Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis
- Xavier Mariette1,
- Marco Matucci-Cerinic2,
- Karel Pavelka3,
- Peter Taylor4,
- Ronald van Vollenhoven5,
- Rebecca Heatley6,
- Claire Walsh6,
- Richard Lawson6,
- Alan Reynolds7,
- Paul Emery8
- 1Hôpital Bicêtre, Institut Pour la Santé et la Recherche Médicale (INSERM) U 1012, Université Paris-Sud 11, Le Kremlin Bicêtre, France
- 2Department of Biomedicine, Division of Rheumatology AOUC, Denothe Centre, University of Florence, Florence, Italy
- 3Institute of Rheumatology and Charles University Prague, Prague, Czech Republic
- 4Kennedy Institute of Rheumatology, Imperial College School of Medicine, London, UK
- 5Unit for Clinical Therapy Research, Inflammatory Diseases, The Karolinska Institute, Stockholm, Sweden
- 6Complete Market Access, Macclesfield, Cheshire, UK
- 7Reynolds Clinical Sciences, Eastleigh, Hampshire, UK
- 8Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust, Leeds, UK
- Correspondence to Professor Xavier Mariette, Service de Rhumatologie, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, Ile de France 92275, France;
Contributors All authors conceived of the study and approved the protocol that was developed by RH and CW. The literature searches were undertaken by RH and CW. RH, CW and AR selected papers for inclusion. All authors agreed to the inclusion of studies and had access to the papers and abstracts included in the review. RH, CW and AR abstracted the data. XM, RH, CW and AR drafted the paper and all authors contributed to the editing and approval of the submitted manuscript. Other than AR, Wyeth and Pfizer employees had no input into the protocol, analyses or content of this manuscript.
- Accepted 11 June 2011
- Published Online First 1 September 2011
Objectives This project was undertaken to assess the risk of malignancy in patients with rheumatoid arthritis treated with tumour necrosis factor inhibitors (TNFi) in clinical practice, as recorded in prospective, observational studies.
Methods The authors undertook comprehensive searches of MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and American College of Rheumatology, European League against Rheumatism and British Society for Rheumatology conference abstracts according to a prespecified protocol.
Results The searches identified 2039 full-text papers and 1979 conference abstracts, of which 21 full texts and eight abstracts met the inclusion criteria. The pooled estimate for the risk of all-site malignancy from seven studies was 0.95 (95% CI 0.85 to 1.05). Two studies reported there was no evidence that longer exposure to TNFi agents increased the risk of malignancy. In patients with previous malignancies there was a higher risk of a new/recurring malignancy. This risk was not increased further by exposure to TNFi, although CI were wide. Results from four studies showed that patients treated with TNFi have a significantly increased risk of developing a non-melanoma skin cancer (1.45, 95% CI 1.15 to 1.76). In addition, patients are at an increased risk of developing melanoma, as the pooled estimate from two studies was 1.79 (95% CI 0.92 to 2.67). The pooled estimate for the risk of lymphoma was 1.11 (95% CI 0.70 to 1.51).
Conclusions This systematic review and meta-analysis shows that TNFi treatments do not increase the risk of malignancy, particularly lymphoma. However, they do appear to increase the risk of skin cancer, including melanoma.
Funding The literature searches and data extraction were funded by a grant from Wyeth Europa (Wyeth was acquired by Pfizer in October 2009) to the Evidence Research Unit. Wyeth Europa paid author travel and accommodation costs to attend meetings at which this systematic review was discussed. None of the authors received payment for their contributions to this manuscript.
Competing interests XM has received honoraria for talks or participation in advisory boards from Roche, UCB, Wyeth (acquired by Pfizer in October 2009). MM-C has received fees for lectures from Wyeth, Pfizer, Actelion, BMS, Roche and research grants from Pfizer, Actelion, Schering-Plough, Centocor. KP has received fees as a consultant to Abbott, Schering-Plough, Roche and Wyeth. PT has received research grants from Merck, UCB, AstraZeneca, GlaxoSmithKline and Roche. He has been an invited speaker and advisor for Abbott, Bristol-Myers Squibb, Centocor, Roche, Schering-Plough, Wyeth and UCB. RvV has received research support and honoraria from Abbott, Bristol. Myers Squibb, Roche, Schering-Plough, UCB Pharma and Wyeth. RH was supported by a grant from Wyeth Europa. CW was supported by a grant from Wyeth Europa. RL was supported by a grant from Wyeth Europa. AR was an employee of Wyeth Europa and had held shares in Wyeth and currently has Pfizer share options. Work undertaken since leaving the company in June 2010 has been funded by Pfizer. PE has received research grants and honoraria from Abbott, Bristol. Myers Squibb, Roche, MSD, UCB Pharma and Wyeth.
Provenance and peer review Not commissioned; externally peer reviewed.