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Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry
  1. X Mariette1,
  2. F Tubach2,
  3. H Bagheri3,
  4. M Bardet4,
  5. J M Berthelot5,
  6. P Gaudin6,
  7. D Heresbach7,
  8. A Martin8,
  9. T Schaeverbeke9,
  10. D Salmon10,
  11. M Lemann11,
  12. O Hermine12,
  13. M Raphael13,
  14. P Ravaud2
  1. 1
    Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Service de rhumatologie, Université Paris-Sud 11, INSERM U802, Le Kremlin-Bicêtre, France
  2. 2
    Université Paris 7 Denis Diderot, UFR de médecine; INSERM, U738; AP-HP, Hôpital Bichat, Département d’Epidémiologie, Biostatistique et Recherche Clinique, Paris, France
  3. 3
    Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Unité de Pharmacoépidémiologie, EA 3696, Université de Toulouse, Faculté de Médecine, Toulouse, France
  4. 4
    Hôpital de la Source, Service de médecine interne et rhumatologie, Orléans, France
  5. 5
    Hôtel Dieu, Service de rhumatologie, Nantes, France
  6. 6
    Centre Hospitalo-Universitaire, Service de rhumatologie, Grenoble, France
  7. 7
    Hôpital Pontchaillou, Service des maladies digestives, Rennes, France
  8. 8
    Hôpital de Saint Brieuc, Service de rhumatologie, Saint Brieuc, France
  9. 9
    Hôpital Pellegrin, Service de rhumatologie, Université Bordeaux II, Bordeaux, France
  10. 10
    AP-HP, Hôpital Cochin, Service de médecine interne, Université Paris V, Paris, France
  11. 11
    AP-HP, Hôpital Saint Louis, Service de gastro-entérologie, Université Paris 7, Paris, France
  12. 12
    AP-HP, Hôpital Necker, Service d’hématologie, CNRS UMR 8143, Université Paris V, Paris, France
  13. 13
    AP-HP, Hôpital Bicêtre, Laboratoire d’hématologie, Université Paris-Sud 11, Le Kremlin-Bicêtre, France
  1. Correspondence to Pr Xavier Mariette, Service de Rhumatologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France; xavier.mariette{at}


Objective: To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare the risks for different anti-TNF agents.

Methods: A national prospective registry was designed (Research Axed on Tolerance of bIOtherapies; RATIO) to collect all cases of lymphoma in French patients receiving anti-TNF therapy from 2004 to 2006, whatever the indication. A case–control analysis was conducted including two controls treated with anti-TNF per case and an incidence study of lymphoma with the French population was used as the reference.

Results: 38 cases of lymphoma, 31 non-Hodgkin’s lymphoma (NHL) (26 B cell and five T cell), five Hodgkin’s lymphoma (HL) and two Hodgkin’s-like lymphoma were collected. Epstein–Barr virus was detected in both of two Hodgkin’s-like lymphoma, three of five HL and one NHL. Patients receiving adalimumab or infliximab had a higher risk than those treated with etanercept: standardised incidence ratio (SIR) 4.1 (2.3–7.1) and 3.6 (2.3–5.6) versus 0.9 (0.4–1.8). The exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma in the case–control study: odds ratio 4.7 (1.3–17.7) and 4.1 (1.4–12.5), respectively. The sex and age-adjusted incidence rate of lymphoma was 42.1 per 100 000 patient-years. The SIR was 2.4 (95% CI 1.7 to 3.2).

Conclusion: The two to threefold increased risk of lymphoma in patients receiving anti-TNF therapy is similar to that expected for such patients with severe inflammatory diseases. Some lymphomas associated with immunosuppression may occur, and the risk of lymphoma is higher with monoclonal-antibody therapy than with soluble-receptor therapy.

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  • ▸ Additional supplementary files and supplementary fig 1 are published online only at

  • For numbered affiliations see end of article

  • Funding The RATIO was supported by a research grant from Institut National pour la Santé et la Recherche Médicale (INSERM) (Réseau de recherche clinique 2003 and 2006) and by an unrestricted grant from Abbott, Schering Plough and Wyeth. The pharmaceutical companies (Abbott, Schering Plough and Wyeth) had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review, or approval of the manuscript.

  • Competing interests Declared. XM received consulting and/or talk honorarium from Abbott, Schering Plough, UCB and Wyeth. TS received consulting and/or talk honorarium from Abbott, Schering Plough and Wyeth. ML received consulting and/or talk honorarium from Abbott, Schering Plough and UCB.

  • Ethics approval This study was authorised by the ethics committee of AP-HP, GHU Nord (Institutional Review Board of Paris North Hospitals, Paris 7 University, AP-HP; authorisation number 162–08).

  • The first two authors contributed equally to the work.

    Contributors: Conception and design: XM, FT, DS, ML, PR. Acquisition of data: XM, HB, MB, JMB, PG, DH, AM, TS, DS, ML, OH, MR. Analysis and interpretation of data: XM, FT, PR. Drafting the article and revising it critically for important intellectual content: XM, FT, PR. Final approval of the version to be published: XM, FT, HB, MB, JMB, PG, DH, AM, TS, DS, ML, OH, MR, PR. XM, FT and PR had full access to the data in the and take responsibility for the integrity of the data and the accuracy of the data analysis. The main analyses were independently performed by two academic statisticians.

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