Our immune system is supposed to protect us from infections, but it can also attack our own tissues if not properly controlled. This can lead to autoimmune diseases like rheumatoid arthritis (RA).... Show moreOur immune system is supposed to protect us from infections, but it can also attack our own tissues if not properly controlled. This can lead to autoimmune diseases like rheumatoid arthritis (RA). People with RA have antibodies to the body’s own proteins (self), but it is not known how they arise. The data described in this thesis show that these antibodies cross-react with self-proteins carrying different post-translational modifications, suggesting that multiple proteins may be involved in the initial loss of the immune system’s ability to discriminate between self- and foreign-proteins. As another unique feature, these antibodies carry additional sugars at an unexpected site in the molecule. Our data show that these sugars (variable domain glycans) can prevent binding to potential self-proteins, affect complement activation, and set the threshold for immune B-cell activation. In addition, our data show that the abundance of these sugars increases toward disease onset and predicts the development of chronic, persistent disease or the chance of subsequent remission. Taken together, these sugars may help B cells to escape the tight control mechanism in our body that are in place to prevent the development autoimmunity. This new “sugar mechanism” could be beneficial for diagnosis and future treatment. Show less
Rheumatoid Arthritis (RA) is an autoimmune disease targeting the synovial joints. Several factors have been shown to be implicated in the onset and disease progression, among also genetic factors.... Show moreRheumatoid Arthritis (RA) is an autoimmune disease targeting the synovial joints. Several factors have been shown to be implicated in the onset and disease progression, among also genetic factors. HLA class II molecules have been implicated in the so called 'second hit' leading to disease onset. The implication of HLA class II molecules suggests that CD4+ T cells are involved in the disease development. In this thesis, several aspects of CD4+ T cells within RA are investigated to get a glimpse of what their role could be in disease onset. Show less
This thesis focused on investigating the early identification of Rheumatoid Arthritis (RA), assessing the burden of disease, and enhancing understanding of disease mechanisms in the earliest... Show moreThis thesis focused on investigating the early identification of Rheumatoid Arthritis (RA), assessing the burden of disease, and enhancing understanding of disease mechanisms in the earliest disease phases. Many of the studies in this thesis focused on data from the Leiden Clinically Suspect Arthralgia (CSA) cohort. The CSA cohort is an inception cohort at the rheumatology outpatient clinic of the Leiden University Medical Centre, in Leiden, the Netherlands. CSA patients had recent-onset (We showed that although early identification is increasingly improving, there remains a large proportion of patients that cannot be accurately identified despite a suspect pattern of signs and symptoms, as well as information on autoantibodies. Furthermore, the burden of disease is already substantial during the symptomatic pre-arthritis phase of CSA. Future studies will have to provide evidence for the effectiveness of preventing persistent RA and functional disability with prescribing Disease-modifying antirheumatic drugs (DMARD) treatment in the phase of CSA. Show less
The general aim of this thesis was to elucidate the immune regulation and breach of tolerance towards modified proteins in Rheumatoid Arthritis(RA). Anti-modified protein antibodies are a hallmark... Show moreThe general aim of this thesis was to elucidate the immune regulation and breach of tolerance towards modified proteins in Rheumatoid Arthritis(RA). Anti-modified protein antibodies are a hallmark of disease and are implicated in the pathogenesis of RA. Recent studies have shown that these autoantibodies can serve as diagnostic and prognostic biomarkers. Most research on the role of autoantibodies in RA has focused on ACPA, which are directed against citrullinated proteins. In the past several years it has become clear that the autoantibody response in RA extends to several other modified proteins, such as proteins modified by carbamylation and acetylation. As all these auto-antibodies recognize post-translationally modified proteins, these antibodies are collectively called anti-modified protein antibodies (AMPA). A variety of AMPAs against different protein modifications (anti-citrullinated, carbamylated and -acetylated protein antibodies) have now been described in RA suggesting a shared common ‘developmental’ basis. The studies described in these thesis aim to understand how autoreactive B cell responses are generated to post-translational modified proteins. Show less
Studies in this thesis focused on the use of MRI in patients with early inflammatory arthritis. Studies were focused on: the diagnostic value of MRI, predictive value of MRI findings for the... Show moreStudies in this thesis focused on the use of MRI in patients with early inflammatory arthritis. Studies were focused on: the diagnostic value of MRI, predictive value of MRI findings for the development of erosions, associations between age and MRI findings, the use of MRI for the development of new disease activity scores and patient reported outcomes in patients with rheumatoid arthritis. Show less
In dit proefschrift hebben wij de invloed van mestcellen in dierexperimentele modellen voor reumatoïde artritis en aderverkalking bestudeerd met een focus op de rol van mestcellen in de (sub)... Show moreIn dit proefschrift hebben wij de invloed van mestcellen in dierexperimentele modellen voor reumatoïde artritis en aderverkalking bestudeerd met een focus op de rol van mestcellen in de (sub)-klinische fases van het ziekteproces, waarin er een actieve immuunrespons ontwikkeld was. Ook hebben wij de aanwezigheid van verschillende soorten antistoffen in het serum van cardiovasculaire patiënten onderzocht. Wij hebben de niveaus van antilichamen gecorreleerd aan klinische observaties zoals body mass index (BMI), lipidenprofiel, klinische diagnose van vaatlijden, samenstelling van de atherosclerotische plaque en de uitkomst van de ziekte. Show less
The main aim of this thesis is to determine the role of magnetic resonance imaging (MRI) in early rheumatoid arthritis (RA). We set out to improve the MRI protocol and sequences used in arthritis... Show moreThe main aim of this thesis is to determine the role of magnetic resonance imaging (MRI) in early rheumatoid arthritis (RA). We set out to improve the MRI protocol and sequences used in arthritis patients, to detect subclinical inflammation in various patient groups and to describe the clinical implications of MRI. Chapter 1 provides a general introduction to this thesis, in chapter 2 the earliest disease stages of rheumatoid arthritis and the concept of pre-rheumatoid arthritis are further explored. In chapters 3-5 various ways are described to optimize the scanning protocol for arthritis patients. In chapters 6-8 we looked at the presence of inflammation on MRI when no inflammation can be detected at physical examination, i.e. subclinical inflammation. In chapters 9 and 10 we explore some of the clinical implications of the MRI findings. Chapter 11 provides a summary of the thesis and a discussion of the main findings. Show less
In this thesis we focussed on so-called 'treat to target' therapy in rheumatoid arthritis (RA). Treat to target relies on repetitive measurements of disease activity using a composite score that... Show moreIn this thesis we focussed on so-called 'treat to target' therapy in rheumatoid arthritis (RA). Treat to target relies on repetitive measurements of disease activity using a composite score that incorporates signs of disease activity such as laboratory results, findings of physical joint assessments, and the opinion of the patient. It is recommended that rheumatologists intensify treatment when a predefined level of disease activity, the target, has not yet been achieved. The implementation of treatment to target in daily practice depends on the faith of the rheumatologist and the patient to rely on a disease activity composite index (for instance the DAS) rather than on some judgemental estimate of disease activity ('the patient is doing well'). It also relies on a consensual opinion that a pre-set treatment target (for instance a DAS=>1.6) meaning clinical remission) is a desirable as well as an achievable target, and especially on the willingness to intensify medication every time the treatment target has not been achieved. Several aspects of treat to target, in particular a plea for the improvement of the rheumatologists' awareness about and the implementation of treat to target recommendations in daily clinical practice, are discussed in the thesis Show less
Het werk beschreven in dit proefschrift richt zich op het identificeren van voorspellende factoren voor het ontwikkelen van reumato_de artritis en het ziekte beloop van reumato_de artritis.... Show moreHet werk beschreven in dit proefschrift richt zich op het identificeren van voorspellende factoren voor het ontwikkelen van reumato_de artritis en het ziekte beloop van reumato_de artritis. Allereerst wordt er gekeken naar voorspellende factoren voor het krijgen van reumato_de artritis in vroege artritis pati_nten, patienten met ongeclassificeerde artritis en artralgie pati_nten (pati_nten met gewrichtspijn zonder gewrichtsontsteking). Daarna wordt er gekeken naar voorspellende factoren voor een ernstiger ziekte beloop van reumato_de artritis, op zowel; genetisch, serologisch als beeldvormend vlak. Concluderend draagt dit proefschrift bij aan het inzicht om vroeger te behandelen/monitoren en aan het inzicht dat __personalized medicine__ en MRI een belangrijke rol verdienen in de behandeling van reumato_de artritis. Show less
Part I of this thesis starts with a description of the Leiden Early Arthritis Clinic, followed by chapters on predicting the progression from Undifferentiated Arthritis to Rheumatoid Arthritis (RA)... Show morePart I of this thesis starts with a description of the Leiden Early Arthritis Clinic, followed by chapters on predicting the progression from Undifferentiated Arthritis to Rheumatoid Arthritis (RA) and predicting the severity of RA by clinical information available early in the disease stage. In part II of this thesis, several studies to genetic factors underlying the differences in the severity of joint destruction, are presented. Most importantly, we report interesting associations between SNPs in the genes encoding Wnt-signalling proteins and the MMP-9 gene and progression of joint destruction. Part III of this thesis is devoted to ACPA-negative RA. Evidence is emerging that we should consider this a distinct pathofysiological entity from ACPA-positive RA. We also report the results of a Genome Wide Association Study (GWAS) to the radiographic progression of RA. In part IV of this thesis, we describe two studies to non-genetic factors that could influence the severity of RA. We did not find any clear seasonal differences for the season of RA onset. We also conclude that although smoking influences the long-term outcome of RA, the effect of smoking is not independent of ACPA-status. Show less
RA has a complex multifactorial aetiology, of which many elements remain unknown. Genetic and environmental risk factors play a major role in disease development. Over the past few years,... Show moreRA has a complex multifactorial aetiology, of which many elements remain unknown. Genetic and environmental risk factors play a major role in disease development. Over the past few years, understanding of the genetic basis of the susceptibility to RA has increased dramatically and the identified risk loci were confirmed to account for 51% of the total genetic effect of which 36% explained by HLA in addition to 15% non-HLA genetic factors. The challenge remains to identify the rest of those genetic effects and explore how these variants interact with each other as well as environmental factors to induce RA. Although autoantibody formation is characteristic for RA, the range of antibodies formed in RA is not entirely specific for RA. Additionally, the majority of studies exploring the test characteristics of RF, anti-CCP and anti-MCV compare RA patients to healthy controls while in clinical practice those tests are used to differentiate early RA from other forms of early inflammatory arthritis. Because the focus is now shifted towards early therapy a new tool to identify early RA replacing the classic 1987 ACR classification criteria was warranted. The ultimate goal of personalized treatment decision making incorporates genetic, serological as well as clinical factors. Show less
Rheumatoid Arthritis (RA) is a chronic autoimmune disease, affecting a ~1% of the population worldwide. Although its causes are largely unknown, a considerable heritable component approximating 50... Show moreRheumatoid Arthritis (RA) is a chronic autoimmune disease, affecting a ~1% of the population worldwide. Although its causes are largely unknown, a considerable heritable component approximating 50-60% has been described. The most prominent genetic association in RA is confined to the human leukocyte antigen (HLA) locus which has been known for ~30 years. The identification of RA-associated genes outside of the HLA region, however, had been a challenge. A few years ago, one such gene, protein tyrosine phosphatase, non-receptor type 22 (lymphoid), was identified in a large genetic-association study utilizing putative functional SNPs. The aim of this thesis was to take a candidate gene approach to identify risk factors involved in rheumatoid arthritis. It is divided into three parts in which part one is dedicated towards the identification of a novel risk factor for RA and autoimmunity. This region of the genome encompasses genes highly involved in the immune system, namely Tumour Necrosis Factor Receptor associated factor 1/Complement component 5 on chromosome 9q33. In the second part, we have investigated the role of an immunoregulatory cytokine interleukin 10 located on chromosome 1q32 and in part three we have investigated the role of additional genetic risk factors in RA. Show less
We hypothesized that shoulder pain, caused by rheumatoid arthritis (RA), can lead to disuse of the affected shoulder joint. In addition to the structural changes caused by rotator cuff tears,... Show moreWe hypothesized that shoulder pain, caused by rheumatoid arthritis (RA), can lead to disuse of the affected shoulder joint. In addition to the structural changes caused by rotator cuff tears, tendonitis or synovitis disuse may play an important role in the aetiology of fatty degeneration (FD) of the rotator cuff muscles. This FD may induce proximal migration due to shoulder muscle force imbalance, causing even more pain due to subacromial impingement. FD is thought irreversible, even when the underlying pathology was treated. Early referral and treatment of shoulder involvement of rheumatoid disease may protect the rheumatoid shoulder from this downward spiral. It is of great importance to screen rheumatoid arthritis patients for shoulder joint involvement at an early stage. The use of the Upward migration Index to assess proximal migration can be used reliably to screen for the presence of rotator degeneration. In order to quantify fatty degeneration we advocate using the Mean Muscle Density measured on CT-images. We underline the importance of these measurements as they were strongly correlated to shoulder pain and functional loss. Measurement of proximal migration in an early stage can therefore play an important role in the initiation of functional and medicinal treatment of RA and may present patients with better possible outcome providing that shoulder surgery is indicated. Show less
This thesis describes the outcomes of 2 year follow-up of the BeSt study (Behandel-Strategieen). This is a multicenter, randomized clinical trial comparing 4 different treatment strategies in... Show moreThis thesis describes the outcomes of 2 year follow-up of the BeSt study (Behandel-Strategieen). This is a multicenter, randomized clinical trial comparing 4 different treatment strategies in patients with recent-onset active rheumatoid arthritis: 1. sequential monotherapy, starting with methotrexate, switching to another antirheumatic drug in case of an insufficient response; 2. step-up combination therapy, also starting with methotrexate, adding other antirheumatic drugs in case of an insufficient response; 3. initial combination therapy with methotrexate, sulphasalazine and high-dose tapered prednisone; 4. initial combination therapy with methotrexate and infliximab. In all groups the goal was to achieve a disease activity score (DAS) __2.4 (low disease activity). The DAS was measured 3-monthly by a research nurse, blinded for the allocated group. The physician then adjusted therapy according to the protocol. During the 2 year follow-up, groups 3 and 4 had a more rapid clinical response, less joint damage and less treatment adjustments than groups 1 and 2. Interestingly, groups 1 and 2 did better than expected. This is probably the result of aimimg for low disease activity. Most patients prefer treatment with the newest drug. The higher costs of infliximab can largely be compensated by savings on productivity. Show less
Rheumatoid arthritis (RA) is a relatively common disease that is characterized by chronic inflammation of joints. The research as described in this thesis focused on the question of whether... Show moreRheumatoid arthritis (RA) is a relatively common disease that is characterized by chronic inflammation of joints. The research as described in this thesis focused on the question of whether adoptive cellular therapy is effective in a mouse model of RA. The most generally known type of adoptive cellular therapy is, probably, bone marrow transplantation (BMT), i.e. BM cells from a healthy donor are transplanted to the patient. Especially, hematological disorders like leukemia are treated with BMT; however, the research presented in this thesis strongly suggests that BMT may also effectively treat diseases, such as RA, in the (near) future. The efficacy of other types of adoptive cellular therapies was also investigated, including the transfer of regulatory T cells. Most strikingly, the disappearance of autoaggressive immune cells was associated with the efficacy of the treatment. These results suggest that these immune cells that, directly or indirectly, cause damage to the patient___s joints were eliminated and/or were kept quiescent. These studies are of importance for the future improvement of the treatment of rheumatic diseases like RA. Show less
This thesis investigated the association between several genetic factors and autoantibodies and the development of undifferentiated arthritis (UA) and rheumatoid arthritits (RA). Second, this... Show moreThis thesis investigated the association between several genetic factors and autoantibodies and the development of undifferentiated arthritis (UA) and rheumatoid arthritits (RA). Second, this thesis described a prediction model that estimates the chance to progress from UA to RA. The most important genetic risk factor for RA are the HLA-Class II alleles that encode for a common amino acid sequence, called the ‘Shared Epitope’. Investigating the progression to RA from UA revealed that the HLA-Shared Epitope alleles are not primarily a risk factor for RA but for the presence of anti-CCP antibodies, that are known to be specific for RA. Smoking in the presence of HLA-Shared Epitope alleles particularly increased the risk on anti-CCP-positive RA.. The HLA-DR3 alleles were associated with anti-CCP-negative RA. The presence of HLA-alleles encoding for D70ERAA correlated with a lower risk on RA and a less severe disease course. The presence of the PTPTN22 T-allele conferred an increased risk for both UA and RA. The knowledge on risk factors for RA-development was translated in a model that estimates the chance to progress to RA in patients that present with UA by using 9 clinical variables. The discriminative ability was high and this model allows individualized treatment decisions in UA. Show less
