150 CHAPTER 7 very interesting to see whether these “switching” B-cells could also be found or even originate from the synovial tissue. However, the procedure to sample synovial biopsies can be rather difficult in preclinical RA, since patients do not experience arthritis (yet). Therefore, phenotyping of B-lineage cells from the ST in pre-RA will likely be limited. Concluding remarks and future directions Over the past twenty years, treatment of rheumatoid arthritis has been dramatically improved. New treatment targets were identified and multiple novel therapeutics became available. This also translated to better control of disease activity and prevention of structural damage in most patients: we hardly see any wheelchairs, nor joint deformities in the outpatient clinic. However, the three parts of this thesis also reveal new questions worthy of addressing in future research and/or trials. The work done in Part I of this thesis shows that in the individual patient shared T- and B-cell responses might be underlying inflammation in different joints. This supports the idea that antigen- and/or receptor-specific therapies targeting a limited set of T-cell and/or B-cell receptor clones might be feasible and effective in patients with rheumatoid arthritis. To further develop this approach of targeted immunotherapy, further characterization of the shared “clones” is indicated (e.g., regarding phenotype, TCR α- and β-chain pairing, Ag specificity, and genomic profiles). Hopefully, novel or improved technologies for single-cell characterization of limited patient samples will rapidly be developed to allow this in the near future. The results described in Part II showed us that early treatment of at-risk individuals may be effective in delaying RA onset, thereby potentially also decreasing disease-related limitations in individuals in the earliest (pre-clinical) phases of RA. Whether this strategy may ultimately lead to prevention of RA remains to be determined. The type of intervention that would be effective may also differ across the different preclinical phases of the disease. As mentioned earlier, investigating various compartments of the immune system could also aid in understanding the immune alterations that are present in the preclinical phase of RA. One can hypothesize that early targeted intervention could result in a larger beneficial effect than the effects of treatment initiated at the time of diagnosis. Numerous components of disease pathogenesis could serve as potential targets for prevention of RA, including autoantibody generation cellular players involved in the autoimmune response, and various other mediators of inflammation. Possible future treatment strategies could be tolerogenic dendritic cell-based therapies through nanoparticles, cellular
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