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Sources of Information on Lymphoma Associated with Anti-Tumour Necrosis Factor Agents

Comparison of Published Case Reports and Cases Reported to the French Pharmacovigilance System

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Abstract

Background: Anti-tumour necrosis factor (TNF) agents, through their intense immunoregulatory effect, have been suspected to increase the risk of malignant lymphoma. However, the classical epidemiological approaches conducted over about the last 10 years have not totally succeeded in addressing the question of a causal or artifactual association. Therefore, the analysis of a substantial set of case reports, although usually considered as poorly generalizable to the general population, could be particularly informative. Two main sources of case reports in postmarketing settings are available; publications in medical journals and reports to pharmacovigilance systems.

Objective: The aim of the study was to compare the characteristics of case reports from both these sources in order to understand whether they provided the same information for the investigation of the causal link between lymphoma and anti-TNF agents.

Methods: All case reports of malignant lymphoma in patients treated with an anti-TNF agent published in MEDLINE and all reports to the French pharmacovigilance system up to 1 February 2010 were identified. Cases of malignant lymphoma identified in postmarketing surveillance from both sources were compared regarding the following variables: age, sex, anti-TNF agent involved, indication for use, type of lymphoma, prior or concomitant immunosuppressive drugs and time to onset of lymphoma.

Results: A total of 81 published case reports and 61 cases reported to the French pharmacovigilance system were compared. In published reports, patients were younger (p = 0.03) and more frequently receiving a first anti-TNF treatment (p = 0.03), particularly infliximab (p = 0.03). Conversely, in the pharmacovigilance system reports, a succession of different anti-TNFs (p = 0.03) and adalimumab (p< 0.0001) were more frequently reported. Lymphomas in patients treated with anti-TNF agents for Crohn’s disease were more prevalent in published cases than in pharmacovigilance reports (p< 0.0001), and in particular involved hepatosplenic T-cell lymphoma. Conversely, rheumatoid arthritis was the main indication for anti-TNF agents in pharmacovigilance reports (p = 0.01). Time to onset was markedly shorter in published cases (median 12 months) than in pharmacovigilance reports (median 30 months; p = 0.0001).

Conclusions: Characteristics of published cases and those reported to the French pharmacovigilance system differed markedly for all characteristics tested, except sex and the use of prior or concomitant immunosuppressive drugs. Published case reports favoured convincing arguments for drug causation whereas cases reported to the pharmacovigilance system were more disparate but could describe more accurately the reality of lymphoma occurrence in this particular population. These results argue for the use of the pharmacovigilance reports when case reports are used to investigate the causal link between lymphoma and anti-TNF agents at the population level. Data from cases notified to the French pharmacovigilance system did not indicate an increased risk of lymphoma during the early phase of anti-TNF treatment. To confirm this hypothesis, a study combining pharmacovigilance reports from several countries, or, if feasible, a cohort study both with a large sample size and a long duration of follow-up would be required.

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Acknowledgements

We thank Philip Robinson (Univ. de Bordeaux) for his advice and help in writing the manuscript. No sources of funding were used to assist in the preparation of the manuscript. Thierry Schaeverbeke has acted as a consultant to Pfizer, Roche, Bristol Myers Squibb, Abbott, Merck Sharp & Dohme and UCB, and received grants from Roche, Bristol-Myers Squibb and UCB. The other authors have no conflicts of interest to declare that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Département de Pharmacologie, Univ. de Bordeaux, Bordeaux, France

    Héle`ne Théophile (PharmD), Thierry Schaeverbeke, Abdelilah Abouelfath & Bernard Bégaud

  2. Centre Régional de Pharmacovigilance, CHU de Bordeaux, Bordeaux, France

    Héle`ne Théophile (PharmD), Ghada Miremont-Salamé, Françoise Haramburu & Bernard Bégaud

  3. ARME-Pharmacovigilance, Bordeaux, France

    Héle`ne Théophile (PharmD), Ghada Miremont-Salamé, Françoise Haramburu & Bernard Bégaud

  4. INSERM U657, Bordeaux, France

    Héle`ne Théophile (PharmD), Ghada Miremont-Salamé, Françoise Haramburu & Bernard Bégaud

  5. Service de Rhumatologie, CHU de Bordeaux, Bordeaux, France

    Thierry Schaeverbeke & Valentine Kahn

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  1. Héle`ne Théophile
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Théophile, H., Schaeverbeke, T., Miremont-Salamé, G. et al. Sources of Information on Lymphoma Associated with Anti-Tumour Necrosis Factor Agents. Drug-Safety 34, 577–585 (2011). https://doi.org/10.2165/11590200-000000000-00000

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