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Background. Rheumatoid arthritis (RA) is a chronic, progressive inflammatory autoimmune disease that mainly affects the small joints. Amongst other, RA can be treated with rituximab (RTX) that works by CD20+ B cells depletion. In Belgium, we make use of the on-flare retreatment strategy, in which a disease flare is needed before retreatment with RTX is reimbursed. According to literature, it seems possible to taper RTX by prolonging the interval between cycles or by reducing the dose. Dose reduction of RTX was found to be safe and efficacious. The aim of this master thesis was to gain insights in the perception of rheumatologists on the on-flare retreatment strategy and dose reduction of RTX in RA. Methods. Belgian rheumatologists were invited via e-mail to take part in our qualitative study. By the means of purposive sampling, the invited group was sought out to be as diverse as possible. The participants filled in a short questionnaire for demographic data and partook in a semi-structured individual online interview. The interview guide contained questions about three main topics: RTX for RA, the retreatment strategy and tapering. After each interview a descriptive, methodologic and substantive report were made. Thereafter, the interviews were transcribed verbatim. The interviews were analysed following the Qualitative Analysis Guide of Leuven (QUAGOL). After this 10-step process themes and subthemes emerged from the interview data. Results. 13 Belgian rheumatologists were interviewed. RTX was found to be used in <5% of the patients with RA by most rheumatologists. Some perceived disadvantages were the route of administration, the slow working mechanism, the long-lasting action, the need for flare-up for retreatment and the infection risk. For selected patient groups, RTX was perceived to be an appropriate choice and had several advantages including efficacy, long-lasting activity, compliance, little drop-out and cost-effectiveness. Opinions on retreatment strategies varied between rheumatologists. On-flare strategy was deemed as appropriate by some, while others preferred a more systematic or fixed retreatment. Tapering of RTX was mainly done by prolonging the interval, with only a few rheumatologists applying dose-reduction in practice. In contrast, many of these rheumatologists would be open to dose reduction of RTX for themselves. A lack of experience and knowledge on dose reduction of RTX was indicated by the rheumatologists. Conclusion. Many Belgian rheumatologists still felt unacquainted regarding the use of RTX. Their opinions on the on-flare strategy were diverse, making it difficult to determine the best perceived retreatment strategy for RTX in patients with RA. Tapering of RTX has many advantages, and is efficacious and safe, but most rheumatologists renounce from reducing the dose of RTX and prefer increasing the time interval between RTX cycles, due to a lack of experience and knowledge. In the future, more studies should be done regarding the retreatment strategy and tapering of RTX. Furthermore, rheumatologists should be informed about the recent literature, such as the success of tapering RTX, to implement the best suited strategy in their practice. Ultimately, the aim for the future is to provide (re)treatment with RTX that is as safe as possible without losing efficacy, taking into account the burden on the patient and aiding the cost-effectiveness of treatment in RA.

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Objective. The primary objective of this thesis is to investigate how different clinical and patient-reported outcome measures affect measures of disease state in patients of early rheumatoid arthritis at different time points and to evaluate prognosis based on these measures cross-sectionally and longitudinally. It is also of interest to understand how different patient-reported outcomes correlate with one another and to understand self-reported characteristics of patients having a high disease state. From a clinical context, the wider and long-term research scope includes developing ways of personalizing treatment to individual patients based on these characteristics. Methods. The Care in Early RA trial is a two-year, investigator-initiated, multicenter, pragmatic randomized control trial. Patient-reported outcome data collected during the trial included questionnaires assessing self-reported status on visual analog scales, functional disability, fatigue, sleep quality, general health status, illness perception, quality of life, social support, self-efficacy, and coping. Disease activity state was measured by the Disease Activity Score in 28 joints using the C-reactive protein level, with remission defined as having a score <2.6. Clusters of patients having a consistently high disease state were identified by K-Means longitudinal clustering, and the patient-reported outcomes of the different groups were compared by ANOVA. Principal component analysis and regression were used to identify the largest sources of variance and for predictive modeling of disease state. Linear regression models were fitted cross-sectionally at baseline and at the three trial endpoints. Linear mixed-effects models were then fitted to take into account the longitudinal grouping structure of the data. Results. Patient-reported outcomes were different on average between baseline and later points in the trial, but mostly did not vary by treatment arm. Patients with a consistently high disease state reported higher serum positive markers, joint counts and other objective physical symptoms. as well as self-reported pain, fatigue, and several aspects of physical well-being. These patients also reported a lower general quality of life and had a comparatively less favorable perception of their illness. Generally, responses to PRO measures of physical condition were more strongly associated with changes in disease state than PROs measuring emotional or mental states, but outcomes related to the latter are also important. Conclusion. Patient-reported outcomes vary by disease state in patients of early rheumatoid arthritis, especially when the outcomes are related to pain, fatigue, functional disability, or other aspects of the physical state of the patient. Methodological challenges in weighting these outcomes in relation to one another remain.

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Objectives: The first aim of this master thesis was to develop a prospective study protocol investigating tapering and different retreatment strategies of rituximab, looking at effectiveness, safety and patient-reported outcomes. Before conducting a randomised controlled trial, a clearer view on the current situation and patient characteristics was necessary. Therefore, the second aim was to analyse the daily practice effectiveness and safety of rituximab in rheumatoid arthritis to further optimise the development of the prospective study protocol. Methods: A retrospective single-center cohort study was conducted in patients with rheumatoid arthritis previously or currently treated with rituximab at the division of Rheumatology, University hospitals Leuven. Data were collected from baseline (01/01/2006) till rituximab discontinuation, death or the end of the data collection (01/12/2019), whatever comes first. Baseline is defined as the moment on which there was decided to start rituximab treatment. Data on demographics, previous rheumatoid arthritis treatment, concomitant medication, disease activity, patient-reported outcomes, dose, number of cycles and adverse events related to rituximab were collected. Drug survival and associated parameters were analysed using the Kaplan-Meier analysis, log-rank test and Cox regression analysis. EULAR responses, defined as the difference in DAS28-CRP/ESR score between baseline or retreat decision and week 16, were calculated for cycle 1 and cycle 2 to evaluate the effectiveness. Spearman correlation was used to investigate a correlation between CD19-levels and DAS28-CRP at any timepoint during the cycle, measured from 01/12/2016 till 01/12/2019. Results: This retrospective study included 104 patients. The median (IQR) follow-up time of the patients was 39.5 (14.3-80.8) months. The median (IQR) interval between cycles increased from 8.0 (6.0-11.0) months (time between cycle 1 and cycle 2) up to 10.0 (7.5-13.5) months (time between cycle 2 and cycle 3) and 13.6 (8.0-16.0) months (time between cycle 3 and 4). The Kaplan-Meier analysis showed an estimated rituximab survival of 77.4% after 127 months from baseline. Cox proportional hazard regression showed that an increasing number of previously used bDMARDs and being female were significantly associated with a lower drug survival. Older patients, patients with erosions and ACPA-positive patients had a higher chance to continue rituximab. At week 16 of cycle 1, 15 (15/71, 21.1%), 25 (25/71, 35.2%) and 31 (31/71, 43.7%) patients showed a low, moderate and good EULAR response respectively and at week 16 of cycle 2, 15 (15/60, 25.0%), 19 (19/60, 31.7%) and 26 (26/60, 43.3%) patients showed a low, moderate and good EULAR response respectively. The Spearman correlation test showed no significant correlation between DAS28-CRP and CD19-level. Only 14 patients (14/104, 13.5%) had rituximab related adverse events. Most frequent adverse events were infections related to rituximab. Conclusion: This retrospective study showed that rituximab can be considered as a highly efficacious drug with increasing intervals between cycles and without major side effects related to rituximab. Survival analysis and EULAR response proved that rituximab is an efficacious drug. A fixed-interval retreatment strategy needs further investigation.

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Objective: The aim of this scoping review was to examine the impact of rheumatoid arthritis on psychological stress and to answer relevant questions for clinicians in this field: 1) What is the stress level of patients with RA compared to a control group? 2) Which types of stress do patients with RA experience? 3) Which are the risk factors to develop stress as a patient with RA? Methods: Four scientific databases, EMBASE, PubMed (including MEDLINE), the Web of Science Core Collection and Cochrane Library, were systematically searched until 19 April 2020. Eligible studies included psychological stress as the outcome in patients with RA. Two reviewers independently screened the titles and abstracts of the studies for eligibility. Qualitative studies, animal studies, case reports, systematic reviews, and non-English studies were excluded. Full text screening excluded studies with mixed study populations with other rheumatologic diseases, studies with a focus on anxiety and/or depression and studies not answering at least one of the three research questions. Quality appraisal was performed by the MINORS tool for longitudinal studies and the AXIS tool for cross-sectional studies. Results: From the 11 115 potentially relevant studies, 46 studies remained after title/abstract screening. After full text screening and snowballing, 16 studies met the inclusion criteria. Work stress and interpersonal stress seem to be more prevalent in patients with RA compared to a healthy control group. Stress at disease onset was more prevalent in patients with RA compared to patients with osteoarthritis. Psychological stress was higher in patients with chronic pain compared to patients with RA. Role stress, social stress and work stress were different types of stress caused by RA. More disability, more pain, less social support, lower income, younger age and personality factors like excessive worrying, pessimism and sensitivity to anxiety, seem to increase the risk for stress. Conclusion: This scoping review is the first review to address the important heterogeneity of the measurement tools and definitions in the stress research field. This review provides the basis for further research with the aim to clarify the stress concept in patients with RA, which is needed to predict different stress trajectories and respond to these with patient-centered interventions.