105 B-cell repopulation after rituximab in rheumatoid arthritis ference in DAS28 changes, or in clinical response at month 6 or 12 post-treatment was observed between the two groups (data not shown). However, there was a significant difference when analyzing the change in DAS28-score after repopulation (Figure 4A). In the early repopulating patients, a larger decrease in DAS28-score was measured between month 6 and 12 (p-value < 0.01; early repopulating: -1.17 ± 0.96, late repopulating: 0.18 ± 0.67, mean ± SD). This was also observed when excluding re-treated patients (online supplementary figure S2E) or excluding imputed data (online supplementary figure S3C). Of note, the DAS28 at month 6 did not differ between the two groups (early repopulating: 3.36 ± 0.89, late repopulating: 3.42 ± 1.53, mean ± SD; p-value = 0.92), thus not explaining this observation. In addition, there was no correlation between early depletion and early repopulation (p-value = 0.41), indicating that early depletion does not lead to early repopulation. Thus, early repopulation of the B cell compartment does not predict treatment outcome at 6 or 12 months, but is associated with improvement of disease activity shortly after repopulation. Effect of anti-drug antibodies on repopulation ADAs are known to increase drug clearance due to the formation of ADA-drug complexes, and patients who develop ADAs show a reduced drug trough concentration in serum [17,18]. We therefore assessed whether development of ADAs against rituximab was associated with early B cell repopulation. In our cohort of 28 patients, 14 developed ADAs within 12 months of treatment. No association between ADA development and depletion (early or late) was observed (data not shown). Ten (71%) out of these 14 ADA positive patients showed B-cell repopulation within 12 months, while 4 out of 13 (30%) of the ADA negative patients did (p-value = 0.06, n.s., 1-sided Fisher exact test; Figure 4B and online supplementary figure S3D. For one patient no repopulation status was available). Hence, even though not significant, there still might be a trend in favor of an association between the development of anti-drugs antibodies within 12 months of treatment and repopulation of the B cell compartment within the same time-span. 5
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