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ObjectivesTo determine how many persons with knee pain have subsequent pain resolution and what factors are associated with resolution, focusing especially on types of physical activity.MethodsUsing data from MOST, an NIH funded longitudinal cohort study of persons with or at risk of knee osteoarthritis, we studied participants who at baseline reported knee pain on most days at both a telephone interview and clinic visit. We defined pain resolution if at 30 and 60 month exams, they reported no knee pain on most days and compared these participants to those who reported persistent pain later. In logistic regression analyses, we examined the association of baseline risk factors including demographic factors, BMI, depressive symptoms, isokinetic quadriceps strength and both overall physical activity (using the PASE survey) and specific activities including walking, gardening, and different intensities of recreational activities with pain resolution.ResultsOf 1,304 participants with knee pain on most days at baseline, 265 (20.3%) reported no knee pain at 30 and 60 months. Lower BMI and stronger quadriceps were associated with higher odds of pain resolution while overall physical activity was not. Of activities, walking decreased the odds of pain resolution (adjOR=0.86 (95% CI 0.76, 0.98)), but gardening (adjOR=1.59 (1.16, 2.18)) and moderate intensity recreational activities ((adjOR=1.24 (1.05, 1.46)) increased it.ConclusionPain resolution is common in those with knee pain. Factors increasing the odds of pain resolution include lower BMI, greater quadriceps strength and gardening and moderately intensive recreational activities.

Objectives To examine whether acetabular dysplasia (AD), cam and/or pincer morphology are associated with radiographic hip osteoarthritis (rHOA) and hip pain in UK Biobank (UKB) and, if so, what distribution of osteophytes is observed.DesignParticipants from UKB with a left hip dual-energy x-ray absorptiometry (DXA) scan had alpha angle (AA), lateral centre-edge angle (LCEA) and joint space narrowing (JSN) derived automatically. Cam and pincer morphology, and AD were defined using AA and LCEA. Osteophytes were measured manually and rHOA grades were calculated from JSN and osteophyte measures. Logistic regression was used to examine the relationships between these hip morphologies and rHOA, osteophytes, JSN, and hip pain.Results6,807 individuals were selected (mean age: 62.7; 3382/3425 males/females). Cam morphology was more prevalent in males than females (15.4% and 1.8% respectively). In males, cam morphology was associated with rHOA [OR 3.20 (95% CI 2.41-4.25)], JSN [1.53 (1.24-1.88)], and acetabular [1.87 (1.48-2.36)], superior [1.94 (1.45-2.57)] and inferior [4.75 (3.44-6.57)] femoral osteophytes, and hip pain [1.48 (1.05-2.09)]. Broadly similar associations were seen in females, but with weaker statistical evidence. Neither pincer morphology nor AD showed any associations with rHOA or hip pain.ConclusionsCam morphology was predominantly seen in males in whom it was associated with rHOA and hip pain. In males and females, cam morphology was associated with inferior femoral head osteophytes more strongly than those at the superior femoral head and acetabulum. Further studies are justified to characterise the biomechanical disturbances associated with cam morphology, underlying the observed osteophyte distribution.

Summary Objective To compare ground reaction force patterns (GRF) during walking among legs defined by presence or absence of knee pain and/or radiographic knee osteoarthritis (ROA). Method Principal component analysis extracted major modes of variation (PCs) in GRF data from the Multicenter Osteoarthritis Study during self-paced walking. Legs were categorized as pain + ROA (n = 168), ROA only (n = 303), pain only (n = 476), or control (n = 1877). Relationships between group and GRF PCs were examined using Generalized Estimating Equations, adjusted for age, sex, body mass index, race, and clinic site with and without additional adjustment for gait speed. Results With or without speed adjustment, pain + ROA had flatter vertical GRF waveforms than control (speed adjusted PC2 difference [95%CI]: −66 [-113,-20]), pain + ROA and ROA only had higher lateral GRF at impact and greater mid-stance medial GRF than control (speed adjusted PC3 difference: 9 [3,16] and 6 [2,10], respectively), and ROA only had higher early vs late medial GRF than control (speed adjusted PC2 difference: 7 [2,13]). Pain only had flatter vertical GRF waveforms and a smaller difference between anterior and posterior GRF than control only without speed adjustment. Conclusion In this large sample, sustained mid-stance loading and higher impact loads were identified in legs with ROA or ROA and pain, even when adjusting for differences in gait speed and other confounders. While it remains to be seen whether these features precede or result from ROA and pain, the presence of these patterns in the speed-adjusted models could have implications on gait interventions aimed to change joint loading.

Summary Objective To compare early hip osteoarthritis (OA) features on magnetic resonance imaging (MRI) in high-impact athletes with and without hip and/or groin pain, and to evaluate associations between early hip OA features, the International Hip Outcome Tool (iHOT33) and Copenhagen Hip and Groin Outcome Score (HAGOS). Design This case-control study evaluated data of the femoroacetabular impingement and hip osteoarthritis cohort (FORCe). One hundred and eighty-two symptomatic (hip and/or groin pain >6 months and positive flexion-adduction-internal-rotation (FADIR) test) and 55 pain-free high-impact athletes (soccer or Australian football (AF)) without definite radiographic hip OA underwent hip MRI. The Scoring Hip Osteoarthritis with MRI (SHOMRI) method quantified and graded the severity of OA features. Each participant completed the iHOT33 and HAGOS. Results Hip and/or groin pain was associated with higher total SHOMRI (0–96) (mean difference 1.4, 95% CI: 0.7–2.2), labral score (adjusted incidence rate ratio (aIRR) 1.33, 95% CI: 1.1–1.6). Differences in prevalence of cartilage defects, labral tears and paralabral cysts between symptomatic and pain-free participants were inconclusive. There was a lower prevalence of effusion-synovitis in symptomatic participants when compared to pain-free participants (adjusted odds ratio (aOR) 0.46 (95% CI: 0.3–0.8). Early hip OA features were not associated with iHOT33 or HAGOS. Conclusions A complex and poorly understood relationship exists between hip and/or groin pain and early hip OA features present on MRI in high-impact athletes without radiographic OA. Hip and/or groin pain was associated with higher SHOMRI and labral scores.

Refereed/Peer-reviewed Background: Colchicine may offer relief in osteoarthritis. This has never been investigated for hand osteoarthritis. Objectives: To investigate the effect of 1 mg daily colchicine vs placebo on hand pain and function over 12 weeks in older adults with hand osteoarthritis. Methods: Community-dwelling adults with diagnosed osteoarthritis of the hand aged 40–80 years were randomised to receive colchicine (0.5 mg twice daily) or matching placebo. Primary outcome measure was VAS hand pain score (0–100 mm). Secondary outcome measures included tender and swollen joint count, grip strength, C-reactive protein, and Michigan Hand Questionnaire total, function and pain scores. In an exploratory assessment, we compared synovial grade and power Doppler. All outcome measures were obtained at baseline and week 12. Stata v16 was used to perform constrained longitudinal data analysis models. Results: 64 adults (54 females, 10 males) aged 48–79 years of age were enrolled. 59 participants completed the study (N = 28 colchicine, N = 31 placebo) (withdrawal rate 8%). Adverse reactions to the study medication occurred in nine patients. VAS score was not significantly different at baseline (61 ± 17 mm in the colchicine, 64 ± 17 mm in the placebo group). Between-group difference for VAS score at week 12 was 7.6 mm (95% CI -3.5-18.7, p-value 0.18). There were no significant differences between groups for any secondary outcomes at baseline or week 12. Conclusions: 1 mg colchicine daily for 12 weeks was not effective for reducing pain, tender and swollen joint count or increasing grip strength in symptomatic hand osteoarthritis. Our results do not support the use of colchicine in hand osteoarthritis.

Summary Objectives Subchondral bone may contribute to knee osteoarthritis (OA) pain. Nerve growth factor (NGF) can stimulate nerve growth through TrkA. We aimed to identify how sensory nerve growth at the osteochondral junction in human and rat knees associates with OA pain. Methods Eleven symptomatic chondropathy cases were selected from people undergoing total knee replacement for OA. Twelve asymptomatic chondropathy cases who had not presented with knee pain were selected post-mortem. OA was induced in rat knees by meniscal transection (MNX) and sham-operated rats were used as controls. Twice-daily oral doses (30 mg/kg) of TrkA inhibitor (AR786) or vehicle were administered from before and up to 28 days after OA induction. Joints were analysed for macroscopic appearances of articular surfaces, OA histopathology and calcitonin gene-related peptide-immunoreactive (CGRP-IR) sensory nerves in medial tibial plateaux, and rats were assessed for pain behaviors. Results The percentage of osteochondral channels containing CGRP-IR nerves in symptomatic chondropathy was higher than in asymptomatic chondropathy (difference: 2.5% [95% CI: 1.1–3.7]), and in MNX-than in sham-operated rat knees (difference: 7.8% [95%CI: 1.7–15.0]). Osteochondral CGRP-IR innervation was significantly associated with pain behavior in rats. Treatment with AR786 prevented the increase in CGRP-IR nerves in osteochondral channels and reduced pain behavior in MNX-operated rats. Structural OA was not significantly affected by AR786 treatment. Conclusions CGRP-IR sensory nerves within osteochondral channels are associated with pain in human and rat knee OA. Reduced pathological innervation of the osteochondral junction might contribute to analgesic effects of reduced NGF activity achieved by blocking TrkA.

Quantitative sensory testing (QST) is a psychophysical test used to quantify somatosensory sensation under normal or pathological conditions including osteoarthritis (OA).OBJECTIVE: This study aimed to conduct a systematic review and meta-analysis of studies using QST in healthy and osteoarthritic cats, registered at Systematic Review Research Facility (#26-06-2017).DESIGN: Hierarchical models with random intercepts for each individual study extracted through the systematic review were fit to subject-level data; QST measures were contrasted between healthy and osteoarthritic cats. Four bibliographic databases were searched; quality and risk of bias assessment were performed using pre-established criteria.RESULTS: Six articles were included; most were of high quality and low risk of bias. Punctate tactile threshold (n=70) and mechanical temporal summation (n=35) were eligible for analysis. Cats with OA have lower punctate tactile threshold [mean difference (95%HDI): -44 (-60; -26) grams] and facilitated temporal summation of pain [hazard ratio (95%HDI): 5.32 (2.19; 14) times] when compared with healthy cats. The effect of sex and body weight on sensory sensitivity remained inconclusive throughout all analyses. Due to the correlation between age and OA status, it remains difficult to assess the effect of OA on sensory sensitivity, independently of age.CONCLUSIONS: Clear and transparent reporting using guidelines are warranted. Similar to people, centralized sensitization is a feature of OA in cats. Future studies should try to elucidate the age effect on feline OA. Research with natural OA in cats is promising with potential to benefit feline health and welfare, and improve translatability to clinical research.

OBJECTIVE: Following destabilization of the medial meniscus (DMM), mice develop experimental osteoarthritis (OA) and associated pain behaviors that are dependent on the stage of disease. We aimed to describe changes in gene expression in knee-innervating dorsal root ganglia (DRG) after surgery, in order to identify molecular pathways associated with three pre-defined pain phenotypes: “post-surgical pain”, “early-stage OA pain”, and “persistent OA pain”. DESIGN: We performed DMM or sham surgery in 10-week old male C57BL/6 mice and harvested L3-L5 DRG 4, 8, and 16 weeks after surgery or from age-matched naïve mice (n=3/group). RNA was extracted and an Affymetrix Mouse Transcriptome Array 1.0 was performed. Three pain phenotypes were defined: “post-surgical pain” (sham and DMM 4-week vs. 14-week old naïve), “early OA pain” (DMM 4-week vs. sham 4-week), and “persistent OA pain” (DMM 8- and 16-week vs. naïve and sham 8- and 16-week). ‘Top hit’ genes were defined as p

To assess the relation of obesity to opioid use in people with or at risk of knee osteoarthritis (OA), and the extent to which this association is mediated by number of painful joints or depressive symptoms.We used data from the Multicenter Osteoarthritis Study, a longitudinal cohort of older adults with or at risk of knee OA. Opioid use was identified by prescription medications and self-report. Obesity was defined as BMI ≥ 30 kg/mWe studied 2,335 participants (mean age: 68; mean BMI 31 kg/mMulti-joint pain and depressive symptoms partially explained greater opioid use among obese persons with knee OA, demonstrating that the negative impact of obesity on knee OA extends beyond its influence on knee pain and structural progression.

Summary Objective To evaluate racial and ethnic disparities in utilization of total knee arthroplasty (TKA) in relation to demographic, health, and socioeconomic status variables. Design Prospective study of 102,767 Women's Health Initiative postmenopausal women initially aged 50–79, examining utilization rates of primary TKA between non-Hispanic Black/African American, non-Hispanic White, and Hispanic/Latina women (hereafter referred to as Black, White, and Hispanic). A total of 8,942 Black, 3,405 Hispanic, and 90,420 White women with linked Medicare claims data were followed until time of TKA, death, or transition from fee-for-service coverage. Absolute disparities were determined using utilization rates by racial/ethnic group and relative disparities quantified using multivariable hazards models in adjusting for age, arthritis, joint pain, mobility disability, body mass index, number of comorbidities, income, education, neighborhood socioeconomic status (SES), and geographic region. Results TKA utilization was higher among White women (10.7/1,000 person-years) compared to Black (8.5/1,000 person-years) and Hispanic women (7.6/1,000 person-years). Among women with health indicators for TKA including diagnosis of arthritis, moderate to severe joint pain, and mobility disability, Black and Hispanic women were significantly less likely to undergo TKA after adjusting for age [Black: HR (95% confidence interval) = 0.70 (0.63–0.79); Hispanic: HR = 0.58 (0.44–0.77)]. Adjustment for SES modestly attenuated the measured disparity, but significant differences remained [Black: HR = 0.75 (0.67–0.89); Hispanic: HR = 0.65 (0.47–0.89)]. Conclusions Compared to White women, Black and Hispanic women were significantly less likely to undergo TKA after considering need and appropriateness for TKA and SES. Further investigation into personal-level and provider-level factors that may explain these disparities is warranted.

Summary Objective To identify the prevalence of sarcopenic obesity, a phenotype of low muscle mass and high adiposity, in adults with end-stage knee osteoarthritis (OA). Various diagnostic criteria, including assessment of muscle/fat mass, muscle strength and physical function, were used to identify patients with and without sarcopenic obesity, and to compare outcomes of pain, function and quality of life. Design Cross-sectional clinical study including adults with a body mass index (BMI) ≥30 kg/m2 and knee OA. Body composition was measured by dual-energy X-ray absorptiometry (DXA). Assessments included gait speed, handgrip strength, six minute walk test, and self-reported pain, physical function, and health-related quality of life using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and EuroQol Foundation (EQ-5D). Results 151 adults (59% female) aged 65.1 ± 7.9 years, mean BMI 37.1 ± 5.5 kg/m2, were included. Prevalence of sarcopenic obesity using diagnostic cut-offs of appendicular skeletal muscle mass (ASM) relevant to height2, weight and BMI varied from 1.3% (95% confidence interval (CI): 0.2–4.7%) to 14.6% (9.4–21.2%) and 27.2% (20.2–35%), respectively. A combined diagnostic approach including low ASM with either low strength or low function yielded a prevalence of 8.6% (4.7–14.3%). Sarcopenic obesity influenced walking speed, endurance, strength, and patient-reported difficulty with self-care activities, regardless of diagnostic approach. Conclusion Prevalence of sarcopenic obesity varied depending on diagnostic criteria. Given the impact of this condition and OA on physical function, we suggest a combined diagnostic approach be used to clarify expected prevalence and enable early clinical identification and management of sarcopenic obesity in patients with knee OA.

This trial evaluated the efficacy and safety of GZ389988A, a tropomyosin receptor kinase A (TrkA) inhibitor, in subjects with painful knee osteoarthritis (OA).In this single center, double-blind, placebo-controlled and randomized trial, 104 subjects with moderate-to-severe knee OA pain were enrolled to receive a single intra-articular (IA) injection of either GZ389988A or placebo. Efficacy measures were assessed over 12 weeks and included walking pain (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] A1), overall knee pain, WOMAC A, B, C and total score, Patient Global Impression of Change (PGIC), OMERACT-OARSI responder rate and rescue medication use. Adverse events (AEs) were monitored up to 24 weeks.The primary efficacy endpoint was met with a between-group difference of -7.49 (VAS 0-100) on WOMAC A1 changes over 4 weeks (P 0.05 favoring GZ389988A). The secondary outcome on WOMAC A1 changes over 12 weeks had a between-group difference of -6.78 (P = 0.064). Among weekly assessments, statistically significant greater improvement in the GZ389988A group was observed in WOMAC A1, overall knee pain and/or WOMAC A at weeks 2-5. Although not statistically significant, improvements over placebo on pain and WOMAC C persisted over 12 weeks. Greater AE incidence was observed in the GZ389988A group including transient and self-limited injection joint inflammatory reactions with a spike of acetaminophen intake within the first week post-injection.IA injection of TrkA inhibitor GZ389988A in knee OA subjects reduced pain with a numerically functional gain and an acceptable safety profile. (ClinicalTrials.gov, NCT02845271).

Summary Objective To examine patterns of prescription opioid use before total joint replacement (TJR) and factors associated with continuous use of opioids before TJR. Design We conducted an observational cohort study among Medicare enrollees aged ≥65 years who underwent TJR between 2010 and 2014. Preoperative opioid use was defined as having any opioid prescription in the 12-month period before TJR. Patients who had an opioid prescription every month for a 12-month period were defined as continuous users. We examined patients' demographics, pain-related conditions, medication use, other comorbidities, healthcare utilization and their association with use of opioids before TJR. Results A total of 473,781 patients underwent TJR:,155,516 THR and 318,265 TKR. Among the total cohort, 60.2% patients had any use of opioids and of those, 12.4% used opioids at least once a month continuously over the 12-month baseline period. Correlates of continuous opioid use included African American race (OR = 2.14, 95% confidence intervals (CI) = 2.01–2.28, compared to White patients), history of drug abuse (OR = 5.18, 95% CI = 3.95–6.79) and back pain (OR = 2.32, 95% CI = 2.24–2.39). Conclusions In this large cohort of patients undergoing TJR, over 60% ever used opioids and 12.4% of them continuously used opioids in the 12-month prior to surgery. Utilization of opioids became more frequent and high-dosed near the surgery. History of drug abuse, back pain, and African American race were strongly associated with continuous use of opioids preoperatively. Further research is needed to determine short-term and long-term risks of preoperative use of opioids in TJR patients and to optimize pre- and post-TJR pain management of patients with arthritis.

Summary Objective To describe associations between presence of patellar tendon enthesis (PTE) abnormalities and symptoms, structural abnormalities, and total knee replacement (TKR) in older adult cohort. Methods PTE abnormalities (presence of abnormal bone signal and/or bone erosion), were measured on T2-weighted magnetic resonance (MR) images at baseline in 961 community-dwelling older adults. Knee pain and function limitation were assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Bone marrow lesions (BMLs), cartilage volume and defects score, and infrapatellar fat pad (IPFP) area were measured using validated methods. Incidence of TKR was determined by data linkage. Results Participants with abnormal PTE bone signal and/or erosion was 20%. Cross-sectionally, presence of PTE abnormalities was associated with greater pain intensity while going up and down stairs (β = 0.22 (95% confidence interval (CI); 0.03, 0.41)), greater risk of femoral BMLs (RR = 1.46 (1.12, 1.90)) and worse tibial cartilage defects score (RR = 1.70 (1.16, 2.47), and smaller IPFP area (β = −0.27 (−0.47, −0.06) cm2), after adjustment of confounders. Longitudinally, presence of baseline PTE abnormalities was associated with a deleterious increase in tibial BML size (RR = 1.52 (1.12, 2.05)) over 10.7 years but not symptoms, other structural changes, or TKR. Conclusion PTE abnormalities are common in older adults. Presence of cross-sectional but not longitudinal associations suggests they are commonly co-exist with other knee structural abnormalities but may not play a major role in symptom development or structural change, excepting tibial BMLs.

Summary Osteoarthritis is the most common form of joint disease and is one of the leading causes of chronic pain. Given the multi-factorial nature, numerous efforts have been made to clarify the multiple factors impacting the pain symptoms and joint pathology, including synovial macrophages in particular. Accumulating evidence from studies involving human participants and experimental animal models suggests that accumulating macrophages in synovial tissue are implicated in peripherally mediated pain sensitization of affected joints in osteoarthritis. Crosstalk between synovial macrophages and the innervating primary nociceptive neurons is thought to contribute to this facilitated pain processing by the peripheral nervous system. Due to high plasticity and complexity of synovial macrophages in the joint, safe therapies targeting single cells or molecules are currently lacking. Using advanced technologies (such as single-cell RNA sequencing and mass cytometry), studies have shown that diverse subpopulations of synovial macrophages exist in the distinct synovial microenvironments of specific osteoarthritis subtypes. Considerable progress has been made in delineating the molecular mechanisms of various subsets of synovial macrophages in the development of osteoarthritis. To develop a novel intra-articular treatment paradigm targeting synovial macrophages, we have summarized in this review the recent advances in identifying the functional consequences of synovial macrophage sub-populations and understanding of the molecular mechanisms driving macrophage-mediated remodeling.

Summary Objective To investigate the longitudinal relationship between physical performance (via real-life accelerometry) and physical capacity (laboratory measurement of gait speed) in patients with knee osteoarthritis (KOA), and to derive accelerometry measured thresholds associated with gait speed decline in KOA that may provide targets for disease-specific physical activity guidelines. Design Longitudinal data from the Osteoarthritis Initiative (OAI) accelerometer sub-study was extracted from 1,229 participants assessed 2 years apart. Extracted data include functional capacity, demographic and anthropometric characteristics, patient-reported outcome measures, and accelerometry-based physical activity measures. A “poor capacity” group was defined based on the gait speed quintile decline between baseline and the 2-yr follow-up. A Random Forest classifier was trained to classify individuals’ capacity status, and the impact of each extracted factor on the prediction outcome was analyzed using a novel machine learning interpretation algorithm. Results The most impactful predicting feature for gait decline is low minutes in the performance of moderate–vigorous activity (count per min 2,500+). Slower sit-to-stand performance, higher age and self-reported knee pain, and lower minutes in performance light activities (count per min 350-2499) also contributed to the model prediction. The overall classification accuracy is 76.3% (75.4% sensitivity, 76.5% specificity). Conclusions We investigated the impact magnitude and direction of each predicting feature on the longitudinal capacity status among KOA patients. Using novel data interpretation method, we established feature thresholds that may increase the probability of gait decline. These identified thresholds may provide meaningful information for establishing specific physical activity guidelines for KOA.

OBJECTIVE: To investigate the impact of hip osteoarthritis (OA) and/or hip symptoms on excess mortality. DESIGN: We analyzed data from 3,919 individuals in a community-based prospective cohort of African Americans and Caucasians age ≥45 years. Women ≥ 50 years of age and all men underwent supine anteroposterior pelvic radiography at baseline, with the participant’s feet in 15 degrees of internal rotation. Hip radiographic (rOA) was defined as a Kellgren-Lawrence grade of >2 in at least one hip. Participants completed questionnaires at baseline to determine presence of hip symptoms and covariate status. Participants with symptomatic hip rOA (SxOA) are a subset of individuals with hip rOA and symptoms in the same hip. Multiple imputation was used to impute missing values of covariates. Mortality was determined through 2015 and follow-up time was calculated from baseline assessment until death or censoring which took place when a participant was lost to follow-up or reached the end of study period. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals. We carried out additional analyses stratified by sex, race, age and obesity. RESULTS: Mean follow-up time was 14.2 years during which 1762 deaths occurred. There were 29.9% participants in our population with hip rOA at baseline. Compared to those with neither hip rOA nor hip symptoms, we observed an increased risk of all-cause mortality in participants with hip symptoms alone (HR=1.28, 95% 0=1.13-1.46), but no association for hip rOA either with or without symptoms. In stratified analyses we observed increased associations for hip symptoms alone and hip sxOA in those

Summary Objective We have reported that fibrotic changes in infrapatellar fat pad (IFP) after acute joint inflammation are closely associated with persistent pain in rats. In this study, to examine the effects of anti-fibrotic treatment on persistent pain, we used C-type natriuretic peptides (CNP) at the recovery phase after acute joint inflammation. Design Thirty-two male Wistar rats were used in this study. Monoiodoacetic acid (MIA) was injected intra-articularly to induce IFP fibrosis and persistent pain. CNP was injected after acute inflammatory phase in the same knee joint. Time-course pain-avoidance behavior tests and histological analyses were performed to examine the effects of CNP. Results Histological evaluations indicated that intra-articular injection of CNP inhibited fibrotic changes in IFP after acute inflammation. Incapacitance tests indicated that MIA injection into rat knee joint quickly decreased the percent weight on ipsilateral limb. In the vehicle group, the decrease was maintained up to day 28, suggesting that pain persistence occurred after acute inflammation (Day 0/Day 28, Est Dif −8.15, CI -10.78∼-5.53, Linear mixed-effect model). In contrast, the pain was alleviated in the CNP group after day 14 (Day0/Day 14, -0.51, −2.62–1.59). In addition, we observed significant improvement in the degree of articular cartilage degeneration at day 14 in the CNP group (OARSI score: vehicle 16.14 ± 4.37 vs CNP 6.87 ± 3.44, P Conclusion Fibrotic changes in IFP may play important roles in both persistent pain and articular cartilage degeneration.

Summary Objective Pain is the main reason patients report Osteoarthritis (OA), yet current analgesics remain relatively ineffective. This study investigated both peripheral and central mechanisms that lead to the development of OA associated chronic pain. Design The monoiodoacetate (MIA) model of OA was investigated at early (2–6 days post injection) and late (>14 days post injection) time points. Pain-like behaviour and knee histology were assessed to understand the extent of pain due to cartilage degradation. Electrophysiological single-unit recordings were taken from spinal wide dynamic range (WDR) neurons to investigate Diffuse Noxious Inhibitory Controls (DNIC) as a marker of potential changes in descending controls. Immunohistochemistry was performed on dorsal root ganglion (DRG) neurons to assess any MIA induced neuronal damage. Furthermore, qPCR was used to measure levels of glia cells and cytokines in the dorsal horn. Results Both MIA groups develop pain-like behaviour but only late phase (LP) animals display extensive cartilage degradation. Early phase animals have a normally functioning DNIC system but there is a loss of DNIC in LP animals. We found no evidence for neuronal damage caused by MIA in either group, yet an increase in IL-1β mRNA in the dorsal horn of LP animals. Conclusion The loss of DNIC in LP MIA animals suggests an imbalance in inhibitory and facilitatory descending controls, and a rise in the mRNA expression of IL-1β mRNA suggest the development of central sensitisation. Therefore, the pain associated with OA in LP animals may not be attributed to purely peripheral mechanisms.

ObjectiveTo facilitate shared decision-making for patients with knee osteoarthritis (OA), we aimed at building clinically applicable models to predict the individual change in pain intensity (VAS scale 0–100), knee-related quality of life (QoL) (KOOS QoL score 0–100) and walking speed (m/sec) immediately following two educational and 12 supervised exercise therapy sessions.MethodsWe used data from patients with knee OA from the ‘Good Life with osteoArthritis in Denmark’ (GLA:D®) registry (n = 6,767). From 51 patient characteristics, we selected the best performing variables to predict the outcomes via random forest regression. We evaluated model performance via R2. Lastly, we validated and compared our models with the average improvements via the mean differences in an independent validation data set from the GLA:D® registry (n = 2,896) collected 1 year later than the data used to build the models.ResultsValidating our models including the best performing variables yielded R2s of 0.34 for pain intensity, 0.18 for knee-related QoL, and 0.07 for walking speed. The absolute mean differences between model predictions and the true outcomes were 14.65 mm, 10.32 points, and 0.14 m/s, respectively, and similar to the absolute mean differences of 17.64, 11.28 and 0.14 observed when we subtracted the average improvements from the true outcomes.ConclusionDespite including 51 potential predictors, we were unable to predict changes in individuals’ pain intensity, knee-related QoL and walking speed with clinically relevant greater precision than the respective group average outcomes. Therefore, average prediction values can be used to inform patients about expected outcomes.

As magnesium mediates bone and muscle metabolism, inflammation, and pain signaling, we aimed to evaluate whether magnesium intake is associated with knee pain and function in radiographic knee osteoarthritis (OA).We investigated the associations between knee pain/function metrics and magnesium intake from food and supplements in 2548 Osteoarthritis Initiative cohort participants with prevalent radiographic knee OA (Kellgren-Lawrence score ≥2). Magnesium intake was assessed by Food Frequency Questionnaire (FFQ) at baseline. WOMAC and Knee Injury and Osteoarthritis Outcome Score (KOOS) scores were reported annually with total follow up of 48 months. Analyses used linear mixed models.Among participants with baseline radiographic knee OA the mean total magnesium intake was 309.9 mg/day (SD 132.6) for men, and 287.9 mg/day (SD 118.1) for women, with 68% of men and 44% of women below the estimated average requirement. Subjects with lower magnesium intake had worse knee OA pain and function scores, throughout the 48 months (P 0.001). After adjustment for age, sex, race, body mass index (BMI), calorie intake, fiber intake, pain medication use, physical activity, renal insufficiency, smoking, and alcohol use, lower magnesium intake remained associated with worse pain and function outcomes (1.4 points higher WOMAC and 1.5 points lower KOOS scores for every 50 mg of daily magnesium intake, P 0.05). Fiber intake was an effect modifier (P for interaction0.05). The association between magnesium intake and knee pain and function scores was strongest among subjects with low fiber intake.Lower magnesium intake was associated with worse pain and function in knee OA, especially among individuals with low fiber intake.

Summary Objective Compare knee pain and disability between African Americans (AAs) and Whites (WHs), with or at risk of knee osteoarthritis (KOA), over 9 years, and evaluate racial disparities in KOA-related symptoms across socioeconomic and clinical characteristics. Design Osteoarthritis Initiative (OAI) participants were evaluated annually over 9 years for pain and disability, assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and a numerical rating scale (NRS) for knee pain severity. Mean annual WOMAC pain, NRS pain, and WOMAC disability levels were estimated by race using mixed effects models, adjusted for age, sex, education, marital status, body mass index (BMI), depression, and baseline Kellgren–Lawrence grade score. Race-specific mean WOMAC pain scores were also estimated in analyses stratified by socioeconomic and clinical characteristics. Results AAs reported worse mean WOMAC pain compared to WHs at baseline (3.69 vs 2.20; P ≤ 0.0001) and over 9 years of follow-up, with similar disparities reflected in NRS pain severity and WOMAC disability. Radiographic severity did not account for the differences in pain and disability, as substantial and significant racial disparities were observed after stratification by Kellgren–Lawrence grade. Depression and low income exacerbated differences in WOMAC pain between AAs and WHs by a substantial and significant magnitude. Conclusions Over 9 years of follow-up, AAs reported persistently greater KOA symptoms than WHs. Socioeconomically and clinically disadvantaged AAs reported the most pronounced disparities in pain and disability.

AIM: To explore risk factors that may influence knee pain (KP) through central or peripheral mechanisms.METHODS: A questionnaire-based prospective community cohort study with KP defined as pain in or around a knee on most days for at least a month. Baseline prevalence, and one year incidence and progression (KP worsening) were examined. Central (e.g., Pain Catastrophizing Scale (PCS)) and peripheral (e.g., significant injury) risk factors were examined. Adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated using logistic regression. Proportional risk contribution (PRC) was estimated using receiver-operator-characteristic (ROC) analysis.RESULTS: Of 9506 baseline participants, 4288 (45%) had KP (men 1826; women, 2462). KP incidence was 12% (men 11%, women 13%), and KP progression 19% (men 16%, women 21%) at one year. While both central and peripheral factors contributed to prevalence, central factors contributed more to progression, and peripheral factors more to incidence of KP. For example, although PCS (OR 2.06, 95% CI 1.88-2.25) and injury (5.62, 4.92-6.42) associated with KP prevalence, PCS associated with progression (2.27, 1.83-2.83) but not incidence (1.14, 0.86-1.52), whereas injury more strongly associated with incidence (69.27, 24.15-198.7) than progression (2.52, 1.48-4.30). The PRC of central and peripheral factors were 19% and 23% for prevalence, 14% and 29% for incidence, and 29% and 5% for progression, respectively.CONCLUSIONS: Both central and peripheral risk factors influence KP but relative contributions may differ in terms of development (mainly peripheral) and progression (mainly central). Further study of such relative contributions may inform primary and secondary prevention strategies.

Summary Objectives To describe prevalence of osteophytes (OPs) detected only by magnetic resonance imaging (MRI) but not by standard X-ray in older adults and to evaluate longitudinal associations with knee structural changes. Methods 837 participants were randomly selected from the local community and had MRI scans to assess knee OPs and other structures. OPs detected only by MRI but not by standard X-ray were defined as MRI-detected early OPs (MRI-OPs for short). OPs detected by both MRI and X-ray were defined as established-OPs. Results The prevalence of MRI-OPs was 50% while the prevalence of established-OPs was 10% and no-OPs was 40% at total tibiofemoral (TF) compartment at baseline. Compared with no-OPs, participants with MRI-OPs had greater risks of increased cartilage defects in all TF compartments (RR 1.37, 95%CI 1.07–1.74) and bone marrow lesions (BMLs) only in medial TF compartment (RR 1.49, 95%CI 1.06–2.11), after adjustment for age, sex, BMI, cartilage defects, BMLs and/or joint space narrowing; participants with established-OPs had greater cartilage volume loss at total (β −2.02, 95%CI −3.86, −0.17) and lateral tibial sites (β −5.63, 95%CI −9.93, −1.32), greater risks of increased cartilage defects in total (RR 1.66, 95%CI 1.15–2.40) and medial TF compartments (RR 1.49, 95%CI 1.20–1.69) and BMLs in all TF compartments (RR 1.88, 95%CI 1.22–2.89), after adjustment for covariates. Conclusion MRI-OPs were associated with changes in knee structures, and the associations were similar but not as prominent as those for established-OPs. These suggest MRI-OPs may have a role to play in knee early-stage osteoarthritic progression.

Summary Objective To investigate radiographic measurements of the hip joint and their associations with hip pain, and the prevalence of acetabular dysplasia defined by radiographic measurements of the hip joint in Japanese men and women using the large-scale population-based cohort of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. Methods From the baseline survey of the ROAD study (cross-sectional study), 2963 participants (1040 men, 1923 women; mean age, 70.2 years) were analyzed. All participants underwent radiographic examinations of both hips using an anteroposterior view under weight-bearing. Minimum joint space width (mJSW), central-edge (CE) angle, acetabular depth-to-width ratio (ADR), and acetabular head index (AHI) were measured. Associations between these radiographic measurements and hip pain were assessed by calculating odds ratios (ORs) using multivariable logistic-regression analysis. Acetabular dysplasia was defined as a CE angle Results Mean radiographic measurements of the hip joint for men were: mJSW, 3.8 mm; CE angle, 30.6°; ADR, 262.1 per 1000; and AHI, 81.4%. For women, these values were: mJSW, 3.4 mm; CE angle, 29.9°; ADR, 262.7 per 1000; and AHI, 81.2%. Associations were seen between hip pain and each of mJSW, CE angle, ADR, and AHI (OR 4.52, 95% confidence interval 3.45–5.97; 1.14, 1.11–1.18; 1.31, 1.24–1.40; and 1.15, 1.12–1.18, respectively). Acetabular dysplasia showed an overall prevalence of 13.9%, and was significantly more prevalent in women than in men ( P = 0.012). Conclusion The present study of radiographic measurements of the hip joint showed that mJSW, CE angle, ADR, and AHI were associated with hip pain.

To develop normative reference data for the Knee injury and Osteoarthritis Outcome Score (KOOS) and KOOS-Child, as well as investigate socio-demographic, psychological and physical factors associated with knee pain and disability among healthy adults.The KOOS or KOOS-Child (each containing five subscales) was administered to participants aged 8-101 years within the 1000 Norms Project, an observational study of 1000 self-reported healthy individuals. Self-efficacy, physical activity, body mass index (BMI), lower limb alignment, knee frontal plane projection angle (FPPA), knee range of motion (ROM), knee and hip strength, six-minute walk, 30-second chair stand and timed up and down stairs tests were collected. KOOS data were dichotomised using established cut-off scores and logistic regression analyses were conducted for each subscale.Socio-demographic characteristics were similar to the Australian population. Normative reference data were generated for children (8-17 years) and adults (18-101 years). Female adults were up to twice as likely to report knee pain, symptoms and sport/recreation (Sport/Rec) limitations compared to males (P .05). Older age, lower self-efficacy, greater BMI, varus lower limb alignment, lower knee flexion ROM and lower hip external rotation (ER) strength were independently associated with knee pain and disability among adults.Age- and gender-stratified reference data for the KOOS and KOOS-Child have been developed to guide interpretation of results in practice and research for individuals with knee disorders. Psychological and physical factors are linked with self-reported knee pain/disability among adults, and longitudinal studies to investigate causation are required.

Summary Objective To investigate whether higher daily cumulative hip moment at baseline is associated with subsequent radiographic progression of hip osteoarthritis (OA) over 12 months. Design Fifty patients with secondary hip OA, excluding patients with end-stage hip OA, participated in this prospective cohort study. Joint space width (JSW) of the hip was measured at baseline and 12 months later. With radiographic progression of hip OA (>0.5 mm/year in JSW) as dependent variable (yes/no), univariable and multivariable logistic regression analyses were performed to assess the association between load-related parameters during gait (i.e., peak hip moment, hip moment impulse, and daily cumulative hip moment [product of hip moment impulse and mean steps/day]) and hip OA progression with and without adjustment for age, body weight, and minimum JSW. Results Of the 50 patients (47.4 ± 10.7 years old), 21 (42.0%) were classified into the progression group. The higher daily cumulative hip moment in the frontal plane at baseline was statistically significantly associated with radiographic progression of hip OA (adjusted odds ratio (OR) [95% confidence interval (CI)], 1.34 [1.06–1.70]; P = 0.013). The higher daily cumulative hip moment in the sagittal plane was also approaching significance in its association with hip OA progression (adjusted OR, 1.80 [0.99–3.26]; P = 0.052). Conclusions In the female patients with secondary hip OA, higher daily cumulative hip moment, particularly in the frontal plane, was a predictor of radiographic progression of hip OA over 12 months. Reduction in daily cumulative hip moment by modification in gait and physical activity may potentially slow hip OA progression.

Summary Objective To examine the clinical impact of coexisting lateral osteoarthritis (OA) in knees with mild medial OA. Design In patients with Kellgren/Lawrence (K/L) grade 2 OA in the medial compartment ( n = 100; age: 56–89 years; 80.0% female), anteroposterior knee radiography was used to assess the presence of lateral OA, using grading systems from the Osteoarthritis Research Society International (OARSI) atlas and the K/L classification. The Japanese Knee Osteoarthritis Measure (JKOM), knee range of motion (ROM), and performance-based functional measures (10 m walk, timed up and go and five repetition chair stand maneuvers) were evaluated. The outcomes were compared between patients with and without lateral OA using an analysis of covariance (ANCOVA) or nonparametric rank ANCOVA. Furthermore, ordinal logistic regression analysis was performed, with responses on individual JKOM pain questionnaires as the outcomes and lateral OA as the predictor. Results Knees with coexisting lateral OA had a significantly worse score of JKOM pain question compared with those without, after adjusting for covariates. The presence of lateral OA was significantly associated with knee pain while ascending/descending stairs and standing. These results were consistent between different definitions of the K/L and OARSI grading systems. The knee ROM and performance-based functional measures were not significantly different between patients with and without lateral OA. Conclusion Knees with concomitant lateral and mild medial OA may be more symptomatic compared to those without lateral OA. These findings might help to define a clinically distinct subgroup based on a simple radiographic finding in mild knee OA.

Summary Objective To determine the association between bone marrow lesions (BMLs) and (teno)synovitis as assessed on magnetic resonance (MR) imaging in patients with pain in hand osteoarthritis (OA). Methods In 105 consecutive primary hand OA patients (83% women, mean age 59 years), who were diagnosed by rheumatologists and included in the HOSTAS (Hand OSTeoArthritis in Secondary care) cohort, contrast enhanced MR imaging of right distal and proximal interphalangeal joints were obtained. In 92 patients joint site specific pain upon palpation was assessed within 3 weeks of magnetic resonance imaging (MRI) examination. MR features were scored (0–3) following the Oslo hand OA score: BMLs, synovitis, cysts, flexor tenosynovitis (FTS). Additionally, extensor tendon inflammation (ETI) (0–3) was scored. Odds ratios (OR, 95% confidence interval (CI)) were calculated using generalized estimating equations for MR features with joint pain, adjusted for putative confounders. Stratified analyses were performed to investigate interaction. Results BMLs, synovitis, cysts, FTS and ETI were demonstrated in 56%, 90%, 22%, 16% and 30% of patients, respectively. BMLs (grade 2/3 vs 0: 3.5 (1.6–7.7)) and synovitis (3 vs 0: OR 3.6 (95% CI 1.9–6.6)) were severity-dependent associated with joint pain, but FTS and ETI were not. Stratified analyses showed that BMLs did not associate with pain in the absence of synovitis, whereas synovitis was associated with pain in the absence of BMLs. Interaction was seen between BMLs and synovitis grade 2 or 3. Conclusion In hand OA patients severe synovitis is associated with joint pain, which is worsened when BMLs co-occur, suggesting synovitis as primary target of treatment.

Summary Objective Emerging evidence suggests that osteoarthritis (OA) has a neuropathic component; however, the identity of the molecules responsible for this peripheral neuropathy is unknown. The aim of this study was to determine the contribution of the bioactive lipid lysophosphatidic acid (LPA) to joint neuropathy and pain. Design Male Lewis rats received an intra-articular injection of 50 μg of LPA into the knee and allowed to recover for up to 21 days. Saphenous nerve myelination was assessed by g-ratio calculation from electron micrographs and afferent nerve damage visualised by activation transcription factor-3 (ATF-3) expression. Nerve conduction velocity was measured electrophysiologically and joint pain was determined by hindlimb incapacitance. The effect of the LPA antagonist Ki-16425 was also evaluated. Experiments were repeated in the sodium monoiodoacetate (MIA) model of OA. Results LPA caused joint nerve demyelination which resulted in a drop in nerve conduction velocity. Sensory neurones were ATF-3 positive and animals exhibited joint pain and knee joint damage. MIA-treated rats also showed signs of demyelination and joint neuropathy with concomitant pain. Nerve damage and pain could be ameliorated by Ki-16425 pre-treatment. Conclusion Intra-articular injection of LPA caused knee joint neuropathy, joint damage and pain. Pharmacological blockade of LPA receptors inhibited joint nerve damage and hindlimb incapacitance. Thus, LPA is a candidate molecule for the development of OA nerve damage and the origin of joint neuropathic pain.

Summary Objective To cross-sectionally determine the quantitative relationship of age-adjusted, sex-specific isometric knee extensor and flexor strength to patient-reported knee pain. Methods Difference of thigh muscle strength by age, and that of age-adjusted strength per unit increase on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain scale, was estimated from linear regression analysis of 4553 Osteoarthritis Initiative (OAI) participants (58% women). Strata encompassing the minimal clinically important difference (MCID) in knee pain were compared to evaluate a potentially non-linear relationship between WOMAC pain levels and muscle strength. Results In OAI participants without pain, the age-related difference in isometric knee extensor strength was −9.0%/−8.2% (women/men) per decade, and that of flexor strength was −11%/−6.9%. Differences in age-adjusted strength values for each unit of WOMAC pain (1/20) amounted to −1.9%/−1.6% for extensor and −2.5%/−1.7% for flexor strength. Differences in torque/weight for each unit of WOMAC pain ranged from −3.3 to −2.1%. There was no indication of a non-linear relationship between pain and strength across the range of observed WOMAC values, and similar results were observed in women and men. Conclusion Each increase by 1/20 units in WOMAC pain was associated with a ∼2% lower age-adjusted isometric extensor and flexor strength in either sex. As a reduction in muscle strength is known to prospectively increase symptoms in knee osteoarthritis (KOA) and as pain appears to reduce thigh muscle strength, adequate therapy of pain and muscle strength is required in KOA patients to avoid a vicious circle of self-sustaining clinical deterioration.

Summary Objective The aims of the present knee osteoarthritis (KOA)-study were to: (1) describe and compare the changes in magnetic resonance imaging (MRI)-measures of synovitis following an exercise program preceded by an intra-articular injection of either corticosteroid or isotonic saline and (2) investigate if any of the changes in patient reported outcome measures (PROMs) were associated with changes in MRI-measures of synovitis. Design We performed a randomized, double-blinded, placebo-controlled clinical trial evaluating the effects of intra-articular corticosteroid vs placebo injections given before exercise therapy in KOA-patients. PROMs were assessed using the KOOS (knee injury and osteoarthritis outcome score). Synovitis was assessed on conventional non-contrast-enhanced, conventional contrast-enhanced (CE) and dynamic contrast-enhanced (DCE) MRI. PROMs and MRIs were obtained prior to the intra-articular injection, after termination of the exercise program (week 14—primary time point) and week 26. Results Of 100 randomized participants (50 in each allocation group), 91 had complete MRI-data at baseline (63% female, mean age: 62 years, median Kellgren–Lawrence-grade: 3). There were no statistically significant differences between the two interventions in regards of changes in MRI-measures of synovitis at any time-point. At week 14, we found no statistical significant MRI-explanatory variables of either of the PROMs. Conclusions The present study does not justify the use of intra-articular corticosteroids over intra-articular saline when combined with an exercise program for reduction of synovitis in KOA. The improvement in pain and function following the intervention with intra-articular corticosteroids/saline and exercise could not be explained by a decrease in synovitis on MRI indicating other pain causing/relieving mechanisms in KOA.

Objective The assessment of racial differences in pain and function outcome following knee arthroplasty (KA) has received little attention despite very substantial literature exploring a variety of other prognostic factors. The present study was undertaken to determine whether race was associated with KA outcome after accounting for potential confounding factors. Methods We conducted a secondary analysis of a randomized clinical trial of 384 participants with moderate-to-high pain catastrophizing who underwent KA. Preoperative measures included race/ethnicity status as well as a variety of potential confounders, including socioeconomic status, comorbidity, and bodily pain. Outcome measures were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scales as well as performance measures. Linear mixed-effects models compared outcomes over a 1-year follow-up period for African American versus non-African American participants. Results WOMAC pain scores differences for African American versus non-African American participants averaged ~2 points in unadjusted analyses and 1-1.5 points in adjusted analyses. In adjusted analyses, follow-up WOMAC function scores differed by 6 points for African Americans compared to non-African Americans (P = 0.002). Conclusion African Americans generally had worse pain, function, and performance prior to KA and worse scores after surgery, but differences were small and attenuated by ~25-50% after adjustment for potential confounding. Only WOMAC function scores showed clinically important postsurgical differences in adjusted analyses. Clinicians should be aware that after adjustment for potential confounders, African Americans have approximately equivalent outcomes compared to others, with the exception of WOMAC function score.

Summary Background Exercise programs rely on the overload principle, yet patients with knee osteoarthritis (OA) may not adequately progress exercises due to fear of exacerbating symptoms. Objective To describe trajectories for perceived exertion and exercise-induced knee pain during a neuromuscular exercise program for patients with knee OA. Design Participants with knee OA completed a 12-week neuromuscular exercise program consisting of weekly supervised sessions plus home exercises. During each supervised session, the Borg's rating of perceived exertion (RPE; 6 = no exertion, 20 = maximal exertion) and knee pain (pre, post, max) using Numeric Rating Scales (NRS; 0 = no pain, 10 = worst imaginable pain) were completed. Mean changes in RPE and pain from weeks 1–12 were calculated. Mixed effects regression was used to investigate trajectories over time (weeks) for RPE, and maximum pain (pre-to-max) and pain-change (pre-to-post) during exercise. Results 56 patients (95%) completed the program. From week 1–12, RPE increased by 2.6 (95%CI, 1.7 to 3.5), from ‘somewhat hard’ to ‘very hard’, while max pain decreased by 1.0 NRS (95%CI, 0.5 to 1.3) and pain-change decreased by 0.9 NRS (95%CI, 0.4 to 1.3). Linear mixed effects regression showed a quadratic increase for RPE over time until between weeks 9 and 10, then RPE plateaued. Maximum pain decreased linearly over time. Pain-change showed a quadratic decrease over time until approximately week 9, then pain-change plateaued. Conclusions In patients with knee OA participating in a 12-week neuromuscular exercise program, perceived exertion during exercise progressed from ‘somewhat hard’ to ‘very hard’ at 9 weeks, while exercise-induced knee pain decreased. Patients were able to work harder while experiencing decreases rather than increases in pain.