TY - JOUR
AU1 - Corona, Rosamaria
AU2 - Bigby, Michael
AB - Commentary on: 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 Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. JAMA. 2006;295:2275-2285 Question: In patients with rheumatoid arthritis treated with infliximab or adalimumab, what is the risk of serious infection or malignancy compared with patients with rheumatoid arthritis who do not receive either anti–tumor necrosis factor (TNF) antibody? Data Sources: The authors performed a meta-analysis to derive estimates of sparse harmful events occurring in randomized trials of infliximab or adalimumab. 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 infliximab and adalimumab. Study Selection: The authors included randomized, placebo-controlled trials of infliximab and adalimumab used for 12 weeks or longer in patients with rheumatoid arthritis. 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: Nine trials met the inclusion criteria, including 3493 patients who received infliximab or adalimumab treatment and 1512 patients who received placebo. The authors calculated a pooled odds ratio (OR) (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 patients treated with infliximab or adalimumab vs those who received placebo. They 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) (Table 1). Malignancies were significantly more common in patients treated with higher doses compared with those who received lower doses of infliximab or adalimumab (OR, 3.4 [95% CI, 1.4-8.2]). Infections were more common in patients treated with higher doses compared with those who received lower doses; however, the difference was not statistically significant (OR, 1.4 [95% CI, 1.0-2.0]; P = .07). For patients treated with infliximab or adalimumab 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. Table 1. View LargeDownload Risk of Infection and Malignancy Authors' 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. Comment This systematic review seems to yield affirmative answers to all of the questions asked when critically appraising a systematic review (Table 2).2 Thus, it is a well executed and reported systematic review and meta-analysis. Of special note, all principal investigators and sponsors were contacted to verify the reported numbers and time points of occurrence of malignancies and serious infections. Table 2. View LargeDownload Critical Appraisal of a Systematic Review* A known difficulty with performing meta-analysis occurs when the number of events is small, especially if no events occur in some cohorts.3 This issue was addressed by the authors by using fixed-effect models for meta-analysis and using the continuity correction of Sweeting et al3 for studies in which a cohort had no events (malignancies or serious infections). The usual practice of adding 0.5 to cohorts with no events to allow calculation of ORs is unsatisfactory and somewhat inexplicable. In addition, the authors performed many sensitivity analyses, including and excluding trials in which there were no events in any cohort, and they used widely different statistical methods to calculate ORs and statistical significance. The results were strikingly consistent and all led to the same conclusions. The results of this meta-analysis indicate that the magnitude of the increased risk for infection for patients treated with anti-TNF antibodies was large, and the narrow 95% CI indicates a clinically significant risk of infection in treated patients (Table 1). The magnitude of the risk for malignancy was also large, but the 95% CI was very wide, reflecting the small numbers of malignancies that occurred and indicating that the point estimate is quite inexact (Table 1). Because the control groups in the studies used in this meta-analysis were composed of patients with rheumatoid arthritis who did not receive anti-TNF antibodies, the risk measured is a direct measure of the increased risk associated with the use of anti-TNF antibodies. Therefore, the studies’ results are likely to be generalizable to other populations of patients who are treated with anti-TNF antibodies (eg, patients with severe psoriasis), but the baseline risk of infection and malignancy may be lower. However, several issues were of concern. Although etanercept is an anti-TNF agent, it was not included in the analysis. The authors state that it was not included because it also binds to lymphotoxin-α. They did not, however, reveal that some of them had received grants or were paid consultants of Amgen (the maker of etanercept) in the original publication (this information was published later as an erratum). Other studies and forums that have addressed the issue of the risk of cancer and serious infection with anti-TNF antibody therapy have included infliximab, adalimumab, and etanercept.4,5 In one such study, solid cancers were not increased in patients treated with anti-TNF antibody compared with other patients with rheumatoid arthritis.4 The risks of infection and malignancy, especially lymphoma, is of concern for all 3 agents.5 Bottom Line: That infliximab and adalimumab were associated with the development of serious infection and malignancy is not surprising.5 However, the magnitude of the risk is higher than one might anticipate. If the results of this study are correct, then for every 154 patients treated with anti-TNF antibody for only 6 to 12 months, 1 additional malignancy will be induced; and for every 59 patients treated with anti-TNF antibody for 3 to 12 months, 1 additional serious infection will be induced. The exclusion of etanercept from the study, study sponsorship, and the need for the authors to correct conflict of interest statements post hoc raise the specter of investigator bias. Correspondence: Rosamaria Corona, MD, DSc, Istituto Dermopatico dell’Immacolata, Via dei Monti Creta 104, 00167 Rome, Italy (r.corona@idi.it). Financial Disclosure: None reported. Accepted for Publication: October 11, 2006. References 1. Sackett DRichardson WRosenberg WHaynes R Evidence-Based Medicine: How to Practice and Teach EBM. Edinburgh, Scotland Churchill Livingstone1996; 2. Therapy worksheets. http://www.cebm.net/downloads/worksheets.rtfAccessed July 5, 2006 3. Sweeting MJSutton AJLambert PC What to add to nothing? use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 2004;231351- 1375PubMedGoogle ScholarCrossref 4. Askling JFored CMBrandt L et al. Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis 2005;641421- 1426PubMedGoogle ScholarCrossref 5. March 4, 2003, briefing information Food and Drug Administration Arthritis Advisory Committee, Food and Drug Administration Arthritis Advisory Committee Web site http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930b1.htmAccessed July 7, 2006Google Scholar
TI - What Are the Risks of Serious Infections and Malignancies for Patients Treated With Anti-Tumor Necrosis Factor Antibodies?
JF - Archives of Dermatology
DO - 10.1001/archderm.143.3.405
DA - 2007-03-01
UR - https://www.deepdyve.com/lp/american-medical-association/what-are-the-risks-of-serious-infections-and-malignancies-for-patients-PLKXmxseLQ
SP - 405
EP - 406
VL - 143
IS - 3
DP - DeepDyve
ER -