Objectives Individuals with rheumatoid arthritis (RA) may experience work disability, yet population-level data on disability prevalence are limited. We quantified the prevalence of working-age individuals with RA with disability-related RA medication claims and assessed disability-related medication claims in the general population for comparison. Methods We conducted a population-based repeated cross-sectional study using Ontario health administrative databases to assess annual trends from 2000 to 2022. We identified medication claims funded through the Ontario Disability Support Program (ODSP) within the Ontario Drug Benefit (ODB) database. We identified individuals with RA from the Ontario Rheumatoid Arthritis Database. Annual denominators comprised the number of RA individuals between the ages of 20-64 years, alive, with Ontario Health Insurance Plan coverage in the given measurement year. Individuals contributed to annual denominators until death, outmigration, attainment of age 65 (transitioning to ODB Seniors Program) or study end date. Annual numerators comprised the number of RA individuals with at least one ODSP-attributed medication claim for biologic, conventional, or targeted synthetic DMARDs, NSAIDs, opioids, or systemic glucocorticoids. We further quantified the total volume and medication-related costs attributed to these claims funded through ODSP. For comparison, we ascertained disability-related claims (for any medication class) among the general Ontario population aged 20 to 64 years. Results Over the 23-year period, the number of RA individuals aged 20-64 years grew from 34,394 to 74,182 individuals, while the number of RA individuals with a disability RA medication claim increased from 2,805 individuals in 2000 to 6,270 individuals in 2022, corresponding to a stable annual disability prevalence of 8-9% of all RA working aged individuals (a pattern driven by individuals transitioning to ODB Senior Program at 65). Regional disability prevalence was lowest in the central region (4.8%) and highest in the Northeast (12.6%). The annual volume of ODSP RA medication claims ranged from 55,611 in 2000 to a peak in 2020 of 255,810 claims, corresponding to annual costs of $1,894,925CAD and $33,215,527CAD respectively (Figure). In contrast, the disability prevalence in the general population ranged from 2.7-3.8% during the study period. Conclusion Over 2 decades, the number of working-age RA individuals receiving disability benefits doubled, and RA disability prevalence was twice that of the general population. Nearly 1 in 11 younger RA adults were on disability annually, contributing to substantial medication use and economic costs. Investment in effective, evidence-based care models is needed to preserve work participation and reduce the long-term impacts of RA-related disability.

Objective Ultrasound (US) permits the assessment of synovial effusion and synovial thickening (hyperplasia) in knee osteoarthritis (OA). We aimed to measure the associations of these features with radiographic OA severity and patient-reported knee-specific pain using a quantitative US image analysis approach. Methods Patients with symptomatic knee OA were included. The Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subscale, Kellgren-Lawrence (KL) grade, and lateral suprapatellar recess B-mode images were acquired for Outcome Measures in Rheumatology (OMERACT) measurement and grading. US images of effusion-synovitis were manually segmented to calculate effusion and hyperplasia area. Correlation was assessed, and associations with KL grade/KOOS pain were modelled using multivariable linear and quadratic regression with and without adjustment for age, sex, and body mass index (BMI). Results Quantitative measures of effusion and hyperplasia area correlated strongly (ρ 0.83 to 0.86) with OMERACT grades and effusion-synovitis depth. Adjusting for age, sex, and BMI, synovial effusion and hyperplasia area are non-linearly related to radiographic severity, a pattern also observed in models of OMERACT global synovitis and effusion-synovitis depth. KOOS pain was associated with effusion-synovitis depth (β=-0.53) and borderline associated with OMERACT hyperplasia (β=-5.55), but not with OMERACT global synovitis, effusion, nor any quantitative effusion-synovitis area measures. Conclusion Minimal US effusion-synovitis among knee OA patients with late-stage disease may indicate maladaptive remodeling of the synovium instead of reduced inflammation. Discriminating between patients with and without maladaptive synovial remodeling in early and late-stage disease should be a priority, as it may improve our ability to predict joint failure.

Objectives Canadian provincial drug funding programs provide universal coverage for prescription medications for adults aged 65+ years, while younger adults can be eligible for publicly funded coverage based on financial need, high medication costs, disability status, or long-term/home care status. Within a population-based rheumatoid arthritis (RA) cohort, we characterized trends in total annual RA medication claims and expenditures across public drug programs and age groups. Methods Using a population-based repeated cross-sectional study design, we ascertained medication dispensation claims from the Ontario Drug Benefit (ODB) database from 2000 to 2022, among individuals with RA identified from the Ontario Rheumatoid Arthritis Database. For each year, RA individuals were required to be alive, 20 years or older, with Ontario Health Insurance Plan coverage, and contributed to annual RA population denominators from diagnosis until death, outmigration, or end of study. RA-related medication claims included biologic, conventional synthetic, or targeted DMARDs, NSAIDs, opioids, and systemic glucocorticoids. ODB funding programs included seniors (for 65+), Ontario Disability Support Program, Trillium/Exceptional Access Program (for high-cost medications), Ontario Works (for unemployment), and a combination of other programs. Analyses included trends in annual number of RA medication claims and cumulative medication expenditures, stratified by funding programs and age groups. Results From 2000 to 2022, the RA population increased from 60,781 individuals [34,394 aged <65); 26,387 aged 65+] to 154,675 individuals [74,182 aged <65; 80,493 aged 65+)]. Among those under 65, the number of individuals with at least one ODB-related RA medication claim rose from 5,069 (15%) in 2000 to 13,121 (18%) in 2022. For RA individuals aged 65+, the number of individuals with at least one ODB-related RA medication claim increased from 22,476 in 2000 to 63,293 in 2022 (representing 78-86% of eligible RA seniors across all years). Trends in total claim volumes and expenditures by age groups are depicted (Figure 1). Total RA medication expenditures peaked in 2022 at $256,907,248 for all ages ($78M under 65, $179M in 65+). Among funding sources, the ODB Seniors Program accounted for the largest share of claims, followed by the Disability and Trillium programs. Conclusion Ontario has seen a significant growth in publicly funded RA medication utilization and spending overtime. Among working-age individuals, nearly 1 in 5 had at least one RA medication claim, while most RA seniors consistently accessed treatment. The substantial increase in RA medication utilization and expenditures alongside the growing RA population underscores the need for more sustainable healthcare planning.

Objectives Articular cartilage degeneration is a hallmark of osteoarthritis (OA); however, underlying molecular mechanisms remain poorly understood. Transforming growth factor alpha (TGFα) and chondrocyte metabolism have been independently implicated in OA pathogenesis; in this study, we investigated whether TGFα affects chondrocyte metabolism. Design Immature murine articular chondrocytes (iMACs) were isolated from 4-6-day-old CD1 mice and treated with TGFα or vehicle control (ddH2O) for 24-72 hours. Global transcriptional changes were assessed at 48 h by bulk RNA sequencing (n = 4) followed by gene set enrichment analysis. Gene expression was validated by qPCR (n = 4). Mitochondrial mass and membrane potential were assessed using MitoTracker Green and JC-1 (n = 6), respectively. Seahorse XFe analysis assessed changes in cellular metabolism following TGFα treatment, in the presence and absence of OA synovial fluid (n = 4). Results TGFα treatment led to differential expression of 1643 genes (1305 upregulated, 338 downregulated), with enrichment in processes related to Response to Reactive Oxygen Species, Glycolysis, and Inflammatory Response. TGFα increased the expression of genes involved in antioxidant defence/ROS production (Sod3, Prdx1, Ucp2, Nox4), mitochondrial quality control (Bnip3), metabolism (Ldha), and inflammation (Tlr4), while inducing depolarization of the mitochondrial membrane potential in chondrocytes. TGFα enhanced extracellular acidification rate (ECAR) in the presence of OA synovial fluid. Conclusion Acute TGFα exposure induces transcriptional changes associated with ROS, glycolysis, and inflammatory signalling. TGFα decreases mitochondrial membrane potential, while increasing glycolysis in the presence of OA synovial fluid, supporting a link between TGFα signalling and metabolic reprogramming.

Canadian healthcare systems face mounting pressures from rising chronic disease prevalence, persistent specialist shortages and escalating healthcare expenditures. Rheumatology exemplifies these challenges, with growing patient demand and a persistently limited rheumatologist workforce caring for patients requiring intensive ongoing specialist care. Population-level data on rheumatology patients demonstrate increasing rheumatic disease prevalence, emergency department utilization, disability and medication expenditures, underscoring the unsustainability of physician-centric care models. Across Canada, there is a broad policy consensus that team-based care is essential to improving access, reducing system pressures and enhancing outcomes for patients with chronic disease. However, team-based models have not been systematically extended to specialty care across jurisdictions. Team-based models of rheumatology care that integrate allied health practitioners in rheumatology practices are essential to improving access, enhancing care quality and optimizing workforce capacity. Leveraging existing interprofessional team funding mechanisms to rheumatology settings represents a pragmatic, evidence-informed policy pathway to modernize specialist care delivery and improve the sustainability of the healthcare system.

Objective. Interdisciplinary healthcare providers (IHPs) can support effective delivery of optimal rheumatology care. To inform widespread implementation efforts, we assessed rheumatology workforce characteristics and determinants of integrating of IHPs within rheumatology practices in Ontario, Canada. Methods. A convergent mixed methods design included an environmental scan to identify clinically active rheumatologists and a workforce survey guided by the Consolidated Framework for Implementation Research (CFIR) 2.0. Quantitative data were analyzed descriptively and stratified by subgroups. Qualitative responses were analyzed using conventional content analysis. Integration of findings enabled a comprehensive understanding of implementation determinants. Results. Of the 293 Ontario rheumatologists identified by the environmental scan (as of 2025), 26 were nearing retirement, leaving potentially 267 eligible for the survey. One hundred ninety-seven rheumatologists participated in the survey, yielding a response rate of 74% and coverage of > 90% of practice sites. Pediatric rheumatologists and those in hospital-based settings had more structural and collaborative supports than community-based rheumatologists. Overall, 177 (91%) indicated they were interested in adding IHPs, with 126 (65%) preferring an extended role/scope provider. Although inadequate funding was the key deterrent to adoption, motivational readiness was high: 92% perceived an IHP team-based model as an improvement, 86% saw it as a good fit, and 83% considered it a priority to better meet patient needs. Many noted a lack of supportive climate, including that of resources and processes, to enable this practice change. Conclusion. Rheumatologists report high motivation for practice change to integrate IHPs. System-and practice-level implementation strategies are needed to support workforce transformation.

Objectives:Metabolic Syndrome (MetS) is associated with OA progression and pain. However, its relationship with outcomes in early-stage disease remains unclear. We assessed associations of MetS with radiographic stage and knee pain in individuals with symptomatic knee OA. Methods:We analysed cross-sectional baseline data from 251 participants in the Western Ontario Registry for Early Osteoarthritis (WOREO) Knee Study. Associations between MetS and radiographic stage were assessed using modified Poisson regression. Associations with knee pain, measured by the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain scale, were evaluated using multiple linear regression accounting for within-participant correlation. Analyses were stratified by OA stage and adjusted for body mass index (BMI). Results:MetS was associated with a higher prevalence of late-stage knee OA [adjusted prevalence ratio 1.45 (95% CI 1.16, 1.81)]. After BMI adjustment, hypertension and haemoglobin A1c remained associated with late-stage disease. Participants with MetS reported worse knee pain, with lower KOOS pain scores [β = -14.70 (95% CI -20.92, -8.47)], particularly in early-stage disease [β = -14.15 (95% CI -20.37, -7.93)]. Dyslipidaemia (elevated triglycerides and reduced high-density lipoprotein cholesterol were also associated with worse pain in early-stage disease. Conclusion:MetS and its components are associated with greater radiographic severity and clinically meaningful worsening of pain, especially in early-stage knee OA, independent of BMI. These findings suggest that early identification and management of metabolic disease may represent a modifiable target to improve OA outcomes.

Objectives To examine (i) the association of adiposity with pain intensity and/or effusion-synovitis in people with knee osteoarthritis (OA), adjusting for body mass index (BMI), and (ii) whether indicators of systemic immune inflammation (i.e., the systemic immune-inflammation index (SII) and the systemic immune response index (SIRI)) moderate the above associations. Methods Individuals with knee OA were sampled from the Western Ontario Registry for Early Osteoarthritis Knee Study. Total body and visceral fat percentages were measured using bioimpedance analysis, and effusion-synovitis was graded using knee ultrasonography. Multiple regression models with interaction terms were used to examine the association between fat percentages and pain intensity (linear)/effusion-synovitis (logistic), and the interaction effect of fat and SII/SIRI on pain intensity/effusion-synovitis. The analyses were adjusted for confounders (age, sex, BMI, radiographic severity of the opposite knee, and anxio-depressive symptoms). Results Data from 225 participants (mean age: 61.1 (10.9), 68% female, mean BMI: 31.7 (7.7)) were analyzed. The associations for adjusted fat and pain intensity models were as follows: total body fat: β): - 0.03 (-0.54 to 0.46) and visceral fat: β (: -0.25 (-1.03 to 0.51)., The odds ratios for adjusted fat and effusion-synovitis models were total body fat: OR): 0.98 (0.92 to 1.05) and visceral fat: OR (): 1.01 (0.91 to 1.11)). Neither the main nor the interaction effects were significant. Conclusion Our preliminary results do not support an association of adiposity and its interaction with generalized inflammation with pain/effusion-synovitis adjusted for BMI. Further studies are needed.

Synovium is home to immune and stromal cell types that orchestrate inflammation following a joint injury; in particular, macrophages are central protagonists in this process. We sought to define the cellular and temporal dynamics of the synovial immune niche in a mouse model of post-traumatic osteoarthritis (PTOA), and to identify stromal-immune crosstalk mechanisms that coordinate macrophage function and phenotype. We induced PTOA in mice using a non-invasive tibial compression model of anterior cruciate ligament rupture (ACLR). Single-cell RNA-sequencing and flow cytometry were used to assess immune cell populations in healthy (Sham) and injured (7 and 28 days post-ACLR) synovium. Characterization of synovial macrophage polarization states was performed, alongside computational modeling of macrophage differentiation, as well as implicated transcriptional regulators and stromal-immune communication axes. Immune cell types are broadly represented in healthy synovium, but experience drastic expansion and speciation in PTOA, most notably in the macrophage portion. We identified several polarization states of macrophages in synovium following joint injury, underpinned by distinct transcriptomic signatures, and regulated in part by stromal-derived macrophage colony-stimulating factor signaling. The transcription factors Pu.1, Cebpα, Cebpβ, and Jun were predicted to control differentiation of systemically derived monocytes into pro-inflammatory synovial macrophages. In summary, we defined different synovial macrophage subpopulations present in healthy and injured mouse synovium. Nuanced characterization of the distinct functions, origins, and disease kinetics of macrophage subtypes in PTOA will be critical for targeting these highly versatile cells for therapeutic purposes.

ObjectiveImmune checkpoint inhibitors (ICIs) have revolutionized cancer outcomes but are limited by immune-related adverse events (irAEs), including rheumatic irAEs (Rh-irAEs). Aging is associated with increased inflammation, referred to as "inflammaging." In this study, we explore the effect of age on severity, frequency, and treatment of Rh-irAEs.MethodsAdults with new Rh-irAEs after ICI exposure are followed prospectively across 10 Canadian sites as part of the Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO) prospective cohort. In this study of patients seen between January 2020 and March 2023, we compare the severity of Rh-irAEs and number of irAEs between patients aged ≥ 65 years and < 65 years and explore potential epidemiologic, treatment-related, and phenotypic differences between the older and younger patients.ResultsA total of 139 patients with de novo Rh-irAEs were included, 58 in the younger (aged < 65 yrs) and 81 in the older (aged ≥ 65 yrs) group. There were no significant differences in severity of Rh-irAEs (P= 0.84) or number of irAEs (P= 0.21), although there was a nonsignificant trend toward more younger patients than older patients with ≥ 3 irAEs (24% vs 14%). Types of treatment for Rh-irAEs were similar between the groups. ICI continuation did not differ. Within the ICI-related inflammatory arthritis subgroup, there was also no significant difference in the incidence of severe Rh-irAEs (P= 0.51).ConclusionSimilar numbers of overall irAEs and severity of Rh-irAEs were observed between older vs younger patients who developed Rh-irAEs after treatment with ICI therapy, suggesting that inflammaging does not play a significant role in Rh-irAEs. Larger studies are needed to explore potential differences in patient phenotypes.

OBJECTIVES:Within the first phase of developing classification criteria for Early-stage Symptomatic Knee Osteoarthritis, among individuals with knee osteoarthritis (OA) we explored: 1) symptoms within the first year of noticing their knee(s); 2) features that indicated OA was the cause; and 3) timing and reasons that initially prompted seeking healthcare. DESIGN:We conducted a cross-sectional online survey of individuals with knee OA recruited from Australia, Canada, the Netherlands, and the USA. Only individuals who indicated they recalled their first symptoms were eligible. Using free-text, participants described changes in how their knee looked, felt, moved, their overall state within the first year of noticing their knee(s), features perceived to indicate knee OA was the cause, and reasons for initially seeking healthcare. We assessed the timing of seeking care by an ordinal scale. Data were analyzed using descriptive statistics and summative content analysis. RESULTS:We included 92 participants (median age 67 years [interquartile range (IQR) 59,75], 69% women, median body mass index (BMI) 26 kg/m2 [IQR 24,30]). Within the first year from onset, frequently reported symptoms were knee pain (70%), swelling (58%), crepitus (42%), stiffness (29%), and instability (24%). While few could provide specific clinical features, approximately half (53%) perceived medical imaging as important to indicate OA. Only 35% sought healthcare within the first year of experiencing symptoms. CONCLUSIONS:Individuals with knee OA recalled varied knee symptoms within the first year and few sought healthcare. We were unable to ascertain, from the perspective of patients, specific clinical features that indicated they had OA and not another condition.

Synovial joints are complex multi-tissue organs that permit movement. A well-functioning synovial joint relies on complex interconnected homeostatic mechanisms to maintain joint organ function in response to biomechanical and metabolic demands. These homeostatic mechanisms include, but are not limited to, appropriate mechanobiological responses to load, nutrient delivery from its vasculature, lubrication, proprioception and pain, immunosurveillance, and maintenance of the extracellular matrix (ECM) composition. In osteoarthritis (OA), joint homeostasis is chronically deranged leading to failure of the synovial joint organ and impairment or loss of function. Maintaining synovial joint organ homeostasis is therefore critical to joint function and relies on complex interconnected physiological process at the joint level. As OA prevalence continues to rise, deepening our understanding of the integrated systems that sustain joint homeostasis may identify fruitful avenues for therapeutic intervention. However, key knowledge gaps will need to be addressed including, characterizing vessel function in joint diseases, understanding the role of novel proteases in ECM catabolism, and determining the role of non-macrophage synovial immune cells in joint immunosurveillance. We believe that future research will find greater success if these homeostatic mechanisms are viewed as a single integrated system that considers the crosstalk between mechanical, vascular, immune, and biochemical factors. Therefore, in this review, we explore the interconnected mechanisms that support joint homeostasis and how dysregulation can lead to failure of the synovial joint organ.

Total knee arthroplasty (TKA) is a surgery with high success rates and good patient outcomes. However, 6.9% of knee replacement surgeries are revisions of old implants due to ongoing pain, stiffness, and loosening. Revision TKA is more expensive and has worse patient outcomes. Recent studies have begun to explore the role of the inflammatory response in poor TKA outcomes. Inflammation is an important predictor of pain in osteoarthritis (OA) and synovial inflammation may play a role in knee stiffness after TKA. Macrophages are the dominant immune cells of the synovium and regulate knee inflammation, and when activated, they upregulate mitochondrial translocator protein (TSPO) expression. Current standard of care features Magnetic Resonance Imaging (MRI) to assess structural changes in the joint. Positron Emission Tomography (PET) can be used to image important biological processes at the cellular level. [18F]FEPPA is a PET tracer that targets TSPO with high specificity. The goal of this work was to validate the use of [18F]FEPPA PET/MRI in the assessment of macrophage activation in knee synovial tissue. This method may allow non-invasive imaging of important inflammatory processes and understand the role of activated macrophages in ongoing pain, stiffness, and loosening after TKA . To validate the use of [18F]FEPPA in imaging activated macrophages in vivo, synovial tissue was gathered from 12 participants with end stage OA who underwent primary TKA. Knee synovial tissue was sectioned and embedded on slides. Tissue sections were incubated in [18F]FEPPA and imaged by autoradiography for 6 hours. Adjacent tissue sections were incubated with DAPI, CD68 antibody, and TSPO antibody for immunofluorescent analysis of the actual macrophage activation. 6 of the full cohort were imaged in a 3T hybrid PET/MRI after injection with [18F]FEPPA and a 45-minute uptake period. MR of both knee joints was performed with sequences including 3D Dual Echo Steady State (DESS), Bilateral T1 weighted and Fast Spin Echo (FSE) with metal artifact reduction if contralateral TKA was present. Standardized Uptake Values (SUV) were calculated from the measured PET signal, injected dose, and patient mass. [18F]FEPPA tracer uptake calculated from autoradiography correlated to the true macrophage activation measured through TSPO+ immunofluorescence with r = 0.85 and p = 0.0029. SUV calculated from PET/MRI was correlated to true macrophage activation found through immunofluorescence with r = 0.90 and p = 0.083. Attenuation correction maps corrected for metal artefacts enabled visualization and measurement of tracer uptake surrounding the femoral and tibial components. Understanding the role of knee joint inflammation may be important in managing pain and stiffness after TKA. The underlying cause of poor TKA outcomes are often unclear.[18F]FEPPA PET/MRI uptake in knee synovial tissue was validated to correlate to the true macrophage activity. This tool may be able to diagnosis a cellular response as the cause of pain or dissatisfaction after TKA. Future work using [18F]FEPPA PET/MRI could assess different reaction types to metal or plastic implant debris, joint stiffness and fibrosis, and periprosthetic infection.

OBJECTIVE:Uncontrolled pain remains a major clinical challenge in the management of knee osteoarthritis (OA), the most common disabling joint disease. Worse pain is associated with synovial innate immune cell infiltration (synovitis), but the role of innate immune-regulatory cells in pain is unknown. Our objective was to identify synovial innate immune cell subsets and pathophysiologic mechanisms associated with worse pain in patients with knee OA. METHODS:Synovial tissue biopsies from 122 patients with mild-to-severe knee OA pain (Knee Injury and OA Outcome Score [KOOS]) were analyzed to identify associations between synovial histopathology and worse pain. We then used spatial transcriptomics and proteomics of synovial tissue microenvironments (n = 32), followed by single-cell RNA sequencing (n = 8), to identify synovial cell composition and cell-cell communication networks in patients with more severe OA pain. RESULTS:Histopathological signs of synovial microvascular dysfunction and perivascular edema were associated with worse KOOS pain (-10.76; 95% confidence interval [CI] -18.90 to -2.61). Patients with worse pain had fewer immune-regulatory macrophages, expanded fibroblast subsets, and enrichment in neurovascular remodeling pathways. Synovial macrophages from patients with worse pain expressed markers of immune exhaustion and decreased phagocytic function (-19.42%; 95% CI -35.96 to -2.89) and their conditioned media increased neuronal cell stress in dorsal root ganglia. CONCLUSION:Although synovitis increases during OA, our findings suggest that exhaustion, dysfunction, and loss of immune-regulatory macrophages is associated with worse pain and may be an important therapeutic target.