148 CHAPTER 7 achieved repopulation later or not at all. This could not be explained by a difference in disease activity at 6 months between the two groups or by the second cycle of rituximab therapy. This might suggest that it is in fact the repopulation following rituximab – rather than depletion itself – that is able to “reset” the (pathological) B-cell compartment, leading to temporal improvement of the disease activity. This observation contrasts with the widely-held view that early repopulation might be a sign of treatment failure, and needs to be confirmed in a larger study. However, it should be noted that earlier studies report opposing results on the correlation between depletion and treatment effect [36]. Further studies are clearly needed in this area. Unfortunately, this study had a relatively short follow-up time. Since most of the patients start to repopulate their B-cell compartment at 6 months post-treatment, having the last follow-up point set at 12 months post treatment was relatively short to detect disease relapse. During this trial the clinicians were allowed to retreat with rituximab in case of insufficient response. However, the treating clinicians did not yet have access to the results of the repopulation analysis to base their decision for retreatment on, but this may change in the near future. An earlier study from Humby et al., suggests that patients with low or absent B-cell lineage expression signature in ST respond more effectively to tocilizumab than rituximab [37,38], however this has not yet been validated in an independent cohort. In hindsight, it would have been interesting if we would have also taken ST biopsies from these patients at baseline to be able to stratify patients. Furthermore, paired synovial tissue biopsies and peripheral blood samples would help to study the recurrence of B-cell clones during disease relapse. Such a study could potentially prove that rituximab does not just eradicate (all) pathological B-cells, but rather prevents them to reach the site of disease activity, i.e. the synovium. This might explain why - despite the temporary amelioration of disease symptoms - CD20-depleting therapy does not cure RA. In Chapter 6, we combined two unique studies performed in RA-risk individuals, yielding novel data in the field of preclinical rheumatoid arthritis. In the PRAIRI study at-risk individuals were randomized and treated with rituximab or placebo over time. This study demonstrated that rituximab treatment in the preclinical phase delayed the onset of RA [21]. Since the intervention was a single infusion with rituximab, in contrast to the majority of clinical trials where rituximab is dosed more than once, the course post-intervention can be studied more accurately. The current data demonstrate that the BCR repertoire of rituximab treated RA-risk individuals
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