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Background  The causes and mechanisms of late-onset neutropenia (LON) following rituximab treatment in patients with rheumatic diseases are not known. In this study, we aimed to investigate the role of established Fcγ receptor gene ( FCGR ) polymorphisms and B-cell-activating factor ( BAFF ) gene promoter polymorphisms for the development of LON and for the efficacy of rituximab in patients with rheumatic diseases.    Methods  A single-center case-control retrospective study was nested in a cohort of 214 consecutive patients with rheumatic diseases treated with rituximab. Eleven patients presented with LON. Fifty non-LON control subjects were matched by diagnosis, age, sex, and treatments. Single-nucleotide polymorphisms of  FCGR  ( FCGR2A  131H/R,  FCGR2B  232I/T,  FCGR3A  158V/F) and  BAFF  promoter polymorphism −871C/T were analyzed with polymerase chain reaction-based techniques, and serum immunoglobulin M (IgM) and BAFF levels were analyzed by enzyme-linked immunosorbent assay. Flare-free survival was related to LON occurrence and polymorphisms.    Results  The  FCGR3A  V allele, but not other  FCGR  polymorphisms, correlated with the occurrence of LON; each V allele conferred a fourfold increased OR for LON ( p  = 0.017).  FCGR3A  158V/V and presentation with LON were associated with a longer flare-free survival ( p  = 0.023 and  p  = 0.031, respectively).  FCGR3A  158V/V was related to lower IgM levels ( p  = 0.016). Serum BAFF levels showed no relationship with LON and  BAFF  −871C/T promoter polymorphism. There was a tendency toward longer flare-free survival in patients with the  BAFF  −871T/T allotype compared with the C/T or C/C allotypes ( p  = 0.096).    Conclusions  The results of the present study suggest that presentation with LON may be a result of the intrinsic efficacy of rituximab in patients with rheumatic diseases. LON could indicate a longer biological and therapeutic activity of rituximab modulated by a certain genotypic polymorphism: the high-affinity  FCGR3A  V allele. This genotype and the occurrence of LON are both related to longer flare-free survival, suggestive of common mechanisms for LON and duration of response to rituximab. The role of the  BAFF  −871C/T promoter polymorphism in LON occurrence is unclear.

Effect of FCGR polymorphism on the occurrence of late-onset neutropenia and flare-free survival in rheumatic patients treated with rituximab