RESEARCH - Anti-TNF antibody therapy in RA and the risk of serious infections and malignancies

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JAMA. 2006;295:2275-2285.

Vol. 295 No. 19, May 17, 2006

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; J. Sutton, PhD; J. Sweeting, MSc; Iain

Buchan, MD, MFPH; L. Matteson, MD, MPH; Victor Montori, MD, MSc

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 the risk of serious infections and malignancies in patients

with rheumatoid arthritis by 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 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 We calculated a pooled odds ratio (Mantel-Haenszel

methods with a continuity correction designed for sparse data) for

malignancies and serious infections (infection that requires antimicrobial

therapy and/or hospitalization) in anti-TNF-treated patients vs placebo

patients. We estimated effects for high and low doses separately. 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

significantly more common in patients treated with higher doses compared

with patients 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, 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 rheumatoid arthritis treated with anti-TNF antibody therapy. The formal

meta-analysis with pooled sparse adverse events data from randomized

controlled trials serves as a tool to assess harmful drug effects.

AUTHOR AFFILIATIONS: Division of Rheumatology and Department of

Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn (Drs

Bongartz and Matteson); Department of Health Sciences, University of

Leicester, Leicester, England (Dr Sutton); MRC Biostatistics Unit, Institute

of Public Health, Cambridge, England (Mr Sweeting); Northwest Institute for

Bio-Health Informatics, University of Manchester, Manchester, England (Dr

Buchan); Knowledge and Encounter Research Unit and Department of Medicine,

Mayo Clinic College of Medicine, Rochester, Minn (Dr Montori).

http://jama.ama-assn.org/cgi/content/short/295/19/2275

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Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org