The American Journal of GASTROENTEROLOGY VOLUME 106 | SEPTEMBER 2011 www.amjgastro.com nature publishing group 1594 REVIEW CLINICAL AND SYSTEMATIC REVIEWS INTRODUCTION he process by which the London Position Statement of the World Congress of Gastroenterology was established is described in the irst paper in this series (1), which addressed when to start and when to stop biological therapy, which drug to choose, and how to predict response. he topic of the current paper is safety and the other paper in the series covers pregnancy and pediatrics (2). he safety proile in randomized controlled studies of all biologi- cal agents is generally favorable, but a few patients experience severe side efects. Biological agents have been approved for marketing by the Food and Drug Administration, European Medicines Agency, Health Canada, and other authorities based on randomized controlled trials not exceeding 1 year. With large enough sample sizes, randomization balances both known/measured and unknown/unmeasured con- founders. his results in a control group of patients with inlammatory bowel disease (IBD) of comparable severity taking similar concomi- tant medications. Statistical analysis can then identify side efects that occur more frequently in patients exposed to the investigational agents than in patients exposed to placebo or the comparator therapy. Important limitations of these controlled trials include low statistical power to identify infrequent side efects and patient selection criteria that exclude subjects with co-morbid disease. More recently, large controlled trials in Crohn ’ s disease (CD) and ulcerative colitis have been designed to include either an open-label induction phase or a cross-over design to active drug for long-term maintenance. his has dramatically reduced the size of the placebo control group unexposed to the investigational therapy, but reduces the power to detect adverse events related to the drug studied. Ater a drug is approved for marketing, surveillance programs monitor signals that the medication may predispose patients to seri- ous adverse events. Post-marketing surveillance is most commonly employed through federal or company-directed pharmacovigilance programs, which ofer the advantage of larger and more hetero- geneous patient populations with long-term exposure. Many new warnings required by regulators, including “black-box” warnings on anti-tumor necrosis factor (TNF) agents and natalizumab (NAT), have been based on reports on infrequently occurring infections in patients exposed to the commercially available drug. he main limitations of post-marketing surveillance are the lack of a control group, inaccurate denominators for deining incidence rates and inaccurate numerators due to misdiagnosis, or under-reporting of side efects. he lack of accurate estimates of incidence rates in The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD With the European Crohn’ s and Colitis Organisation: Safety Gert Van Assche, MD 1 , James D. Lewis, MD, MSCE 2 , Gary R. Lichtenstein, MD 3 , Edward V. Lotus, MD 4 , Qin Ouyang, MD 5 , Julian Panes, MD 6 , Corey A. Siegel, MD 7 , William J. Sandborn, MD 8 , Simon P.L. Travis, MD 9 and Jean-Frederic Colombel, MD 10 This paper in the series from the World Congress of Gastroenterology addresses the safety and immunogenicity of biological therapy. The safety profile in randomized controlled studies of all biological agents in Crohn’ s disease (CD) and ulcerative colitis has been generally favorable, but a small percentage of patients experience severe side effects on biological therapy, including pneumonia, tuberculosis, lymphoma, demyelination, drug-induced lupus, or hepatotoxicity. Although there is unequivocal evidence of an increased risk of serious infection among patients with rheumatoid arthritis treated with anti-tumor necrosis factor therapy, the evidence is less clear in CD. The risk of infection may be increased by combination therapy with steroids and/or immunomodulators. There is a specific risk of the rare γ δ hepatosplenic lymphoma that appears to have a predeliction for young males on combination therapy. The α4 integrin antagonist natalizumab also carries a specific risk of progressive multifocal leucoencephalopathy and reactivation of JC virus infection. The immunogenicity of biological therapy is complex: all agents are potentially immunogenic and this can be reduced by combination with immunomodulators. This may enhance both therapeutic efficacy and the risk of infection or malignancy, so the balance of risk and benefit must be judged for individual patients. Am J Gastroenterol 2011; 106:1594–1602; doi:10.1038/ajg.2011.211; published online 16 August 2011 1 Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium; 2 Center for Clinical Epidemiology and Biostatistics Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; 3 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA; 4 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester , Minnesota, USA; 5 Department of Gastroenterology, West China Hospital, Sichuan University , Chengdu, China; 6 Hospital Clínic Barcelona, IDIBAPS, CIBERehd, Spain; 7 Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA; 8 Division of Gastroenterology, University of California San Diego, La Jolla, California, USA; 9 John Radcliffe Hospital, Oxford, England; 10 Hopital Huriez, CHRU Lille, France. Correspondence: Gert Van Assche, MD, Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. E-mail: gert.vanassche@uz.kuleuven.be Received 1 March 2010; accepted 27 May 2011 CME