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Summary Introduction Rheumatoid Arthritis (RA) is an autoimmune-induced inflammatory disease with a worldwide prevalence of about 5 per 1000 adults. This chronic systemic disease is characterized by inflammation of mainly the small joints of hands and feet with pain, swelling and stiffness. If insufficiently treated, this inflammatory process can lead to worse physical functioning, impaired work and social participation and eventually joint damage through loss of articular cartilage and bone erosions. It is crucial to start an effective treatment in patients with RA as soon as possible to reach the target of remission or at least low disease activity. Treatment should be rapidly adapted in case the target is not yet met, according to the 'treat to target' principle. Objectives This PhD research project is based on data of the 2-year Care in early RA (CareRA) trial and the 3-year observational CareRA plus follow-up study. The overall objective of this thesis was to evaluate the long-term effectiveness of intensive treatment strategies used in CareRA, in order to define an optimal approach for treating patients with early RA. In this perspective, the efficacy, safety, sustainability of treatment response and need for treatment adaptations, associated with these regimes, were assessed up until 2 and 5 years after treatment initiation. Additionally, the applicability of these regimens in clinical practice was investigated, by addressing the following questions: whether presence of significant comorbidities would affect outcomes, which maintenance therapy should be used once patients reach a sufficient clinical response and to what extent do rheumatologists adhere to these strategies in a setting close to daily clinical practice. Results The first chapter explored the effectiveness of initial treatment strategies for patients with early RA on the long term. We concluded that an initial combination of methotrexate (MTX) and a glucocorticoids (GCs) bridging scheme (COBRA Slim) including a subsequent treat-to-target approach, can lead to a good and sustained disease control on the long term, irrespective of patient's prognosis. This COBRA Slim regimen resulted in comparable outcomes after 2 and 5 years as more complex regimens, and showed a more favourable safety profile. Therefore, this strategy with fewer drugs may avoid unnecessary overtreatment in patients sufficiently responding. Furthermore, the COBRA-Slim strategy with its consecutive adaptation steps seemed to result in biologicals being initiated at a later stage, assuming a better cost-effectiveness, which was confirmed in a separate cost-effectiveness analysis by our research group. Therefore, the COBRA Slim scheme was considered as an efficacious, safe and cost-effective treatment strategy for every patient with RA. In the first part of the second chapter we explored how we could further refine the optimal treatment strategy for early RA, by investigating the effectiveness of different maintenance therapies once patients achieved a well-controlled disease state. Firstly, we compared the effectiveness of stepping down treatment to either MTX or to leflunomide (LEF) in a randomized setting, in patients who achieved low disease activity after an initial combination of MTX, LEF and a GCs bridging scheme. Our results indicated that within this setting, it was more beneficial to step down to MTX than to LEF, since this maintenance therapy led to numerically better clinical outcomes after 65 weeks, had a better retention rate with 20% more patients remaining on MTX monotherapy and was tolerated equally well. These findings could also hold true for patients achieving low disease activity after addition of LEF to MTX monotherapy because of an initial insufficient response, although we were unable to formally demonstrate this based on this trial design. In the second part of the second chapter, we evaluated to what extent rheumatologists adhered to the treat-to-target (T2T) approach within the treatment strategies studied. We defined adherence as performing a dose escalation or changing/adding DMARDs in case low disease activity was not achieved. Results indicated that applying T2T strictly during the first 2 years of treatment was challenging, since in only half of visits theoretically requiring a DMARD adaptation, treatment was intensified. The most frequent reason not to intensify treatment, given by rheumatologists during the first study year, was that they considered the disease already well-controlled. Strict application of T2T guidance at every visit was associated with higher remission rates after 2 years, after adjusting for factors known to potentially influence chances at remission. However, an exact cause-effect relationship could not be demonstrated, due to the potential effect of various other factors. Furthermore, stating that T2T should always be applied without restriction, could also lead to a risk for overtreatment in certain cases and hence increased occurrence of (dose related) DMARD side effects. Therefore, we advocate for a flexible tight control, which states that decisions to adapt treatment should not be made blindly based on ambiguous or too ambitious target measures but should be based on the individual clinical picture. In the third chapter, we evaluated the prevalence of comorbidities in early RA patients before initiation of DMARD treatment and the impact of comorbidities on treatment response. We demonstrated that even in this early phase of the disease there was a high prevalence of comorbidities with nearly half of patients in our sample having at least one clinically relevant comorbidity. Additionally, we showed that having a comorbidity, but also the degree of comorbidity before treatment initiation was significantly related to worse functionality, worse disease control and worse physical health related quality of life as well as more hospitalizations. This effect of comorbidity on treatment response, could apparently not be mitigated by using intensive treatment regimens and applying the treat-to-target principle. Because of this impact of comorbidity on clinically important outcomes, the focus of caring for patients with newly diagnosed RA should not only be on controlling disease activity as soon as possible, which is necessary for all patients, but also on the management of comorbidities. Since many comorbidities are amenable to preventive and therapeutic measures, they should be detected and taken care of at an early stage, in order to reduce their impact on the outcomes in RA. Conclusion This doctoral thesis gives indications on how care for patients with early RA can be improved. Firstly, an initial combination of MTX and a GC bridging scheme led to sustained effectiveness and was well tolerated in patients with early RA. Secondly, stepping down treatment to MTX instead of to LEF was more beneficial in patients who achieved a good disease control after an initial intensive combination of both these drugs. Thirdly, it seems that we should be strict in our evaluation of the disease status but flexible in our approach to improve it further. And lastly, comorbidities should be screened for and managed already from disease onset since they affect clinical outcomes despite intensive treatment. These results provide directions to optimize pharmacological treatment and management of early RA, with the overall aim to improve patients' health related quality of life.

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Introduction. Since the publication of the recommendations for treating rheumatoid arthritis (RA) to target in 2010, measuring disease activity of a patient with RA using composite scores has become an important concept in the daily clinical practice of a rheumatologist. Although this protocol approach has shown great benefits, the reliability of the scores is under discussion. Furthermore, a discrepancy between components of the scores obtained from patient and is frequently observed. The aim of this master thesis was to reveal how Belgian rheumatologists use these disease activity scores in their daily clinical practice. Methods. A mixed method study was performed including interviews and a survey. The interviews were part of a qualitative study performed and analyzed with the Qualitative Analysis Guide of Leuven (QUAGOL) and served as input for the construction of the survey. For the survey, the Maximum Difference Scaling (MDS) method was used with the aim of revealing the most informative disease activity indicators according to the Belgian rheumatologists (1) in general and (2) in case of discrepancy between the patient’s and physician’s perception on the disease activity. The mean relative importance score (RIS) for each indicator was calculated using hierarchical Bayes modelling. Participants were also asked to indicate their routinely used disease activity score and to explain their choice. Additionally, different characteristics of the rheumatologists were compared for these outcomes. Results. Six Belgian rheumatologists were interviewed. The survey was sent to all Belgian rheumatologists (n=244) and had a total response rate of 83/244 (34%). The number of completely and incompletely filled out surveys was 66/244 (27%) and 17/244 (7%), respectively. The SJC obtained the highest mean±SD RIS (22.54±2.64), followed by the DAS28 (20.61±4.06), echography (16.47±7.97), CRP (13.34±6.11) and PhGA (12.59±7.83). PROs obtained the lowest mean RIS, ranging from 0.34±1.47 to 2.54±2.98. Remarkably, the ESR was less preferred than the CRP, especially for the French-speaking rheumatologists. No important differences were seen in case of discrepancy between the patient and physician. Of the participating rheumatologists, 75/81 (93%) indicated to routinely use a disease activity score, wherefrom the DAS28-CRP (68/81, 84%) and the DAS28-ESR (49/81, 60%) were the most preferred scores. Conclusion. In Belgian rheumatology practice, physician derived measures, the DAS28 and the rheumatologist’s judgement on the disease activity of a patient with RA are the most used indicators to evaluate the disease activity of a patient with RA. More attention needs to be paid on the improvement of the use of PROs.

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Patients who suffer from rheumatoid arthritis (RA) experience a diminished fertility more often than same-aged, healthy people. The reason behind this is still unknown and probably multifactorial. The effect of DMARDs on teratogenicity and birth outcome has already been studied more thoroughly, but the effect DMARDs have on the fertility in patients with RA is not well known. Our aim is to gather the existing evidence about this possible effect on fertility so even better care can be provided for these patients. This effect might be non-trivial, seeing that a big portion of the patients with recent onset RA are in their fertile period and still looking to have children in the future. We searched three databases, namely Pubmed, Embase and Web of Science, with a specifically composed search string for which we searched help from a health sciences librarian. The duplicates were removed. Subsequently, the results were investigated by two independent researchers (LB and IS) who first screened the results based on title and then on abstract and in- and exclusion criteria, reaching out to a third researcher (DDC) when needing consensus. The patient population should be diagnosed with RA and on a DMARD treatment. The outcome searched for was a fertility parameter. Systematic reviews, meta-analyses, case reports, case series and animal studies were excluded. The snowballing method was applied. A quality check of the four papers was performed using the CASP Appraisal Checklists. After deduplication of the initial results, 9030 articles remained. After screening based on title, 82 articles remained. Further screening ended with four articles to be included. The snowballing method did not supply any extra articles. Four papers could be included in our systematic review (summarized in table 1). The papers discussed the following DMARDs: methotrexate, certolizumab pegol, etanercept and sulfasalazine. The four studies did not report any negative effect of these DMARDs on different aspects of fertility, being time-to-pregnancy (TTP), serum level of anti-Müllerian hormone or presence of a history of infertility. Some studies did find however rather positive effects on fertility (e.g. shortening of the TTP). Only studies about women could be included, seeing that the evidence found about men was all in papers with exclusion criteria for our systematic review. In general, no negative effects of the investigated DMARDs on fertility was demonstrated, but rather positive effects, possibly because the disease activity was better under control with the DMARDs. Seeing we could only include four papers of variable quality and these were all about women, we cannot make definite assumptions yet. More research is necessary for the best guidance of these patients.

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ACHTERGROND: De toegankelijkheid van zorg in de reumatologie is onder druk komen te staan. Om te voldoen aan de vereiste opvolging volgens de nieuwe inzichten heeft er een verschuiving van intramurale naar ambulante zorg plaatsgevonden. Ook de schaarste aan reumatologen doet de druk op het ambulante zorgmodel voor RA-patiënten stijgen. Om te voldoen aan deze uitdagingen werden nurse led clinics ontwikkeld. Nurse led clinics (NLC’s) zijn verpleegkundige consultaties waarbij de eindverantwoordelijkheid ligt bij een verpleegkundige zonder tussenkomst van een arts. De verpleegkundige gaat ook kijken naar het ziekteverloop en de behandeling. NLC’s voor patiënten met reumatoïde artritis bestaan nog niet in België. In andere landen zijn nurse led clinics positief gebleken voor onder andere patiënten met reumatoïde artritis op vlak van een betere levenskwaliteit, patiënten tevredenheid en kosteneffectiviteit. DOEL: Het doel van deze studie is om na te gaan wat volgens de ‘stakeholders’ de hinderpalen en faciliterende factoren zijn van een nurse led zorgmodel bij patiënten met reumatoïde artritis in de Vlaamse praktijksetting. DESIGN: Cross-sectioneel fenomenologisch design. METHODOLOGIE: Deze studie is een kwalitatieve studie met focusgroep interviews. In totaal werden er vijf focusgroepen georganiseerd. Twee focusgroepen met reumaverpleegkundigen, twee patiëntengroepen en één focusgroep met reumatologen. Voor het analyseren van de interviews werd er gebruik gemaakt van de Qualitative Analysis Guide of Leuven (QUAGOL). RESULTATEN: Er worden reumaverpleegkundigen (n=16), patiënten (n=17) en reumatologen (n=9) geïnterviewd. In deze studie worden voordelen van NLC’s aangehaald door de verschillende stakeholders zoals tijdsefficiëntie, een goede vertrouwensband tussen patiënt en verpleegkundige, een financiële besparing, een verbeterde patiënten educatie en een vermindering van de werkbelasting van de reumatoloog. Er zijn ook nadelen aan verbonden zoals de grotere verantwoordelijkheid voor verpleegkundigen, het gebrek aan een wettelijk kader, gebrek aan flexibiliteit door protocollair werken, de twijfel aan de kennis van de verpleegkundige en het tekort aan (gespecialiseerde) verpleegkundigen. CONCLUSIE: Voordat nurse led clinics in RA kunnen worden opgestart zijn er nog aan een aantal voorwaarden te voldoen. Zo is er nog nood aan een wettelijk kader, een specifieke opleiding en een afbakening van het takenpakket voor de verpleegkundige. RELEVANTIE VOOR DE PRAKTIJK: Volgens de verschillende stakeholders kunnen nurse led clinics in België een groot voordeel betekenen voor patiënten met RA, zorgverleners en maatschappij. Echter lijkt het op dit moment niet implementeerbaar zonder bepaalde voorbereidende stappen. In de huidige setting zal er als eerste stap moeten overgegaan worden naar een verbreding van het takenpakket in het wettelijk kader van de reumaverpleegkundige alvorens volledig zelfstandige nurse led clinics kunnen georganiseerd worden. De weg naar nurse led clinics zal dus stapsgewijs dienen te gebeuren.