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Rituximab combined with belimumab for adult ITP
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Figure 3. B-cell activating factor and B-cell subsets in immune thrombocytopenia patients receiving the combination therapy or rituximab alone. (A) B-cell activating factor (BAFF) concentrations were assessed by enzyme-linked immunosorbent assay in serum of patients receiving rituximab and belimumab (in blue) or rituximab alone (in red) at week 0 (W0), W12, W24, W36 and W52. Data are mean ± standard error of the mean (pg/mL). (B) Gating strategy of B-cell subpopulations. Single lymphoid cells on peripheral blood mononuclear cells (PBMC) were gated by using scatter parameters, and dead cells were eliminated by using zombie violet. Plasmablasts/plasma cells (PB/PC) were defined as CD27hiCD38hi cells among CD3-CD14-CD16- cells. After excluding CD3/CD14/CD16-positive cells and PB/PC from the CD19+ gate, B-cell subsets were separated according to their expression of CD27 and IgD and defined as memory B cells (CD27+IgD-), CD27+IgD+ B cells, and naïve B cells (CD27–IgD+). Transitional B cells were defined as CD38hiCD24hiCD10+ cells among naïve B cells. (C) Circulating B-cell subset count per million PBMC at W0, W4, W12, W24, W36 and W52. ****P<0.0001
ab had an unexpected effect on activated cTfh cells, which are essential for germinal center formation, B-cell affinity maturation and plasmablast generation.29 In humans, the majority of cTfh are central memory T cells expressing PD1 but no ICOS,16 but germinal center recruitment and support for B-cell differentiation requires up-regulation of ICOS.30 Splenic Tfh cells can contribute to ITP pathogeny and, as previously reported,7 the number of activated cTfh cells was increased at baseline in the peripheral blood of ITP patients. Although some cTfh cells were shown to express BAFF-R in systemic lupus erythematosus, this was not the case in ITP (data not shown),31 so their sensitivity to belimumab remains unexplained so far. Of note, local BAFF production by Tfh cells has been identified as an
important factor for promoting germinal center B-cell sur- vival.32 Belimumab might also prevent, through such pleiotropic effects, the re-emergence of germinal centers in lymphoid organs at the time of B-cell repopulation, an effect that would be further strengthened by extending the duration of its administration. These preliminary results support a new rationale for the addition of BAFF blockade to B-cell depletion in auto-immune diseases.
The main limitations of this pilot exploratory and sin- gle-center trial are the sample size and the open design. These results should be confirmed in a multi-center dou- ble-blind randomized prospective trial.
In conclusion and despite these limitations, in adult ITP, adding belimumab to RTX at the initial phase of B-cell
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