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Etanercept therapy in rheumatoid arthritis and the risk of malignancies. A systematic review and individual patient data meta-analysis of Randomized Controlled Trials
  1. Tim Bongartz (bongartz.tim{at}
  1. Mayo Clinic, United States
    1. Fiona C Warren (fcw2{at}
    1. Department of Health Sciences, University of Leicester, United Kingdom
      1. Daniel Mines (minesd{at}
      1. Global Safety Surveillance and Epidemiology, Wyeth Research, Collegeville, Pennsylvania, United States
        1. Eric L Matteson (matteson.eric{at}
        1. Mayo Clinic, United States
          1. Keith R Abrams (kra1{at}
          1. Department of Health Sciences, University of Leicester, United Kingdom
            1. Alex J Sutton (ajs22{at}
            1. Department of Health Sciences, University of Leicester, United Kingdom


              Purpose: Tumor necrosis factor (TNF) plays an important role in inflammation and may affect tumor growth control. To assess the risk of malignancy with etanercept, a fusion protein that inhibits TNF action, we performed a meta-analysis using individual patient data from randomized controlled trials (RCTs) in patients with rheumatoid arthritis (RA).

              Methods: We conducted a search of bibliographic databases, abstracts from annual meetings and any unpublished studies on file with manufacturers of etanercept through December 2006. We included only RCTs of etanercept used for 12 weeks or more in patients with RA. Nine trials met our inclusion criteria. To adjudicate endpoints, the case narratives of potential cases were reviewed. Patient-level data were extracted from the clinical trials databases.

              Results: The nine trials included 3316 patients, 2244 who received etanercept (contributing 2484 person-years (PY) of follow up) and 1072 who received control therapy (1051 PY). Malignancies were diagnosed in 26 patients in the etanercept group (incidence rate (IR) 10.47/1000 PY) and 7 patients in the control group (IR 6.66/1000 PY). A Cox’s proportional hazards, fixed-effect model stratified by trial yielded a hazard ratio of 1.84 (95% CI: 0.79 to 4.28) for the etanercept group compared to the control group.

              Conclusions: In this analysis, the point estimate of malignancy risk was higher in etanercept-treated patients, although the results were not statistically significant. The approach of obtaining individual patient data of randomized controlled trials in co-operation with trial sponsors allowed important insights into the methodological advantages and challenges of sparse adverse event data meta-analysis.

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