Search

Objective: To investigate if knee osteoarthritis (OA) is associated with lower physical activity in the general middle-aged Dutch population, and if physical activity is associated with patient-reported outcomes in knee OA. Design: Clinical knee OA was defined in the Netherlands Epidemiology of Obesity population using the ACR criteria, and structural knee OA on MRI. We assessed knee pain and function with the Knee Injury and Osteoarthritis Score (KOOS), health-related quality of life (HRQoL) with the Short Form-36, and physical activity (in Metabolic Equivalent of Task (MET) hours) with the Short Questionnaire to Assess Health-enhancing physical activity. We analysed the associations of knee OA with physical activity, and of physical activity with knee pain, function, and HRQoL in knee OA with linear regression adjusted for potential confounders. Results: Clinical knee OA was present in 14% of 6,212 participants, (mean age 56 years, mean BMI 27 kg/m(2), 55% women, 24% having any comorbidity) and structural knee OA in 12%. Clinical knee OA was associated with 9.60 (95% CI 3.70; 15.50) MET hours per week more physical activity, vs no clinical knee OA. Structural knee OA was associated with 3.97 (-7.82; 15.76) MET hours per week more physical activity, vs no structural knee OA. In clinical knee OA, physical activity was not associated with knee pain, function or HRQoL. Conclusions: Knee OA was not associated with lower physical activity, and in knee OA physical activity was not associated with patient-reported outcomes. Future research should indicate the optimal treatment advice regarding physical activity for individual knee OA patients. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Objective: To investigate the association of postprandial and fasting plasma saturated fatty acid (SFAs), monounsaturated fatty acid (MUFAs) and polyunsaturated fatty acid (PUFAs) concentrations with hand and knee osteoarthritis (OA).Design: In the population-based NEO study clinical hand and knee OA were defined by the ACR classification criteria. Structural knee OA was defined on MRI. Hand and knee pain was determined by Australian/Canadian Hand Osteoarthritis Index (AUSCAN) and KOOS, respectively. Plasma was sampled fasted and 150 min after a standardized meal, and subsequently analysed using a nuclear magnetic resonance platform. Logistic regression analyses were used to investigate the association of total fatty acid, SFA, MUFA, total PUFA, omega-3 PUFA and omega-6 PUFA concentrations with clinical hand and knee OA, structural knee OA and hand and knee pain. Fatty acid concentrations were standardized (mean 0, SD 1). Analyses were stratified by sex and corrected for age, education, ethnicity and total body fat percentage.Results: Of the 5,328 participants (mean age 56 years, 58% women) 7% was classified with hand OA, 10% with knee OA and 4% with concurrent hand and knee OA. In men, postprandial SFAs (OR (95% CI)) 1.23 (1.00; 1.50), total PUFAs 1.26 (1.00; 1.58) and omega-3 PUFAs 1.24 (1.01; 1.52) were associated with hand OA. SFAs and PUFAs were associated with structural, but not clinical knee OA. Association of fasting fatty acid concentrations were weaker than postprandial concentrations.Conclusion: Plasma postprandial SFA and PUFA levels were positively associated with clinical hand and structural knee OA in men, but not in women. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Background and aims Inflammation may underlie the association between obesity, atherosclerosis and cardiovascular disease. We investigated to what extent markers of inflammation mediate associations between overall and visceral body fat and subclinical atherosclerosis. Methods and results In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study we estimated total body fat (TBF) by bio-impedance analysis, carotid artery intima media thickness (cIMT) by ultrasound, C-reactive protein (hs-CRP) and glycoprotein acetyls (GlycA) concentrations in fasting blood samples (n = 5627), and visceral adipose tissue (VAT) by magnetic resonance imaging (n = 2247). We examined associations between TBF and VAT, and cIMT using linear regression, adjusted for potential confounding factors, and for mediators: cardiometabolic risk factors (blood pressure, glucose and low-density lipoprotein cholesterol), and inflammation using CRP and GlycA as proxies. Mean (SD) cIMT was 615 (90) μm. Per SD of TBF (8%), cIMT was 19 μm larger (95% confidence interval, CI: 10, 28). This association was 17 μm (95% CI: 8, 27) after adjustment for cardiometabolic risk factors, and did not change after adjustment for markers of inflammation. Per SD (56 cm2) VAT, cIMT was 9 μm larger (95% CI: 2, 16) which changed to 5 μm (95% CI: −3, 12) after adjustment for cardiometabolic risk factors, and did not change after adjustment for inflammatory markers. Conclusion Our results suggest that associations between measures of overall and visceral body fat and subclinical atherosclerosis are not mediated by inflammation as measured by CRP and GlycA. Obesity may exert cardiovascular risk via other markers of systemic inflammation.

Objective: To investigate the performance of the Michigan Hand Outcomes Questionnaire (MHQ) in hand osteoarthritis (OA) by evaluating truth, discrimination and feasibility.Design: Symptomatic hand OA patients from the Hand Osteoarthritis in Secondary Care (HOSTAS) cohort completed questionnaires (demographics, MHQ, Australian/Canadian Hand Osteoarthritis Index [AUSCAN], Functional Index for Hand Osteoarthritis [FIHOA] and visual analogue scale [VAS] pain) at baseline (n = 383), 1- and 2-year follow-up (n = 312, n = 293). Anchor questions at follow-up assessed whether pain/function levels were (un) acceptable and had changed compared to baseline. Correlations between MHQ and other pain/function questionnaires were calculated. Validity of unique MHQ domains (work performance, aesthetics, satisfaction), discrimination across disease stages, and responsiveness were assessed by categorizing patients by external anchors (employment, joint deformities, erosions, and anchor questions). Between-group differences were assessed with linear regression, probability plots and comparison of medians.Results: MHQ pain and function subscales correlated moderately-to-good with other instruments (r(s) 0.63-0.81). Work performance scores were worse in patients with reduced working capacity than in employed patients. Aesthetics scores were worse in patients with more deformities. Patients with unacceptable complaints had worse satisfaction scores. All pain/function instruments discriminated between patients with acceptable vs unacceptable pain/function, while only MHQ activities of daily living (ADL), FIHOA, and MHQ aesthetics could discriminate between erosive and non-erosive disease. MHQ and AUSCAN were most responsive.Conclusions: MHQ has several unique aspects and advantages justifying its use in hand OA, including the unique assessment of work performance, aesthetics, and satisfaction. However, MHQ, AUSCAN and FIHOA appear to measure different aspects of pain and function. (c) 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Aims: To examine the feasibility and validity of obtaining International Classification of Primary Care (ICPC)-coded diagnoses of diabetes mellitus (DM) from general practice electronic health records for case definition in epidemiological studies, as alternatives to self-reported DM.Methods: The Netherlands Epidemiology of Obesity study is a population-based cohort study of 6671 persons aged 45-65 years at baseline, included between 2008 & minus;2012. Data from electronic health records were collected between 2012 & minus;2014. We defined a reference standard using diagnoses, prescriptions and consultation notes and investigated its agreement with ICPC-coded diagnoses of DM and self-reported DM.Results: After a median follow-up of 1.8 years, data from 6442 (97%) participants were collected. With the reference standard, 506 participants (79/1000 person-years) were classified with prevalent DM at baseline and 131 participants (11/1000 person-years) were classified with incident DM during follow-up. The agreement of prevalent DM between self-report and the reference standard was 98% (kappa 0.86), the agreement between ICPC-coded diagnoses and the reference standard was 99% (kappa 0.95). The agreement of incident DM between ICPC-coded diagnoses and the reference standard was >99% (kappa 0.92).Conclusions: ICPC-coded diagnoses of DM from general practice electronic health records are a feasible and valid alternative to self-reported diagnoses of DM.(c) 2020 The Author(s). Published by Elsevier Ltd on behalf of Primary Care Diabetes Europe. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

An exploratory study to determine the role of effusion, i.e., fluid in the joint, in pain, and radiographic progression in patients with hand osteoarthritis. Distal and proximal interphalangeal joints (87 patients, 82% women, mean age 59 years) were assessed for pain. T2-weighted and Gd-chelate contrast-enhanced T1-weighted magnetic resonance images were scored for enhanced synovial thickening (EST, i.e., synovitis), effusion (EST and T2-high signal intensity [hsi]) and bone marrow lesions (BMLs). Effusion was defined as follows: (1) T2-hsi > 0 and EST = 0; or 2) T2-hsi = EST but in different joint locations. Baseline and 2-year follow-up radiographs were scored following Kellgren-Lawrence, increase ≥ 1 defined progression. Associations between the presence of effusion and pain and radiographic progression, taking into account EST and BML presence, were explored on the joint level. Effusion was present in 17% (120/691) of joints, with (63/120) and without (57/120) EST. Effusion on itself was not associated with pain or progression. The association with pain and progression, taking in account other known risk factors, was stronger in the absence of effusion (OR [95% CI] 1.7 [1.0–2.9] and 3.2 [1.7–5.8]) than in its presence (1.6 [0.8–3.0] and 1.3 [0.5–3.1]). Effusion can be assessed on MR images and seems not to be associated with pain or radiographic progression but attenuates the association between synovitis and progression. Key Points• Effusion is present apart from synovitis in interphalangeal joints in patients with hand OA.• Effusion in finger joints can be assessed as a separate feature on MR images.• Effusion seems to be of importance for its attenuating effect on the association between synovitis and radiographic progression.

Background The adipocyte-derived hormone leptin has been associated with altered blood coagulation in in vitro studies. However, it is unclear whether this association is relevant in vivo and to what extent this association is influenced by total body fat. Therefore, we aimed to examine the association between serum leptin and blood coagulation while taking total body fat into account in a population-based cohort study. Methods We performed a cross-sectional analysis with baseline measurements of 5797 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort of middle-aged men and women. We examined associations between serum leptin concentration and coagulation factor concentrations and parameters of platelet activation in linear regression analyses. All analyses were adjusted for multiple covariates, including total body fat. Results In multivariable adjusted analyses a 1 μg/L higher serum leptin concentration was associated with a 0.22 IU/dL (95% CI: 0.11, 0.32) higher FVIII concentration and a 0.20 IU/dL (95% CI: 0.14, 0.27) higher FIX concentration (3.5 IU/dL FVIII and 3.2 IU/dL FIX per SD leptin). Serum leptin concentration was not associated with FXI, fibrinogen, platelet count, mean platelet volume and platelet distribution width in multivariable adjusted analyses. Discussion This study showed that serum leptin concentration was associated with higher concentrations of FVIII and FIX in an observational study, which could be clinically relevant.

Essentials The risk of recurrent venous thrombosis (VT) after leg-cast in patients with prior VT is unknown. In a nested case-control study within the MEGA follow-up study we aimed to estimate this risk. Patients with a history of VT who require lower-leg cast have a 4.5-fold risk for recurrence. This relative risk translates to an absolute risk for recurrent VT of about 3.2% within 3 months. SUMMARY: Background Patients with lower-leg cast immobilization have a substantially increased risk of developing a first venous thrombosis (VT), whereas the risk in patients with a history of VT is as yet unknown. Aims To estimate the risk of recurrent VT after lower-leg cast immobilization in patients with a history of VT. Methods A case-control study nested within a cohort of 4597 patients with a first VT who were followed over time for recurrence from 1999 to 2010 (MEGA follow-up study). Participants completed a questionnaire on risk factors for recurrent thrombosis, including having a cast in the first 3 months before a recurrence (cases) or a random 3-month period during follow-up for participants without recurrence (controls). In total, 2723/4597 (59%) participants returned the questionnaire. Odds ratios (ORs), adjusted for age and sex, were calculated to compare risks of recurrence between subjects with and without a cast. Results A total of 2525/2723 participants (93%) filled out information on cast immobilization and were included in the analysis (451 cases; 2074 controls). Twenty (1.0%) controls and 10 (2.2%) cases reported having had a lower-leg cast in the 3 months before the control or recurrence date (adjusted OR, 2.4; 95% confidence Interval [CI], 1.1-5.3). We cross-checked the data with these patients' medical records. Cast application within 3 months was verified in seven (0.3%) controls vs. six (1.3%) cases, leading to an adjusted OR of 4.5 (95% CI, 1.5-14.0) and corresponding cumulative incidence of 3.2%. Conclusions Lower-leg cast immobilization increases the risk of recurrent VT in the 3 months after its application in patients with a history of VT.

Summary Objective To determine the association between bone marrow lesions (BMLs) and (teno)synovitis as assessed on magnetic resonance (MR) imaging in patients with pain in hand osteoarthritis (OA). Methods In 105 consecutive primary hand OA patients (83% women, mean age 59 years), who were diagnosed by rheumatologists and included in the HOSTAS (Hand OSTeoArthritis in Secondary care) cohort, contrast enhanced MR imaging of right distal and proximal interphalangeal joints were obtained. In 92 patients joint site specific pain upon palpation was assessed within 3 weeks of magnetic resonance imaging (MRI) examination. MR features were scored (0–3) following the Oslo hand OA score: BMLs, synovitis, cysts, flexor tenosynovitis (FTS). Additionally, extensor tendon inflammation (ETI) (0–3) was scored. Odds ratios (OR, 95% confidence interval (CI)) were calculated using generalized estimating equations for MR features with joint pain, adjusted for putative confounders. Stratified analyses were performed to investigate interaction. Results BMLs, synovitis, cysts, FTS and ETI were demonstrated in 56%, 90%, 22%, 16% and 30% of patients, respectively. BMLs (grade 2/3 vs 0: 3.5 (1.6–7.7)) and synovitis (3 vs 0: OR 3.6 (95% CI 1.9–6.6)) were severity-dependent associated with joint pain, but FTS and ETI were not. Stratified analyses showed that BMLs did not associate with pain in the absence of synovitis, whereas synovitis was associated with pain in the absence of BMLs. Interaction was seen between BMLs and synovitis grade 2 or 3. Conclusion In hand OA patients severe synovitis is associated with joint pain, which is worsened when BMLs co-occur, suggesting synovitis as primary target of treatment.

Essentials The role of lipid levels in the risk of recurrent venous thrombosis is unclear. Lipids were assessed in patients with a first venous thrombosis (n = 2106) followed for 6.9 years. Lipids were not associated with recurrence, overall or in patients with unprovoked first events. Testing lipid levels is not useful to identify patients at an increased risk of recurrence.Background Knowledge of risk factors for recurrent venous thrombosis may guide decisions on duration of anticoagulation. The association between lipid levels and first venous thrombosis has been studied extensively. However, data on the role of lipids in the risk of recurrence are scarce. Objective To assess the association between lipid levels and recurrent venous thrombosis. Patients/Methods Patients with a first venous thrombosis from the MEGA study were included. Follow-up started at the date of end of anticoagulant treatment. Percentile categories of total/low-density lipoprotein/high-density lipoprotein cholesterol, triglycerides and apolipoproteins B and A1 were established (10th, 10th-25th, 25th-75th [reference], 75th-90th,90th percentile). Lipids were measured at least 3 months after discontinuing anticoagulation. Results Of 2106 patients followed for a median of 6.9 years, 326 developed recurrence (incidence rate, 2.7/100 patient-years; 95% confidence interval [CI], 2.5-3.1). With hazard ratios ranging from 0.88 (95% CI, 0.55-1.42) to 1.33 (95% CI, 0.86-2.04) in the highest percentile category vs. the reference, we found no association across percentile categories between recurrence and lipid levels in age- and sex-adjusted models, nor after further adjustments for body mass index, diabetes, estrogen and statin use, and duration of anticoagulation. Subgroup analyses stratified by unprovoked or provoked first events, location (deep vein thrombosis or pulmonary embolism) and sex also did not reveal an association with any of the lipid levels studied. Conclusions Testing lipid levels did not identify patients at an increased risk of recurrent venous thrombosis in this study, including those with unprovoked first events, and these should not influence decisions on duration of anticoagulation.

Objective: To investigate determinants of decrease and increase in joint pain in symptomatic finger osteoarthritis (OA) on magnetic resonance (MR) imaging over 2 years.Design: Eighty-five patients (81.2% women, mean age 59.2 years) with primary hand OA (89.4% fulfilling American College of Rheumatology (ACR) classification criteria) from a rheumatology outpatient clinic received contrast-enhanced MR imaging (1.5T) and physical examination of the right interphalangeal finger joints 2-5 at baseline and at follow-up 2 years later. MR images were scored paired in unknown time order, following the Hand OA MRI scoring system (HOAMRIS). Joint pain upon palpation was assessed by research nurses. Odds ratios (ORs; 95% confidence intervals) were estimated on joint level (n = 680), using generalized estimating equations (GEE) to account for the within patient effects. Additional adjustments were made for change in MR-defined osteophytes, synovitis, and bone marrow lesions (BMLs).Results: Of 116 painful joints at baseline, at follow-up: 76 had less pain, 21 less synovitis, and 13 less BMLs. A decrease in synovitis (OR = 5.9; 1.12-31.0), but not in BMLs (OR = 0.39; 0.10-1.50), was associated with less pain. Of 678 joints without maximum baseline pain, at follow-up: 115 had increased pain, 132 increased synovitis, 96 increased BMLs, and 44 increased osteophytes. Increased synovitis (OR = 1.81; 1.11-2.94), osteophytes (OR = 2.75; 1.59-4.8), but not BMLs (OR = 1.14; 0.81-1.60), was associated with increased pain. Through stratification it became apparent that BMLs were mainly acting as effect modifier of the synovitisepain association.Conclusion: Decrease in MR-defined synovitis is associated with reduced joint pain, identifying synovitis as a possible target for treatment of finger OA. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Essentials Elevated procoagulant levels are associated with an increased risk of venous thrombosis (VT). The dependency on concurrent increased factor levels and VT was analyzed in a large study. Factor VIII (FVIII) and von Willebrand factor (VWF) were associated with the highest VT risk. The risks for other procoagulant factor levels were largely explained by FVIII and VWF. SUMMARY: Background Coagulation factors are essential for robust clot formation. However, elevated levels of procoagulant factors are associated with an increased risk of venous thrombosis (VT). The precise contribution of these factors to the development of VT is not yet understood. Objectives We determined the thrombosis risk for the highest levels of eight selected coagulation factors. Furthermore, we analyzed which of these coagulation factors had the strongest impact on the supposed association. Methods We used data of 2377 patients with a first VT and 2940 control subjects in whom fibrinogen, von Willebrand factor (VWF), factor II, FVII, FVIII, FIX, FX and FXI levels were measured. Results The odds ratios (ORs) for the various coagulation factor levels (> 99th percentile versus ≤ 25th percentile) varied between 1.8 and 4, except for FVIII (OR 23.0; 95% confidence interval [CI] 14.7-36.0) and VWF (OR 24.0; 95% CI 15.3-37.3). Adjustment for FVIII and VWF in a mediation analysis reduced the risks of the other factors to unity, with the exception of FIX and FXI (remaining ORs between 1.7 and 1.9). Conversely, the ORs for FVIII and VWF levels remained high after adjustment for all other procoagulant factors (FVIII: 16.0; 95% CI 9.7-26.3; VWF: 17.6; 95% CI 10.7-28.8). Conclusions Our results imply that the observed relationship between VT and coagulation factor levels can be largely explained by FVIII and VWF. FVIII and VWF levels were also associated with the highest VT risk.

Essentials Genetic variation may provide valuable insight into the role of the contact system in thrombosis. Explored associations of genetic variants with activity, antigen, and disease in RATIO study. Two novel loci were identified: KLKB1 rs4253243 for prekallikrein; KNG1 rs5029980 for HMWK levels. Contact system variants and haplotypes were not associated with myocardial infarction or stroke. SUMMARY: Background The complex, interdependent contact activation system has been implicated in thrombotic disease, although few genetic determinants of levels of proteins from this system are known. Objectives Our primary aim was to study the influence of common F11, F12, KLKB1, and KNG1 variants on factor (F) XI activity and FXI, FXII, prekallikrein (PK) and high-molecular-weight kininogen (HMWK) antigen levels, as well as the risk of myocardial infarction and ischemic stroke. Patients/methods We analyzed samples from all 630 healthy participants, 182 ischemic stroke patients and 216 myocardial infarction patients in the RATIO case-control study of women aged < 50 years. Forty-three tagging single nucleotide variants (SNVs) were genotyped to represent common genetic variation in the contact system genes. Antigen and activity levels were measured with sandwich-ELISA-based and one-stage clotting assays. We performed single variant, age-adjusted, linear regression analyses per trait and disease phenotype, assuming additive inheritance and determined conditionally independent associations. Haplotypes based on the lead SNV and all conditionally independent SNVs were tested for association with traits and disease. Results We identified two novel associations of KLKB1 SNV rs4253243 with PK antigen (βconditional = -12.38; 95% CI, -20.07 to -4.69) and KNG1 SNV rs5029980 with HMWK antigen (βconditional = 5.86; 95% CI, 2.40-9.32) and replicated previously reported associations in a single study. Further analyses probed whether the observed associations were indicative of linkage, pleiotropic effects or mediation. No individual SNVs or haplotypes were associated with the disease outcomes. Conclusion This study adds to current knowledge of how genetic variation influences contact system protein levels and clarifies interdependencies.

Background: \ud Characteristics and risk factors associated with electrocardiographic borderline Q-waves are not fully elucidated, especially in individuals without overt cardiovascular disease (CVD). Also, the relation of isolated and non-isolated borderline Q-waves with subclinical atherosclerosis and vascular stiffness is unknown.\ud \ud Methods and results: \ud We included 5746 Netherlands Epidemiology of Obesity study participants without overt CVD. Participants were divided in three groups: no Q-waves (93.7%), isolated (4.6%) and non-isolated borderline Q-waves (1.7%). Borderline Q-waves were defined as Minnesota Codes 1.2.x and 1.3.x and non-isolated as ≥1 of abnormal QRS axis, left ventricular hypertrophy or ST/T abnormalities. Several characteristics and measures of body fat were assessed. Vascular stiffness was assessed by pulse wave velocity (PWV) and subclinical atherosclerosis by carotid intima-media thickness (cIMT). Percentage of men, alcohol intake, blood pressure and fasting glucose concentrations were, compared with no Q-waves, higher in the isolated and highest in the non-isolated borderline Q-wave group. Isolated borderline Q-waves were associated with higher body mass index (difference compared with no Q-waves: 1.0 kg/m2; 95%CI: 0.3–1.7; p-value: 0.006), waist circumference (3.4 cm; 1.0–5.8; 0.005), and visceral adipose tissue (21.9 cm2; 7.4–36.3; 0.003) and differences were even larger for non-isolated borderline Q-waves. Compared with no Q-waves, non-isolated borderline Q-waves were associated with higher PWV (1.2 m/s; 0.4–2.0; 0.004) and cIMT (23.4 μm; 3.0–43.8; 0.024), whereas isolated borderline Q-waves were not.\ud \ud Conclusion: \ud Cardiovascular risk factors and measures of body fat, especially abdominal adiposity, were higher in participants with isolated borderline Q-waves, compared with no Q-waves, and highest in the non-isolated borderline Q-wave group. Non-isolated borderline Q-waves were associated with subclinical atherosclerosis and vascular stiffness. Future studies should investigate potential added value of borderline Q-waves in CVD prediction.

Background:Pain is a common, difficult to manage symptom in hand osteoarthritis (OA). Multiple pain mechanisms may play a role in hand OA.Objectives:To investigate presence of neuropathic pain symptoms in patients with inflammatory hand OA, characteristics of those patients, their impact on health related quality of life (HR-QoL), and the influence of anti-inflammatory treatment on neuropathic pain symptoms.Methods:Data from a randomised, double-blind, placebo-controlled trial of prednisolone including 92 patients with hand OA fulfilling ACR criteria were used. At baseline patients had signs of synovial inflammation, a VAS finger pain of ≥30 mm and who flared ≥20 mm upon NSAID washout. The primary endpoint was VAS finger pain (0-100) at week 6.Neuropathic pain symptoms were measured at baseline and week 6 using the validated painDETECT questionnaire, consisting of questions on pain quality, pain intensity over time and radiating pain. Scores range -1 to 38 and patients are classified as having unlikely (18) neuropathic pain. HR-QoL was measured with physical component scale (PCS) of Short-Form 36 (SF36; 0-100), comorbidities with the Self-administered Comorbidities Questionnaire (SCQ; 0-45), radiographic severity with Kellgren-Lawrence (KL) sum score (0-120), and treatment response with OMERACT-OARSI responder criteria.Association of patient characteristics with neuropathic pain symptoms was analysed with univariate and multivariate ordinal logistic regression, with painDETECT as dependent variable. Association of neuropathic pain symptoms with HR-QoL was analysed with multivariate linear regression, adjusted for age, sex, BMI, VAS finger pain, SCQ score and KL sum score, with PCS as dependent variable. Response of neuropathic pain symptoms and VAS pain to prednisolone was analysed with generalised estimating equations. Association of neuropathic pain symptoms at baseline with response to treatment was analysed using χ2-tests and GEE.Results:91 patients had complete painDETECT data at baseline (mean painDETECT score 12.8 [SD 5.9]). Scores were 18 in 16%. Higher painDETECT score categories were associated with less radiographic damage, more comorbidities, female sex and higher VAS finger pain in multivariate analysis. (table 1)Table 1.Ordinal logistic regression with painDETECT categories as dependent variableVariablesMean (SD) N=91 (100%)Odds ratio (95% CI)Age64 (9)0.96 (0.90 to 1.02)Female sex; N (%)72 (79%)3.84 (1.19 to 12.39)*BMI; median (SD)27 (24 to 29)0.97 (0.89 to 1.06)SCQ score; median (SD)2 (1 to 5)1.04 (1.04 to 1.36)*VAS finger pain53.8 (2.1)1.02 (1.00 to 1.04)*KL sum score37 (16)0.96 (0.93 to 1.00)**pPatients with painDETECT scores >18 had a lower HR-QoL (PCS -6.5 [95%CI -10.4 to -2.6]) than those with painDETECT scores PainDETECT scores remained unchanged throughout the trial in both prednisolone-treated and placebo-treated patients, and there was no between-group difference at week 6. VAS pain improved more in the prednisolone group than in the placebo group (mean between-group difference -16.5 [95%CI -26.1 to -6.9]) (figure 1). No association between the presence of neuropathic pain symptoms at baseline and OMERACT-OARSI response to treatment was found.Conclusion:Patients with inflammatory hand OA and additional neuropathic pain symptoms are more often female and have more comorbidities, and report a lower QoL, than those without. Neuropathic pain symptoms seem unresponsive to anti-inflammatory therapy. Clinicians should be aware of neuropathic pain symptoms in their patients as they might benefit from additional, specific treatment.Acknowledgements:The authors thank all patients for their participation in the HOPE study, and participating rheumatologists for inclusion of patients in the HOPE study. We also thank research nurses B.A.M.J. van Schie-Geyer and S. Wongsodihardjo, and technicians J.C. Kwekkeboom and E.I.H. van der Voort, for their contributions.Disclosure of Interests:Coen van der Meulen: None declared, Lotte van de Stadt: None declared, Féline Kroon: None declared, Marion Kortekaas: None declared, Annelies Boonen Speakers bureau: Lecture for UCB; paid to department., Consultant of: Yes. Advisory board meetings at Galapagos, Eli Lilly and Abvvie; paid to department., Grant/research support from: Yes. Grants by Celgene and Abbvie; paid to department., Stefan Böhringer: None declared, Marieke Niesters: None declared, Monique Reijnierse: None declared, Frits Rosendaal: None declared, Naghmeh Riyazi: None declared, M. Starmans: None declared, Franktien Turkstra: None declared, Jende van Zeben: None declared, Cornelia Allaart: None declared, Margreet Kloppenburg Consultant of: For Abbvie, Pfizer, Levicept, GlaxoSmithKline, Merck-Serono, Kiniksa, Flexìon, Galapagos, Jansen, CHDR and local investigator of industry-driven trial (Abbvie). All fees were paid to the institution., Grant/research support from: Grant by the Dutch Arthritis Society

ObjectiveTo study the association of magnetic resonance (MR) features with radiographic progression of hand osteoarthritis over 2 years.MethodsOf 87 primary patients with hand osteoarthritis (82% women, mean age 59 years), baseline distal and proximal interphalangeal joint contrast-enhanced MR images were scored 0–3 for bone marrow lesions (BMLs) and synovitis following the Oslo score. Baseline and 2-year follow-up radiographs were scored following Kellgren-Lawrence (KL) (0–4) and OsteoArthritis Research Society International (OARSI) scoring methods (0–3 osteophytes, joint space narrowing (JSN)). Increase ≥1 defined progression. Associations between MR features and radiographic progression were explored on joint and on patient level, adjusting for age, sex, body mass index, synovitis and BML. Joints in end-stage were excluded.ResultsOf 696 analysed joints, 324 had baseline KL=0, 28 KL=4 and after 2 years 78 joints progressed. BML grade 2/3 was associated with KL progression (2/3 vs 0: adjusted risk ratio (RR) (95% CI) 3.3 (2.1 to 5.3)) and with osteophyte or JSN progression, as was synovitis. Summated scores were associated with radiographic progression on patient level (RR crude BML 1.08 (1.01 to 1.2), synovitis 1.09 (1.04 to 1.1), adjusted synovitis 1.08 (1.03 to 1.1)).ConclusionsBMLs, next to synovitis, show, already after 2 years, graded associations with radiographic progression, suggesting that both joint tissues could be important targets for therapy.

Background:Little is known about mortality in patients with systemic lupus erythematosus (SLE) presenting with neuropsychiatric (NP) symptoms.Objectives:We aimed to evaluate all-cause and cause-specific mortality in patients with SLE and NP symptoms.Methods:All patients with the clinical diagnosis of SLE of 18 years and older that visited the tertiary referral NPSLE clinic of the Leiden University Medical Center between 2007-2018 and signed informed consent were included in this study. Patients were classified as NPSLE if NP symptoms were attributed to SLE and immunosuppressive or anticoagulant therapy was initiated, otherwise patients were classified as non-NPSLE. Municipal registries were checked for current status (alive/deceased). Electronical medical files were studied for clinical characteristics and cause of death. Standardized mortality ratios (SMRs) and 95% confidence intervals were calculated using data from the general Dutch population. In addition, a rate ratio (RR) was calculated using direct standardization to compare mortality in NPSLE with non-NPSLE patients.Results:351 patients with the clinical diagnosis of SLE were included, of which 149 patients were classified as NPSLE (42.5%). Compared with the general population, mortality was increased five times in NPSLE (SMR 5.0, 95% CI: 2.6-8.5) and nearly four times in non-NPSLE patients (SMR 3.7, 95% CI: 2.2-6.0), as shown in Table 1. Risk of death due to cardiovascular disease (CVD) was increased in non-NPSLE patients (SMR 6.2, 95% CI: 2.0-14.6) and an increased risk of death to infections was present in both NPSLE and non-NPSLE patients ((SMR 29.9, 95% CI: 3.5 – 105) and SMR 91.3 (95% CI: 18.8 – 266) respectively). However, mortality did not differ between NPSLE and non-NPSLE patients (RR 1.0, 95% CI: 0.5 – 2.0).Table 1.All-cause mortality in SLE patients presenting with neuropsychiatric symptoms attributed to SLE (NPSLE) or to other causes (non-NPSLE)NPSLE(N = 149)Non-NPSLE(N = 202)Deaths (N, %)13 (8.7)17 (8.4)Age at death (median, range)49 (32 – 79)59 (20 – 89)Follow-up time (years)9061047Crude mortality rate (per 1000 PY)14.316.2All-cause mortality*Female5.5 (2.8 – 9.6)3.4 (1.9 – 5.7)Male2.3 (0.1 - 12.8)6.2 (1.3 – 18.2)Combined5.0 (2.6 – 8.5)3.7 (2.2 – 6.0)*Standardized mortality ratio, ratio of the observed and expected number of deathsConclusion:Mortality was increased in both NPSLE and non-NPSLE patients in comparison with the general population, but there was no difference in mortality between NPSLE and non-NPSLE patients. Risk of death due to infections was increased in both groups.Disclosure of Interests:Rory Monahan: None declared, Rolf Fronczek: None declared, Jeroen Eikenboom: None declared, Huub Middelkoop: None declared, L.J.J. Beaart- van de Voorde: None declared, Gisela Terwindt: None declared, Nic van der Wee: None declared, Frits Rosendaal: None declared, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Margreet Kloppenburg: None declared, G.M. Steup-Beekman: None declared

Objective: Osteoarthritis in thumb base joints (first carpometacarpal (CMC-1), scaphotrapeziotrapezoid (STT)) is prevalent and disabling, yet focussed studies are scarce. Our aim was to investigate associations between ultrasonographic and magnetic resonance imaging (MRI) inflammatory features, radiographic osteophytes, and thumb base pain in hand osteoarthritis patients. Design: Cross-sectional analyses were performed in cohorts with MRI (n = 202) and ultrasound measurements (n = 87). Pain upon thumb base palpation was assessed. Radiographs were scored for CMC-1/STT osteophytes. Synovial thickening, effusion and power Doppler signal in CMC-1 joints were assessed with ultrasound. MRIs were scored for synovitis and bone marrow lesions (BMLs) in CMC-1 and STT joints using OMERACT-TOMS. Associations between ultrasound/MRI features, osteophytes, and thumb base pain were assessed. Interaction between MRI features and osteophytes was explored. Results: In 289 patients (mean age 60.2, 83% women) 139/376 thumb bases were painful. Osteophyte presence was associated with pain (MRI cohort: odds ratio (OR) 5.1 (2.7-9.8)). Ultrasound features were present in 25-33% of CMC-1 joints, though no associations were seen with pain. MRI-synovitis and BMLs grade >= 2 were scored in 25% and 43% of thumb bases, and positively associated with pain (OR 3.6 (95% CI 1.7-7.6) and 3.0 (1.6-5.5)). Associations attenuated after adjustment for osteophyte presence. Combined presence of osteophytes and MRI-synovitis had an additive effect. Conclusions: Ultrasonographic and MRI inflammatory features were often present in the thumb base. Osteophytes were more strongly associated with thumb base pain than inflammatory features, in contrast to findings in finger OA studies, supporting thumb base osteoarthritis as a distinct phenotype. (c) 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Dutch Arthritis Foundation

Essentials Data on product-related immunogenicity in previously treated haemophilia A patients is scarce. A systematic review and meta-analysis of all currently available evidence was conducted. The overall incidence rate was 2.06 per 1000 person-years (95% confidence interval: 1.06-4.01). Some recombinant factor VIII products were associated with increased immunogenicity. Summary: Background Patients with severe hemophilia A who have been treated extensively with factor VIII products have a low but potentially serious risk of inhibitor development. It is unknown why these patients develop inhibitors, and data on product-related immunogenicity are scarce. Aims To summarize the currently available evidence on the relationship between inhibitor development and recombinant FVIII product type in previously treated patients (PTPs) with severe hemophilia A. Methods Longitudinal studies were included that reported on de novo inhibitor formation in patients with baseline FVIII activity levels of

Background: Several tools are available to measure hand pain and function in hand osteoarthritis (OA), though all have their disadvantages, e.g. being not freely available (Australian/Canadian Hand OA Index, AUSCAN), outdated (Functional assessment In Hand OA, FIHOA) or a single-item tool (Visual Analogue Scale, VAS). The MHQ is free to use, validated in other diseases, and has 6 scales assessing pain, function (overall function and activities of daily living [ADL]), and 3 unique domains: work performance, aesthetics, satisfaction (all range 0–100, and higher is better except for pain). Objectives: To investigate truth and discrimination of MHQ in hand OA. Methods: At baseline (n=383) and two-year follow-up (n=293) symptomatic hand OA patients from the Hand OSTeoArthritis in Secondary care (HOSTAS) cohort completed questionnaires (MHQ, AUSCAN, FIHOA, VAS pain). Work status was categorized into (fulltime/part-time) employed, reduced working capacity (sick leave or partial/complete disability to work), or not in the workforce (unemployed or retired). Reduced working capacity could be due to hand OA or other causes. Anchor questions assessed whether level of pain/function was acceptable or unacceptable, and different (worse, unchanged or improved) compared to baseline. Number of joints with deformities was assessed, and split into tertiles ( 5). To appraise validity of MHQ pain and function domains correlation with existing instruments (Spearman correlation coefficients, rs) was evaluated. Using external anchors to categorize patients, validity of the unique domains and discrimination of all domains was visualized in cumulative probability plots (figure 1), and mean between-group difference (MD) was calculated with linear regression. Results: At baseline patients (84% women, median age 60.3, 90% fulfilling ACR criteria) reported moderate pain (median, interquartile range MHQ pain 45, 31.3–60) and functional impairment (MHQ overall function 57.5, 50–67.5; ADL 80.5, 68.2–89.6). MHQ pain and function scales correlated well with existing instruments (table 1). Patients with reduced working capacity had worse MHQ work performance scores than employed patients (MD -25.7, 95% confidence interval [CI] -32.8;-18.6), and scores were worse if it was due to hand OA than when there was another cause (MD -21.4, -37.1;-5.8). MHQ aesthetics scores were worse in patients with more deformities (MD -1.03, -1.60;-0.45 per additional deformity). Patients with ‘unacceptable’ pain/function had worse MHQ satisfaction scores (eg. pain: MD -27.2, -37.1;-17.3). All instruments measuring pain/function could discriminate between patients with acceptable vs. unacceptable pain/function (not shown). MHQ ADL scale and AUSCAN function outperformed MHQ overall function and FIHOA in discriminating between patients whose function improved vs. worsened over time (not shown). For discrimination of change in pain over time, MHQ and AUSCAN pain both outperformed VAS pain. Conclusions: MHQ performs at least as good and may replace existing instruments in measuring pain and function in hand OA. In addition, MHQ provides information on work performance, aesthetics and satisfaction, which is not measured by other questionnaires. Sensitivity-to-change has to be assessed in future trials. Disclosure of Interest: None declared

Background Current treatment options to alleviate pain in hand osteoarthritis (OA) are limited in number, efficacy, and safety. Local inflammation and subchondral bone activity are interesting as potential treatment targets, since synovitis and bone marrow lesions (BMLs) have the ability to change over time and were shown to have positive cross-sectional associations with joint tenderness. Objectives To investigate the longitudinal associations between features on magnetic resonance (MR) imaging and joint tenderness in patients with primary hand OA over two years. Methods Eighty-five consecutively included patients (81.2% women, mean age 59.2 years) with primary hand OA (89.4% fulfilling ACR classification criteria) from a rheumatology outpatient clinic received contrast-enhanced MR imaging (1.5T) and physical examination of the right hand interphalangeal joints of digits 2–5 at baseline and at follow-up two years later. MR images were scored paired in unknown time order, following the Hand OA MRI scoring system: synovitis, BMLs, and osteophytes on a 0–3 scale (higher score reflects worse condition), with half-point increments allowed for synovitis and BMLs delta-scores. Joint tenderness upon palpation was assessed by trained research nurses on a 0–3 ordinal scale. We tested the associations between decreased MR features and decreased tenderness by calculating odds ratios on joint level (n=680), using generalised estimating equations to account for the within patient effects. Additional adjustments were made for change in MR-defined osteophytes, synovitis, and BMLs, when appropriate. Similarly, we tested the associations between increased MR features and increased tenderness, and we explored interactions between the different MR features by stratifying for one another. Results Decrease in synovitis was seen in 90 joints and decrease in BMLs in 56, however when restricted to the 116 joints with baseline tenderness, at follow-up: 76 had reduced tenderness, 21 decreased synovitis, and 13 decreased BMLs. A decrease in synovitis, but not in BMLs, was associated with attenuated tenderness (table 1). Of 678 joints without maximum baseline tenderness, at follow-up: 115 had increased tenderness, 132 increased synovitis, 96 increased BMLs, and 44 increased osteophytes. An increase in synovitis, osteophytes, and, to a lesser extent, BMLs, was associated with increased tenderness (table 2). Through stratification it became apparent that BMLs were merely an effect modifier of the synovitis-tenderness association. Conclusions In hand OA, a decrease in MR-defined synovitis is associated with a decrease in joint tenderness. Furthermore, an increase in synovitis or osteophytes is associated with increased tenderness, which is further augmented by co-occurrence of BMLs. These findings support targeting synovitis in hand OA. Disclosure of Interest None declared

Background and aims We investigated the interrelationship of rs7903146-T in TCF7L2 with measures of glucose metabolism and measures of adiposity. Methods and results This cross-sectional analysis was conducted in 5744 middle-aged participants (mean (standard deviation [SD]) age is 55.9 (6.0) years) from the Netherlands Epidemiology of Obesity (NEO) Study. Associations between rs7903146-T and Type 2 diabetes mellitus (T2D) were assessed with logistic regression. Additive (per-allele) associations with measures of glucose metabolism (e.g., fasting insulin) and adiposity (e.g., body mass index [BMI]) were examined with multivariable linear regression. In the total study population, rs7903146-T was associated with a higher risk of T2D (additive odds ratio: 1.42; 95% confidence interval: 1.17; 1.72), and specifically with T2D treated with insulin analogs (2.31 [1.19; 4.46]). After exclusion of participants treated with glucose-lowering medication, rs7903146-T was associated with lower mean insulin concentration (additive mean difference: −0.07 SD [−0.14; 0.00]), but not with higher mean glucose concentration (0.03 SD [−0.01; 0.07]). Furthermore, rs7903146-T was associated with, among other measures of adiposity, a lower mean BMI (−0.04 SD [−0.09; −0.00]), and a lower mean total body fat (−0.04 SD [−0.08; −0.00]). The association between rs7903146-T and T2D increased after adjustment for BMI (odds ratio: 1.51 [1.24; 1.86]); the association between rs7903146-T and fasting insulin diminished after adjustment (−0.05 SD [−0.11; 0.02]). Conclusion rs7903146-T is associated with a decreased insulin concentration and increased risk of T2D with opposing effects of adjustment for adiposity.

Essentials Risk of venous thrombosis (VT) related to valve thickness and valvular reflux in unknown. Venous valves and reflux were measured by ultrasonography in cases and controls aged 70+. Risk of VT was associated with increased valve thickness and valvular reflux >1second. Thickening of valves is a generic process: there was no difference between right and left legs. Summary Background Increasing age is the strongest risk factor for venous thrombosis (VT). Increasing age has been related to a thickening of the venous valves and a decreased valvular function. The association between valve thickness and the risk of VT is not known. Objectives To assess the association between increased valve thickness and valve closure time (VCT) and the risk of VT. Methods Analyses were performed in the BATAVIA study, including 70 cases aged 70 + with a first VT and 96 controls. We performed an ultrasound examination of the valves in the popliteal veins. The valves were imaged with a 9 MHz linear probe using B-mode ultrasonography. VCT was measured as an indicator for valve function using an automatic inflatable cuff. To estimate the risk of VT, valve thickness was dichotomized at the 90th percentile as measured in controls and VCT was dichotomized at 1 s. Results Mean valve thickness of controls was similar in the left (0.36 mm, 95% CI 0.34-0.37) and right (0.36 mm, 95% CI 0.35-0.38) leg. In 45 cases a valve was observed in the contralateral leg with a mean valve thickness of 0.39 mm (95% CI 0.36-0.42). Cases had an increased valve thickness compared with controls: mean difference 0.028 mm (95%CI 0.001-0.055). Valve thickness > 90th percentile increased the risk of VT 2.9-fold. Mean VCT in controls was 0.38 s, in contralateral leg of cases 0.58 s. VCT > 1 s increased the risk of VT 2.8-fold (95% CI 0.8-10.4). Conclusions Risk of VT was associated with increased valve thickness and valvular reflux of > 1 s.

In wetenschappelijk onderzoek wordt vaak geschermd met de p-waarde: als deze significant is, is de bevinding waar. Anders niet. De werkelijkheid is dat een significante p-waarde niets zegt over het waarheidsgehalte van een bepaalde conclusie en dat een niet-significante p-waarde zo mogelijk nog minder zegt over het klinisch belang van een onderzoeksresultaat. Het lijkt of p-waarden vooral populair zijn bij artsen. De noodzaak tot ja-neebeslissingen in de klinische praktijk (wel of niet insturen, wel of niet opereren) passen zij ook toe in het denken over wetenschappelijke resultaten, met een dichtome interpretatie van de p-waarde die echter contraproductief is.

Summary Background D-dimer and thrombin generation have been associated with the risk of recurrent venous thrombosis. However, for both measurements, different assays are available, and in vitro thrombin generation may be affected by the problem of contact activation during blood sampling. Objectives To determine the association between hypercoagulability and first and recurrent thrombosis by the use of different D-dimer and thrombin generation assays, to assess whether the addition of corn trypsin inhibitor (CTI) prior to blood sampling to inhibit contact activation improved the association between thrombin generation and thrombosis risk, and to calculate the DASH score with two different D-dimer assays. Methods A case–control study (626 patients and 361 controls) with subsequent follow-up of the cases was performed (2987 patient-years after stopping of anticoagulant therapy). Blood was drawn 2–3 months after discontinuation of anticoagulation for the first event in citrate tubes with and without CTI. Results/Conclusions An elevated D-dimer level and elevated thrombin generation were associated with an increased risk of a first event regardless of the assay used (odds ratios: 1.8–3.4). An elevated D-dimer level but not elevated thrombin generation was associated with the risk of recurrence. Patients with elevated D-dimer levels had a more than two-fold increased recurrence rate (Vidas – hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.4–3.8; HemosIL – HR 2.4, 95% CI 1.5–3.9; Thrombinoscope and Technoclone assay – HR 1.3). Elimination of contact factor activation did not improve the predictive value of thrombin generation. In patients with unprovoked first events, the DASH score had a similar predictive value for deep vein thrombosis and pulmonary embolism, both when calculated with Vidas D-dimer and when calculated with HemosIL D-dimer.

Summary Background In individuals with borderline von Willebrand factor (VWF) plasma levels, second-level tests are required to confirm or exclude von Willebrand disease (VWD). These tests are time-consuming and expensive. Objective To assess which parameters can predict VWD diagnosis in individuals with borderline VWF levels (30–60 IU dL−1). Methods Nine hundred and fifty individuals with bleeding episodes or abnormal coagulation test results were investigated with first-level tests (blood count, prothrombin time, activated partial thromboplastin time, blood clotting factor VIII, VWF ristocetin cofactor activity [VWF:RCo], and VWF antigen), and 93 (62 females and 31 males; median age, 28 years; interquartile range 15–44) had borderline VWF:RCo levels. All underwent second-level investigations to confirm or exclude VWD. A multivariable logistic regression model was fitted with sex, age, bleeding score, family history, VWF:RCo and ABO blood group as predictors, and used to predict VWD diagnosis. Results Forty-five of the 93 individuals (48%) had VWD (84% type 1). A negative linear relationship between VWF:RCo levels and risk of VWD diagnosis was present, and was particularly evident with blood group non-O [adjusted odds ratio 7.00 (95% confidence interval [CI] 1.48–33.11) for every 5 IU dL−1 decrease in VWF:RCo]. The other variable clearly associated with VWD diagnosis was female sex (adjusted odds ratio 5.76 [95% CI 1.47–22.53]). The area under the receiver operating characteristic curve of the full logistic model was 0.89 (95% CI 0.82–0.95). Conclusions In individuals with borderline VWF, the two strongest predictors of VWD diagnosis are low VWF:RCo levels (particularly in those with blood group non-O) and female sex. This predictive model has a promising discriminative ability to identify patients with borderline VWF levels who are likely to have VWD.

Summary. Background: Vitamin K1 (VK1) reverses the effects of vitamin K antagonists (VKAs). The literature shows that the bioavailability from solutions might be higher than that from tablets, possibly resulting in different effects. Objectives: To compare the bioavailability and effect on the International Normalized Ratio (INR) of 5-mg VK1 tablets and solution in three randomized clinical trials. Methods and results: The bioavailability was determined in a crossover trial with 25 healthy volunteers. VK1 plasma concentrations were assessed at 0, 2, 4, 5, 6, 8, 10 and 24 h, and the area under the curve was higher in the solution group than in the tablet group (mean difference 365 l gL 1 h, 95% confidence interval [CI] 230– 501, P < 0.0001). In the other two trials, the effects of both formulations on the INR were measured at 0, 24 and 48 h. In the second trial, on 72 patients on phenprocoumon with planned invasive procedures, both formulations were similarly effective, because all patients reached an INR of < 2.0, which was the primary endpoint. In the last trial, on 72 patients on phenprocoumon with an INR of 7.0–11.0, the INR decreased slightly more in the solution group (4.7, 95% CI 4.3–5.1) than in the tablet group (4.2, 95% CI 3.8–4.6). The solution group had a 3.3-fold increased likelihood (95% CI 0.7–15.1) of reaching an INR of < 2.0 at 48 h. Additionally, the increases in VK1 concentrations were similar (tablets, 3.2 l gL 1 ; solution, 3.4 l gL 1 ; P = 0.99) after 24 h. Conclusions: VK1 tablets are at least as clinically effective as the solution in countering VKAs.

The fat mass and obesity-associated (FTO) gene harbors the strongest common genetic variant associated with obesity. Recently, rs1421085-T to -C substitution mapped in FTO was shown to induce a developmental shift of human adipocytes from an energy-combusting beige to an energy-storing white phenotype in vitro. As browning of adipocytes selectively enhances fat oxidation (FatOx), we hypothesized that rs1421085-C in FTO is associated with deceased FatOx compared with carbohydrate oxidation (CarbOx) and an increased respiratory quotient (RQ).In the Netherlands Epidemiology of Obesity study, a population-based cohort study of middle-aged individuals (45-65 years), anthropometry and genotyping was performed (n=5744), in addition to indirect calorimetry (n=1246). With linear regression analyses, we examined associations of rs1421085 genotype with FatOx, CarbOx and RQ.In the total study population, 36.7% carried the rs1421085-TT genotype, 47.6% rs1421085-CT and 15.7% rs1421085-CC. Mean (s.d.) age was 56 (6) years, mean (s.d.), body mass index (BMI) was 26.3 (4.4) kg mWe observed no evidence for associations of rs1421085 in FTO with FatOx and RQ. This indicates that the rs1421085-C allele in FTO induces obesity likely via other pathways than via reduced FatOx.

Background Low-dose aspirin is the cornerstone of secondary prevention of cardiovascular disease. Previous studies suggested that the use of aspirin is associated with an increased fracture risk. However, there is uncertainty whether this is due to an effect of aspirin on bone mineral density (BMD). Methods Between 2008 and 2012, information on medication use and dual X-ray absorptiometry measured vertebral and femoral BMD of 916 participants was collected in the Netherland Epidemiology of Obesity study. The cross-sectional association between chronic low-dose aspirin use and BMD was estimated using linear regression, controlling for demography, body composition, comorbidity and other medication use which could affect BMD. A subgroup analysis in postmenopausal women (n = 329) was conducted. Results After full adjustment, there was no difference between aspirin users and non-users for vertebral BMD (adjusted mean difference: 0.036 (95% CI − 0.027 to 0.100) g/cm2) and femoral BMD (adjusted mean difference: 0.001 (− 0.067 to 0.069) g/cm2). Also in the subgroup of postmenopausal women, aspirin use was not associated with lower vertebral (adjusted mean difference: 0.069 (− 0.046 to 0.184) g/cm2) or femoral BMD (adjusted mean difference: − 0.055 (− 0.139;0.029) g/cm2). Conclusion Chronic use of low-dose aspirin is not associated with lower BMD in the general population. The increased risk of fractures observed in aspirin users in previous studies is therefore more likely to be the result of common causes of aspirin use and fractures, but not of direct effects of aspirin on BMD.

Essentials Why venous thrombosis is more prevalent in chronic kidney disease is unclear. We investigated whether renal and vascular function are associated with hypercoagulability. Coagulation factors showed a procoagulant shift with impaired renal and vascular function. This suggests that renal and vascular function play a role in the etiology of thrombosis. SUMMARY Background Impaired renal and vascular function have been associated with venous thrombosis, but the mechanism is unclear. Objectives We investigated whether estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and pulse wave velocity (PWV) are associated with a procoagulant state. Methods In this cross-sectional analysis of the NEO Study, eGFR, UACR, fibrinogen, and coagulation factors (F)VIII, FIX and FXI were determined in all participants (n = 6536), and PWV was assessed in a random subset (n = 2433). eGFR, UACR and PWV were analyzed continuously and per percentile: per six categories for eGFR (> 50th [reference] to 99th), and per four categories ( 95th percentile) for PWV. Linear regression was used and adjusted for age, sex, total body fat, smoking, education, ethnicity, total cholesterol, C-reactive protein (CRP) and vitamin K antagonists use (FIX). Results Mean age was 55.6 years, mean eGFR 86.0 (12SD) mL 1.73 m- ² and median UACR 0.4 mg mmol-1 (25th, 75th percentile; 0.3, 0.7). All coagulation factors showed a procoagulant shift with lower renal function and albuminuria. For example, FVIII was 22 IU dL-1 (95% CI, 13-32) higher in the eGFR 50th percentile, and FVIII was 12 IU dL-1 (95% CI, 3-22) higher in the UACR > 99th percentile compared with the

Background Associations between adiposity and osteoarthritis (OA) in non-weight-bearing joints suggest that besides mechanical factors also systemic influences contribute to OA. Systemically active substances secreted by adipose tissue, including leptin and adiponectin, are hypothesized to play a role in OA. Objectives To examine whether leptin and adiponectin mediate the association between body mass index (BMI) and hand and knee OA. Methods Cross-sectional data of a population-based study were used. Participants completed questionnaires and underwent standardized physical examination of hands and knees to define OA according to clinical American College of Rheumatology criteria. Fasting serum leptin and adiponectin were measured with immunoassays. Potential mediation was investigated using the Baron and Kenny framework. Four assumptions were investigated: associations between (1) BMI and OA (pathway C), (2) BMI and adipokines (pathway A), (3) adipokines and OA (pathway B), and (4) attenuation of the total association between BMI and OA after including adipokines (pathway C9). No exposure-mediator interaction and mediator-outcome confounding was assumed. Assumptions were investigated using logistic and linear regression analyses as appropriate. Odds Ratios (ORs) were calculated per standard deviation (SD) difference in BMI, and per ten and five units difference in leptin and adiponectin, respectively. Percentage mediation with 95% confidence intervals (CIs) was estimated, only when all four assumptions were fulfilled. Models were adjusted for age, ethnicity and education, and stratified by sex. Results In 6462 participants (56% women, median age 56 years (range 45–65), mean BMI 26.3 kg/m2), prevalence of hand OA, knee OA and combined hand and knee OA were 8%, 10% and 4%, respectively. Median leptin and adiponectin concentrations were 7.1 ug/L (range 0.9–60.9) and 6.0 mg/L (0.5–23.7) in men, and 19.1 ug/L (0.5–262.0) and 10.5 mg/L (0.5–98.6) in women. BMI was positively associated with OA presence and serum leptin in both men and women (Table). A negative association was observed between BMI and serum adiponectin (-0.73 mg/L per SD BMI, 95% CI -0.55;-0.91). Leptin was positively associated with most OA types, except knee OA in men. Leptin partially mediated the association of BMI with hand OA in men (9% mediation, 95% CI 5;17) and women (30%, 13;198), and the association of BMI with knee OA in women (15%, 12;21). Similar analyses for adiponectin revealed a negative association of adiponectin with hand OA in men and partial mediation of the association of BMI with hand OA in men (19%, 12;37), whereas mediation was absent in other subgroups. Conclusions Leptin partially mediated the association of BMI and hand OA in both men and women, as did adiponectin in men. In addition, mediation by leptin for the association of BMI and knee OA was demonstrated in women. These findings suggest that systemic mediators contribute to hand OA, and to a lesser extent to knee OA. Disclosure of Interest None declared

The development of anti-FVIII neutralizing alloantibodies (inhibitors), occurring in about one-third of previously untreated patients (PUPs) with severe haemophilia A, depends on various genetic and environmental risk factors. Several previous studies have reported on the immunogenicity of FVIII concentrates, and due to differences in study design, study period, inhibitor testing frequency and follow-up duration the results were inconclusive. The first randomized trial on this unresolved question (SIPPET) included 251 previously untreated or minimally treated patients with severe haemophilia A treated with either a single plasma-derived FVIII (pdFVIII) containing VWF or a recombinant FVIII (rFVIII). The results showed an 87% higher rate of inhibitor development for rFVIII than pdFVIII during the first 50 exposure days of treatment. These results generated interest by patient organizations, physicians and regulatory agencies. This manuscript summarizes answers to the main questions that arose after the full publication of SIPPET.

Contains fulltext : 138169.pdf (Publisher’s version ) (Closed access) BACKGROUND: Thyroid hormone affects the coagulation system, but its effect on clinical disease is not clear. We determined the associations of levels of free thyroxine (FT4), thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase antibodies (antiTPO) with levels of coagulation factors and the risk of venous thrombosis. METHODS: In a large population based case-control study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study) on the etiology of venous thrombosis, we determined the levels of FT4, TSH, antiTPO, factor FII, FVII, FVIII, FIX, FX, von Willebrand factor (VWF), antithrombin, protein C, protein S and fibrinogen in 2177 cases and 2826 controls. RESULTS: High levels of FT4 were associated with increased concentrations of procoagulant factors, and not with levels of anticoagulant factors. High levels of FT4 were also associated with the risk of venous thrombosis, up to an odds ratio (OR) of 2.2 (95% confidence interval [CI] 1.0-4.6) for levels above 24.4 pm relative to FT4 levels between 15.5 and 18.9 pm. In 11 cases and one control, clinical hyperthyroidism had been diagnosed within a year of the thrombotic event, leading to an OR of 17.0 (95% CI 2.2-133.0) for thrombosis. The ORs approached unity after adjustment for FVIII and VWF, which suggests that the effect was mediated by these factors. Low TSH levels were also, but less evidently, associated with thrombosis, whereas there was no association between antiTPO and venous thrombosis risk. CONCLUSIONS: High levels of FT4 increase the concentrations of the procoagulant proteins FVIII, FIX, fibrinogen, and VWF, and by this mechanism increase the risk of venous thrombosis.

Summary Background The risk of venous thrombosis (VT) associated with oral hormone therapy (HT) may differ by type of estrogen compound. Objective To compare the thrombotic profile of women using oral conjugated equine estrogens (CEE) with that of women using oral estradiol (E2). Methods In postmenopausal, female, health maintenance organization (HMO) members with no history of VT, we measured thrombin generation, levels of factor VII activity, antithrombin activity and total protein S antigen. Mean levels of hemostasis biomarkers were cross-sectionally compared by use and type of estrogen using multiple linear regressions. The type of estrogen used was determined primarily by the HMO formulary, which changed its preferred estrogen from CEE to E2 during the study period. Results The sample included 92 E2 users and 48 CEE users, with a mean age of 64.1 years and mean BMI of 29.1 kg m−2. Twenty-seven per cent of HT contained medroxyprogesterone acetate. Compared with E2 users, CEE users had greater thrombin generation peak values and endogenous thrombin potential, and lower total protein S (multivariate adjusted differences of 49.8 nm (95% CI, 21.0, 78.6), 175.0 nm × Min (95% CI, 54.4, 295.7) and −13.4% (95% CI, −19.8, −6.9), respectively). Factor VII and antithrombin levels were not different between E2 and CEE users. Results were similar in subgroups of users of unopposed HT, opposed HT, low-dose estrogen and standard dose estrogen. Conclusion The hemostatic profile of women using CEE is more prothrombotic than that of women using E2. These findings provide further evidence for a different thrombotic risk for oral CEE and oral E2.

Summary. Background: Venous thromboembolism (VTE) is a multicausal disorder involving environmental and genetic risk factors. In many thrombophilic families the clustering of thrombotic events cannot be explained by known genetic risk factors, indicating that some remain to be discovered. Objectives: We aimed to identify novel thrombosis susceptibility alleles in a large panel of small thrombophilic families: the Genetics In Familial Thrombosis (GIFT) study. Patients/Methods: In the GIFT study, 201 families were recruited consisting of 438 siblings with an objectively confirmed VTE at a young age. Multipoint linkage analysis (402 SSR markers) and fine mapping were performed, followed by genotyping of tagging SNPs in positional candidate genes. Results: Established genetic risk factors such as factor V Leiden, ABO blood group non-O, prothrombin 20210A, fibrinogen gamma 10034T and deficiencies of antithrombin, protein C and protein S were more frequent in GIFT patients than in unselected VTE patients. Linkage supported the presence of novel thrombosis susceptibility loci on 7p21.3–22.2 (LOD score = 3.23) and Xq24–27.3 (LOD score = 1.95). Simulation analysis showed that the chr7 signal was genome-wide statistically significant (P = 0.022). Tagging SNPs (n = 157) in eight positional candidate genes (LOD drop 1.5 regions) were genotyped in GIFT patients and 332 healthy controls. Five chr7 SNPs associated with VTE. SNP THSD7A rs2074597 was responsible for part of the chr7 signal. Conclusions: The GIFT panel is rich in established genetic risk factors for VTE, but genetic factors remain unidentified in many families. Genome-wide linkage failed to identify the previously established genetic risk factors for VTE, but identified a novel VTE susceptibility locus on chr7.

Essentials Men have an unexplained higher risk of a first and recurrent venous thrombosis (VT) than women. We studied the role of the major European Y chromosome haplogroups in first and recurrent VT. In contrast to a study on coronary artery disease, haplogroup I was not linked to VT risk. Haplogroup E-carriers may have an increased risk of recurrent VT, but a larger study is needed. SummaryBackground The risk of venous thrombosis (VT) recurrence is higher in men than in women. When reproductive risk factors are excluded, this sex difference is also apparent for a first VT. The current explanations for this difference are insufficient. Objectives To study the association between chromosome Y haplogroups and the risks of a first and recurrent VT. Methods Y chromosomes of 3742 men (1729 patients; 2013 controls) from the MEGA case–control study were tracked into haplogroups according to the phylogenetic tree. We calculated the risk of a first VT by comparing the major haplogroups with the most frequent haplogroup. For recurrence risk, 1645 patients were followed for a mean of 5 years, during which 350 developed a recurrence (21%; MEGA follow-up study). We calculated recurrence rates for the major haplogroups, and compared groups by calculating hazard ratios. Results We observed 13 haplogroups, of which R1b was the most frequent (59%). The major haplogroups were not associated with a first VT, with odds ratios ranging from 1.01 to 1.15. Haplogroup E carriers had the highest recurrence rate (53.5 per 1000 person-years, 95% confidence interval [CI] 33.3–86.1), whereas haplogroup R1a carriers had the lowest recurrence rate (24.3 per 1000 person-years, 95% CI 12.6–46.6). As compared with haplogroup R1b carriers, both haplogroups were not significantly associated with recurrence risk. Conclusions In contrast to a study on coronary artery disease, our results do not show a clear predisposing effect of Y haplogroups on first and recurrent VT risk in men. It is therefore unlikely that Y variation can explain the sex difference in VT risk.

Essentials Risk of venous thrombosis (VT) related to common genetic variants in those aged 70+ is unknown. We studied Factor V Leiden, prothrombin mutation, non-O blood group and family history (FH) of VT. Risk of VT was increased 2.2-, 1.4-, 1.3- and 2.1-fold respectively. FH is easy to obtain and can be implemented in clinical decision rules of VT risk in the elderly. Click to hear Prof. Reitsma discuss genetic risk factors of arterial and venous thrombosis SummaryBackground As the incidence of venous thrombosis (VT) increases steeply with age and the number of elderly people is on the rise, studies of VT in this age group are important. Objectives We aimed to study the associations of common genetic risk factors (i.e. the factor V Leiden and prothrombin G20210A mutations, non-O blood group and family history of VT) with risk of a first VT in older age (> 70 years). Methods Four hundred and one consecutive cases with a first-time thrombosis and 431 controls (all ≥ 70 years) were included in the AT-AGE case–control study. Information on risk factors for VT, including family history of VT in first-degree relatives, was obtained by interview. Unprovoked VT was defined as thrombosis not related to surgery, fracture, plaster cast or immobility within 3 months prior to VT. Results The risk of VT was 2.2-fold increased in factor V Leiden carriers (95% confidence interval [CI], 1.2–3.9), 1.4-fold increased in prothrombin mutation carriers (95% CI, 0.5–3.9), and 1.3-fold increased in those with non-O blood group (95% CI, 1.0–1.8). Positive family history of VT was associated with a 2.1-fold increased risk of VT (95% CI, 1.5–3.1). The highest risk of VT was found in individuals who had both a positive family history and were carriers of one of the two prothrombotic mutations. Conclusions Genetic factors clearly related to VT in younger populations were also risk factors in older age and a positive family history was also important in this age group.