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.

Hand osteoarthritis phenotypes based on a biopsychosocial approach, and their associations with cross-sectional and longitudinal pain.

OBJECTIVE: Hand osteoarthritis (OA) pain is characterized as heterogeneous and multifactorial. Differences in pain may be explained by underlying phenotypes, which have not been previously explored DESIGN: Latent class analysis determined classes of participants with hand OA from the Nor-Hand study baseline examination (2016-17) based on a biopsychosocial framework. Outcomes were hand and overall bodily pain intensity (Numeric Rating Scale, 0-10) at baseline and follow-up (2019-21), The relations of the classes to pain outcomes at baseline, follow-up, and change over time were analysed in separate models by linear regression, using the overall healthiest class as reference. RESULTS: Five classes differing in radiographic hand OA burden and OA burden in the lower extremities by ultrasound, demographic factors, psychosocial burden and pain sensitization was identified. Persons with the least severe OA but higher burden of biopsychosocial factors reported the most hand pain (beta 3.65, 95% CI 2.53, 4.75). Pain was less pronounced in persons with the most severe hand OA but low burden of biopsychosocial factors (beta 1.03, 95% CI 0.41, 1.65). Results were similar for overall bodily pain and at follow-up. Changes in pain were small, but the association between a separate class defined by higher levels of biopsychosocial burden and pain changes was significant. CONCLUSION: The five hand OA phenotypes were associated with pain at baseline and 3.5 years later. The phenotype with the least OA severity, but higher burden of biopsychosocial factors reported more pain than the phenotype with the most severe OA, reflecting the symptom-structure discordance of the hand OA pain experience.

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.

Osteoarthritis of zygapophysial joints as a cause of back pain and neck pain: a scoping review.

BACKGROUND: Zygapophysial joints (Z joints) can be a source of back pain and of neck pain, but the cause of pain is not known. Some authors attribute the pain to osteoarthritis but without citing evidence. OBJECTIVES: The present review was undertaken to determine if there was sufficient evidence of association between spinal pain and osteoarthritis of Z joints to justify osteoarthritis being held to be the cause of pain. The null hypothesis was that osteoarthritis of Z joints does not cause back pain or neck pain. ELIGIBILITY CRITERIA: Relevant studies were ones that provided primary data on the association between pain and osteoarthritis of Z joints. These could be population studies, diagnostic studies, or case-control studies. SOURCES OF EVIDENCE: The database of PubMed was searched using the terms: Lumbar or cervical, zygapophysial or facet, pain, and osteoarthritis or degeneration or degenerative. CHARTING METHODS: Data pertinent to the research question were extracted from original articles and tabulated for reporting. Odds ratios for associations were calculated, as were the prevalence rates of osteoarthritis in subjects with pain, and conversely the prevalence rates of pain in subjects with osteoarthritis. RESULTS: The searches retrieved 11 population studies, 4 diagnostic studies, and 3 cases control studies. No study showed any positive association between osteoarthritis of Z joints and pain. All studies found pain to be independent of the presence or severity of osteoarthritis. Osteoarthritis was as common in subjects with no pain as in subjects with pain. The null hypothesis was not refuted. CONCLUSION: The published evidence does not support the belief that osteoarthritis causes Z joint pain. All the evidence contradicts this belief.

People with osteoarthritis have a higher component of neuropathic pain as compared to those with rheumatoid arthritis: A cross-sectional study.

Neuropathic pain may be present in a proportion of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Its presence may lead to the requirement of altered management approaches in these conditions. This study investigated the prevalence of neuropathic pain in OA as compared to that in RA. Patients with OA and RA were included cross-sectionally if they had no other known neuropathic disorder. The PainDETECT questionnaire was used to assess neuropathic pain. WOMAC and CDAI scores were used to assess disease severity in OA and RA respectively. 69 patients with OA with a mean WOMAC score of 53.30 ± 16.39 and 98 patients with RA with a mean CDAI of 25.48 ± 16.99 were compared. The median PainDETECT score for OA was 13 (0-30) and RA was 5 (0-37) [p<0.001]. 15 patients with OA and six patients with RA were highly likely to have neuropathic pain, while 15 patients with OA and 30 patients with RA were classified as possibly having neuropathic pain. Thus, the proportion of patients free from neuropathic pain was higher in the RA group (63.3%) than in the OA group (39.1%) [p = 0.003]. Both the prevalence and the severity of neuropathic pain were significantly higher in OA than in RA. These findings suggest that neuropathic pain is an important factor in OA, as in RA, and must be considered in management as well as in future research in both these conditions.

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.

Diet modification reduces pain and improves function in adults with osteoarthritis: a systematic review.

BACKGROUND: The effect of dietary modifications on pain and joint function in adults with osteoarthritis (OA) is an emerging area of study. This systematic review aimed to evaluate if adults with OA who consume diets with a higher proportion of plant phenols and omega-3 fatty acids would have less pain and improved joint function than those with a higher proportion of saturated fatty acids, omega-6 fatty acids and refined carbohydrates. METHODS: Database searches of CINAHL (EBSCO), Clinical Trials (NIH-NLM), Cochrane Library (Wiley), Dissertation & Thesis Global (ProQuest), Embase (Elsevier), Medline (OVID), PubMed (NLM), Scopus (Elsevier), Web of Sciences (Clarivate) for clinical trials identified 7763 articles published between January 2015 and May 2023. After an independent review of the articles, seven randomised clinical trials and one nonrandomised clinical trial were included in the analysis. Because of the heterogeneity of the outcome measures, a meta-analysis was not possible. RESULTS: Participants who were instructed to consume high-phenol/high-omega-3 fatty acid diets reported significant improvements in pain and physical function scores. The greatest improvement was reported by those who consumed a diet that had the most omega-3 fatty acids. CONCLUSION: Because of the high risk of bias, the strength of the evidence is limited. However, there is evidence that counselling adults with OA to replace refined grains and processed foods with whole plant foods, fish and plant oils may have a favourable effect on pain and physical function. Routine follow-up care regarding these diet modifications may be necessary to ensure adherence to this therapy.

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.

A case of Melkersson-Rosenthal syndrome with temporomandibular joint osteoarthritis: multidisciplinary treatment and autoimmune etiological hypothesis.

BACKGROUND: Melkersson-Rosenthal syndrome (MRS) is a rare neuro-mucocutaneous disorder characterized by recurrent edema, facial palsies, and nerve dysfunctions often associated with the plicata tongue. Although the etiology of MRS is not well understood, there is growing evidence suggesting an autoimmune involvement. CASE PRESENTATION: This paper presents a case report of a 25-year-old male with MRS as the initial symptom, followed by temporomandibular joint osteoarthritis (TMJ-OA). A comprehensive diagnosis and multidisciplinary treatment approach including surgery, local injections, and oral medication were implemented, resulting in a favorable prognosis. CONCLUSIONS: These findings support the hypothesis that MRS is a systemic granulomatous disease caused by autoimmunity, which may also influence the occurrence and development of TMJ-OA through immune-related mechanisms. This study emphasizes the significance of systemic immune regulation in the treatment of patients with MRS and TMJ-OA comorbid conditions.

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.