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.
- B cells
- rheumatoid arthritis
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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 ClinicalTrials.gov.
Provenance and peer review Not commissioned; externally peer reviewed.