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Methotrexate and BAFF interaction prevents immunization against TNF inhibitors
  1. Samuel Bitoun1,2,
  2. Gaetane Nocturne1,2,
  3. Bineta Ly1,2,
  4. Roman Krzysiek3,4,
  5. Pierre Roques5,
  6. Alain Pruvost6,
  7. Audrey Paoletti1,2,
  8. Juliette Pascaud1,2,
  9. Pierre Dönnes7,
  10. Kimberly Florence8,
  11. Aude Gleizes3,9,
  12. Agnes Hincelin-Mery10,
  13. Matthieu Allez11,
  14. Salima Hacein-Bey-Abina3,12,
  15. Fabienne Mackay13,
  16. Marc Pallardy2,9,
  17. Roger Le Grand5,
  18. Xavier Mariette1,2
  1. 1 Rheumatology Department, Université Paris-Sud–CEA-INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, Hôpitaux Universitaires Paris-Sud–Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France
  2. 2 LabEX LERMIT, Université Paris-Sud, Le Kremlin Bicêtre, France
  3. 3 Clinical Immunology Laboratory, Hôpitaux Universitaires Paris-Sud, Hôpital Kremlin Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France
  4. 4 Immunoregulation, Chemokines and Viral Persistence, INSERM, Université Paris-Sud, Clamart, France
  5. 5 Immunology of Viral Infections and Autoimmune Diseases, IDMIT Infrastructure CEA–Université Paris-Sud–INSERM U1184, Fontenay-Aux-Roses, France
  6. 6 Service de Pharmacologie et Immunoanalyse (SPI), Plateforme SMArt-MS, CEA, INRA, Université Paris-Sud, Gif-sur-Yvette Cedex, France
  7. 7 R&D, SciCross AB, Skövde, Sweden
  8. 8 Immunogenicity and Clinical Immunology, GlaxoSmithKline, King of Prussia, Pennsylvania, USA
  9. 9 Inflammation, Chimiokines et Immunopathologie, INSERM, Fac de pharmacie–Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
  10. 10 Translational Medecine and Clinical Pharmacology Department, Sanofi, Chilly Mazarin, France
  11. 11 Department of Gastroenterology, Hôpital Saint-Louis, AP-HP, Université Paris-Diderot, Paris, France
  12. 12 UTCBS, CNRS UMR 8258, INSERM U1022, Faculté de Pharmacie de Paris, Université Paris Descartes, Paris, France
  13. 13 Department of Immunology, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), Melbourne, Victoria, Australia
  1. Correspondence to Professor Xavier Mariette, Service de Rhumatologie, Hôpitaux Universitaires Paris-Sud 78, Le Kremlin-Bicêtre 94270, France; xavier.mariette{at}


Objectives TNF inhibitors (TNFi) can induce anti-drug antibodies (ADA) in patients with autoimmune diseases (AID) leading to clinical resistance. We explored a new way of using methotrexate (MTX) to decrease this risk of immunisation.

Methods We treated BAFF transgenic (BAFFtg) mice, a model of AID in which immunisation against biologic drugs is high, with different TNFi. We investigated the effect of a single course of MTX during the first exposure to TNFi. Wild-type (WT) and BAFFtg mice were compared for B-Cell surface markers involved in MTX-related purinergic metabolism, adenosine production and regulatory B-cells (Bregs).

We translated the study to macaques and patients with rheumatoid arthritis from the ABIRISK cohort to determine if there was an interaction between serum BAFF levels and MTX that prevented immuniation.

Results In BAFFtg but not in WT mice or macaques, a single course of MTX prevented immunisation against TNFi and maintained drug concentration for over 52 weeks. BAFFtg mice B-cells expressed more CD73 and CD39 compared to WT mice. MTX induced adenosine release from B cells and increased Bregs and precursors. Use of CD73 blocking antibodies reversed MTX-induced tolerance. In patients from the ABIRISK cohort treated with TNFi for chronic inflammatory diseases, high BAFF serum level correlated with absence of ADA to TNFi only in patients cotreated with MTX but not in patients on TNFi monotherapy.

Conclusion MTX and BAFF interact in mice where CD73, adenosine and regulatory B cells were identified as key actors in this phenomenon. MTX and BAFF also interact in patients to prevent ADA formation.

  • methotrexate
  • anti-TNF
  • B cells
  • rheumatoid arthritis
  • spondyloarthritis

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  • Handling editor Josef S Smolen

  • Contributors SB, GN and XM designed the study, and supervised the experimental design and the data analysis. SB, GN, BL, PR, RK, RLG, APruvost, APaoletti, JP, KF, FM and AG made the experiments. PD and AHM performed statistical analysis. MA, AG, SHBA and MP gave substantial contributions from the ABIRISK cohort. SB and XM wrote the original draft of the manuscript. All authors reviewed and edited the manuscript, and provided final approval of the version published.

  • Funding The research leading to these results was supported by the Labex in Research on Medication and Therapeutic Innovation (LERMIT) (ANR10), the Innovative Medicines Initiative Joint Undertaking, ABIRISK (Anti-Biopharmaceutical Immunization Risk) project under grant agreement number 115303, the resources of which comprise financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and in-kind contributions from EFPIA companies, and the Fondation pour la Recherche Médicale DEQ20150934719: Sjögren’s syndrome and Autoimmunity-associated Lymphomas (SAIL). The IDMIT infrastructure is supported by the French government ‘Programme d’Investissements d’Avenir’ (PIA) under grant ANR-11-INBS-0008. SB was supported by two PhD grants from Société Française de Rhumatologie and INSERM.

  • Competing interests KF is an employee of GSK, PD is employed by SciCross and AHM is an employee of Sanofi.

  • Patient consent Not required.

  • Ethics approval The mouse study was approved by the regional Animal Care and Ethics Committee (Comité Régional d’Ethique sur l’Expérimentation Animale Île de France Sud, Fontenay-Aux-Roses, France; decision number 4281). Animal care and use was in accordance with the EU Directive 2010/63/EEU. The macaque study was approved by the regional Animal Care and Ethics Committee (Comité Régional d’Ethique sur l’Expérimentation Animale Île de France Sud, Fontenay-Aux-Roses, France; decision number A15_016). The CEA Institute was approved as compliant with ETS123 recommendations for animal breeding (European Union Directive 2010/63/EU, 22 September 2010) and with Standards for Human Care and Use of Laboratory Animals (Animal Welfare Assurance, OLAW No A5826-01). The study was also approved by the French department of education and research (MENESR; study number 2015070114504151v3) as defined in French law ‘décret 2013-118 from 2013 Feb 1st’. The human study was approved by the local IRB named ‘Paris Ile de France VII’ under number 13-048 and by the French agency for drugs (ANSM) under number 2013-A01268-37. The ABIRISK study was registered as study NCT02116504 by

  • Provenance and peer review Not commissioned; externally peer reviewed.

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