Platelet‐associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia

Abstract

SummaryRituximab is widely used in autoimmune diseases including immune thrombocytopenia (ITP), although the mechanism of effect remains unclear. This study describes the effects of rituximab on platelet‐associated antibodies (PA‐APAs), B and T cell counts and clonality ( IGHV and TRG@ gene rearrangements), FCGR3A (FcγRIIIa) and FCGR2A (FcγRIIa) polymorphisms and correlation to anti‐CD40 ligand (CD40L) response. PA‐APA levels fell more frequently in responders (6/8) than in non‐responders (2/10: P = 0·08–0·15). Two responders had no PA‐APAs. Two non‐responders with a fall in PA‐APAs had very high CD8 levels. One non‐responder had a B cell clone, one responder and one non‐responder had a T cell clone. 15/16 patients had the same responses to rituximab and antiCD40L. Patients with FCGR3A V/V polymorphisms were more likely to respond to rituximab (P = 0·03). In summary, the fall in PA‐APAs in responders confirms the humoural effect of rituximab. Failure to respond in patients with very high CD8 levels, despite PA‐APA fall indicates a role for T cell‐mediated platelet/megakaryocyte destruction. Concordance of response to anti‐CD40L suggests autoantibody‐producing cells are under T cell control. Finally, the effect of FCGR polymorphisms on response confirms the importance of FCGR‐mediated depletion of B cells in autoimmunity. This has implications on the pathology of ITP as well as the immunological effect of B cell depletion.

The effect of rituximab on vaccine responses in patients with immune thrombocytopenia

“…35 An indirect effect of rituximab on T cells is consistent with other data showing an improvement of T-cell dysregulation after treatment. [36][37][38] A significant proportion of adults with chronic ITP will eventually undergo splenectomy to control their disease. 39,40 Splenectomy itself is associated with a risk of infection that is ;2.6-fold higher than nonsplenectomized ITP patients in the first 90 days after splenectomy, and 1.4-fold higher beyond 1 year.…”

CD20+ B-cell depletion therapy suppresses murine CD8+ T-cell–mediated immune thrombocytopenia

“…18,19,25 Of interest, the interruption of B-and T-cell interactions by, for example, CD40L antibody, shows a similar therapeutic effect as rituximab in ITP, suggesting that a direct interaction between B cells and T cells is essential for ITP induction. 12 In conclusion, our study suggests that the effectiveness of anti-CD20 therapy is due to induction of a significant CD8 1 T-cell activation/proliferation defect via IL-2 blockade that correlates with their inability to induce thrombocytopenia. This may provide an additional explanation for the therapeutic effects of rituximab in T-cell-mediated ITP.…”

“…10,11 Moreover, patients with ITP, whether antiplatelet antibody positive or not, can respond to rituximab and in those antibody-positive patients, their autoantibody titers do not necessarily change. 12 This suggests that anti-CD20 can significantly affect T-cell compartments and this was originally confirmed by Stasi et al showing that rituximab normalizes the observed CD4…”

Pyrosequencing for Classification of Human FcγRIIIA Allotypes: A Comparison with PCR-Based Techniques

“…Genotyping methodology used for testing FCGR3A variance at nucleotide 559 may result in erroneous interpretation of genotype distribution [10]. The separation of the V/V, V/F and F/F allotypes from each other is technically challenging because of the very close similarities between the FCGR3A and FCGR3B genes [25,33,34]. The high degree of homology between these genes, which are separated by only a single base difference at codon 148 (FCGR3A GAC vs. FCGR3B GAT), may result in a misinterpretation of the genotypes.…”