Abatacept and non-melanoma skin cancer in patients with rheumatoid arthritis: a comprehensive evaluation of randomised controlled trials and observational studies.

OBJECTIVES: This study aims to evaluate non-melanoma skin cancer (NMSC) risk associated with abatacept treatment for rheumatoid arthritis (RA). METHODS: This evaluation included 16 abatacept RA clinical trials and 6 observational studies. NMSC incidence rates (IRs)/1000 patient-years (p-y) of exposure were compared between patients treated with abatacept versus placebo, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and other biological/targeted synthetic (b/ts)DMARDs. For observational studies, a random-effects model was used to pool rate ratios (RRs). RESULTS: ~49 000 patients receiving abatacept were analysed from clinical trials (~7000) and observational studies (~42 000). In randomised trials (n=4138; median abatacept exposure, 12 (range 2-30) months), NMSC IRs (95% CIs) were not significantly different for abatacept (6.0 (3.3 to 10.0)) and placebo (4.0 (1.3 to 9.3)) and remained stable throughout the long-term, open-label period (median cumulative exposure, 28 (range 2-130 months); 21 335 p-y of exposure (7044 patients over 3 years)). For registry databases, NMSC IRs/1000 p-y were 5-12 (abatacept), 1.6-10 (csDMARDs) and 3-8 (other b/tsDMARDs). Claims database IRs were 19-22 (abatacept), 15-18 (csDMARDs) and 14-17 (other b/tsDMARDs). Pooled RRs (95% CIs) from observational studies for NMSC in patients receiving abatacept were 1.84 (1.00 to 3.37) vs csDMARDs and 1.11 (0.98 to 1.26) vs other b/tsDMARDs. CONCLUSIONS: Consistent with the warnings and precautions of the abatacept label, this analysis suggests a potential increase in NMSC risk with abatacept use compared with csDMARDs. No significant increase was observed compared with b/tsDMARDs, but the lower limit of the 95% CI was close to unity.

Comparison of evaluation metrics of deep learning for imbalanced imaging data in osteoarthritis studies.

PURPOSE: To compare the evaluation metrics for deep learning methods that were developed using imbalanced imaging data in osteoarthritis studies. MATERIALS AND METHODS: This retrospective study utilized 2996 sagittal intermediate-weighted fat-suppressed knee MRIs with MRI Osteoarthritis Knee Score readings from 2467 participants in the Osteoarthritis Initiative study. We obtained probabilities of the presence of bone marrow lesions (BMLs) from MRIs in the testing dataset at the sub-region (15 sub-regions), compartment, and whole-knee levels based on the trained deep learning models. We compared different evaluation metrics (e.g., receiver operating characteristic (ROC) and precision-recall (PR) curves) in the testing dataset with various class ratios (presence of BMLs vs. absence of BMLs) at these three data levels to assess the model's performance. RESULTS: In a subregion with an extremely high imbalance ratio, the model achieved a ROC-AUC of 0.84, a PR-AUC of 0.10, a sensitivity of 0, and a specificity of 1. CONCLUSION: The commonly used ROC curve is not sufficiently informative, especially in the case of imbalanced data. We provide the following practical suggestions based on our data analysis: 1) ROC-AUC is recommended for balanced data, 2) PR-AUC should be used for moderately imbalanced data (i.e., when the proportion of the minor class is above 5% and less than 50%), and 3) for severely imbalanced data (i.e., when the proportion of the minor class is below 5%), it is not practical to apply a deep learning model, even with the application of techniques addressing imbalanced data issues.

Characterization of adverse joint outcomes in patients with osteoarthritis treated with subcutaneous tanezumab.

OBJECTIVE: Due to the risk of rapidly progressive osteoarthritis (RPOA), the phase III studies of subcutaneous (SC) tanezumab in patients with moderate to severe hip or knee osteoarthritis (OA) included comprehensive joint safety surveillance. This pooled analysis summarizes these findings. METHOD: Joint safety events in the phase III studies of SC tanezumab (2 placebo- and 1- nonsteroidal anti-inflammatory drug [NSAID]-controlled) were adjudicated by a blinded external committee. Outcomes of RPOA1 and RPOA2, primary osteonecrosis, subchondral insufficiency fracture, and pathological fracture comprised the composite joint safety endpoint (CJSE). Potential patient- and joint-level risk factors for CJSE, RPOA, and total joint replacement (TJR) were explored. RESULTS: Overall, 145/4541 patients (3.2%) had an adjudicated CJSE (0% placebo; 3.2% tanezumab 2.5 mg; 6.2% tanezumab 5 mg; 1.5% NSAID). There was a dose-dependent risk of adjudicated CJSE, RPOA1, and TJR with tanezumab vs NSAID. Patient-level cross-tabulation found associations between adjudicated RPOA with more severe radiographic/symptomatic (joint pain, swelling, and physical limitation) OA. Risk of adjudicated RPOA1 was highest in patients with Kellgren-Lawrence (KL) grade 2 or 3 OA at baseline. Risk of adjudicated RPOA2 or TJR was highest in patients with KL grade 4 joints at baseline. A higher proportion of joints with adjudicated RPOA2 had a TJR (14/26) than those with adjudicated RPOA1 (16/106). CONCLUSION: In placebo- and NSAID controlled studies of SC tanezumab for OA, adjudicated CJSE, RPOA, and TJR most commonly occurred in patients treated with tanezumab and with more severe radiographic or symptomatic OA. NCT02697773; NCT02709486; NCT02528188.

Effect of Multicomponent Home-Based Training on Gait and Muscle Strength in Older Adults After Hip Fracture Surgery: A Single Site Randomized Trial.

OBJECTIVE: To investigate the effect of 16-week home-based physical therapy interventions on gait and muscle strength. DESIGN: A single-blinded randomized controlled trial. SETTING: General community. PARTICIPANTS: Thirty-four older adults (N=34) post hip fracture were randomly assigned to either experimental group (a specific multi-component intervention group [PUSH], n=17, 10 women, age=78.6±7.3 years, 112.1±39.8 days post-fracture) or active control (a non-specific multi-component intervention group [PULSE], n=17, 11 women, age=77.8±7.8 years, 118.2±37.5 days post-fracture). INTERVENTION: PUSH and PULSE groups received 32-40 sessions of specific or non-specific multi-component home-based physical therapy, respectively. Training in the PUSH group focused on lower extremity strength, endurance, balance, and function for community ambulation, while the PULSE group received active movement and transcutaneous electrical nerve stimulation on extremities. MAIN OUTCOME MEASURES: Gait characteristics, and ankle and knee muscle strength were measured at baseline and 16 weeks. Cognitive testing of Trail Making Test (Part A: TMT-A; Part-B: TMT-B) was measured at baseline. RESULTS: At 16 weeks, both groups demonstrated significant increases in usual (P<.05) and fast (P<.05) walking speed, while there was no significant difference in increases between the groups. There was only 1 significant change in lower limb muscle strength over time (non-fractured side) between the groups, such that PUSH did better (mean: 4.33%, 95% confidence interval:1.43%-7.23%). The increase in usual and fast walking speed correlated with the baseline Trail-making Test-B score (r=-0.371, P=.037) and improved muscle strength in the fractured limb (r=0.446, P=.001), respectively. CONCLUSION: Gait speed improved in both home-based multicomponent physical therapy programs in older adults after hip fracture surgery. Muscle strength of the non-fractured limb improved in the group receiving specific physical therapy training. Specific interventions targeting modifiable factors such as muscle strength and cognitive performance may assist gait recovery after hip fracture surgery.

Did COVID-19 impact osteoarthritis - clinical perspective?

PURPOSE OF REVIEW: To assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on patients with osteoarthritis (OA). RECENT FINDINGS: The COVID-19 pandemic negatively affected patients with OA irrespective of them contracting the infection. Patients with OA had a disruption in access to the healthcare system, which resulted in delays in joint replacement surgeries from cancellations of elective surgical procedures. On the other hand, the pandemic accelerated the drive towards telemedicine and telerehabilitation, with many nonurgent services being delivered remotely whenever possible. Cross-sectional studies showed that the majority of patients with OA were willing to accept the increased risks of contracting the COVID-19 infection and proceed with elective joint replacement surgeries. SUMMARY: The American College of Rheumatology and the European League Against Rheumatism issued guidelines for managing immune-mediated rheumatic diseases during the pandemic. However, these guidelines did not include recommendations for patients with OA.Healthcare providers, including physical therapists, should aim to schedule more frequent telemedicine follow-up appointments to maximize medical management while patients await elective joint procedures.

Management of hand osteoarthritis: from an US evidence-based medicine guideline to a European patient-centric approach.

Hand osteoarthritis is the most common joint condition and is associated with significant morbidity. It is of paramount importance that patients are thoroughly assessed and examined when complaining of hand stiffness, pain, deformity or disability and that the patient's concerns and expectations are addressed by the healthcare professional. In 2019 the American College of Rheumatology and Arthritis Foundation (ACR/AF) produced guidelines which included recommendations for the treatment of hand osteoarthritis. An ESCEO expert working group (including patients) was convened and composed this paper with the aim to assess whether these guidelines were appropriate for the treatment of hand osteoarthritis therapy in Europe and whether they met with the ESCEO patient-centered approach. Indeed, patients are the key stakeholders in healthcare and eliciting the patient's preference is vital in the context of an individual consultation but also for informing research and policy-making. The patients involved in this working group emphasised the often-neglected area of aesthetic changes in hand osteoarthritis, importance of developing pharmacological therapies which can alleviate pain and disability and the need of the freedom to choose which approach (out of pharmacological, surgical or non-pharmacological) they wished to pursue. Following robust appraisal, it was recommended that the ACR/AF guidelines were suitable for a European context (as described within the body of the manuscript) and it was emphasised that patient preferences are key to the success of individual consultations, future research and future policy-making.

Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study.

OBJECTIVE: The FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results. METHODS: Patients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40-90, a subgroup at risk (SAR) of progression. RESULTS: 378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, p<0.001) and a 0.05 mm mean difference with sprifermin 100 µg q6mo versus placebo (95% CI 0.00 to 0.10; p=0.015) were sustained to year 5. WOMAC pain scores improved ~50% from baseline in all groups. No patient in the 100 µg q6mo group had replacement of the treated knee. 96%-98% of patients receiving sprifermin and 98% placebo reported adverse events, most were mild or moderate and deemed unrelated to treatment. Adverse event-related study withdrawals were <10%. Differentiation in WOMAC pain between sprifermin 100 µg q6mo and placebo in the SAR (n=161) at year 3 was maintained to year 5 (-10.08; 95% CI -25.68 to 5.53). CONCLUSION: In the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR. TRIAL REGISTRATION NUMBER: NCT01919164.

Depressive symptom heterogeneity among older adults after hip fracture.

OBJECTIVE: to evaluate patterns of depressive symptoms after hip fracture and examine their impact on functional recovery. METHODS: participants (n = 304) included older adults from the Baltimore Hip Studies 7th cohort who experienced a hip fracture. Depressive symptoms were measured at baseline or 2-, 6- or 12-month post-hip fracture using the 20-item Center for Epidemiologic Studies Depression scale. Gait speed was measured after hip fracture at 2-, 6- or 12-month follow-up. Latent class analysis was used to identify individuals with similar patterns of depressive symptoms after hip fracture. Item response probabilities characterised symptom profiles, and posterior probability estimates were used to assign participants to a baseline depressive symptom subtype. Weighted estimated equations compared post-fracture gait speed between baseline symptomatic and asymptomatic groups. RESULTS: four patterns of depressive symptoms were identified: asymptomatic (50.8%), somatic (28.6%), melancholic (11.4%) and anhedonic (9.2%). The somatic subtype was characterised by difficultly concentrating and reduced energy and movement, whereas anhedonic symptoms were associated with the inability to experience pleasure. Melancholic symptoms corresponded to anhedonia, decreased physical activity and other psychological and somatic complaints. Compared with the asymptomatic group, somatic symptoms were consistently associated with slower gait speed, -0.03 metres per second (m/s) and between-group differences for melancholic symptomology were as large as -0.05 m/s, but the associations were not statistically significant. CONCLUSION: findings demonstrate unique depressive symptom subtypes in older adults after hip fracture and provide confirmatory evidence of unique clinical phenotypes; however, their impact on functional recovery after hip fracture remains unclear.

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of location in the femorotibial joint: post-hoc analysis of a randomised, placebo-controlled phase II clinical trial.

OBJECTIVES: In the phase II FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses (FORWARD) study, sprifermin demonstrated cartilage modification in the total femorotibial joint and in both femorotibial compartments by MRI in patients with knee osteoarthritis. Here, we evaluate whether sprifermin reduces cartilage loss and increases cartilage thickness, independent of location. METHODS: Patients were randomised 1:1:1:1:1 to three once-weekly intra-articular injections of 30 µg sprifermin every 6 months (q6mo); 30 µg sprifermin every 12 months (q12mo); 100 µg sprifermin q6mo; 100 µg sprifermin q12mo; or placebo. Post-hoc analysis using thinning/thickening scores and ordered values evaluated femorotibial cartilage thickness change from baseline to 24 months independent of location. Changes were indirectly compared with those of Osteoarthritis Initiative healthy subjects. RESULTS: Thinning scores were significantly lower for sprifermin 100 µg q6mo versus placebo (mean (95% CI) difference: 334 µm (114 to 554)), with a cartilage thinning score similar to healthy subjects. Thickening scores were significantly greater for sprifermin 100 µg q6mo, 100 µg q12mo and 30 µg q6mo versus placebo (mean (95% CI) difference: 425 µm (267 to 584); 450 µm (305 to 594) and 139 µm (19 to 259), respectively) and more than doubled versus healthy subjects. CONCLUSIONS: Sprifermin increases cartilage thickness, and substantially reduces cartilage loss, expanding FORWARD primary results. TRIAL REGISTRATION NUMBER: NCT01919164.

Interleukin 1 receptor antagonist (IL1RN) gene variants predict radiographic severity of knee osteoarthritis and risk of incident disease.

OBJECTIVE: In these studies, we examined the association of single nucleotide polymorphisms (SNPs) of the IL1RN gene with radiographic severity of symptomatic knee osteoarthritis (SKOA) and the risk of incident OA. We also explored these genetic polymorphisms in patients with new onset rheumatoid arthritis (RA). METHODS: Over 1000 subjects who met American College of Rheumatology criteria for tibiofemoral OA were selected from three independent, National Institute of Health (NIH)-funded cohorts. CTA and TTG haplotypes formed from three SNPs of the IL1RN gene (rs419598, rs315952, rs9005) were assessed for association with radiographic severity, and risk for incident radiographic OA (rOA) in a nested case-control cohort. These IL1RN haplotypes were also assessed for association with disease activity (DAS28) and plasma inflammatory markers in patients with RA. RESULTS: Carriage of the IL1RN TTG haplotype was associated with increased odds of more severe rOA compared with age-matched, sex-matched and body mass index-matched individuals. Examination of the osteoarthritis initiative Incidence Subcohort demonstrated that carriage of the TTG haplotype was associated with 4.1-fold (p=0.001) increased odds of incident rOA. Plasma IL-1Ra levels were lower in TTG carriers, while chondrocytes from TTG carriers exhibited decreased secretion of IL-1Ra. In patients with RA, the TTG haplotype was associated with increased DAS28, decreased plasma IL-1Ra and elevations of plasma inflammatory markers (hsCRP, interleukin 6 (IL-6)). CONCLUSION: Carriage of the IL1RN TTG haplotype is associated with more severe rOA, increased risk for incident OA, and increased evidence of inflammation in RA. These data suggest that the IL1RN TTG risk haplotype, associated with decreased IL-1Ra plasma levels, impairs endogenous 'anti-inflammatory' mechanisms.

Association between disease progression and depression onset in persons with radiographic knee osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) disease progression may lead to deteriorating psychosocial function, but it is unclear what aspects of disease severity are related to the onset of depression. This study assessed which components of OA disease progression cumulatively contribute to depression onset in persons with radiographic knee OA. METHODS: Osteoarthritis Initiative participants (n = 1651) with radiographic disease (Kellgren-Lawrence grade ≥2) in one or both knees and below the screening threshold for probable depression [Center for Epidemiological Studies Depression (CES-D) scale <16] at baseline were included. Disease severity was measured from baseline to the third annual follow-up visit using joint space width, 20-meter gait speed, and the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale, each categorized into quintiles. Depression onset (CES-D ≥ 16) was assessed annually at four follow-up visits. Marginal structural models that account for time-dependent confounding and attrition evaluated the association between each time-varying disease severity measure and depression onset. RESULTS: Each disease severity measure exhibited a non-linear relationship concerning the probability of depression onset, with the higher quintiles generally being associated with a larger risk. The highest quintile (relative to the lowest) of joint space width and gait speed were both significantly associated with depression onset. By contrast, none of the higher pain quintiles compared with the lowest were significantly associated with the onset of depression. CONCLUSION: Faster disease progression as measured by either worsening structural severity or decreasing physical performance corresponds to an increased risk of depression among individuals with radiographic knee OA.

Development and validation of risk stratification trees for incident slow gait speed in persons at high risk for knee osteoarthritis.

OBJECTIVES: Disability prevention strategies are more achievable before osteoarthritis disease drives impairment. It is critical to identify high-risk groups, for strategy implementation and trial eligibility. An established measure, gait speed is associated with disability and mortality. We sought to develop and validate risk stratification trees for incident slow gait in persons at high risk for knee osteoarthritis, feasible in community and clinical settings. METHODS: Osteoarthritis Initiative (derivation cohort) and Multicenter Osteoarthritis Study (validation cohort) participants at high risk for knee osteoarthritis were included. Outcome was incident slow gait over up to 10-year follow-up. Derivation cohort classification and regression tree analysis identified predictors from easily assessed variables and developed risk stratification models, then applied to the validation cohort. Logistic regression compared risk group predictive values; area under the receiver operating characteristic curves (AUCs) summarised discrimination ability. RESULTS: 1870 (derivation) and 1279 (validation) persons were included. The most parsimonious tree identified three risk groups, from stratification based on age and WOMAC Function. A 7-risk-group tree also included education, strenuous sport/recreational activity, obesity and depressive symptoms; outcome occurred in 11%, varying 0%-29 % (derivation) and 2%-23 % (validation) depending on risk group. AUCs were comparable in the two cohorts (7-risk-group tree, 0.75, 95% CI 0.72 to 0.78 (derivation); 0.72, 95% CI 0.68 to 0.76 (validation)). CONCLUSIONS: In persons at high risk for knee osteoarthritis, easily acquired data can be used to identify those at high risk of incident functional impairment. Outcome risk varied greatly depending on tree-based risk group membership. These trees can inform individual awareness of risk for impaired function and define eligibility for prevention trials.

Residual Disability, Mortality, and Nursing Home Placement After Hip Fracture Over 2 Decades.

OBJECTIVE: To examine trends in 12-month postfracture residual disability, nursing home placement, and mortality among patients with a hip fracture between 1990 and 2011. DESIGN: Secondary analysis of 12-month outcomes from 3 cohort studies and control arms of 2 randomized controlled trials. SETTING: Original studies were conducted as part of the Baltimore Hip Studies (BHS). PARTICIPANTS: Community-dwelling patients ≥65 years of age hospitalized for surgical repair of a nonpathologic hip fracture (N=988). MAIN OUTCOME MEASURES: Twelve-month residual disability, mortality, and nursing home residency were examined in case-mix adjusted models by sex and study. Residual disability was calculated by subtracting prefracture scores of Lower Extremity Physical Activities of Daily Living from scores at 12 months postfracture. We also examined the proportion of individuals with a 12-month score higher than their prefracture score (residual disability>0). RESULTS: Only small improvements were seen in residual disability between 1990 and 2011. No significant differences were seen for men between BHS2 (enrollment 1990-1991; mean residual disability=3.1 activities; 95% confidence interval [CI], 2.16-4.10) and BHS7 (enrollment 2006-2011; mean=3.1 activities; 95% CI, 2.41-3.82). In women, residual disability significantly improved from BHS2 (mean=3.5 activities; 95% CI, 2.95-3.99) to BHS3 (enrollment 1992-1995; mean=2.7 activities; 95% CI, 2.01-3.30) with no significant improvements in later studies. After adjustment, a substantial proportion (91% of men and 79% of women) had a negative outcome (residual disability, died, or nursing home residence at 12 months) in the most recently completed study (BHS7). CONCLUSIONS: Over 2 decades, patients undergoing usual care post-hip fracture still had substantial residual disability. Additional clinical and research efforts are needed to determine how to improve hip fracture treatment, rehabilitation, and subsequent outcomes.

Trunk Muscle Composition 2 Months After Hip Fracture: Findings From the Baltimore Hip Studies.

OBJECTIVE: To determine if hip fracture patients would have smaller cross-sectional area (CSA) and lower radiological attenuation (suggesting greater fat infiltration) in all trunk muscles as compared to older adults without hip fractures. DESIGN: Cross-sectional analysis of computed tomography (CT) scans. SETTING: Clinical imaging facility. PARTICIPANTS: Forty-one white participants (19 men, 22 women) from the Baltimore Hip Studies seventh cohort at 2 months postfracture were compared to 693 white participants (424 men, 269 women) from the Health, Aging and Body Composition (Health ABC) study at the year 6 visit (N=734). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Trunk muscle CSA and attenuation values were obtained from a single 10-mm, axial CT scan completed at the L4-L5 disc space in each participant. RESULTS: The hip fracture cohort had significantly smaller CSA for all trunk muscles (range: 12.1%-38% smaller) compared to the Health ABC cohort (P<.01), with the exception of the rectus abdominus muscle in men (P=.12). But, hip fracture patients, particularly female patients, had higher attenuation levels (lower intramuscular fat) in all trunk muscles (P<.0001). CONCLUSIONS: Findings are consistent with atrophy of the trunk muscles in the hip fracture population without a high level of intramuscular fat. Future work should evaluate the role of trunk muscle composition in the functional recovery of older adults after hip fracture.

Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis: The FORWARD Randomized Clinical Trial.

Importance: Sprifermin is under investigation as a disease-modifying osteoarthritis drug. Objective: To evaluate the effects of sprifermin on changes in total femorotibial joint cartilage thickness in the more symptomatic knee of patients with osteoarthritis. Design, Setting, and Participants: FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) was a 5-year, dose-finding, multicenter randomized clinical trial conducted at 10 sites. Eligible participants were aged 40 to 85 years with symptomatic, radiographic knee osteoarthritis and Kellgren-Lawrence grade 2 or 3. Enrollment began in July 2013 and ended in May 2014; the last participant visit occurred on May 8, 2017. The primary outcome at 2 years and a follow-up analysis at 3 years are reported. Interventions: Participants were randomized to 1 of 5 groups: intra-articular injections of 100 µg of sprifermin administered every 6 months (n = 110) or every 12 months (n = 110), 30 µg of sprifermin every 6 months (n = 111) or every 12 months (n = 110), or placebo every 6 months (n = 108). Each treatment consisted of weekly injections over 3 weeks. Main Outcomes and Measures: The primary end point was change in total femorotibial joint cartilage thickness measured by quantitative magnetic resonance imaging at 2 years. The secondary end points (of 15 total) included 2-year change from baseline in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. The minimal clinically important difference (MCID) is unknown for the primary outcome; for total WOMAC score in patients with hip and knee osteoarthritis, the absolute MCID is 7 U (95% CI, 4 to 10 U) and the percentage MCID is 14% (95% CI, 9% to 18%). Results: Among 549 participants (median age, 65.0 years; 379 female [69.0%]), 474 (86.3%) completed 2-year follow-up. Compared with placebo, the changes from baseline to 2 years in total femorotibial joint cartilage thickness were 0.05 mm (95% CI, 0.03 to 0.07 mm) for 100 µg of sprifermin administered every 6 months; 0.04 mm (95% CI, 0.02 to 0.06 mm) for 100 µg of sprifermin every 12 months; 0.02 mm (95% CI, -0.01 to 0.04 mm) for 30 µg of sprifermin every 6 months; and 0.01 mm (95% CI, -0.01 to 0.03 mm) for 30 µg of sprifermin every 12 months. Compared with placebo, there were no statistically significant differences in mean absolute change from baseline in total WOMAC scores for 100 µg of sprifermin administered every 6 months or every 12 months, or for 30 µg of sprifermin every 6 months or every 12 months. The most frequently reported treatment-emergent adverse event was arthralgia (placebo: n = 46 [43.0%]; 100 µg of sprifermin administered every 6 months: n = 45 [41.3%]; 100 µg of sprifermin every 12 months: n = 50 [45.0%]; 30 µg of sprifermin every 6 months: n = 40 [36.0%]; and 30 µg of sprifermin every 12 months: n = 48 [44.0%]). Conclusions and Relevance: Among participants with symptomatic radiographic knee osteoarthritis, the intra-articular administration of 100 µg of sprifermin every 6 or 12 months vs placebo resulted in an improvement in total femorotibial joint cartilage thickness after 2 years that was statistically significant, but of uncertain clinical importance; there was no significant difference for 30 µg of sprifermin every 6 or 12 months vs placebo. Durability of response also was uncertain. Trial Registration: ClinicalTrials.gov Identifier: NCT01919164.

Persistence of depressive symptoms and gait speed recovery in older adults after hip fracture.

OBJECTIVE: Depression after hip fracture in older adults is associated with worse physical performance; however, depressive symptoms are dynamic, fluctuating during the recovery period. The study aim was to determine how the persistence of depressive symptoms over time cumulatively affects the recovery of physical performance. METHODS: Marginal structural models estimated the cumulative effect of persistence of depressive symptoms on gait speed during hip fracture recovery among older adults (n = 284) enrolled in the Baltimore Hip Studies 7th cohort. Depressive symptoms at baseline and at 2-month and 6-month postadmission for hip fracture were evaluated by using the Center for Epidemiological Studies Depression Scale, and persistence of symptoms was assessed as a time-averaged severity lagged to standardized 3 m gait speed at 2, 6, and 12 months. RESULTS: A 1-unit increase in time-averaged Center for Epidemiological Studies Depression score was associated with a mean difference in gait speed of -0.0076 standard deviations (95% confidence interval [CI]: -0.0184, 0.0032; P = .166). The association was largest in magnitude from baseline to 6 months: -0.0144 standard deviations (95% CI: -0.0303, 0.0015; P = 0.076). Associations for the other time intervals were smaller: -0.0028 standard deviations (95% CI: -0.0138, 0.0083; P = .621) at 2 months and -0.0121 standard deviations (95% CI: -0.0324, 0.0082; P = .238) at 12 months. CONCLUSION: Although not statistically significant, the magnitude of the numerical estimates suggests that expressing more depressive symptoms during the first 6 months after hip fracture has a meaningful impact on functional recovery.

Identification of pain categories associated with change in pain in patients receiving placebo: data from two phase 3 randomized clinical trials in symptomatic knee osteoarthritis.

BACKGROUND: Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinical characteristics and pain categories particularly associated with this phenomenon is needed. The purpose of this post-hoc analysis was to investigate clinical characteristics and pain categories and their association with radiographic progression and placebo pain reduction (PPR) in OA patients as measured the Western Ontario and McMasters Arthritis (WOMAC). METHODS: Pooled data from the placebo groups of two phase III randomized clinical trials in patients with knee OA followed for 2 years were analyzed. Differences between individual sub-scores and pain categories of weight-bearing and non-weight bearing pain over time were assessed. Selected patient baseline characteristics were assessed for association with PPR. Association between pain categories and radiographic progression was analyzed. RESULTS: The reduction of pain in placebo-treated patients was significantly higher in the composite of questions related to weight-bearing pain compared to non-weight-bearing pain of the target knee. Baseline BMI, age and JSW were not associated with pain change. Pain reduction was higher in the Target knee, compared to the Non-Target knee at all corresponding time-points. A very weak correlation was found between weight-bearing pain and progression in the non-target knee. CONCLUSIONS: These results indicate that the reduction in pain in patients treated with placebo is significantly different between pain categories, as weight-bearing pain was significantly more reduced compared to non-weight-bearing pain. Further research in pain categories in OA is warranted. TRIAL REGISTRATION: NCT00486434 (trial 1) and NCT00704847 (trial 2).

Clinical significance of worsening versus stable preradiographic MRI lesions in a cohort study of persons at higher risk for knee osteoarthritis.

BACKGROUND: Whether preradiographic lesions in knees at risk for osteoarthritis are incidental versus disease is unclear. We hypothesised, in persons without but at higher risk for knee osteoarthritis, that: 12-48 month MRI lesion status worsening is associated with 12-48 month incident radiographic osteoarthritis (objective component of clinical definition of knee osteoarthritis) and 48-84 month persistent symptoms. METHODS: In 849 Osteoarthritis Initiative participants Kellgren/Lawrence (KL) 0 in both knees, we assessed cartilage damage, bone marrow lesions (BMLs), and menisci on 12 month (baseline) and 48 month MRIs. Multivariable logistic regression was used to evaluate associations between 12-48 month worsening versus stable status and outcome (12-48 month incident KL ≥1 and KL ≥2, and 48-84 month persistent symptoms defined as frequent symptoms or medication use most days of ≥1 month in past 12 month, at consecutive visits 48-84 months), adjusting for age, gender, body mass index (BMI), injury and surgery. RESULTS: Mean age was 59.6 (8.8), BMI 26.7 (4.2) and 55.9% were women. 12-48 month status worsening of cartilage damage, meniscal tear, meniscal extrusion, and BMLs was associated with 12-48 month incident radiographic outcomes, and worsening of cartilage damage and BMLs with 48-84 month persistent symptoms. There was a dose-response association for magnitude of worsening of cartilage damage, meniscal tear, meniscal extrusion, and BMLs and radiographic outcomes, and cartilage damage and BMLs and persistent symptoms. CONCLUSIONS: In persons at higher risk, worsening MRI lesion status was associated with concurrent incident radiographic osteoarthritis and subsequent persistent symptoms. These findings suggest that such lesions represent early osteoarthritis, and add support for a paradigm shift towards investigation of intervention effectiveness at this stage.

Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib.

OBJECTIVES: To compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH) versus celecoxib in patients with knee osteoarthritis and severe pain. METHODS: Double-blind Multicentre Osteoarthritis interVEntion trial with SYSADOA (MOVES) conducted in France, Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with Kellgren and Lawrence grades 2-3 knee osteoarthritis and moderate-to-severe pain (Western Ontario and McMaster osteoarthritis index (WOMAC) score ≥301; 0-500 scale). Patients were randomised to receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D. RESULTS: The adjusted mean change (95% CI) in WOMAC pain was -185.7 (-200.3 to -171.1) (50.1% decrease) with CS+GH and -186.8 (-201.7 to -171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin of -40: -1.11 (-22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6 months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a similar reduction was seen for effusion. No differences were observed for the other secondary outcomes. Adverse events were low and similarly distributed between groups. CONCLUSIONS: CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile. TRIAL REGISTRATION NUMBER: NCT01425853.