R N Fedorak

University of Alberta, Edmonton, Alberta, Canada

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Publications (138)935.65 Total impact

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    ABSTRACT: Inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are poorly understood disorders affecting the intestinal tract. The current model for disease suggests that genetically susceptible patients develop intolerance to gut microflora, and chronic inflammation develops as a result of environmental insults. Although interest has mainly focused on studying genetic variants and gut bacterial flora, little is known about the potential of viral infection to contribute to disease. Accordingly, we conducted a metagenomic analysis to document the baseline virome in colonic biopsy samples from patients with IBD in order to assess the contribution of viral infection to IBD. Libraries were generated from colon RNA to create approximately 2 GB sequence data per library. Using a bioinformatic pipeline designed to detect viral sequences, more than 1000 viral reads were derived directly from tissue without any coculture or isolation procedure. Herein, we describe the complexity and abundance of viruses, bacteria/bacteriophage, and human endogenous retroviral sequences from 10 patients with IBD and 5 healthy subjects undergoing surveillance colonoscopy. Differences in gut microflora and the abundance of mammalian viruses and human endogenous retroviruses were readily detected in the metagenomic analyses. Specifically, patients with herpesviridae sequences in their colon demonstrated increased expression of human endogenous viral sequences and differences in the diversity of their microbiome. This study provides a promising metagenomic approach to describe the colonic microbiome that can be used to better understand virus-host and phage-bacteria interactions in IBD.
    Inflammatory Bowel Diseases 05/2015; DOI:10.1097/MIB.0000000000000344 · 5.48 Impact Factor
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    ABSTRACT: Intestinal resections are frequently required for treatment of diseases involving the gastrointestinal tract, with Crohn's disease and colon cancer being two common examples. Despite the frequency of these procedures, a significant knowledge gap remains in describing the inherent effects of intestinal resection on host physiology and disease pathophysiology. This article provides detailed instructions for an ileocolic resection with primary end-to-end anastomosis in mice, as well as essential aspects of peri-operative care to maximize post-operative success. When followed closely, this procedure yields a 95% long-term survival rate, no failure to thrive, and minimizes post-operative complications of bowel obstruction and anastomotic leak. The technical challenges of performing the procedure in mice are a barrier to its wide spread use in research. The skills described in this article can be acquired without previous surgical experience. Once mastered, the murine ileocolic resection procedure will provide a reproducible tool for studying the effects of intestinal resection in models of human disease.
    Journal of Visualized Experiments 10/2014; DOI:10.3791/52106
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    ABSTRACT: Background The efficacy of adalimumab in maintaining remission in Crohn's disease patients may wane over time, leading to secondary loss of response that is often managed with dose escalation. However, the response to adalimumab dose escalation and long-term outcomes after escalation have not been well evaluated.AimsTo characterise the short- and long-term clinical responses to adalimumab dose escalation for secondary loss of response.MethodsA retrospective cohort study evaluating Crohn's disease out-patients requiring adalimumab dose escalation for secondary loss of response from 2003 to 2013 was conducted. The primary outcome was the proportion of patients achieving symptomatic clinical response to dose escalation and subsequent development of tertiary loss of response. Duration of regained response was assessed by Kaplan–Meier analysis.ResultsNinety-two CD patients met inclusion criteria with mean duration of follow-up of 170.2 weeks (±129.6 weeks). Disease distribution was predominantly ileal (37/92, 40.2%) or ileocolonic (43/92, 46.7%), with equal distribution of inflammatory (34.8%), stricturing (27.2%), and penetrating (38.0%) disease phenotypes. At 24 weeks post-dose escalation, 74/92 (80.4%) patients had symptomatic clinical response. Among responders, median duration of sustained response was 69.2 weeks (IQR 29.4–107.1) but 42/74 (56.8%) responders experienced subsequent tertiary loss of response at a median time of 47.9 weeks (IQR 24.7–80.3). C-reactive protein >10.0 mg/L at the time of dose escalation predicted tertiary loss of response in univariate analysis (OR 3.32, 95% CI: 1.18–9.37).Conclusions In patients with Crohn's disease, adalimumab dose escalation is effective for recapturing symptomatic response after secondary loss of response, but more than half will eventually experience a tertiary loss of response.
    Alimentary Pharmacology & Therapeutics 09/2014; 40(9). DOI:10.1111/apt.12940 · 4.55 Impact Factor
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    ABSTRACT: Background Medical therapy is standard treatment for ulcerative colitis with colectomy reserved for medically refractory disease or malignancy. The introductions of ciclosporin in 1994 and anti-TNF therapy in 2005 have extended medical management options.AimThe aim of this study was to determine whether the colectomy incidence rate for medically refractory ulcerative colitis has changed since the introduction of anti-TNF therapy.Methods Adult patients with a diagnosis of ulcerative colitis and who subsequently underwent an urgent or elective colectomy for medically refractory disease in Edmonton, Canada between 1 January 1998 and 31 December 2011 were identified. Log-linear regression was used to estimate the annual percent change in the total colectomy incidence rate (urgent and elective combined) and the urgent and elective incidence rates individually, before and after 2005, the year infliximab was approved for use in ulcerative colitis. Temporal trends of drug utilisation in this study population were also described.ResultsDuring 1998–2011, 481 patients with ulcerative colitis underwent a colectomy for medically refractory disease. There was negligible change in the total colectomy incidence rate from 1998 to 2005, with an annual percent change of 4.4% (95% confidence interval (CI): −1.12% to 10.16%). From 2005-2011, following the approval and increasing use of anti-TNF therapy, the total colectomy incidence rate decreased by 16.1% (95% CI: −21.32% to −10.54%) every year to 0.9 per 100 ulcerative colitis patients in 2011.Conclusion The total incidence rate of colectomy for medically refractory ulcerative colitis has declined substantially since 2005, paralleling the increased use of anti-TNF therapy in this patient population.
    Alimentary Pharmacology & Therapeutics 07/2014; 40(6). DOI:10.1111/apt.12873 · 4.55 Impact Factor
  • Journal of Crohn s and Colitis 02/2014; 8:S282. DOI:10.1016/S1873-9946(14)60633-4 · 3.56 Impact Factor
  • Journal of Crohn s and Colitis 02/2014; 8:S229. DOI:10.1016/S1873-9946(14)60512-2 · 3.56 Impact Factor
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    ABSTRACT: The Epstein-Barr Virus (EBV) is truly prolific, with a prevalence of more than 90% in the adult human population. There are, however, little data available on the prevalence of EBV among patients with Inflammatory Bowel Disease (IBD), a population that is frequently immunosuppressed and thus at risk for severe, often fatal, primary infection. To identify the prevalence of EBV in a population of patients with IBD and to compare it with that of the general population. A database of 2500 IBD patients previously followed at the University of Alberta IBD Centre was queried; 60 of these patients were randomly chosen to participate. A total of 220 patients attending the IBD Centre for clinical appointment were also prospectively asked to participate. Participants completed serological testing for VCA-IgM, VCA-IgG and EBNA-IgG, to determine prior EBV exposure. A total of 263 patients underwent testing. Results for EBV seroprevalence of specific age groups were as follows: 18-20 years (n = 17), 29% seronegative; 21-25 years (n = 31), 29% seronegative; 26-30 years (n = 35), 31-35 years (n = 18) and 36-40 years (n = 25), 100% seropositive. Finally, 3% of those older than 40 (n = 117) were seronegative. EBV seroprevalence was similar for Crohn's disease and ulcerative colitis. Azathioprine was associated with seropositivity (P = 0.048). The prevalence of EBV seronegativity in the IBD population aged 18-25 years was similar to that described in the general population, and above age 25 years, seropositivity approached 100%.
    Alimentary Pharmacology & Therapeutics 09/2013; DOI:10.1111/apt.12503 · 4.55 Impact Factor
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    ABSTRACT: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.
    Alimentary Pharmacology & Therapeutics 07/2013; 38(5). DOI:10.1111/apt.12407 · 4.55 Impact Factor
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    Alimentary Pharmacology & Therapeutics 02/2013; 37(4):496-497. DOI:10.1111/apt.12196 · 4.55 Impact Factor
  • Journal of Crohn s and Colitis 02/2013; 7:S173-S174. DOI:10.1016/S1873-9946(13)60430-4 · 3.56 Impact Factor
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    ABSTRACT: BACKGROUND: Corticosteroids are effective for induction of clinical remission in inflammatory bowel disease (IBD), but are neither safe nor effective for maintenance of remission. Given their adverse effects and association with poor long-term outcomes, minimization of steroid use is a goal of therapy, and the use of steroid-sparing agents is indicated in patients that are steroid-dependent. We examined the patterns of steroid utilization within Canada.METHODS: Health claims data was purchased from IMS Brogan (including regional-private and national-private aggregate, and two different public plans). These databases do not contain ICD-9 codes and did not allow for differentiation of IBDs. As 5-ASA is a unique therapy for IBD, patients were indexed based on a claim for 5-ASA in the first month and followed for 12 consecutive months. We measured steroid utilization amongst 5-ASA claimants as follows: Fraction with >= 2 prednisone claims/year, fraction with a first and last prednisone claim >90 days apart, and median days elapsed between first and last prednisone claim in those with >= 2 prednisone claims. Utilization was characterized amongst different database types (public/private), genders, calendar years, age categories, and concomitant IBD therapies.RESULTS: The databases comprised 19,613 patients with a claim for a 5-ASA product in January 2011. The group was ~50% male, and 70% were aged 20-65 years old. The median number of 5-ASA claims was 8/year. The patterns of steroid utilization were generally consistent between the databases (see Table 1), with little variation across database type, gender, or calendar years. However, geriatric claimants (aged >65) in the Quebec-public database had higher rates of steroid use than the other groups. Overall, 58%-73% of patients with a claim for 5-ASA and prednisone have >= 2 claims for prednisone. Within this group, at least half the claimants (53%-69%) had >90 days between their first and last prednisone claim, with a median time between the first and last prednisone claim ranging from 103 to 222 days. Some prednisone claimants (~40%) also had claims for steroid-sparing therapies. After excluding those with any immunosuppressive or biologic claim, the rates of steroid dependence remained largely unchanged.DISCUSSION: Multiple treatment guidelines define steroid-dependence as: An inability to completely taper steroids within 90 days of initiation, frequent use of steroid courses (>1 course/year), and/or relapse within 3 months of stopping. The 3 measures of steroid utilization used in this analysis approximate that definition, although not without caveats. After excluding those with claims for steroid-sparing therapies, prednisone-claimants had a median of 2-4 prednisone claims per year. They also had a median time between first and last prednisone claim of at least 100 days, and more than 52% had a claim for prednisone >90 days apart. Any of these measures taken individually suggests a prevalence of steroid-dependence despite access to steroid-sparing therapies.CONCLUSIONS: The data suggest that >50% of patients on 5-ASA that are prescribed prednisone become steroid-dependent within 1 year. Steroid-sparing therapies appear underused in this group of patients, and show little change despite a shifting treatment paradigm.(C) Crohn's & Colitis Foundation of America, Inc.
    Inflammatory Bowel Diseases 01/2013; 19:S46-S47. DOI:10.1097/01.MIB.0000438729.46835.90 · 5.48 Impact Factor
  • Richard Fedorak, Denny Demeria
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    ABSTRACT: Definitive curative strategies for inflammatory bowel disease remain challenging for physicians and patients. For decades, probiotic organisms have been used in various gastrointestinal diseases. Only recently has comprehension of the pathophysiology of inflammatory bowel disease developed to the point where the significance of the host gastrointestinal microbial population is seen to have marked influence on the initiation and ongoing inflammatory processes of Crohn disease and ulcerative colitis. Well-designed, large randomized controlled trials using probiotics in patients with inflammatory bowel disease are required for probiotics to become mainstream therapy.
    Gastroenterology clinics of North America 12/2012; 41(4):821-42. DOI:10.1016/j.gtc.2012.08.003 · 1.92 Impact Factor
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    ABSTRACT: BACKGROUND: Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet (GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. AIM: To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. METHODS: This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol (LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels. RESULTS: No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005) and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. CONCLUSIONS: Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.
    Alimentary Pharmacology & Therapeutics 11/2012; 37(2). DOI:10.1111/apt.12147 · 4.55 Impact Factor
  • Journal of clinical gastroenterology 07/2012; 46(6):468-81. DOI:10.1097/MCG.0b013e3182549092 · 3.19 Impact Factor
  • Journal of Crohn s and Colitis 02/2012; 6:S137. DOI:10.1016/S1873-9946(12)60339-0 · 3.56 Impact Factor
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    T W Lee, R Singh, R N Fedorak
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    ABSTRACT: Infliximab is a chimeric monoclonal antibody to tumour necrosis factor alpha (TNFα) with efficacy in inducing and maintaining remission of inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis and psoriasis. Infliximab is generally administered over 2h with a further 1-h postinfusion observation. This time interval has substantial impact on healthcare resources and is costly in terms of patient's time away from work. To examine the safety and tolerability of a 1-h, relative to a 2-h maintenance of infusion of infliximab, and to determine the effect of corticosteroid premedication and concurrent immunosuppressor use on infusion reaction rates. A prospective cohort study with variable follow-up duration of 2165 consecutive infliximab infusions in 415 patients during 2009 was conducted. Diagnosis, infusion episode number, infusion rate, premedication, concurrent immunosuppressor therapy, the nature and the outcome of infusion reactions were examined. The majority of infusions (74%) were for management of inflammatory bowel disease. Infusion reactions clustered within the first eight infusions with subsequent sporadic reactions. The infusion reaction incidence rate per 1000 person days in 274 1-h infusions from 54 patients and 1356 2-h infusions from 256 patients were 0.08 and 0.28 respectively (P=0.07). Poisson regression model confirmed that the concurrent use of immunosuppressor therapy was associated with a lower infusion reaction rate, whereas corticosteroid premedication was not. During maintenance therapy, infliximab infusion can be safely administered over 1h in patients with no past history of significant infliximab infusion reaction. Corticosteroid premedication had no impact on the infusion reaction rates.
    Alimentary Pharmacology & Therapeutics 07/2011; 34(2):181-7. DOI:10.1111/j.1365-2036.2011.04699.x · 4.55 Impact Factor
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    ABSTRACT: Three-dimensional digitization of highly reflective and transparent objects using multi-wavelength range sensing." Machine Vision and Applications, 12 Pages, December 2010.Mind the gaps: Confocal endomicroscopy revealed increased density of small bowel epithelial gaps in inflammatory bowel disease.
    Computers & Graphics 03/2011; 55(35):978-1. · 1.03 Impact Factor
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    ABSTRACT: Tumour necrosis factor-blockade with infliximab has advanced the treatment of Crohn's disease. While infliximab is efficacious, it remains to be determined whether patients who enter clinical remission with an anti-tumour necrosis factor therapy can have their treatment stopped and retain the state of remission. To assess in patients with Crohn's disease who obtained infliximab-induced remission, the proportion who relapsed after infliximab discontinuation. This longitudinal cohort study examined patients from a University-based IBD referral centre. Forty eight patients with Crohn's disease in full clinical remission and who then discontinued infliximab were followed up for up to 7 years. Crohn's disease relapse was defined as an intervention with Crohn's disease medication or surgery. Kaplan-Meier analysis of the proportion of patients with sustained clinical benefit demonstrated that 50% relapsed within 477 days after infliximab discontinuance. In contrast, 35% of patients remained well, and without clinical relapse, up to the end of the nearly 7-year follow-up. In patients with Crohn's disease with an infliximab-induced remission, stopping infliximab results in a predictable relapse in a majority of patients. Nevertheless, a small percentage of patients sustain a long-term remission.
    Alimentary Pharmacology & Therapeutics 11/2010; 32(9):1129-34. DOI:10.1111/j.1365-2036.2010.04446.x · 4.55 Impact Factor
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    N Gies, K I Kroeker, K Wong, R N Fedorak
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    ABSTRACT: Aliment Pharmacol Ther 2010; 32: 522-528 Summary Background Randomized, controlled trials have demonstrated that anti-TNF agents are efficacious in inducing remission in cases of Crohn's disease and ulcerative colitis. However, response rates for anti-TNF agents in 'real life' clinical practice are less well-defined. Aims To examine the response rates and long-term outcomes of infliximab and adalimumab treatment for out-patients with ulcerative colitis and to study the variables associated with response rates. Methods In a prospective study, a single-centre out-patient cohort was treated and followed up according to a structured protocol of clinical care. Response to treatment was assessed using a physician's global assessment that focused on normalization of bowel frequency, absence of blood with defecation and tapering of corticosteroids to zero. Results Fifty-three ulcerative colitis patients were included in the study. Responses to induction therapy were 96.4% (27/28) for infliximab and 80% (20/25) for adalimumab (P = 0.0889). Responses to maintenance therapy were similar: infliximab 77.8% (14/18) and adalimumab 70.0% (14/20) (P = 0.7190). Multivariate analyses of the induction and maintenance responses did not reveal confounding elements. No new safety signals were identified. Conclusions This long-term follow-up of a single-centre cohort of ulcerative colitis patients demonstrates that 'real-life' out-patient treatment with infliximab and adalimumab is effective in induction and maintenance of response.
    Alimentary Pharmacology & Therapeutics 08/2010; 32(4):522-8. DOI:10.1111/j.1365-2036.2010.04380.x · 4.55 Impact Factor

Publication Stats

4k Citations
935.65 Total Impact Points

Institutions

  • 1989–2014
    • University of Alberta
      • • Division of Gastroenterology
      • • Department of Agricultural, Food, and Nutritional Science
      • • Division of General Internal Medicine
      • • Department of Medical Microbiology and Immunology
      • • Department of Medicine
      Edmonton, Alberta, Canada
  • 2012
    • University Hospital Vall d'Hebron
      Barcino, Catalonia, Spain
  • 2007
    • Mayo Clinic - Rochester
      • Department of Gastroenterology and Hepatology
      Rochester, Minnesota, United States
  • 1999
    • Canadian Association of Gastroenterology
      Edmonton, Alberta, Canada
  • 1997
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States