The initial manuscript draft was written with the help of a medical writer based on guidance from PM, DJZ, CAW, and DJL; all authors critically reviewed and revised drafts; and all authors approved the final version

The initial manuscript draft was written with the help of a medical writer based on guidance from PM, DJZ, CAW, and DJL; all authors critically reviewed and revised drafts; and all authors approved the final version. Acknowledgements Holly Brenza Zoog, PhD, Adiphenine HCl of Amgen Inc. does not appear to be an increased risk of malignancy overall with the use of etanercept. Among etanercept-exposed patients aged 4 to 17 years, the estimated worldwide and US reporting rates for lymphoma were approximately 0.01 per 100 patient-years (1 in 10,000 pt-yrs). While the reported rate of lymphoma is higher in pediatric patients treated with etanercept than in normal children, the expected rate of lymphoma in biologic na?ve JIA patients is currently unknown. The risk of TNF inhibitors in the development of malignancies in children and adolescents is difficult to assess because of the rarity of malignant events, Adiphenine HCl the absence of knowledge of Adiphenine HCl underlying frequency of leukemia and lymphoma in JIA, and the confounding use of concomitant immunosuppressive medications. Background Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that plays a role in host defenses and appears in excess in various inflammatory conditions. TNF has been suggested to play a major role in apoptosis and as an antineoplastic in the immunologic response to tumor cells. However, TNF has been shown in other experiments to promote proliferation, invasion, and metastasis of tumor cells [1,2]. Consequently, there is a theoretical but uncertain effect of TNF inhibition on malignancy. Anti-TNF therapies are used to treat several pediatric diseases including juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD) and psoriasis (PsO). JIA is a broad term encompassing a heterogeneous group of persistent inflammatory PRL arthritides in children, including psoriatic arthritis and ankylosing spondylitis [3]. The course of these diseases is variable with some patients developing a progressive destructive arthritis and others experiencing a milder course. JIA has traditionally been treated with anti-inflammatory medications such as NSAIDs, corticosteroids, methotrexate, and other standard disease modifying agents. More recently, biologic therapies such as tumor necrosis factor (TNF) inhibitors have been added to the treatment armamentarium with dramatic improvement in both the signs and symptoms of JIA as well as outcomes [4-9]. However, concerns have been raised recently about a potential link between the use of TNF inhibitors and the development of malignancy [10-12]. Conflicting reports have appeared in the literature regarding the influence of TNF inhibitors on rates of lymphomas and solid malignancies in adults [1,13-18]. In addition, several case reports have suggested the use of TNF inhibitors may be associated with development of malignancies in children [19,20]. The difficulty in the interpretation of the data stems, in large part, from the low number of JIA patients, the rarity of malignant events, and the lack of an appropriate comparator group of untreated JIA patients. Furthermore, at certain age ranges during childhood, there is an increased background risk to develop either leukemia (younger ages) or lymphoma (teen years) [21,22]. One of the most commonly used TNF inhibitors to treat JIA is etanercept, a fully human soluble receptor Fc fusion protein that binds specifically to TNF. Etanercept has been approved since 1999 for the treatment of polyarticular course JIA in children 2 years and older [10]. Here we present the worldwide experience of etanercept use in pediatric patients and the occurrence of potential malignancies as reported from clinical trials, registry studies, and post-marketing surveillance over the 11-year period from 1998 to 2009. The purpose of this communication is to fully disclose all malignant events in pediatric patients in the entire worldwide etanercept safety database in an attempt to provide information for providers and patients’ families to use in their decisions about appropriate JIA therapy. Methods All reports of “malignancy” in pediatric patients (defined as patients who.