Methotrexate to treat hand osteoarthritis with synovitis (METHODS): an Australian, multisite, parallel-group, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hand osteoarthritis is a disabling condition with few effective therapies. Hand osteoarthritis with synovitis is a common inflammatory phenotype associated with pain. We aimed to examine the efficacy and safety of methotrexate at 6 months in participants with hand osteoarthritis and synovitis. METHODS: In this multisite, parallel-group, double-blind, randomised, placebo-controlled trial, participants (aged 40-75 years) with hand osteoarthritis (Kellgren and Lawrence grade ≥2 in at least one joint) and MRI-detected synovitis of grade 1 or more were recruited from the community in Melbourne, Hobart, Adelaide, and Perth, Australia. Participants were randomly assigned (1:1) using block randomisation, stratified by study site and self-reported sex, to receive methotrexate 20 mg or identical placebo orally once weekly for 6 months. The primary outcome was pain reduction (measured with a 100 mm visual analogue scale; VAS) in the study hand at 6 months assessed in the intention-to-treat population. Safety outcomes were assessed in all randomly assigned participants. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000877381). FINDINGS: Between Nov 22, 2017, and Nov 8, 2021, of 202 participants who were assessed for eligibility, 97 (48%) were randomly assigned to receive methotrexate (n=50) or placebo (n=47). 68 (70%) of 97 participants were female and 29 (30%) were male. 42 (84%) of 50 participants in the methotrexate group and 40 (85%) of 47 in the placebo group provided primary outcome data. The mean change in VAS pain at 6 months was -15·2 mm (SD 24·0) in the methotrexate group and -7·7 mm (25·3) in the placebo group, with a mean between-group difference of -9·9 (95% CI -19·3 to -0·6; p=0·037) and an effect size (standardised mean difference) of 0·45 (0·03 to 0·87). Adverse events occurred in 31 (62%) of 50 participants in the methotrexate group and 28 (60%) of 47 participants in the placebo group. INTERPRETATION: Treatment of hand osteoarthritis and synovitis with 20 mg methotrexate for 6 months had a moderate but potentially clinically meaningful effect on reducing pain, providing proof of concept that methotrexate might have a role in the management of hand osteoarthritis with an inflammatory phenotype. FUNDING: National Health and Medical Research Council of Australia.

30 Years of MRI-based cartilage & bone morphometry in knee osteoarthritis: From correlation to clinical trials.

OBJECTIVE: The first publication on morphometric analysis of articular cartilage using magnetic resonance imaging (MRI) in 1994 set the scene for a game change in osteoarthritis (OA) research. The current review highlights milestones in cartilage and bone morphometry, summarizing the rapid progress made in imaging, its application to understanding joint (patho-)physiology, and its use in interventional clinical trials. METHODS: Based on a Pubmed search of articles from 1994 to 2023, the authors subjectively selected representative work illustrating important steps in the development or application of magnetic resonance-based cartilage and bone morphometry, with a focus on studies in humans, and on the knee. Research on OA-pathophysiology is addressed only briefly, given length constraints. Compositional and semi-quantitative assessment are not covered here. RESULTS: The selected articles are presented in historical order as well as by content. We review progress in the technical aspects of image acquisition, segmentation and analysis, advances in understanding tissue growth, physiology, function, and adaptation, and a selection of clinical trials examining the efficacy of interventions on knee cartilage and bone. A perspective is provided of how lessons learned may be applied to future research and clinical management. CONCLUSIONS: Over the past 30 years, MRI-based morphometry of cartilage and bone has contributed to a paradigm shift in understanding articular tissue physiology and OA pathophysiology, and to the development of new treatment strategies. It is likely that these technologies will continue to play a key role in the development and (accelerated) approval of therapy, potentially targeted to different OA phenotypes.

Association between knee magnetic resonance imaging markers and knee symptoms over 6-9 years in young adults.

OBJECTIVES: To describe associations between MRI markers with knee symptoms in young adults. METHODS: Knee symptoms were assessed using the WOMAC scale during the Childhood Determinants of Adult Health Knee Cartilage study (CDAH-knee; 2008-2010) and at the 6- to 9-year follow-up (CDAH-3; 2014-2019). Knee MRI scans obtained at baseline were assessed for morphological markers (cartilage volume, cartilage thickness, subchondral bone area) and structural abnormalities [cartilage defects and bone marrow lesions (BMLs)]. Univariable and multivariable (age, sex, BMI adjusted) zero-inflated Poisson (ZIP) regression models were used for analysis. RESULTS: The participants' mean age in CDAH-knee and CDAH-3 were 34.95 (s.d. 2.72) and 43.27 (s.d. 3.28) years, with 49% and 48% females, respectively. Cross-sectionally, there was a weak but significant negative association between medial femorotibial compartment (MFTC) [ratio of the mean (RoM) 0.99971084 (95% CI 0.9995525, 0.99986921), P < 0.001], lateral femorotibial compartment (LFTC) [RoM 0.99982602 (95% CI 0.99969915, 0.9999529), P = 0.007] and patellar cartilage volume [RoM 0.99981722 (95% CI 0.99965326, 0.9999811), P = 0.029] with knee symptoms. Similarly, there was a negative association between patellar cartilage volume [RoM 0.99975523 (95% CI 0.99961427, 0.99989621), P = 0.014], MFTC cartilage thickness [RoM 0.72090775 (95% CI 0.59481806, 0.87372596), P = 0.001] and knee symptoms assessed after 6-9 years. The total bone area was negatively associated with knee symptoms at baseline [RoM 0.9210485 (95% CI 0.8939677, 0.9489496), P < 0.001] and 6-9 years [RoM 0.9588811 (95% CI 0.9313379, 0.9872388), P = 0.005]. The cartilage defects and BMLs were associated with greater knee symptoms at baseline and 6-9 years. CONCLUSION: BMLs and cartilage defects were positively associated with knee symptoms, whereas cartilage volume and thickness at MFTC and total bone area were weakly and negatively associated with knee symptoms. These results suggest that the quantitative and semiquantitative MRI markers can be explored as a marker of clinical progression of OA in young adults.

Associations of Osteoarthritis with Prevalence and Incidence of Cardiovascular Disease over 10 Years in Community-Dwelling Older Adults: The Sydney Memory and Ageing Study.

INTRODUCTION: The data are limited for the association between osteoarthritis (OA) and cardiovascular disease (CVD) in community-based older populations and whether there is sex difference. This study aimed to examine the relationship between OA and prevalence and incidence of CVD over 10 years in community-dwelling older adults. METHODS: Data on self-reported OA, high cholesterol, hypertension, and type 2 diabetes were collected from 1,025 community-dwelling participants aged 70-90 years in the Sydney Memory and Ageing Study. The presence of CVD at baseline was defined as self-reported presence of stroke, heart attack, transient ischaemic attack, angina, aortic aneurysm, or claudication. The incidence of CVD was defined by a combination of incident self-reported CVD or CVD mortality at different follow-up timepoints over 10 years. RESULTS: At baseline, 395 (38.5%) participants self-reported OA (252 [44.6%] women, 143 [31.1%] men). Self-reported OA was associated with increased prevalence of CVD in women (OR 1.67, 95% CI 1.12-2.47) but not men (1.26, 0.80-1.98). In the total population, self-reported OA at baseline was associated with increased incidence of CVD at 4 years (OR 1.77, 95% CI 1.10-2.83), 6 years (1.59, 1.03-2.46), 8 years (1.56, 1.02-2.38), and 10 years (1.66, 1.10-2.50), but not at 2 years (1.43, 0.79-2.57). Significant associations were observed in female participants at 4, 8, and 10 years, with no significant associations seen in male participants. CONCLUSION: OA was associated with increased prevalence at baseline and incidence of CVD over 10 years in community-based older adults, especially women. Identifying those with OA to target their cardiovascular risk factors while managing their OA has the potential to reduce the burden of CVD in older people, particularly women.

Association between medial meniscal extrusion and knee structural progression in adults with symptomatic knee osteoarthritis - a prospective cohort study.

OBJECTIVE: To examine the association between medial meniscal extrusion and structural progression in adults with symptomatic knee osteoarthritis (OA). METHODS: This prospective cohort study examined 176 participants with symptomatic knee OA recruited into a randomised controlled trial. The participants underwent magnetic resonance imaging (MRI) of the study knee at baseline and approximately 2 years later. Meniscal extrusion, tibial cartilage volume, and tibiofemoral bone marrow lesions (BMLs) were measured from MRI using validated methods. RESULTS: Participants with medial meniscal extrusion ≥ 3 mm had a higher prevalence of lateral tibiofemoral BMLs at baseline (OR = 2.21, 95% CI 1.06-4.61, p = 0.035), and those with medial meniscal extrusion 2-3 mm had a higher likelihood of lateral BML worsening over 2 years (OR = 3.76, 95% CI 1.35-10.52, p = 0.011), compared with those with medial meniscal extrusion < 2 mm. Participants with stable medial meniscal extrusion had a lower likelihood of lateral BML worsening compared with those with regression of medial meniscal extrusion over 2 years (OR = 0.20, 95% CI 0.07-0.56, p = 0.002). There were no associations between medial meniscal extrusion and tibial cartilage volume or medial tibiofemoral BMLs. CONCLUSIONS: Our study showed associations between medial meniscal extrusion and baseline prevalence and worsening over 2 years of lateral tibiofemoral BMLs in people with symptomatic knee OA. Although the reasons for the lack of associations in the medial compartment are not clear, our results suggest a role of medial meniscal extrusion in predicting structural progression in lateral knee OA and that meniscal extrusion might be a potential target in the management of knee OA.

Krill Oil for Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Knee osteoarthritis is disabling, with few effective treatments. Preliminary evidence suggested that krill oil supplementation improved knee pain, but effects on knee osteoarthritis remain unclear. Objective: To evaluate efficacy of krill oil supplementation, compared with placebo, on knee pain in people with knee osteoarthritis who have significant knee pain and effusion-synovitis. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled clinical trial in 5 Australian cities. Participants with clinical knee osteoarthritis, significant knee pain, and effusion-synovitis on magnetic resonance imaging were enrolled from December 2016 to June 2019; final follow-up occurred on February 7, 2020. Interventions: Participants were randomized to 2 g/d of krill oil (n = 130) or matching placebo (n = 132) for 24 weeks. Main Outcomes and Measures: The primary outcome was change in knee pain as assessed by visual analog scale (range, 0-100; 0 indicating least pain; minimum clinically important improvement = 15) over 24 weeks. Results: Of 262 participants randomized (mean age, 61.6 [SD, 9.6] years; 53% women), 222 (85%) completed the trial. Krill oil did not improve knee pain compared with placebo (mean change in VAS score, -19.9 [krill oil] vs -20.2 [placebo]; between-group mean difference, -0.3; 95% CI, -6.9 to 6.4) over 24 weeks. One or more adverse events was reported by 51% in the krill oil group (67/130) and by 54% in the placebo group (71/132). The most common adverse events were musculoskeletal and connective tissue disorders, which occurred 32 times in the krill oil group and 42 times in the placebo group, including knee pain (n = 10 with krill oil; n = 9 with placebo), lower extremity pain (n = 1 with krill oil; n = 5 with placebo), and hip pain (n = 3 with krill oil; n = 2 with placebo). Conclusions and Relevance: Among people with knee osteoarthritis who have significant knee pain and effusion-synovitis on magnetic resonance imaging, 2 g/d of daily krill oil supplementation did not improve knee pain over 24 weeks compared with placebo. These findings do not support krill oil for treating knee pain in this population. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12616000726459; Universal Trial Number: U1111-1181-7087.

Association between popliteal artery wall thickness and structural progression in patients with symptomatic knee osteoarthritis.

OBJECTIVE: There is increasing evidence for the involvement of vascular disease in the pathogenesis of knee OA. Popliteal artery wall thickness can be used as a surrogate marker of atherosclerosis. We examined the association between popliteal artery wall thickness and knee cartilage volume in individuals with symptomatic knee OA. METHODS: This prospective cohort study analysed 176 participants from a randomized placebo-controlled trial examining the effect of atorvastatin on structural progression in knee OA. The participants underwent MRI of the study knee at baseline and 2-year follow-up. Popliteal artery wall thickness and tibial cartilage volume were measured from MRI using validated methods. The top quartile of the rate of tibial cartilage volume loss was defined as rapid progression. RESULTS: At baseline, every 10% increase in popliteal artery wall thickness was associated with 120.8 mm3 (95% CI 5.4, 236.2, P = 0.04) lower of medial tibial cartilage volume and 151.9 mm3 (95% CI 12.1, 291.7, P = 0.03) lower of lateral tibial cartilage volume. Longitudinally, for every 10% increase in popliteal artery wall thickness, the annual rate of medial tibial cartilage volume loss was increased by 1.14% (95% CI 0.09%, 2.20%, P = 0.03), and there was a 2.28-fold (95% CI 1.07, 4.83, P = 0.03) risk of rapid progression of medial tibial cartilage loss, adjusted for age, sex, BMI, tibial bone area, smoking, vigorous physical activity, and intervention group allocation. CONCLUSION: The findings support a role for vascular pathology in the progression of knee OA. Targeting atherosclerosis has the potential to improve outcomes in knee OA.

Negative back beliefs are associated with increased odds of low back pain and disability: a 10-year cohort study in men.

OBJECTIVE: Although negative back beliefs are associated with high-intensity low back pain (LBP)/disability, whether they influence incident high-intensity LBP/high-disability over the long-term is unknown. This study aimed to investigate whether negative back beliefs were associated with developing high-intensity LBP and/or high-disability over 10 years in men. METHODS: Men with no or low-intensity LBP and/or disability attending the Geelong Osteoporosis Study between 2006-2010 were included. Data on age, body mass index, mobility, education, back beliefs (Back Beliefs Questionnaire), LBP and disability (Graded Chronic Pain Scale) were collected between 2006-2010. Beliefs, LBP and disability were re-assessed in 2016-2021. Binary logistic regression was used to examine the association between negative back beliefs and incident high-intensity pain and/or high-disability, adjusting for age, body mass index, mobility, and education. RESULTS: At baseline, 705 participants (mean age 53.8 years) had no or low LBP and no or low-disability; 441 (62.6%) participants completed a 10-year follow-up. Of these, 37 (8.4%) developed high-intensity pain and/or high-disability. In multivariate analyses, participants with more negative back beliefs at baseline were more likely to develop high-intensity pain and/or high-disability (Odds ratio 1.05, 95% CI 1.00-1.11). Developing more negative back beliefs was also associated with incident high-intensity pain and/or high-disability (Odds Ratio 1.20, 95% CI 1.12-1.30). CONCLUSION: In a male community-based population, negative beliefs regarding the consequences of LBP were associated with an increased likelihood of developing high-intensity pain and/or high-disability. Addressing negative back beliefs in the community may reduce the incidence of high-intensity pain and/or high-disability over 10 years in men.

Functional outcomes following knee replacement in community-dwelling older adults.

BACKGROUND: Knee replacements are increasingly performed in older adults but uncertainty remains regarding their benefits in the context of age-related decline in physical function and other comorbidities. This study aimed to examine (1) the effect of knee replacement on functional outcomes in the context of age-related decline in physical function and (2) the factors associated with minimal important improvement in physical function after knee replacement in community-dwelling older adults aged ≥ 70 years. METHODS: This cohort study was performed within the ASPREE trial, with 889 participants undergoing knee replacement during the trial and 858 age- and sex-matched controls without knee or hip replacement identified from 16,703 Australian participants aged ≥ 70 years. Health-related quality of life was assessed annually using the SF-12, including its physical and mental component summary (PCS and MCS). Gait speed was measured biennially. Multiple linear regression and analysis of covariance were used to adjust for potential confounders. RESULTS: Participants with knee replacement had significantly lower pre- and post-replacement PCS scores and gait speed compared with age- and sex-matched controls. Participants with knee replacement had significant improvement in PCS score following knee replacement (mean change 3.6, 95% CI 2.9-4.3) while PCS score remaining unchanged in age- and sex-matched controls (-0.02, 95% CI -0.6 to 0.6) during follow-up period. The greatest improvements were observed for bodily pain and physical function. Following knee replacement, 53% of participants experienced minimal important improvement in PCS score (increased by ≥ 2.7), while 24% experienced worsened PCS score (reduced by > 2.7). Participants experiencing improved PCS score postoperatively had significantly lower PCS and higher MCS scores pre-surgery. CONCLUSIONS: Although community-based older adults experienced a significant improvement in PCS scores after knee replacement, their postoperative physical functional status remained significantly lower than age- and sex-matched controls. The degree of preoperative physical function impairment was a strong predictor of functional improvement, suggesting that this could be an important consideration when identifying older people most likely to benefit from knee replacement surgery.

Single nucleotide polymorphism genes and mitochondrial DNA haplogroups as biomarkers for early prediction of knee osteoarthritis structural progressors: use of supervised machine learning classifiers.

BACKGROUND: Knee osteoarthritis is the most prevalent chronic musculoskeletal debilitating disease. Current treatments are only symptomatic, and to improve this, we need a robust prediction model to stratify patients at an early stage according to the risk of joint structure disease progression. Some genetic factors, including single nucleotide polymorphism (SNP) genes and mitochondrial (mt)DNA haplogroups/clusters, have been linked to this disease. For the first time, we aim to determine, by using machine learning, whether some SNP genes and mtDNA haplogroups/clusters alone or combined could predict early knee osteoarthritis structural progressors. METHODS: Participants (901) were first classified for the probability of being structural progressors. Genotyping included SNP genes TP63, FTO, GNL3, DUS4L, GDF5, SUPT3H, MCF2L, and TGFA; mtDNA haplogroups H, J, T, Uk, and others; and clusters HV, TJ, KU, and C-others. They were considered for prediction with major risk factors of osteoarthritis, namely, age and body mass index (BMI). Seven supervised machine learning methodologies were evaluated. The support vector machine was used to generate gender-based models. The best input combination was assessed using sensitivity and synergy analyses. Validation was performed using tenfold cross-validation and an external cohort (TASOAC). RESULTS: From 277 models, two were defined. Both used age and BMI in addition for the first one of the SNP genes TP63, DUS4L, GDF5, and FTO with an accuracy of 85.0%; the second profits from the association of mtDNA haplogroups and SNP genes FTO and SUPT3H with 82.5% accuracy. The highest impact was associated with the haplogroup H, the presence of CT alleles for rs8044769 at FTO, and the absence of AA for rs10948172 at SUPT3H. Validation accuracy with the cross-validation (about 95%) and the external cohort (90.5%, 85.7%, respectively) was excellent for both models. CONCLUSIONS: This study introduces a novel source of decision support in precision medicine in which, for the first time, two models were developed consisting of (i) age, BMI, TP63, DUS4L, GDF5, and FTO and (ii) the optimum one as it has one less variable: age, BMI, mtDNA haplogroup, FTO, and SUPT3H. Such a framework is translational and would benefit patients at risk of structural progressive knee osteoarthritis.

Association of serum levels of inflammatory markers and adipokines with joint symptoms and structures in participants with knee osteoarthritis.

OBJECTIVE: To investigate the longitudinal associations of serum inflammatory markers and adipokines with joint symptoms and structures in participants with knee OA. METHODS: Two hundred participants (46.5% female, mean age 63.1 years, mean BMI 29.5 kg/m2) from Tasmania, part of the VIDEO (Vitamin D Effect on OA) study, were randomly selected in the current study. Serum levels of 19 biomarkers, scores of WOMAC and MRI-assessed knee structures were evaluated at baseline and month 24. The patterns of biomarkers were derived from principal component analysis and their association with knee symptoms and structures were examined using adjusted generalized estimating equations. RESULTS: Five components explained 78% of the total variance. IL-1ß, -2, -4, -6, -8, -17 A, -17 F, -21, -22 and -23 loaded the highest on the first component, which was associated with increased bone marrow lesions (BMLs) and WOMAC dysfunction score. IL-10, -12 and GM-CSF loaded on the second component, which was associated with increased cartilage volume, and decreased effusion synovitis and WOMAC scores. Leptin, adipsin and CRP loaded on the third component, which was positively associated with WOMAC scores. Resistin loaded on the fourth component, which was associated with increased BMLs and cartilage defects. Apelin-36 and adiponectin loaded on the fifth component, which was associated with increased BMLs. CONCLUSION: Various inflammatory and metabolic components were associated differently with joint symptoms and structural changes in knee OA, suggesting a complex inflammatory and metabolic interrelationship in the pathogenesis of knee OA.

Association between diet quality in adolescence and adulthood and knee symptoms in adulthood: a 25-year cohort study.

We aimed to describe associations between diet quality in adolescence and adulthood and knee symptoms in adulthood. Two hundred seventy-five participants had adolescent diet measurements, 399 had adult diet measurements and 240 had diet measurements in both time points. Diet quality was assessed by Dietary Guidelines Index (DGI), reflecting adherence to Australian Dietary Guidelines. Knee symptoms were collected using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Data were analysed using zero-inflated negative binomial regressions. The overall adolescent DGI was not associated with adult knee symptoms, although lower intake of discretionary foods (e.g. cream, alcohol, bacon and cake) in adolescence was associated with lower pain (mean ratio (MR) 0·96) and dysfunction (MR 0·94). The overall adult DGI was not associated with knee symptoms; however, limiting saturated fat was associated with lower WOMAC (Pain: MR 0·93; stiffness: MR 0·93; dysfunction: MR 0·91), drinking water was associated with lower stiffness (MR 0·90) and fruit intake was associated with lower dysfunction (MR 0·90). Higher DGI for dairy products in adulthood was associated with higher WOMAC (Pain: MR 1·07; stiffness: MR 1·13; dysfunction: MR 1·11). Additionally, the score increases from adolescence to adulthood were not associated with adult knee symptoms, except for associations between score increase in limiting saturated fat and lower stiffness (MR 0·89) and between score increase in fruit intake and lower dysfunction (MR 0·92). In conclusion, the overall diet quality in adolescence and adulthood was not associated with knee symptoms in adulthood. However, some diet components may affect later knee symptoms.

Association between arthritis and cardiovascular risk factors in community-based adults: an opportunity to target cardiovascular risk.

BACKGROUND: Undertreated risk factors are major contributors to the burden of cardiovascular disease (CVD). Those with arthritis have an increased prevalence of CVD risk factors. CVD risk factors are often asymptomatic, which may be a barrier their treatment. Arthritis causes pain and immobility, and is a common reason for individuals to seek healthcare. Our aims were to (1) examine the relationship between arthritis and CVD risk factors in Australian adults, and (2) calculate the proportion of CVD risk factors that could be reduced if individuals with arthritis were targeted. METHODS: This cross-sectional study uses data from the 2017-18 Australian National Health Survey which included 13,776 participants, categorised into young (18-39 years), middle aged (40-64 years) and older (≥ 65 years) adults. Hypertension, height and weight were measured. Arthritis, dyslipidemia and diabetes were self-reported. The associations between arthritis and CVD risk factors were examined using logistic regression, and the population attributable fraction (PAF) of arthritis for each CVD risk factor was calculated. RESULTS: Arthritis was reported by 4.0% of young adults, 28.8% of middle-aged adults and 54.5% of older adults. Those with arthritis were at increased odds of obesity (2.07 fold in young, 1.75 fold in middle-aged and 1.89 fold in older adults), increased odds of diabetes (5.70 fold in young, 1.64 fold in middle-aged and 1.37 fold in older adults), increased odds of hypertension (2.72 fold in young, 1.78 fold in middle-aged and 1.48 fold in older adults) and an increased odds of dyslipidaemia (4.64 fold in young, 2.14 fold in middle-aged and 1.22 fold in older adults) compared to those without arthritis. This elevated chance remained significant even after adjusting for obesity, with the exception of diabetes in the older population. This elevated chance remained significant even after adjusting for obesity, with the exception of diabetes in the older population. The PAF of the presence of arthritis for having at least one CVD risk factor was 30.7% in middle-aged adults and 70.4% in older adults. CONCLUSION: Australian adults of all ages with arthritis are at increased odds of having CVD risk factors. For young and middle-aged adults, this increased odds remains significant even when adjusted for obesity. Presentation to healthcare practitioners with arthritis is an opportunity to screen for asymptomatic CVD risk factors with the potential of improving outcomes for both diseases. By adopting an approach of managing arthritis and CVD risk factors in parallel, rather than in silos, we could reduce the burden of CVD risk factors by 20-30%.

Antidepressants for hip and knee osteoarthritis.

BACKGROUND: Although pain is common in osteoarthritis, most people fail to achieve adequate analgesia. Increasing acknowledgement of the contribution of pain sensitisation has resulted in the investigation of medications affecting pain processing with central effects. Antidepressants contribute to pain management in other conditions where pain sensitisation is present. OBJECTIVES: To assess the benefits and harms of antidepressants for the treatment of symptomatic knee and hip osteoarthritis in adults. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was January 2021. SELECTION CRITERIA: We included randomised controlled trials of adults with osteoarthritis that compared use of antidepressants to placebo or alternative comparator. We included trials that focused on efficacy (pain and function), treatment-related adverse effects and had documentation regarding discontinuation of participants. We excluded trials of less than six weeks of duration or had participants with concurrent mental health disorders. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Major outcomes were pain; responder rate; physical function; quality of life; and proportion of participants who withdrew due to adverse events, experienced any adverse events or had serious adverse events. Minor outcomes were proportion meeting the OARSI (Osteoarthritis Research Society International) Response Criteria, radiographic joint structure changes and proportion of participants who dropped out of the study for any reason. We used GRADE to assess certainty of evidence. MAIN RESULTS: Nine trials (2122 participants) met the inclusion criteria. Seven trials examined only knee osteoarthritis. Two also included participants with hip osteoarthritis. All trials compared antidepressants to placebo, with or without non-steroidal anti-inflammatory drugs. Trial sizes were 36 to 388 participants. Most participants were female, with mean ages of 54.5 to 65.9 years. Trial durations were 8 to 16 weeks. Six trials examined duloxetine. We combined data from nine trials in meta-analyses for knee and hip osteoarthritis. One trial was at low risk of bias in all domains. Five trials were at risk of attrition and reporting bias. High-certainty evidence found that antidepressants resulted in a clinically unimportant improvement in pain compared to placebo. Mean reduction in pain (0 to 10 scale, 0 = no pain) was 1.7 points with placebo and 2.3 points with antidepressants (mean difference (MD) -0.59, 95% confidence interval (CI) -0.88 to -0.31; 9 trials, 2122 participants). Clinical response was defined as achieving a 50% or greater reduction in 24-hour mean pain. High-certainty evidence demonstrated that 45% of participants receiving antidepressants had a clinical response compared to 28.6% receiving placebo (RR 1.55, 95% CI 1.32 to 1.82; 6 RCTs, 1904 participants). This corresponded to an absolute improvement in pain of 16% more responders with antidepressants (8.9% more to 26% more) and a number needed to treat for an additional beneficial effect (NNTB) of 6 (95% CI 4 to 11). High-certainty evidence showed that the mean improvement in function (on 0 to 100 Western Ontario and McMaster Universities Arthritis Index, 0 = best function) was 10.51 points with placebo and 16.16 points with antidepressants (MD -5.65 points, 95% CI -7.08 to -4.23; 6 RCTs, 1909 participants). This demonstrates a small, clinically unimportant response. Moderate-certainty evidence (downgraded for imprecision) showed that quality of life measured using the EuroQol 5-Dimension scale (-0.11 to 1.0, 1.0 = perfect health) improved by 0.07 points with placebo and 0.11 points with antidepressants (MD 0.04, 95% CI 0.01 to 0.07; 3 RCTs, 815 participants). This is clinically unimportant. High-certainty evidence showed that total adverse events increased in the antidepressant group (64%) compared to the placebo group (49%) (RR 1.27, 95% CI 1.15 to 1.41; 9 RCTs, 2102 participants). The number needed to treat for an additional harmful outcome (NNTH) was 7 (95% CI 5 to 11). Low-certainty evidence (downgraded twice for imprecision for very low numbers of events) found no evidence of a difference in serious adverse events between groups (RR 0.94, 95% CI 0.46 to 1.94; 9 RCTs, 2101 participants). The NNTH was 1000.  Moderate-certainty evidence (downgraded for imprecision) showed that 11% of participants receiving antidepressants withdrew from trials due to an adverse event compared to 5% receiving placebo (RR 2.15, 95% CI 1.56 to 2.97; 6 RCTs, 1977 participants). The NNTH was 17 (95% CI 10 to 35). AUTHORS' CONCLUSIONS: There is high-certainty evidence that use of antidepressants for knee osteoarthritis leads to a non-clinically important improvement in mean pain and function. However, a small number of people will have a 50% or greater important improvement in pain and function. This finding was consistent across all trials. Pain in osteoarthritis may be due to a variety of causes that differ between individuals. It may be that the cause of pain that responds to this therapy is only present in a small number of people. There is moderate-certainty evidence that antidepressants have a small positive effect on quality of life with heterogeneity between trials. High-certainty evidence indicates antidepressants result in more adverse events and moderate-certainty evidence indicates more withdrawal due to adverse events. There was little to no difference in serious adverse events (low-certainty evidence due to low numbers of events). This suggests that if antidepressants were being considered, there needs to be careful patient selection to optimise clinical benefit given the known propensity for adverse events with antidepressant use. Future trials should include alternative antidepressant agents or phenotyping of pain in people with osteoarthritis, or both.

Association between socioeconomic status and joint replacement of the hip and knee: a population-based cohort study of older adults in Tasmania.

BACKGROUND: A socioeconomic gradient exists in the utilisation of total hip replacements (THR) and total knee replacements (TKR) for osteoarthritis. However, the relations between socioeconomic status (SES) and time to THR or TKR is unknown. AIM: To describe the association between SES and time to THR and TKR. METHODS: One thousand and seventy-two older adults residing in Tasmania, Australia, were studied. Incident primary THR and TKR were determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. At baseline, each participant's area-level SES was determined using the Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) from the Australian Bureau of Statistics' 2001 census data. The IRSAD was analysed in two ways: (i) categorised into quartiles, whereby quartile 1 represented the most socioeconomically disadvantaged group; and (ii) the cohort dichotomised at the quartile 1 cut-point. RESULTS: The mean age was 63.0 (±7.5) years and 51% were women. Over the median follow up of 12.9 (interquartile range: 12.2-13.9) years, 56 (5%) participants had a THR and 79 (7%) had a TKR. Compared with the most disadvantaged quartile, less disadvantaged participants were less likely to have a THR (i.e. less disadvantaged participants had a longer time to THR; hazard ratio (HR): 0.56; 95% confidence interval (CI) 0.32, 1.00) but not TKR (HR: 0.90; 95% CI 0.53, 1.54). However, the former became non-significant after adjustment for pain and radiographic osteoarthritis, suggesting that the associations may be mediated by these factors. CONCLUSIONS: The present study suggests that time to joint replacement was determined according to the symptoms/need of the participants rather than their SES.

Television-viewing time and bodily pain in Australian adults with and without type 2 diabetes: 12-year prospective relationships.

BACKGROUND: Bodily pain is a common presentation in several chronic diseases, yet the influence of sedentary behaviour, common in ageing adults, is unclear. Television-viewing (TV) time is a ubiquitous leisure-time sedentary behaviour, with a potential contribution to the development of bodily pain. We examined bodily pain trajectories and the longitudinal relationships of TV time with the bodily pain severity; and further, the potential moderation of the relationships by type 2 diabetes (T2D) status. METHOD: Data were from 4099 participants (aged 35 to 65 years at baseline) in the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), who took part in the follow-ups at 5 years, 12 years, or both. Bodily pain (from SF36 questionnaire: a 0 to 100 scale, where lower scores indicate more-severe pain), TV time, and T2D status [normal glucose metabolism (NGM), prediabetes, and T2D] were assessed at all three time points. Multilevel growth curve modelling used age (centred at 50 years) as the time metric, adjusting for potential confounders, including physical activity and waist circumference. RESULTS: Mean TV time increased, and bodily pain worsened (i.e., mean bodily pain score decreased) across the three time points. Those with T2D had higher TV time and more-severe bodily pain than those without T2D at all time points. In a fully adjusted model, the mean bodily pain score for those aged 50 years at baseline was 76.9(SE: 2.2) and worsened (i.e., bodily pain score decreased) significantly by 0.3(SE: 0.03) units every additional year (p <0.001). Those with initially more-severe pain had a higher rate of increase in pain severity. At any given time point, a one-hour increase in daily TV time was significantly associated with an increase in pain severity [bodily pain score decreased by 0.69 (SE: 0.17) units each additional hour; p <0.001], accounting for the growth factor (age) and confounders' effects. The association was more-pronounced in those with T2D than in those without (prediabetes or NGM), with the effect of T2D on bodily pain severity becoming more apparent as TV time increases, significantly so when TV time increased above 2.5 hours per day. CONCLUSION: Bodily pain severity increased with age in middle-aged and older Australian adults over a 12-year period, and increments in TV time predicted increased bodily pain severity at any given period, which was more pronounced in those with T2D. While increasing physical activity is a mainstay of the prevention and management of chronic health problems, these new findings highlight the potential of reducing sedentary behaviours in this context.

Does aerobic exercise effect pain sensitisation in individuals with musculoskeletal pain? A systematic review.

BACKGROUND: Pain sensitisation plays a major role in musculoskeletal pain. However, effective treatments are limited, and although there is growing evidence that exercise may improve pain sensitisation, the amount and type of exercise remains unclear. This systematic review examines the evidence for an effect of aerobic exercise on pain sensitisation in musculoskeletal conditions. METHODS: Systematic searches of six electronic databases were conducted. Studies were included if they examined the relationship between aerobic physical activity and pain sensitisation in individuals with chronic musculoskeletal pain, but excluding specific patient subgroups such as fibromyalgia. Risk of bias was assessed using Cochrane methods and a qualitative analysis was conducted. RESULTS: Eleven studies (seven repeated measures studies and four clinical trials) of 590 participants were included. Eight studies had low to moderate risk of bias. All 11 studies found that aerobic exercise increased pressure pain thresholds or decreased pain ratings in those with musculoskeletal pain [median (minimum, maximum) improvement in pain sensitisation: 10.6% (2.2%, 24.1%)]. In these studies, the aerobic exercise involved walking or cycling, performed at a submaximal intensity but with incremental increases, for a 4-60 min duration. Improvement in pain sensitisation occurred after one session in the observational studies and after 2-12 weeks in the clinical trials. CONCLUSIONS: These findings provide evidence that aerobic exercise reduces pain sensitisation in individuals with musculoskeletal pain. Further work is needed to determine whether this translates to improved patient outcomes, including reduced disability and greater quality of life.

Efficacy of corticosteroids for hand osteoarthritis - a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: There is some evidence that corticosteroids may have a beneficial effect in hand osteoarthritis. We examined the efficacy of corticosteroids on symptoms and structural outcomes in hand osteoarthritis. METHODS: Ovid MEDLINE, Embase and Cochrane Central Register of Controlled Trials were searched from inception to October 2021 for randomized controlled trials investigating the efficacy of corticosteroids in hand osteoarthritis. Two authors independently screened records, extracted data, and assessed risk of bias using the RoB 2 tool. Standardized mean difference (SMD) or mean difference (MD) was calculated, and random-effects meta-analyses were performed. RESULTS: Of 13 included trials, 3 examined oral corticosteroids and clinical outcomes in any hand joints, 9 examined intra-articular injection of corticosteroids and clinical outcomes at the first carpometacarpal joint and one in the interphalangeal joints. In meta-analysis, oral corticosteroids reduced pain (SMD -0.53, 95% CI -0.79 to -0.28) and improved stiffness (MD -5.03, 95% CI -9.91 to -0.15; Australian Canadian Osteoarthritis Hand Index stiffness subscale) and function (SMD -0.37, 95% CI -0.63 to -0.12) at 4-6 weeks. However, there was no significant persistent effect on pain and function at 3 months which was 6-8 weeks after study medication was stopped. There was no significant effect of intra-articular corticosteroids on pain or function at 4-6 weeks or over 3-12 months in first carpometacarpal osteoarthritis. Two trials evaluated joint structure at 4-6 weeks: one study showed oral corticosteroids reduced synovial thickening, neither showed an effect on synovitis. CONCLUSIONS: There was low-certainty evidence for a medium effect of oral corticosteroids on pain relief and stiffness improvement and small-to-medium effect on functional improvement at 4-6 weeks, with no significant effect for intra-articular corticosteroids. Corticosteroids had no significant effect on any outcomes over longer term (3-12 months) off treatment. No trials examined the effect of corticosteroids on disease progression. The role of corticosteroids in hand osteoarthritis is limited.

Smartphone-Based Ecological Momentary Assessment for Collecting Pain and Function Data for Those with Low Back Pain.

Smartphone-based ecological momentary assessment (EMA) methods are widely used for data collection and monitoring in healthcare but their uptake clinically has been limited. Low back pain, a condition with limited effective treatments, has the potential to benefit from EMA. This study aimed to (i) determine the feasibility of collecting pain and function data using smartphone-based EMA, (ii) examine pain data collected using EMA compared to traditional methods, (iii) characterize individuals' progress in relation to pain and function, and (iv) investigate the appropriation of the method. Our results showed that an individual's 'pain intensity index' provided a measure of the burden of their low back pain, which differed from but complemented traditional 'change in pain intensity' measures. We found significant variations in the pain and function over the course of an individual's back pain that was not captured by the cohort's mean scores, the approach currently used as the gold standard in clinical trials. The EMA method was highly acceptable to the participants, and the Model of Technology Appropriation provided information on technology adoption. This study highlights the potential of the smartphone-based EMA method for enhancing the collection of outcome data and providing a personalized approach to the management of low back pain.

Associations of blood pressure and arterial stiffness with knee cartilage volume in patients with knee osteoarthritis.

OBJECTIVE: To describe the associations of blood pressure and arterial stiffness with knee cartilage volume in patients with knee OA. METHODS: A secondary analysis was performed on the data from participants in a randomized controlled trial that identified the effects of vitamin D supplementation on knee structures and symptoms among patients with symptomatic knee OA. Brachial and central blood pressure, arterial stiffness indicators and knee cartilage volume were measured at baseline and the 2 year follow-up. Associations were assessed using generalized estimating equations. RESULTS: Among 231 participants (average age 63.2 years), 48.9% were females. Higher supine systolic and diastolic pressures were significantly associated with lower tibial cartilage volume (systolic: lateral ß -6.23, medial ß -5.14, total ß -11.35 mm3/mmHg; diastolic: lateral ß -10.25, medial ß -11.29, total ß -21.50 mm3/mmHg). Higher supine systolic pressure was associated with lower femoral cartilage volume (lateral ß -17.35, total ß -28.31 mm3/mmHg). Central systolic pressure and arterial stiffness indicators (including pulse wave velocity, central pulse pressure and peripheral pulse pressure) were largely not associated with knee cartilage volume; however, higher augmentation index was associated with lower tibial and femoral cartilage volume (tibial: medial ß -8.24, total ß -19.13 mm3/%; femoral: lateral ß -23.70, medial ß -26.42, total ß -50.12 mm3/%). CONCLUSIONS: Blood pressure and arterial stiffness are associated with knee cartilage volume at several sites in knee OA patients. This supports that blood pressure and arterial stiffness may involve in the progression of knee OA.