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Effect of FCGR polymorphism on the occurrence of late-onset neutropenia and flare-free survival in rheumatic patients treated with rituximab
Karolinska Inst, Dept Med Huddinge, S-14186 Stockholm, Sweden..
Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, S-14186 Stockholm, Sweden.;Roche AB, Med Affairs, S-10074 Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
Karolinska Inst, Inst Environm Med, Unit Mol Toxicol, S-17177 Stockholm, Sweden..
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2017 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 19, article id 44Article in journal (Refereed) Published
Abstract [en]

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 Fc gamma 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.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD , 2017. Vol. 19, article id 44
Keywords [en]
Late-onset neutropenia, Rituximab, FCGR, BAFF, Polymorphism, Rheumatic disease
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:uu:diva-320256DOI: 10.1186/s13075-017-1241-0ISI: 000396276000003PubMedID: 28270182OAI: oai:DiVA.org:uu-320256DiVA, id: diva2:1089223
Funder
The Karolinska Institutet's Research FoundationStockholm County CouncilSwedish Rheumatism AssociationAvailable from: 2017-04-19 Created: 2017-04-19 Last updated: 2017-11-29Bibliographically approved

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