D space and Euclidean distances were calculated using the initial and final positions of the stylus and were compared between systems to quantify POC tracking system error. Results indicated that the overall mean absolute tracking error of the POC system was 3.08 ± 2.01 mm with no statistically significant difference between the POC and optical systems (p = 0.965). The POC system has the potential to enable clinicians and researchers to obtain additional information without added complexity or discomfort to patients.

Objective: To explore mechanisms of mechanoinflammation, we investigated the association between the presence of knee synovial perivascular edema and gait biomechanics that serve as surrogate measures of knee load in patients with knee osteoarthritis (OA). Design: Patients with symptomatic, radiographic knee OA and neutral to varus alignment undergoing total knee arthroplasty or high tibial osteotomy participated in this cross-sectional analysis. All participants underwent 3D gait analysis prior to surgery. Synovial biopsies were obtained during surgery for histopathological assessment. The association between the presence of synovial perivascular edema (predictor) and the external knee moment (outcome) in each orthogonal plane was analyzed using multivariate linear regression and polynomial mixed effects regression models, while adjusting for age, sex, BMI, and gait speed. Results: Ninety-two patients with complete gait and histopathological data were included. When fitted over 100% of stance, regression models indicated substantial differences between patients with and without synovial perivascular edema for knee moments in frontal, sagittal and transverse planes. The knee adduction moment was higher in patients with edema from 16 to 74% of stance, with the largest difference at 33% of stance (beta = 6.87 Nm [95%CI 3.02, 10.72]); whereas the knee flexion-extension moment differed from 15 to 92% of stance, with the largest difference in extension at 60% of stance (beta = -10.80 Nm [95%CI -16.20, -5.40]). Conclusions: In patients with knee OA, the presence of synovial perivascular edema identified by histopathology is associated with aberrant patterns of knee loading throughout stance, supporting the link between biomechanics and synovial inflammation. (C) 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Purpose: Synovial inflammation is associated with pain and disease progression in knee OA and may adversely affect joint biomechanics. The presence of knee inflammation is associated with quadriceps avoidance gait (decreased external knee flexion moment) and decreased quadriceps and hamstring strength. The effect of decreasing knee inflammation on gait biomechanics and strength is unknown. Here, we investigate the effects of inflammation on gait biomechanics in patients with knee OA and inflammation on ultrasound (US), testing the effects of knee aspiration and intra-articular corticosteroid injection on gait, strength, and clinical outcomes. Methods: Forty-five patients with knee OA, synovitis and effusion underwent US, gait biomechanics and strength assessments, and completed the Knee Injury and Osteoarthritis Outcome Score (KOOS), before and 3 weeks after receiving a knee aspiration and 40 mg triamcinolone injection under US guidance (Table 1). Ultrasound assessments were performed by a Canadian Rheumatology Ultrasound Society (CRUS) trained examiner using a 12 Hz linear probe. The suprapatellar recess was scanned in the long axis view medially, laterally and in the midline with the knee flexed to 30o. All US exams were graded using previously validated OMERACT grading criteria for synovitis, synovial hyperplasia, effusion, and power Doppler (6-point scale). Three-dimensional quantitative gait analysis was completed using a 12-camera motion capture system and floor mounted force plate and used to calculate knee angles and moments during walking. Strength testing was completed using an isokinetic dynamometer. Patients completed three maximal knee extension and flexion trials at 90 degrees per second. US, gait and strength tests were completed by the same examiner. Paired t-tests were used to assess mean differences in gait, strength and KOOS scores. Results: There was a significant (p < 0.05) increase in external knee flexion moment [mean change (95%CI)]: 0.32 %BW*ht (0.07, 0.57), peak quadriceps strength [5.95 Nm (0.99, 10.91)], and peak hamstring strength [4.03 Nm (0.56, 7.51)] 3 weeks after injection. There were significant (p < 0.05) improvements in US composite scores [-0.86 (-1.30, -0.42)], and KOOS Subscales for Symptoms [6.16 (1.63, 10.69)], Pain [6.43 (1.17, 11.69)], Function in Daily Living [5.61 (0.80, 10.42)] and Function in Sport and Recreation [9.37 (0.56, 18.18)]. There were no other significant changes in gait (Table 2). Conclusions: Patients undergoing aspiration and injection for knee synovitis and effusion experience increased knee flexion moments during walking and increased maximal quadriceps and hamstring strength. These results suggest a link between inflammation and joint biomechanics in patients with knee OA; interventions that induce changes in knee inflammation detectable by US can improve knee biomechanics during walking.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

The most common chronic inflammatory and chronic joint diseases in Canada are rheumatoid arthritis (RA) and osteoarthritis (OA) respectively. The current methods for monitoring the development of these diseases and their response to treatment involve acquiring x-ray and magnetic resonance imaging (MRI) images and comparing the results to the patient's symptoms during examination However, x-ray imaging is associated with difficulties when trying to interpret 3D anatomy, and MRI is associated with high operating costs, long waitlists, long scan times, and is inaccessible to mobility-impaired patients. Our solution to these limitations is the use of three-dimensional ultrasound (3D US) imaging for providing bedside monitoring of RA and OA progression and their response to treatment. This project validates two 3D US acquisition devices: tilt acquisition and linear acquisition scanning methods. The linear and volumetric measurement capabilities were validated through scanning phantoms and segmenting resulting images at repeated time points. A proof-of-concept volunteer scan was conducted to compare the capabilities of 3D US against MRI for measuring articular cartilage volumes. Results indicated that the linear measurement errors for both the tilt and linear scanners were <5% of the known phantom dimensions. The volumetric measurement errors were <5% for the linear scanner and >10% (29.84%) for the tilt scanner. The percent difference between the volumes of the articular cartilage measured using 3D US and MRI of a healthy volunteer's knee was 6.46%. The linear scanner is therefore better suited for clinical scanning than the tilt scanner due to its smaller linear and volumetric errors.

Purpose: The complex pathophysiology of osteoarthritis (OA) is likely the result of a combination of local changes in the joint and systemic changes throughout the body. There are relatively few large-scale studies with clearly defined patient cohorts that have profiled molecular differences in circulating factors in OA. Next generation sequencing is considered to be the gold-standard approach for unbiased profiling of targets of interest in tissues of interest. When applied to circulating factors, this method presents the opportunity to comprehensively profile factors that may be associated with particular stages of disease, offering the sensitivity and specificity required to identify novel and low abundance transcripts. Among the circulating factors that can be profiled are microRNAs, small non-coding RNAs that negatively regulate target gene expression. Poised as good biomarkers, microRNAs are relatively stable, easy to detect, and easy to quantify. Traditionally profiled using PCR panels and microarray, microRNAs can also be profiled using next generation sequencing, which enables discovery of novel microRNAs. Here we use next generation sequencing to profile circulating microRNAs in carefully defined cohorts of patients with early and late stage radiographic knee OA. We hypothesize that a unique profile of known and novel circulating microRNAs is associated with early stage radiographic knee OA, and that this can be used to better understand and characterize early stages of OA. Methods: Plasma samples from knee OA patients (N=91) were obtained from the Arthritis Program Knee Osteoarthritis BioBank at the University Health Network in Toronto, Canada and the Western Ontario Registry for Early Osteoarthritis (WOREO) Knee Study in London, Canada. Samples included Kellgren-Lawrence grades 0 and 1 for early OA (N=41), and Kellgren-Lawrence grades 3 and 4 for late OA (N=50). Patients with Kellgren-Lawrence grade 2 were excluded in an effort to clearly differentiate the two cohorts of interest into early stage and late stage disease. Patient data were collected for age, sex, body mass index, race, pain (Western Ontario and McMaster Universities Osteoarthritis Index), and comorbidities. MicroRNAs were isolated from plasma samples and subjected to library preparation and sequencing on the Illumina NextSeq550 platform. Sequencing reads were aligned to both miRBase v22.1 and the human reference genome (Version GRCh38), counts were generated and normalized, and differential expression analysis was performed. Bioinformatics tools were applied to predict novel microRNAs based on secondary structure and lack of homology with mouse microRNAs. Ongoing computational biology analyses include target gene and pathway predictions. Results: After filtering sequencing reads for microRNAs with greater than 10 counts per million in at least 2 samples, 417 microRNAs were identified. Unbiased analysis of the data using principal component analysis showed a clear separation of samples according to Kellgren-Lawrence grade. Late stage samples clustered distinctly from early stage samples, with component 1 explaining 58.2% of the variability in the dataset. Exploring other variables, age, race, and pain were statistically different between early and late groups. Age and race were among the factors included in a multivariate model to identify differentially expressed microRNAs by Kellgren-Lawrence grade. Using a false discovery rate threshold of 0.01, there were 215 microRNAs identified, with 10 decreased and 205 increased in the early OA group as compared to the late OA group. A separate multivariate model exploring pain did not identify any significantly different microRNAs between high pain and low pain groups, however a higher percentage of patients with early radiographic OA reported high pain as compared to patients with late OA (P=0.03). Furthermore, when exploring novel microRNAs, 2 were identified to be associated with both early radiographic OA and high pain. Conclusions: The early OA cohort used in the current study represents a highly relevant clinical population, showing early radiographic features of OA and high pain. Our results indicate that next generation sequencing is a useful approach for identifying circulating microRNAs in OA. We discover that there is a unique profile of known and novel microRNAs associated with early stages of radiographic knee OA. Next steps include validation of these findings in a larger and longitudinal cohort.