15 General introduction and outline individuals has the theoretical potential to delay or even prevent disease onset. In Chapter 4, we perform a systematic literature review in order to provide an overview of all preventive strategies applied to at-risk individuals, taking into account all studies that have hitherto been performed and ongoing clinical trials, as well as patient perspectives to understand the feasibility of these types of interventions. In Part III of this thesis, the behaviour of B-cells before and after B-cell depletion is investigated. To gain more insight in the pathophysiology of B-cells in both RA and at-risk individuals. In Chapter 5, we investigate the depletion and repopulation of B-cells after B-cell depletion with rituximab treatment in RA patients. Although B-cell depleting therapy in RA is clearly effective, response is variable and does not always correlate with B-cell depletion itself. Time points of achieved depletion and repopulation are defined based on the percentage of unmutated BCR-clones in the repertoire. Furthermore, the predictive value of early depletion and early repopulation on clinical response is assessed to gain more insight into how this correlates with clinical response. In Chapter 6, we focus on B-cells in individuals at-risk of developing RA. We investigate changes in the BCR repertoire over time and the effects of a single dose of rituximab in at-risk individuals. For this, we use data from the earlier mentioned randomized controlled trial, the PRAIRI study, in combination with data from a longitudinal cohort, the “DOMINant clones in the Onset of RA” (DOMINO) study. In addition, a phenotypic analysis of B lineage cells is performed in a similar cohort of at-risk-individuals. Finally, in Chapter 7 a summary of the studies presented in this thesis is provided and discussed in light of current literature, with an outlook to future perspectives. 1
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