Infliximab and other immunomodulating drugs in patients with inflammatory bowel disease and the risk of serious bacterial infections

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 021205, USA.
Alimentary Pharmacology & Therapeutics (Impact Factor: 5.73). 06/2009; 30(3):253-64. DOI: 10.1111/j.1365-2036.2009.04037.x
Source: PubMed


There remain concerns about the safety of infliximab therapy in patients with inflammatory bowel disease (IBD).
To assess the association between the initiation of infliximab and other immunomodulating drugs and the risk of serious bacterial infection in the treatment of IBD.
We assembled a cohort study of patients with IBD, including Crohn's disease (CD) and ulcerative colitis (UC). All patients initiating an immunomodulating drug between January 2001 and April 2006 were identified in British Columbia from linked health care utilization databases. Exposure of interest was initiation of infliximab or corticosteroids compared with initiation of other immunosuppressive agents, including azathioprine, mercaptopurine (MP) and methotrexate (MTX). Outcome of interest was serious bacterial infections requiring hospitalization, including Clostridium difficile.
Among 10 662 IBD patients, the incidence rate of bacteriaemia ranged from 3.8 per 1000 person-years (95% confidence interval 2.1-6.2) for other immunosuppressive agents to 7.4 (3.3-19.3) for infliximab with slightly higher rate for serious bacterial infections resulting in an adjusted relative risk 1.4 (0.47-4.24). Clostridium difficile infections occurred in 0/1000 (0-5.4) among 521 infliximab initiations and 14/1000 (10.6-18.2) for corticosteroids. Corticosteroid initiation tripled the risk of C. difficile infections (RR = 3.4; 1.9-6.1) compared with other immunosuppressant agents. This corticosteroid effect was neither dose-dependent nor duration-dependent. Bacteriaemia and other serious bacterial infections were not increased by corticosteroids or infliximab (5 events).
In a population-based cohort of patients with IBD, we found no meaningful association between infliximab and serious bacterial infections, although some subgroups had few events. Corticosteroid initiation increased the risk for C. difficile infections in these patients.

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    • "A notable example is infliximab , a chimeric monoclonal antibody targeting TNF-a, which has exhibited satisfactory performances in alleviating IBD in clinical trials [5]. However, in systemically, non-selectively blocking TNF-a, this drug also brought about obvious side effects, such as causing immunodeficiency-related infections and generating antibodies against the drugs [6] [7]. Therefore, anti-TNF-a therapies have proven effective, but they need to be limited at the specific site of inflammation. "
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    ABSTRACT: Tumor necrosis factor-alpha (TNF-α) plays a central role in the pathogenesis of inflammatory bowel disease (IBD). Anti-TNF-α therapies have shown protective effects against colitis, but an efficient tool for target suppression of its secretion - ideally via oral administration - remains in urgent demand. In the colon tissue, TNF-α is mainly secreted by the colonic macrophages. Here, we report an orally-administrated microspheric vehicle that can target the colonic macrophages and suppress the local expression of TNF-α for IBD treatment. This vehicle is formed by cationic konjac glucomannan (cKGM), phytagel and an antisense oligonucleotide against TNF-α. It was given to dextran sodium sulfate (DSS) colitic mice via gastric perfusion. The unique swelling properties of cKGM enabled the spontaneous release of cKGM& antisense nucleotide (ASO) nano-complex from the phytagel scaffold into the colon lumen, where the ASO was transferred into colonic macrophages via receptor-mediated phagocytosis. The treatment significantly decreased the local level of TNF-α and alleviated the symptoms of colitis in the mice. In summary, our study demonstrates a convenient, orally-administrated drug delivery system that effectively targets colonic macrophages for suppression of TNF-α expression. It may represent a promising therapeutic approach in the treatment of IBD. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biomaterials 04/2015; 48. DOI:10.1016/j.biomaterials.2015.01.013 · 8.56 Impact Factor
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    • "Another risk factor is treatment with glucocorticoids. In a large cohort study in 2009, Schneeweiss et al. showed a three-fold higher risk of CDAD in patients with IBD treated with steroids, with no correlation between dose and duration of use [13]. Studies on other immunosuppressants and immunomodulators, including azathioprine, 6-mercaptopurine, methotrexate and infliximab, are ambiguous or have only been carried out in small groups [4]. "
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    ABSTRACT: Clostridium difficile is a bacterium widely distributed in the human environment. In the last decade the incidence and severity of Clostridium difficile infection has grown, particularly in Europe and North America, making it one of the more common nosocomial infections. A group particularly susceptible to Clostridium difficile infection are patients with inflammatory bowel disease, especially those with involvement of the colon. This paper presents relevant data on Clostridium difficile infections in inflammatory bowel disease patients, including epidemiology, pathogenesis, diagnosis and treatment.
    Przegląd Gastroenterologiczny 06/2014; 9(3):125-9. DOI:10.5114/pg.2014.43572 · 0.38 Impact Factor
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    • "A study of IBD patients in British Columbia between 2001 and 2006 showed a threefold increase in risk of CDI with corticosteroid use, with or without immunomodulators therapy (RR 3.3 95% CI 1.88–6.10) [36]. It is not clear if the immunomodulating drugs like azathioprine, 6- mercaptopurine, and methotrexate enhance the risk of CDI. "
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    ABSTRACT: The incidence of Clostridium difficile infection (CDI) has significantly increased in the last decade in the United States adding to the health care burden of the country. Patients with inflammatory bowel disease (IBD) have a higher prevalence of CDI and worse outcomes. In the past, the traditional risk factors for CDI were exposure to antibiotics and hospitalizations in elderly people. Today, it is not uncommon to diagnose CDI in a pregnant women or young adult who has no risk factors. C. difficile can be detected at the initial presentation of IBD, during a relapse or in asymptomatic carriers. It is important to keep a high index of suspicion for CDI in IBD patients and initiate prompt treatment to minimize complications. We summarize here the changing epidemiology, pathogenesis, risk factors, clinical features, and treatment of CDI in IBD.
    Gastroenterology Research and Practice 09/2011; 2011(3):136064. DOI:10.1155/2011/136064 · 1.75 Impact Factor
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