- Rheumatoid arthritis
- From the at risk phases all the way up to the development of the disease
- Award date
- 12 May 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. The local processes leading to initiation of the disease have not yet been elucidated. Although the synovium is the most important site of pathology in the established phase of RA, it is most probably not the site where the disease is initiated. The analysis of serum and tissues from articular as well as from extra-articular sites obtained from individuals at risk of RA and/or from early RA patients, may aid understanding of the processes leading to synovial tissue inflammation and detrimental autonomous disease progression. Therefore, we systematically review data from studies on various tissues collected during at risk phases leading up to the development of RA.
During the last couple of years, RA research has focused more on the earliest stages of the disease, leading to the discovery that circulating autoantibodies and elevated acute phase reactants, cytokines and chemokines can be present years before the clinical signs of the disease appear. Furthermore, multiple genes determine RA disease susceptibility, as well as lifestyle and environmental factors, such as overweight and smoking. Unaffected first degree relatives (FDRs) of RA patients share at least some genetic and environmental risk factors with RA patients and may therefore provide an opportunity to enrich the population at risk of developing RA. Therefore, we determined the prevalence of ACPA and IgM-RF in a large cohort of 577 FDRs of RA patients.
Obesity has also been suggested as an important risk factor in the development of RA. As obesity is characterized by an increased volume of adipose tissue, producing adipokines, we hypothesized that serum levels in autoantibody-positive individuals at risk of developing RA could be of importance in the development of RA. We show that serum vaspin levels were associated with the development of arthritis in these individuals, even after adjustment for being overweight.
Increased angiogenesis is also considered an important factor in the pathogenesis of RA. The nuclear factor-κB (NF-κB) family of transcription factors is highly important in the development and perpetuation. The noncanonical NF-κB pathway is strictly dependent on NF-κB-inducing kinase (NIK). We investigated NIK expression in the earliest phases of RA compared to other forms of arthritis.
The analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using pharmacokinetic modeling (PKM) provides quantitative measures that mirror microvessel integrity and can be used as objective markers of the level of synovial inflammation and as a non-invasive marker of synovial angiogenesis. We investigated the value of the Tofts DCE-MRI PKM parameters (Ktrans, Kep and ve), in a prospective cohort of DMARD naive early arthritis patients. Our results show that they differ between diagnostic groups and thereby suggest that they may be used as a diagnostic biomarker in early inflammatory joint disease.
Some patients with inflammatory oligoarthritis or polyarthritis initially not meeting RA classification criteria who are classified as undifferentiated arthritis (UA) based on clinical and laboratory assessments, might later fulfil classification criteria for RA. Classifying these patients earlier as RA would enable evaluation of therapeutic intervention and suppression of RA disease activity during an earlier stage of the disease. The multi-biomarker disease activity (MBDA) score, calculated from the concentrations of 12 serum biomarkers, is an objective validated disease activity measure for patients with RA. We investigated whether the MBDA score might inform RA diagnosis in patients with UA. This was not the case. Tissue destruction of the extracellular matrix (ECM) in RA is mediated by enzymatic cleavage by proteinases, predominantly by matrix metalloproteinases (MMPs). Consequently, a range of proteindegradation products are generated. We investigated the concentration of 5 products (C1M, C2M, C3M, VICM, CRPM), markers of joint destruction and inflammation, in a cohort of early arthritis patients. We demonstrated that there was a significant difference in C1M, C3M, CRPM and connective tissue degradation levels between patients classified as RA and UA at baseline, with higher concentrations in the early RA patients. Finally, we showed that C2M concentrations are significantly higher in early RA patients that progress to erosive disease after 2 years of follow up. Taken together, these epitopes may improve the current diagnostic and/or prognostic process in early arthritis patients.
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