B.J.F van den Bemt

Medication adherence in patients with rheumatoid arthritis: a critical appraisal of the existing literature

Adherence to medication in patients with rheumatoid arthritis is low, varying from 30 to 80%. Improving adherence to therapy could therefore dramatically improve the efficacy of drug therapy. Although indicators for suboptimal adherence can be useful to identify nonadherent patients, and could function as targets for adherence-improving interventions, no indicators are yet found to be consistently and strongly related to nonadherence. Despite this, nonadherence behavior could conceptually be categorized into two subtypes: unintentional (due to forgetfulness, regimen complexity or physical problems) and intentional (based on the patient’s decision to take no/less medication). In case of intentional nonadherence, patients seem to make a benefit–risk analysis weighing the perceived risks of the treatment against the perceived benefits. This weighing process may be influenced by the patient’s beliefs about medication, the patient’s self-efficacy and the patient’s knowledge of the disease. This implicates that besides tackling practical barriers, clinicians should be sensitive to patient’s personal beliefs that may impact medication adherence.

Adherence Rates and Associations with Nonadherence in Patients with Rheumatoid Arthritis Using Disease Modifying Antirheumatic Drugs

Objective. Nonadherence in patients with rheumatoid arthritis (RA) using disease modifying antirheumatic drugs (DMARD) may result in unnecessarily high levels of disease activity and function loss. The aim of this descriptive study was to assess adherence rates with self-report measures in a large random population, and to identify potential risk factors for nonadherence. Methods. A randomly selected sample of 228 patients with RA using DMARD was invited for a standardised interview. For each medicine, the patients were asked about adherence, consumption and perceived (side) effects. After the interview, the patients received self-report questionnaires to assess adherence [Compliance Questionnaire on Rheumatology (CQR) and the Medication Adherence Scale (MARS)], coping, beliefs about medicines, satisfaction about medicine information, and physical functioning. Subsequently, associations between adherence and demographics, clinical characteristics, and patient attitudes were examined. Results. Depending on the instrument used, 68% (CQR) and 60% (MARS) of the patients were adherent to DMARD. Nonadherence was not associated with demographic and clinical characteristics, satisfaction about information, medication concerns, and coping styles. The disease duration, the number of perceived side-effects, and beliefs about the necessity of the medicine were weakly associated with adherence. Conclusion. In this large study with a random RA population, 32%–40% of the patients did not adhere to their DMARD prescription. As none of the possible risk factors was strongly related to adherence, no general risk factor seems to be powerful enough as a possible screening tool or target for adherence-improving interventions. This implies that nonadherence barriers should be assessed on an individual basis.

Down-titration and discontinuation of infliximab in rheumatoid arthritis patients with stable low disease activity and stable treatment: an observational cohort study

Down-titration, or discontinuing infliximab, has proven to be feasible in RA patients. Therefore, our local treatment protocol includes tapering infliximab dose. This observational study describes the prevalence of successful down-titration in daily clinical practice and its effect on costs and quality of life (QoL). Methods Infliximab was down-titrated with 25% of the original dose (3 mg/kg) every 8–12 weeks without interval change until discontinuation or flare in all RA patients with stable low 28-joint disease activity score (DAS28) and stable treatment for >6 months. During 1 year DAS28, RA medication, outpatient clinic visits, RA related absenteeism and EuroQoL5D (European QoL questionnaire, EQ5D) were documented. Prevalence of successful down-titration and changes in DAS28, QoL and costs were described. Results In 16% (95% CI 6 to 26) and 45% (95% CI 31 to 59), respectively, infliximab could be discontinued or down-titrated. Mean infliximab dose decreased significantly from 224 mg (95% CI 212 to 236 mg) at start, to 130 mg (95% CI 105 to 154 mg) after 1 year. Median DAS28 increased from 2.5 (p25–75=2.0–2.9) to 2.8 (2.2–3.6) (p=0.002). Extra corticosteroids were given in 8% of the visits. Disease modifying antirheumatic drugs were seldom changed. There was no statistical difference in QoL after down-titration. Mean reduction in the costs was €3474 (95% CI 2457 to 4492) per patient. Conclusion In the majority of patients with stable low DAS28 and stable treatment, infliximab can be down-titrated or discontinued, which results in a considerable reduction in costs without influencing QoL.

Sustained effect after lowering high-dose infliximab in patients with rheumatoid arthritis: a prospective dose titration study

Objectives: In clinical trials only a small subset of patients with rheumatoid arthritis (RA) benefits from higher than standard dose of infliximab (>3 mg/kg/8 weeks). However, dose escalation of infliximab is frequently applied in clinical practice. Individual adjustment of infliximab treatment based on actual disease activity, instead of subjective clinical judgement, could prevent possible unwarranted dose escalation. Methods: The infliximab dose of all patients with RA treated at our centre was decreased from 5 mg/kg to 3 mg/kg, leaving dosing intervals unaltered. Subsequently patients were followed for at least three infusions. At every visit, 28-joint Disease Activity Score (DAS28), infliximab serum trough levels and anti-infliximab antibody levels were assessed. Inversed European League Against Rheumatism (EULAR) criteria (flare criteria) were used as the endpoint. Results: A total of 18 patients were included in the study. Mean (SD) DAS28 scores before dose reduction and after first and second low dose were 3.2 (1.2), 3.2 (1.8) and 3.3 (1.2), respectively (values not significant). One patient (6%, 95% CI 0% to 17%) developed a persistent flare that subsided after increasing infliximab doses and one patient stopped infliximab because of a lupus-like reaction. In all other patients (n = 16) lowering infliximab resulted in unaltered disease activity. Infliximab levels showed that most patients had either low- (<1 mg/litre) or high (>5 mg/litre) serum trough levels. Anti-infliximab antibodies were detected in four patients. Conclusion: Infliximab dosages of 5 mg/kg can be lowered in the majority of patients with RA using DAS28-guided dose titration without increase of disease activity. Lowering the dose of infliximab should be considered in every patient receiving higher doses infliximab.

Patient-centred care in established rheumatoid arthritis

Review of the evidence on patient-centred care (PCC) in rheumatoid arthritis (RA) shows that involving the patient as an individual - with unique needs, concerns and preferences - has a relevant impact on treatment outcomes (safety, effectiveness and costs). This approach empowers patients to take personal responsibility for their treatment. Because clinicians are only able to interact personally with their patients just a few hours per year, patients with a chronic condition such as RA should be actively involved in the management of their disease. To stimulate this active role, five different PCC activities can be distinguished: (1) patient education, (2) patient involvement/shared decision-making, (3) patient empowerment/self-management, (4) involvement of family and friends and (5) physical and emotional support. This article reviews the existing knowledge on these five PCC activities in the context of established RA management, especially focused on opportunities to increase medication adherence in established RA.

Adalimumab and etanercept serum (anti)drug levels are not predictive for successful dose reduction or discontinuation in rheumatoid arthritis

Tapering of TNF inhibitors (TNFi) is feasible in many patients with rheumatoid arthritis (RA), but sometimes leads to flaring. TNFi trough serum levels and antidrug antibodies (ADAs) have been proposed as predictors for successful dose reduction or discontinuation,1–3 suggesting that: (1) a patient with low or undetectable serum levels (with or without ADAs) should be able to successfully stop the TNFi and (2) a patient with high serum levels should be able to reduce the dose. As obtaining trough levels is often not practical, our aim was to investigate whether random timed serum drug levels and ADAs of adalimumab and etanercept are predictive for successful dose reduction or discontinuation of these TNFi in patients with RA doing well. For these analyses 118 patients with RA from an open randomised clinical trial investigating a dose reduction strategy of adalimumab or etanercept with 18 months follow-up were included . 4 Serum samples were collected at baseline (before start of dose reduction) at a regular visit, unrelated to time …

Does non-adherence to DMARDs influence hospital-related healthcare costs for early arthritis in the first year of treatment?

Introduction Non-adherence to disease-modifying antirheumatic drugs (DMARDs) is suspected to relate to health care costs. In this study we investigated this relation in the first year of treatment. Methods In a multi-center cohort study with a one year follow up, non-adherence was continuously measured using electronic monitored medication jars. Non-adherence was defined as the number of days with a negative difference between expected and observed opening of the container. Cost measurement focused on hospital costs in the first year: consultations, emergency room visits, hospitalization, medical procedures, imaging modalities, medication costs, and laboratory tests. Cost volumes were registered from patient medical files. We applied multivariate regression analyses for the association between non-adherence and costs, and other variables (age, sex, center, baseline disease activity, diagnosis, socioeconomic status, anxiety and depression) and costs. Results Of the 275 invited patients, 206 were willing to participate. 74.2% had rheumatoid arthritis, 20.9% had psoriatic arthritis and 4.9% undifferentiated arthritis. 23.7% of the patients were more than 20% non-adherent over the follow-up period. Mean costs are € 2117.25 (SD € 3020.32). Non-adherence was positively related to costs in addition to baseline anxiety. Conclusion Non-adherence is associated with health care costs in the first year of treatment for arthritis. This suggests that improving adherence is not only associated with better outcome, but also with savings.

Drug-related problems in a clinical setting: a literature review and cross-sectional study evaluating factors to identify patients at risk

Objectives This study aims to summarise existing evidence on risk factors for drug-related problems (DRPs) in hospitals as well as ambulatory care or nursing homes and adds additional empirical evidence on risk factors for DRPs in non-elective hospitalised patients. Methods A comprehensive literature review was performed to compose an overview of demographic, clinical and pharmacological risk factors associated with DRPs in different settings (ambulatory care, nursing homes and hospitals). A cross-sectional study on rehabilitation, cardiology and pulmonology wards of three hospitals in Nijmegen, the Netherlands, was performed to assess possible risk factors for DRPs in a clinical setting. Results The comprehensive review identified 21 papers discussing risk factors for drug-related hospital admissions, use of potential inappropriate drugs, adverse drug reactions and other types of DRPs. The majority of these studies had been carried out in ambulatory care (11 papers; 52%). Polypharmacy, comorbidity and the use of specific drugs (antithrombotics, antidiabetics) were most often positively associated with the occurrence of DRPs. Our cross-sectional study demonstrated that admission to the rehabilitation ward, admission at the intensive care unit and comorbidity were associated with the occurrence of potential DRPs in a clinical setting. Conclusions Although risk factors associated with DRPs differ greatly among published papers, comorbidity, polypharmacy and the use of specific drugs (antithrombotics, antidiabetics) were frequently associated with DRPs. Although several guidelines advise to use prespecified risk factors (like age, polypharmacy and renal impairment), one should be aware that most of these risk factors are insufficiently grounded on empirical evidence.

Open-Label, Non-Mandatory Transitioning From Originator Etanercept to Biosimilar SB4 Six-Month Results From a Controlled Cohort Study

To evaluate the effects of non‐mandatory transitioning from the originator biologic drug etanercept (ETN) to its biosimilar, SB4, on drug survival and effectiveness in a controlled cohort study of patients with an inflammatory rheumatic disease.

Prediction of successful dose reduction or discontinuation of adalimumab, etanercept, or infliximab in rheumatoid arthritis patients using serum drug levels and antidrug antibody measurement

ABSTRACT Background: To evaluate if TNF inhibitor serum drug levels (DL) or anti-drug antibodies (ADAb) can predict successful dose reduction (in patients with high DL) or discontinuation (in patients with no/low DL or ADAb) in rheumatoid arthritis (RA) patients. Research design and methods: RA patients that were using adalimumab (n = 42), etanercept (n = 76) or infliximab (n = 51) and were doing well, were tapered until discontinuation or flare (1–1.5 year follow up). Random timed DL for adalimumab and etanercept and trough DL for infliximab were measured before dose reduction: Receiver-Operator-Curves (ROC) analyses with optimal cut-off DL were determined. Results: No predictive value of adalimumab and infliximab DL for all outcomes were found, except for an inverse association of lower etanercept DL and higher chance for successful dose reduction (Area Under the Curve (AUC) 0.36, 95% CI 0.23–0.49; cut-off <2.6 mg/l). In sub analyses, higher adalimumab trough DL predicted successful dose reduction (AUC 0.86, 0.58–1.00; cut-off >7.8). ADAb were infrequent and not predictive of successful discontinuation. Conclusions: No predictive value of baseline adalimumab, etanercept and infliximab DL or ADAb for successful dose reduction or discontinuation in RA was found in this context, with the possible exception of high adalimumab trough levels for successful dose reduction.