107 B-cell repopulation after rituximab in rheumatoid arthritis depletion might thus be extremely useful in clinical practice, allowing the physicians to more closely monitor disease progression during repopulation and eventually take an informed decision on intensification of treatment. Using the same approach, we observed that depletion does not predict clinical response at 6 and 12 months. On top of that, we showed that patients that achieve depletion within one month of treatment did not show any improvement in disease activity in the same time-span. This confirms previous reports showing that timing and depth of B cell depletion does not correlate with clinical response to rituximab during 0.5 and 1 year of follow-up [4,19]. This lack of correlation is thus not due to a lack of sensitivity of previously used methods. The observed association of early BCR repertoire depletion with less response at 1 and 3 months after rituximab therapy is interesting. This might be the result of the fact that in our cohort late depleting patients had a slightly higher baseline DAS28 score (late depleting: 4.6 ± 0.9 vs. early depleting: 4.1 ± 1.1; p-value = 0.2, n.s.), thus resulting in more potential to improve in disease activity [19,20]. However, if indeed an influx of naïve, unmutated B cells explains the clinical effect of rituximab, an alternative explanation might be that part of the patients have a higher baseline influx of naïve, unmutated B-cells before treatment; this increase in B-cell turnover might explain both later depletion with better amelioration of disease activity, and earlier repopulation with better disease amelioration. In case of rituximab, this would lead to a complicated relation between anti-drug antibodies (ADA) development and clinical response. In patients newly starting on rituximab, some will develop ADA after 3 to 6 months [6]. In these patients, ADA is likely to be correlated with earlier clearance of the drug and earlier repopulation (p = 0.06 in our data) leading to better clinical response. However, in patients with pre-existing ADA, these antibodies will interfere with the primary effect of rituximab, i.e. B-cell depletion, and therefore lead to clinical non-response. In this situation the net effect of both mechanisms will determine the clinical response in each individual patient. This study has several limitations. One is the 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. The second limitation is that the protocol did allow intensification of treatment in cases of insufficient response. However, clinicians did not have access to the results of the repopulation analysis, and the decision to retreat with rituximab after 6 months did not correlate with early repopulation (p = 0.7). It would have been nice to correlate the BCR repertoire in paired synovial tissue samples with that in peripheral blood to study the recurrence of B 5
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