Safety of Infliximab in Inflammatory Bowel Disease Needs to Be Debated
Article Outline
Dear Editor:
With great interest we read the article by Caspersen et al1 in which they investigated the long-term safety of infliximab in patients with inflammatory bowel disease (IBD) in a national Danish population-based cohort. They scored adverse events in up to 47% of all patients and concluded that infliximab was generally well tolerated. Their conclusion based on these numbers is debatable, and is also based on a retrospective study, with subsequent nonstandardized underreporting of adverse events as compared with prospective clinical trials. Moreover, the data of the Danish IBD cohort was gathered over a relatively short follow-up period.
In Table 1, we compare their study with 3 other recently published retrospective cohort studies about the long-term safety of infliximab in patients with IBD from Belgium, Scotland, and The Netherlands.2, 3, 4 The Denmark IBD population treated with infliximab developed fewer malignancies (4; 0.6%) compared with the cohorts from Belgium (21; 2.8%), Scotland (6; 3.0%), and The Netherlands (9; 6.1%). Most likely this could be explained by a relatively short follow-up period (median follow-up period, 29.1 mo) compared with the cohorts from Belgium and The Netherlands (median follow-up periods, 58 and 59 mo, respectively), and therefore underestimation of the true rate of malignancies. The raised concern of developing malignancies in patients treated with anti–tumor necrosis factor, in combination with the fact that carcinogenesis is a process requiring many years of exposure to disease or treatment, makes it necessary to have a long-term follow-up period to detect malignancies. This is emphasized further with the significant association with duration of disease and the development of malignancies in the studies from Belgium and The Netherlands. This indicates that thorough follow-up evaluation of patients with IBD for the development of malignancies is warranted.
Table 1. Characteristics of the Four Recently Reported Studies on the Long-Term Safety of Infliximab
| Caspersen et al1 | Fidder et al2 | Lees et al3 | de Vries et al4 | |
|---|---|---|---|---|
| Number of treated patients | 651 | 734 | 202 | 147 |
| Median age at start of therapy, y | 31.6 (range,9.7–92.4) | 35(IQR,25–35) | 30.8(IQR,22.0–42.9) | 38(SD,12) |
| Median disease duration before first infusion, y | 5(range,0–38) | 7(IQR,2–15) | 4.9(IQR,1.2–11.0) | 16(range,0–41) |
| Number of infusions | 3351 | 7276 | 718 | 1941 |
| Median number of infusions per patient | 3 | 6 | 3 for CD, 1 for UC | 10 |
| Follow-up period (patient-years) | — | 3775 | 620 | 674 |
| Median follow-up period, mo | 29.1 | 58 | 28.8 | 59 |
| Number of infections, %a | 69(63patients) | 59(48patients) | 60(42patients) | 57(36patients) |
| Annual infection rate, % | — | 1.3 | 7 | 5 |
| Number of malignancies, % | 4(0.6) | 21(2.8) | 6(3.0) | 9b(6.1) |
| Mortality, % | 13(2.0) | 12(1.6) | 7(3.5) | 8(5.4) |
| Annual mortality rate, % | — | 0.3 | 1.1 | 1.2 |
aIn some of the studies (de Vries et al), only those patients who underwent hospitalization for their infections were included. In others, hospitalization was not required in case of an infection. Therefore, the given numbers are not completely comparable since inclusion criteria are different between these studies. |
bThere were 9 malignancies in 8 patients. |
The question remains whether the high rate of malignancies is related to disease, treatment, or a synergistic effect. The Belgian cohort did include a control group of IBD patients treated in the same center and period. They compared IBD patients treated with infliximab with patients not receiving any biological therapy and found no differences in terms of mortality, infection rates, and malignancies.2 These findings need to be reproduced in other centers, but give us some first impressions regarding causality with IBD.
References
- Infliximab for inflammatory bowel disease in Denmark 1999-2005: clinical outcome and follow-up evaluation of malignancy and mortality. Clin Gastroenterol Hepatol. 2008;6:1212–1217
- Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single center cohort study. Gut. 2008;Nov 18 [Epub ahead of print]
- The safety profile of anti-tumour necrosis factor therapy in inflammatory bowel disease in clinical practice: analysis of 620 patient-years follow-up. Aliment Pharmacol Ther. 2009;29:286–297
- . Serious events with infliximab in patients with inflammatory bowel disease: a 9-year cohort study in The Netherlands. Drug Saf. 2008;31:1135–1144
Conflicts of Interest The authors disclose the following: Dr de Jong received speaker's fees from Abbott, Schering Plough, Falk Pharma GmbH, UCB Pharma, and Ferring BV. The remaining authors disclose no conflicts.
PII: S1542-3565(08)01248-2
doi:10.1016/j.cgh.2008.12.021
© 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.
Refers to article:
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Infliximab for Inflammatory Bowel Disease in Denmark 1999–2005: Clinical Outcome and Follow-Up Evaluation of Malignancy and Mortality
, 10 October 2008
