Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease causing limited mobility and pain, with no curative treatment available. Recent in vivo studies suggested autonomic alterations during OA progression in patients, yet clinical evidence is scarce. Therefore, autonomic tone was analyzed in OA patients via heart rate variability (HRV) measurements. METHODS: Time-domain (SDRR, RMSSD, pRR50) and frequency-domain (LF, HF, LF/HF) HRV indices were determined to quantify sympathetic and parasympathetic activities. In addition, perceived stress, WOMAC pain as well as serum catecholamines, cortisol and dehydroepiandrosterone-sulphate (DHEA-S) were analyzed. The impact of the grade of disease (GoD) was evaluated by linear regression analysis and correlations with clinical data were performed. RESULTS: GoD significantly impacted the autonomic tone in OA patients. All time-domain parameters reflected slightly decreased HRV in early OA patients and significantly reduced HRV in late OA patients. Moreover, frequency-domain analysis revealed decreased HF and LF power in all OA patients, reflecting diminished parasympathetic and sympathetic activities. However, LF/HF ratio was significantly higher in early OA patients compared to late OA patients and implied a clear sympathetic dominance. Furthermore, OA patients perceived significantly higher chronic stress and WOMAC pain levels compared to healthy controls. Serum cortisol and cortisol/DHEA-S ratio significantly increased with GoD and positively correlated with WOMAC pain. In contrast, serum catecholamines only trended to increase with GoD and pain level. CONCLUSIONS: This prospective study provides compelling evidence of an autonomic dysfunction with indirect sympathetic dominance in early and late knee OA patients for the first time based on HRV analyses and further confirmed by serum stress hormone measurements. Increased sympathetic activity and chronic low-grade inflammation in OA as well as in its major comorbidities reinforce each other and might therefore create a vicious cycle. The observed autonomic alterations coupled with increased stress and pain levels highlight the potential of HRV as a prognostic marker. In addition, modulation of autonomic activity represents an attractive future therapeutic option.

Spatial working memory in a disappearing object task is impaired in female but not male dogs with chronic osteoarthritis.

Chronic pain in humans is associated with impaired working memory but it is not known whether this is the case in long-lived companion animals, such as dogs, who are especially vulnerable to developing age-related chronic pain conditions. Pain-related impairment of cognitive function could have detrimental effects on an animal's ability to engage with its owners and environment or to respond to training or novel situations, which may in turn affect its quality of life. This study compared the performance of 20 dogs with chronic pain from osteoarthritis and 21 healthy control dogs in a disappearing object task of spatial working memory. Female neutered osteoarthritic dogs, but not male neutered osteoarthritic dogs, were found to have lower predicted probabilities of successfully performing the task compared to control dogs of the same sex. In addition, as memory retention interval in the task increased, osteoarthritic dogs showed a steeper decline in working memory performance than control dogs. This suggests that the effects of osteoarthritis, and potentially other pain-related conditions, on cognitive function are more clearly revealed in tasks that present a greater cognitive load. Our finding that chronic pain from osteoarthritis may be associated with impaired working memory in dogs parallels results from studies of human chronic pain disorders. That female dogs may be particularly prone to these effects warrants further investigation.

Metabolic syndrome increases osteoarthritis risk: findings from the UK Biobank prospective cohort study.

OBJECTIVE: The association between Metabolic Syndrome (MetS), its components, and the risk of osteoarthritis (OA) has been a topic of conflicting evidence in different studies. The aim of this present study is to investigate the association between MetS, its components, and the risk of OA using data from the UK Biobank. METHODS: A prospective cohort study was conducted in the UK Biobank to assess the risk of osteoarthritis (OA) related to MetS. MetS was defined according to the criteria set by the International Diabetes Federation (IDF). Additionally, lifestyle factors, medications, and the inflammatory marker C-reactive protein (CRP) were included in the model. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). The cumulative risk of OA was analyzed using Kaplan-Meier curves and log-rank tests. To explore potential nonlinear associations between MetS components and OA risk, a restricted cubic splines (RCS) model was employed. In addition, the polygenic risk score (PRS) of OA was calculated to characterize individual genetic risk. RESULTS: A total of 45,581 cases of OA were identified among 370,311 participants, with a median follow-up time of 12.48 years. The study found that individuals with MetS had a 15% higher risk of developing OA (HR = 1.15, 95%CI:1.12-1.19). Additionally, central obesity was associated with a 58% increased risk of OA (HR = 1.58, 95%CI:1.5-1.66), while hyperglycemia was linked to a 13% higher risk (HR = 1.13, 95%CI:1.1-1.15). Dyslipidemia, specifically in triglycerides (HR = 1.07, 95%CI:1.05-1.09) and high-density lipoprotein (HR = 1.05, 95%CI:1.02-1.07), was also found to be slightly associated with OA risk. When stratified by PRS, those in the high PRS group had a significantly higher risk of OA compared to those with a low PRS, whereas no interaction was found between MetS and PRS on OA risks. Furthermore, the presence of MetS significantly increased the risk of OA by up to 35% in individuals with elevated CRP levels (HR = 1.35, 95% CI:1.3-1.4). CONCLUSION: MetS and its components have been found to be associated with an increased risk of OA, particularly in individuals with elevated levels of CRP. These findings highlight the significance of managing MetS as a preventive and intervention measure for OA.

Risk factors for postoperative delirium in orthopaedic hip surgery patients: a database review.

BACKGROUND: Postoperative delirium is a common problem affecting admitted patients that decreases patient satisfaction and increases the cost and complexity of care. The purpose of this study was to use the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to compare rates and risk factors of postoperative delirium for total hip arthroplasty (THA) and hemiarthroplasty patients indicated for osteoarthritis or proximal femur fracture. METHODS: The 2021 NSQIP database was queried for patients using Current Procedural Terminology (CPT) codes for THA and hemiarthroplasty and ICD-10 codes for osteoarthritis or proximal femur fracture. Demographic, past medical history, preoperative labs, and functional status data were recorded. Procedural data were also collected. Finally, postoperative outcomes and complications were reviewed. RESULTS: Overall, 16% of patients had postoperative delirium. Delirium patients were older on average (82.4 years vs. 80.7 years, p < 0.001), had a lower BMI (19.5 vs. 24.8, p < 0.001), were more likely to have a history of dementia (54.6% vs. 13.6%, p < 0.001), were less likely to have an independent functional status (p < 0.001) or live alone (p < 0.001), and were more likely to have sustained a recent fall (p < 0.001). Delirium patients were more likely to be hyponatremic or hypernatremic (p = 0.002), anemic (p < 0.001), and severely dehydrated (p < 0.001), among other lab abnormalities. Delirium patients were also more likely to experience additional postoperative complications, including pneumonia, pulmonary embolism, urinary tract infection, stroke, cardiac arrest, sepsis, and unplanned reoperation and readmission after discharge (all p < 0.05). CONCLUSIONS: In this study, factors associated with postoperative delirium in patients undergoing hemiarthroplasty and THA were identified, including older age, lower BMI, certain medical conditions, decreased functional status, certain lab abnormalities, and postoperative complications. These findings can be used by clinicians to better inform care and to determine when orthopaedic joint replacement patients may be at an increased risk for postoperative delirium.

No Difference in Patient-Reported Outcomes for Periacetabular Osteotomy and Hip Arthroscopy With Capsular Plication in the Setting of Borderline Hip Dysplasia: A Propensity-Matched Multicenter Study With Minimum 5-Year Follow-Up.

PURPOSE: To compare minimum 5-year patient-reported outcome measures after hip arthroscopy (HA) and periacetabular osteotomy (PAO) for borderline hip dysplasia. METHODS: Hips with a lateral center-edge angle (LCEA) between 18° and less than 25° that underwent either PAO or HA were selected from 2 institutions. The exclusion criteria were as follows: LCEA less than 18°, Tönnis osteoarthritis grade greater than 1, prior hip surgical procedures, active inflammatory disease, Workers' Compensation, and concomitant surgery. Patients underwent propensity matching based on age, sex, body mass index, and Tönnis osteoarthritis grade. Patient-reported outcome measures included the modified Harris Hip Score, as well as calculation of the minimal clinically important difference, patient acceptable symptom state, and maximum outcome improvement satisfaction threshold. Preoperative radiographic predictors included comparison of the Femoro-epiphyseal Acetabular Roof index and ligamentum teres lesions. RESULTS: A total of 28 PAO patients underwent propensity matching to 49 HA patients. The 2 groups were similar in terms of mean age, sex, preoperative body mass index, and LCEA. The PAO group had a longer mean follow-up period (95.8 months vs 81.3 months, P = .001). The mean Femoro-epiphyseal Acetabular Roof index was significantly lower preoperatively in the HA group (P < .001). The 2 groups showed similar and significant improvements in the mean modified Harris Hip Score from preoperatively to latest follow-up (P < .001). The relative risk of subsequent surgery in the PAO group was 3.49 (P = .024), mostly attributed to hardware removal (25%). The revision rate was 3.6% in the PAO group and 8.2% in the HA group (P = .65). One patient in the PAO group required revision HA for intra-articular adhesions. Three of the patients requiring revision in the HA group underwent PAO because of persistent pain, and one underwent revision HA alone. Conversion to total hip arthroplasty was required in 1 patient in the HA group and no patients in the PAO group. CONCLUSIONS: Both PAO and HA with capsular plication provide borderline hip dysplasia patients with clinically significant improvements and low revision rates at a minimum of 5 years postoperatively. LEVEL OF EVIDENCE: Level III, retrospective, comparative therapeutic trial.

Postoperative Radiographic Outcomes Following Primary Open Coracoid Transfer (Bristow-Latarjet) Vary in Definition, Classification, and Imaging Modality: A Systematic Review.

PURPOSE: To analyze radiographic outcomes by conventional radiography, computed tomography (CT), or both and complication rates of open coracoid transfer at a minimum of 12-months follow-up. METHODS: A literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using PubMed, Medline (Ovid), and EMBASE library databases. Inclusion criteria were clinical studies reporting on open Latarjet as the primary surgical procedure(revision coracoid transfer after failed prior stabilization excluded) with postoperative radiographic outcomes at a minimum mean 1-year follow-up. Patient demographics, type of postoperative imaging modality, and radiographic outcomes and complications including graft union, osteoarthritis, and osteolysis were systematically reviewed. Data were summarized as ranges of reported values for each outcome metric. Each radiographic outcome was graphically represented in a Forest plot with point estimates of the incidence of radiographic outcomes with corresponding 95% confidence intervals and I2. RESULTS: Thirty-three studies met inclusion criteria, with a total of 1,456 shoulders. The most common postoperative imaging modality was plain radiography only (n = 848 [58.2%]), both CT and radiography (n = 287 [19.7%]), and CT only (n = 321 [22.1%]). Overall, the reported graft union rate ranged from 75% to 100%, of which 79.8% (n = 395) were detected on plain radiography. The most common reported postoperative radiographic complications after the open coracoid transfer were osteoarthritis (range, 0%-100%, pooled mean 28%), graft osteolysis (range, 0%-100%, pooled mean 30%), nonunion (range, 0%-32%, pooled mean 5.1%), malpositioned graft (range, 0%-75%, pooled mean 14.75%), hardware issues (range, 0%-9.1%, pooled mean 5%), and bone block fracture (range, 0%-8%, pooled mean 2.1%). Graft healing was achieved in a majority of cases (range, 75%-100%). CONCLUSION: Postoperative radiographic outcomes after open coracoid transfer vary greatly in definition, classification, and imaging modality of choice. Greater consistency in postoperative radiographic outcomes is essential to evaluate graft healing, osteolysis, and nonunion. LEVEL OF EVIDENCE: Level IV, systematic review of Level III-IV studies.

Shoulder arthroplasty for inflammatory arthritis is associated with higher rates of medical and surgical complications: a nationwide matched cohort analysis from 2016-2020.

BACKGROUND: Inflammatory arthritis (IA) represents a less common indication for anatomic and reverse total shoulder arthroplasty (TSA) than osteoarthritis (OA). The safety and efficacy of anatomic and reverse TSA in this population has not been as well studied compared to OA. We analyzed the differences in outcomes between IA and OA patients undergoing TSA. METHODS: Patients who underwent primary anatomic total shoulder arthroplasty (aTSA) and reverse total shoulder arthroplasty (rTSA) from 2016-2020 were identified in the Premier Healthcare Database. Inflammatory arthritis (IA) patients were identified using International Classification of Diseases, Tenth Revision, diagnosis codes and compared to osteoarthritis controls. Patients were matched in a 1:8 fashion by age (±3 years), sex, race, and presence of pertinent comorbidities. Patient demographics, hospital factors, and patient comorbidities were compared. Multivariate regression was performed following matching to account for any residual confounding and 90-day complications were compared between the 2 cohorts. Descriptive statistics and regression analysis were employed with significance set at P < .05. RESULTS: Prior to matching, 5685 IA cases and 93,539 OA controls were identified. Patients with IA were more likely to be female, have prolonged length of stay and increased total costs (P < .0001). After matching and multivariate analysis, 4082 IA cases and 32,656 controls remained. IA patients were at increased risk of deep wound infection (OR 3.14, 95% CI 1.38-7.16, P = .006), implant loosening (OR 4.11, 95% CI 1.17-14.40, P = .027), and mechanical complications (OR 6.34, 95% CI 1.05-38.20, P = .044), as well as a decreased risk of postoperative stiffness (OR 0.36, 95% CI 0.16-0.83, P = .002). Medically, IA patients were at increased risk of PE (OR 2.97, 95% CI 1.52-5.77, P = .001) and acute blood loss anemia (OR 1.27, 95% CI 1.12-1.44, P < .0001). DISCUSSION AND CONCLUSION: Inflammatory arthritis represents a distinctly morbid risk profile compared to osteoarthritis patients with multiple increased surgical and postoperative medical complications in patients undergoing aTSA and rTSA. Surgeons should consider these potential complications and employ a multidisciplinary approach in preoperative risk stratification of IA undergoing shoulder replacement.

Reverse shoulder arthroplasty for primary glenohumeral osteoarthritis: significantly different characteristics and outcomes in shoulders with intact vs. torn rotator cuff.

PURPOSE: To compare outcomes of reverse shoulder arthroplasty (RSA) for primary osteoarthritis (OA) with and without rotator cuff (RC) tears to those with secondary OA due to RC tears. METHODS: We reviewed records of all patients who received RSA for primary OA or secondary OA. All patients had preoperative radiographs, computed tomographic arthrography (CTA), and/or magnetic resonance imaging (MRI) scans of their shoulders to assess their etiology, glenoid morphology, and fatty infiltration. Pre- and postoperative (at minimum follow-up of 2 years) Constant scores and range of motion were compared between patients who had RSA for primary OA with and without RC tears to those with secondary OA due to RC tears. RESULTS: Of the initial cohort of 605 shoulders (583 patients), 153 were lost to follow-up (25.3%), 25 required revision with implant removal (4.1%), and 13 died of causes unrelated to the surgery (2.1%), and left a final cohort of 414 patients. Of the final cohort, 97 had primary OA with intact RC, 62 had primary OA with RC tears, and 255 had secondary OA. Postoperative Constant scores were significantly higher for primary OA with intact RC (73.8 ± 14.3), compared with both primary OA with RC tears (66.1 ± 14.6, P < .001) and secondary OA (64.1 ± 14.8, P < .001). There were no differences in pre- or postoperative scores between primary OA with RC tears and secondary OA. CONCLUSION: At 2 or more years following RSA, Constant scores were significantly higher for primary OA with intact RC, compared to either primary OA with RC tears or secondary OA, whereas there were no differences in pre- or postoperative scores of shoulders that had primary OA with RC tears vs. secondary OA. The authors recommend distinguishing primary OA with intact RC from primary OA with RC tears, as the two have considerably different characteristics and prognosis following RSA.

Relationship between arthritis of the second and third tarsometatarsal joints and incongruity of the first tarsometatarsal joint in patients with hallux valgus.

OBJECTIVES: Hallux valgus is associated with tarsometatarsal arthritis; its pathophysiology remains unknown. Therefore, we aimed to elucidate the relationship between arthritis of the second and third tarsometatarsal joints and incongruity of the first tarsometatarsal joint in the sagittal plane. METHODS: Forty-three patients (64 feet) with hallux valgus who underwent surgery at University Hospital Kyoto Prefectural University of Medicine were included and divided into two groups: control (without second and third tarsometatarsal joint degeneration) and osteoarthritis (with second and third tarsometatarsal joint degeneration). Intergroup comparisons of the incongruity of the first tarsometatarsal joint in the sagittal plane, age, body mass index, hallux valgus angle, first-second intermetatarsal angle, metatarsus adductus angle, Meary's angle, and calcaneal pitch angle were performed. RESULTS: The proportion of patients with incongruity of the first tarsometatarsal joint was significantly higher in the osteoarthritis group than in the control group. Logistic regression analysis identified incongruity of the first tarsometatarsal joint and metatarsus adductus angle as significant related factors for arthritis of the second and third tarsometatarsal joints. CONCLUSIONS: Incongruity of the first tarsometatarsal joint in the sagittal plane was involved in the development of arthritis of the second and third tarsometatarsal joints in patients with hallux valgus.

Superior humeral head osteophytes are associated with rotator cuff insufficiency in glenohumeral osteoarthritis: a retrospective analysis.

PURPOSE: The primary goal of this study was to investigate whether superior humeral head osteophyte (SHO) size is associated with rotator cuff insufficiency, including rotator cuff tear (RCT), supraspinatus tendon thickness, and fatty infiltration of the rotator cuff muscles. METHODS: Patients ≥ 18 years who were diagnosed with glenohumeral osteoarthritis were retrospectively reviewed. SHO size was determined by radiograph. MRI measured SHO and RCT presence, type, and size; supraspinatus tendon thickness; and fatty infiltration of rotator cuff musculature. RESULTS: A total of 461 patients were included. Mean SHO size was 1.93 mm on radiographs and 2.13 mm on MRI. Risk ratio for a RCT was 1.14. For each 1-mm increase in SHO size on radiograph, supraspinatus tendon thickness decreased by 0.20 mm. SHO presence was associated with moderate-to-severe fatty infiltration of the supraspinatus with a risk ratio of 3.16. CONCLUSION: SHOs were not associated with RCT but were associated with higher risk of supraspinatus FI and decreased tendon thickness, which could indicate rotator cuff insufficiency. LEVEL OF EVIDENCE: IV.

Invited Commentary: A Step Toward Safer and More Precise Management of Osteoarthritis Pain.

In this issue of the Journal, Wei et al. (Am J Epidemiol. 2023;192(9):1432-1448); demonstrate the modification of effect of nonselective nonsteroidal antiinflammatory drugs in the setting of aspirin use for the outcome of cardiovascular events. This study is distinctive in its aim to compare 2 similar therapies in the setting of 2 clinical scenarios (aspirin use vs. not) based on some mechanistic rationale. The use of an active comparator design with a prehypothesized evaluation of treatment heterogeneity can provide compelling evidence to support relevant clinical decisions for which clinical trial evidence is not likely or possible.

Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect.

OBJECTIVES: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA. METHODS: We performed meta-analysis of EHOA in 1484 cases and 550 680 controls, from 5 populations. To identify causal genes, we performed eQTL and plasma pQTL analyses, and developed one zebrafish mutant. We analysed associations of variants with other traits and estimated shared genetics between EHOA and other traits. RESULTS: Four common sequence variants associated with EHOA, all with relatively high effect. Rs17013495 (SPP1/MEPE, OR=1.40, p=8.4×10-14) and rs11243284 (6p24.3, OR=1.35, p=4.2×10-11) have not been associated with OA, whereas rs11631127 (ALDH1A2, OR=1.46, p=7.1×10-18), and rs1800801 (MGP, OR=1.37, p=3.6×10-13) have previously been associated with hand OA. The association of rs1800801 (MGP) was consistent with a recessive mode of inheritance in contrast to its additive association with hand OA (OR homozygotes vs non-carriers=2.01, 95% CI 1.71 to 2.37). All four variants associated nominally with finger OA, although with substantially lower effect. We found shared genetic components between EHOA and other OA measures, grip strength, urate levels and gout, but not rheumatoid arthritis. We identified ALDH1A2, MGP and BMP6 as causal genes for EHOA, with loss-of-function Bmp6 zebrafish mutants displaying EHOA-like phenotypes. CONCLUSIONS: We report on significant genetic associations with EHOA. The results support the view of EHOA as a form of severe hand OA and partly separate it from OA in larger joints.

Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort.

BACKGROUND: The iron overload condition hereditary hemochromatosis (HH) can cause liver cirrhosis and cancer, diabetes, and arthritis. Males homozygous for the p.C282Y missense mutation in the Homeostatin Iron Regulator (HFE) gene have greatest risk; yet, only a minority develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or liver disease risk in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers. METHODS: We studied 1294 male and 1596 female UK Biobank HFE p.C282Y homozygous participants of European ancestry with medical records up to 14 years after baseline assessment. Polygenic scores quantified genetic effects of blood iron biomarkers and relevant diseases (identified in the general population). Analyses were also performed in other HFE p.C282Y/p.H63D genotype groups. RESULTS: In male p.C282Y homozygotes, a higher iron polygenic score increased the risk of liver fibrosis or cirrhosis diagnoses (odds ratio for the top 20% of iron polygenic score vs. the bottom 20% = 4.90: 95% confidence intervals, 1.63-14.73; p = 0.005), liver cancer, and osteoarthritis but not diabetes. A liver cirrhosis polygenic score was associated with liver cancer diagnoses. In female p.C282Y homozygotes, the osteoarthritis polygenic score was associated with increased osteoarthritis diagnoses and type-2 diabetes polygenic score with diabetes. However, the iron polygenic score was not robustly associated with diagnoses in p.C282Y female homozygotes or in other p.C282Y/p.H63D genotypes. CONCLUSIONS: HFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population, including polygenic scores in HH screening and diagnosis, may help in estimating prognosis and treatment planning.

Associations between pain sensitization and measures of physical function in people with hand osteoarthritis: Results from the Nor-Hand study.

OBJECTIVE: To examine whether pain sensitization is associated with hand and lower extremity function in people with hand osteoarthritis (OA) in the Nor-Hand study. DESIGN: Pain sensitization was assessed by pressure pain thresholds (PPTs) and temporal summation (TS). Hand function was assessed by Australian/Canadian Osteoarthritis Hand Index (AUSCAN) (range: 0-36), grip strength and Moberg pick-up test, and lower extremity function was assessed by Western Ontario and McMaster Universities Osteoarthritis Index (range: 0-68), 30-s chair stand test, and 40-m walk test. We examined whether sex-standardized PPT and TS values were cross-sectionally associated with measures of physical function using linear regression analyses. Beta coefficients were presented per sex-specific standard deviation of PPT and TS. The mediating effect of pain was examined by causal-inference based mediation analysis. RESULTS: In 206 participants, higher PPTs at/near the hand, indicative of less peripheral and/or central pain sensitization, were associated with greater grip strength and better self-reported hand function (beta for PPT at finger joint on AUSCAN function: -1.41, 95% CI -2.40, -0.42). Higher PPTs at/near the hand, near the knee and at trapezius were associated with lower extremity function, although not statistically significant for all outcomes. Self-reported pain severity mediated the effect of PPT on self-reported function. TS was not associated with hand or lower extremity function. CONCLUSION: Peripheral sensitization, and possibly central sensitization, was associated with impaired function. Effects of PPTs on self-reported function were mediated by self-reported pain, whereas there might be a direct effect of sensitization or effects through other mediators on performance-based function.

Reflections from the OARSI 2022 clinical trials symposium: The pain of OA-Deconstruction of pain and patient-reported outcome measures for the benefit of patients and clinical trial design.

OBJECTIVE: Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field. METHOD: The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development. RESULTS: Signs or symptoms indicative of nociceptive pain occur in 50-70% of OA patients, neuropathic-like pain in 15-30% of patients, and nociplastic pain in 15-50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions. CONCLUSIONS: The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials.

Intensive cholesterol-lowering treatment reduces synovial inflammation during early collagenase-induced osteoarthritis, but not pathology at end-stage disease in female dyslipidemic E3L.CETP mice.

INTRODUCTION: The association between metabolic syndrome (MetS) and osteoarthritis (OA) development has become increasingly recognized. In this context, the exact role of cholesterol and cholesterol-lowering therapies in OA development has remained elusive. Recently, we did not observe beneficial effects of intensive cholesterol-lowering treatments on spontaneous OA development in E3L.CETP mice. We postulated that in the presence of local inflammation caused by a joint lesion, cholesterol-lowering therapies may ameliorate OA pathology. MATERIALS AND METHODS: Female ApoE3∗Leiden.CETP mice were fed a cholesterol-supplemented Western type diet. After 3 weeks, half of the mice received intensive cholesterol-lowering treatment consisting of atorvastatin and the anti-PCSK9 antibody alirocumab. Three weeks after the start of the treatment, OA was induced via intra-articular injections of collagenase. Serum levels of cholesterol and triglycerides were monitored throughout the study. Knee joints were analyzed for synovial inflammation, cartilage degeneration, subchondral bone sclerosis and ectopic bone formation using histology. Inflammatory cytokines were determined in serum and synovial washouts. RESULTS: Cholesterol-lowering treatment strongly reduced serum cholesterol and triglyceride levels. Mice receiving cholesterol-lowering treatment showed a significant reduction in synovial inflammation (P = 0.008, WTD: 95% CI: 1.4- 2.3; WTD + AA: 95% CI: 0.8- 1.5) and synovial lining thickness (WTD: 95% CI: 3.0-4.6, WTD + AA: 95% CI: 2.1-3.2) during early-stage collagenase-induced OA. Serum levels of S100A8/A9, MCP-1 and KC were significantly reduced after cholesterol-lowering treatment (P = 0.0005, 95% CI: -46.0 to -12.0; P = 2.8 × 10-10, 95% CI: -398.3 to -152.1; P = 2.1 × 10-9, -66.8 to -30.4, respectively). However, this reduction did not reduce OA pathology, determined by ectopic bone formation, subchondral bone sclerosis and cartilage damage at end-stage disease. CONCLUSION: This study shows that intensive cholesterol-lowering treatment reduces joint inflammation after induction of collagenase-induced OA, but this did not reduce end stage pathology in female mice.

Biomarkers and longitudinal changes in lumbar spine degeneration and low back pain: the Johnston County Osteoarthritis Project.

OBJECTIVE: To determine if baseline biomarkers are associated with longitudinal changes in the worsening of disc space narrowing (DSN), vertebral osteophytes (OST), and low back pain (LBP). DESIGN: Paired baseline (2003-2004) and follow-up (2006-2010) lumbar spine radiographs from the Johnston County Osteoarthritis Project were graded for severity of DSN and OST. LBP severity was self-reported. Concentrations of analytes (cytokines, proteoglycans, and neuropeptides) were quantified by immunoassay. Pressure-pain threshold (PPT), a marker of sensitivity to pressure pain, was measured with a standard dolorimeter. Binary logistic regression models were used to estimate odd ratios (OR) and 95% confidence intervals (CI) of biomarker levels with DSN, OST, or LBP. Interactions were tested between biomarker levels and the number of affected lumbar spine levels or LBP. RESULTS: We included participants (n = 723) with biospecimens, PPT, and paired lumbar spine radiographic data. Baseline Lumican, a proteoglycan reflective of extracellular matrix changes, was associated with longitudinal changes in DSN worsening (OR = 3.19 [95% CI 1.22, 8.01]). Baseline brain-derived neuropathic factor, a neuropeptide, (OR = 1.80 [95% CI 1.03, 3.16]) was associated with longitudinal changes in OST worsening, which may reflect osteoclast genesis. Baseline hyaluronic acid (OR = 1.31 [95% CI 1.01, 1.71]), indicative of systemic inflammation, and PPT (OR = 1.56 [95% CI 1.02, 2.31]) were associated with longitudinal increases in LBP severity. CONCLUSION: These findings suggest that baseline biomarkers are associated with longitudinal changes occurring in structures of the lumbar spine (DSN vs OST). Markers of inflammation and perceived pressure pain sensitivity were associated with longitudinal worsening of LBP.

Axial rotation and pain are associated with facet joint osteoarthritis in adolescent idiopathic scoliosis.

OBJECTIVE: Facet joints are crucial for spinal stability but develop premature osteoarthritis in patients with adolescent idiopathic scoliosis (AIS). Here, we evaluated the association between facet joint cartilage and subchondral bone homeostasis, perceived back pain and 3-dimensional spinal deformity to better understand the role of facet joint degeneration in AIS progression and pain. METHOD: The osteoarthritic state of cartilage and bone of AIS facet joint surgical samples were characterized using histological OARSI scoring, visual morphological grading and µCT analysis, respectively. Back pain was self-reported using a numerical rating scale and expressed relative to the location on the patient's back. The scoliotic curves from our patient cohort were digitally reconstructed using biplanar radiographs and the eOS system (EOS imaging). The deformity was then reduced to three intervertebral angles (coronal, sagittal and axial) for each pair of bilateral facet joints. Statistical associations between the intervertebral angles, osteoarthritis parameters and pain intensity were performed using the Spearman method and Friedman test. RESULTS: Facet joint cartilage degeneration was associated with decreased subchondral bone volume and quality. Most importantly, asymmetrical, and overall degeneration of facet joints was strongly correlated to intervertebral axial rotation. Additionally, kyphotic intervertebral segments in the sagittal plane were good predictors of increased facet joint degeneration and back pain. CONCLUSION: Facet joint degeneration is associated with axial deformity, kyphotic intervertebral angle and back pain intensity in AIS. These results suggest that facet joints are important features to consider for rotational instability in AIS spines and related disease progression and perceived back pain.

Obesity and its chronic inflammation as pain potentiation factor in rats with osteoarthritis.

BACKGROUND: Obesity produces the accumulation of adipose tissue and a chronic inflammatory process, while osteoarthritis (OA) is also an inflammatory disorder. OBJECTIVES: to evaluate whether obesity associated to OA may be a factor that increases inflammation and pain. METHODS: Male animals (M) were divided into groups: control (CM), OA-induced pain (MP), obese (OM) and obese with OA-induced pain (OMP). Similarly, females (F) were divided into groups: control (CF), OA-induced pain (FP), obese (OF) and obese with OA-induced pain (OFP). All the groups except for control and obese groups were submitted to OA induction by sodium monoiodoacetate injection and monitored until day 65. Their adiposity index, thermal, mechanical and spontaneous pain nociceptive profile were investigated. At the end of the experiment (t = 65 days) hematological parameters, biochemical parameters, andcytokines were assessed. RESULTS: Rats with obesity induction showed alterations in mechanical and thermal nociceptive profile, and increase in systemic inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-8 and leptin) with reduction in anti-inflammatory cytokines (adiponectin and IL-10). These profile changes were investigated by principal component analysis (PCA), in which the first two principal components explained near 90% of the data variability. Obesity, when present together with OA in OMP and OFP groups, yielded the highest levels of inflammatory cytokines and pain scores and the lowest levels on anti-inflamatory cytokines. CONCLUSION: Obesity modified the nociceptive profile when inflammatory process is produced. When obesity occurs concomitantly with OA, inflammatory progression is intensified, yelding increase in pain scores.