Exploring the Early Molecular Pathogenesis of Osteoarthritis Using Differential Network Analysis of Human Synovial Fluid.

The molecular mechanisms that drive the onset and development of osteoarthritis (OA) remain largely unknown. In this exploratory study, we used a proteomic platform (SOMAscan assay) to measure the relative abundance of more than 6000 proteins in synovial fluid (SF) from knees of human donors with healthy or mildly degenerated tissues, and knees with late-stage OA from patients undergoing knee replacement surgery. Using a linear mixed effects model, we estimated the differential abundance of 6251 proteins between the three groups. We found 583 proteins upregulated in the late-stage OA, including MMP1, collagenase 3 and interleukin-6. Further, we selected 760 proteins (800 aptamers) based on absolute fold changes between the healthy and mild degeneration groups. To those, we applied Gaussian Graphical Models (GGMs) to analyze the conditional dependence of proteins and to identify key proteins and subnetworks involved in early OA pathogenesis. After regularization and stability selection, we identified 102 proteins involved in GGM networks. Notably, network complexity was lost in the protein graph for mild degeneration when compared to controls, suggesting a disruption in the regular protein interplay. Furthermore, among our main findings were several downregulated (in mild degeneration versus healthy) proteins with unique interactions in the healthy group, one of which, SLCO5A1, has not previously been associated with OA. Our results suggest that this protein is important for healthy joint function. Further, our data suggests that SF proteomics, combined with GGMs, can reveal novel insights into the molecular pathogenesis and identification of biomarker candidates for early-stage OA.

A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects.

Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that heterozygous Drosophila with the AOS-like Su(H) allele behave in an opposing manner to heterozygous flies with a Su(H) null allele, due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants have decreased DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian co-repressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby the AOS-associated RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation.

Exercise for knee osteoarthritis pain: Association or causation?

Exercise is universally recommended as a primary strategy for the management of knee osteoarthritis (OA) pain. The recommendations are based on results from more than 100 randomized controlled trials (RCTs) that compare exercise to no-attention control groups. However, due to the inherent difficulties with adequate placebo control, participant blinding and the use of patient-reported outcomes, the existing RCT evidence is imperfect. To better understand the evidence used to support a causal relationship between exercise and knee OA pain relief, we examined the existing evidence through the Bradford Hill considerations for causation. The Bradford Hill considerations, first proposed in 1965 by Sir Austin Bradford Hill, provide a framework for assessment of possible causal relationships. There are 9 considerations by which the evidence is reviewed: Strength of association, Consistency, Specificity, Temporality, Biological Gradient (Dose-Response), Plausibility, Coherence, Experiment, and Analogy. Viewing the evidence from these 9 viewpoints did neither bring forward indisputable evidence for nor against the causal relationship between exercise and improved knee OA pain. Rather, we conclude that the current evidence is not sufficient to support claims about (lack of) causality. With our review, we hope to advance the continued global conversation about how to improve the evidence-based management of patients with knee OA.

Frequent Use of Prescription NSAIDs among People with Knee or Hip Osteoarthritis Despite Contraindications to or Precautions with NSAIDs.

OBJECTIVE: To describe use of Non-steroidal Anti-inflammatory Drugs (NSAID), opioid, and physiotherapy (PT) among persons with newly diagnosed knee or hip osteoarthritis (OA) with and without NSAID contraindications or precautions. DESIGN: We used population-based register data to identify adults aged ≥35 as of January 1, 2014 residing in Skåne region (Sweden) between 2004-2013, without a previous knee or hip OA diagnosis. Among this cohort, we identified people with incident knee or hip OA diagnosis between 2014-2018, and presence of contraindications to or precautions for oral NSAIDs at the time of OA diagnosis. We estimated the risk of: 1) regular oral NSAID use; 2) regular opioid use; 3) PT during the first year after diagnosis among those with vs. without contraindications or precautions using confounder-adjusted logistic regression with standardization. RESULTS: We identified 35,173 persons with newly diagnosed OA, of whom 3,257 and 8,351 had ≥1 contraindication to oral NSAIDs and ≥1 precaution, respectively. Overall, 27% of individuals used oral NSAIDs (with or without opioids or PT), 10% used opioids, and 57% attended PT. Among patients with contraindications, 21% used oral NSAIDs compared to 31% without (absolute adjusted difference -0.06 (95% CIs: -0.08, -0.05)), 53% vs 59% used PT (adjusted difference -0.03 (-0.05, -0.01)), while 14% vs 8% had prescribed dispensed opioids (adjusted difference 0.02 (0.01, 0.03)). Similar results were observed for those with precautions. CONCLUSIONS: We highlight the need for safer treatment options. People with OA and contraindications/precautions to NSAIDs have higher risk of opioid use, slightly lower risk of PT use, and continue to be prescribed NSAIDs. AVAILABILITY OF DATA AND MATERIALS: All the data used in the study are available upon request to the appropriate Swedish National authorities.

The coexistence of diabetes, hypertension and obesity is associated with worse pain outcomes following exercise for osteoarthritis: A cohort study on 80,893 patients.

OBJECTIVES: To investigate how the co-occurrence of diabetes, hypertension and overweight/obesity is associated with pain following an exercise intervention for knee and hip osteoarthritis (OA). METHODS: Register-based cohort study. We included people from the Swedish Osteoarthritis Register who underwent education and exercise for knee or hip OA. Diabetes and hypertension were defined using medical records and dispensation of medication. Body Mass Index (BMI) was used to identify people with overweight (≥25 to <30), and obesity (≥30). We used linear mixed-effect models with patients nested into clinics to estimate the associations between the exposures and pain (Numeric Rating Scale 0-10), adjusting for age, sex, education, and physical activity. RESULTS: We analysed 80,893 patients with knee or hip OA. The accumulation of metabolic conditions was associated with worse pain at baseline and follow-ups. When obesity, hypertension and diabetes coexisted, patients treated for knee OA reported more pain at baseline (adjusted mean pain difference 0.9 [95 %CI: 0.8; 1.0]), 3 months (1.0 [0.9; 1.1]) and 12 months (1.3 [1.1; 1.4]) compared to those without any of the conditions. Similar results were observed for patients treated for hip OA when obesity, hypertension and diabetes coexisted (baseline (0.7 [0.5; 0.8], 3 (0.8[0.6; 1.0]) and 12 months (1.1[0.8; 1.3]). CONCLUSIONS: When diabetes, hypertension and obesity coexist with OA, patients not only experience heightened baseline pain compared to metabolically healthy individuals, but the disparity increases after an education and exercise intervention suggesting that a one-size-fits-all approach may be inadequate in addressing the complex interplay between metabolic health and OA.

Proteomics Profiling of Human Synovial Fluid Suggests Increased Protein Interplay in Early-Osteoarthritis (OA) That Is Lost in Late-Stage OA.

The underlying molecular mechanisms in osteoarthritis (OA) development are largely unknown. This study explores the proteome and the pairwise interplay of proteins in synovial fluid from patients with late-stage knee OA (arthroplasty), early knee OA (arthroscopy due to degenerative meniscal tear), and from deceased controls without knee OA. Synovial fluid samples were analyzed using state-of-the-art mass spectrometry with data-independent acquisition. The differential expression of the proteins detected was clustered and evaluated with data mining strategies and a multilevel model. Group-specific slopes of associations were estimated between expressions of each pair of identified proteins to assess the co-expression (i.e., interplay) between the proteins in each group. More proteins were increased in early-OA versus controls than late-stage OA versus controls. For most of these proteins, the fold changes between late-stage OA versus controls and early-stage OA versus controls were remarkably similar suggesting potential involvement in the OA process. Further, for the first time, this study illustrated distinct patterns in protein co-expression suggesting that the interplay between the protein machinery is increased in early-OA and lost in late-stage OA. Further efforts should focus on earlier stages of the disease than previously considered.

Arthroscopic Partial Meniscectomy for a Degenerative Meniscus Tear Is Not Cost Effective Compared With Placebo Surgery: An Economic Evaluation Based on the FIDELITY Trial Data.

BACKGROUND: In patients with a degenerative tear of the medial meniscus, recent meta-analyses and systematic reviews have shown no treatment benefit of arthroscopic partial meniscectomy (APM) over conservative treatment or placebo surgery. Yet, advocates of APM still argue that APM is cost effective. Giving advocates of APM their due, we note that there is evidence from the treatment of other musculoskeletal complaints to suggest that a treatment may prove cost effective even in the absence of improvements in efficacy outcomes, as it may lead to other benefits, such as diminished productivity loss and reduced costs, and so the question of cost effectiveness needs to be answered for APM. QUESTIONS/PURPOSES: (1) Does APM result in lower postoperative costs compared with placebo surgery? (2) Is APM cost-effective compared with placebo surgery? METHODS: One hundred forty-six adults aged 35 to 65 years with knee symptoms consistent with a degenerative medial meniscus tear and no knee osteoarthritis according to the American College of Rheumatology clinical criteria were randomized to APM (n = 70) or placebo surgery (n = 76). In the APM and placebo surgery groups, mean age was 52 ± 7 years and 52 ± 7 years, and 60% (42 of 70) and 62% (47 of 76) of participants were men, respectively. There were no between-group differences in baseline characteristics. In both groups, a standard diagnostic arthroscopy was first performed. Thereafter, in the APM group, the torn meniscus was trimmed to solid meniscus tissue, whereas in the placebo surgery group, APM was carefully mimicked but no resection of meniscal tissue was performed; as such, surgical costs were the same in both arms and were not included in the analyses. All patients received identical postoperative care including a graduated home-based exercise program. At the 2-year follow-up, two patients were lost to follow-up, both in the placebo surgery group. Cost effectiveness over the 2-year trial period was computed as incremental net monetary benefit (INMB) for improvements in quality-adjusted life years (QALY), using both the societal (primary) and healthcare system (secondary) perspectives. To be able to consider APM cost effective, the CEA analysis should yield a positive INMB value. Nonparametric bootstrapping was used to assess uncertainty. Several one-way sensitivity analyses were also performed. RESULTS: APM did not deliver lower postoperative costs, nor did it convincingly improve quality of life scores when compared with placebo surgery. From a societal perspective, APM was associated with € 971 (95% CI -2013 to 4017) higher costs and 0.015 (95% CI -0.011 to 0.041) improved QALYs over 2-year follow-up compared with placebo surgery. Both differences were statistically inconclusive (a wide 95% CI that crossed the line of no difference). Using the conventional willingness to pay (WTP) threshold of € 35,000 per QALY, APM resulted in a negative INMB of € -460 (95% CI -3757 to 2698). In our analysis, APM would result in a positive INMB only when the WTP threshold rises to about € 65,000 per QALY. The wide 95% CIs suggests uncertain cost effectiveness irrespective of chosen WTP threshold. CONCLUSION: The results of this study lend further support to clinical practice guidelines recommending against the use of APM in patients with a degenerative meniscus tear. Given the robustness of existing evidence demonstrating no benefit or cost effectiveness of APM over nonsurgical treatment or placebo surgery, future research is unlikely to alter this conclusion.Level of Evidence Level III, economic analysis.

Identification and quantification of degradome components in human synovial fluid reveals an increased proteolytic activity in knee osteoarthritis patients vs controls.

Synovial fluid (SF) may contain cleavage products of proteolytic activities. Our aim was to characterize the degradome through analysis of proteolytic activity and differential abundance of these components in a peptidomic analysis of SF in knee osteoarthritis (OA) patients versus controls (n = 23). SF samples from end-stage knee osteoarthritis patients undergoing total knee replacement surgery and controls, that is, deceased donors without known knee disease were previously run using liquid chromatography mass spectrometry (LC-MS). This data was used to perform new database searches generating results for non-tryptic and semi-tryptic peptides for studies of degradomics in OA. We used linear mixed models to estimate differences in peptide-level expression between the two groups. Known proteolytic events (from the MEROPS peptidase database) were mapped to the dataset, allowing the identification of potential proteases and which substrates they cleave. We also developed a peptide-centric R tool, proteasy, which facilitates analyses that involve retrieval and mapping of proteolytic events. We identified 429 differentially abundant peptides. We found that the increased abundance of cleaved APOA1 peptides is likely a consequence of enzymatic degradation by metalloproteinases and chymase. We identified metalloproteinase, chymase, and cathepsins as the main proteolytic actors. The analysis indicated increased activity of these proteases irrespective of their abundance.

Does lower educational attainment increase the risk of osteoarthritis surgery? a Swedish twin study.

BACKGROUND: Previous studies have reported an inverse association between educational attainment and different osteoarthritis (OA) outcomes. However, none of the previous studies have accounted for potential confounding by early-life environment and genetics. Thus, we aimed to examine the association between educational attainment and knee and hip OA surgery using twin data. METHODS: From the Swedish Twin Registry (STR), we identified dizygotic (DZ) and monozygotic (MZ) twins. All twins in the STR aged 35 to 64 years were followed from January the 1st 1987 or the date they turned 35 years until OA surgery, relocation outside Sweden, death or the end of 2016 (18,784 DZ and 8,657 MZ complete twin pairs). Associations between educational attainment and knee and hip OA surgery were estimated in models matched on twin pairs, using Weibull within-between (WB) shared frailty model. RESULTS: For knee OA surgery, the analysis matched on MZ twins yielded a within-estimate hazard ratio (HR) per 3 years of education, of 1.06 (95% CI: 0.81, 1.32), suggesting no association between the outcome and the individual´s education. Rather, there seemed to be a so called familial effect of education, with a between-pair estimate of HR = 0.71 (95% CI: 0.41, 1.01). For hip OA surgery, the within- and between-pair estimates for MZ twins were 0.92 (95% CI: 0.69, 1.14) and 1.15 (95% CI: 0.87, 1.42), respectively. CONCLUSIONS: Our results suggest that the inverse associations between education and knee/hip OA surgery observed in cohort studies are potentially confounded by unobserved familial factors like genetics and/or early life exposures.

Evidence of ACL healing on MRI following ACL rupture treated with rehabilitation alone may be associated with better patient-reported outcomes: a secondary analysis from the KANON trial.

OBJECTIVES: Evaluate the natural course of anterior cruciate ligament (ACL) healing on MRI within 5 years of acute ACL rupture and compare 2-year and 5-year outcomes based on healing status and treatment group. METHODS: Secondary analysis of 120 Knee Anterior Cruciate Ligament Nonsurgical vs Surgical Treatment (KANON) trial participants randomised to rehabilitation and optional delayed ACL reconstruction (ACLR) or early ACLR and rehabilitation. ACL continuity on MRI (Anterior Cruciate Ligament OsteoArthritis Score 0-2) was considered evidence of ACL healing. Outcomes included Knee Injury and Osteoarthritis Outcome Score (KOOS), KOOS patient acceptable symptomatic state (PASS) and treatment failure criteria. Linear mixed models were used to estimate adjusted mean differences (95% CIs) in patient-reported sport and recreational function (KOOS-Sport/Rec) and quality of life (KOOS-QOL) at 2 and 5 years, between participants with MRI evidence of ACL healing and those who had (1) no evidence of ACL healing, (2) delayed ACLR or (3) early ACLR. RESULTS: MRI evidence of ACL healing at 2-year follow-up was observed in 16 of 54 (30%, 95% CI 19 to 43%) participants randomised to optional delayed ACLR. Excluding participants who had delayed ACLR, 16 of 30 (53%, 36-70%) participants managed with rehabilitation-alone displayed MRI evidence of ACL healing. Two-year outcomes were better in the healed ACL group (n=16) compared with the non-healed (n=14) (mean difference (95% CI) KOOS-Sport/Rec: 25.1 (8.6-41.5); KOOS-QOL: 27.5 (13.2-41.8)), delayed ACLR (n=24) (KOOS-Sport/Rec: 24.9 (10.2-39.6); KOOS-QOL: 18.1 (5.4-30.8)) and early ACLR (n=62) (KOOS-Sport/Rec: 17.4 (4.1-30.7); KOOS-QOL: 11.4 (0.0-22.9)) groups. Five-year KOOS-QOL was better in the healed versus non-healed group (25.3 (9.4-41.2)). Of participants with MRI evidence of ACL healing, 63-94% met the PASS criteria for each KOOS subscale, compared with 29-61% in the non-healed or reconstructed groups. CONCLUSIONS: MRI appearance of ACL healing after ACL rupture occurred in one in three adults randomised to initial rehabilitation and one in two who did not cross-over to delayed ACLR and was associated with favourable outcomes. The potential for spontaneous healing of the ACL to facilitate better clinical outcomes may be greater than previously considered. TRIAL REGISTRATION NUMBER: ISRCTN84752559.

Knee and hip osteoarthritis and risk of nine cancers in a large real-world matched cohort study.

OBJECTIVES: Joint replacement due to end-stage OA has been linked to incidence of several cancers. We aimed to estimate the association between newly diagnosed knee and hip OA and incidence of nine common cancer types. METHODS: We identified persons with incident knee or hip OA, aged ≥40 years, between 2009 and 2015 in the SIDIAP database in Catalonia, Spain. We matched up to three OA-free controls on age, sex and general practitioner. We followed participants from 1 year after OA diagnosis until migration, death, end of study at 31 December 2017 or incident cancer of: stomach, colorectal, liver, pancreas, lung, skin, breast, prostate and bladder. We used flexible parametric survival models, adjusted for confounders. Estimates were corrected for misclassification using probabilistic bias analysis. RESULTS: We included 117 750 persons with knee OA and matched 309 913 persons without, with mean (s.d.) age of 67.5 (11.1) years and 63% women. The hip cohort consisted of 39 133 persons with hip OA and 116 713 controls. For most of the included cancers, the hazard ratios (HRs) were close to 1. The HR of lung cancer for knee OA exposure was 0.80 (95% CI: 0.71, 0.89) and attenuated to 0.98 (0.76, 1.27) in non-smokers. The hazard of colorectal cancer was lower in persons with both knee and hip OA by 10-20%. CONCLUSIONS: Knee and hip OA are not associated with studied incident cancers, apart from lower risk of colorectal cancer. The often-reported protective association of knee OA with lung cancer is explained by residual confounding.

Epidemiology of biopsy-confirmed giant cell arteritis in southern Sweden-an update on incidence and first prevalence estimate.

OBJECTIVE: To characterize the epidemiology of temporal artery biopsy-positive (TAB+) GCA, including trends in incidence, seasonal variation and prevalence in Skåne, the southernmost region of Sweden. METHODS: All histopathology reports of TABs from 1997 through 2019 were reviewed to identify patients diagnosed with TAB+ GCA. Incidence rates based on the 23-year period and the point-prevalence at 31 December 2014 were determined. An alternative prevalence calculation included only TAB+ GCA patients living in the study area and receiving immunosuppressant therapy on the point-prevalence date. RESULTS: One thousand three hundred and sixty patients were diagnosed with TAB+ GCA (71% female). The average annual incidence 1997-2019 was 13.3 (95% CI: 12.6, 14.0) per 100 000 inhabitants aged ≥50 years and was higher in females (17.8; 95% CI: 16.7, 18.9) than in males (8.2; 95% CI: 7.4, 9.0). The age- and sex-standardized incidence declined from 17.3 in 1997 to 8.7 in 2019, with incidence ratio (IR) of 0.98 per year (95% CI: 0.98, 0.99). A seasonal variation was observed with higher incidence during spring than winter [IR = 1.19 (95% CI: 1.03, 1.39)]. The overall point-prevalence of TAB+ GCA was 127.1/100 000 (95% CI: 117, 137.3) and was 75.5 (95% CI: 67.7, 83.3) when including only patients receiving immunosuppressants. CONCLUSION: Over the past 2 decades, the incidence of biopsy-confirmed GCA has decreased by ∼2% per year. Still, a high prevalence of GCA on current treatment was observed. More cases are diagnosed during spring and summer than in the winter.

What Are the Patient-reported Outcomes of Trapeziectomy and Tendon Suspension at Long-term Follow-up?

BACKGROUND: There are multiple options for the treatment of thumb carpometacarpal joint osteoarthritis (CMC1 OA), with evidence for pain relief and improved function. Although simple trapeziectomy has the lowest complication risk, tendon suspension of the first metacarpal and interposition is still the most commonly used surgical procedure in patients with CMC1 OA. Although there are several reports of good short-term results after trapeziectomy and tendon suspension-interposition arthroplasty, few studies have evaluated long-term outcomes. This study is one of the largest and longest follow-up evaluations of a cohort of patients with CMC1 OA who were treated with trapeziectomy and suspension-interposition arthroplasty, capturing 96% of the original cohort for evaluation. QUESTIONS/PURPOSES: (1) After trapeziectomy and tendon suspension surgery, what are the long-term, patient-reported outcomes and clinical measurements (strength and ROM); and in unilateral procedures, how do these parameters compare with those of the contralateral hand that was not operated on? (2) What is the mean subsidence (unloaded trapezial space), and does pinch strength correlate with the amount of subsidence? METHODS: From 1998 to 2005, 130 patients underwent trapeziectomy and abductor pollicis longus (APL) suspension-interposition arthroplasty for CMC1 OA at one orthopaedic department. During this period, 15 patients were treated with CMC1 arthrodesis and four were treated with implant arthroplasty, for a total of 149 patients. The surgeons used APL suspensionplasty for most patients, based on age and expected postoperative function; they also employed this procedure to avoid hardware or implant failure issues. The 100 living patients were asked to participate in this retrospective study, 96% (96) of whom were enrolled. The mean age at surgery was 58 ± 7 years. The patients completed a two-item thumb pain scale (modified from the SF-36 body pain scale), a hand pain VAS (average level of pain experienced over the week preceding measurement), and the 11-item QuickDASH. Patient-reported outcomes data were obtained from all 96 patients, and 83% (80) of patients underwent bilateral hand radiography and a physical examination at a mean follow-up of 17 ± 2.4 years. We calculated outcome data for each patient, and in 39 patients with unilateral surgery and intact contralateral CMC1 joint, we compared the operated side with the contralateral side. We compared our outcome data with that from the Swedish National Quality Registry for Hand Surgery (HAKIR), noting comparable outcomes for pain and QuickDASH scores. RESULTS: At long-term follow-up after trapeziectomy and APL suspension surgery, the mean thumb pain score was 19 ± 26, hand pain VAS score 23 ± 25, and QuickDASH score 26 ± 21. In the patients with unilateral surgery and intact contralateral CMC1 joint, the thumb pain score for the operated side was lower than the contralateral side, specifically 19 ± 25 compared with 29 ± 30 (mean difference -9.8 [95% CI -19.5 to -0.2]; p = 0.045); hand pain VAS score was 24 ± 23 versus 30 ± 25 (mean difference -6.1 [95% CI -15.2 to 3.1]; p = 0.19), and the QuickDASH score was 27 ± 19. Grip strength showed no differences between the operated and contralateral sides (mean 16.7 ± 7.3 kg versus 16.6 ± 6.9 kg, mean difference 0.1 [95% CI -1.6 to 1.8]; p = 0.90), while pinch was different (4.4 ± 1.4 versus 5.0 ± 1.5 kg, mean difference -0.6 [95% CI -0.9 to -0.3]; p = 0.001). The mean trapezial space was 4.4 ± 2.2 mm, and there was no association between the trapezial space and pinch strength (0.07 kg [95% CI -0.04 to 0.18] per mm of space; p = 0.17). CONCLUSION: The finding of comparable pain and function between operated and unoperated sides at long-term follow-up suggests that trapeziectomy and tendon suspension-interposition arthroplasty provides predictable outcomes, and surgeons can use these data to counsel patients that surgery can potentially return them to comparable use. However, as patients often have asymptomatic radiographic OA on the contralateral side, future studies are needed to examine the impact of asymptomatic disease on function. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes.

Importance: Although tramadol is increasingly used to manage chronic noncancer pain, few safety studies have compared it with other opioids. Objective: To assess the associations of tramadol, compared with codeine, with mortality and other adverse clinical outcomes as used in outpatient settings. Design, Setting, and Participants: Retrospective, population-based, propensity score-matched cohort study using a primary care database with routinely collected medical records and pharmacy dispensations covering more than 80% of the population of Catalonia, Spain (≈6 million people). Patients 18 years or older with 1 or more year of available data and dispensation of tramadol or codeine (2007-2017) were included and followed up to December 31, 2017. Exposures: New prescription dispensation of tramadol or codeine (no dispensation in the previous year). Main Outcomes and Measures: Outcomes studied were all-cause mortality, cardiovascular events, fractures, constipation, delirium, falls, opioid abuse/dependence, and sleep disorders within 1 year after the first dispensation. Absolute rate differences (ARDs) and hazard ratios (HRs) with 95% confidence intervals were calculated using cause-specific Cox models. Results: Of the 1 093 064 patients with a tramadol or codeine dispensation during the study period (326 921 for tramadol, 762 492 for codeine, 3651 for both drugs concomitantly), a total of 368 960 patients (184 480 propensity score-matched pairs) were included after study exclusions and propensity score matching (mean age, 53.1 [SD, 16.1] years; 57.3% women). Compared with codeine, tramadol dispensation was significantly associated with a higher risk of all-cause mortality (incidence, 13.00 vs 5.61 per 1000 person-years; HR, 2.31 [95% CI, 2.08-2.56]; ARD, 7.37 [95% CI, 6.09-8.78] per 1000 person-years), cardiovascular events (incidence, 10.03 vs 8.67 per 1000 person-years; HR, 1.15 [95% CI, 1.05-1.27]; ARD, 1.36 [95% CI, 0.45-2.36] per 1000 person-years), and fractures (incidence, 12.26 vs 8.13 per 1000 person-years; HR, 1.50 [95% CI, 1.37-1.65]; ARD, 4.10 [95% CI, 3.02-5.29] per 1000 person-years). No significant difference was observed for the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders. Conclusions and Relevance: In this population-based cohort study, a new prescription dispensation of tramadol, compared with codeine, was significantly associated with a higher risk of subsequent all-cause mortality, cardiovascular events, and fractures, but there was no significant difference in the risk of constipation, delirium, falls, opioid abuse/dependence, or sleep disorders. The findings should be interpreted cautiously, given the potential for residual confounding.

Probabilistic Quantification of Bias to Combine the Strengths of Population-Based Register Data and Clinical Cohorts-Studying Mortality in Osteoarthritis.

We propose combining population-based register data with a nested clinical cohort to correct misclassification and unmeasured confounding through probabilistic quantification of bias. We have illustrated this approach by estimating the association between knee osteoarthritis and mortality. We used the Swedish Population Register to include all persons resident in the Skåne region in 2008 and assessed whether they had osteoarthritis using data from the Skåne Healthcare Register. We studied mortality through year 2017 by estimating hazard ratios. We used data from the Malmö Osteoarthritis Study (MOA), a small cohort study from Skåne, to derive bias parameters for probabilistic quantification of bias, to correct the hazard ratio estimate for differential misclassification of the knee osteoarthritis diagnosis and confounding from unmeasured obesity. We included 292,000 persons in the Skåne population and 1,419 from the MOA study. The adjusted association of knee osteoarthritis with all-cause mortality in the MOA sample had a hazard ratio of 1.10 (95% confidence interval (CI): 0.80, 1.52) and was thus inconclusive. The naive association in the Skåne population had a hazard ratio of 0.95 (95% CI: 0.93, 0.98), while the bias-corrected estimate was 1.02 (95% CI: 0.59, 1.52), suggesting high uncertainty in bias correction. Combining population-based register data with clinical cohorts provides more information than using either data source separately.

Occupational load as a risk factor for clinically relevant base of thumb osteoarthritis.

OBJECTIVE: It is postulated that increased load from pinch and grasp in occupational tasks increases the risk of thumb carpometacarpal (CMC1) osteoarthritis (OA). We sought to characterise the relationship between doctor-diagnosed CMC1 OA and occupation in a large working population. METHODS: We performed a matched case-control study using a Swedish healthcare register. We identified residents aged 30-65 years in 2013 with physician-diagnosed CMC1 OA from 1998 to 2013. We matched four controls per person with CMC1 OA by age, sex, education and postcode. Swedish Standard Classification of Occupations was used to assign occupation. Occupation was categorised as light, light-moderate, moderate and heavy labour. We used conditional logistic regression to estimate ORs with 95% CIs. RESULTS: We identified 3462 patients with CMC1 OA and matched 13 211 controls. The mean age of the CMC1 OA group was 63 (SD 7) years, with 81% women. The ORs for CMC1 OA in men were 1.31 (95% CI 0.96 to 1.79) for light-moderate, 1.76 (95% CI 1.29 to 2.40) for moderate and 2.00 (95% CI 1.59 to 2.51) for heavy compared with light work. Women had ORs for CMC1 OA of 1.46 (95% CI 1.32 to 1.61) for light-moderate, 1.27 (95% CI 1.10 to 1.46) for moderate and 1.31 (95% CI 1.07 to 1.59) for heavy compared with light work. CONCLUSIONS: The association between increased manual load in occupation and risk of CMC1 OA is more pronounced in men than in women, likely due to higher workload in the heavy labour category.

Long-term effects on function, health-related quality of life and work ability after structured physiotherapy including a workplace intervention. A secondary analysis of a randomised controlled trial (WorkUp) in primary care for patients with neck and/or back pain.

Objective: To study the long-term effects of a workplace intervention in addition to structured physiotherapy regarding self-reported measures in patients with acute/subacute neck and/or back pain.Design: WorkUp - a cluster-randomised controlled trial in 32 primary care centers in Sweden, from January 2013 through December 2014 (ClinicalTrials.gov ID: NCT02609750).Intervention: Structured physiotherapy with the workplace dialogue 'Convergence Dialogue Meeting' (CDM), conducted by the treating physiotherapist as an add-on. Reference group received structured physiotherapy.Subjects: Adults, 18-67 years (mean 43.7, standard deviation (SD) 12.2), 65.3% women with acute/subacute neck and/or back pain who had worked ≥4 weeks past year, considered at risk of sick leave or were on short-term sick leave (≤60 days) were included (n = 352).Outcome measures: Self-reported function, functional rating index (FRI), health-related quality of life (EQ-5D-3L) and work ability (Work Ability Score, WAS) at 12 months follow-up.Results: The mean differences in outcomes between intervention and reference group were; -0.76 (95% confidence interval (CI): -2.39, 0.88; FRI), 0.02 (95% CI: -0.04, 0.08; EQ-5D-3L) and -0.05 (95% CI: -0.63, 0.53; WAS). From baseline to 12 months, the intervention group improved function from 46.5 (SD 19.7) to 10.5 (SD 7.3) on FRI; health-related quality of life from 0.53 (SD 0.29) to 0.74 (SD 0.20) on EQ-5D and work ability from 5.7 (SD 2.6) to 7.6 (SD 2.1) on WAS.Conclusion: Despite a clinically relevant improvement over time, there were no significant differences in improvement between groups, thus we conclude that CDM had no effect on self-reported measures in this study.Key pointsIn earlier analysis of the primary outcome (work ability measured by absenteeism) in this trial, a positive effect was found when the workplace intervention 'Convergence Dialogue Meeting' (CDM) was added to structured physiotherapy for patients with neck or back pain.By contrast, in this new analysis of secondary outcomes (self-reported function, health and perceived work ability), there was no added effect of CDM above structured physiotherapy alone, although patients in both the intervention and reference group improved over time.The addition of CDM to physiotherapy is therefore justified by its specific effect on behavior (work absence) rather than any effect on clinical outcomes.

High genetic contribution to anterior cruciate ligament rupture: Heritability ~69.

OBJECTIVES: We aimed to determine the lifetime genetic risk for anterior cruciate ligament (ACL) rupture. METHODS: We used a twin study approach, linking the Swedish Twin Register with national healthcare data to form a 30 year, population wide, longitudinal twin cohort. We studied ACL rupture in this cohort of 88 414 identical and fraternal twins, aged ≥17 years, to determine the familial risk and heritability of ACL rupture. RESULTS: The incidence rate of ACL rupture was 70 (95% CI 66 to 74) per 100 000 person years. The familial risk, which is the excess risk ratio (RR) of the second twin having ACL rupture given that the first twin has had such a rupture, was higher in identical twin pairs (RR=8.6, 95% CI 6.2 to 11.0) than in fraternal twin pairs (RR=1.9, 95% CI 0.9 to 3.0). The overall heritability of ACL rupture was high, 69% (95% CI 47 to 91), increasing from 60% at age 17 years to 80% at age 60 years. Women and men had similar familial risk and heritability of ACL rupture. CONCLUSION: The genetic contribution to ACL rupture of ~69% is high and suggests strong familial clustering. If clinicians recognise the high genetic risk of such injury, they may be better able to counsel athletes whose near relatives have had ACL rupture.

Does early anterior cruciate ligament reconstruction prevent development of meniscal damage? Results from a secondary analysis of a randomised controlled trial.

OBJECTIVES: To determine development of new and worsening meniscal damage over 5 years after acute anterior cruciate ligament (ACL) injury comparing rehabilitation plus early ACL reconstruction ('early-ACLR') versus rehabilitation with optional delayed ACL reconstruction ('optional-delayed-ACLR'). METHODS: We used knee MRIs from the only randomised controlled trial in the field including 121 young adults. One musculoskeletal radiologist read baseline and 5-year follow-up images using the Anterior Cruciate Ligament Osteoarthritis Score (ACLOAS). We defined development (ie, new and worsening) of meniscal damage both dichotomously and as a sum score representing severity (based on the reclassified ACLOAS meniscus grades). In the full analysis set, we analysed development of meniscal damage (yes/no) with logistic regression and severity with zero-inflated Poisson regression and adjusted for age, sex and baseline meniscal damage. RESULTS: Over 5 years, new or worsening meniscal damage developed in 45% of subjects with early-ACLR and in 53% of subjects with optional-delayed-ACLR. The relative risk for development of meniscal damage on knee level was 1.3 (95% CI 0.9 to 1.9) in optional-delayed-ACLR versus early-ACLR. For medial and lateral meniscal damage, respectively, the relative risks were 2.1 (95% CI 1.1 to 3.9) and 1.0 (95% CI 0.6 to 1.5). The mean severity score was 1.5 higher (more severe damage) on knee level in optional-delayed-ACLR versus early-ACLR (95% CI 1.1 to 1.9) among those with meniscal damage at 5 years. For medial and lateral meniscal damage, respectively, the corresponding scores were 1.7 (95% CI 1.2 to 2.5) and 1.1 (95% CI 0.8 to 1.4). CONCLUSION: A strategy of early-ACLR may reduce development of medial meniscal damage following acute ACL injury. For the lateral meniscus, ACLR seems neither to be protective nor to increase the risk of damage. TRIAL REGISTRATION NUMBER: ISRCTN 84752559.

Risk of knee osteoarthritis after different types of knee injuries in young adults: a population-based cohort study.

OBJECTIVES: To estimate the risk of clinically diagnosed knee osteoarthritis (OA) after different types of knee injuries in young adults. METHODS: In a longitudinal cohort study based on population-based healthcare data from Skåne, Sweden, we included all persons aged 25-34 years in 1998-2007 (n=149 288) with and without diagnoses of knee injuries according to International Classification of Diseases (ICD)-10. We estimated the HR of future diagnosed knee OA in injured and uninjured persons using Cox regression, adjusted for potential confounders. We also explored the impact of type of injury (contusion, fracture, dislocation, meniscal tear, cartilage tear/other injury, collateral ligament tear, cruciate ligament tear and injury to multiple structures) on diagnosed knee OA risk. RESULTS: We identified 5247 persons (mean (SD) age 29.4 (2.9) years, 67% men) with a knee injury and 142 825 persons (mean (SD) age 30.2 (3.0) years, 45% men) without. We found an adjusted HR of 5.7 (95% CI 5.0 to 6.6) for diagnosed knee OA in injured compared with uninjured persons during the first 11 years of follow-up and 3.4 (95% CI 2.9 to 4.0) during the following 8 years. The corresponding risk difference (RD) after 19 years of follow-up was 8.1% (95% CI 6.7% to 9.4%). Cruciate ligament injury, meniscal tear and fracture of the tibia plateau/patella were associated with greatest increase in risk (RD of 19.6% (95% CI 13.2% to 25.9%), 10.5% (95% CI 6.4% to 14.7%) and 6.6% (95% CI 1.1% to 12.2%), respectively). CONCLUSION: In young adults, knee injury increases the risk of future diagnosed knee OA about sixfold with highest risks found after cruciate ligament injury, meniscal tear and intra-articular fracture.