Patient acceptable symptom state and treatment failure threshold values for work productivity and activity Impairment and EQ-5D-5L in osteoarthritis.

OBJECTIVE: To estimate patient acceptable symptom state (PASS) and treatment failure (TF) threshold values for Work Productivity and Activity Impairment (WPAI) measure and EQ-5D-5L among people with hip or knee osteoarthritis (OA) 3 and 12 months following participation in a digital self-management intervention (Joint Academy®). METHODS: Among the participants, we computed work and activity impairments scores (both 0-100, with a higher value reflecting higher impairment) and the Swedish hypothetical- (range: - 0.314 to 1) and experience-based (range: 0.243-0.976) EQ-5D-5L index scores (a higher score indicates better health status) at 3- (n = 14,607) and 12-month (n = 2707) follow-ups. Threshold values for PASS and TF were calculated using anchor-based adjusted predictive modeling. We also explored the baseline dependency of threshold values according to pain severity at baseline. RESULTS: Around 42.0% and 48.3% of the participants rated their current state as acceptable, while 4.2% and 2.8% considered the treatment had failed at 3 and 12 months, respectively. The 3-month PASS/TF thresholds were 16/29 (work impairment), 26/50 (activity impairment), 0.92/0.77 (hypothetical EQ-5D-5L), and 0.87/0.77 (the experience-based EQ-5D-5L). The thresholds at 12 months were generally comparable to those estimated at 3 months. There were baseline dependencies in PASS/TF thresholds with participants with more severe baseline pain considering poorer (more severe) level of WPAI/EQ-5D-5L as satisfactory. CONCLUSION: PASS and TF threshold values for WPAI and EQ-5D-5L might be useful for meaningful interpretation of these measures among people with OA. The observed baseline dependency of estimated thresholds limits their generalizability and values should be applied with great caution in other settings/populations.

Weekly pain trajectories among people with knee or hip osteoarthritis participating in a digitally delivered first-line exercise and education treatment.

OBJECTIVE: Digital self-management programs are increasingly used in the management of osteoarthritis (OA). Little is known about heterogeneous patterns in response to these programs. We describe weekly pain trajectories of people with knee or hip OA over up to 52-week participation in a digital self-management program. METHODS: Observational cohort study among participants enrolled between January 2019 and September 2021 who participated at least 4 and up to 52 weeks in the program (n = 16 274). We measured pain using Numeric Rating Scale (NRS 0-10) and applied latent class growth analysis to identify classes with similar trajectories. Associations between baseline characteristics and trajectory classes were examined using multinomial logistic regression and dominance analysis. RESULTS: We identified 4 pain trajectory classes: "mild-largely improved" (30%), "low moderate-largely improved" (34%), "upper moderate-improved" (24%), and "severe-persistent" (12%). For classes with decreasing pain, the most pain reduction occurred during first 20 weeks and was stable thereafter. Male sex, older age, lower body mass index (BMI), better physical function, lower activity impairment, less anxiety/depression, higher education, knee OA, no walking difficulties, no wish for surgery and higher physical activity, all measured at enrolment, were associated with greater probabilities of membership in "mild-largely improved" class than other classes. Dominance analysis suggested that activity impairment followed by wish for surgery and walking difficulties were the most important predictors of trajectory class membership. CONCLUSIONS: Our results highlight the importance of reaching people with OA for first-line treatment prior to developing severe pain, poor health status and a wish for surgery.

Digital Self-Management, Analgesic Use, and Patient-Reported Outcomes in Knee or Hip Osteoarthritis.

OBJECTIVE: To investigate changes in analgesic use before and after participation in a digital first-line treatment program (exercise, patient education) in persons with knee or hip osteoarthritis (OA) and to explore associations between these changes in medication use and participant-reported pain and function. DESIGN: Retrospective cohort study with pre-post measures. SETTING: Community setting. PARTICIPANTS: Individuals (N=4100; mean age ± SD, 64.5±9.3y; 73.3% women) participating in the digital program. INTERVENTIONS: A digital supervised education and exercise therapy. MAIN OUTCOME MEASURES: Self-reported analgesic use for knee/hip pain during the past month at baseline and 12-week follow-up, knee/hip numeric rating scale pain (0-10, a higher value indicating more pain), and Knee Injury and Osteoarthritis Outcome Score 12 or Hip Disability and Osteoarthritis Outcome Score 12 function subscale (0-100, higher values indicating better function). McNemar test, multivariable logistic regression, and linear random intercept model were used for statistical analyses. RESULTS: Among participants, 61.4% and 49.4% were analgesic users at baseline and 12-week follow-up, respectively, (absolute reduction 12.0%; 95% confidence interval, 10.5-13.5). Being female, having hip OA, lower education, higher body mass index, living outside large metropolitan cities, coexisting rheumatoid arthritis, and walking difficulties were associated with higher odds of analgesic use at baseline. At both time points, persons not using analgesics at the time reported better outcomes. All groups but "new users" experienced improvements in their pain and function following participation in digital program with the greatest improvements observed among "quitters." CONCLUSIONS: Engaging in a digital exercise and patient education program as a primary treatment for knee or hip OA was associated with a reduction in the use of analgesics. The greatest improvements were seen for those who stopped analgesic use. These results highlight the importance of providing effective first-line treatment to people with knee or hip OA.

Within-person change in patient-reported outcomes and their association with the wish to undergo joint surgery during a digital first-line intervention for osteoarthritis.

AIM: To study the association between within-person changes in patient-reported outcomes (PROMs) and wish for joint surgery during participation in a digital first-line intervention comprising exercise and education for knee/hip osteoarthritis (OA). METHODS: Retrospective observational registry study. Participants enrolled between June 1, 2018 and October 30, 2021, with follow-up data at three months (n = 13,961). We used asymmetric fixed effect (conditional) logistic regressions to study the association between change in wish to undergo surgery at last available time point (3, 6, 9, or 12 months) and improvement or worsening of PROMs pain (0-10), quality of life (QoL) (EQ5D-5L, 0.243-0.976), overall health (0-10), activity impairment (0-10), walking difficulties (yes/no), fear of movement (yes/no), and Knee/Hip injury and Osteoarthritis Outcome Score 12 Items (KOOS-12/HOOS-12, 0-100) function and QoL subscales. RESULTS: The proportion of participants wishing to undergo surgery declined by 2% (95% CI: 1.9, 3.0), from 15.7% at the baseline to 13.3% at 3 months. Generally, improvements in PROMs were associated with reduced likelihood of wishing for surgery, while worsening was associated with increased likelihood. For pain, activity impairment EQ-5D and KOOS/HOOS QoL, a worsening led to a change in the probability of wish for surgery of larger absolute magnitude than an improvement in the same PROM. CONCLUSIONS: Within-person improvements in PROMs are associated with reduced wish for surgery while worsenings with an increased wish for surgery. Larger improvements in PROMs may be needed to match the magnitude of the change in wish for surgery associated with a worsening in the same PROM.

Digital self-management of hip and knee osteoarthritis and trajectories of work and activity impairments.

OBJECTIVE: To investigate the trajectories of work and activity impairments among people participating in a digital self-management program for osteoarthritis (OA). METHODS: We conducted an observational longitudinal study using data for baseline, 3, 6, 9 and 12 months follow ups from people participating in a digital OA treatment between June 2018 and September 2021. The Work Productivity and Activity Impairment-Osteoarthritis (WPAI-OA) questionnaire was used to measure work and activity impairments. We applied linear mixed models and group-based trajectory modelling (GBTM) to assess the trajectories of work and activity impairments and their variability. Dominance analysis was performed to explore the relative importance of baseline characteristics in predicting the trajectory subgroup membership. RESULTS: A total of 14,676 participants with mean (± standard deviation) age 64.0 (± 9.1) years and 75.5% females were included. The adjusted mean improvements in work impairment from baseline were 5.8% (95% CI 5.3, 6.4) to 6.1% (95% CI 5.5, 6.8). The corresponding figures for activity impairment were 9.4% (95% CI 9.0, 9.7) to 11.3% (95% CI 10.8, 11.8). GBTM identified five (low baseline-declining, moderate baseline-declining, high baseline-declining, very high baseline-substantially declining, and very high baseline-persistent) and three (low baseline-declining, mild baseline-declining, high baseline-declining) subgroups with distinct trajectories of activity and work impairments. Dominance analysis showed that baseline pain was the most important predictor of membership in trajectory subgroups. CONCLUSION: While participation in a digital self-management program for OA was, on average, associated with improvements in work and activity impairments, there were substantial variations among the participants. Baseline pain may provide useful insights to predict trajectories of work and activity impairments.

The role of cartilage glycosaminoglycan structure in gagCEST.

Glycosaminoglycan (GAG) chemical exchange saturation transfer (gagCEST) is a potential method for cartilage quality assessment. The aim of this study was to investigate how the gagCEST effect depends on the types and molecular organization of GAG typically found in articular cartilage. gagCEST was performed on different concentrations of GAG in various forms: free chains of chondroitin sulfate (CS) of different types (-A and -C) and GAG bound to protein in aggregated and nonaggregated aggrecan extracted from calf articular cartilage. The measured magnetization transfer ratio asymmetry (MTRasym ) was compared with known GAG concentrations or GAG concentrations determined through biochemical analysis. The gagCEST effect was assessed through the linear regression coefficient with 95% confidence interval of MTRasym per GAG concentration. We observed a lower gagCEST effect in phantoms containing a mixture of CS-A and CS-C compared with phantoms containing mainly CS-A. The difference in response corresponds well to the difference in CS-A concentration. GAG bound in aggrecan from calf articular cartilage, where CS-A is assumed to be the major type of GAG, produed a similar gagCEST effect as that observed for free CS-A. The effect was also similar for aggregated (ie, bound to hyaluronic acid) and nonaggregated aggrecan. In conclusion, our results indicate that the aggrecan structure in itself does not impact the gagCEST effect, but that the effect is strongly dependent on GAG type. In phantoms, the current implementation of gagCEST is sensitive to CS-A while for CS-C, the main GAG component in mature human articular cartilage, the sensitivity is limited. This difference in gagCEST sensitivity between GAG types detected in phantoms is a strong motivation to also explore the possibility of a similar effect in vivo.

Socioeconomic status of patients in a Swedish national self-management program for osteoarthritis compared with the general population-a descriptive observational study.

BACKGROUND: First-line treatment for hip and knee osteoarthritis (OA) including education and supervised exercises, delivered as a self-management program, is considered one of the mainstays in OA treatment. However, the socioeconomic profile of the population that utilizes first-line treatment for hip and knee OA is unclear. The aim of this study was to describe the socioeconomic status (SES) of a population referred to a self-management program for OA, in comparison with that of the general Swedish population. METHODS: This is a cross-sectional study including 72,069 patients with hip or knee OA enrolled in the National Quality Register for Better management of patients with Osteoarthritis (BOA) between 2008 and 2016, and registered before participation in a structured OA self-management program. A reference cohort (n = 216,207) was selected from the general Swedish population by one-to-three matching by year of birth, sex and residence. Residential municipality, country of birth, marital status, family type, educational level, employment, occupation, disposable income and sick leave were analyzed. RESULTS: The BOA population had higher educational level than the reference group, both regarding patients with hip OA (77.5% vs 70% with ≥10 years of education), and with knee OA (77% vs 72% with ≥10 years of education). Their average disposable income was higher (median [IQR] in Euro (€), for hip €17,442 [10,478] vs €15,998 [10,659], for knee €17,794 [10,574] vs €16,578 [11,221]). Of those who worked, 46% of patients with hip OA and 45% of the reference group had a blue-collar occupation. The corresponding numbers for knee OA were 51 and 44% respectively. Sick leave was higher among those with hip and knee OA (26%) than those in the reference groups (13% vs 12%). CONCLUSIONS: The consistently higher SES in the BOA population compared with the general population indicates that this self-management program for OA may not reach the more socioeconomically disadvantaged groups, who are often those with a higher disease burden.

Pre-contrast T1 and cartilage thickness as confounding factors in dGEMRIC when evaluating human cartilage adaptation to physical activity.

BACKGROUND: The dGEMRIC (delayed Gadolinium-Enhanced MRI of Cartilage) technique has been used in numerous studies for quantitative in vivo evaluation of the relative glycosaminoglycan (GAG) content in cartilage. The purpose of this study was to determine the influence of pre-contrast T1 and cartilage thickness when assessing knee joint cartilage quality with dGEMRIC. METHODS: Cartilage thickness and T1 relaxation time were measured in the central part of the femoral condyles before and two hours after intravenous Gd-DTPA2- administration in 17 healthy volunteers from a previous study divided into two groups: 9 sedentary volunteers and 8 exercising elite runners. Results were analyzed in superficial and a deep weight-bearing, as well as in non-weight-bearing regions of interest. RESULTS: In the medial compartment, the cartilage was thicker in the exercising group, in weight-bearing and non-weight-bearing segments. In most of the segments, the T1 pre-contrast value was longer in the exercising group compared to the sedentary group. Both groups had a longer pre-contrast T1 in the superficial cartilage than in the deep cartilage. In the superficial cartilage, the gadolinium concentration was independent of cartilage thickness. In contrast, there was a linear correlation between the gadolinium concentration and cartilage thickness in the deep cartilage region. CONCLUSION: Cartilage pre-contrast T1 and thickness are sources of error in dGEMRIC that should be considered when analysing bulk values. Our results indicate that differences in cartilage structure due to exercise and weight-bearing may be less pronounced than previously demonstrated.

Impact of a national guideline on use of knee arthroscopy: An interrupted time-series analysis.

OBJECTIVE: To assess the impact of the Swedish health authority recommendation against the use of knee arthroscopy in patients aged ≥40 years with knee osteoarthritis (OA). DESIGN: Interrupted time series analysis. SETTING: Public health care in Skåne region. PARTICIPANTS: Patients aged ≥40 years who underwent knee arthroscopy from January 2010 to December 2015. INTERVENTION(S): National guideline's recommendation against the use of knee arthroscopy in patients with knee OA. MAIN OUTCOME MEASURE(S): 1) proportion of patients aged ≥40 years with a main diagnosis of Knee OA and/or degenerative meniscal lesions (DML) who underwent knee arthroscopy, and 2) overall knee arthroscopy rate per 100,000 Skåne population aged ≥40 years. RESULTS: A total of 6,155 knee arthroscopy were performed among people aged ≥40 years during study period. Of 42,044 patients with Knee OA/DML, 3,728 had knee arthroscopy. The recommendation was associated with reductions in the use of knee arthroscopy and two years after the recommendation, there was a reduction of 28.6% (95% CI: 9.3, 47.8) and 34.7% (23.9, 45.4) in proportion of Knee OA/DML patients with knee arthroscopy and the overall knee arthroscopy rate, respectively, relative to that expected if pre-recommendation trend continued. Our sensitivity analysis showed that the use of total knee replacement was stable over the study period. CONCLUSION: The national recommendation was associated with reduction in use of knee arthroscopy in public health care in southern Sweden. However, still 4.5% of these patients underwent knee arthroscopy in 2015 implying that more efforts are required to achieve the recommended target.

Association between thigh muscle strength four years after partial meniscectomy and radiographic features of osteoarthritis 11 years later.

BACKGROUND: Meniscus injury and meniscectomy both entail increased risk of knee osteoarthritis (OA). Thigh muscle weakness is a suggested mediator of OA but there is little evidence of its importance for knee OA development after meniscectomy. This study aimed to examine the association between thigh muscle strength after partial meniscectomy in middle-aged subjects with a non-traumatic meniscal tear and later radiographic knee OA changes. METHODS: Thirty-four out of 45 participants in an exercise-trial underwent testing for isokinetic thigh muscle strength 4 years after arthroscopic partial meniscectomy and had radiographic examination 11 years later (15 years post-surgery, mean age at follow-up of 57 years (range 50-61)). Outcomes were grade of joint space narrowing and osteophyte score in the medial tibiofemoral compartment of the operated knee and the contralateral knee. We tested the association between muscle strength at baseline and the radiographic outcomes at follow-up using logistic regression analyses adjusted for sex and overweight. RESULTS: At follow-up, 33/34 subjects had joint space narrowing and 27/34 subjects had osteophytes in the operated knee, in the contralateral knee joint space narrowing was found in 23 subjects. In the operated knee baseline knee extensor and flexor strength were negatively associated with grade of joint space narrowing at follow-up (OR 0.972 and 0.956, p = 0.028 and 0.026, respectively) and also with osteophyte score (OR 0.968 and 0.931, p = 0.017 and 0.011, respectively). In the contralateral knee longitudinal associations between strength and radiographic OA features were similar, OR 0.949-0.972, p < 0.05. CONCLUSION: The finding that stronger thigh muscles 4 years after meniscectomy were associated with less severe osteoarthritic changes in the medial tibiofemoral compartment of both the operated and contralateral knee 11 years later, may suggest that strong thigh muscles can help to preserve joint integrity in middle-aged subjects at risk of knee OA.

The effect of education and supervised exercise on physical activity, pain, quality of life and self-efficacy - an intervention study with a reference group.

BACKGROUND: Individuals with knee and hip osteoarthritis (OA) are less physically active than people in general, and many of these individuals have adopted a sedentary lifestyle. In this study we evaluate the outcome of education and supervised exercise on the level of physical activity in individuals with knee or hip OA. We also evaluate the effect on pain, quality of life and self-efficacy. METHODS: Of the 264 included individuals with knee or hip OA, 195 were allocated to the intervention group. The intervention group received education and supervised exercise that comprised information delivered by a physiotherapist and individually adapted exercises. The reference group consisted of 69 individuals with knee or hip OA awaiting joint replacement and receiving standard care. The primary outcome was physical activity (as measured with an accelerometer). The secondary outcomes were pain (Visual Analog Scale), quality of life (EQ-5D), and self-efficacy (Arthritis Self-Efficacy Scale, pain and other symptoms subscales). Participants in both groups were evaluated at baseline and after 3 months. The intervention group was also evaluated after 12 months. RESULTS: No differences were found in the number of minutes spent in sedentary or in physical activity between the intervention and reference groups when comparing the baseline and 3 month follow-up. However, there was a significant difference in mean change (mean diff; 95% CI; significance) between the intervention group and reference group favoring the intervention group with regard to pain (13; 7 to 19; p < 0.001), quality of life (- 0.17; - 0.24 to - 0.10; p < 0.001), self-efficacy/other symptoms (- 5; - 10 to - 0.3; p < 0.04), and self-efficacy/pain (- 7; - 13 to - 2; p < 0.01). Improvements in pain and quality of life in the intervention group persisted at the 12-month follow-up. CONCLUSIONS: Participation in an education and exercise program following the Swedish BOA program neither decreased the average amount of sedentary time nor increased the level of physical activity. However, participation in such a program resulted in decreased pain, increased quality of life, and increased self-efficacy. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov. Registration number: NCT02022566 . Retrospectively registered 12/18/2013.

Poor outcome after a surgically treated chondral injury on the medial femoral condyle: early evaluation with dGEMRIC and 17-year radiographic and clinical follow-up in 16 knees.

Background and purpose - The optimal treatment for traumatic cartilage injuries remains unknown. Contrast-enhanced MRI of cartilage (dGEMRIC) evaluates cartilage quality and a low dGEMRIC index may predict radiographic osteoarthritis (OA). The purpose of this study was (a) to explore the results 17 years after surgical treatment of an isolated cartilage knee injury and (b) to evaluate the predictive value of dGEMRIC. Patients and methods - 16 knees with an isolated traumatic cartilage injury of the medial femoral condyle had cartilage repair surgery either by microfracture or autologous cartilage implantation. dGEMRIC of the injured knee was performed 2 years after surgery and radiographic examinations were performed 17 years after the operation. Results - Radiographic OA was present in 12 of 16 knees. Irrespective of surgical method, the dGEMRIC index was lower in repair tissue compared with adjacent cartilage in the medial compartment, 237 ms vs. 312 ms (p < 0.001), which in turn had lower value than in the non-injured lateral cartilage, 312 ms vs. 354 ms (p < 0.008). The dGEMRIC index in the cartilage adjacent to the repair tissue correlated negatively with radiographic osteophyte score, r = -0.75 (p = 0.03). Interpretation - A traumatic cartilage injury is associated with a high prevalence of OA after 17 years. The low dGEMRIC index in the repair tissue 2 years postoperatively indicates fibrocartilage of low quality. The negative correlation between the dGEMRIC index in the adjacent cartilage and future OA suggests that the quality of the surrounding cartilage influences outcome after cartilage repair surgery.

A 6-Week Web-Based Osteoarthritis Treatment Program: Observational Quasi-Experimental Study.

BACKGROUND: Osteoarthritis (OA) is one of the most common causes of disability, with a burden of disease estimated to increase over time. Joint Academy, a Web-based treatment for individuals with clinically verified knee or hip OA, was developed to increase access to and facilitate implementation of evidence-based nonsurgical OA treatment in accordance with international guidelines. OBJECTIVE: The primary aim of this study was to evaluate joint pain, physical function, and health-related quality of life (HRQoL) over time of users of the Joint Academy program. METHODS: We enrolled 350 patients who were recruited online and completed the initial health journal in the 6-week program. We asked patients to complete an eHealth journal and e-questionnaires, including pain level assessed by a numerical rating scale, as well as a physical function evaluation using the 30-second chair-stand test. In addition, we assessed HRQoL using the 3-level version of the EQ-5D. We also asked participants whether they experienced difficulty walking and were afraid of physical activity due to their OA and their desire for surgery. We collected descriptive data and compared pre- versus postintervention data. As a reference group, we included results retrieved from the Swedish well-structured face-to-face self-supportive OA management program Better Management of Patients With Osteoarthritis (BOA). RESULTS: Of the study cohort (n=350 patients; 239 women, mean age 62 years, mean body mass index 27 kg/m2), 71.4% (n=250) completed the program and were included in the study. We used the questionnaires to secure a clinical diagnosis of OA and to establish baseline study values. After 6 weeks of treatment, the change in mean numerical rating scale was larger than the minimal clinical difference (5.4 vs 4.1; P<.001), while physical function increased (from 10.88 to 13.14; P<.001). The percentage of participants having walking difficulties decreased from 81.7% (196/240) to 62.1% (149/240; P<.001), those afraid of being physically active decreased from 22.1% (53/240) to 6.7% (16/240; P<.001), and 22.0% (55/250) reported that they had reduced the amount of OA-related medication. After 6 weeks, 24% (13/54) of those desiring surgery at the start of the program were no longer interested. In addition, the comparison between Joint Academy and the BOA program showed similar levels of pain at 3 months, but suggested greater reduction with the use of Joint Academy due to a higher level of pain at baseline. CONCLUSIONS: The reported data suggest that participation in Joint Academy is associated with a clinically relevant decrease in pain and an increase in physical function and HRQoL, as well as a decreasing fear of physical activity. This innovative Web-based OA treatment is scalable, is population specific, and can reach a large number of individuals with impaired joints who have Internet access.

Sick leave in Sweden before and after total joint replacement in hip and knee osteoarthritis patients.

Background and purpose - Little is know about patterns of sick leave in connection with total hip and knee joint replacement (THR and TKR) in patients with osteoarthritis (OA). Patients and methods - Using registers from southern Sweden, we identified hip and knee OA patients aged 40-59 years who had a THR or TKR in the period 2004-2012. Patients who died or started on disability pension were excluded. We included 1,307 patients with THR (46% women) and 996 patients with TKR (56% women). For the period 1 year before until 2 years after the surgery, we linked individual-level data on sick leave from the Swedish Social Insurance Agency. We created a matched reference cohort from the general population by age, birth year, and area of residence (THR: n = 4,604; TKR: n = 3,425). The mean number of days on sick leave and the proportion (%) on sick leave 12 and 24 months before and after surgery were calculated. Results - The month after surgery, about 90% of patients in both cohorts were on sick leave. At the two-year follow-up, sick leave was lower for both cohorts than 1 year before surgery, except for men with THR, but about 9% of the THR patients and 12-17% of the TKR patients were still sick-listed. In the matched reference cohorts, sick leave was constant at around 4-7% during the entire study period. Interpretation - A long period of sick leave is common after total joint replacement, especially after TKR. There is a need for better knowledge on how workplace adjustments and rehabilitation can facilitate the return to work and can postpone surgery.

A first-in-human, double-blind, randomised, placebo-controlled, dose ascending study of intra-articular rhFGF18 (sprifermin) in patients with advanced knee osteoarthritis.

OBJECTIVES: To evaluate the safety of intra-articular sprifermin (primary), and to evaluate systemic exposure, biomarkers, histology, and other cartilage parameters in patients with advanced osteoarthritis (OA). METHODS: This was a first-in-human, double-blind, randomised, placebo-controlled trial of single and multiple ascending doses of sprifermin from 3-300 µg in knee OA patients scheduled for total knee replacement. Patients were randomised 3:1 to sprifermin or placebo, injected into the target knee once or once weekly for 3 weeks, and followed-up for 24 weeks. RESULTS: Fifty-five patients were treated with sprifermin, 25 with single and 30 with multiple doses, 18 received placebo. There was no clear difference between the active and placebo groups in incidence, severity, and nature of reported treatment emergent adverse events. Acute inflammatory reactions were slightly more common with sprifermin 300 µg, but none led to discontinuation. No clear difference was seen between placebo and sprifermin in physician-assessed local tolerability, pain, or swelling in the knee. No meaningful changes over time, or differences between treatment groups, were observed for safety laboratory parameters or ECG. Although individual abnormalities were observed, no patterns were evident suggesting a relation to treatment or potential safety concern. No systemic sprifermin exposure, anti-FGF18 antibodies, or clear-cut effects on systemic biomarkers were detected. CONCLUSIONS: This first clinical trial of sprifermin revealed no serious safety concerns, although larger studies are needed. The possibility of positive effects of intra-articular sprifermin on histological and other cartilage parameters in knee OA also warrant further investigation.

A combination of clinical balance measures and FRAX® to improve identification of high-risk fallers.

BACKGROUND: The FRAX® algorithm quantifies a patient's 10-year probability of a hip or major osteoporotic fracture without taking an individual's balance into account. Balance measures assess the functional ability of an individual and the FRAX® algorithm is a model that integrates the individual patients clinical risk factors [not balance] and bone mineral density. Thus, clinical balance measures capture aspects that the FRAX® algorithm does not, and vice versa. It is therefore possible that combining FRAX® and clinical balance measures can improve the identification of patients at high fall risk and thereby high fracture risk. Our study aim was to explore whether there is an association between clinical balance measures and fracture prediction obtained from FRAX®. METHOD: A cross-sectional study design was used where post hoc was performed on a dataset of 82 participants (54 to 89 years of age, mean age 71.4, 77 female), with a fall-related wrist-fracture between 2008 and 2012. Balance was measured by tandem stance, standing one leg, walking in the figure of eight, walking heel to toe on a line, walking as fast as possible for 30 m and five times sit to stand balance measures [tandem stance and standing one leg measured first with open and then with closed eyes] and each one analyzed for bivariate relations with the 10-year probability values for hip and major osteoporotic fractures as calculated by FRAX® using Spearman's rank correlation test. RESULTS: Individuals with high FRAX® values had poor outcome in balance measures; however the significance level of the correlation differed between tests. Standing one leg eyes closed had strongest correlation to FRAX® (0.610 p = < 0.01) and Five times sit to stand was the only test that did not correlate with FRAX® (0.013). CONCLUSION: This study showed that there is an association between clinical balance measures and FRAX®. Hence, the use of clinical balance measures and FRAX® in combination, might improve the identification of individuals with high risk of falls and thereby following fractures. Results enable healthcare providers to optimize treatment and prevention of fall-related fractures. TRIAL REGISTRATION: The study has been registered in Clinical Trials.gov, registration number NCT00988572 .

Delayed gadolinium-enhanced MRI of meniscus (dGEMRIM) and cartilage (dGEMRIC) in healthy knees and in knees with different stages of meniscus pathology.

BACKGROUND: Lesions in the meniscus are risk factors for developing knee osteoarthritis (OA), not least because of the role of the meniscus in the pathological progression of OA. Delayed gadolinium enhanced MRI of cartilage (dGEMRIC) has extensively been used to identify pre-radiographic cartilage changes in OA. In contrast, its counterpart with regard to examination of the meniscus, gadolinium enhanced MRI of meniscus (dGEMRIM), has been less utilized. In this study we use 3D dGEMRIM in patients with meniscus lesions and compare them with previous results of healthy individuals. METHODS: Eighteen subjects with MRI-verified posteromedial meniscus lesions and 12 healthy subjects with non-injured and non-symptomatic knee joints, together 30 volunteers, were examined using 3D Look-Locker sequence after intravenous injection of Gd-DTPA2- (0.2 mmol/kg body weight). Relaxation time (T1) was measured in the posterior meniscus and femoral cartilage before and 60, 90, 120 and 180 min after injection. Relaxation rate (R1 = 1/T1) and change in relaxation rate (ΔR1) were calculated. For statistical analyses, Student's t-test and Analysis of Variance (ANOVA) were used. RESULTS: The pre-contrast diagnostic MRI identified two sub-cohorts in the 18 patients with regard to meniscus injury: 1) 11 subjects with MRI verified pathological intrameniscal changes (grade 2) in the posteromedial meniscus only and no obvious cartilage changes. The lateral meniscus showed no pathology. 2) 7 subjects with MRI verified pathological rupture (grade 3) of the posteromedial meniscus and pathological changes in the lateral meniscus and/or medial and lateral joint cartilage. Comparisons of pathological and healthy posteromedial meniscus revealed opposite patterns in both T1Gd and ΔR1 values between pathological meniscus grade 2 and grade 3. The concentration of the contrast agent was lower than in healthy meniscus in grade 2 lesions (p = 0.046) but tended to increase in grade 3 lesions (p = 0.110). Maximum concentration of contrast agent was reached after 180 min in both cartilage and menisci (except for grade 3 menisci where the maximum concentration was reached after 90 min). CONCLUSION: dGEMRIM and dGEMRIC may be feasible to combine in vivo, preferably with one examination before and one 2 h after contrast injection. Possible different dGEMRIM patterns at different stages of meniscus lesions must be taken into account when evaluating meniscus pathology.

Knee arthroscopies: who gets them, what does the radiologist report, and what does the surgeon find? An evaluation from southern Sweden.

BACKGROUND AND PURPOSE: Several randomized controlled trials have not shown any added benefit of arthroscopy over placebo surgery or physiotherapy in middle-aged patients with knee symptoms without trauma. We studied the characteristics of the knee arthroscopies performed in southern Sweden. PATIENTS AND METHODS: From the orthopedic surgical records from 2007-2009 in the Skåne region of Sweden (with a population of 1.2 million), we retrieved ICD-10 diagnostic codes and selected all 4,096 arthroscopies that were diagnosed peroperatively with code M23.2 (derangement of meniscus due to old tear or injury) or code M17 (knee osteoarthritis). We extracted information on cartilage and meniscus status at arthroscopy, and we also randomly sampled 502 of these patients from the regional archive of radiology and analyzed the preoperative prevalence of radiographic or magnetic resonance imaging (MRI)-defined osteoarthritis. RESULTS: 2,165 (53%) of the 4,096 arthroscopies had the diagnostic code M23.2 or M17. In this subgroup, 1,375 cases (64%) had typical findings consistent with degenerative meniscal tear (i.e. that correspond to a degenerative meniscal tear in at least a third of all arthroscopies). Of the randomly sampled patients, the preoperative prevalence of radiological knee osteoarthritis was 46%. INTERPRETATION: There is a discrepancy between evidence-based medicine treatment guidelines and clinical practice regarding the amount of knee arthroscopies performed in patients with symptoms of degenerative knee disease.

Novel cartilage oligomeric matrix protein (COMP) neoepitopes identified in synovial fluids from patients with joint diseases using affinity chromatography and mass spectrometry.

To identify patients at risk for progressive joint damage, there is a need for early diagnostic tools to detect molecular events leading to cartilage destruction. Isolation and characterization of distinct cartilage oligomeric matrix protein (COMP) fragments derived from cartilage and released into synovial fluid will allow discrimination between different pathological conditions and monitoring of disease progression. Early detection of disease and processes in the tissue as well as an understanding of the pathologic mechanisms will also open the way for novel treatment strategies. Disease-specific COMP fragments were isolated by affinity chromatography of synovial fluids from patients with rheumatoid arthritis, osteoarthritis, or acute trauma. Enriched COMP fragments were separated by SDSPAGE followed by in-gel digestion and mass spectrometric identification and characterization.Using the enzymes trypsin, chymotrypsin, and Asp-N for the digestions, an extensive analysis of the enriched fragments could be accomplished. Twelve different neoepitopes were identified and characterized within the enriched COMP fragments. For one of the neoepitopes, Ser77, an inhibition ELISA was developed. This ELISA quantifies COMP fragments clearly distinguishable from total COMP. Furthermore, fragments containing the neoepitope Ser77 were released into the culture medium of cytokine (TNF-α and IL-6/soluble IL-6 receptor)-stimulated human cartilage explants. The identified neoepitopes provide a complement to the currently available commercial assays for cartilage markers. Through neoepitope assays, tools to pinpoint disease progression, evaluation methods for therapy, and means to elucidate disease mechanisms will be provided.

Vestibular Rehabilitation Affects Vestibular Asymmetry among Patients with Fall-Related Wrist Fractures - A Randomized Controlled Trial.

BACKGROUND: Fall-related fractures are an increasing problem for society. Dizziness is identified as a risk factor for falls and vestibular asymmetry is often found among patients with fall-related fractures. An option to prevent fall-related fractures may be to identify patients with vestibular asymmetry and to improve their balance and asymmetry by exercise. OBJECTIVE: To examine whether vestibular rehabilitation improves vestibular function, balance and self-rated health among patients with fall-related wrist fractures. METHODS: Sixty-eight persons (65 women) with fall-related wrist fractures, mean age 72 years (54-89) participated in this randomized controlled trial. The following tests and measurements were performed: head shake test to evaluate vestibular asymmetry as primary outcome measure, five clinical balance measures, a force plate to measure postural sway, a tuning fork to measure vibration and the EQ5D questionnaire to measure self-rated health. The intervention comprised group-based vestibular rehabilitation sessions conducted twice a week for 9 weeks. RESULTS: Nystagmus occurred in the head shake test in 65% (44 of 68) of the patients, indicating vestibular asymmetry. More patients in the intervention group (6 of 21) than in the control group (0 of 23) changed from having nystagmus in the head shake test at baseline (indicating vestibular asymmetry) to not having nystagmus at follow-up, and more patients in the control group (3 of 9) than in the intervention group (0 of 3) changed from not having nystagmus at baseline to have nystagmus at follow-up (p < 0.00). No other changes occurred between the two groups between baseline and follow-up. At baseline, patients with vestibular asymmetry had more balance deficits and increased postural sway compared to patients without (p = 0.00-0.05). CONCLUSION: Group sessions with vestibular rehabilitation twice a week for 9 weeks affected the occurrence of vestibular asymmetry positively among patients having vestibular asymmetry. Patients with vestibular asymmetry had more balance deficits and increased postural sway than patients without vestibular asymmetry. Vestibular assessment is important, and, in patients with diagnosed vestibular asymmetry, vestibular rehabilitation may prove beneficial on balance and possibly reduce the risk of future falls.