Treatment of BAFF Transgenic Mice with Anti-TNF: Monoclonals Are Associated with a Higher Risk of Lymphoma Than Etanercept

Gaetane Nocturne^1,2, Bineta Ly³, Saida Boudaoud⁴, raphaèle seror^5,6, Carole Nicco⁷, Christiane Chereau⁷, Niloufar Kavian^7,8, Frederic Batteux^7,8, Fabienne Mackay⁹, Fabien Vincent⁹, Thierry Lazure¹⁰, Sophie Ferlicot¹⁰, Lev Stimmer¹¹, Roman Krzysiek¹⁰, Salima Hacein-Bey¹⁰ and Xavier Mariette^12,13, ¹Rheumatology Service, Bicêtre University Hospital, Le Kremlin Bicetre, France, ²INSERM U1184, Université Paris Sud, Le Kremlin Bicêtre, France, ³INSERM U1184, Paris Sud University, Kremlin Bicetre, France, ⁴INSERM U1184, Paris Sud University, Le Kremlin Bicêtre, France, ⁵Assistance Publique-Hôpitaux de Paris (APHP), Hôpitaux universitaires Paris Sud, Université Paris Sud, kremlin bicetre, France, ⁶INSERM U1184, Paris Sud University, Le Kremlin Bicetre, France, ⁷Institut Cochin, Paris, France, ⁸Immunology, APHP Hopital Cochin, Paris, France, ⁹Monash university, Melbourne, Australia, ¹⁰APHP Hopitaux universitaires Paris sud, Le Kremlin Bicetre, France, ¹¹CEA - MIRCen, Fontenay aux Roses, France, ¹²Department of Rheumatology, APHP - Hopitaux universitaire Paris Sud, Le Kremlin Bicetre, France, ¹³INSERM U1184, Université Paris-Sud, Paris, France, Le Kremlin Bicetre, France

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Anti-TNF therapy and rheumatoid arthritis (RA), BAFF

Session Information

Date: Monday, November 14, 2016

Session Title: Rheumatoid Arthritis – Animal Models - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Patients suffering from rheumatoid arthritis (RA) have an increased risk of lymphoma and disease activity is the main risk factor. The impact of treatment, and notably of anti- (TNF), is unclear. They might decrease the risk of lymphoma by controlling activity. But they also might alter anti-tumor immunosurveillance. Large epidemiologic studies have demonstrated that anti-TNF were not associated with an increased risk of lymphoma. However, some data support that this risk might vary according to the type or to the dose of anti-TNF. The aim of our study was to assess if the risk of lymphoma might differ according to the type of anti-TNF, comparing monoclonals to soluble receptor. For that, we used BAFF transgenic (Tg) mice as a model of autoimmunity-associated lymphomas. They develop lupus and Sjögren and 3% of them spontaneously developed lymphoma at 12-18 months.

Methods: Six months aged BAFF-Tg mice were treated with anti-TNF for 12 months: etanercept (ETA) (n=15, 8 mg/kgx3/week), monoclonal anti-mouse TNF (TN3 19.12, n=15, 20 mg/kg/week), adalimumab(ADA) (n=13, 20 mg/kg/week) or controls (n=22). Sera were assessed monthly to monitor drug trough level and anti-drug antibodies, auto-antibodies (antinuclear factor and rheumatoid factor) and immunoglobulins (Ig). Crude mortality was compared among the different groups (log rank test). Histologic examination of kidneys and of lymphoid tissue (spleen and lymph nodes) was performed at the end of the treatment period. The Fisher’s exact test was used to compare the incidence of of lymphoma among the groups.

Results: Adjunction of low dose of methotrexate during the 3 first days of treatment with biologics prevented immunization in the 3 groups of treatment for life. Mean level of ETA, TN3 and ADA were 7 µg/ml, 69 µg/ml and 105 µg/ml, respectively. The level of auto-antibodies and serum Ig did not significantly differ among the groups. However, crude mortality was significantly higher in mice treated with monoclonals compared to controls (p=0.0001 for ADA and p=0.0003 for TN3) but not for mice treated with ETA (figure). Incidence of lymphoma was higher in mice treated with monoclonals: 5/15 (33%) with TN3 (p=0.03 / controls), 4/13 (31%) with ADA (p=0.054 / controls), 0/15 with ETA and 1/22 (5%) in controls.

Conclusion: Higher mortality and increased risk of lymphoma were observed in BAFF Tg mice treated with monoclonal anti-TNF compared to etanercept. This result may be linked either to the different mechanism of action between the soluble receptor and the monoclonals or to a difference of trough level observed in the different groups and new experiments with lower dose of monoclonals are ongoing. This study demonstrates the negative impact of a prolonged anti-TNF treatment on the risk of lymphoma in the context of BAFF increase. Negative impact on NK cells might explain this finding (accompanying abstract submitted).

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Figure: Crude survival of BAFF Tg mice exposed to anti-TNF or controls

Disclosure: G. Nocturne, None; B. Ly, None; S. Boudaoud, None; R. seror, None; C. Nicco, None; C. Chereau, None; N. Kavian, None; F. Batteux, None; F. Mackay, None; F. Vincent, None; T. Lazure, None; S. Ferlicot, None; L. Stimmer, None; R. Krzysiek, None; S. Hacein-Bey, None; X. Mariette, None.

To cite this abstract in AMA style:

Nocturne G, Ly B, Boudaoud S, seror R, Nicco C, Chereau C, Kavian N, Batteux F, Mackay F, Vincent F, Lazure T, Ferlicot S, Stimmer L, Krzysiek R, Hacein-Bey S, Mariette X. Treatment of BAFF Transgenic Mice with Anti-TNF: Monoclonals Are Associated with a Higher Risk of Lymphoma Than Etanercept [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/treatment-of-baff-transgenic-mice-with-anti-tnf-monoclonals-are-associated-with-a-higher-risk-of-lymphoma-than-etanercept/. Accessed June 4, 2020.

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