Select a research article, other than the articles from your assignments, from the GCU library. Provide an overview of the study and describe the strategy that was used to select the sample from the p

A population-based sample of Crohn’s disease patients from Cardiff, UK, diagnosed during 1986–2003 were assessed for changes in outcomes by different time-periods (1986–1991, 1992–1997, and 1998–2003). Smoking rates were not significantly different between the periods of follow-up.

Five-year follow-up data were available for 97% of the subjects. At 5 years after diagnosis, the use of thiopurines had increased from 11% to 28% to 45% over the three time- periods (p=0.001). The median time to start thiopurines was 77 months, 21 months, and 11 months, respectively. The median duration of use increased from 14 months in the first cohort to 23 months in the most recent one (p=0.001). There was also a significant reduction in long-term steroid use at 5 years post-diagnosis (44%, 31%, and 19%, respectively, p=0.001). A significant reduction was also seen in surgery rates at 5 years post-diagnosis, from 59% to 37% to 25% per cohort period (p=0.001). Intestinal surgery was affected by year of diagnosis, disease location (colonic disease reduced the likelihood), and steroid use within 3 months of diagnosis. The study showed that, in the more recent years evaluated, there was a reduction in early (within 5 years) surgery rates and an increase in the use of thiopurines. The authors suggest that these two observations may be linked. They do present some alternative hypotheses including less aggressive and early use of surgery over time, and possibly even more attention to smoking cessation in recent years. There were too few subjects using infliximab (in the more recent years) to assess its impact on surgery rates. The study’s main strength was its population- based nature and reasonable sample size.

Address for reprints: AB Hawthorne, University Hospital of Wales, Cardiff, CF14 4XW, UK.

Email: [email protected] A population-based study of health-care resource use among infliximab users Nugent Z, Blanchard JF, Bernstein CN.

Am J Gastroenterol 2010;105:2009–16.

Anti-tumor necrosis factor (anti-TNF) agents have been used in IBD patients in Canada since 2001. They are reserved for those IBD patients who are most ill – patients who are most likely to be hospitalized or require surgery, for example. Anti-TNF agents are expensive; therefore, it is important to determine whether their use is cost-effective in terms of their influence on healthcare resource utilization (e.g. surgery, hospitalization). Nugent and colleagues used the population-based data of the University of Manitoba IBD Epidemiology Database to examine such healthcare resource utilization among infliximab users.

This study aimed to describe the characteristics of healthcare utilization among patients with Crohn’s disease using infliximab. Using the population-based data of the University of Manitoba IBD Epidemiology Database, the authors created four cohorts of subjects dating back to 1996 (from when reliable population-based data on prescription drug use became available). One cohort included subjects who were newly prescribed infliximab, a second was a cohort of those who were newly prescribed thiopurines without infliximab, a third cohort was newly prescribed steroids (without infliximab or purine analogues) after 2001 (when infliximab became available in Canada for Crohn’s disease), and a fourth cohort was those not prescribed any of these drugs. All of the subjects must have had healthcare utilization data available for 5 years prior to their initial prescription and for 3 years thereafter. The numbers of physician visits, hospital visits, and surgeries were analyzed. IBD-associated physician visits were consistently higher for infliximab users, both pre- and post-initial dosing, although overall physician visits were similar between the infliximab, thiopurine, and steroid cohorts. There was a steep rise in hospitalizations in the 6 months prior to the initial prescription of infliximab, thiopurines, and steroids; in addition, hospitalizations were higher in the infliximab cohort until 18–24 months after the first prescription, at which point levels fell to those evident 2–5 years prior to initiating infliximab and to levels in the other drug groups. The likelihood of surgery post-dosing was greater in the infliximab than in the thiopurine or no drug groups for up to 36 months, but was not different than that of the steroid-using cohort. The authors concluded that, in a jurisdiction practicing a “step-up” approach to infliximab use, it took 2 years for the rate of physician visits to reduce to 2-year pre-dosing rates, and 18–24 months to reach hospitalization rates that were evident 2 years pre-dosing and equivalent to hospitalization rates of the thiopurine and steroid groups. Surgical rates to 3 years post- dosing were still higher in the infliximab group than in the thiopurine or no drug groups. An advantage of this study is that it was population-based, assessing all-comers initiating infliximab therapy and assessing their outcomes for ≥ 3 years post initiation of therapy. Further, comparator groups were drawn from the same population of Crohn’s disease subjects to provide a context in which to understand healthcare utilization among infliximab users. As the infliximab cohort was among the most ill of the Crohn’s disease patients, these findings could be interpreted as positive on behalf of infliximab (that they ever reached the levels of other treated patient groups). Furthermore, the infliximab cohort reduced their hospitalizations to levels they experienced 2–5 years prior to their initial dosing. Unfortunately, they still had higher rates of surgery than most other Crohn’s disease patients except those who required an acute course of steroids. Therefore, hospitalization and outpatient visit aspects of healthcare utilization did decrease over time but it took longer than 1 year to get there. These authors could not show that infliximab use decreased healthcare utilization to levels below pre-infliximab therapy or levels below those of the other Crohn’s disease patient groups. Hence, considering the high expense of infliximab, it may be difficult to prove cost-effectiveness in a “step-up” approach to initiating the drug where it is reserved for the most ill patients, unless indirect costs and quality of life are accounted for.

Address for reprints: CN Bernstein, University of Manitoba, 804F-715 McDermot Avenue, Winnipeg, MB, Canada, R3E3P4. Email: [email protected] PAtHoGEnEsis Pept1 mediates transport of the proinflammatory bacterial tripeptide L-Ala-{gamma}-d -Glu- meso-d AP in intestinal epithelial cells Dalmasso G, Nguyen HT, Charrier-Hisamuddin L et al.

Am J Physiol Gastrointest Liver Physiol 2010;299:G687–96.

In this study, Dalmasso and colleagues showed that the PepT1 (SLC15A1) di- and tri-peptide transporter can transport an immune-active bacterial component, l-Ala-γ - d-Glu-meso-diaminopimelic acid (Tri-DAP), into intestinal epithelial cells, with subsequent activation of nuclear factor-κ B and interleukin-8 production.

The PepT1 peptide transporter is highly expressed in the small bowel and is induced in chronic inflammation in the colon.

PepT1 is of relevance to IBD, with recent work demonstrating upregulation of PepT1 in IBD and association with a genetic polymorphism in IBD [1,2]. Dalmasso and colleagues investigated the role of PepT1 in the transport of l-Ala-γ- d-Glu- meso-diaminopimelic acid (Tri-DAP), a peptide released during bacterial peptidoglycan degradation. Tri-DAP is recognized by NOD1, an intracellular innate immune receptor. In a series of in vitro studies using the Caco2 small intestinal epithelial cell line, the authors showed that Tri-DAP competes with a known PepT1-specific substrate, confirming that Tri-DAP is transported by PepT1. TriDAP activated nuclear factor-κ B and mitogen activated protein kinase pathways; these effects were abolished on gene knockdown of PepT1. Stable transfection of PepT1 in HT29 colonic epithelial cells, a cell line not expressing PepT1, restored the effects of Tri-DAP. Finally, ex vivo culture of a colonic fragment from transgenic PepT1 mice with Tri-DAP resulted in higher production of KC (the murine homologue of human IL-8) compared with colonic cultures from wild-type mice.

These findings suggest that PepT1 actively promotes a pro- inflammatory epithelial response during inflammation, likely by transporting Tri-DAP into the cells.

1. Wojtal KA, Eloranta JJ, Hruz P et al. Changes in mRNA expression levels of solute carrier transporters in inflammatory bowel disease patients. Drug Metab Dispos 2009;37:1871–7.

2. Zucchelli M, Torkvist L, Bresso F et al. PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease. Inflamm Bowel Dis 2009;15:1562–9.

Address for reprints: G Dalmasso, Emory University, Department of Medicine, Division of Digestive Diseases, 615 Michael Street, Atlanta, GA 30322, USA. Email: [email protected] induction and rescue of nod2-dependent th1-driven granulomatous inflammation of the ileum Biswas A, Liu YJ, Hao L et al.

Proc Natl Acad Sci U S A 2010;107:14739–44.

Despite the identification of the NOD2 gene as a risk factor for Crohn’s disease over a decade ago, the understanding of how the NOD2 gene contributes to the pathogenesis of the disease is not firmly established. In this study, Biswas et al. provide further data to support the suggestion that dysregulation of NOD2 function in Paneth cells occurs via a receptor-interacting serine/ threonine-protein 2 kinase (Rip2K)-dependent pathway influencing α-defensin production.

Mutations of the NOD2 gene represent the strongest genetic susceptibility factor in Crohn’s disease, although the exact mechanism for this remains unclear at present. Three competing hypotheses exist: “gain of function”, leading to increased sensitivity to the muramyl dipeptide (MDP) ligand; “loss of function”, via the tonic inhibition of the Toll-like receptor 2 (TLR2)-mediated Th1 immune response; and finally, an “indirect” effect on the host–microbiota interaction mediated by loss of NOD2 function in Paneth cells and subsequent reduced antimicrobial peptide production. Of interest, NOD2-deficient mice do not develop spontaneous colitis. Here, the authors showed that colonization of NOD2- deficient mice with Helicobacter hepaticus resulted in increased numbers of Peyer’s patches, an increase in the size of mesenteric lymph nodes and Peyer’s patches, and ileal granulomatous inflammation. The ileal localization is a notable finding although H hepaticus is a common commensal that can induce intestinal inflammation in susceptible mouse strains. The expression of proinflammatory cytokines, interleukin-1β (IL-1β) and IL-6, as well | CLINICAL REVIEWS | PATHOGENESIS 123 Copyright of Inflammatory Bowel Disease Monitor is the property of Remedica Medical Education & Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.