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To assess the association between education and all-cause and cause-specific mortality among patients with osteoarthritis (OA) in comparison to an OA-free reference cohort.Using data from the Skåne Healthcare Register, we identified all residents age ≥45 years in the region of Skåne in southern Sweden with doctor-diagnosed OA of peripheral joints between 1998 and 2013 (n = 123,993). We created an age- and sex-matched reference cohort without OA diagnosis (n = 121,318). Subjects were followed until death, relocation outside Skåne, or the end of 2014. The relative index of inequality (RII) and the slope index of inequality (SII) were estimated by the Cox model and Aalen's additive hazard model, respectively.We found an inverse association between education and mortality. The magnitude of relative inequalities in all-cause mortality were comparable in the OA, with an RII of 1.53 (95% confidence interval [95% CI] 1.46, 1.61), and reference cohorts (RII 1.54 [95% CI 1.47, 1.62]). The absolute inequalities were smaller in the OA cohort (all-cause deaths per 100,000 person-years, SII 937 [95% CI 811, 1,063]) compared with the reference cohort (SII 1,265 [95% CI 1,109, 1,421]). Cardiovascular mortality contributed more to the absolute inequalities in the OA cohort than in the reference cohort (60.1% versus 48.1%) while the opposite was observed for cancer mortality (8.5% versus 22.3%).We found higher all-cause and cause-specific mortality in OA patients with lower education. The observed inequalities in the OA cohort reflect the inequalities in the population at large. The greater burden of cardiovascular diseases in OA patients suggests that proper management of cardiovascular risk factors in OA patients is important.

Summary Objective To assess which structural abnormalities on knee MRI are associated with development of osteophytes in middle-aged subjects without radiographic knee osteoarthritis. Design We included subjects from the Osteoarthritis Initiative, aged 40–55 years, Kellgren & Lawrence grade 0 in both knees, and knee MRIs from both knees available at baseline, 24, 48 and 72 months. Structural exposures on MRI assessed using MOAKS included cartilage damage, bone marrow lesions, meniscal tear, meniscal extrusion, and Hoffa/effusion synovitis. We assessed whether each structural exposure was associated with the development of osteophytes on MRI in the medial and lateral tibiofemoral, and patellofemoral compartment. We estimated hazard ratios (HR) including 95% confidence intervals (CI) for osteophyte development using a mixed complementary log–log regression model adjusted for age, sex, and body mass index. Results We included 680 knees from 340 subjects with a mean (SD) age of 50 years (3.0), and 51% men. In the medial tibiofemoral compartment, the absolute risk of osteophyte development in the first 24-month period was 4% in knees without, and 15% in knees with medial meniscal tear. Corresponding adjusted HR was 6.6 (95%CI = 3.4–12.9). In the lateral tibiofemoral compartment, the adjusted HR for developing osteophytes having a lateral meniscal tear was 3.3 (95%CI = 1.3–8.4). In the patellofemoral compartment, patellofemoral cartilage damage was most clearly associated with developing osteophytes (HR = 2.6, 95%CI = 1.8–3.7). Conclusions Meniscal tear seem to be the strongest structural risk factor for the development of tibiofemoral osteophytes, and patellofemoral cartilage damage for the development of patellofemoral osteophytes, respectively. Local biomechanical factors are important in early osteophyte development.

Objectives To identify variables associated with longitudinal change in meniscal extrusion, which might be used as possible targets for knee osteoarthritis (KOA) prevention. Methods In a high-risk population of middle-aged overweight women, meniscal extrusion was assessed with magnetic resonance imaging (1.5 T, coronal proton density, in-plane resolution 0.5 mm2, Sante DICOM Editor) at baseline and after 30 months. Outcomes were the absolute change in medial and lateral extrusion (mm) and relative change in extrusion (%). Based upon literature, 11 factors were hypothesized to be associated with longitudinal change. Generalized estimating equations were used to model the effect on meniscal change (P Results In total, 677 knees of 343 women were available for analysis, with a mean age of 55.7 years (+/−3.2) and a mean BMI of 32.3 kg/m2 (+/−4.2). The greatest change in meniscal extrusion appeared medially with incident meniscal tear (4.4%; absolute 0.9 mm (95% CI: 0.3, 1.5; P =0.004); relative 14.5% (4.4, 24.7; 0.005)). Varus malalignment was associated with an increase of medial extrusion of 0.6 mm (37.6%; 0.1, 1.0; 0.009). A 5 kg/m2 higher baseline BMI was associated with absolute and relative increase of medial extrusion of 0.2 mm and 2.96% (0.1, 0.3; Conclusion Meniscal tears, varus malalignment and BMI were significantly associated with change in meniscal extrusion in middle-aged overweight women, providing viable therapeutic targets to prevent or reduce extrusion and thereby decelerate KOA development.

Objective To explore whether magnetic resonance imaging (MRI) features suggestive of knee osteoarthritis (OA) are associated with presence of knee pain in possible early‐stage OA development. Methods We included 294 participants from the Osteoarthritis Initiative (mean ± SD age 50 ± 3 years; 50% women) with baseline Kellgren/Lawrence grade of 0 in both knees, all of whom had received knee MRIs at 4 different time points over 6 years (baseline, 24, 48, and 72 months). Using a linear mixed model (knees matched within individuals), we studied whether MRI features (meniscal body extrusion [in mm], cartilage area loss [score 0–39], cartilage full thickness loss [range 0–16], osteophytes [range 0–29], meniscal integrity [range 0–10], bone marrow lesions [BMLs] including bone marrow cysts [range 0–20], Hoffa‐ or effusion‐synovitis [absent/present], and popliteal cysts [absent/present]) were associated with knee‐specific pain as reported on the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire using a 0–100 scale (worst to best). Results The differences in KOOS knee pain score for a knee with a 1 unit higher score on MRI were the following: meniscal extrusion –1.52 (95% confidence interval [95% CI] –2.35, –0.69); cartilage area loss –0.23 (95% CI –0.48, 0.02); cartilage full thickness loss –1.04 (95% CI –1.58, –0.50); osteophytes –0.32 (95% CI –0.61, –0.03); meniscal integrity –0.28 (95% CI –0.58, 0.02); BMLs including potential cysts –0.19 (95% CI –0.55, 0.16); synovitis 0.23 (95% CI –1.14, 1.60); and popliteal cysts 0.86 (95% CI –0.56, 2.29). Conclusion Meniscal extrusion, full thickness cartilage loss, and osteophytes are associated with having more knee pain. Although these features may be relevant targets for future trials, the clinical relevance of our findings is unclear because no feature was associated with a clinically important difference in knee pain.

Objective To estimate the risk of developing comorbidities in patients after physician-diagnosed knee or hip osteoarthritis (OA). Methods This was a cohort study using Swedish longitudinal health care register data; we studied residents in the Skåne region age ≥35 years on January 1, 2010 who were free from diagnosed hip or knee OA (n = 548,681). We then identified subjects with at least 1 new diagnosis of knee or hip OA (incident OA) between 2010 and 2017 (n = 50,942 considered exposed). Subjects without diagnosed OA were considered unexposed. From January 2010 both unexposed and exposed subjects were observed for the occurrence of 18 different predefined comorbidities until either relocation outside of the region, death, occurrence of the comorbidity, or December 2017, whichever came first. We calculated unadjusted hazard ratios (HRs) and adjusted HRs of comorbidities using Cox models with knee and hip OA as time-varying exposures. Results Subjects with incident knee or hip OA had 7% to 60% higher adjusted HRs (range 1.07–1.60) of depression, cardiovascular diseases, back pain, and osteoporosis than individuals without an OA diagnosis. An increased risk of diabetes mellitus was found only for knee OA (adjusted HR 1.19 [95% confidence interval 1.13–1.26]). For the rest of the diagnoses, we found either no increased risk or estimates with wide confidence intervals, excluding clear interpretations of the direction or size of effects. Conclusion Incident physician-diagnosed knee and hip OA is associated with an increased risk of depression, cardiovascular diseases, back pain, osteoporosis, and diabetes mellitus. However, the latter was only found for knee OA.

Osteoarthritis (OA) remains the most challenging arthritic disorder, with a high burden of disease and no available disease-modifying treatments. Symptomatic early-stage OA of the knee (the focus of this Review) urgently needs to be identified and defined, as efficient early-stage case finding and diagnosis in primary care would enable health-care providers to proactively and substantially reduce the burden of disease through proper management including structured education, exercise and weight management (when needed) and addressing lifestyle-related risk factors for disease progression. Efforts to define patient populations with symptomatic early-stage knee OA on the basis of validated classification criteria are ongoing. Such criteria, as well as the identification of molecular and imaging biomarkers of disease risk and/or progression, would enable well-designed clinical studies, facilitate interventional trials, and aid the discovery and validation of cellular and molecular targets for novel therapies. Treatment strategies, relevant outcomes and ethical issues also need to be considered in the context of the cost-effective management of symptomatic early-stage knee OA. To move forwards, a multidisciplinary and sustained international effort involving all major stakeholders is required.

Purpose To investigate the impact of COVID-19 in Sweden on rates of knee and hip surgeries. Methods We used healthcare data for the population of the southernmost region in Sweden (1.4 million inhabitants). We did an interrupted time-series analysis to estimate changes in rates and trends of joint replacements (JR), arthroscopies, and fracture surgeries for knee or hip in April–December 2020 compared to pre-COVID-19 levels adjusting for seasonal variations. Results We found a drop of 54% (95% CI 42%; 68%) and 42% (95% CI 32%; 52%), respectively, in the rate of JRs and arthroscopies in April 2020 when compared to the counterfactual scenario. This was followed by an increase that brought the rates of JRs and arthroscopies back to their predicted levels also during the beginning of the second wave (November–December 2020). Acute fracture surgeries were largely unaffected, i.e. did not show any decrease as observed for the other surgeries. Conclusions In southern Sweden, we observed a marked decrease in elective knee and hip surgeries following the first wave of Covid-19. The rates remained close to normal during the beginning of the second wave suggesting that important elective surgeries for patients with end-stage osteoarthritis can still be offered despite an ongoing pandemic provided adequate routines and hospital resources.

Objective To assess the proportion of participants reconsidering their willingness to undergo surgery after 3 and 12 months. Secondary aims were to analyze and compare the characteristics of individuals willing and unwilling to undergo joint surgery for osteoarthritis (OA) before a first‐line intervention, and to study the association between pain intensity, walking difficulties, self‐efficacy, and fear of movement with the willingness to undergo surgery. Methods This was an observational study based on Swedish register data. We included 30,578 individuals with knee or hip OA who participated in a first‐line intervention including education and exercise. Results Individuals willing to undergo surgery at baseline showed a higher proportion of men (40% versus 27%) and more severe symptoms and disability. Respectively, 45% and 30% of the individuals with knee and hip OA who were willing to undergo surgery at baseline became unwilling after the intervention. At the end of the study period (12 months), 35% and 19% of those with knee and hip OA, respectively, who were willing to undergo surgery at baseline became unwilling. High pain intensity, walking difficulties, and fear of movement were associated with higher odds of being willing to undergo surgery at both follow‐ups, while increased self‐efficacy showed the opposite association. Conclusion A first‐line intervention for OA is associated with reduced willingness to undergo surgery, with a greater proportion among patients with knee OA than hip OA. Due to its temporal variability, willingness to undergo surgery should be used with care to deem surgery eligibility.

Background and purpose — Meniscal repair may reduce long-term risk of knee osteoarthritis compared with arthroscopic partial meniscectomy (APM), whereas patient-reported outcomes may be poorer at short term than for APM. We compared patient-reported outcomes in young adults undergoing meniscal repair or APM up to ∼5 years after surgery. Patients and methods — We included 150 patients aged 18–40 years from the Knee Arthroscopy Cohort Southern Denmark (KACS) undergoing meniscal repair or APM. Between-group differences in change in a composite of 4 of 5 Knee injury and Osteoarthritis Outcome Score (KOOS) subscales (pain, symptoms, sport and recreation, and quality of life—KOOS4) from baseline, 12, and 52 weeks, and a median of 5 years (range 4–6 years) were analyzed using adjusted mixed linear models, with 52 weeks being the primary endpoint. Results — 32 patients had meniscal repair (mean age 26 [SD 6]), and 118 patients underwent APM (mean age 32 [SD 7]). The repair and APM groups improved in KOOS4 from before to 52 weeks after surgery (least square means 7 and 19, respectively; adjusted mean difference –12, [95% CI –19 to –4] in favor of APM). Both groups improved further from 52 weeks to 5 years after surgery with the difference in KOOS4 scores between the groups remaining similar. Interpretation — Patients having meniscal repair experienced less improvements in patient-reported outcomes from baseline to 52 weeks and 5 years post-surgery. The findings highlight the need for randomized trials comparing these interventions in terms of patient-reported outcomes and knee OA development.

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.

This overview of progress made in preventing post-traumatic osteoarthritis (PTOA) was delivered in a workshop at the Orthopaedics Research Society Annual Conference in 2019. As joint trauma is a major risk factor for OA, defining the molecular changes within the joint at the time of injury may enable the targeting of biological processes to prevent later disease. Animal models have been used to test therapeutic targets to prevent PTOA. A review of drug treatments for PTOA in rodents and rabbits between 2016 and 2018 revealed 11 systemic interventions, 5 repeated intra-articular or topical interventions, and 5 short-term intra-articular interventions, which reduced total Osteoarthritis Research Society International scores by 30%-50%, 20%-70%, and 0%-40%, respectively. Standardized study design, reporting of effect size, and quality metrics, alongside a "whole joint" approach to assessing efficacy, would improve the translation of promising new drugs. A roadblock to translating preclinical discoveries has been the lack of guidelines on the design and conduct of human trials to prevent PTOA. An international workshop addressing this in 2016 considered inclusion criteria and study design, and advocated the use of experimental medicine studies to triage candidate treatments and the development of early biological and imaging biomarkers. Human trials for the prevention of PTOA have tested anakinra after anterior cruciate ligament rupture and dexamethasone after radiocarpal injury. PTOA offers a unique opportunity for defining early mechanisms of OA to target therapeutically. Progress in trial design and high-quality preclinical research, and allegiance with patients, regulatory bodies, and the pharmaceutical industry, will advance this field.

Summary Purpose To estimate the excess healthcare use and work disability attributable to knee osteoarthritis (OA) in the first 5 years following diagnosis. Methods Among individual aged 40–80 years who resided in Skane on 31st December 2008, we identified those with a main diagnosis of knee OA during 2009–2014 and no previous diagnosis of any OA from 1998 (n = 16,888). We created a comparison cohort matched (1:1) by sex, age, and municipality from individuals with no OA diagnosis (at any site) during 1998–2016. We compared healthcare use and net disability days for 60 months following diagnosis between the two groups. We applied a survival-adjusted regression technique controlling for sociodemographic characteristics as well as pre-diagnosis outcome and comorbidity. Results The estimated 5-year incremental effects of knee OA per-patient were 16.8 (95% CI: 15.8, 17.7) healthcare consultations, 0.7 (0.4, 1.1) inpatient days, 420 (372, 490) defined daily dose of prescribed medications, and 21.8 (15.2, 30.0) net disability days. Primary care consultations constituted about 73% of the excess healthcare consultations. Most of these incremental effects occurred in the first year after diagnosis. Better survival in the knee OA group accounted for 0.7 (95% CI: 0.5, 0.8) and 1.4 (0.7, 2.6) of the excess healthcare consultations and net disability days, respectively. Both estimated total and incremental resources use were generally greater for women than men with knee OA. Conclusion Knee OA was associated with considerable excess healthcare use and work disability independent of pre-diagnosis resources use, comorbidity, and sociodemographic characteristics.

Objective To determine the association between OA and risk of hospitalization for ambulatory care-sensitive conditions (HACSCs). Methods We included all individuals aged 40–85 years who resided in Skåne, Sweden on 31 December 2005 with at least one healthcare consultation during 1998–2005 (n = 515 256). We identified those with a main diagnosis of OA between 1 January 1998 and 31 December 2016. People were followed from 1 January 2006 until an HACSC, death, relocation outside Skåne, or 31 December 2016 (whichever occurred first). OA status was treated as a time-varying covariate (those diagnosed before 1 January 2006 considered as exposed for whole study period). We assessed relative [hazard ratios (HRs) using Cox proportional hazard model] and absolute (hazard difference using additive hazard model) effects of OA on HACSCs adjusted for potential confounders. Results Crude incidence rates of HACSCs were 239 (95% CI: 235, 242) and 151 (150, 152) per 10 000 person-years among OA and non-OA persons, respectively. The OA persons had an increased risk of HACSCs [HR (95% CI) 1.11 (1.09, 1.13)] and its subcategories of medical conditions except chronic obstructive pulmonary disease [HR (95% CI) 0.86 (0.81, 0.90)]. There were 20 (95% CI: 16, 24) more HACSCs per 10 000 person-years in OA compared with non-OA persons. While HRs for knee and hip OA were generally comparable, only knee OA was associated with increased risk of hospitalization for diabetes. Conclusion OA is associated with an increased risk of HACSCs, highlighting the urgent need to improve outpatient care for OA patients.

OBJECTIVE: To examine how intersections of multiple sociodemographic variables explain the individual heterogeneity in risk of being diagnosed with any of following chronic rheumatic diseases (CRDs): osteoarthritis (OA), gout, rheumatoid arthritis (RA), or spondyloarthritis (SpA).METHODS: We identified people aged 40-65 years residing in Skane, Sweden, by 31st December 2013 and having done so from 1st January 2000 (N=342,542). We used Skane healthcare register to identify those with a diagnosis of the CRD of interest between 1st January 2014 and 31st December 2015 with no previous such diagnosis during 2000-2013. We created 144 intersectional social strata (ISS) using categories of age, gender, education, income, civil status, and immigration. With individuals nested within ISS, we applied multilevel logistic regression models to estimate: 1) variance partition coefficient (VPC) as a measure of discriminatory accuracy of the ISS and 2) predicted absolute risks and 95% credible intervals for each stratum.RESULTS: In overall, 3.5%, 0.5%, 0.2%, and 0.2% of the study population were diagnosed with OA, gout, RA, and SpA, respectively. The VPC ranged from 16.2% for gout to 0.5% for SpA. Gender explained the largest proportion of between-strata variation in risk of RA, gout, and SpA while age was the most important factor for OA. The most between-strata differences in risk of these CRDs were due to the additive main effects.CONCLUSION: Despite meaningful between-strata inequalities in the risk of being diagnosed with CRDs (except SpA), there were substantial within-strata heterogeneities that remains unexplained. There were limited evidence of intersectional interaction effects. (Less)

ObjectivesTo assess the long-term effects of arthroscopic partial meniscectomy (APM) on the development of radiographic knee osteoarthritis, and on knee symptoms and function, at 5 years follow-up.DesignMulticentre, randomised, participant- and outcome assessor-blinded, placebo-surgery controlled trial.SettingOrthopaedic departments in five public hospitals in Finland.Participants146 adults, mean age 52 years (range 35–65 years), with knee symptoms consistent with degenerative medial meniscus tear verified by MRI scan and arthroscopically, and no clinical signs of knee osteoarthritis were randomised.InterventionsAPM or placebo surgery (diagnostic knee arthroscopy).Main outcome measuresWe used two indices of radiographic knee osteoarthritis (increase in Kellgren and Lawrence grade ≥1, and increase in Osteoarthritis Research Society International (OARSI) atlas radiographic joint space narrowing and osteophyte sum score, respectively), and three validated patient-relevant measures of knee symptoms and function (Western Ontario Meniscal Evaluation Tool (WOMET), Lysholm, and knee pain after exercise using a numerical rating scale).ResultsThere was a consistent, slightly greater risk for progression of radiographic knee osteoarthritis in the APM group as compared with the placebo surgery group (adjusted absolute risk difference in increase in Kellgren-Lawrence grade ≥1 of 13%, 95% CI −2% to 28%; adjusted absolute mean difference in OARSI sum score 0.7, 95% CI 0.1 to 1.3). There were no relevant between-group differences in the three patient-reported outcomes: adjusted absolute mean differences (APM vs placebo surgery), −1.7 (95% CI −7.7 to 4.3) in WOMET, −2.1 (95% CI −6.8 to 2.6) in Lysholm knee score, and −0.04 (95% CI −0.81 to 0.72) in knee pain after exercise, respectively. The corresponding adjusted absolute risk difference in the presence of mechanical symptoms was 18% (95% CI 5% to 31%); there were more symptoms reported in the APM group. All other secondary outcomes comparisons were similar.ConclusionsAPM was associated with a slightly increased risk of developing radiographic knee osteoarthritis and no concomitant benefit in patient-relevant outcomes, at 5 years after surgery.Trial registrationClinicalTrials.gov (NCT01052233andNCT00549172).

Summary Objective To evaluate progression of individual radiographic features 5 years following exercise therapy or arthroscopic partial meniscectomy as treatment for degenerative meniscal tear. Design Randomized controlled trial including 140 adults, aged 35–60 years, with a magnetic resonance image verified degenerative meniscal tear, and 96% without definite radiographic knee osteoarthritis. Participants were randomized to either 12-weeks of supervised exercise therapy or arthroscopic partial meniscectomy. The primary outcome was between-group difference in progression of tibiofemoral joint space narrowing and marginal osteophytes at 5 years, assessed semi-quantitatively by the OARSI atlas. Secondary outcomes included incidence of radiographic knee osteoarthritis and symptomatic knee osteoarthritis, medial tibiofemoral fixed joint space width (quantitatively assessed), and patient-reported outcome measures. Statistical analyses were performed using a full analysis set. Per protocol and as treated analysis were also performed. Results The risk ratios (95% CI) for progression of semi-quantitatively assessed joint space narrowing and medial and lateral osteophytes for the surgery group were 0.89 (0.55–1.44), 1.15 (0.79–1.68) and 0.77 (0.42–1.42), respectively, compared to the exercise therapy group. In secondary outcomes (full-set analysis) no statistically significant between-group differences were found. Conclusion The study was inconclusive with respect to potential differences in progression of individual radiographic features after surgical and non-surgical treatment for degenerative meniscal tear. Further, we found no strong evidence in support of differences in development of incident radiographic knee osteoarthritis or patient-reported outcomes between exercise therapy and arthroscopic partial meniscectomy. Trial registration www.clinicaltrials.gov (NCT01002794).

Bad habits in attempts to relieve certain patient groups of their knee pain are hard to break. Arthroscopic partial meniscectomy (APM) is a procedure that became highly popular with the breakthroug...

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.

Carpal tunnel syndrome (CTS) is a common cause of work disability. The association with occupational load and education level has not been established in general-population studies. The purpose of this study was to investigate the association of clinically relevant CTS with work and education. From the Healthcare Register of Skane region (population 1.2 million) in southern Sweden we identified all individuals, aged 17–57 years, with first-time physician-made CTS diagnosis during 2004–2008. For each case we randomly sampled 4 referents, without a CTS diagnosis, from the general population matched by sex, age, and residence. We retrieved data about work and education from the national database. The study comprised 5456 individuals (73% women) with CTS and 21,667 referents. We found a significant association between physician-diagnosed CTS and type of work and level of education in both women and men. Compared with white-collar workers, the odds ratio (OR) for CTS among blue-collar workers was 1.67 (95% CI 1.54–1.81) and compared with light work, OR in light-moderate work was 1.37 (1.26–1.50), moderate work 1.70 (1.51–1.91), and heavy manual labor 1.96 (1.75–2.20). Compared with low-level education, OR for CTS in intermediate level was 0.82 (0.76–0.89) and high-level 0.48 (0.44–0.53). In women and men there is significant association with a dose–response pattern between clinically relevant CTS and increasing manual work load and lower education level. These findings could be important in design and implementation of preventive measures.

Objective: To explore the interplay between (changes in) medial meniscus volume, meniscus extrusion and radiographic knee osteoarthritis (OA) development over 30 months follow-up (FU). Methods: Data from the PRevention of knee Osteoarthritis in Overweight Females study were used. This cohort included 407 middle-aged women with a body mass index ≥27 kg/m2, who were free of knee OA at baseline. Demographics were collected by questionnaires at baseline. All menisci at both baseline and FU were automatically segmented from MRI scans to obtain the meniscus volume and the change over time (delta volume). Baseline and FU meniscus body extrusion was quantitatively measured on mid-coronal proton density MR images. A structural equation model was created to assess the interplay between both medial meniscus volume and central extrusion at baseline, delta volume, delta extrusion, and incident radiographic knee OA at FU. Results: The structural equation modeling yielded a fair to good fit of the data. The direct effects of both medial meniscus volume and extrusion at baseline on incident OA were statistically significant (Estimate = 0.124, p = 0.029, and Estimate = 0.194, p < 0.001, respectively). Additional indirect effects on incident radiographic OA through delta meniscus volume or delta meniscus extrusion were not statistically significant. Conclusion: Baseline medial meniscus volume and extrusion were associated to incidence of radiographic knee OA at FU in middle-aged overweight and obese women, while their changes were not involved in these effects. To prevent knee OA, interventions might need to target the onset of meniscal pathologies rather than their progression.

ObjectiveIt 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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.

ObjectivesTo estimate the risk of clinically diagnosed knee osteoarthritis (OA) after different types of knee injuries in young adults.MethodsIn 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.ResultsWe 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).ConclusionIn 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.

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.

BackgroundDespite absence of evidence of a clinical benefit of arthroscopic partial meniscectomy (APM), many surgeons claim that subgroups of patients benefit from APM.ObjectiveWe developed a prognostic model predicting change in patient-reported outcome 1 year following arthroscopic meniscal surgery to identify such subgroups.MethodsWe included 641 patients (age 48.7 years (SD 13), 56% men) undergoing arthroscopic meniscal surgery from the Knee Arthroscopy Cohort Southern Denmark. 18 preoperative factors identified from literature and/or orthopaedic surgeons (patient demographics, medical history, symptom onset and duration, knee-related symptoms, etc) were combined in a multivariable linear regression model. The outcome was change in Knee injury and Osteoarthritis Outcome Score (KOOS4) (average score of 4 of 5 KOOS subscales excluding the activities of daily living subscale) from presurgery to 52 weeks after surgery. A positive KOOS4change score constitutes improvement. Prognostic performance was assessed using R2statistics and calibration plots and was internally validated by adjusting for optimism using 1000 bootstrap samples.ResultsPatients improved on average 18.6 (SD 19.7, range −38.0 to 87.8) in KOOS4. The strongest prognostic factors for improvement were (1) no previous meniscal surgery on index knee and (2) more severe preoperative knee-related symptoms. The model’s overall predictive performance was low (apparent R2=0.162, optimism adjusted R2=0.080) and it showed poor calibration (calibration-in-the-large=0.205, calibration slope=0.772).ConclusionDespite combining a large number of preoperative factors presumed clinically relevant, change in patient-reported outcome 1 year following meniscal surgery was not predictable. This essentially quashes the existence of ‘subgroups’ with certain characteristics having a particularly favourable outcome after meniscal surgery.Trial registration numberNCT01871272.

ObjectiveTo investigate the risk of cancer in patients with biopsy-proven giant cell arteritis (GCA) from a defined population in southern Sweden.Methods.The study cohort consisted of 830 patients (mean age at GCA diagnosis was 75.3 yrs, 74% women) diagnosed with biopsy-proven GCA between 1997 and 2010. Temporal artery biopsy results were retrieved from a regional database and reviewed to ascertain GCA diagnosis. The cohort was linked to the Swedish Cancer Registry. The patients were followed from GCA diagnosis until death or December 31, 2013. Incident malignancies registered after GCA diagnosis were studied. Based on data on the first malignancy in each organ system, age- and sex-standardized incidence ratios (SIR) with 95% CI were calculated compared to the background population.Results.One hundred seven patients (13%) were diagnosed with a total of 118 new malignancies after the onset of GCA. The overall risk for cancer after the GCA diagnosis was not increased (SIR 0.98, 95% CI 0.81–1.17). However, there was an increased risk for myeloid leukemia (2.31, 95% CI 1.06–4.39) and a reduced risk for breast cancer (0.33, 95% CI 0.12–0.72) and upper gastrointestinal tract cancer (0.16, 95% 0.004–0.91). Rates of other site-specific cancers were not different from expected.Conclusion.In this Swedish population-based cohort of GCA, the overall risk for cancer was not increased compared to the background population. However, there was an increased risk for leukemia and a decreased risk for breast and upper gastrointestinal tract cancer.

Summary Purpose To estimate cause-specific mortality in osteoarthritis patients compared to the general population. Methods We identified all residents in southern Sweden aged 45–84 years in 2003. Through the Skane Healthcare Register (SHR) we identified those diagnosed with osteoarthritis in peripheral joints between 1998 and 2003. We followed all residents from 2004 until relocation outside of the region, death, or end of 2014. We classified the underlying cause of death from death certificates into: cardiovascular and neoplasms, diabetes, infections, dementia, diseases of digestive system, or other causes. For estimation, we used multi-state adjusted Cox proportional hazards models. Results We identified 15,901 patients (mean age [SD] 67 years [10], 41% men) with prevalent doctor-diagnosed osteoarthritis in knee, 9347 in hip, 4004 in hand and 5447 in other peripheral joints among 469,177 residents. For most causes of death in osteoarthritis patients, we found no increased mortality, with hazard ratios (HRs) close to 1, similar for men and women. However, for knee and hip osteoarthritis and cardiovascular death, HRs were non proportional and increased to 1.19 (95%CI 1.10, 1.28) and 1.13 (1.03, 1.24) during 9–11 years of follow-up, mostly due to excess mortality from chronic ischemic heart diseases and heart failure. Conclusions The risk of cardiovascular excess deaths increases with duration of knee and hip osteoarthritis. The major contributors are chronic ischemic heart diseases and heart failure. Our results call for improved implementation of osteoarthritis treatment guidelines, with major focus on interventions to address mobility limitations and maintaining or increase physical activity level.

Summary Objective To investigate the relationship between meniscus magnetic resonance (MR) relaxation parameters and meniscus degradation through quantitative imaging of ex vivo posterior horns of menisci from subjects with and without knee osteoarthritis (OA). Design We sampled medial and lateral menisci from ten medial compartment knee OA patients (mean age 63 years) undergoing total knee replacement and from ten deceased donors (references, mean age 51 years). MR relaxation parameters T2*, T2 and T1 of the posterior horn were measured at a 9.4 T scanner. Comparisons were made between OA patients and references (with adjustment for age) as well as between medial and lateral menisci from the same knees. Results Mean values (standard deviation) of mean T2* were 13 (3.8), 6.9 (2.3), 7.2 (1.9) and 7.2 (1.7) ms for the medial and lateral patient menisci and the medial and lateral reference menisci, respectively. Corresponding values were 17 (3.7), 9.0 (2.2), 12 (4) and 9.0 (1.3) ms for T2 and 1810 (150), 1630 (30), 1580 (90) and 1560 (50) ms for T1. All three relaxation times were significantly longer in medial OA menisci compared to the other groups. Among medial reference menisci, relaxation times (mainly T1) tended to increase with age. Conclusions MR relaxation times T2*, T2 and T1 in the posterior horn are longer in the medial menisci of patients with end-stage medial compartment knee OA compared to the corresponding lateral menisci and to reference menisci. The meniscus seems to undergo intrasubstance alterations related to both OA and ageing.

Objective: To estimate the genetic contribution to traumatic and degenerative meniscus tears for men and women across the lifespan. Methods: We linked the Swedish Twin Register with individual-level national healthcare data to form a 30-year, population-wide, longitudinal twin cohort. To study genetic contribution to meniscus tears, we estimated the heritability and familial risk using incident traumatic and degenerative tear diagnostic codes in a cohort of 88,414 monozygotic and dizygotic twin-pairs, aged ≥17 years. Results: During follow-up, 3,372 (3.8%) of 88,414 twins were diagnosed with a traumatic or degenerative meniscus tear. The heritability was 0.39 (95% CI = 0.32–0.47) for men and 0.43 (95% CI = 0.36–0.50) for women, and did not vary by age. Environmental factors that were unique to each twin in a pair explained a greater proportion of the variance than genetic factors, both for men (0.61, 95% CI = 0.53–0.68) and women (0.57, 95% CI = 0.50–0.64). Separate analyses of traumatic vs degenerative meniscus tears yielded similar results. Conclusion: For the first time, we have estimated the genetic contribution to doctor-diagnosed meniscus tears using a twin study design. We found a relatively low to modest heritability for meniscus tears (∼40%). The heritability was also fairly stable over the lifespan, and equal in both men and women. Our findings suggest that environmental risk factors are a more important contributor to both traumatic and degenerative doctor-diagnosed meniscus tears than genetic factors.

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. (Less)

Background MRI is used to evaluate structural joint changes after anterior cruciate ligament (ACL) injury, but no long-term data are available for comparing different treatment approaches. Purpose To describe structural joint damage with MRI over a 5-year period in the Knee Anterior Cruciate Ligament, Nonsurgical versus Surgical Treatment (KANON) study and to compare frequencies of such tissue damage for a nonsurgical versus a surgical treatment strategy. Materials and Methods In this secondary analysis of a prospective trial (ISRCTN 84752559), 119 participants with an acute ACL injury were evaluated. Participants were enrolled from 2002 through 2006, the 2-year follow-up started in 2008, and the 5-year follow-up started in 2011. A 1.5-T MRI examination was performed at baseline and at 2- and 5-year follow-up. MRI scans were read according to a validated scoring instrument. Kruskal-Wallis tests were used to assess whether the frequencies of structural damage differed between the three as-treated groups. Results Of 119 participants (mean age, 26 years ± 5 [standard deviation]), 91 men were evaluated. At 2- and 5-year follow-up, respectively, 13% (15 of 117) and 13% (15 of 115) of knees showed incident cartilage damage in the medial tibiofemoral joint, 11% (13 of 117) and 17% (20 of 115) of knees showed incident cartilage damage in the lateral tibiofemoral joint, and 4% (five of 117) and 8% (nine of 115) of knees showed incident cartilage damage in the patellofemoral joint. Osteophyte development was seen in 23% (27 of 117) and 29% (33 of 115) of knees in the medial tibiofemoral joint, in 36% (42 of 117) and 43% (49 of 115) of knees in the lateral tibiofemoral joint, and in 35% (41 of 117) and 37% (42 of 115) of knees in the patellofemoral joint. No major differences between the groups were found for incident or worsening cartilage damage, bone marrow lesions, and osteophytes at 2 or 5 years. The rehabilitation-alone group showed less Hoffa-synovitis at 2 (

ObjectiveTo estimate the healthcare resource utilization (HRU) in patients with giant cell arteritis (GCA) compared with the general population in southern Sweden.MethodsThe study sample comprised 653 patients with GCA along with 10 age-, sex-, and residency area–matched reference subjects per patient. Data on public and private healthcare consultations and hospitalizations were extracted from the Skåne Healthcare Register. We assessed trajectories of primary and specialist healthcare visits, as well as hospital admissions and inpatient days from 3 years before through 5 years after the date of GCA diagnosis for patients and matched references. HRU was analyzed using generalized estimating equations adjusted for sex, age at the index year, calendar year of diagnosis, education, income, marital status, place of birth, and Charlson Comorbidity Index. Inverse probability weighting was used to account for dropout during study.ResultsPatients with GCA had higher rates of healthcare visits than the references from the year before GCA diagnosis and up to 4 years after diagnosis, with the largest relative (rate ratio 1.85, 95% CI 1.68–2.05) and absolute (mean difference 10.2, 95% CI 8.1–12.3 visits per person) differences in the year of diagnosis. Similar trajectories were observed for primary and specialist healthcare visits. For hospital admissions and inpatient days, the differences disappeared 1 year after diagnosis date.ConclusionPatients with GCA utilized healthcare services at a significantly higher rate than the reference population. The increased utilization among Swedish patients with GCA was evident 1 year before and prolonged up to 4 years after diagnosis date.

Objective Hemarthrosis after knee trauma often indicates serious joint injury. Few studies have evaluated agreement between clinical examination and findings from magnetic resonance imaging (MRI). We aimed to describe the agreement between acute clinical examination and subacute MRI findings after acute knee trauma with hemarthrosis and the importance of the subspecialty of the examiner. Design Longitudinal cohort study. Agreement with MRI findings was evaluated by logistic regression. Setting Helsingborg hospital. Patients Thousand one hundred forty-five consecutive patients with hemarthrosis after knee trauma. Interventions Clinical examination and MRI. Main outcome measures agreement between clinical examination and findings from MRI. We considered the radiologist's report as the gold standard. Results Median time (25th, 75th percentile) from injury to clinical examination was 2 (1, 7) days, and from injury to imaging was 8 (5, 15) days. The overall sensitivity and specificity of clinical examination versus MRI for major ligament injury or lateral patella dislocation (LPD) were 70% [95% confidence interval 67-73) and 66% (61-72), respectively. Orthopedic subspecialist knee had the highest agreement with anterior cruciate ligament rupture (adjusted odds ratios were 1.7 (95% confidence interval 1.2-2.3), 1.9 (1.2-3.0) and 5.9 (3.7-9.5) for orthopedic trainees, orthopedic subspecialists other, and orthopedic subspecialist knee, respectively]. For other ligament injuries and LPD, we did not find statistically significant differences. Conclusions Clinical diagnosis after acute knee injury is relatively unreliable versus MRI findings even when performed by orthopedic specialists. However, the agreement is improved when the examination is performed by an orthopedic knee subspecialist.

Objectives: To investigate whether the association between pain intensity and willingness to undergo surgery is explained by walking difficulties, in patients with knee or hip osteoarthritis (OA). Methods: This is an observational study using data from the Better management of patients with Osteoarthritis (BOA) register, which collects data from a publicly financed self-management programme for people with OA in Sweden. We included all patients with knee or hip OA who attended the baseline visit between 2008 and 2016. We conducted separate mediation analyses within a counterfactual framework to estimate the mediation effect of walking difficulties (yes/no) on willingness to undergo surgery (yes/no) for each one-point increase in pain (0–10 on a numeric rating scale), adjusted for relevant confounders. Results: We included 72,131 patients (69% women, mean age 66, mean pain 5.4, 81% had walking difficulties, 27% was willing to undergo surgery). A one-point increase in pain intensity was associated with 1.53 (95% CI: 1.51; 1.55) higher odds of being willing to undergo surgery. Walking difficulties mediated 10%–25% of the effect of one-point increase in pain when pain was

Summary Functional analysis has become a common approach to incorporate biological knowledge into the analysis of omics data, and to explore molecular events that govern a disease state. It is though only one step in a wider analytical pipeline that typically requires use of multiple individual analysis software. There is currently a need for a well-integrated omics analysis tool that performs all the steps. The ProteoMill portal is developed as an R Shiny application and integrates all necessary steps from data-upload, converting identifiers, to quality control, differential expression and network-based functional analysis into a single fast, interactive easy to use workflow. Further, it maintains annotation data sources up to date, overcoming a common problem with use of outdated information and seamlessly integrates multiple R-packages for an improved user-experience. The functionality provided in this software can benefit researchers by facilitating the exploratory analysis of proteomics data. Availability and implementation ProteoMill is available at https://proteomill.com.

Objective: We evaluated whether patient-reported outcome trajectories (i.e., changes over time) differed by intraoperative compartmental cartilage lesion pattern over 4–6 years following arthroscopic meniscal surgery. Methods: In this ancillary study of the Knee Arthroscopy Cohort Southern Denmark cohort, we intraoperatively categorized cartilage lesions as isolated patellofemoral, isolated tibiofemoral, or combined patellofemoral/tibiofemoral. Participants completed the Knee injury and Osteoarthritis Outcome Score (KOOS) pre-operatively, at 3 and 12 months, and at 4–6 years post-operatively and reported overall satisfaction at final follow-up. Our main outcome was KOOS4 (grand mean of four subscale means). We evaluated whether KOOS4 scores changed over time according to cartilage lesion patterns using adjusted mixed linear regression. We also estimated probability of treatment satisfaction using logistic regression. Results: Of 630 participants with complete cartilage scores, 280 (44%) were women, mean (standard deviation) age was 49 (13) years, and BMI was 27.3 (4.4) kg/m2. KOOS4 scores at baseline were slightly lower in all lesion groups compared to the no lesion group, yet only the combined group was statistically significantly lower. KOOS4 trajectories were similar across cartilage lesion patterns, but by final follow-up, adjusted mean KOOS4 scores were 6.8 (95% CI 2.2, 11.4) to 9.8 (1.1, 18.5) points lower in groups with cartilage lesions compared to the no lesion group. Probability of patient-reported satisfaction did not differ statistically by group. Conclusions: Though KOOS4 scores were slightly lower in groups with arthroscopically assessed cartilage lesions compared to the no lesion group, trajectories were similar across all groups.

Objective To determine the burden of comorbidities in OA and their temporal relationships in the UK. Methods The Clinical Practice Research Datalink (CPRD) GOLD was used to identify people with incident OA and age, gender and practice matched non-OA controls from UK primary care. Controls were assigned the same index date as matched cases (date of OA diagnosis). Associations between OA and 49 individual comorbidities and multimorbidities (two or more comorbidities excluding OA) both before and after OA diagnosis were estimated, adjusting for covariates, using odds ratios (aORs) and hazard ratios (aHRs), respectively. Results During 1997–2017, we identified 221 807 incident OA cases and 221 807 matched controls. Of 49 comorbidities examined, 38 were associated with OA both prior to and following the diagnosis of OA and 2 (dementia and systemic lupus erythematosus) were associated with OA only following the diagnosis of OA. People with OA had a higher risk of developing heart failure [aHR 1.63 (95% CI 1.56, 1.71)], dementia [aHR 1.62 (95% CI 1.56, 1.68)], liver diseases [aHR 1.51 (95% CI 1.37, 1.67)], irritable bowel syndrome [aHR 1.51 (95% CI 1.45, 1.58)], gastrointestinal bleeding [aHR 1.49 (95% CI 1.39, 1.59)], 10 musculoskeletal conditions and 25 other conditions following OA diagnosis. The aOR for multimorbidity prior to the index date was 1.71 (95% CI 1.69, 1.74), whereas the aHR for multimorbidity after the index date was 1.29 (95% CI 1.28, 1.30). Conclusions People with OA are more likely to have other chronic conditions both before and after the OA diagnosis. Further study on shared aetiology and causality of these associations is needed.

Summary Objectives To study bone shape changes as a potential early feature of post-traumatic structural knee OA development, we estimated the association between meniscal status in the anterior cruciate ligament (ACL) injured knee and longitudinal condyle changes in bone surface area. Design We used data from the KANON trial, including 121 young ACL-injured adults. We obtained baseline and 2-year follow-up knee MRIs. Our outcome was change in the bone surface areas (mean mm2, log-transformed) in 4 locations (femur, tibia, patella, and trochlea femur) in the medial and lateral compartment from baseline to 2 years. Meniscal pathology was defined as both present at baseline and newly developed (i.e., incident or progressed) using ACLOAS. We used multilevel linear regression adjusted for baseline bone area, age, sex, body mass index, treatment arm (i.e., early or optional delayed ACL reconstruction), and location. We analyzed medial and lateral compartment separately. We present results as percentage (%) bone area change difference with 95% confidence intervals (CI). Results We analyzed 109 subjects (median 27 (18–36) years, 83% men) due to missing MRI information. The bone surface area increased on average by ∼2% over 2 years. The differences between knees with and without baseline meniscal pathology were 1.1% (95%CI 0.0–2.3%) and 1.4% (95%CI 0.6–2.2%) in the medial and lateral compartment, respectively, and 1.2% (95%CI 0.3–2.0%) and 1.3% (95%CI 0.6–2.0%) for medial and lateral newly developed pathology, respectively. Conclusion Our finding of ∼1% increase bone area in compartment with meniscal pathology suggests a potentially important association between meniscal integrity and early bone surface area changes after ACL injury. Trial registration number ISRCTN 84752559.

ObjectivesWe aimed to determine the lifetime genetic risk for anterior cruciate ligament (ACL) rupture.MethodsWe 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.ResultsThe 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.ConclusionThe 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.

Objective.To investigate the association between infections and the subsequent development of giant cell arteritis (GCA) in a large population-based cohort from a defined geographic area in Sweden.Methods.Patients diagnosed with biopsy-confirmed GCA between 2000 and 2016 were identified through the database of the Department of Pathology in Skåne, the southernmost region of Sweden. For each GCA case, 10 controls matched for age, sex, and area of residence were randomly selected from the general population. Using the Skåne Healthcare Register, we identified all infection events prior to patients’ date of GCA diagnosis and controls’ index date. With infection as exposure, a conditional logistic regression model was employed to estimate the OR for developing GCA. The types of infections contracted nearest in time to the GCA diagnosis/index date were identified.Results.A total of 1005 patients with biopsy-confirmed GCA (71% female) and 10,050 controls were included in the analysis. Infections were more common among patients subsequently diagnosed with GCA compared to controls (51% vs 41%, OR 1.78, 95% CI 1.53–2.07). Acute upper respiratory tract infection (OR 1.77, 95% CI 1.47–2.14), influenza and pneumonia (OR 1.72, 95 % CI 1.35–2.19), and unspecified infections (OR 5.35, 95 % CI 3.46–8.28) were associated with GCA. Neither skin nor gastrointestinal infections showed a correlation.Conclusion.Infections, especially those of the respiratory tract, were associated with subsequent development of biopsy-confirmed GCA. Our findings support the hypothesis that a range of infections may trigger GCA.

IntroductionArthroscopic partial meniscectomy (APM) after degenerative meniscus tears is one of the most frequently performed surgeries in orthopaedics. Although several randomised controlled trials (RCTs) have been published that showed no clear benefit compared with sham treatment or non-surgical treatment, the incidence of APM remains high. The common perception by most orthopaedic surgeons is that there are subgroups of patients thatdoneed APM to improve, and they argue that each study sample of the existing trials is not representative for the day-to-day patients in the clinic. Therefore, the objective of this individual participant data meta-analysis (IPDMA) is to assess whether there are subgroups of patients with degenerative meniscus lesions who benefit from APM in comparison with non-surgical or sham treatment.Methods and analysisAn existing systematic review will be updated to identify all RCTs worldwide that evaluated APM compared with sham treatment or non-surgical treatment in patients with knee symptoms and degenerative meniscus tears. Time and effort will be spent in contacting principal investigators of the original trials and encourage them to collaborate in this project by sharing their trial data. All individual participant data will be validated for missing data, internal data consistency, randomisation integrity and censoring patterns. After validation, all datasets will be combined and analysed using a one-staged and two-staged approach. The RCTs’ characteristics will be used for the assessment of clinical homogeneity and generalisability of the findings. The most important outcome will be the difference between APM and control groups in knee pain, function and quality of life 2 years after the intervention. Other outcomes of interest will include the difference in adverse events and mental health.Ethics and disseminationAll trial data will be anonymised before it is shared with the authors. The data will be encrypted and stored on a secure server located in the Netherlands. No major ethical concerns remain. This IPDMA will provide the evidence base to update and tailor diagnostic and treatment protocols as well as (international) guidelines for patients for whom orthopaedic surgeons consider APM. The results will be submitted for publication in a peer-reviewed journal.PROSPERO registration numberCRD42017067240.

Objective: To determine the role of inflammatory biomarkers at 2 years post–anterior cruciate ligament (ACL) injury to predict radiographic knee osteoarthritis (OA) and magnetic resonance imaging (MRI)–defined knee OA at 5 years postinjury, with a secondary aim of estimating the concordance of inflammatory biomarkers assessed by MRI and synovial fluid (SF) analysis. Methods: We studied 113 patients with acute ACL injury. Knee scans using 1.5T MRIs were read for Hoffa- and effusion-synovitis. Biomarkers of inflammation that we assessed included interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor, and interferon-ɣ in serum and SF, and IL-12p70 in serum. We defined the outcome as radiographic knee OA (ROA) or MRI-defined OA (MROA) at 5 years. The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were evaluated in models that included MRI features only (model 1), inflammation biomarkers only (serum [model 2a] or SF [model 2b]), both MRI features and serum biomarkers (model 3a), or both MRI features and SF (model 3b) biomarkers. Linear regression analysis was used to evaluate the association between MRI features and SF biomarkers. Results: At 5 years postinjury, ROA was present in 26% of the injured knees, and MROA was present in 32%. The AUCs for ROA in each model were 0.44 (95% confidence interval [95% CI] 0.42, 0.47) for model 1, 0.62 (95% CI 0.59, 0.65) for model 2a, 0.53 (95% CI 0.50, 0.56) for model 2b, 0.58 (95% CI 0.55, 0.61) for model 3a, and 0.50 (95% CI 0.46, 0.53) for model 3b. The AUCs for MROA in each model were 0.67 (95% CI 0.64, 0.70) for model 1, 0.49 (95% CI 0.47, 0.52) for model 2a, 0.56 (95% CI 0.52, 0.59) for model 2b, 0.65 (95% CI 0.61, 0.68) for model 3a, and 0.69 (95% CI 0.66, 0.72) for model 3b. The concordance between MRI and SF biomarkers was statistically significant only for effusion-synovitis and IL-8. Conclusion: Neither MRI-detected inflammation nor selected SF/serum inflammation biomarkers at 2 years postinjury predicted ROA or MROA at 5 years postinjury. Concordance between MRI and SF inflammatory biomarkers was weak. (Less)

Background Proteomics is an emerging field in the study of joint disease. Our two aims with this pilot analysis were to compare healthy human knee articular cartilage with meniscus, two tissues both known to become affected in the osteoarthritic disease process, and to compare two mass spectrometry (MS)-based methods: data-dependent acquisition (DDA) and data-independent acquisition (DIA). Methods Healthy knee articular cartilage taken from the medial tibial condyle and medial meniscus samples taken from the body region were obtained from three adult forensic medicine cases. Proteins were extracted from tissue pieces and prepared for MS analysis. Each sample was subjected to liquid chromatography (LC)-MS/MS analysis using an Orbitrap mass spectrometer, and run in both DDA and DIA mode. Linear mixed effects models were used for statistical analysis. Results A total of 653 proteins were identified in the DDA analysis, of which the majority was present in both tissue types. Only proteins with quantitation information in both tissues (n = 90) were selected for more detailed analysis, of which the majority did not statistically significantly differ in abundance between the two tissue types, in either of the MS analyses. However, 21 proteins were statistically significantly different (p

Objectives To determine meniscal extrusion and cartilage coverage on magnetic resonance (MR) images and factors associated with these parameters in knees of middle-aged and elderly persons free from radiographic tibiofemoral osteoarthritis (OA). Methods Seven hundred eighteen persons, free of radiographic tibiofemoral OA, aged 50–90 years from Framingham, MA, USA, were included. We measured meniscal extrusion on 1.5 T MRI of both knees to evaluate both medial and lateral meniscal body extrusion and cartilage coverage. We also determined meniscal morphology and structural integrity. The multivariable association with age, body mass index (BMI), and ipsilateral meniscal damage was also evaluated. Results The mean meniscal body extrusion medially was 2.7 mm and laterally 1.8 mm. The tibial cartilage coverage was about 30% of ipsilateral cartilage surface (both compartments). The presence of ipsilateral meniscal damage was associated with more extrusion in only the medial compartment, 1.0 mm in men and 0.6 mm in women, and less cartilage coverage proportion, -5.5% in men and -4.6% in women. Conclusions Mean medial meniscal body extrusion in middle-aged or older persons without radiographic tibiofemoral OA approximates the commonly used cutoff (3 mm) to denote pathological extrusion. Medial meniscal damage is a factor associated with medial meniscal body extrusion and less cartilage coverage. Key Points • Medial meniscal extrusion in middle-aged/older persons without OA is around 3 mm. • Lateral meniscal extrusion in middle-aged/older persons without OA is around 2 mm. • Meniscal damage is associated with medial meniscal extrusion and less cartilage coverage. Electronic supplementary material The online version of this article (10.1007/s00330-018-5741-3) contains supplementary material, which is available to authorized users.

Background and purpose - Few data are available regarding structural changes present in knees without radiographically evident osteoarthritis (OA). We evaluated the prevalence of findings suggestive of knee OA by magnetic resonance imaging (MRI) in middle-aged subjects without radiographic OA with or without OA risk factors. Patients and methods - 340 subjects from the Osteoarthritis Initiative, aged 45-55 years (51% women) with Kellgren-Lawrence grade 0 in both knees, who had 3T knee MR images were eligible. 294 subjects had risk factors and 46 were without risk factors. MR images were assessed using the MOAKS scoring system. Results - At least 1 MR-detected feature was found in 96% (283/294) of subjects with risk factors and in 87% (40/46) of those without. Cartilage damage (82%), bone marrow lesions (60%), osteophytes (45%), meniscal body extrusion (32%), and synovitis-effusion (29%) were the most common findings in subjects with risk factors, while cartilage damage (67%), osteophytes (46%), meniscal body extrusion (37%), and bone marrow lesions (35%) were most common in subjects without. The prevalence of any abnormality was higher in subjects with OA risk factors than in subjects without (prevalence ratio adjusted for age and sex 1.3 [95% CI 1.1-1.6]), so was prevalence of subchondral cysts and bone marrow lesions. MR-detected structural changes were more frequent in patellofemoral joints. Interpretation - Our findings highlight the great challenge in distinguishing pathological features of early knee OA from what could be considered part of "normal ageing." Bone marrow lesions were more frequently found in subjects with multiple OA risk factors.

Background Hyperuricemia (HU) is in the causal pathway for developing clinical gout. There are few population-based assessments of the absolute and relative risk of clinically diagnosed incident gout in subjects with HU. We aimed to explore the long-term risk of developing incident gout among asymptomatic adults with different levels of serum urate (SU). Methods Malmö Preventive Project was a population-based screening program for cardiovascular risk factors, alcohol abuse, and breast cancer in Malmö, Sweden. The study population was screened between 1974 and 1992. At baseline, subjects were assessed with a questionnaire, physical examination, and laboratory tests. Follow-up ended at first gout diagnosis, death, moving from area, or December 31, 2014. Incident gout (using ICD10 codes) was diagnosed based on national registers for specialized inpatient and outpatient care, and from 1998 onward in the Skåne Healthcare Register including primary healthcare. Incidence rates, absolute risk, hazard ratios (HRs) and potentially associated factors were analyzed by baseline SU levels, i.e. normal levels (≤ 360 μmol/L); 361–405 (levels below tissue solubility of SU), and > 405 (HU), overall, and by sex. Results Overall, 1275 individuals [3.8%; 1014 men (4.5%) and 261 women (2.4%)] of the 33,346 study participants (mean age: 45.7 (SD: 7.4), 67% men), developed incident gout during follow-up (mean 28.2 years). Of those with HU, 14.7% of men and 19.5% of women developed gout. Compared to subjects in the lowest SU category, the age-adjusted HR in men increased from 2.7 to 6.4, and in women from 4.4 to 13.1 with increasing baseline SU category, and with a statistically significant interaction of sex (p