147 General discussion and future perspectives Of note, a good balance between under- and overtreatment is essential when developing preventive strategies in at-risk individuals, who are strictly speaking not yet patients: There may be substantial adverse effects of disease-modifying therapies, and it should not be assumed that evidence on the balance of benefits and harms found for patients with RA diagnosed following presentation with typical symptoms is generalizable to the at-risk population [30,33]. The time preceding disease manifestation, also known as ’pre-RA’, must therefore be recognized as a different entity from RA. Potential harms of a strategy that will label patients as having pre-RA must be considered, such as increased anxiety, reluctance to undertake usual levels of activity due to perceived disability, or wider social implications such as increased costs of insurance policies or restriction of occupational opportunities. The scale of such “potential harms” will depend on the extent of overdiagnosis that can be expected. The optimal primary and secondary care service models to monitor and support patients, and the associated workload and resource implications, also require further research [30]. Potentially modifiable lifestyle risk factors such as increased body mass index and smoking are strongly associated with the development of RA [34]. A recent, other systematic review highlighted that individuals at risk of RA have a need for more knowledge about RA and their potentially modifiable risk factors, which in turn could support their engagement with preventive interventions [35]. However, as yet there is no clear indication that modifying these lifestyle risk factors will prevent or delay the onset of disease [30]. Part III Dynamics in the B-cell repertoire after B-cell depletion in different phases of RA In the last section of this thesis, we investigated the B-cell repertoire after B-cell depleting therapy in RA patients. In Chapter 5, we demonstrated in RA patients undergoing B-cell depletion using rituximab, that deletion and recurrence of naive B-cells carrying unmutated BCRs proved to be a sensitive marker for depletion and repopulation. We speculated that the percentage of unmutated BCR clonotypes in the repertoire could be used as a proxy to monitor the fraction of naive B-cells. We showed this using BCR repertoire sequencing in RA patients undergoing B-cell depletion therapy with rituximab. Using this parameter, we observed that timing of depletion and repopulation does not predict response after 6 or 12 months. However, repopulation within the first 6 months did significantly correlate with decrease in disease activity in the subsequent period (i.e. 6-12 months after treatment), in comparison with patients who 7
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