The effect of subcutaneous and sublingual birch pollen immunotherapy on birch pollen-related food allergy: a systematic review.

Background: Birch pollen-related food allergy (BPFA) is the most common type of food allergy in birch-endemic areas such as Western and Central Europe. Currently, there is no treatment available for BPFA. Due to the cross-reactivity between birch pollen and a range of implicated plant foods, birch pollen allergen immunotherapy (AIT) may be effective in the treatment of BPFA. In this study, we systematically evaluate the effectiveness of birch pollen-specific subcutaneous or sublingual immunotherapy in treating BPFA. Methods: A search was performed in the PubMed, Embase, and Cochrane libraries. Studies were independently screened by two reviewers against predefined eligibility criteria. The outcomes of interest were changes in (1) severity of symptoms during food challenge, (2) eliciting dose (ED), and (3) food allergy quality of life (FA-QoL). The validity of the selected articles was assessed using the revised Cochrane risk of bias tool. We focused on studies with the lowest risk of bias and considered studies with a high risk of bias as supportive. Data were descriptively summarized. Results: Ten studies were selected that included 475 patients in total. Seven studies were categorized into "high risk of bias" and three into "moderate risk of bias." The three moderate risk of bias studies, with a total of 98 patients, reported on severity of symptoms during challenge and on the ED. All three studies had a control group. Compared to the control group, improvement in severity of symptoms was observed during challenge in two out of the three studies and on the eliciting dose in one out of three. Only one study investigated the effect of birch pollen AIT on FA-QoL, showing that there was no significant difference between patients receiving subcutaneous immunotherapy or a placebo. Of the seven supportive studies, four had a control group and of those, three showed improvement on both severity of symptoms and ED. None of the supportive studies investigated the effect of the therapy on FA-QoL. Conclusion: This systematic review shows that there is not enough evidence to draw firm conclusions about the effect of AIT on BPFA. Future research is warranted that uses robust clinical studies that include long-term effects, QoL, and multiple BPFA-related foods.

A European-Japanese study on peach allergy: IgE to Pru p 7 associates with severity.

BACKGROUND: Pru p 3 and Pru p 7 have been implicated as risk factors for severe peach allergy. This study aimed to establish sensitization patterns to five peach components across Europe and in Japan, to explore their relation to pollen and foods and to predict symptom severity. METHODS: In twelve European (EuroPrevall project) and one Japanese outpatient clinic, a standardized clinical evaluation was conducted in 1231 patients who reported symptoms to peach and/or were sensitized to peach. Specific IgE against Pru p 1, 2, 3, 4 and 7 and against Cup s 7 was measured in 474 of them. Univariable and multivariable Lasso regression was applied to identify combinations of parameters predicting severity. RESULTS: Sensitization to Pru p 3 dominated in Southern Europe but was also quite common in Northern and Central Europe. Sensitization to Pru p 7 was low and variable in the European centers but very dominant in Japan. Severity could be predicted by a model combining age of onset of peach allergy, probable mugwort, Parietaria pollen and latex allergy, and sensitization to Japanese cedar pollen, Pru p 4 and Pru p 7 which resulted in an AUC of 0.73 (95% CI 0.73-0.74). Pru p 3 tended to be a risk factor in South Europe only. CONCLUSIONS: Pru p 7 was confirmed as a significant risk factor for severe peach allergy in Europe and Japan. Combining outcomes from clinical and demographic background with serology resulted in a model that could better predict severity than CRD alone.

Performance of knee image digital analysis of radiographs of patients with end-stage knee osteoarthritis.

OBJECTIVE: Knee Image Digital Analysis (KIDA) is standardized radiographic analysis software for measuring osteoarthritis (OA) characteristics. It was validated in mild OA, but used for severe OA as well. The current goal was to evaluate the performance of KIDA in severe OA. DESIGN: Of 103 patients, standardized radiographs were performed before and one and 2 years after treatment for severe OA. All radiographs were evaluated on subchondral bone density, joint space width (JSW), osteophytes, eminence height, and joint angle, twice within years by the same observer. Part of the radiographs were randomly selected for reevaluation twice within 1 month and evaluation by another observer. The intraclass correlation coefficient (ICC), smallest detectable difference (SDD) and coefficient of variation (CV) were calculated; the SDD and CV were compared to those in mild OA. The relation of severity with KIDA parameters and with observer differences was calculated with linear regression. RESULTS: Intra-observer ICCs were higher in the 98 severe radiographs reanalyzed within 1 month (all >0.8) than the 293 reanalyzed within years (all >0.5; most >0.8) and than inter-observer ICCs (all >0.7). SDDs and CVs were smaller when reanalyzed within a month and comparable to those in mild OA. Some parameters showed bias between readings. Severity showed significant relation with osteophytes and JSW parameters, and with the observer variation in these parameters (all P < 0.04). CONCLUSIONS: KIDA is a well-performing tool also for severe OA. In order to decrease variability and SDDs, images should be analyzed in a limited time frame and randomized order.

The multi-biomarker disease activity test for assessing response to treatment strategies using methotrexate with or without prednisone in the CAMERA-II trial.

OBJECTIVES: The CAMERA-II trial compared two tight-control, treat-to-target strategies, initiating methotrexate with prednisone (MTX+pred) or MTX with placebo (MTX+plac), in early RA-patients. The multi-biomarker disease activity (MBDA) blood test objectively measures RA disease activity with a score of 1-100. In CAMERA-II, response profiles of the MBDA score, its individual biomarkers, and DAS28 were assessed. METHODS: We evaluated 92 patients from CAMERA-II of whom clinical data and serum for MBDA testing at baseline and ≥ 1 time-point from months 1, 2, 3, 4, 5, 6, 9, or 12 were available. Changes (∆) from baseline for DAS28 and MBDA score and comparisons of ∆DAS28 and ∆MBDA score over time within the MTX+pred versus the MTX+plac strategy were tested for significance with t tests. Changes in biomarker concentration from baseline to months 1-5 were tested with Wilcoxon signed rank test and tested for difference between treatment arms by Mann-Whitney U test. RESULTS: MBDA and DAS28 showed similar response profiles, with gradual improvement over the first 6 months in the MTX+plac group, and in the MTX+pred group faster improvement during month 1, followed by gradual improvement. The 12 MBDA biomarkers could be grouped into 4 categories of response profiles, with significant responses for 4 biomarkers during the MTX+plac strategy and 9 biomarkers during the MTX+pred strategy. CONCLUSIONS: MBDA tracked treatment response in CAMERA-II similarly to DAS28. More individual MBDA biomarkers tracked treatment response to MTX+pred than to MTX+plac. Four response profiles could be observed. TRIAL REGISTRATION: CAMERA-II International Standard Randomised Controlled Trial Number: ISRCTN 70365169 . Registered on 29 March 2006, retrospectively registered.

An automated workflow based on hip shape improves personalized risk prediction for hip osteoarthritis in the CHECK study.

OBJECTIVE: To design an automated workflow for hip radiographs focused on joint shape and tests its prognostic value for future hip osteoarthritis. DESIGN: We used baseline and 8-year follow-up data from 1,002 participants of the CHECK-study. The primary outcome was definite radiographic hip osteoarthritis (rHOA) (Kellgren-Lawrence grade ≥2 or joint replacement) at 8-year follow-up. We designed a method to automatically segment the hip joint from radiographs. Subsequently, we applied machine learning algorithms (elastic net with automated parameter optimization) to provide the Shape-Score, a single value describing the risk for future rHOA based solely on joint shape. We built and internally validated prediction models using baseline demographics, physical examination, and radiologists scores and tested the added prognostic value of the Shape-Score using Area-Under-the-Curve (AUC). Missing data was imputed by multiple imputation by chained equations. Only hips with pain in the corresponding leg were included. RESULTS: 84% were female, mean age was 56 (±5.1) years, mean BMI 26.3 (±4.2). Of 1,044 hips with pain at baseline and complete follow-up, 143 showed radiographic osteoarthritis and 42 were replaced. 91.5% of the hips had follow-up data available. The Shape-Score was a significant predictor of rHOA (odds ratio per decimal increase 5.21, 95%-CI (3.74-7.24)). The prediction model using demographics, physical examination, and radiologists scores demonstrated an AUC of 0.795, 95%-CI (0.757-0.834). After addition of the Shape-Score the AUC rose to 0.864, 95%-CI (0.833-0.895). CONCLUSIONS: Our Shape-Score, automatically derived from radiographs using a novel machine learning workflow, may strongly improve risk prediction in hip osteoarthritis.

Dalteparin and anti-Xa: a complex interplay of therapeutic drug monitoring.

BACKGROUND: Monitoring low-molecular-weight heparins is generally not required. However, guidelines advise to monitor anti-Xa levels in patients with renal insufficiency or a BMI above 50, and in pregnancy. Measuring anti-Xa levels is a complex challenge since sampling should be performed three to five hours after subcutaneous injection and after steady state concentrations have been reached. Strict compliance is pivotal for justified dose adjustments. OBJECTIVES: We questioned compliance to our protocol and performed this study to explore that. METHODS: This retrospective cohort study included patients ≥ 18 years receiving therapeutic dalteparin in a Dutch academic medical centre. Patients with a first anti-Xa level measured between February 23rd and December 30th, 2017 were selected. According to our local guideline, monitoring anti-Xa activity is indicated in patients on therapeutic doses of dalteparin who are pregnant, morbidly obese (BMI > 50), or have renal insufficiency (clearance < 60 ml/min). Accurate sampling was defined as measuring levels after at least three injections (after which a patient may reach steady state) and then four hours after the injection with dalteparin. The frequency of compliance to our protocol was assessed. RESULTS: We included 158 patients with 396 anti-Xa levels, of which 41% (65/158) of all first anti-Xa levels were drawn without appropriate indication. Almost half, 48% (211/396), were sampled incorrectly and 25% of these (53/211) were followed by a dose adjustment. In total, 74% (293/396) of the samples were not indicated or were taken at the wrong time. CONCLUSIONS: Monitoring anti-Xa levels is a complex clinical challenge. This study showed that non-compliance with recommendations for anti-Xa monitoring was high, often resulting in unjustified dose adjustments.

Measurement error in continuous endpoints in randomised trials: Problems and solutions.

In randomised trials, continuous endpoints are often measured with some degree of error. This study explores the impact of ignoring measurement error and proposes methods to improve statistical inference in the presence of measurement error. Three main types of measurement error in continuous endpoints are considered: classical, systematic, and differential. For each measurement error type, a corrected effect estimator is proposed. The corrected estimators and several methods for confidence interval estimation are tested in a simulation study. These methods combine information about error-prone and error-free measurements of the endpoint in individuals not included in the trial (external calibration sample). We show that, if measurement error in continuous endpoints is ignored, the treatment effect estimator is unbiased when measurement error is classical, while Type-II error is increased at a given sample size. Conversely, the estimator can be substantially biased when measurement error is systematic or differential. In those cases, bias can largely be prevented and inferences improved upon using information from an external calibration sample, of which the required sample size increases as the strength of the association between the error-prone and error-free endpoint decreases. Measurement error correction using already a small (external) calibration sample is shown to improve inferences and should be considered in trials with error-prone endpoints. Implementation of the proposed correction methods is accommodated by a new software package for R.

Effectiveness of Remission Induction Strategies for Early Rheumatoid Arthritis: a Systematic Literature Review.

PURPOSE OF REVIEW: To review the effectiveness of remission induction strategies compared to single csDMARD-initiating strategies according to current guidelines in early RA. RECENT FINDINGS: Twenty-nine studies, heterogeneous on, e.g., specific treatment strategy and remission outcome used, were identified. Using DAS28-remission over 12 months, 13 (76%) of 17 remission induction strategies showed significantly more patients achieving remission. Pooled relative "risk" was 1.73 [95%CI 1.59-1.88] for bDMARD-based remission induction strategies and 1.20 [95%CI 1.03-1.40] for combination csDMARD-based remission induction strategies compared to single csDMARD-initiating strategies. When additional glucocorticoid "bridging therapy" was used in single csDMARD-initiating strategies, the higher proportion patients achieving remission in remission induction strategies was no longer statistically significant (pooled RR 1.06 [95%CI 0.83-1.35]). For other remission outcomes, results were in line with above. Remission induction strategies are more effective in achieving remission compared to single csDMARD-initiating strategies, possibly more so in bDMARD-based induction strategies. However, compared to single csDMARD-initiating strategies with glucocorticoids, induction strategies may not be more effective.

Can optical spectral transmission assess ultrasound-detected synovitis in hand osteoarthritis?

OBJECTIVE: To determine whether optical spectral transmission (OST) can be used to assess synovitis in hand and wrist joints of patients with hand osteoarthritis (OA). DESIGN: Hand and wrist joints of 47 primary hand OA patients with at least one clinically inflamed hand or wrist joint were assessed for synovitis by OST and ultrasound (US). Associations between standardized OST and US synovitis were studied in linear mixed effects models, across all joint types together and individually for wrist, proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints, and were adjusted for OA features that showed associations with US synovitis. Diagnostic performance was determined using receiver operator characteristic (ROC) curves analysis, with US as reference standard. RESULTS: Altogether, 6.7% of joints showed US synovitis. Statistically significant associations between OST scores and US synovitis were found for all joints combined (Δ0.37SD, p<0.001) and PIP joints (Δ0.81SD, p<0.001), but not for DIP (Δ0.14SD, p = 0.484) or wrist joints (Δ0.37SD, p = 0.178). All associations were independent of other OA features, i.e. osteophytes and dorsal vascularity. Analysis of diagnostic performance of OST, revealed an area under the ROC curve (AUC-ROC) of 0.74 for all joints together (p<0.001), 0.69 for PIP joints (p<0.001), 0.54 for DIP joints (p = 0.486), and 0.61 for wrist joints (p = 0.234). CONCLUSIONS: OST scores and US synovitis are statistically significantly associated, independent of osteophytes and dorsal vascularity. At this stage, OST performs fair in the assessment of synovitis in PIP joints of hand OA patients.

Local and systemic inflammatory lipid profiling in a rat model of osteoarthritis with metabolic dysregulation.

OBJECTIVE: Bioactive oxidised lipids (oxylipins) are important signalling mediators, capable of modulating the inflammatory state of the joint and anticipated to be of importance in joint homeostasis and status of osteoarthritis. The aim of this study was to quantify oxylipin levels in plasma and synovial fluid from rats with experimentally induced osteoarthritis to investigate the potential role of oxylipins as a marker in the disease process of early osteoarthritis. DESIGN: Forty rats were randomly allocated to a standard or high-fat diet group. After 12 weeks, local cartilage damage was induced in one knee joint in 14 rats of each diet group. The remaining 6 rats per group served as controls. At week 24, samples were collected. Oxylipin levels were quantified by liquid chromatography-mass spectrometry. RESULTS: Overall, 31 lipid-derived inflammatory mediators were detected in fasted plasma and synovial fluid. Principal component analysis identified four distinct clusters associated with histopathological changes. Diet induced differences were evident for 13 individual plasma oxylipins, as well as 5,6-EET in synovial fluid. Surgical-model induced differences were evident for three oxylipins in synovial fluid (15-HETE, 8,9-DHET and 17R-ResolvinD1) with a different response in lipid concentrations for synovial fluid and plasma. CONCLUSIONS: We demonstrate the quantification of oxidised lipids in rat plasma and synovial fluid in a model of early experimental osteoarthritis. Oxylipins in the synovial fluid that were altered as consequence of the surgically induced osteoarthritis were not represented in the plasma. Our findings suggest differential roles of the oxylipins in the local versus peripheral compartment.

Disease burden of knee osteoarthritis patients with a joint replacement compared to matched controls: a population-based analysis of a Dutch medical claims database.

OBJECTIVE: On a population level, the incidence of knee prostheses (KPs) has increased, but excess health care costs per patient, compared to matched controls without a KP, in the years surrounding these procedures and their determinants are largely unknown. We therefore aimed to provide estimates of age- and sex-specific incidence of KPs, revision KPs, and prosthesis complications in patients with knee osteoarthritis (OA) and to determine excess health care costs in the years surrounding surgery compared with matched controls. METHODS: All KPs in OA patients in the Achmea Health Database were identified as well as up to four controls. Incidence rates of KPs, revisions, and complications from 2006 to 2013 were determined. Annual health care cost and excess costs (over matched controls) preceding, during, and after surgery were calculated and their determinants were evaluated. RESULTS: The increased incidence of KPs, revisions, and complications was strongest in younger age categories and men. The average costs per patient were relatively stable between 2006 and 2012. KP patient's annual health care costs increased towards the year of surgery. After surgery, costs decreased, but remained higher as compared to costs prior to surgery. High post-surgery costs were mainly associated with subsequent revisions or additional KPs, but costs were also higher in females, lower age categories, and lower social economic status. CONCLUSION: These results underscore the increasing burden and medical need associated with end-stage OA, especially in younger age categories. Improvement of guidelines tailored to individual patient groups aimed at avoiding complications and revisions is required to counteract this increasing burden.

A sex-specific association between incident radiographic osteoarthritis of hip or knee and incident peripheral arterial calcifications: 8-year prospective data from Cohort Hip and Cohort Knee (CHECK).

OBJECTIVES: There is sparse evidence for a relationship between cardiovascular disease (CVD) and osteoarthritis (OA). We investigated the association between incidence of arterial calcifications and incidence of radiographic knee and/or hip OA. DESIGN: We used baseline and 8-year follow-up data of Cohort Hip and Cohort Knee (CHECK). Knees and hips were either Kellgren-Lawrence (KL) grade 0 or 1 at baseline. Arterial calcifications were scored on hip and knee radiographs using a four-grade scale. Scores were summed for patient-level analyses. To investigate incidence, participants with arterial calcifications at baseline or missing follow-up were excluded. Incident OA was defined per joint as KL ≥ 2 or prosthesis at year eight. The association between incidenct of arterial calcifications and incident OA was studied using mixed-effects logistic regression. RESULTS: Of 763 participants included, 623 (82%) were women. Mean (sd) age was 56 (5.1) years, mean (sd) body mass index (BMI) 26.2 (4.1) kg/m2. Arterial calcifications developed in 174 participants (283 joints). OA developed in 456 participants (778 joints). Sex modified the association between arterial calcification and OA. In women, incident arterial calcification around a joint was positively associated with incident OA in that joint (adjusted OR 2.51 (95% CI 1.57-4.03)). In men, no association was observed on joint-level, but at patient-level the arterial calcification sum score was negatively associated with incident OA (adjusted OR per point increase 0.70 (95% CI 0.54-0.90)) indicating a systemic effect. CONCLUSIONS: We observed sex-dependent associations between incident arterial calcification and incident radiographic knee and/or hip OA, which differs between joint- and patient-level.

Prediction of cartilaginous tissue repair after knee joint distraction.

BACKGROUND: For young patients (<65years), knee joint distraction (KJD) may be a joint-saving treatment option for end-stage knee osteoarthritis. Distracting the femur from the tibia by five millimeters for six to eight weeks using an external fixation frame results in cartilaginous tissue repair, in addition to clinical benefits. This study is a first attempt to predict the degree of cartilaginous tissue repair after KJD. METHODS: Fifty-seven consecutive patients received KJD. At baseline and at one year of follow-up, mean and minimum joint space width (JSW) of the most-affected compartment was determined on standardized radiographs. To evaluate the predictive ability of baseline characteristics for JSW at one year of follow-up, multivariable linear regression analysis was performed. RESULTS: Mean JSW±SD of the most affected compartment increased by 0.95±1.23mm to 3.08±1.43mm at one year (P<0.001). The minimum JSW increased by 0.94±1.03mm to 1.63±1.21mm at one year of follow-up (P<0.001). For a larger mean JSW one year after KJD, only Kellgren & Lawrence grade (KLG) at baseline was predictive (Regression coefficient (ß)=0.47, 95% CI=0.18 to 0.77, P=0.002). For a larger minimum JSW, KLG (ß=0.46, 95% CI=0.19 to 0.73, P=0.001) and male gender (ß=0.52, 95% CI=0.06 to 0.99, P=0.028) were statistically predictive. Eight weeks of distraction time neared significance (ß=0.44, 95% CI=-0.05 to 0.93, P=0.080). CONCLUSIONS: In our cohort of patients treated with KJD, males with higher KLG had the best chance of cartilaginous tissue repair by distraction.

Knee Joint Distraction Compared to Total Knee Arthroplasty for Treatment of End Stage Osteoarthritis: Simulating Long-Term Outcomes and Cost-Effectiveness.

OBJECTIVE: In end-stage knee osteoarthritis the treatment of choice is total knee arthroplasty (TKA). An alternative treatment is knee joint distraction (KJD), suggested to postpone TKA. Several studies reported significant and prolonged clinical improvement of KJD. To make an appropriate decision regarding the position of this treatment, a cost-effectiveness and cost-utility analysis from healthcare perspective for different age and gender categories was performed. METHODS: A treatment strategy starting with TKA and a strategy starting with KJD for patients of different age and gender was simulated. To extrapolate outcomes to long-term health and economic outcomes a Markov (Health state) model was used. The number of surgeries, QALYs, and treatment costs per strategy were calculated. Costs-effectiveness is expressed using the cost-effectiveness plane and cost-effectiveness acceptability curves. RESULTS: Starting with KJD the number of knee replacing procedures could be reduced, most clearly in the younger age categories; especially revision surgery. This resulted in the KJD strategy being dominant (more effective with cost-savings) in about 80% of simulations (with only inferiority in about 1%) in these age categories when compared to TKA. At a willingness to pay of 20.000 Euro per QALY gained, the probability of starting with KJD to be cost-effective compared to starting with a TKA was already found to be over 75% for all age categories and over 90-95% for the younger age categories. CONCLUSION: A treatment strategy starting with knee joint distraction for knee osteoarthritis has a large potential for being a cost-effective intervention, especially for the relatively young patient.

A Personalized Approach to Biological Therapy Using Prediction of Clinical Response Based on MRP8/14 Serum Complex Levels in Rheumatoid Arthritis Patients.

OBJECTIVES: Measurement of MRP8/14 serum levels has shown potential in predicting clinical response to different biological agents in rheumatoid arthritis (RA). We aimed to develop a treatment algorithm based on a prediction score using MRP8/14 measurements and clinical parameters predictive for response to different biological agents. METHODS: Baseline serum levels of MRP8/14 were measured in 170 patients starting treatment with infliximab, adalimumab or rituximab. We used logistic regression analysis to develop a predictive score for clinical response at 16 weeks. MRP8/14 levels along with clinical variables at baseline were investigated. We also investigated how the predictive effect of MRP8/14 was modified by drug type. A treatment algorithm was developed based on categorizing the expected response per drug type as high, intermediate or low for each patient and optimal treatment was defined. Finally, we present the utility of using this treatment algorithm in clinical practice. RESULTS: The probability of response increased with higher baseline MRP8/14 complex levels (OR = 1.39), differentially between the TNF-blockers and rituximab (OR of interaction term = 0.78), and also increased with higher DAS28 at baseline (OR = 1.28). Rheumatoid factor positivity, functional disability (a higher HAQ), and previous use of a TNF-inhibitor decreased the probability of response. Based on the treatment algorithm 80 patients would have been recommended for anti-TNF treatment, 8 for rituximab, 13 for another biological treatment (other than TNFi or rituximab) and for 69 no recommendation was made. The predicted response rates matched the observed response in the cohort well. On group level the predicted response based on the algorithm resulted in a modest 10% higher response rate in our cohort with much higher differences in response probability in individual patients treated contrary to treatment recommendation. CONCLUSIONS: Prediction of response using MRP8/14 levels along with clinical predictors has potential in personalizing treatment for RA patients starting biological anti-rheumatic treatment, and might increase cost-effectiveness.

Economic evaluation of a tight-control treatment strategy using an imaging device (handscan) for monitoring joint inflammation in early rheumatoid arthritis.

OBJECTIVES: To evaluate the cost-effectiveness of a tight-control treatment strategy using the handscan (TCHS) compared to using only clinical assessments (TC) and compared to a general non-tight-control treatment strategy (usual care; UC) in early rheumatoid arthritis (RA). METHODS: Data from 299 early RA patients from the CAMERA trial were used. Clinical outcomes were extrapolated to Quality Adjusted Life Years (QALYs) and costs using a Markov model. Costs and QALYs were compared between the TC and UC treatment strategy arm of the CAMERA trial and a simulated tight-control treatment strategy using the handscan (TCHS). Incremental Cost-Effectiveness Ratios (ICERs) were calculated and several scenario analyses performed. All analyses were performed probabilistically to obtain confidence intervals and costs-effectiveness planes and acceptability curves. RESULTS: In TCHS, €4,660 (95% CI -€11,516 to €2,045) was saved and 0.06 (95% CI 0.01 to 0.11) QALYs were gained when compared to UC, with an ICER of €77,670 saved per QALY gained. Ninety-one percent (91%) of simulations resulted in less costs and more QALYs. TCHS resulted in comparable costs or even limited savings €642 (95% CI -€6,903 to €5,601)) and comparable QALYs to TC. In all scenario analyses, TCHS and TC were found to be cost effective as compared to UC. CONCLUSIONS: A tight-control treatment strategy is highly cost-effective compared to a non-tight-control approach in early RA. Using the handscan as a monitoring device might facilitate implementation of tight-control treatment strategy at comparable costs and with comparable effects. This approach should be investigated further.

Anti-osteoporosis drug prescribing after hip fracture in the UK: 2000-2010.

UNLABELLED: The probability of initiating with anti-osteoporosis therapy increased from 7 % in 2000 to 46 % in 2010. This improvement was greater for patients over the age of 75 years. Men, those overweight, having dementia or exposed to antipsychotics, sedatives/hypnotics or opioid analgesics were significantly less likely to receive anti-osteoporosis drugs. INTRODUCTION: The objective of this study was to examine trends and determinants of anti-osteoporosis drug prescribing after hip fracture in the UK between 2000 and 2010. METHODS: Data were extracted from the UK Clinical Practice Research Datalink for patients ≥50 years who had a first hip fracture between 2000 and 2010 and who did not currently (≤6 months prior) receive anti-osteoporosis drugs (bisphosphonates, strontium ranelate, parathyroid hormone, calcitonin and raloxifene) (n = 27,542). The cumulative incidence probability of being prescribed anti-osteoporosis drugs within 1 year after hip fracture was estimated by Kaplan-Meier life-table analyses. Determinants for treatment initiation were estimated by Cox proportional hazards models. RESULTS: The probability of being prescribed any anti-osteoporosis drug after hip fracture increased from 7 % in 2000 to 46 % in 2010. This trend was more marked in patients ≥75 years. The increase in prescribing of anti-osteoporosis drugs was complemented by a similar increase in vitamin D/calcium provision. Cumulative incidence of receiving anti-osteoporosis therapy was greater at any given point in time in women (8 % in 2000, 51 % in 2010) compared to men (4 % in 2000, 34 % in 2010). In addition to male gender, multivariable Cox regression identified reduced likelihood of receiving anti-osteoporosis drugs for those being overweight, having dementia and exposed to psychotropic drugs (antipsychotics, sedatives/hypnotics) or opioid analgesics. CONCLUSION: Although the prescribing of anti-osteoporosis drugs after hip fracture has increased substantially since 2000, the overall rate remained inadequate, particularly in men. With the continuing increase in the absolute number of hip fractures, further research should be made into the barriers to optimise osteoporosis management.

The ability of systemic biochemical markers to reflect presence, incidence, and progression of early-stage radiographic knee and hip osteoarthritis: data from CHECK.

OBJECTIVE: To relate systemic biochemical markers of joint metabolism to presence, incidence, and progression of early-stage radiographic knee and/or hip osteoarthritis (OA). METHOD: The cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, and synovial markers sHA and sPIIINP were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of CHECK (Cohort Hip and Cohort Knee), a cohort study of early-stage symptomatic knee and/or hip OA. Knee and hip radiographs were obtained at baseline and 5-year follow-up. Presence of OA at baseline was defined as Kellgren and Lawrence (K&L) = 1 (maximum observed). Incidence of OA was defined as K&L = 0 at baseline and K&L ≥ 1 at 5-year follow-up. Progression of OA was defined as K&L = 1 at baseline and K&L ≥ 2 at 5-year follow-up. RESULTS: Data were available for 801 subjects at baseline and for 723 subjects at both baseline and 5-year follow-up. Multiple cartilage and synovial markers showed positive associations with presence and progression of knee and hip OA and with incidence of hip OA, except for negative associations of uCTX-II and sCOMP with incidence of knee OA. uCTX-II and sCOMP showed multiple interactions with other biomarkers in their associations with knee and hip OA. Bone markers were positively associated with presence of radiographic knee OA, but negatively associated with progression of radiographic hip OA. CONCLUSION: Especially metabolism in cartilage and synovial matrix appear to be of relevance in knee and hip OA. The role of bone metabolism appears to differ between knee and hip OA.

Long-term persistence with anti-osteoporosis drugs after fracture.

UNLABELLED: Long-term persistence with anti-osteoporosis drugs and determinants for discontinuation among fracture patients were examined. Persistence was 75.0 and 45.3 % after 1 and 5 years, respectively. Those aged ≥80 years were at increased risk of early discontinuation. Within 1 year after discontinuation, 24.3 % restarted therapy, yet 47.0 % persisted for 1 year. INTRODUCTION: The risk of osteoporotic fracture can effectively be reduced with use of anti-osteoporosis drugs. However, little is known about persistence with these drugs after fracture where subsequent fracture risk is high. The aims were to determine long-term persistence with anti-osteoporosis drugs among fracture patients, including its determinants, and to describe restart and subsequent persistence. METHODS: A cohort study was conducted within the Dutch PHARMO Database Network. Patients aged ≥50 years (n = 961) who received anti-osteoporosis drugs within 1 year after fracture, but not in the preceding year, were included (2002-2011). Persistence (defined as the proportion on treatment) and the proportion restarting after discontinuation were estimated using Kaplan-Meier analyses. Time-dependent Cox regression was used to identify determinants of non-persistence including age, sex, initial dosage regime, fracture type, comorbidities, and drug use. RESULTS: Persistence with anti-osteoporosis drugs was 75.0 % (95 % confidence interval (CI) 72.0-77.7) and 45.3 % (95 % CI 40.4-50.0) after 1 and 5 years, respectively. A significant determinant of non-persistence was age ≥80 years (reference 50-59 years: adjusted hazard ratio [adj. HR] 1.65; 95 % CI 1.15-2.38). This effect was not constant over time (≤360 days following initiation: adj. HR 2.07; 95 % CI 1.27-3.37; >360 days: adj. HR 1.08; 95 % CI 0.62-1.88). Within 1 year after discontinuation, 24.3 % (95 % CI 20.1-29.2) restarted therapy, yet 47.0 % persisted for 1 year. CONCLUSIONS: This study identified suboptimal persistence with anti-osteoporosis drugs among fracture patients. Major target groups for measures aimed to improve persistence may be those aged >80 years and those restarting therapy.

Systemic biochemical markers of joint metabolism and inflammation in relation to radiographic parameters and pain of the knee: data from CHECK, a cohort of early-osteoarthritis subjects.

OBJECTIVE: To investigate associations of biochemical markers of joint metabolism and inflammation with minimum joint space width (JSW) and osteophyte area (OP area) of knees showing no or doubtful radiographic osteoarthritis (OA) and to investigate whether these differed between painful and non-painful knees. DESIGN: Serum (s-) and urinary (u-) levels of the cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, synovial markers sPIIINP and sHA, and inflammation markers hsCRP and erythrocyte sedimentation rate (ESR) were assessed in subjects from CHECK (Cohort Hip and Cohort Knee) demonstrating Kellgren and Lawrence grade ≤1 OA on knee radiographs. Minimum JSW and OP area of these knees were quantified in detail using Knee Images Digital Analysis (KIDA). RESULTS: uCTX-II levels showed negative associations with minimum JSW and positive associations with OP area. sCOMP and sHA levels showed positive associations with OP area, but not with minimum JSW. uCTX-I and uNTX-I levels showed negative associations with minimum JSW and OP area. Associations of biochemical marker levels with minimum JSW were similar between painful and non-painful knees, associations of uCTX-II, sCOMP, and sHA with OP area were only observed in painful knees. CONCLUSIONS: In these subjects with no or doubtful radiographic knee OA, uCTX-II might not only reflect articular cartilage degradation but also endochondral ossification in osteophytes. Furthermore, sCOMP and sHA relate to osteophytes, maybe because synovitis drives osteophyte development. High bone turnover may aggravate articular cartilage loss. Metabolic activity in osteophytes and synovial tissue, but not in articular cartilage may be related to knee pain.