TY - JOUR
AU - MD, Hans Herfarth,
AB - Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry. Clin Gastroenterol Hepatol. 2006;4:621–630. The study by Lichtenstein et al. analyzed the long-term safety of infliximab in patients with Crohn's disease using data of the large Crohn's Therapy, Resource, Evaluation, and Assessment Tool (TREAT) registry. A total of 6290 patients were prospectively enrolled in this registry, among whom 3179 received infliximab and 3111 received other therapies. Eighty-seven percent of the patients in the infliximab group were treated with at least 2 infusions. The mean length of follow-up evaluation was 1.9 years, ranging from 6 months to 4.9 years. The follow-up data of the enrolled patients, collected semiannually from community (82%) and academic (18%) centers, included assessment of disease severity, medication use, adverse events, dates of infliximab infusions, and outcome of each infusion. At the time of enrollment, patients in the infliximab-treated group differed significantly from patients in the comparison group: they were more likely to have both their ileum and colon involved (43.2% versus 35.4%), to have moderate to severe or severe to fulminant disease (33.3% versus 10.9%), and to have been admitted to the hospital more often for either surgical (17.5% versus 13.8%) or medical (14.4% versus 9.1%) therapy in the year before enrollment. In addition, they were more likely to have received prednisone (27.4% versus 16.1%), immunomodulators (49.4% versus 32.2%), and narcotic agents (9.8% versus 5.4%). Overall, 55 of the 6290 patients died. The mortality rate per 100 patient-years and the relative risk (RR) of death were similar for patients who had received infliximab and those who had not. This was found both for total exposure to infliximab (defined as the time between the first infliximab infusion and the last follow-up evaluation) and for infliximab exposure within the previous 3 months (mortality rate per 100 patient-years: 0.53 versus 0.43, RR = 1.24 [95% confidence interval, CI: 0.73–2.10]; RR of death within 3 months of receiving infliximab: 0.83 [95% CI: 0.47–1.49]). Age (odds ratio [OR] 1.07; P < 0.001), duration of disease (OR 1.03; P < 0.006), and use of prednisone (OR 2.10; P < 0.016) were independent predictors of death. Serious infection occurred in 106 patients (1.7%). In both the analysis of total exposure to infliximab and the analysis of exposure to infliximab in the last 3 months, the unadjusted rate of infection was significantly higher in the infliximab group (serious infection rate per 100 patient-years: 1.37 versus 0.65; RR 2.15 [95% CI: 1.44–3.21]; RR for serious infection within 3 months of receiving infliximab: 1.86 [95% CI: 1.27–2.72, P < 0.001]). However, after adjusting for other variables, infliximab did not remain a significant predictor of serious infection, whereas a significant association was found between serious infection with duration of Crohn's disease (OR 1.02; 95% CI: 1.01–1.04); moderate to severe disease (OR 2.11; 95% CI: 1.10–4.05), use of steroids (OR 2.21; 95% CI: 1.46–3.34), and use of narcotic analgesics (OR 2.38; 95% CI: 1.56–3.63). Comments The authors of this study present a large, prospective long-term analysis of the potential mortality and risk of infection of exposure to infliximab. In addition, the registry investigated the associated risk for Crohn's disease of other medications (prednisone, immunomodulators, narcotic agents) as well as several demographic and disease variables (age, sex, race, severity, location of disease, and duration of disease). The outcome demonstrates infliximab-treated and infliximab-untreated patients had similar mortality rates, with the infliximab group showing an increased infection rate, which the mathematical model used indicated was most likely a result of concurrent steroid use, narcotic analgesic use, and more severe disease activity. The currently available data analyzing the risks of exposure to anti-TNF therapy are controversial. The TREAT results suggest there is not a significant increase in the mortality rate with exposure to infliximab. Two retrospective analyses, of 500 patients at the Mayo clinic and of 217 patients in Stockholm County, Sweden, observed infliximab-associated mortality of 1% (median observation period 17 months) and 2.8% (observation period 28 months), respectively.1,2 However, neither study had a comparator group, which hampers interpretation of the data. The results of a recently published population-based cohort study investigating cause-specific mortality in patients with inflammatory bowel diseases in Olmsted County, Minnesota, suggested mortality was slightly increased in patients with Crohn's disease, but no significant difference was observed between patients receiving immunosuppressive therapies and those not receiving them.3 Serious infection rates of 4% to 8% during infliximab therapy have been reported in the literature.4 Many case reports have described the risk in particular of opportunistic infections such as nocardiosis, histoplasmosis, and aspergillosis. This excludes tuberculosis, which is a well-recognized risk of infliximab therapy that necessitates screening for tuberculosis before starting infliximab therapy. The independently increased risk of serious infections after steroid exposure found in the TREAT registry is well recognized for patients with chronic inflammatory disorders, especially at doses of more than 10 mg/day prednisone equivalent.5 Also probably predisposing to infectious complications is preexisting lymphopenia of T-helper cells, with counts less than 250, which also may be a consequence of immunosuppressive therapy, for example, with azathioprine. Unfortunately, the TREAT registry did not monitor either the dose or start and stop dates of corticosteroid application in correlation with infectious events or the extent of lymphopenia. Beginning to monitor them may be worthwhile future additions to this ongoing registry. In weighing the results reported in the TREAT study, several drawbacks of this registry have to take into account. The study was not rigorously monitored, which could have resulted in underreporting and incomplete data collection. Twenty-one percent of the enrolled patients were discontinued from the registry for a wide variety of reasons, somewhat hindering interpretation of the data. Also of note, the TREAT registry is sponsored by the manufacturer of infliximab, not by an independent facility.6 The reported TREAT data require also an interpretation in context of a recently published meta-analysis investigating the risk of infections and malignancies of anti-TNF therapy in patients with rheumatoid arthritis.7 This meta-analysis 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 and calculated the risk of malignancies and serious infections in 3493 patients receiving anti-TNF antibody treatment versus 1512 patients receiving placebo. Importantly, the authors did find a significant risk for serious infections (OR 2.0; 95% CI: 1.3–3.1) with a number needed to harm of 59 (95% CI: 39–125) within a treatment period of 3 to 12 months with an anti-TNF agent. Additionally, they found a pooled odds ratio for any malignancy of 3.3 (95% CI: 1.2–9.1). The frequency of malignancies and especially of lymphomas in association with infliximab in patients with rheumatoid arthritis is still controversial,8 and no data about malignancies in inflammatory bowel disease patients have been reported yet from the TREAT registry. In light of the recent announcements of a rare form of hepatosplenic natural killer T-cell lymphomas, which occurred in several young patients treated with infliximab (Remicade package insert), there is an urgent need for further exploration of the possible association of anti-TNF therapy and malignancies. Considering the anticipated near-future FDA approval of 2 new anti-TNF agents for the therapy of inflammatory bowel diseases, adalimumab and certolizumab pegol, independent prospective registries or even mandatory patient registration programs would be the right approach for the monitoring mortality and adverse events associated with these therapies. References 1 Ljung T, Karlen P, Schmidt D, et al.   Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut.  2004; 53: 849– 853. CrossRef Search ADS PubMed  2 Colombel JF, Loftus EV Jr, Tremaine WJ, et al.   The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. Gastroenterology.  2004; 126: 19– 31. CrossRef Search ADS PubMed  3 Jess T, Loftus EV Jr, Harmsen WS, et al.   Survival and cause specific mortality in patients with inflammatory bowel disease: a long term outcome study in Olmsted County, Minnesota, 1940–2004. Gut.  2006; 55: 1248– 1254. CrossRef Search ADS PubMed  4 Rutgeerts P, Van Assche G, Vermeire S. Review article: Infliximab therapy for inflammatory bowel disease—seven years on. Aliment Pharmacol Ther.  2006; 23: 451– 463. CrossRef Search ADS PubMed  5 Gluck T, Kiefmann B, Grohmann M, Falk W, Straub RH, Scholmerich J. Immune status and risk for infection in patients receiving chronic immunosuppressive therapy. J Rheumatol.  2005; 32: 1473– 1480. PubMed  6 Gluud LL. Bias in Clinical intervention research. Am J Epidemiol.  2006; 163: 493– 501. CrossRef Search ADS PubMed  7 Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. 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– 2285. CrossRef Search ADS PubMed  8 Scott DL, Kingsley GH. Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med.  2006; 355: 704– 712. CrossRef Search ADS PubMed  Copyright © 2007 Crohn's & Colitis Foundation of America, Inc.
TI - Infliximab in Crohn's disease: TREAT your friend as if he might become an enemy?
JF - Inflammatory Bowel Diseases
DO - 10.1002/ibd.20120
DA - 2007-07-01
UR - https://www.deepdyve.com/lp/oxford-university-press/infliximab-in-crohn-s-disease-treat-your-friend-as-if-he-might-become-L6eRUS8yV3
SP - 933
EP - 934
VL - 13
IS - 7
DP - DeepDyve
ER -