title: Effect of FCGR polymorphism on the occurrence of late-onset neutropenia and flare-free survival in rheumatic patients treated with rituximab.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Medicine Huddinge, Karolinska Institutet, 14186, Stockholm, Sweden. sodia.ajeganova@ki.se.
authors.forename: Sofia
authors.identifier: 0000-0001-9162-9717
authors.initials: S
authors.lastname: Ajeganova
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186, Stockholm, Sweden.|Medical Affairs, Roche AB, 10074, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tesfa
authors.affiliation: Department of Hematology, Uppsala University Hospital, 75185, Uppsala, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Hägglund
authors.affiliation: Unit of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186, Stockholm, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Vedin
authors.affiliation: Center for Systemic Manifestations of Hepatitis Viruses, Department of Internal Medicine, University of Florence, 50134, Florence, Italy.
authors.forename: Anna Linda
authors.initials: AL
authors.lastname: Zignego
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Palmblad
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics*; D012189:Retrospective Studies; D012216:Rheumatic Diseases / Q000188:drug therapy*; D000069283:Rituximab / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; C445323:FCGR2A protein, human; C499173:FCGR2B protein, human; C496124:FCGR3A protein, human; D017452:Receptors, IgG; D000069283:Rituximab
keywords: BAFF; FCGR; Late-onset neutropenia; Polymorphism; Rheumatic disease; Rituximab