This thesis focussed on inflammation observed on magnetic resonance imaging (MRI) in the early phases of rheumatoid arthritis (RA) and was divided into two parts. In the first part we explored the... Show moreThis thesis focussed on inflammation observed on magnetic resonance imaging (MRI) in the early phases of rheumatoid arthritis (RA) and was divided into two parts. In the first part we explored the prevalence of inflammation and erosions detected on MRI in the general population. In the second part, we studied the early phases of RA and assessed factors which could be associated with radiographic joint damage or local inflammation detected on MRI. Show less
The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED)-study is a multicentre two-step randomized single-blinded clinical trial in 610 early... Show moreThe Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED)-study is a multicentre two-step randomized single-blinded clinical trial in 610 early rheumatoid arthritis (RA) and undifferentiated arthritis (UA) patients. Intensive induction therapy (methotrexate (MTX) and a tapered high dose of prednisone) was started in the first 4 months. Treatment adjustments aimed at clinical remission (Disease Activity Score (DAS)<1.6): if DAS<1.6, medication was tapered and stopped, if DAS≥1.6, medication was intensified or restarted. Patients not in DAS-remission after 4 months were randomized to triple therapy (MTX, hydroxychloroquine and sulfasalazine) with prednisone (arm 1) or MTX+adalimumab (arm 2).After 4 months 61% was in DAS-remission (early DAS-remission group). After 5 years, 48% were in DAS-remission and 22% in drug-free remission (DFR). Patients in early DAS-remission group had better functional ability and more often achieved DAS-remission and DFR than patients that were randomized, without differences between the arms. UA patients had lower DAS and less autoantibody positivity at baseline compared to the RA patients. DAS-remission percentages were comparable between RA and UA patients, but more UA patients did achieve DFR (33% vs 19%). Autoantibody (rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA)) negative patients more often achieved DFR. Show less
This dissertation describes the development of glyco-bioinformatics tools that facilitate the high-throughput data processing of glycomics and glycoproteomics experiments, specifically for both... Show moreThis dissertation describes the development of glyco-bioinformatics tools that facilitate the high-throughput data processing of glycomics and glycoproteomics experiments, specifically for both MALDI-TOF-MS (Chapter 2) and LC-ESI-MS (Chapter 3). The developed methods also provide various quality control parameters that assist the researcher in curating both the measured spectra and quantified analytes, thereby providing high-quality data in a high-throughput manner.The tools that were developed within this thesis have been used to identify the influence of glycosylation on trypsin efficacy of Immunoglobulin G (Chapter 3) and two biological cohorts. Specifically, to investigate the serum N-glycosylation during and after pregnancy (Chapter 5) and to identify the differences in the N-glycosylation between maternal and fetal serum and IgG (Chapter 6). Show less
This thesis describes the characterisation of citrullinated antigen-specific B cells in patients with rheumatoid arthritis (RA). These cells express and secrete anti-citrullinated protein... Show moreThis thesis describes the characterisation of citrullinated antigen-specific B cells in patients with rheumatoid arthritis (RA). These cells express and secrete anti-citrullinated protein antibodies (ACPA), which represent the most specific autoantibody system in RA. We started out by identifying ACPA-producing B cells in peripheral blood. FACS sort followed by culture showed that these cells are not confined to the memory B cell subpopulation, as circulating plasmablasts/cells were found that spontaneously produced ACPA in culture (chapter 2). Further characterisation showed an increased frequency of ACPA-secreting plasma cells in synovial fluid (SF), i.e. at the site of inflammation, which harbours the capacity to form a survival niche in culture that promotes sustained (auto-)antibody production (chapter 3). Next, ACPA-expressing B cells were identified directly after isolation using a streptavidin tetramer-based flow cytometry staining technique developed in chapter 4. Furthermore, we provided evidence for altered development of ACPA-producing B cells, as these cells were found to express lambda light chains (LC) more frequently than non-autoreactive B cells (chapter 5). Finally, we investigated CD28 expression on ACPA-expressing B cells and total B cells in RA patients as relevant molecule for an enhanced live span of long-lived plasma cells (chapter 6). Show less
The adaptive immune system is the part of the immune system that is highly specific and generates memory resulting in a fast and specific immune response upon a second infection with the same... Show moreThe adaptive immune system is the part of the immune system that is highly specific and generates memory resulting in a fast and specific immune response upon a second infection with the same pathogen. However, when this response is specific for a part of the body itself instead of a pathogen, inflammation and autoimmune disease can develop. Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joints leading to cartilage and bone destruction. This thesis focused on the role of the adaptive immune system in the development, treatment and diagnosis of rheumatic disorders. The cells of the adaptive immune system play a pivotal role in the development of RA as cross-reactive CD4+ T cells can provide help to B cells which subsequently produce autoantibodies leading to autoantibody-positive RA. They can be a target in therapy as the biological Abatacept inhibits activation of T-cells, however, it potentially targets several players of the adaptive immune system making it an effective treatment strategy. Cells of the adaptive immune system can also be very useful as biomarker or to monitor response to therapy, which makes them very interesting players in the development of new treatment strategies for arthritis. Show less
On the basis of systems thinking, in this thesis metabolomics, Chinese medicine (CM), as well as Western medicine (WM) were combined to achieve a more comprehensive systems diagnosis of patients... Show moreOn the basis of systems thinking, in this thesis metabolomics, Chinese medicine (CM), as well as Western medicine (WM) were combined to achieve a more comprehensive systems diagnosis of patients with chronic diseases. Specifically, metabolomics has been applied to characterize patients by small molecule profiles, which can be applied in phenotyping patients and matching these with optimal therapies. Chinese and Western medicine have different perspectives on diagnosis and could be highly complementary to each other, so combining both could have advantages in personalized diagnosis. Therefore, in this thesis a combination of systems approaches is used, including metabolomics, CM-based diagnosis principles as well as WM to provide systems diagnosis of patients with chronic diseases, in particular rheumatoid arthritis (RA). With systems diagnosis, we could better identify potential biomarkers to predict the WM therapeutic response of patients with RA and monitoring disease progression. Show less
