Late-stage Knee Osteoarthritis Research Articles

Linking Intra-Articular Inflammatory Biomarkers with Peripheral and Central Sensitization in Late-Stage Knee Osteoarthritis Pain: A Pilot Study.

Background/Objectives: To investigate if intra-articular biomarkers relate to peripheral and central sensitization in patients with late-stage knee osteoarthritis (KOA). Methods: A total of 17 (6M, 11F) patients (aged 69 ± 10 years) were assessed for peripheral (pressure pain thresholds (PPT)) and central (temporal summation (TS) and conditioned pain modulation (CPM)) sensitization the day before total knee arthroplasty. Synovial fluid was collected during surgery and assayed for IL-6, IL-8, IL-10, TNF-α, CXCL-10, BDNF, NGF, CCL2, CCL5, VEGF, IL-1RI, MMP-1, MMP-7, IL-1β, and CXCL-9. Associations of biomarkers and their combinations reflecting chronic (CXCL-9) and acute ((CCL2×CXCL-10)/IL-10)) inflammation, cartilage degeneration (MMP-1×MMP-7), and neurotrophy (NGF×BDNF) with PPT, TS, and CPM were analyzed by bivariate correlations and by multiple linear regression analyses corrected for BMI, sex, and age. Results: The medial joint line and the superior medial joint region showed the lowest PPT. Higher acute inflammation related significantly to worse pressure tenderness at the superior medial joint region (R2 = 0.642; p = 0.010). Cartilage degeneration and chronic inflammation were associated with both absolute (R2 = 0.827; p = 0.001) and relative CPM (R2 = 0.882; p < 0.001). Acute inflammation and neurotrophy were related to relative TS at the m. tibialis anterior (R2 = 0.728; p = 0.02). Conclusions: This study demonstrates that increased levels of intra-articular biomarkers of acute inflammation are related to peripheral sensitization and that biomarkers of cartilage degeneration and chronic inflammation are associated with central sensitization. These results may be a stepping-stone toward a better understanding of the working mechanism of peripheral and central sensitization in KOA pain and the development of more targeted therapeutic interventions.

Serum fibulin-3 as a diagnostic and prognostic biomarker in patients with knee osteoarthritis.

Osteoarthritis is a chronic degenerative disorder with rising prevalence. Early detection of structural damage is difficult. Consequently, there is a pressing demand for reliable biomarkers that enable an earlier diagnosis of osteoarthritis. The aim is to investigate the level of serum fibulin-3 in patients with primary knee osteoarthritis and its correlation with disease severity. A case-control study was conducted at the Baqubah Teaching Hospital from November 2023 to January 2024. One hundred twenty persons participated in this study (eighty females with the diagnosis of knee osteoarthritis in its early and late stages, and forty age-matched, apparently healthy control. Serum fibulin-3, ESR, CRP, and calcium levels were measured for all participants. Ethical approval was obtained. SPSS was used for data analysis. Patients with osteoarthritis had considerably higher serum levels of fibulin-3. In patients with late-stage knee osteoarthritis, this rise was greater than in earlier stages. Serum fibulin and ESR are positively correlated. Fibulin's area under the curve is 0.830 for diagnosis and 0.709 for differentiating between osteoarthritis's early and late stages. Serum levels of fibulin-3 can act as diagnostic markers for OA and may be useful in determining the severity of knee osteoarthritis.

Association between synovial tissue damage and pain in late-stage knee osteoarthritis: A cross-sectional study

ObjectiveTo identify the presence and distribution of histopathological features of synovial inflammation and tissue damage, and to test their associations with US imaging measures of synovitis and patient-reported measures of pain in knee osteoarthritis (OA). DesignIn the cross-sectional study of 122 patients undergoing surgery for painful late-stage (Kellgren-Lawrence Grade 3 or 4) knee OA, we compared ultrasound (US) measures of synovitis (n=118) and pain (Knee Injury and Osteoarthritis Outcome Score) to histopathological measures of inflammation vs. synovial tissue damage in synovial tissue biopsies. Associations of histopathological features with US measures of inflammation or pain were assessed using linear or logistic regression, while controlling for covariates. ResultsHistopathological features of inflammation were associated with higher odds of moderate/severe US synovitis (OR=1.34 [95%CI 1.04, 1.74), whereas features of synovial tissue damage were associated with lower odds of moderate/severe US synovitis (OR = 0.77 [95%CI 0.57, 1.03]). Worse histopathological scores for synovial tissue damage were associated with more pain (-1.47 [95%CI -2.88, -0.05]), even while adjusting for synovial inflammation (-1.61 [95%CI -3.12, -0.10]). ConclusionsSynovial tissue damage is associated with pain in late-stage knee OA, independent from inflammation and radiographic damage. These novel findings suggest that preventing synovial tissue damage may be an important goal of disease-modifying OA therapy.

The development of postoperative pain in patients with late-stage knee osteoarthritis is associated with impaired metabolism and transport of fatty acids in blood cells

Objective: to evaluate differences in the expression of genes associated with β-oxidation and de novo synthesis of fatty acids (FAs) in the blood of patients with the late stage of knee osteoarthritis (OA) before total knee arthroplasty (TA) depending on the development of postoperative pain (POP) in order to determine the molecular mechanisms responsible for the development of chronic POP. Material and methods. Blood of 50 patients with stage III–IV knee OA complaining of constant pain and joint dysfunction was analyzed prior to TA. The control group consisted of 26 healthy individuals. Pain intensity was assessed using a visual analogue scale (VAS) and the BPI questionnaire. In addition, pain, stiffness and physical functioning were assessed using WOMAC index and the presence of neuropathic pain was assessed using the DN4 and PainDETECT questionnaires. The development of POP was assessed 3 and 6 months after TA. Total RNA isolated from blood was used to determine the expression of ACLY, ACC1, MLYCD, FASN and CPT1A genes by real-time quantitative reverse transcriptase-polymerase chain reaction. Results and discussion. POP ≥ 30 mm by VAS was detected in 17 patients. Before TA, the expression of most of the analyzed genes was significantly increased compared to controls, while the expression of the FASN gene was comparable in patients with OA and healthy individuals. There were no differences in clinical and functional parameters between the groups of patients with and without POP. Before surgery, patients who subsequently developed POP had significantly higher expression of ACLY and CPT1A genes than patients who were satisfied with the results of TA. At the same time, no differences in the expression of ACC1, MLYCD and FASN were found in the groups analyzed. Conclusion. The development of POP is associated with an increased supply of FAs to the mitochondria caused by overexpression of the CPT1A gene, as well as with the accumulation of acetyl-CoA, a product of high expression of the ACLY gene, which can be measured in the blood of OA patients before TA.

The role and place of arthroscopy in the early diagnosis of monoarthrosis (literature review)

Background. Knee osteoarthritis is a progressive incurable disease that in severe cases leads to total joint replacement, which requires significant economic costs and medical and social adaptation, has a number of postoperative complications and adverse outcomes. Therefore, special attention has recently been paid to the prevention and treatment of the early stages of the disease. The purpose of the study was to conduct a systematic analysis of scientific literature on the prospects and possibilities of using arthroscopy in the early diagnosis of monoarthrosis. Material and methods. A literature search was conducted in the PubMed and MEDLINE databases for 2010–2024 using the following medical subject headings and keywords: “deforming osteoarthritis of the knee joint”, “osteoarthritis of the knee joint”, “unilateral deforming osteoarthritis of the knee joint”, “unilateral osteoarthritis of the knee joint”, “gonarthrosis”, “monoarthrosis”, “arthroscopy”, “diagnosis”, “treatment”. If necessary, literature sources beyond the search period were used in some cases. A general search revealed 48 references on the use of arthroscopy as a diagnostic and therapeutic method in the early stages of monoarthrosis. The primary exclusion concerned the literature in which arthroscopy was used for the diagnosis and treatment of late-stage knee osteoarthritis (n = 38). The secondary exclusion included literature sources that contained only background information (summary, figures, references) (n = 12). As a result, only relevant full-text articles in professional journals remained (n = 15). Results. The lack of correlation between clinical symptoms and radiological signs of knee osteoarthritis causes low availability of orthopaedic care: more than 30 % of newly diagnosed patients have a severe stage of the disease, and in some cases the pathology is detected only in connection with the manifestation of complications; the diagnosis of osteoarthritis due to a large percentage of painless development of the disease (40 %) is often established at terminal stages. All of this suggests the need for further research into the various factors that influence the frequency, prevalence, economic and social burden of knee osteoarthritis. Arthroscopy is potentially the gold standard for validating non-invasive assessment methods such as magnetic resonance imaging, as it provides high magnification and direct view of articular cartilage with non-destructive interactive assessment of its structure and functional properties. Arthroscopy allows for a more detailed description of the depth and extent of lesions, as well as the detection of subtle changes such as cartilage softening, fibrillations, and tangential peeling. Clinical symptoms and structural changes in the knee joint elements visualised during arthroscopy in patients with monoarthrosis are covered in a few studies, some of which were published 10 years ago. The results of modern arthroscopic studies can be an important contribution to the development of diagnostic and differential diagnostic criteria for the early stages of monoarthrosis. Conclusions. Based on information and analytical studies of modern scientific literature, it has been found that knee osteoarthritis is accompanied by persistent pain, significant limitation of the lower limb function, and reduced ability to work, which often leads to joint replacement. Diagnosis of osteoarthritis in the early stages is difficult due to the absence of pathognomonic clinical, radiological and laboratory parameters, and in case of monoarthrosis with synovitis, it is complicated by differentiation with specific arthritis of the knee joint. Arthroscopy allows performing the necessary scope of diagnostic and therapeutic measures with verification of the pathological process and determination of gonarthrosis stage.

Association of a high rate of glycolysis and the activity of the uncoupling of oxidation and phosphorylation in the blood cells of patients with late-stage knee osteoarthritis and the development of postoperative pain

Objective: to investigate the relationship between the expression of genes mediating cellular energy production and the development of chronic postoperative pain (CPP) after total knee arthroplasty (TKA) in patients with osteoarthritis (OA).Material and methods. Prior to TKA, the blood of 50 patients with stage III–IV knee OA and complaints of constant pain and joint dysfunction was analyzed. The control group consisted of 26 healthy individuals. Pain intensity was assessed using a visual analogue scale (VAS), a short BPI questionnaire and the WOMAC index, and the presence of neuropathic pain was assessed using the DN4 and PainDETECT questionnaires. The development of CPP was determined 3 and 6 months after TKA. Total RNA isolated from blood was used to determine the expression of PKM2, LDH, SDH, AMPKα, PDH, IDH, MDH and ATP synthase genes by real-time quantitative reverse transcriptase-polymerase chain reaction.Results and discussion. CPP ≥30 mm according to VAS was detected in 17 patients. Before TKA, the expression of all analyzed genes was significantly increased compared to that of the control group. However, there were no differences in clinical, pain-related and functional indicators in the analyzed group of patients with OA. Before surgery, patients who subsequently developed CPP had significantly higher expression of genes related to glycolysis (PKM2, LDH), Krebs cycle – KC (SDH) and master regulator of energy metabolism (AMPKα) than patients who were satisfied with the results of TKA. At the same time, no differences were found in the expression of PDH and other KC enzyme genes (IDH, MDH) and ATP synthase in patients with and without CPP.Conclusion. The development of CPP is associated with a higher rate of glycolysis and energy deficiency, presumably due to the higher uncoupling activity of oxidation and phosphorylation that can be observed before TKA.

WITHDRAWN: Efficacy of intra-operative periarticular local infiltration for pain control and ambulation in total knee arthroplasty

Total knee replacement (TKR) is a leading operative procedure for late-stage knee osteoarthritis. Pain, post-replacement hinders an effective rehabilitation protocol. Many preoperative, perioperative, and postoperative analgesia modes have been reported but have some undesirable side effects. To overcome these side effects, an intraoperative local analgesic cocktail can be used. We conducted this study to assess the benefits of intra-operative local infiltration of cocktail in TKR patients in terms of pain, amount of additional analgesia required post-operatively, and ambulation time. 50 patients were chosen and split into two groups of 25 each. The case group received the cocktail injection whereas the control group were injected locally with normal saline. Post-operatively VAS score was assessed at 3, 6,12 and 24 h post-surgery, the amount of analgesics used and ambulation time was assessed. Compared to the control group, the case group had significantly less pain in the first 24 h and a lower amount of additional analgesia and earlier ambulation. Pain reduction with early ambulation was noted in a significant number of individuals with the use of this intraoperative local cocktail injection.

OSTEOARTHRITIS PATIENTS DEVELOP AN AUTONOMIC DYSFUNCTION

Osteoarthritis (OA) is the most common degenerative joint disorder. Its multifactorial etiology includes age, sex, joint overloading, genetic or nervous influences. In particular, the autonomic nervous system is increasingly gaining in importance. Its two branches, the sympathetic (SNS) and parasympathetic nervous system, are well-balanced under healthy conditions. OA patients seem to be prone to an autonomic imbalance and therefore, we analyzed their autonomic status.More than 200 participants including patients with early and late stage knee OA (before and 1 year after knee replacement surgery) and healthy probands (age-matched) were analyzed. Heart rate variability was measured via electrocardiogram to assess long-term sympathetic (low-frequency=LF) and parasympathetic (high-frequency=HF, pRR50) activities or general variability (RMSSD, SDRR). Serum cortisol concentrations were measured by ELISA. Perceived chronic stress (PSQ) was assessed via questionnaire. Multivariant regression was performed for data analysis. LF/HF value of early OA was slightly increased compared to healthy controls but significantly higher compared to late OA patients before (p&gt;0.05) and after TKR (p&gt;0.01). HF in late OA patients before TKR was significantly decreased compared to patients after TKR (p&gt;0.001) or healthy controls (p&gt;0.05). Healthy probands exhibited the highest SDRR values, early OA patients had slightly lower levels and late OA patients before TKR displayed significantly reduced SDRR (p&gt;0.001). The same differences were observed in pRR50 and RMSSD. Serum cortisol concentrations and PSQ scores increased in late OA patients before TKR. At the time point of TKR, women with beta blocker medication had significantly higher age (71 ± 9 years) than those without (63 ± 12 years)(p&gt;0.01). An autonomic dysfunction with sympathetic dominance occurs in OA patients. The fact that beta blocker medication in women delayed the need of TKR indicates that SNS inhibition might counteract OA. Future therapeutic interventions for OA should consider a systemic approach with special regard on the ANS.

Characterization of miR-335-5p and miR-335-3p in human osteoarthritic tissues

ObjectiveWe aimed to characterize the expression patterns, gene targets, and functional effects of miR-335-5p and miR-335-3p among seven primary human knee and hip osteoarthritic tissue types.MethodsWe collected synovial fluid, subchondral bone, articular cartilage, synovium, meniscus/labrum, infrapatellar/acetabular fat, anterior cruciate ligament/ligamentum teres, and vastus medialis oblique/quadratus femoris muscle (n = 7–20) from surgical patients with early- or late-stage osteoarthritis (OA) and quantified miR-335-5p and miR-335-3p expression by real-time PCR. Predicted gene targets were measured in knee OA infrapatellar fat following miRNA inhibitor transfection (n = 3), and prioritized gene targets were validated following miRNA inhibitor and mimic transfection (n = 6). Following pathway analyses, we performed Oil-Red-O staining to assess changes in total lipid content in infrapatellar fat.ResultsShowing a 227-fold increase in knee OA infrapatellar fat (the highest expressing tissue) versus meniscus (the lowest expressing tissue), miR-335-5p was more abundant than miR-335-3p (92-fold increase). MiR-335-5p showed higher expression across knee tissues versus hip tissues, and in late-stage versus early-stage knee OA fat. Exploring candidate genes, VCAM1 and MMP13 were identified as putative direct targets of miR-335-5p and miR-335-3p, respectively, showing downregulation with miRNA mimic transfection. Exploring candidate pathways, predicted miR-335-5p gene targets were enriched in a canonical adipogenesis network (p = 2.1e − 5). Modulation of miR-335-5p in late-stage knee OA fat showed an inverse relationship to total lipid content.ConclusionOur data suggest both miR-335-5p and miR-335-3p regulate gene targets in late-stage knee OA infrapatellar fat, though miR-335-5p appears to be more prominent, with tissue-, joint-, and stage-specific effects.

Impaired Efferocytosis by Synovial Macrophages in Patients With Knee Osteoarthritis.

Osteoarthritis (OA) exposes all joint tissues to physiologic stresses, increasing the need to clear apoptotic cells from tissues, including the synovium. We undertook this study to assess the burden of apoptotic cells in synovial tissue in patients with late-stage knee OA and to investigate whether OA impairs the macrophage-mediated clearance of apoptotic cells via efferocytosis. Synovial tissue was collected from individuals with healthy knees and patients with late-stage knee OA during arthroplasty. Synovial apoptotic cell burden was assessed by immunofluorescence for cleaved caspase 3. Efferocytosis of apoptotic Jurkat cells by CD14+ synovial tissue macrophages and peripheral blood-derived macrophages was quantified using immunofluorescence microscopy. Effects of OA on macrophage-mediated efferocytosis were modeled by stimulating blood-derived macrophages with synovial fluid collected from individuals with healthy knees and patients with early- or late-stage knee OA. Patients with late-stage knee OA had more apoptotic synovial cells compared to healthy individuals. There was a marked reduction in the fraction of synovial tissue macrophages engaging in efferocytosis and the quantity of material efferocytosed by individual macrophages in OA patients. Blood-derived macrophages exposed to synovial fluid from patients with knee OA recapitulated the defective efferocytosis, with the greatest effect from patients with early-stage knee OA and higher disease activity (pain and inflammation). Apoptotic cells accumulate in the synovium of patients with late-stage knee OA. Our results suggest that OA impairs critical homeostatic functions of synovial macrophages, leading to accumulation of apoptotic cells.

Acute loading has minor influence on human articular cartilage gene expression and glycosaminoglycan composition in late-stage knee osteoarthritis: a randomised controlled trial

Osteoarthritis (OA) remains clinically challenging. Regular physical exercise improves symptoms though it is unclear whether exercise influences cartilage at the molecular level. Thus, we aimed to determine the effect of acute loading on gene expression and glycosaminoglycan (GAG) content in human OA cartilage. Patients with primary knee OA participated in this single-blind randomised controlled trial initiated 3.5h prior to scheduled joint replacement surgery with or without loading by performing one bout of resistance exercise (one-legged leg press). Cartilage from the medial tibia condyle was sampled centrally, under the meniscus, and from peripheral osteophytes. Samples were analysed for gene expression by real-time reverse transcriptase polymerase chain reaction, and hyaluronidase-extracted matrix was analysed for GAG composition by immuno- and dimethyl-methylene blue assays. Of 32 patients randomised, 31 completed the intervention: mean age 69±7.5 years (SD), 58% female, BMI 29.4±4.4kg/m2. Exercise increased chondroitin sulphate extractability [95% CI: 1.01 to 2.46; P=0.0486] but cartilage relevant gene expression was unchanged. Regionally, the submeniscal area showed higher MMP-3, MMP-13, IGF-1Ea, and CTGF, together with lower lubricin and COMP expression compared to the central condylar region. Further, osteophyte expression of MMP-1, MMP-13, IGF-1Ea, and TGF-β3 was higher than articular cartilage and lower for aggrecan, COMP, and FGF-2. Hyaluronidase-extracted matrix from central condylar cartilage contained more GAGs but less chondroitin sulphate compared to submeniscal cartilage. Acute exercise had minor influence on cartilage GAG dynamics, indicating that osteoarthritic cartilage is not significantly affected by acute exercise. However, the regional differences suggest a chronic mechanical influence on human cartilage. NCT03410745.

Negative Effects of Knee Replacement

Introduction Total knee arthroplasty is the treatment of choice in orthopedic practice for patients with late stage knee osteoarthritis. However, arthroplasty has not only benefit results and the service life of the endoprothesis is limited. The use of modern conservative therapy and joint-preserving surgions allowed to delay or to avoid knee arthroplasty.&#x0D; Purpose. The study purpose is the analysis of publications with negative results of knee arthroplasty in patients with knee osteoarthritis.&#x0D; Materials and methods. The electronic Pub-Med/MEDLINE and eLibrary databases were searched for reviews published between 2002 and 2022. A keyword search was also done using the terms: knee joint osteoarthritis, total knee replacement/arthroplasty, complications, patient satisfaction, indications/contraindications for surgery; related definitions and descriptions were extracted.&#x0D; Results. The negative consequences of total knee arthroplasty are heterogeneous. Complications can be local and systemic such as surgical site infection, periprosthetic fracture, aseptic loosening (asepticinstability) of theendoprosthesis and its wearand the implant failure. The researchers data indicate increasing the number of patients who are not satisfied with the results of arthroplasty both in the short term and in the long-term after the operation, due to the natural wear of the prosthesis. Patients are not satisfied with the results of the operation 8% -30%. In recent years, there have been more publications devoted to the limitation of indication for arthroplasty in pftients with knee osteoarthritis. The replacement of the knee joint with an implant was done unreasonably in great number of cases.A number of patients after total knee arthroplasty require revision surgery within the first 5 years. Currently, the risk of failure of knee arthroplasty with the revision surgery in 10 years after primary arthroplasty is 5-6.8%. The main reasons for revision surgery after primary knee arthroplasty are periprosthetic infection and instability of the implant components, while the results of revision surgery are worse than the primary arthroplasty.

Tensile strain and altered synovial tissue metabolism in human knee osteoarthritis

Synovium is critical for maintaining joint homeostasis and may contribute to mechanobiological responses during joint movement. We investigated mechanobiological responses of whole synovium from patients with late-stage knee osteoarthritis (OA). Synovium samples were collected during total knee arthroplasty and assigned to histopathology or cyclic 10% tensile strain loading, including (1) static (control); (2) low-frequency (0.3 Hz); and iii) high-frequency (1.0 Hz) for 30-min. After 6-h incubation, tissues were bisected for RNA isolation and immunostaining (3-nitrotyrosine; 3-NT). RNA sequencing was analyzed for differentially expressed genes and pathway enrichment. Cytokines and lactate were measured in conditioned media. Compared to controls, low-frequency strain induced enrichment of pathways related to interferon response, Fc-receptor signaling, and cell metabolism. High-frequency strain induced enrichment of pathways related to NOD-like receptor signaling, high metabolic demand, and redox signaling/stress. Metabolic and redox cell stress was confirmed by increased release of lactate into conditioned media and increased 3-NT formation in the synovial lining. Late-stage OA synovial tissue responses to tensile strain include frequency-dependent increases in inflammatory signaling, metabolism, and redox biology. Based on these findings, we speculate that some synovial mechanobiological responses to strain may be beneficial, but OA likely disturbs synovial homeostasis leading to aberrant responses to mechanical stimuli, which requires further validation.

Costs of Nonoperative Procedures for Knee Osteoarthritis in the Year Prior to Primary Total Knee Arthroplasty.

The convergence of national priorities to reduce health-care costs and deliver high-value care warrants the need to examine health-care utilization. The objective of this study was to describe the costs associated with nonoperative procedures in the 1-year period leading up to primary total knee arthroplasty (TKA). An observational cohort study was conducted using the IBM Watson Health MarketScan databases. Patients with late-stage knee osteoarthritis (OA) who underwent unilateral, isolated primary TKA from January 1, 2018, to December 31, 2019, were included. The main outcome was the cost of knee OA-related payments for identified nonoperative procedures in the 1-year period before surgery. Nonoperative procedures examined were (1) physical therapy (PT); (2) bracing; (3) intra-articular injections: professional fee, hyaluronic acid (IA-HA), and corticosteroids (IA-CS); (4) medication: nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and acetaminophen; and (5) knee-specific imaging. The study population included 24,492 TKA patients with a mean age of 60.4 ± 8.0 years. The average total cost of nonoperative procedures per patient was $1,355 ± $2,087. The most common nonoperative treatment prescribed was IA-CS (54.3%). The nonoperative procedure with the highest cost per patient was IA-HA ($1,019 ± $913 per patient). The total cost of nonoperative procedures was higher among female compared with male patients ($1,440 ± $2,159 versus $1,254 ± $1,992 per patient; p < 0.01). The highest costs were found for patients in the Northeast ($1,740 ± $2,437 per patient). A total of 14,346 (58.6%) and 7,831 (32.0%) of the patients had >1 and ≥3 nonoperative treatments, respectively. There is substantial variation in the type and the cost of nonoperative treatment for patients with late-stage OA. Future studies should investigate the effectiveness of nonoperative treatments at different stages of the disease. Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Prediction of the development of postoperative pain in patients with late-stage knee osteoarthritis based on the expression of genes for degradation of the extracellular matrix, inflammation and apoptosis in the blood

About 10–40% of patients with osteoarthritis (OA) are not satisfied with the results of total arthroplasty (TA) of large joints. At the same time, the most common complication associated with the ineffectiveness of TA is postoperative pain (PP).Objective: to identify genes whose expression in the peripheral blood before TA is associated with an increased risk of PP developing. Patients and methods. Before TA, the blood of 50 patients with late-stage knee OA was examined; the control group consisted of 26 healthy individuals. The level of pain was assessed using the visual analog scale (VAS), the BPI short questionnaire, and the WOMAC index; the presence of neuropathic pain was assessed using the DN4 and PainDETECT questionnaires. The development of PP was determined 3 and 6 months after TA. The levels of matrix metalloproteinase protein (MMP) 9 and tissue inhibitor of metalloproteinase (TIMP) 1 were quantified by ELISA. Total RNA isolated from blood was used to determine the expression of caspase 3, MMP9, TIMP1, cathepsins K and S, tumor necrosis factor (TNF) α, interleukin (IL) 1β, and cyclooxygenase 2 genes using a quantitative real-time reverse transcriptase polymerase chain reaction.Results and discussion. PP according to VAS ≥30 mm was noted in 17 patients. Before TA, these patients had significantly increased expression of cathepsins K and S, caspase 3, TIMP1, IL1β, and TNFα genes compared to other patients with OA. ROC analysis revealed a statistically significant relationship between the expression of these genes and the likelihood of developing pain after TA.Conclusion. High expression of genes associated with degradation of the extracellular matrix (catepsins S and K, TIMP1), inflammation (IL1β, TNFα), and apoptosis (caspase 3) can serve as an important biomarker for the development of PP in patients with knee OA. To confirm the value of preoperative gene expression testing in predicting the onset of PP, further studies involving large cohorts of patients are needed.

Sex-Differences and Associations Between Complement Activation and Synovial Vascularization in Patients with Late-Stage Knee Osteoarthritis.

PurposeSynovial inflammation in knee osteoarthritis (OA) causes disorganized synovial angiogenesis and complement activation in synovial fluid, but links between complement and synovial microvascular pathology have not been established. Since complement causes vascular pathology in other diseases and since sex-differences exist in complement activation and in OA, we investigated sex differences in synovial fluid complement factors, synovial tissue vascular pathology, and associations between complement and synovial vascular pathology in patients with late-stage knee OA.MethodsPatients with symptomatic, late-stage radiographic knee OA undergoing total knee arthroplasty or high tibial osteotomy provided matched synovial fluid and tissue biopsies during surgery. Complement factors (C2, C5, adipsin, MBL, and CFI) and terminal complement complex (sC5b-C9) were measured in synovial fluid by multiplex or enzyme-linked immunosorbent assay, respectively. Features of synovial vascular pathology (vascularization, perivascular edema, and vasculopathy) were assessed by histopathology. Multivariate linear regression models were used to assess associations between synovial fluid complement factors and histopathological features of vascular pathology, with adjustment for age, sex, body mass index, and sex interaction. Sex-disaggregated comparisons were completed.ResultsSynovial fluid biomarker and histopathology data were included from 97 patients. Most synovial fluid complement factors and synovial tissue histopathological features were similar between sexes. Synovial fluid C5 trended to lower levels in males (-20.93 ng/mL [95%CI -42.08, 0.23] p=0.05). Median vasculopathy scores (0.42 [95%CI 0.07, 0.77] p=0.02) were higher in males. In the full cohort, C5 concentration was associated with lower vascularization scores (-0.005 [95%CI -0.010, -0.0001] p=0.04) while accounting for sex*C5 interaction. In sex-disaggregated analyses, increased C5 concentration was associated with lower vascularization scores (-0.005 [95%CI –0.009, -0.0001] p=0.04) in male patients, but not in female patients. Males had higher sC5b-C9 compared to females. Additionally, males with high C5 had a higher synovial fluid concentration of sC5b-C9 compared to males with low C5. No differences were found in females.ConclusionHigher synovial fluid C5 levels were associated with increased complement activation and decreased synovial vascularization in males but not in females with OA. Future studies should test whether synovial fluid complement activation suppresses synovial angiogenesis and identify mechanisms accounting for C5-related sex-differences in synovial fluid complement activation in patients with knee OA.

Drivers of Unequal Healthcare Costs in the Nonoperative Treatment of Late-Stage Knee Osteoarthritis Prior to Primary Total Knee Arthroplasty

BackgroundIn the United States, patients with late-stage knee osteoarthritis (OA) often undergo several nonoperative treatments and related procedures prior to total knee arthroplasty. The costs of these treatments and procedures are substantial, and the variation in healthcare costs among different groups of patients may exist. The purpose of this study is to examine these costs and determine the drivers of costs in patients with the highest healthcare expenditure. MethodsAn observational cohort study was conducted using the IBM Watson Health MarketScan databases from January 1, 2017 to December 31, 2019. The primary outcome was the cost of payments for nonoperative procedures which included (i) physical therapy (PT), (ii) bracing, (iii) intra-articular injections: professional fee, hyaluronic acid (IA-HA), and corticosteroids (IA-CS), (iv) medication: nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and acetaminophen, and (v) knee-specific imaging. ResultsAmong the 24,492 patients included in the study, the total payments per patient for nonoperative care were $3,735 ± 3,049 in the highest payment quartile (Q4) and $137 ± 70 in the lowest payment quartile (Q1). Per-patient-per-month costs generally increased across quartiles for procedures. Comparing Q4 to Q1, the largest changes in prevalence were found in IA-HA (348×), bracing (10×), and PT (7×). Patients who were prescribed IA-HA and PT had a 28.3-times and 4.8-times greater likelihood, respectively, to be a higher-paying patient. ConclusionUnequal healthcare costs in the nonoperative treatment of late-stage knee OA are driven by differences in prevalent management strategies. Overall healthcare expenditure may be reduced if only guideline-concordant treatments are used.

Identification of a differential metabolite-based signature in patients with late-stage knee osteoarthritis

ObjectiveMultiple disease phenotypes have been identified in knee osteoarthritis (OA) patients based on anthropometric, sociodemographic and clinical factors; however, differential systemic metabolite-based signatures in OA patients are not well understood. We sought to identify differential plasma metabolome signatures in a cross-sectional sample of late-stage knee OA patients. MethodsPlasma from 214 (56.5% female; mean age ​= ​67.58 years) non-diabetic, non-obese (BMI <30 ​kg/m2, mean ​= ​26.25 ​kg/m2), radiographic KL 3/4 primary knee OA patients was analyzed by metabolomics. Patients with post-traumatic OA and rheumatoid arthritis were excluded. Hierarchical clustering was used to identify patient clusters based on metabolite levels. A refined metabolite signature differentiating patient clusters was determined based on ≥ 10% difference, significance by FDR-adjusted t-test (q-value < 0.05), and random forests importance score ≥1, and analyzed by AUROC. Bioinformatics analysis was used to identify genes linked to ≥2 annotated metabolites. Associated enriched pathways (q ​< ​0.05) were determined. ResultsTwo patient clusters were determined based on the levels of 151 metabolites identified. Metabolite signature refinement found 24 metabolites could accurately predict cluster classification within the sample (AUC ​= ​0.921). Fifty-six genes were linked to at least 2 ​KEGG annotated metabolites. Pathway analysis found 26/56 genes were linked to enriched pathways including tRNA acylation and B-vitamin metabolism. ConclusionThis study demonstrates systemic metabolites can classify a cross-sectional cohort of OA patients into distinct clusters. Links between metabolites, genes and pathways can help determine biological differences between OA patients, potentially improving precision medicine and decision-making.

Multimodal prediction of pain and functional outcomes 6 months following total knee replacement: a prospective cohort study

BackgroundKnee osteoarthritis (OA) is among the most common and disabling persistent pain conditions, with increasing prevalence and impact around the globe. In the U.S., the rising prevalence of knee OA has been paralleled by an increase in annual rates of total knee arthroplasty (TKA), a surgical treatment option for late-stage knee OA. While TKA outcomes are generally good, post-operative trajectories of pain and functional status vary substantially; a significant minority of patients report ongoing pain and impaired function following TKA. A number of studies have identified sets of biopsychosocial risk factors for poor post-TKA outcomes (e.g., comorbidities, negative affect, sensory sensitivity), but few prospective studies have systematically evaluated the unique and combined influence of a broad array of factors.MethodsThis multi-site longitudinal cohort study investigated predictors of 6-month pain and functional outcomes following TKA. A wide spectrum of relevant biopsychosocial predictors was assessed preoperatively by medical history, patient-reported questionnaire, functional testing, and quantitative sensory testing in 248 patients undergoing TKA, and subsequently examined for their predictive capacity.ResultsThe majority of patients had mild or no pain at 6 months, and minimal pain-related impairment, but approximately 30% reported pain intensity ratings of 3/10 or higher. Reporting greater pain severity and dysfunction at 6 months post-TKA was predicted by higher preoperative levels of negative affect, prior pain history, opioid use, and disrupted sleep. Interestingly, lower levels of resilience-related “positive” psychosocial characteristics (i.e., lower agreeableness, lower social support) were among the strongest, most consistent predictors of poor outcomes in multivariable linear regression models. Maladaptive profiles of pain modulation (e.g., elevated temporal summation of pain), while not robust unique predictors, interacted with psychosocial risk factors such that the TKA patients with the most pain and dysfunction exhibited lower resilience and enhanced temporal summation of pain.ConclusionsThis study underscores the importance of considering psychosocial (particularly positively-oriented resilience variables) and sensory profiles, as well as their interaction, in understanding post-surgical pain trajectories.

SYNOVIAL TISSUE DAMAGE AND SHIFTING IMMUNE PROFILES: ASSOCIATIONS WITH WORSE PAIN IN LATE-STAGE KNEE OSTEOARTHRITIS

Purpose: Tissue damage is associated with chronic inflammation in diseases such as systemic sclerosis, steatohepatitis, and atherosclerosis, marking a transition from earlier to later disease stages and is usually associated with worse clinical outcomes. Osteoarthritis (OA) causes synovial inflammation, which may cause synovial tissue damage, thereby leading to impaired joint health and poor outcomes. Although previous studies have shown associations between histopathological and imaging (MRI, US) features of synovial inflammation, associations of histopathological features of inflammation and/or damage with pain and immune cell profiles have not been established. The objectives of this study were to 1) assess the relationship between pain and histopathological features of synovial inflammation and/or damage in patients with late-stage knee OA, and 2) compare synovial tissue cellular profiles in subgroups of patients reporting high/severe and low/moderate pain using single-cell RNA sequencing.