Rheumatoid arthritis (RA) is a chronic, symmetrical, autoimmune disease characterized by inflammation of the joints, as well as damage to a variety of body systems, including the skin, eyes, lungs,... Show moreRheumatoid arthritis (RA) is a chronic, symmetrical, autoimmune disease characterized by inflammation of the joints, as well as damage to a variety of body systems, including the skin, eyes, lungs, heart and blood vessels. Therefore, to prevent (potential) damage with a more favorable course of the disease, it is important to intervene both early and agressively with medication in the treatment of RA. Typically, methotrexate is used as the first treatment, possibly in conjuction with other disease-modifying antirheumatic drugs, or with prednisolone to reduce inflammation rapidly. While the treatment of RA has improved considerably in recent decades, drug treatment does not work for everyone due to toxicity or lack of responsiveness. Therefore, it is suspected that genetics plays a major role in the both efficacy and toxicity of current RA medication. The goal of this thesis is to identify the genetic factors that influence the effectiveness or toxicity of the drugs used in RA. Show less
In this thesis we aimed to investigate ways to optimize treatment strategies and the choice of treatment for individual patients, to be implemented in a worldwide context. Although major advances... Show moreIn this thesis we aimed to investigate ways to optimize treatment strategies and the choice of treatment for individual patients, to be implemented in a worldwide context. Although major advances have been made in the treatment of RA, it is still uncertain which treatment is the best choice for each individual patient. This can result in both overtreatment and undertreatment, increasing the burden of RA for patients as well as for society. In clinical trials and daily practice there appears to be a development towards earlier treatment, with higher dosages of medication and more stringent treatment targets. In part 1 of this thesis, some of these developments were investigated and challenged. In countries across the world, patients do not benefit similarly from recent advances in the treatment of RA. In part 2 of this thesis, we aimed to identify contributing factors to inequalities in access to treatment and care and clinical outcomes across countries, as a first step towards improvement. Show less
This thesis focuses on different aspects of treatment of patients with rheumatoid arthritis (RA) and undifferentiated arthritis (UA), based on the results of three intervention studies; the... Show moreThis thesis focuses on different aspects of treatment of patients with rheumatoid arthritis (RA) and undifferentiated arthritis (UA), based on the results of three intervention studies; the IMPROVED-study, the BeSt study and the PROMPT study. This thesis discusses the results of different treatment strategies for patients with RA and UA; the percentage of patients that achieves remission , the mean disease activity, radiographic damage progression and daily functioning. I then analysed the factors that effect the response to treatment and the achievement of drug free remission . Then radiological damage progression is discussed. Are there patients with early arthritis who have rapid radiographic progression in the first year after diagnosis or we can prevent this with effective treatment? We also assessed whether patients with early RA have metacarpal bone mineral density loss after 4 months, measured with digital X-ray radiogrammetry, and whether this predicts radiological damage progression after 1 year of anti-rheumatic treatment. Finally , I analyzed how the IMPROVED population was doing with regard to psychological well-being (mood and optimism), quality of life and the relationship of these so-called patient-reported outcomes with disease activity and achievement of remission. Show less
Major advances have been made in the treatment of rheumatoid arthritis, a potentially chronic disabling disease which poses a large burden on both patients and society. By early start of disease... Show moreMajor advances have been made in the treatment of rheumatoid arthritis, a potentially chronic disabling disease which poses a large burden on both patients and society. By early start of disease-modifying antirheumatic drugs, including methotrexate as a prominent drug, the use of combination therapies including prednisone or biologicals, and tight control of disease activity, many patients are able to reach a state of clinical remission and some can even taper and stop antirheumatic therapy. Challenges lie in correctly identifying the earliest manifestations of the disease, starting the right treatment sufficiently early, tailored to the individual patient, and setting the optimal treatment goal at which to steer therapy adjustments. This thesis has made a start towards tackling several of these challenges and discusses further necessary steps that may lead to a fundamental change in the outlook of patients with rheumatoid arthritis. Show less
In this thesis clinical and immunological studies in patients with undifferentiated (UA) and rheumatoid arthritis (RA) are described. Depending on the study population 6-55% of the patients who... Show moreIn this thesis clinical and immunological studies in patients with undifferentiated (UA) and rheumatoid arthritis (RA) are described. Depending on the study population 6-55% of the patients who presented with UA actually fulfilled the criteria for RA as defined by the ACR in 1987 over time. In the first four years, radiographic joint damage, disease activity and HAQ were comparable in patients with RA presenting with UA and patients presenting with RA. Treatment of UA patients with methotrexate resulted in postponing progression to RA and retarding radiographic joint damage. In UA patients who had low/intermediate pretreatment ACPA-levels and were treated with methotrexate, the incidence of RA was lower than in patients with high levels. The disease activity score that was used in RA patients was validated in patients with UA. To identify which patient with UA will progress to RA, a prediction rule was developed. In patients with RA, treatment with TNF-alpha resulted in recovery of regulatory T cells. The importance of these regulatory T cells was emphasized in the strength of the anti-inflammatory response to the human cartilage glycoprotein 39 in healthy individuals: it even suppressed other pro-inflammatory responses, whereas patients with RA reacted with a pro-inflammatory response Show less
Results from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in... Show moreResults from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in patients with RA was validated in two cohorts indicating that predicting efficacy by a pharmacogenetic model is feasible in RA patients treated with MTX. Importantly, definitive conclusions about the role of genetic predictive factors in treatment outcome to DMARDS could not be drawn, since these results have to be further validated and replicated in future pharmacogenetic studies. Large randomized prospective studies should be planned to demonstrate its legitimate predictive and cost-effective value before a genetically individualized approach is applicable in daily clinical practice. The potential role of pharmacogenetics in the prediction of efficacy and adverse events in RA patients treated with DMARDs is presented in this thesis. Hereby, new knowledge is added to the relatively young research field of pharmacogenetics, which may hopefully lead to a better treatment strategy for RA patients Show less
Patients with recent onset RA benefit from dynamic treatment strategies in which treatments are continuously being adjusted on the basis of regular assessments of disease activity, according to a... Show morePatients with recent onset RA benefit from dynamic treatment strategies in which treatments are continuously being adjusted on the basis of regular assessments of disease activity, according to a predefined treatment protocol. Remission, with and even without maintenance therapy, is a realistic goal. Pharmacogenetics may provide useful information on initial treatment decisions, but as long as accurate prediction of response to treatment and disease severity is not possible, all patients with RA should be treated with initial combination therapy shortly after symptom onset. Which is the best combination to start with is not crystallized, and depends on the long term outcomes of drug-free remission, safety and cost-utility analyses. By incorporating the newest treatment options into these strategies, hopefully in the future rheumatoid arthritis will no longer be a chronic disease. Show less
