Bart van den Bemt

Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial

Objective To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care. Design Randomised controlled, open label, non-inferiority strategy trial. Setting Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014. Participants 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care. Interventions Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated. Main outcome measures Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events. Results Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval −12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care. Conclusions A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients. Trial registration Dutch trial register (www.trialregister.nl), NTR 3216.

The accuracy, precision and sustainability of different techniques for tablet subdivision: breaking by hand and the use of tablet splitters or a kitchen knife

INTRODUCTION Tablets are frequently subdivided to lower the dose, to facilitate swallowing by e.g. children or older people or to save costs. Splitting devices are commonly used when hand breaking is difficult or painful. METHODS Three techniques for tablet subdivision were investigated: hand breaking, tablet splitter, kitchen knife. A best case drug (paracetamol), tablet (round, flat, uncoated, 500 mg) and operator (24-year student) were applied. Hundred tablets were subdivided by hand and by three devices of each of the following types: Fit & Healthy, Health Care Logistics, Lifetime, PillAid, PillTool, Pilomat tablet splitter; Blokker kitchen knife. The intra and inter device accuracy, precision and sustainability were investigated. The compliance to (adapted) regulatory requirements was investigated also. RESULTS The accuracy and precision of hand broken tablets was 104/97% resp. 2.8/3.2% (one part per tablet considered; parts right/left side operator). The right/left accuracies of the splitting devices varied between 60 and 133%; the precisions 4.0 and 29.6%. The devices did not deteriorate over 100-fold use. Only hand broken tablets complied with all regulatory requirements. CONCLUSION Health care professionals should realize that tablet splitting may result in inaccurate dosing. Authorities should undertake appropriate measures to assure good function of tablet splitters and, where feasible, to reduce the need for their use.

Anti-infliximab antibodies are already detectable in most patients with rheumatoid arthritis halfway through an infusioncycle: an open-label pharmacokinetic cohort study

BackgroundThis study in patients with rheumatoid arthritis (RA) treated with infliximab describes prospectively the course of (anti)infliximab levels within an infusioncycle to assess at what moment patients develop low/no infliximab trough levels and/or detectable anti-infliximab levels.MethodsInfliximab treated RA patients were included in this descriptive open-label cohort study. During one infusioncycle (anti-)infliximab levels were assessed just before and one hour after infusion, and subsequently at 50%, 75% and at the end of the infusioncycle (pre-infusion).Results27 patients were included. The median infliximab levels decreased from 77.0 mg/l (p25-p75: 65-89) one hour after the infusion to pre-infusion levels of 0.0 mg/l (p25-p75: 0.0-3.1). In 7 (26%) patients pre-infusion anti-infliximab antibodies were detected; these antibodies were already present halfway through the infusioncycle in 5 of the 7 individuals. Patients with detectable pre-infusion anti-infliximab antibodies have significantly more often low/no infliximab levels (< 1 mg/l) halfway trough the infusioncycle (in 5/7 patients) compared to patients without detectable pre-infusion anti-infliximab antibodies (0/20 patients, p < 0.001).ConclusionsMost anti-infliximab forming patients have detectable anti-infliximab antibodies halfway through an infusioncycle, which implies that these patients are exposed to nontherapeutical infliximab levels during more than halve of their infusion cycle. As none of the patients without anti-infliximab antibodies had no/low-infliximab levels halfway through the infusioncycle, the presence of pre-infusion anti-infliximab antibodies seems a sensitive and specific predictor for no/low infliximab-levels

Dual-tasking interferes with obstacle avoidance reactions in healthy seniors.

Dual-tasking can lead to falls, as does a deterioration of obstacle avoidance (OA) skills. Hence, it is expected that a combination of both would be even more detrimental, especially when OA is time-critical. Previous studies confirmed this expectation, however, due to several limitations in their design it is yet too early to draw any definitive conclusions on the allocation of attentional resources in OA under dual-task conditions. Therefore, attentionally demanding primary and secondary tasks were used with the instruction to perform as well as possible on both tasks. Nineteen healthy senior individuals (60±4.7 years, 8 females) performed an OA task on a treadmill while walking at 3 km/h as a single task and combined with an auditory Stroop task. Biceps femoris (BF) muscle response times, OA failure rates and composite scores were used to evaluate the data. Increased OA failure rates (3%, p=0.03) and delayed BF response times (21 ms, p<0.001) were found under dual-task conditions. Composite scores were reduced during (p<0.001) and just after obstacle crossing (p=0.003). In conclusion, dual-tasking during time-critical OA affects the motor as well as the cognitive task when subjects are instructed to keep up performance on both tasks. This adds to the evidence indicating an increased risk of tripping or falling when attention is divided during walking in the presence of unexpected obstacles.

Subjective Complaints as the Main Reason for Biosimilar Discontinuation After Open-Label Transition From Reference Infliximab to Biosimilar Infliximab

To evaluate drug survival, effectiveness, pharmacokinetics, immunogenicity, and safety in daily practice after transitioning treatment from original reference infliximab (Remicade [REM]) to a biosimilar infliximab (CT‐P13 [Remsima; Inflectra]) in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.

Perceived need to take medication is associated with medication non-adherence in patients with rheumatoid arthritis

Background This is the first cross-sectional study that aims to examine associations between beliefs about medication and non-adherence in patients with rheumatoid arthritis (RA) using disease-modifying antirheumatic drugs, taking potential psychological confounders into account. Methods Eligible patients (diagnosed with RA for ≥1 year or ≥18 years, using greater than or equal to one disease-modifying antirheumatic drug) were included by their rheumatologist during regular outpatient visits between September 2009 and September 2010. Included patients received questionnaires. The Beliefs about Medicines Questionnaire was used to measure the perceived need to take medication (necessity beliefs), the concerns about taking medication (concern beliefs), general medication beliefs, and attitudes toward taking medication. Medication non-adherence (no/yes) was measured using the Compliance Questionnaire Rheumatology (CQR). Associations between beliefs and non-adherence, and the influence of demographical, clinical, and psychological factors (symptoms of anxiety/depression, illness cognitions, self-efficacy) were assessed using logistic regression. Results A total of 580 of the 820 eligible patients willing to participate were included in the analyses (68% female, mean age 63 years, 30% non-adherent to their medication). Weaker necessity beliefs (OR [odds ratio]: 0.8, 95% CI [confidence interval]: 0.8–0.9) and an unfavorable balance between necessity and concern beliefs (OR: 0.9, 95% CI: 0.9–1.0) were associated with CQR non-adherence. Also, having an indifferent attitude toward medication (no/yes) was associated with CQR non-adherence (OR: 5.3, 95% CI: 1.1–25.8), but the prevalence of patients with an indifferent attitude toward medication was low. The associations were barely confounded by demographical, clinical, and psychological factors. Conclusion Increasing necessity beliefs about medication in clinical practice might be worthwhile in improving medication adherence in RA patients.

Low infliximab serum trough levels and anti-infliximab antibodies are prevalent in rheumatoid arthritis patients treated with infliximab in daily clinical practice: results of an observational cohort study

BackgroundTo get insight in the prevalence of high, or low/no serum infliximab trough levels in patients with low disease activity and if serum trough levels are stable and reliable longitudinally we conducted a prospective cohort studyMethodsIn a longitudinal, observational cohort of RA patients treated with infliximab for at least 6 months, treatment interval, DAS28, infliximab trough levels and anti-infliximab antibodies were assessed. Prevalence of low (<1 mg/l) and high (>5 mg/l) infliximab serum trough levels and anti-infliximab antibodies was recorded. Relationship of a change in anti-infliximab antibodies and treatment interval was described. Reliability of consecutive infliximab serum trough levels and anti-infliximab antibodies in patients with stable DAS28 and treatment was analysed with Spearman correlation and kappa-analysis.Results147 patients with a mean disease duration of 11 years (sd7) and DAS28 of 3.5 (sd1.3) at baseline were followed during 1.5 years. Inter-individual variability in infliximab levels in patients with low DAS28 was high (median 1.4 mg/L, IQR 3.35), with 31% (95%CI: 20-42%) having low (<1 mg/L) and 14% (95%CI 5–22) high trough levels (>5 mg/L). Interestingly also in RA patients with DAS28 ≤ 3.2, anti-infliximab antibodies were found in one-third of the patients, with half of them having antibodies every visit during a median of more than one year. Agreement for consecutive measurements of serum trough levels and anti-infliximab antibodies was high in stable patients: r = 0.97 (p = 0.00001) and kappa = 1.0 (SE 0.14) Anti-infliximab antibody appearance was influenced by interval increases (relative risk (RR) 5.2, 2.6-10.7), but patients still showed low infliximab levels.ConclusionsLow (and high) infliximab serum trough levels are prevalent, interestingly also in patients with low disease activity. Consecutive measurements of serum trough levels and anti-infliximab antibodies are reliable in stable patients. These test could be used to lower or stop infliximab in selected patients.

Psychosocial predictors of non-adherence to chronic medication: systematic review of longitudinal studies.

Objectives Several cross-sectional studies suggest that psychosocial factors are associated with non-adherence to chronic preventive maintenance medication (CPMM); however, results from longitudinal associations have not yet been systematically summarized. Therefore, the objective of this study was to systematically synthesize evidence of longitudinal associations between psychosocial predictors and CPMM non-adherence. Materials and methods PUBMED, EMBASE, CINAHL, and PsychINFO databases were searched for studies meeting our inclusion criteria. The reference lists and the ISI Web of Knowledge of the included studies were checked. Studies were included if they had an English abstract, involved adult populations using CPMM living in Western countries, and if they investigated associations between psychosocial predictors and medication non-adherence using longitudinal designs. Data were extracted according to a literature-based extraction form. Study quality was independently judged by two researchers using a framework comprising six bias domains. Studies were considered to be of high quality if ≥four domains were free of bias. Psychosocial predictors for non-adherence were categorized into five pre-defined categories: beliefs/cognitions; coping styles; social influences and social support; personality traits; and psychosocial well-being. A qualitative best evidence synthesis was performed to synthesize evidence of longitudinal associations between psychosocial predictors and CPMM non-adherence. Results Of 4,732 initially-identified studies, 30 (low-quality) studies were included in the systematic review. The qualitative best evidence synthesis demonstrated limited evidence for absence of a longitudinal association between CPMM non-adherence and the psychosocial categories. The strength of evidence for the review’s findings is limited by the low quality of included studies. Conclusion The results do not provide psychosocial targets for the development of new interventions in clinical practice. This review clearly demonstrates the need for high-quality, longitudinal research to identify psychosocial predictors of medication non-adherence.

Gastroprotection among new chronic users of non-steroidal anti-inflammatory drugs: a study of utilization and adherence in the Netherlands

ABSTRACT Objective: To describe the use of gastroprotection (GP) among new chronic users of NSAIDs in the Netherlands by gastrointestinal (GI) risk factor (RF) score. Methods: Data for this retrospective follow-up study were extracted from the PHARMO database. We selected new chronic users of COX-2 inhibitors (coxibs) or traditional NSAIDs (tNSAIDs) between 1st January 2000 and 31st December 2004. GP strategies were defined as: use of proton pump inhibitors (PPI), coxibs or both. GI RF score at index date was based on: history of GI drug use, high dose of NSAIDs, age > 60 years, use of corticosteroids/anticoagulants/SSRIs, rheumatoid arthritis, heart failure or diabetes, with each condition accounting for one factor. Switching was assessed among those with ≥ 1 GI RF during the first year of follow-up. Results: Among 58 770 new chronic NSAID users at index date, 80% used tNSAIDs alone, 8% used tNSAID + PPI, 10% used a coxib alone and 2% used coxib + PPI. Mean (SD) number of GI RF among these groups was 1.6 (2.1), 3.1 (1.3), 1.5 (1.5) and 2.8 (1.3), respectively. Among 48 390 patients (82.3%) with a GI RF score of ≥ 1, 20.9% used a GP strategy, this increased with number of GI RFs. Within the first year, 5.3% (n = 2067) and 4.8%(n = 1 843) of tNSAID users with ≥ 1 GI RF switched to tNSAID+PPI and coxib alone, respectively. Conclusions: Gastroprotection in users of tNSAIDs was inadequate. Over 80% of NSAID users with ≥ 1 GI RF did not receive any gastroprotection, and even when prescribed, a PPI is used only half the time. More research should show if gastroprotection was used for prevention.

The combined use of disease activity and infliximab serum trough concentrations for early prediction of (non‐)response to infliximab in rheumatoid arthritis

AIM Early prediction of (non-)response to infliximab therapy can improve therapeutic benefit by avoiding unnecessary periods of high disease activity during ineffective therapy. This prospective cohort study therefore aimed to study the predictive value of (1) disease activity alone and (2) infliximab serum trough concentrations in addition to disease activity 6 weeks after start of treatment for achieving low disease activity after 6 months. METHODS Disease activity and infliximab serum trough concentrations were assessed in all rheumatoid arthritis (RA) patients at 2, 6 and 26 weeks after initiation of infliximab therapy. Receiver operating characteristic (ROC) curves and Youden indices were used to calculate specificity for prediction of good response after 6 months while aiming for maximum sensitivity. RESULTS Fifty-seven consecutive RA patients starting with infliximab therapy were included. After 6 months, 15 (26%, 95 % CI 15, 38%) patients reached good European League against Rheumatism (EULAR) response. A disease activity score <4.2 at 6 weeks after initiation of therapy was a moderate predictor for reaching EULAR response after 6 months (sensitivity 100%, specificity 49%). Infliximab serum trough concentrations (>2.5 mg l(-1)) as predictor complimentary to disease activity (<4.2) slightly increased the specificity from 49% to 54% without changing the sensitivity (100%). As 39% of the patients did not fulfill at least one of these criteria at week 6, these patients could already be switched to another therapy after 6 weeks. CONCLUSIONS The combination of disease activity and infliximab serum trough concentrations could be a fair predictor to identify early (after 6 weeks) patients who have insufficient response after 6 months of therapy.