Modified neonatal B-cell repertoire as a consequence of rituximab administration to a pregnant woman

Sir, In cases of refractory immune-mediated thrombocytopenic purpura (ITP), when there is no response to conventional therapy with third- and fourth-line medications, the approaches include rituximab (RTX) [1, 2]. RTX, a chimeric monoclonal antibody directed against B-cell surface antigen CD20 [2], contains an immunoglobulin G1κ construct and can, in consequence, cross the placenta [3]. We describe the effects of the administration of this B-cell depletion therapy on B-cell subsets, including CD79a, in the offspring of a pregnant patient diagnosed with ITP. A 21-year-old woman was diagnosed with ITP from week 15 of her third pregnancy. She was initially treated with high doses of methylprednisolone and azathioprine, but, due to a persisting low platelet count, she received RTX (375 mg/m2) at 24 weeks of pregnancy. At 34 weeks and 1 day of gestation, the patient presented with preterm labour, a girl was born, with physical examination revealing no abnormalities. The neonate did not have any infectious complications and was discharged 7 days later. Blood samples were taken (mother and her offspring) at the time of delivery, and flow cytometry was performed. The Ethics Committee approved the drug application in our patient. They approved the samples taken from mother and child and the controls. Both the RTX-treated mother and the mother of the control infant gave informed written consent. The number of CD19+ B cells was undetectable by flow cytometry at the time of delivery in either newborn or mother, with a high number of CD79a+CD19− (28.9%) in the offspring, a percentage that was lower at 3 months after delivery (7.68%); the mother did not present CD79a+CD19− in peripheral blood. To evaluate whether levels of CD79a+CD19− are influenced by gestational age in the newborn, we performed flow cytometry of a control newborn (same gestational age at delivery) and found an absence of CD79a+CD19− (0%) and 6% of CD19+ B cells (Fig. 1). Flow cytometric analysis of peripheral blood lymphocytes. Dot plots show CD79a+CD19+ and CD79a+CD19−: (A) RTX-treated offspring; (B) control offspring. The B-cell receptor is characterized by a complex hetero-oligomeric structure in which ligand-binding signal transduction domains are compartmentalized into distinct receptor subunits. The ligand-binding portion is a surface immunoglobulin (usually IgM or IgD), and the signal transduction portions are CD79a and CD79b [4]. CD79a and CD79b expression precedes immunoglobulin heavy-chain gene rearrangement and CD20 expression during B-cell ontogeny and disappears later than CD20 in the late (plasma cell) stage of B-cell differentiation [4, 5]. However, the earliest stage of B-lineage development can be recognized as a CD45+ subset that lacks CD19 [6]. Rituximab depletes the CD20+ subset of B cells of patients with RA, not only in peripheral blood but also in bone marrow and synovium [7]. Our finding of a high percentage of CD79a+CD19− cells in peripheral blood may have different explanations: one of these could be just enhanced B-cell repopulation in response to RTX [8], but we encourage practitioners to report information on B-cell markers in the offspring of mothers receiving RTX, including this type of immature B cell (CD79a+CD19−). To date (1 year of follow-up) the offspring has no clinical consequences, but long-term follow-up is needed to assess the potential late effects of this drug. Disclosure statement: The authors have declared no conflicts of interest.