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Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry
  1. D Salmon-Ceron1,
  2. F Tubach2,
  3. O Lortholary3,
  4. O Chosidow4,
  5. S Bretagne5,
  6. N Nicolas2,
  7. E Cuillerier6,
  8. B Fautrel7,
  9. C Michelet8,
  10. J Morel9,
  11. X Puéchal10,
  12. D Wendling11,
  13. M Lemann12,
  14. P Ravaud13,
  15. X Mariette14,
  16. for the RATIO group
  1. 1Université Paris Descartes Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital Cochin Broca Hôtel Dieu, Unité de Maladies Infectieuses, Pôle de médecine, Paris, France
  2. 2Université Paris 7 Denis Diderot, UFR de médecine; INSERM, U738; INSERM CIE801; AP-HP, Hôpital Bichat, Département d'Epidémiologie, Biostatistique et Recherche Clinique, Paris, France
  3. 3Université Paris Descartes; AP-HP, Hôpital Necker-Enfants malades, Service de maladies infectieuses et tropicales, Centre d'Infectiologie Necker-Pasteur, Paris, France
  4. 4Université Paris-EST; AP-HP, Hôpital Henri Mondor, Service de dermatologie, Paris, France
  5. 5Université Paris-EST; AP-HP, Hôpital Henri Mondor, Service de parasitologie-mycologie, Créteil, France
  6. 6Centre Hospitalier Général, Service de gastro-entérologie, Dreux, France
  7. 7Université Paris 6 - Pierre et Marie Curie, UFR de Médecine; AP-HP, Hôpital Pitié-Salpétrière, Service de rhumatologie, Paris, France
  8. 8Université Rennes 2, Hôpital Pontchaillou, Service des maladies infectieuses et réanimation médicale, Rennes, France
  9. 9Université de Montpellier; Hôpital Lapeyronie, Service d'immuno-rhumatologie, Montpellier, France
  10. 10Hôpital du Mans, Service de rhumatologie, Le Mans, France
  11. 11Université de Franche Comté; Hôpital Jean Minjoz, Service de rhumatologie, Besançon, France
  12. 12Université Paris 7 Denis Diderot, AP-HP, Hôpital Saint Louis, Service de gastro-entérologie, Paris, France
  13. 13Université Paris Descartes; INSERM, U738; AP-HP, Hôpital Cochin Broca Hôtel Dieu, Centre d'épidémiologie clinique et de médecine basée sur les preuves, Paris, France
  14. 14Université Paris-Sud 11, AP-HP, Hôpital Bicêtre, Service de rhumatologie; INSERM, U1012, Le Kremlin-Bicêtre, France
  1. Correspondence to Professor Xavier Mariette, Service de Rhumatologie, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre; xavier.mariette{at}


Background Anti-tumour necrosis factor (TNF) therapy may be associated with opportunistic infections (OIs).

Objective To describe the spectrum of non-tuberculosis OIs associated with anti-TNF therapy and identify their risk factors.

Methods A 3-year national French registry (RATIO) collected all cases of OI in patients receiving anti-TNF treatment for any indication in France. A case–control study was performed with three controls treated with anti-TNF agents per case, matched for gender and underlying inflammatory disease.

Results 45 cases were collected of non-TB OIs in 43 patients receiving infliximab (n=29), adalimumab (n=10) or etanercept (n=4) for rheumatoid arthritis (n=26), spondyloarthritides (n=3), inflammatory colitis (n=8), psoriasis (n=1) or other conditions (n=5). One-third (33%) of OIs were bacterial (4 listeriosis, 4 nocardiosis, 4 atypical mycobacteriosis, 3 non-typhoid salmonellosis), 40% were viral (8 severe herpes zoster, 3 varicella, 3 extensive herpes simplex, 4 disseminated cytomegalovirus infections), 22% were fungal (5 pneumocystosis, 3 invasive aspergillosis, 2 cryptococcosis) and 4% were parasitic (2 leishmaniasis). Ten patients (23%) required admission to the intensive care unit, and four patients (9%) died. Risk factors for OIs were treatment with infliximab (OR=17.6 (95% CI 4.3 - 72.9); p<0.0001)or adalimumab (OR=10.0 (2.3 to 44.4); p=0.002) versus etanercept, and oral steroid use >10 mg/day or intravenous boluses during the previous year (OR=6.3 (2.0 to 20.0); p=0.002).

Conclusion Various and severe OIs, especially those with intracellular micro-organisms, may develop in patients receiving anti-TNF treatment. Monoclonal anti-TNF antibody rather than soluble TNF receptor therapy and steroid use >10 mg/day are independently associated with OI.

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  • Marc Lemann is deceased and this paper is dedicated to him.

  • DSC, FT, PR and XM contributed equally to the work.

  • Funding RATIO was supported by a research grant from 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 study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data and had final responsibility for the decision to submit for publication.

  • Competing interests ML received consulting and/or talk honoraria from Abbott, Schering Plough and UCB (<US$10 000each), XM received consulting and/or talk honoraria from UCB and Wyeth (<US$10 000 each).

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

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

  • The RATIO GROUP includes Bagheri Haleh; Blandin Bernadette; Breban Maxime; Bretagne Stéphane; Castot Anne; Chichmanian Rose-Marie; Chosidow Olivier; Dautzenberg Bertrand, Dellamonica Pierre; Dufeu-Demazes Nadine; Emilie Dominique; Gillet Claudine; Hugot Jean Pierre; Kreft-Jais Carmen; Lemann Marc; Leport Catherine; Lortholary Olivier; Mariette Xavier; Michelet Christian; Montastruc Jean Louis; Nicolas Nathalie; Prieur Anne Marie; Ravaud Philippe; Roux Christian; Salmon Dominique; Tubach Florence; Vittecoq Daniel.The validation-cases expert committee comprised three infectious disease specialists: Salmon Ceron Dominique, Lortholary Olivier, Bretagne Stéphane.