Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2017

Open Access 01-12-2017 | Research article

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

Authors: Sofia Ajeganova, Daniel Tesfa, Hans Hägglund, Bengt Fadeel, Inger Vedin, Anna Linda Zignego, Jan Palmblad

Published in: Arthritis Research & Therapy | Issue 1/2017

Login to get access

Abstract

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.
Literature
1.
Tesfa D, Palmblad J. Late-onset neutropenia following rituximab therapy: incidence, clinical features and possible mechanisms. Expert Rev Hematol. 2011;4:619–25.CrossRefPubMed
2.
Wolach O, Shpilberg O, Lahav M. Neutropenia after rituximab treatment: new insights on a late complication. Curr Opin Hematol. 2012;19:32–8.CrossRefPubMed
3.
Tesfa D, Ajeganova S, Hägglund H, Sander B, Fadeel B, Hafström I, et al. Late-onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections. Arthritis Rheum. 2011;63:2209–14.CrossRefPubMed
4.
Abdulkader R, Dharmapalaiah C, Rose G, Shand LM, Clunie GP, Watts RA. Late-onset neutropenia in patients with rheumatoid arthritis after treatment with rituximab. J Rheumatol. 2014;41:858–61.CrossRefPubMed
5.
Salmon JH, Cacoub P, Combe B, Sibilia J, Pallot-Prades B, Fain O, et al. Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry. RMD Open. 2015;1:e000034.CrossRefPubMedPubMedCentral
6.
Knight A, Sundström Y, Börjesson O, Bruchfeld A, Malmström V, Gunnarsson I. Late-onset neutropenia after rituximab in ANCA-associated vasculitis. Scand J Rheumatol. 2016;45:404–7.CrossRefPubMed
7.
8.
Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AE, de Haas M. FcγRIIIa-158 V/F polymorphism influences the binding of IgG by natural killer cell FcγRIIIa, independently of the FcγRIIIa-48 L/R/H phenotype. Blood. 1997;90:1109–14.PubMed
9.
Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene. Blood. 2002;99:754–8.CrossRefPubMed
10.
Ahlgrimm M, Pfreundschuh M, Kreuz M, Regitz E, Preuss KD, Bittenbring J. The impact of Fc-γ receptor polymorphisms in elderly patients with diffuse large B-cell lymphoma treated with CHOP with or without rituximab. Blood. 2011;118:4657–62.CrossRefPubMedPubMedCentral
11.
Persky DO, Dornan D, Goldman BH, Braziel RM, Fisher RI, Leblanc M, et al. Fcγ receptor 3a genotype predicts overall survival in follicular lymphoma patients treated on SWOG trials with combined monoclonal antibody plus chemotherapy but not chemotherapy alone. Haematologica. 2012;97:937–42.CrossRefPubMedPubMedCentral
12.
Ruyssen-Witrand A, Rouanet S, Combe B, Dougados M, Le Loët X, Sibilia J, et al. Fcγ receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab. Ann Rheum Dis. 2012;71:875–7.CrossRefPubMed
13.
Anolik JH, Campbell D, Felgar RE, Young F, Sanz I, Rosenblatt J, et al. The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 2003;48:455–9.CrossRefPubMed
14.
Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:613–20.CrossRefPubMed
15.
Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999;285:260–3.CrossRefPubMed
16.
Cambridge G, Stohl W, Leandro MJ, Migone TS, Hilbert DM, Edwards JC. Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum. 2006;54:723–32.CrossRefPubMed
17.
Bosello S, Youinou P, Daridon C, Tolusso B, Bendaoud B, Pietrapertosa D, et al. Concentrations of BAFF correlate with autoantibody levels, clinical disease activity, and response to treatment in early rheumatoid arthritis. J Rheumatol. 2008;35:1256–64.PubMed
18.
Emmerich F, Bal G, Barakat A, Milz J, Mühle C, Martinez-Gamboa L, et al. High-level serum B-cell activating factor and promoter polymorphisms in patients with idiopathic thrombocytopenic purpura. Br J Haematol. 2007;136:309–14.CrossRefPubMed
19.
Gragnani L, Piluso A, Giannini C, Caini P, Fognani E, Monti M, et al. Genetic determinants in hepatitis C virus-associated mixed cryoglobulinemia: role of polymorphic variants of BAFF promoter and Fcγ receptors. Arthritis Rheum. 2011;63:1446–51.CrossRefPubMed
20.
Fabris M, Quartuccio L, Vital E, Pontarini E, Salvin S, Fabro C, et al. The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers. Arthritis Rheum. 2013;65:88–97.CrossRefPubMed
21.
Ruyssen-Witrand A, Rouanet S, Combe B, Dougados M, Le Loët X, Sibilia J, et al. Association between −871C > T promoter polymorphism in the B-cell activating factor gene and the response to rituximab in rheumatoid arthritis patients. Rheumatology (Oxford). 2013;52:636–41.CrossRef
22.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725.CrossRefPubMed
23.
Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum. 1994;37:187–92.CrossRefPubMed
24.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.CrossRefPubMed
25.
Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, et al. Fcγ receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum. 2002;46:1242–54.CrossRefPubMed
26.
Novak AJ, Grote DM, Ziesmer SC, Kline MP, Manske MK, Slager S, et al. Elevated serum B-lymphocyte stimulator levels in patients with familial lymphoproliferative disorders. J Clin Oncol. 2006;24:983–7.CrossRefPubMed
27.
Cattaneo C, Spedini P, Casari S, Re A, Tucci A, Borlenghi E, et al. Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma. 2006;47:1013–7.CrossRefPubMed
28.
Cairoli R, Grillo G, Tedeschi A, D’Avanzo G, Marenco P, Morra E. High incidence of neutropenia in patients treated with rituximab after autologous stem cell transplantation. Haematologica. 2004;89:361–3.PubMed
29.
Nitta E, Izutsu K, Sato T, Ota Y, Takeuchi K, Kamijo A, et al. A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphoma: a single-institution study. Ann Oncol. 2007;18:364–9.CrossRefPubMed
30.
Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6:443–6.CrossRefPubMed
31.
Kastbom A, Cöster L, Arlestig L, Chatzidionysiou A, van Vollenhoven RF, Padyukov L, et al. Influence of FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis: an observational cohort study. BMJ Open. 2012;2:e001524.CrossRefPubMedPubMedCentral
32.
Concetti F, Napolioni V. Insights into the role of Fcγ receptors (FcγRs) genetic variations in monoclonal antibody-based anti-cancer therapy. Recent Pat Anticancer Drug Discov. 2010;5:197–204.CrossRefPubMed
33.
Niederer HA, Willcocks LC, Rayner TF, Yang W, Lau YL, Williams TN, et al. Copy number, linkage disequilibrium and disease association in the FCGR locus. Hum Mol Genet. 2010;19:3282–94.CrossRefPubMedPubMedCentral
34.
Li SC, Chen YC, Evens AM, Lee CC, Liao HF, Yu CC, et al. Rituximab-induced late-onset neutropenia in newly diagnosed B-cell lymphoma correlates with Fc receptor FcγRIIIa 158(V/F) polymorphism. Am J Hematol. 2010;85:810–2.CrossRefPubMed
35.
Weng WK, Negrin RS, Lavori P, Horning SJ. Immunoglobulin G Fc receptor FcγRIIIa 158 V/F polymorphism correlates with rituximab-induced neutropenia after autologous transplantation in patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2010;28:279–84.CrossRefPubMed
36.
Baerenwaldt A, Lux A, Danzer H, Spriewald BM, Ullrich E, Heidkamp G, et al. Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo. Proc Natl Acad Sci U S A. 2011;108:18772–7.CrossRefPubMedPubMedCentral
37.
Scapini P, Nardelli B, Nadali G, Calzetti F, Pizzolo G, Montecucco C, et al. G-CSF-stimulated neutrophils are a prominent source of functional BLyS. J Exp Med. 2003;197:297–302.CrossRefPubMedPubMedCentral
38.
Andrès E, Maloisel F. Idiosyncratic drug-induced agranulocytosis or acute neutropenia. Curr Opin Hematol. 2008;15:15–21.CrossRefPubMed
Metadata
Title
Effect of FCGR polymorphism on the occurrence of late-onset neutropenia and flare-free survival in rheumatic patients treated with rituximab
Authors
Sofia Ajeganova
Daniel Tesfa
Hans Hägglund
Bengt Fadeel
Inger Vedin
Anna Linda Zignego
Jan Palmblad
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2017
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-017-1241-0

Other articles of this Issue 1/2017

Arthritis Research & Therapy 1/2017 Go to the issue

Research Article

Comprehensive analysis of treatment response phenotypes in rheumatoid arthritis for pharmacogenetic studies

Research article

Calgizzarin (S100A11): a novel inflammatory mediator associated with disease activity of rheumatoid arthritis

Research article

Profiling microRNAs in individuals at risk of progression to rheumatoid arthritis

Research article

Similar short-term clinical response to high-dose versus low-dose methotrexate in monotherapy and combination therapy in patients with rheumatoid arthritis

Research article

The cumulative number of micro-haemorrhages and micro-thromboses in nailfold videocapillaroscopy is a good indicator of disease activity in systemic sclerosis: a validation study of the NEMO score

Research article

Platelets are activated in ANCA-associated vasculitis via thrombin-PARs pathway and can activate the alternative complement pathway
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits