Sequencing identifies a distinct signature of circulating microRNAs in early radiographic knee osteoarthritis.

OBJECTIVE: MicroRNAs act locally and systemically to impact osteoarthritis (OA) pathophysiology, but comprehensive profiling of the circulating miRNome in early vs late stages of OA has yet to be conducted. Sequencing has emerged as the preferred method for microRNA profiling since it offers high sensitivity and specificity. Our objective was to sequence the miRNome in plasma from 91 patients with early [Kellgren-Lawrence (KL) grade 0 or 1 (n = 41)] or late [KL grade 3 or 4 (n = 50)] symptomatic radiographic knee OA to identify unique microRNA signatures in each disease state. DESIGN: MicroRNA libraries were prepared using the QIAseq miRNA Library Kit and sequenced on the Illumina NextSeq 550. Counts were produced for microRNAs captured in miRBase and for novel microRNAs. Statistical, bioinformatics, and computational biology approaches were used to refine and interpret the final list of microRNAs. RESULTS: From 215 differentially expressed microRNAs (FDR < 0.01), 97 microRNAs showed an increase or decrease in expression in ≥85% of samples in the early OA group as compared to the median expression in the late OA group. Increasing this threshold to ≥95%, seven microRNAs were identified: hsa-miR-335-3p, hsa-miR-199a-5p, hsa-miR-671-3p, hsa-miR-1260b, hsa-miR-191-3p, hsa-miR-335-5p, and hsa-miR-543. Four novel microRNAs were present in ≥50% of early OA samples and had 27 predicted gene targets in common with the prioritized set of predicted gene targets from the 97 microRNAs, suggesting common underlying mechanisms. CONCLUSION: Sequencing of well-characterized patient cohorts produced unbiased profiling of the circulating miRNome and identified a unique panel of 11 microRNAs in early radiographic knee OA.

Neuropathic pain in end-stage hip and knee osteoarthritis: differential associations with patient-reported pain at rest and pain on activity.

OBJECTIVE: We investigated whether pain at rest and pain on activity were differentially associated with neuropathic pain scores in individuals with end-stage hip and knee OA. DESIGN: Study participants were 843 patients with hip or knee OA scheduled for total joint arthroplasty. In pre-surgery questionnaires, measures of socio-demographics, health status, medication use, neuropathic pain (painDETECT), pain at rest and pain on activity (WOMAC pain items), depression (HADS) and pain catastrophizing (PCS) were collected. Multivariable linear regression models were estimated for men and women separately to examine the association between neuropathic pain scores (outcome) and study measures, entered in blocks. RESULTS: Sample mean age was 65.1 years (SD: 9.6); 57.1% were women. Mean painDETECT scores were significantly higher (P ≤Ö¹ 0.001) for women (11.2 ± 6.6 out of 38) than men (9.3 ± 7.0), with 35.6% of women and 27.7% of men meeting cut-offs for possible or likely neuropathic pain. In the final regression model for women, the coefficients for both types of pain were statistically significant, although the coefficient for pain at rest was 1.6 times greater than that for pain on activity. For men, only pain at rest was significantly associated with neuropathic pain scores. CONCLUSIONS: Findings support that possible neuropathic pain is experienced by a notable proportion of patients with end-stage hip and knee OA and is more strongly associated with pain at rest than pain on activity, particularly in men. Clinical presentation of pain at rest may warrant more thorough evaluation for potential neuropathic pain and have implications for appropriate pain management.

A prospective cohort study examining medical and social factors associated with engagement in life activities following total hip replacement.

OBJECTIVES: Studies show limited improvement in the frequency of engaging in life activities after joint replacement. However, there is a paucity of research that has examined factors, including other life events, which influence engagement following total hip replacement (THR). This research sought to identify factors associated with engaging in life activities following THR. METHODS: A prospective cohort study was conducted with 376 people who had a THR for osteoarthritis (OA). Data were collected pre-surgery and 1 year post-surgery. The primary outcome was change in frequency in engagement in life activities (Late Life Disability Index (LLDI): higher scores indicate higher frequency of engagement (range 0-80)). Analyses included multivariable regression. Factors considered included: positive/negative life events, a new comorbidity, another joint replacement and complications post-surgery. RESULTS: Participants' mean age was 64 years; 46% were male. 68% of participants had at least one comorbidity pre-surgery; 36% reported at least one new comorbidity after surgery. The mean change in LLDI frequency was an increase of 6.29 (±8.10). 36% reported one or more positive impact life events in the year following surgery; 63% reported one or more negative life events. The number of positive life events (beta = 1.24; 95% CI: 0.49, 1.99) was significantly associated with change in LLDI frequency after adjusting for age, sex, education, body mass index (BMI), comorbidities pre-surgery, number of symptomatic joints and pre-surgery pain and function, LLDI limitations and depression. CONCLUSIONS: These findings highlight the significant influence of social factors and life circumstances on engagement in life activities following THR.

Systemic inflammation and painful joint burden in osteoarthritis: a matter of sex?

OBJECTIVE: We investigated the association between serum levels of C-reactive protein (CRP) and the extent of multijoint pain among individuals with hip/knee osteoarthritis (OA) and determined whether the association differs by sex. DESIGN: Serum CRP and cartilage oligomeric matrix protein (COMP) were determined by enzyme-linked immunosorbent assay (ELISA) in 189 individuals (101 female, 88 male) scheduled for total hip/knee arthroplasty for OA. Patients indicated on a homunculus all painful joints; a summed count was derived. A series of negative binomial regression models was used to investigate the cross-sectional association between painful joint count (outcome) and serum CRP concentrations, adjusting for age, sex, body mass index (BMI), comorbidity count and COMP. An interaction between sex and these biomarkers was tested. RESULTS: Mean age: 66 among women, 65 among men. Women had higher mean joint count (3.7 vs 2.5, P < 0.01; 4+ joint count reported by 37% women, 25% men). Median CRP concentration was higher in women (15.4 mg/l vs 9.3, P = 0.07). From adjusted analyses, the effects of both ln(CRP) and ln(COMP) were modified by sex (P < 0.05). Increasing ln(CRP) was associated with greater painful joint count among women, but not men. CONCLUSIONS: There may be a dose-response association between painful joint burden in OA and systemic inflammation, and it appears the association is sex-specific, which may in part explain inconsistent findings in the literature. Our results underline the importance of showing sex-specific associations in OA, especially when studying the influence of inflammation.

Putting the baby back in the bathwater: the interpretation of randomised trials in surgery.

Recently, several high impact randomised controlled trials have been published suggesting no greater benefit from orthopaedic surgery over conservative treatment, or limited surgical intervention. These studies can have profound effects on clinical practice, leading to the abandonment of previously widely-used operations. How do surgeons who believe these operations are beneficial over conservative treatment rationalise these findings, and justify their use with hospital administrators and health care funders who require evidence for the value and efficacy of surgical treatment?

Do women have poorer outcomes following total knee replacement?

OBJECTIVE: To investigate whether women have poorer pain and functional outcomes following total knee replacement (TKR) and to investigate factors that may contribute to this poorer outcome. METHODS: In a cohort of 494 people, outcomes were the Pain and Function/Daily Activity subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS) at 6 and 12 months post-surgery. Sequential multivariable regression analyses evaluated the following independent variables: (1) sex; (2) sex and age; (3) sex, age and pre-surgery score for respective outcome measures; and, (4) model 3 and body mass index (BMI), education, low back pain (LBP), depression, comorbidities, and symptomatic joint count. RESULTS: The sample included 323 women and 171 men. Women were significantly worse on several factors pre-surgery: pain: 39.0 vs 44.9, P = 0.002; function: 47.7 vs 55.0, P < 0.0001; depression 5.6 vs 4.7, P = 0.006; obesity (BMI ≥30): 54.2 vs 36.3%, P = 0.0002; and, symptomatic joint count: ≥4: 61.3 vs 44.4%, P = 0.002. Women had worse outcomes for pain (72.2 vs 76.1, P = 0.04) and function (75.2 vs 80.5, P = 0.007) at 6 months. This effect was attenuated by adding pre-surgery pain/function. However, the magnitude of the association of pre-surgery pain/function was reduced when LBP, depression, BMI, education level, joint count and comorbidity count were added suggesting association with pre-surgery pain and function. Twelve month results were similar. CONCLUSION: Women appear to have worse outcomes than men possibly due to a putative pre-operative profile across many factors. Consideration of TKR when impairments in pain and function are less severe along with interventions that address mood and comorbidity may improve outcomes for women having TKR.

Understanding why people do or do not engage in activities following total joint replacement: a longitudinal qualitative study.

OBJECTIVE: Numerous studies report large and significant improvements in basic mobility and activities of daily living following total hip or knee replacement (TJR). Nevertheless, quantitative research has shown minimal increase in participation in activities that benefit overall health. This study explored why people do or do not engage in activities following hip or knee TJR. METHOD: This was a longitudinal qualitative study. Sampling was guided by constructivist grounded theory and data collected using open-ended, semi-structured interviews. Participants were recruited using maximum variation sampling based on age, sex and joint replaced (hip or knee). Data were analysed using a constant comparative approach and coded for thematic patterns and relationships from which overarching themes were constructed. RESULTS: Twenty-nine patients participated in interviews prior to, and 8 and 18 months post following TJR. A high degree of variability with regard to participants' return to activities was found and five emergent themes were identified that accounted for this variability. These themes highlight the importance of issues beyond medical factors alone, such as socio-cultural factors that partially determine participants' participation in activity following TJR. CONCLUSION: Findings suggest that multi-faceted experiences impact participation in activity following TJR. These experiences include changes in identity and lifestyle that preclude a 'return to normal'. There is an urgent need for supports to increase people's activity post-TJR in order to facilitate enhancement of post-surgery levels of engagement. Approaches that take into consideration more personalized interventions may be critical to promoting healthy aging in people with TJR.

Understanding recovery: changes in the relationships of the International Classification of Functioning (ICF) components over time.

The International Classification of Functioning, Disability and Health framework describes human functioning through body structure and function, activity and participation in the context of a person's social and physical environment. This work tested the temporal relationships of these components. Our hypotheses were: 1) there would be associations among physical impairment, activity limitations and participation restrictions within time; 2) prior status of a component would be associated with future status; 3) prior status of one component would influence status of a second component (e.g. prior activity limitations would be associated with current participation restrictions); and, 4) the magnitude of the within time relationships of the components would vary over time. Participants from Canada with primary hip or knee joint replacement (n = 931), an intervention with predictable improvement in pain and disability, completed standardized outcome measures pre-surgery and five times in the first year post-surgery. These included physical impairment (pain), activity limitations and participation restrictions. ICF component relationships were evaluated cross-sectionally and longitudinally using path analysis adjusting for age, sex, BMI, hip vs. knee, low back pain and mood. All component scores improved significantly over time. The path coefficients supported the hypotheses in that both within and across time, physical impairment was associated with activity limitation and activity limitation was associated with participation restriction; prior status and change in a component were associated with current status in another component; and, the magnitude of the path coefficients varied over time with stronger associations among components to three months post surgery than later in recovery with the exception of the association between impairment and participation restrictions which was of similar magnitude at all times. This work enhances understanding of the complexities of the ICF component relationships in evaluating disability over time. Further longitudinal studies including evaluation of contextual factors are required.

Multiple joint involvement in total knee replacement for osteoarthritis: Effects on patient-reported outcomes.

OBJECTIVE: To determine whether symptomatic (painful/problematic) joints pre-total knee replacement (TKR) surgery influence 1) pre- and 12-month post-TKR patient-reported outcomes (pain, physical function, and mood [fatigue, anxiety, and depression]) and 2) postsurgical pain and function mediated through mood. METHODS: A total of 494 participants completed the patient-reported outcome measures pre- and 12-months post-TKR. Symptomatic (painful/problematic) joints affected by arthritis were indicated on a homunculus presurgery. Covariate data included age, sex, educational attainment, body mass index, and comorbidity. Pre- and postsurgical outcome scores were regressed on symptomatic joint sites and covariates using linear regression analyses; postsurgical scores additionally were regressed on presurgery scores. Path analyses examined whether the effects of symptomatic joint sites on postsurgical pain and function were mediated through mood. RESULTS: The age range was 35-88 years (mean 65 years) and 65% were women. Forty-six percent reported ≥4 symptomatic joints (other than the surgical knee). Pre- and postsurgery, worse outcome scores were observed with increasing joint count. Adjusted for covariates, individuals reporting symptomatic ankles/feet/toes, neck, and spine/lower back had worse presurgery fatigue and anxiety. Adjusted for covariates and presurgery status, worse fatigue for the neck and spine/lower back and worse depression, pain, and function for the ankles/feet/toes and neck were observed postsurgery. The influence of symptomatic ankles/feet/toes on postsurgical pain and function was in part direct and partially mediated through depression. Full mediation was found for the neck through fatigue, anxiety, and depression, and for the spine/lower back through fatigue. CONCLUSION: Findings suggest that a comprehensive approach to osteoarthritis management/care is warranted, and identify important associations between symptomatic joints and mood that negatively impact post-TKR pain and physical function.

The trajectory of recovery and the inter-relationships of symptoms, activity and participation in the first year following total hip and knee replacement.

OBJECTIVE: Primary total hip (THR) and knee (TKR) replacement outcomes typically include pain and function with a single time of follow-up post-surgery. This research evaluated the trajectory of recovery and inter-relationships within and across time of physical impairments (PI) (e.g., symptoms), activity limitations (AL), and social participation restrictions (PR) in the year following THR and TKR for osteoarthritis. DESIGN: Participants (hip: n=437; knee: 494) completed measures pre-surgery and at 2 weeks, 1, 3, 6 and 12 months post-surgery. These included PI (Hip Disability and Osteoarthritis Outcome Score (HOOS)/Knee Injury and Osteoarthritis Outcome Score (KOOS) symptoms and Chronic Pain Grade); AL (HOOS/KOOS activities of daily living and sports/leisure activities); and, PR (Late Life Disability and the Calderdale community mobility). Repeated measures analysis of variance (RANOVA) was used to evaluate the trajectory of recovery of outcomes and the inter-relationships of PI, AL and PR were evaluated using path analysis. All analyses were adjusted for age, sex, obesity, THR/TKR, low back pain and mood. RESULTS: THR: age 31-86 years with 55% female; TKR: age 35-88 years with 65% female. Significant improvements in outcomes were observed over time. However, improvements were lagged over time with earlier improvements in PI and AL and later improvements in PR. Within and across time, PI was associated with AL and AL was associated with PR. The magnitude of these inter-relationships varied over time. CONCLUSION: Given the lagged inter-relationship of PI, AL and PR, the provision and timing of interventions targeting all constructs are critical to maximizing outcome. Current care pathways focusing on short-term follow-up with limited attention to social and community participation should be re-evaluated.

Psychometric properties of the French translation of the reduced KOOS and HOOS (KOOS-PS and HOOS-PS).

OBJECTIVE: To evaluate the psychometric properties of the French KOOS physical function (KOOS-PS) and HOOS physical function (HOOS-PS), specifically its feasibility, reliability, construct validity, and responsiveness. METHODS: Consecutive outpatients consulting for primary knee or hip osteoarthritis (OA) in a rheumatology department were included. During the initial assessment, patients were asked to complete the Knee injury and Osteoarthritis Outcome Score (KOOS) or Hip disability and Osteoarthritis Outcome Score (HOOS) questionnaire and the OsteoArthritis Knee and Hip Quality Of Life questionnaire (OAKHQOL). The patients were given a second KOOS or HOOS questionnaire to complete and return by mail 2 weeks later. Feasibility was assessed by calculating the percentage of missing items and the floor and ceiling effects. Test-retest reliability was evaluated using the intra-class correlation coefficient (ICC). Convergent and divergent construct validity was determined by comparing the results of the KOOS-PS or HOOS-PS and OAKHQOL questionnaires using Spearman's rank test. Responsiveness was evaluated using data obtained in other hip or knee OA patients prior to and 1 month after intra-articular hyaluronic acid injection, using standardized response mean (SRM) and effect-size (ES). RESULTS: Eighty-seven patients with knee OA and 50 hip OA patients were included. The KOOS-PS and HOOS-PS scores were obtained for all patients as there were no missing items. Neither a floor nor a ceiling effect was observed. The ICC of KOOS-PS and HOOS-PS was 0.861 (0.763-0.921) and 0.859 (0.725-0.929), respectively. A strong or moderate correlation was observed, as expected, between KOOS-PS, HOOS-PS, and the OAKHQOL physical activities, pain, and mental health domains. A weak correlation was observed, as expected, between KOOS-PS, HOOS-PS, and the other OAKHQOL domains, except for a moderate correlation between the KOOS-PS and social functioning. The responsiveness was demonstrated with SRM and ES of 0.80 and 0.51 (KOOS-PS), 1.10 and 0.62 (HOOS-PS), respectively. CONCLUSION: The French versions of KOOS-PS and HOOS-PS are reliable, valid, and responsive questionnaires for capturing functional disability in people with knee and hip OA.

Comparative, validity and responsiveness of the HOOS-PS and KOOS-PS to the WOMAC physical function subscale in total joint replacement for osteoarthritis.

OBJECTIVE: To evaluate the internal consistency of the Hip disability and Osteoarthritis Outcome Score-Physical Function Short-form (HOOS-PS) and the Knee injury and Osteoarthritis Outcome Score-Physical Function Short-form (KOOS-PS) in total hip replacement (THR) and total knee (TKR) replacement. Construct validity and responsiveness were compared to the Western Ontario McMaster Universities' Osteoarthritis Index (WOMAC) Likert 3.0 physical function (PF) subscale and the PF excluding the items in the short measures (PF-exclusions). METHODS: Participants completed the full HOOS or KOOS, measures of fatigue, anxiety, depression and the Chronic Pain Grade (CPG) pre-surgery and the HOOS or KOOS 6 months post-surgery. Internal consistency for the HOOS-PS and KOOS-PS was calculated using Cronbach's alpha. For construct validity, it was hypothesized that correlations between the HOOS-PS or KOOS-PS and PF and PF-exclusions with fatigue, CPG, anxiety and depression and HOOS/KOOS pain scales would differ by magnitudes of <0.1. Standardized response means (SRMs) were calculated for the HOOS-PS, KOOS-PS, PF and PF-exclusions and hypothesized to be >1. RESULTS: The THR group (n=201) had a mean age of 62.3 years; 53.2% were female. The TKR group (n=248) had a mean age of 64.5 years; 63.7% were female. Cronbach's alpha was 0.79 and 0.89 for the HOOS-PS and KOOS-PS, respectively, confirming that the measures represented a homogeneous construct. The correlation of the HOOS-PS to the PF and PF-exclusions was 0.90 and 0.86, respectively; r=0.90 (PF) and r=0.85 (PF-exclusions) for the KOOS-PS. The results supported the construct validity hypotheses. For THR, the SRM was 1.5, 1.7 and 1.7 for the HOOS-PS, PF and PF-exclusions; for TKR, the SRM was 1.4, 1.5 and 1.7, respectively. CONCLUSIONS: The short HOOS-PS and KOOS-PS represent homogenous short measures of PF with similar construct validity and responsiveness to the 17-item PF. The HOOS-PS and KOOS-PS are parsimonious, valid and responsive for evaluating PF in THR and TKR.

The development of a short measure of physical function for knee OA KOOS-Physical Function Shortform (KOOS-PS) - an OARSI/OMERACT initiative.

OBJECTIVE: To develop a short measure of physical function for knee osteoarthritis (OA) using multi-national data from individuals with varying degrees of severity of knee OA. METHODS: Rasch analysis, based on the partial credit model, was conducted on Knee injury and Osteoarthritis Outcome Score and Western Ontario McMaster Universities' Osteoarthritis Index data from individuals with knee OA, ranging from community to pre-total knee replacement samples from five countries. Fit of the data to the Rasch model was evaluated by overall model fit and item-level fit statistics (chi(2), size of residual, F-test). Invariance across age, gender and country was evaluated. Unidimensionality was evaluated by factor analysis of residuals. The derived short measure was further tested for fit through re-analyses in individual sub-samples. A nomogram converting raw summed scores to Rasch-derived interval scores was developed. RESULTS: Thirteen data sets were included (n=2145), with an age range of 26-95 years, and a male/female ratio of 1:1.4. The final model included seven of the original 22 items. From easiest to most difficult, the items (logit) were as follows: rising from bed (1.366), putting on socks/stockings (1.109), rising from sitting (0.537), bending to the floor (0.433), twisting/pivoting on injured knee (-0.861), kneeling (-1.292) and squatting (-1.292). Sub-sample analyses confirmed findings. CONCLUSION: Based on the use of accepted Rasch-based measurement methods and the compliment of countries, languages and OA severity represented in this study, our seven item short measure of physical function for knee OA is likely generalizable and widely applicable. This measure has potential for use as the function component in an OA severity scoring system.

The development of a short measure of physical function for hip OA HOOS-Physical Function Shortform (HOOS-PS): an OARSI/OMERACT initiative.

OBJECTIVE: To derive a cross-culturally valid, short measure of physical function using function subscales (daily living and sports and recreation) of the Hip disability and Osteoarthritis Outcome Score (HOOS). METHODS: Rasch analysis was conducted on data from individuals from multiple countries who had hip osteoarthritis (OA). Fit of the data to the Rasch model was evaluated by model chi(2) and item fit statistics (chi(2), size of residual, and F-test). Differential item functioning was evaluated by gender, age and country. Unidimensionality was evaluated by factor analysis of residuals. Individual data sets were analyzed and data pooled and re-analyzed for fit to the model. Regression modeling was conducted to derive a nomogram converting raw summed scores to Rasch derived interval scores. RESULTS: Seven data sets were included (n=2991), ages 19-96 years, male/female ratio was 1:1.23. The final model included five HOOS items. From the easiest to most difficult, the items (logit) were as follows: sitting (1.832), descending stairs (0.729), getting in/out of bath or shower (0.255), twisting/pivoting on loaded leg (-0.221) and running (-2.595). The separation index was 0.80. CONCLUSION: The daily activity and sports and recreational items of the HOOS were reduced to five items achieving a feasible, short measure of physical function with interval level properties. This tool has potential for use as the function component of an OA severity scoring system. Further testing of this measure is warranted.