151 General discussion and future perspectives therapies with tolerogenic antigen-presenting cells (i.e. dendritic cells), chimeric antigen or auto-antibody receptor (CAR and CAAR, respectively) T-cells, regulatory T-cells and mesenchymal stem cells, immune checkpoint receptor agonists (e.g. PD-1, CD200R or BTLA stimulation) and co-stimulatory molecule blockade, as well as depletion strategies for (subsets of) T and B-cells [40,41]. Based on our results in Part III, we hypothesize that interindividual differences in the clinical response to rituximab are defined by patient-specific differences in B-cell turnover in both established and preclinical RA. This could be caused by the different immunopathotypes or gene signatures in the inflamed ST. We propose further studies are indicated to validate these observations, analyze the underlying mechanisms, and assess which cell populations are involved, with a particular emphasis on the B-cells that switch their phenotype over time. This select group of “switching clones” could potentially be involved in autoantibody production and therefore may be of great interest in future studies investigating the B-cell lineage in the preclinical phase of RA, especially in relation to developing new targeted therapies and/or prevention strategies. Lastly, it is logical to start investigating novel concepts and biological processes such as changes in the BCR/TCR-repertoire over time to elucidate certain pathophysiological aspects in more prevalent diseases, such as rheumatoid arthritis. However, the research performed in this thesis should also be expanded to the “immune-mediated inflammatory diseases (IMIDs)”-group at large, both common (e.g. rheumatoid arthritis, Crohn’s disease, spondyloarthropathy, or psoriasis) and rare (e.g. Castleman’s disease, hyper-IgD syndrome, dermatomyositis, or relapsing polychondritis). This would give us better understanding of the pathogenesis of these debilitating diseases. Obviously, this is not feasible for one research group and (inter)national collaborations should be sought. Fortunately, many of these partnerships already exist, including the “Autoimmune Research & Collaboration Hub (ARCH)”, a Dutch, multi-disciplinary network for systemic auto-immune diseases; the “Rational Use of Biologics in rare Refractory IMIDs Consortium (RUBRIC)” registry, a Dutch online registry for patients with rare IMIDs treated with biologics (www.rubricregistry.nl); and the “Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK (ABIRISK)” consortium, an international consortium analyzing the mechanisms and consequences of immunization against biologics in several common IMIDs [42–44]. Of note, by including primary health care physicians in (some of) these projects we could gain even more insights, especially in the earlier stages of these diseases. 7
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