This thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of... Show moreThis thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of circulating adiponectin can predict radiographic progression in patients with early RA. In contrast, in patients with hand OA, this association appears protective. Therefore, to obtain insight into the mechanisms underlying these associations, we investigated the high-molecular-weight isoform of adiponectin (hmwAPN), which is one of the most biologically active isoforms of adiponectin. We show that the associations of total adiponectin with radiographic progression are not mediated by hmwAPN, in either RA or HOA. In the second part, we present the immunological characterization of the infrapatellar fat pad (IFP), a joint associated adipose tissue, in patients with advanced knee OA. We observed profound differences in secreted inflammatory factors and immune cell composition between the IFP and paired subcutaneous adipose tissue samples. Interestingly, we observed obesity-related changes in the IFP phenotype, and in macrophages and adipocytes, Therefore, we investigated the modulatory effects of adipocytes on the phenotype of human macrophages in vitro and we observed that adipocyte-derived lipids can mediate the obesity-related changes in the phenotype of adipose tissue macrophages in humans Show less
The identification of ACPA has been a major breakthrough in the understanding of pathogenesis in RA. It has become clear that this unique autoantibody response identifies more homogenous subsets of... Show moreThe identification of ACPA has been a major breakthrough in the understanding of pathogenesis in RA. It has become clear that this unique autoantibody response identifies more homogenous subsets of patients with RA than those characterized by levels of other autoantibodies, and that differing disease courses possibly reflect the involvement of ACPA in disease pathogenesis. The elucidation of the characteristics of the ACPA response have shown that ACPA are not pathogenic per se, as illustrated by the fact that most patients are ACPA-positive a while before they develop disease. Possibly, a more mature ACPA response__as illustrated by more extensive isotype switching, enhanced antigen-recognition profile and higher titers__might be required for these autoantibodies to contribute to disease pathogenesis. Once RA is established, the ACPA response does not seem to mature. Nonetheless, ACPA status is important for clinical decision making, as it is the factor that is most predictive of disease outcome and associates with the effectiveness of various interventions 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
Gvozdenovic, E.; Koevoets, R.; Wolterbeek, R.; Heijde, D. van der; Huizinga, T.W.J.; Allaart, C.F.; Landewe, R.B.M. 2014
Dit proefschrift richt zich op het monitoren van ziekte bij zowel RA als UA pati_nten en kijkt daarbij naar de waarde van de beeldvorming, het beoordelen van de ziekteactiviteit, het vast te... Show moreDit proefschrift richt zich op het monitoren van ziekte bij zowel RA als UA pati_nten en kijkt daarbij naar de waarde van de beeldvorming, het beoordelen van de ziekteactiviteit, het vast te stellen behandeldoel en de implementatie van monitoring in de dagelijkse praktijk. Naar aanleiding van dit proefschrift kunnen de volgende conclusies worden getrokken: -Systematisch literatuur onderzoek laat zien dat afwijkingen op conventionele r_ntgenfoto__s waardevol zijn voor het voorspellen van de prognose van UA pati_nten. Voor de aanvullende waarde van echografie en MRI in UA pati_nten werd weinig bewijs gevonden. -Gewrichtsschade ter plaatste van de pols, met name erosieve schade, heeft een belangrijke invloed op het dagelijks functioneren van pati_nten met reumato_de artritis. -Een versimpelde DAS zonder gegradeerde of gegroepeerde pijnscore kan goed worden gebruikt voor het in kaart brengen van ziekteactiviteit, zowel met een VAS voor algemene gezondheid als met een VAS voor ziekteactiviteit. -De mate van ziekteactiviteit gescoord door pati_nten en artsen komt niet goed overeen. Pati_nten scoren over het algemeen hoger waarbij pijn een belangrijke factor van invloed is. Artsen baseren hun score meer op de bezinking en het aantal gezwollen gewrichten. -De relatie tussen verschillende definities van remissie (inclusief de nieuwe ACR/EULAR remissie criteria) en radiologische schade of HAQ is vergelijkbaar. -Verbetering in ziekteactiviteit geeft een verbetering in kwaliteit van leven gemeten met de Physical Component Scale van de SF-36. Dit geldt ook voor pati_nten met reeds een lage ziekteactiviteit die in remissie komen. -Pati_nten zijn bereid tot het online monitoren van lichamelijk functioneren, maar doen dit in de thuissituatie weinig. Meer begeleiding en het benadrukken van het nut van regelmatige ziektemonitoring voor het uiteindelijke behandelresultaat is nodig om dit te kunnen verbeteren. Show less
Rheumatoid Arthritis (RA) is a chronic autoimmune disorder that affects approximately 0.5-1% of the population. RA leads to inflammation of the joints and leads to irreversible destruction of... Show moreRheumatoid Arthritis (RA) is a chronic autoimmune disorder that affects approximately 0.5-1% of the population. RA leads to inflammation of the joints and leads to irreversible destruction of joints with subsequently to significant morbidity, disability for patients. Remarkably the amount of joint destruction differs substantially between patients. Currently medication mainly aims at diminishing inflammation. Because joint destruction seems to develop even when the inflammation level is low, since RA is still not curable and finally because joint destruction is irreversible, joint destruction becomes an increasingly important feature in patients with RA. In this dissertation, different aspects of joint destruction in RA were investigated. To highlight the most important findings: first of all the heritability of joint destruction was demonstrated. In addition several genes were further studied. Two genetic findings were of most interest: IL2RA was associated with joint destruction. Since there is already medication available that aims at IL2RA, this finding creates a new treatment option for the nearby future. More intriguingly, SPAG16, an thus far with sperm association gene, appears to be relevant in joint destruction in RA as well. This put a totally new light on the gene. Naturally, most of the newly discovered associations will need further research before they can be applied in clinical practice. Show less
