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ACP Journal Club

Anti-tumor necrosis factor antibody therapy for rheumatoid arthritis increases risk for serious infection and malignancy. ACP Journal Club, v145(3):65, November/December, 2006.


Question: In patients with RA, does treatment with TNFα inhibitors increase the risk for serious infection and malignancy? Methods: Search of MEDLINE, EMBASE/Excerpta Medica, Cochrane Library (2005), abstracts from scientific meetings of the European League against Rheumatism and the American College of Rheumatology (1996 to 2005), and drug manufacturers. Study selection and assessment: RCTs that compared infliximab or adalimumab with placebo (with or without a traditional disease-modifying antirheumatic drug in each group) in patients with RA, with duration of treatment ≥ 12 weeks (range 12 to 54 wk). 9 RCTs (n = 5014) met the selection criteria. 2 reviewers independently assessed the RCTs for methodological quality, including randomisation, allocation concealment, blinding, intention-to-treat analysis, follow-up, outcome assessment, and attrition. All RCTs were double-blinded. Outcomes: Serious infection (requiring antimicrobial therapy or hospitalisation) and malignancy. Main results: TNFα inhibitor therapy increased risk for both serious infection and malignancy more than placebo. For malignancy, risk was greater in patients receiving a high dose of TNFα inhibitor compared with placebo (OR 4.3, 95% CI 1.6 to 12) than in those receiving a low dose (OR 1.4, CI 0.3 to 5.7). Direct comparison of high and low dose also showed increased risk for malignancy with high-dose treatment (OR 3.4, CI 1.4 to 8.2). A dose effect was not observed for serious infection (high dose vs low dose, OR 1.4, CI 1.0 to 2.0). Conclusion: In patients with RA, treatment with TNFα inhibitor increases risk for serious infection and malignancy.

American Gastroenterological Association Institute

Lichtenstein GR, Abreu MT, Cohen R, et al.

American Gastroenterological Association Institute Medical Position Statement on Corticosteroids, Immunomodulators, and Infliximab in Inflammatory Bowel Disease. Gastroenterology 2006;130:935–939.


Recommendations in UC

Current indications for infliximab include the treatment of moderately to severely active UC in patients who have not responded despite complete and adequate therapy with a corticosteroid or an immunosuppressive agent (azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]). These patients are individuals who are resistant to medical therapy (complete and adequate therapy with a corticosteroid or an immunosuppressive agent) or who cannot receive such therapies due to intolerance to medications (corticosteroids or medical contraindications [therapy intolerant]).

The recommended initial dose of infliximab for all IBD indications is 5 mg/kg body wt, administered by intravenous infusion over 2 hours in an induction regimen of 3 doses at weeks 0, 2, and 6. This should be followed by maintenance therapy every 8 weeks in patients who respond. For patients with CD who respond and then lose their response, consideration may be given to treatment with 10 mg/kg. In the case of nonresponse to 3 infusions, further treatment with infliximab is not recommended. The treatment should be administered under the supervision and control of a specialised health care deliverer, with emergency equipment for severe infusion reactions available. A follow-up observation period of approximately 1 hour is advocated. If a patient is on infliximab and achieves remission, an attempt to withdraw or taper any concomitant corticosteroid therapy is sensible.

Although there is evidence-based data to support the use of corticosteroids, immunomodulators, and infliximab in the treatment of patients with IBD, there are many aspects of therapy with these agents for which the data are lacking or inadequate. Additional prospective data are needed to resolve the areas of controversy. The gastroenterologist who uses these agents must have a clear understanding of the proven benefits and risks of these therapies to provide optimal care to the patient with IBD.


Bongartz T, Sutton AJ, Sweeting MJ et al.

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. JAMA 2006; 295:2275-85


This paper assesses the extent to which TNFα inhibitors may increase the risk of serious infections and malignancies in patients with RA by performing a meta-analysis to derive estimates of sparse harmful events occurring in RCTs of TNFα inhibitors. 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 TNFα inhibitors. STUDY SELECTION: The authors included RCTs of the 2 licensed TNFα inhibitors (infliximab and adalimumab) used for 12 weeks or more in patients with RA. Nine trials met the inclusion criteria, including 3493 patients who received TNFα inhibitors and 1512 patients who received placebo. DATA EXTRACTION: Data on study characteristics to assess study quality and intention-to-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: The authors calculated a pooled OR (Mantel-Haenszel methods with a continuity correction designed for sparse data) for malignancies and serious infections (infection that requires antimicrobial therapy and/or hospitalisation) in TNFα inhibitor-treated patients vs placebo patients. The authors estimated effects for high and low doses separately. The pooled OR 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 significantly more common in patients treated with higher doses compared with patients who received lower doses of TNFα inhibitors. For patients treated with TNFα inhibitors in the included trials, the number needed to harm was 154 (95% CI, 91-500) for 1 additional malignancy within a treatment period of 6 to 12 months. For serious infections, the number needed to harm was 59 (95% CI, 39-125) within a treatment period of 3 to 12 months. CONCLUSIONS: There is evidence of an increased risk of serious infections and a dose-dependent increased risk of malignancies in patients with RA treated with TNFα inhibitors. The formal meta-analysis with pooled sparse adverse events data from RCTs serves as a tool to assess harmful drug effects.

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