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
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
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
