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Anti-TNF Antibody Therapy in Rheumatoid Arthritis and the Risk of Serious Infections and Malignancies Systematic Review and Meta-analysis of Rare Harmful Effects in Randomized Controlled Trials
Tim Bongartz, MD Alex J. Sutton, PhD Michael J. Sweeting, MSc Iain Buchan, MD, MFPH Eric L. Matteson, MD, MPH Victor Montori, MD, MSc IT IS UNCERTAIN TO WHAT EXTENT therapy with anti–tumor necrosis factor(anti-TNF)agentsforrheumatoidarthritis(RA)mightbeassociatedwithanincreaseinseriousinfections and malignancies. This uncertaintyisbasedonthedifficulties that generally emerge from the analysis and interpretation of sparse adverseeventdataderivedfromrandomized controlled trials, which have not beenpoweredtodetectrareadverseeffects.Inaddition,postlicensureobservational studies usually lack an adequate control group, leaving open to interpretation whether events are associated with the therapeutic agent or with the disease itself. 

Two types of anti-TNF antibodies currently licensed forclinica lusein RA are infliximab and adalimumab, the former being a partially and the latter a fully humanized monoclonal antibody specific for TNF. They neutralize both extracellular and membrane formsof TNF,a cytokineconsidered to be of major importance in the pathophysiology of RA.1 Basic science research suggests that infectious complications and malignancies should be seriously
 consider. Author Affiliations are listed at the end of this article. Corresponding Author: Tim Bongartz, MD, Division of Anti-Rheumatology,MayoClinic,200FirstStSW,Rochester, MN 55905 (bongartz.tim@mayo.edu).

Context Tumor necrosis factor (TNF) plays an important role in host defense and tumor growth control. Therefore, anti-TNF antibody therapies may increase the risk of serious infections and malignancies. Objective To assess the extent to which anti-TNF antibody therapies may increase theriskofseriousinfectionsandmalignanciesinpatientswithrheumatoidarthritisby performing a meta-analysis to derive estimates of sparse harmful events occurring in randomized trials of anti-TNF therapy. Data Sources A systematic literature search of EMBASE, MEDLINE, Cochrane Library, and electronic abstract databases of the annual scientific meetings of both the European League Against Rheumatism and the American College of Rheumatology was conducted through December 2005. This search was complemented with interviews of the manufacturers of the 2 licensed anti-TNF antibodies. Study Selection We included randomized, placebo-controlled trials of the 2 licensed anti-TNF antibodies (infliximab and adalimumab) used for 12 weeks or more in patients with rheumatoid arthritis. Nine trials met our inclusion criteria, including 3493 patients who received anti-TNF antibody treatment and 1512 patients who received placebo.

Data Extraction Dataonstudycharacteristicstoassessstudyqualityandintentionto-treat data for serious infections and malignancies were abstracted. Published information from the trials was supplemented by direct contact between principal investigators and industry sponsors. Data Synthesis We calculated apooledod dsratio (Mantel-Haenszel methods with a continuity correction designed for sparse data) for malignancies and serious infections(infection that requires antimicrobial therapy and/orhospitalization) inanti-TNF– treated patientsvsplacebopatients.Weestimatedeffectsforhighandlowdosesseparately. The pooled odds ratio for malignancy was 3.3 (95% confidence interval [CI], 1.2-9.1) and for serious infection was 2.0 (95% CI, 1.3-3.1). Malignancies were significantlymorecommoninpatientstreatedwithhigherdosescomparedwithpatients who received lower doses of anti-TNF antibodies. 

For patients treated with anti-TNF antibodies in the included trials, the number needed to harm was 154 (95% CI, 91500) for 1 additional malignancy within a treatment period of 6 to 12 months. For seriousinfections,thenumberneededtoharmwas59(95%CI,39-125) with in a treatment period of 3 to 12 months. Conclusions There is evidence of an increased risk of serious infections and a dosedependentincreasedriskofmalignanciesinpatientswithrheumatoidarthritistreatedwith anti-TNF anti body therapy.
Theformalmeta-analysiswithpooledsparseadverseevents data from randomized controlled trials serves as a tool to assess harmful drug effects. JAMA. 2006;295:2275-2285 www.jama.com
©2006 American Medical Association. All rights reserved. (Reprinted) JAMA, May 17, 2006—Vol 295, No. 19 2275