Extended report Mariette X, Matucci-Cerinic M, Pavelka K, et al. Ann Rheum Dis (2011). doi:10.1136/ard.2010.149419 1 of 10 Accepted 11 June 2011 ABSTRACT 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. Patients with inflammatory arthritis, especially rheumatoid arthritis (RA), have an increased risk of developing a malignancy, particularly lymphoma and lung cancer, but have a reduced risk of devel- oping colorectal and breast cancer. 1 The effect of treatments acting on the immune system may affect these risks; however, randomised controlled trials (RCT) may be unable to determine the existence of such effects due to the relatively short dura- tion of exposure to treatment and limited patient numbers. Tumour necrosis factor (TNF) alpha is a key cytokine in the inflammatory cascade. It plays an important role in host defence against infec- tions 2 and cancer, 3 and was identified as a poten- tial therapeutic target for autoimmune disease. 4 Three tumour necrosis factor inhibitors (TNFi) were approved in the early part of the last decade for the treatment of RA, psoriatic arthritis (PsA) and ankylosing spondylitis. Infliximab and adalimumab are monoclonal antibodies (MAb) directed against TNF, whereas etanercept is a fusion protein of human p75 soluble TNF receptor and human IgG 1 . Differences in kinetics and mode of action between etanercept and the MAb have been reported. 5 Recent meta-analyses of clinical trial data reported a significantly increased risk of cancer with adali- mumab and infliximab. 6 An analysis of pooled indi- vidual patient data for etanercept studies by the same group showed a non-significant increased HR com- pared with controls. 7 Registration trials, however, exclude patients with significant comorbidities and so the results may not be generalisable to RA patients as a whole. Indeed, risks may be greater in clinical practice compared with those identified during drug testing due to the presence of these comorbidities. As a result of these concerns, proposals to establish observational registries to examine the long-term safety of the TNFi in usual clinical care were published, 8 9 and were subsequently set up in a number of European countries by the national professional societies or local groups, usually with financial support from the relevant pharmaceutical companies. The aim of the present work was to perform a systematic review of prospective observational studies in patients with inflammatory arthritides that include malignancy data. MATERIALS AND METHODS Search strategies The authors have undertaken a systematic review of prospective observational studies of TNFi in usual clinical settings. The search strategy was designed to capture such studies that were then evaluated for the outcomes of interest; in this publication we report on malignancy. In accordance with a prespecified protocol (see supplementary appendix 1, available online only), an experienced medical information special- ist conducted comprehensive literature searches using DataStar (http://www.datastarweb.com) of MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews (RH). The search strategy for MEDLINE (MEYY) is available online (see sup- plementary appendix 2, available online only). ▶ Additional supplementary appendices are published online only. To view this file please visit the journal online (http://ard. bmj.com). 1 Hôpital Bicêtre, Institut Pour la Santé et la Recherche Médicale (INSERM) U 1012, Université Paris-Sud 11, Le Kremlin Bicêtre, France 2 Department of Biomedicine, Division of Rheumatology AOUC, Denothe Centre, University of Florence, Florence, Italy 3 Institute of Rheumatology and Charles University Prague, Prague, Czech Republic 4 Kennedy Institute of Rheumatology, Imperial College School of Medicine, London, UK 5 Unit for Clinical Therapy Research, Inflammatory Diseases, The Karolinska Institute, Stockholm, Sweden 6 Complete Market Access, Macclesfield, Cheshire, UK 7 Reynolds Clinical Sciences, Eastleigh, Hampshire, UK 8 Section 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; xavier.mariette@bct.aphp.fr Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis Xavier Mariette, 1 Marco Matucci-Cerinic, 2 Karel Pavelka, 3 Peter Taylor, 4 Ronald van Vollenhoven, 5 Rebecca Heatley, 6 Claire Walsh, 6 Richard Lawson, 6 Alan Reynolds, 7 Paul Emery 8 ARD Online First, published on September 1, 2011 as 10.1136/ard.2010.149419 Copyright Article author (or their employer) 2011. 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