Crohn Disease: Fedorak RN

Sadowski DC, Bernstein CN, Bitton A, Croitoru K, Fedorak RN, Griffiths A, Anonymous00036. · Royal Alexandra Hospital, Edmonton, Canada. · Can J Gastroenterol. · Pubmed #19319383 No free full text.

Abstract: BACKGROUND: Guidelines regarding the use of infliximab in Crohn's disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines. OBJECTIVE: To review and update Canadian guidelines regarding the use of tumour necrosis factor-alpha antibody therapy in both luminal and fistulizing Crohn's disease. METHODS: A consensus group of 25 voting participants developed a series of recommendation statements that addressed pertinent clinical questions and gaps in existing knowledge. An iterative voting and feedback process was used in advance of the consensus meeting in conjunction with a systematic literature review to refine the voting statements. These statements were brought to a formal consensus meeting held in Montreal, Quebec (March 2008), wherein each statement underwent discussion, reformulation, voting and subsequent revision until group consensus was obtained (at least 80% agreement). OUTCOME: The 47 voting statements addressed three themes: induction therapy, maintenance therapy and safety issues. As a result of the iterative process, 23 statements achieved consensus and were submitted for publication. CONCLUSION: In the past five years, tumour necrosis factor-alpha antagonist therapy has become a cornerstone in the management of moderate-to-severe Crohn's disease refractory to conventional treatment algorithms. The evidentiary base supporting the use of these drugs in Crohn's disease is substantial and strengthened by results from longterm clinical and molecular studies. However, significant gaps in knowledge exist, particularly with regard to treatment failure. Confidence in the safety of these drugs is increasing, provided that therapy is administered in a clinical setting in which potential complications can be readily recognized and treated.

Panaccione R, Fedorak RN, Aumais G, Bernstein CN, Bitton A, Croitoru K, Enns R, Feagan B, Fishman M, Greenberg G, Griffiths A, Marshall JK, Rasul I, Sadowski D, Seidman E, Steinhart H, Sutherland L, Walli E, Wild G, Williams CN, Zachos M, Anonymous00234. · University of Calgary, Calgary, Canada. · Can J Gastroenterol. · Pubmed #15372114 links to  free full text

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Fedorak RN, Anonymous00256. · University of Alberta, Edmonton, Canada. · Can J Gastroenterol. · Pubmed #11429665 links to  free full text

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Narula N, Fedorak RN. · Division of Gastroenterology, Zeidler Ledcor Centre, University of Alberta, Edmonton, Canada. · Can J Gastroenterol. · Pubmed #19214288 No free full text.

Abstract: Crohn's disease (CD) is an idiopathic inflammatory bowel disease and has no known cure. CD symptoms are treated using an array of medicines, including biological agents such as infliximab. However, infliximab therapy is expensive; therefore, identifying variables that can help predict response to infliximab is worthwhile. The present article reviews the impact of tobacco smoking on the efficacy of infliximab in CD. Earlier studies have speculated that smoking has a negative effect on the response to infliximab in CD, but the current literature is largely unable to identify a significant relationship between the two. Although smoking is known to have a negative effect on the course of CD, as well as other organ systems, presently, a CD patient's smoking status should not influence treatment decisions regarding infliximab therapy.

Fedorak RN, Dieleman LA. · Division of Gastroenterology, University of Alberta, Edmonton, Alberta. · J Clin Gastroenterol. · Pubmed #18542034 No free full text.

Abstract: Probiotic research and clinical trials have been forging ahead over the last decade. Although much has been learnt in relation to probiotic intestinal epithelial-mucosal immune interactions, the evidence for substantial clinical efficacy of probiotics continues to progress much slower. This review outlines the probiotic clinical studies before 2005 that formed the foundation of probiotic clinical trials in inflammatory bowel disease and then examines indepth those inflammatory bowel disease probiotic clinical trials published after 2005 that are leading to new understanding of the role of probiotics in the induction and remission of inflammatory bowel disease in humans.

Narula N, Fedorak RN. · Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada. · Can J Gastroenterol. · Pubmed #18478136 links to  free full text

Abstract: Crohn's disease and ulcerative colitis are both idiopathic inflammatory bowel diseases (IBDs) that affect 0.5% of Canadians. As yet, there is no known cure for either disease, and symptoms are treated with an array of medicines. The objective of the present review was to present the role of exercise and its impact on all facets of IBD. Exercise has been speculated to be protective against the onset of IBD, but the literature is inconsistent and weak. Preliminary studies reveal that exercise training may be beneficial to reduce stress and symptoms of IBD. Current research also recommends exercise to help counteract some IBD-specific complications by improving bone mineral density, immunological response, psychological health, weight loss and stress management ability. However, the literature advises that some patients with IBD may have limitations to the amount and intensity of exercise that they can perform. In summary, exercise may be beneficial to IBD patients, but further research is required to make a convincing conclusion regarding its role in the management of IBD and to help establish exercise regimens that can account for each IBD patient's unique presentation.

Floch MH, Madsen KK, Jenkins DJ, Guandalini S, Katz JA, Onderdonk A, Walker WA, Fedorak RN, Camilleri M. · Yale University School of Medicine, New Haven, CT 06520-8019, USA. · J Clin Gastroenterol. · Pubmed #16633136 No free full text.

Abstract: Probiotics are live microbial organisms that are administrated as supplements or in foods to benefit the host. It is the recommendation that they may be helpful in the prevention and treatment of acute diarrhea in adults and children, the prevention of antibiotic-associated diarrhea in adults and children, and the maintenance of remission and prevention of pouchitis. Although early results indicate that probiotics may also be useful in immunologic modulation to prevent atopy, treatment of radiation intestinal disease, vaginosis, ulcerative colitis, and the irritable bowel syndrome, the studies available are not sufficient to say they are definitely helpful. Even fewer data are available to recommend probiotics for the treatment of H pylori and Crohn disease and for the prevention of cardiovascular risk factors or other degenerative diseases. Clearly, larger and better-designed studies of probiotics are necessary, including comparative and dose-ranging trials.

Rioux KP, Fedorak RN. · Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Al, Canada. · J Clin Gastroenterol. · Pubmed #16633133 No free full text.

Abstract: The demonstration that immune and epithelial cells can discriminate between different microbial species has extended our understanding of the actions of probiotics beyond simple antimicrobial concepts. Several probiotic mechanisms of action, relative to inflammatory bowel disease, have been elucidated: (1) competitive exclusion, whereby probiotics compete with microbial pathogens; (2) immunomodulation and/or stimulation of an immune response; (3) antimicrobial activity and suppression of pathogen growth; (4) enhancement of barrier activity; and (5) induction of T cell apoptosis. The unraveling of these mechanisms of action has led to new support for the use of probiotics in the management of clinical inflammatory bowel disease. While level 1 evidence now supports the therapeutic use of some probiotics in the maintenance treatment of pouchitis, only level 2 and 3 evidence are currently available in support of the use of probiotics in the treatment of ulcerative colitis and Crohn's disease. Nevertheless, one significant and consistent finding has emerged over the course of research in the past year: not all probiotic bacteria have similar therapeutic effects. Rigorously designed, controlled clinical trials, to investigate the unresolved issues related to efficacy, dose, duration of use, single or multistrain formulation, and the concomitant use of prebiotics, synbiotics or antibiotics, are vital.

Penner RM, Madsen KL, Fedorak RN. · Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada. · Inflamm Bowel Dis. · Pubmed #16043993 No free full text.

Abstract: More than three quarters of patients with Crohn's disease (CD) will require surgery. After resection, disease recurs postoperatively with a median time to second resection of about 10 years. Despite its importance, the postoperative period remains one of the most poorly understood clinical settings in the field. Postoperatively, CD may exhibit unique pathophysiologic features, but the current state of knowledge does not allow for identification of patients at risk for relapse, and leaves clinicians without guidance on optimal maintenance treatment. Therapies used as maintenance for CD in other settings may have different efficacies when used after surgery, and clinical research in patients requiring surgery is limited by the subset of patients available for study. Despite the many limitations in current knowledge of postoperative CD, it is an exciting field because new developments have improved patient care, and ongoing research has the potential for further gains.

Fedorak RN. · Division of Gastroenterology University of Alberta, T6G 2C8 Edmonton AB, Alberta, Canada. · Best Pract Res Clin Gastroenterol. · Pubmed #15588801 No free full text.

Abstract: From the original anatomic classification of Crohn's disease in 1975, there have been three subsequent published classifications. The most recent, the Vienna Classification arose from a 1998 World Congress of Gastroenterology Working Party that attempted to prospectively design a simple and objective Crohn's disease phenotypic classification that encompassed components of age at onset, anatomic location and disease behavior. Subsequent application of the Vienna Classification to clinical practice has demonstrated that the Crohn's disease phenotype changes markedly over time, with nearly 80% of inflammatory disease ultimately evolving into a stricturing or penetrating pattern of behavior, and 15% undergoing a change in anatomic location. Furthermore, in controlled studies, the ability of inflammatory bowel disease experts to similarly identify the disease phenotypes, using the Vienna classification, ranges from poor to fair. Taken together, these failings markedly limit the utilization of the Vienna classification of Crohn's disease in clinical trails or disease management. Recent advances in determining the genetic linkages associated with Crohn's disease will undoubtedly lead to a revised Crohn's disease classification that will combine genotype with phenotype. Nevertheless, before this new classification can become a reality we will need to reconcile a number of key elements, including; (1) localization and grouping of all inflammatory bowel disease(IBD) gene mutations, (2) discovering the function of the IBD genes, (3) understanding the impact of the environment on phenotypic expression, and, (4) linking to well-defined phenotypic databases that will permit accurate prediction of disease natural history and therapeutic response. Indeed, the consistency of the phenotypic data available may be the greatest single challenge in unraveling the complexities of inflammatory bowel disease and developing a new classification of Crohn's disease.

Fedorak RN, Madsen KL. · Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada. · Inflamm Bowel Dis. · Pubmed #15290926 No free full text.

Abstract: The demonstration that immune and epithelial cells can discriminate between different microbial species has extended our understanding of the actions of probiotics beyond simple barrier and antimicrobial concepts. Several probiotic mechanisms of action, relative to inflammatory bowel disease, have been elucidated: (1) competitive exclusion, whereby probiotics compete with microbial pathogens for a limited number of receptors present on the surface epithelium; (2) immunomodulation and/or stimulation of an immune response of gut-associated lymphoid and epithelial cells; (3) antimicrobial activity and suppression of pathogen growth; (4) enhancement of barrier function; and (5) induction of T cell apoptosis in the mucosal immune compartment. The unraveling of these mechanisms of action has led to new support for the use of probiotics in the management of clinical inflammatory bowel disease. Though level 1 evidence now supports the therapeutic use of probiotics in the treatment of postoperative pouchitis, only levels 2 and 3 evidence is currently available in support of the use of probiotics in the treatment of ulcerative colitis and Crohn's disease. Nevertheless, one significant and consistent finding has emerged during the course of research in the past year: not all probiotic bacteria have similar therapeutic effects. Rigorously designed, controlled clinical trials are vital to investigate the unresolved issues related to efficacy, dose, duration of use, single or multi-strain formulation, and the concomitant use of probiotics, synbiotics, or antibiotics.

Feagan BG, Enns R, Fedorak RN, Panaccione R, Paré P, Steinhart AH, Wild G. · London Clinical Trials Research Group, London, Canada. · Can J Clin Pharmacol. · Pubmed #11743591 No free full text.

Abstract: Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract. From the perspective of the patient, symptoms of the disease significantly impair quality of life and interfere with activities of daily living. Conventional medical treatment of Crohn's disease includes the use of nonspecific anti-inflammatory drugs, immunosuppressives and antibiotics. These therapies are characterized by a delayed onset of action, incomplete response rates and a substantial risk of adverse effects. Although surgery is frequently used to treat complications, postoperative recurrence is an important problem. Infliximab, a chimeric monoclonal antibody directed toward tumour necrosis factor alpha, is highly effective for the treatment of active Crohn's disease. In randomized, placebo-controlled clinical trials, 82% of patients who received 5 mg/kg of infliximab had a clinically significant response, compared with 17% of those given placebo (P<0.001). Moreover, infliximab is the only medical therapy that has been shown to be effective for the treatment of fistulizing Crohn's disease. Infusion reactions are the most common adverse effect. Whether treatment with infliximab is associated with an increased risk of neoplasia, infection or autoimmune disease is unknown. Therefore, further long term safety studies are required. Despite the relatively high cost of drug acquisition, preliminary pharmacoeconomic analysis indicates that infliximab is cost effective compared with existing treatments. Infliximab is recommended for the treatment of active Crohn's disease refractory to conventional drugs, and is the treatment of choice for fistulizing Crohn's disease.

Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, Bernstein CN, Staun M, Thomsen OØ, Innes A, Anonymous00002. · Hospital for General Internal Medicine, Christian-Albrechts University, Klinik für Allgemeine Innere Medizin, Kiel, Germany. · Gastroenterology. · Pubmed #16143120 No free full text.

Abstract: BACKGROUND & AIMS: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab' fragment of anti-tumor necrosis factor, CDP870) in Crohn's disease. METHODS: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn's disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn's Disease Activity Index decrease of > or = 100 points or remission [Crohn's Disease Activity Index < or = 150 points]) in the intent-to-treat population. RESULTS: All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [P = .033]; 200 mg, 30.6% [P = .026]; 400 mg, 33.3% [P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. CONCLUSIONS: Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn's disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab.

Siffledeen JS, Fedorak RN, Siminoski K, Jen H, Vaudan E, Abraham N, Steinhart H, Greenberg G. · Division of Gastroenterology, University of Alberta, Edmonton, Canada. · Clin Gastroenterol Hepatol. · Pubmed #15704046 No free full text.

Abstract: BACKGROUND & AIMS: Crohn's disease causes an increase in osteopenia and osteoporosis. This study assessed the efficacy of adding etidronate to calcium and vitamin D supplementation for treatment of low bone mineral density in Crohn's disease. METHODS: One hundred fifty-four patients with Crohn's disease with decreased bone mineral density, determined by using dual-energy x-ray absorptiometry, were randomly assigned to receive etidronate (400 mg orally) or not for 14 days; both groups were then given daily calcium (500 mg) and vitamin D (400 IU) supplementation for 76 days. This cycle was repeated 8 times during a period of 24 months. Biochemical characteristics and bone mineral densities were assessed at 6, 12, and 24 months. RESULTS: After 24 months bone mineral density significantly increased from baseline in both the etidronate- and the non-etidronate-treated groups (both groups receiving calcium and vitamin D supplementation) at the lumbar spine (P < .001), ultradistal radius (P < .001), and trochanter (P = .004) sites, but not at the total hip. The increase in bone mineral density was similar in each treatment group. No bone mineral density differences were found when groups were analyzed according to gender, corticosteroid use, bone mineral density at baseline, or age. CONCLUSIONS: Low bone mineral density is frequently associated with Crohn's disease. Supplementation with daily calcium and vitamin D is associated with increases in bone mineral density. The addition of oral etidronate does not further enhance bone mineral density.

Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ. · Gastrointestinal Unit, Massachusetts General Hospital, and Harvard Medical School, Boston 02114, USA. · N Engl J Med. · Pubmed #14985485 links to  free full text

Abstract: BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas. METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization. RESULTS: The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009). CONCLUSIONS: Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.

Fedorak RN, Gangl A, Elson CO, Rutgeerts P, Schreiber S, Wild G, Hanauer SB, Kilian A, Cohard M, LeBeaut A, Feagan B. · Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. · Gastroenterology. · Pubmed #11113068 No free full text.

Abstract: BACKGROUND & AIMS: Interleukin 10 (IL-10) is an anti-inflammatory, immunomodulatory cytokine that regulates mucosal inflammation. This study evaluated the safety, tolerance, and efficacy of recombinant human IL-10 (rhuIL-10) for mild to moderately active Crohn's disease. METHODS: We conducted a 24-week multicenter, prospective, randomized, double-blind, placebo-controlled, and sequential-escalating-dose study. Ninety-five patients with Crohn's Disease Activity Index of 200-350, not presently undergoing corticosteroid, mesalamine, or immunosuppressive therapy, were treated with subcutaneous rhuIL-10 (1, 5, 10, or 20 microg/kg) or placebo once daily for 28 consecutive days. Patients were followed up for 20 weeks after treatment. Evaluation of safety and tolerance was the first objective, and efficacy was the second objective. RESULTS: Adverse effects were dose-related, mild-to-moderate in severity, and reversible. Asymptomatic and reversible anemia and thrombocytopenia were observed at higher doses. No withdrawal or delayed adverse effects were evident during 20 weeks of follow-up. At the end of treatment (day 29), intent-to-treat analysis showed that 23.5% (confidence interval [CI], 6.8%-49.9%) of patients receiving 5 micro/kg rhuIL-10 experienced clinical remission and endoscopic improvement; 0% (CI, 0%-14.8%) of patients in the placebo group did. Higher doses of recombinant human IL-10 were less effective than 5 microg/kg. No rhuIL-10 serum accumulation and no antibody against IL-10 were detected after 4 weeks. CONCLUSIONS: Subcutaneous rhuIL-10 administered daily for 28 days to patients with mild to moderately active Crohn's disease is safe, well-tolerated, and shows clinical and endoscopic improvement.

Schreiber S, Fedorak RN, Nielsen OH, Wild G, Williams CN, Nikolaus S, Jacyna M, Lashner BA, Gangl A, Rutgeerts P, Isaacs K, van Deventer SJ, Koningsberger JC, Cohard M, LeBeaut A, Hanauer SB. · Charité University Hospital, Fourth Medical Department, Humboldt University, Berlin, Germany. · Gastroenterology. · Pubmed #11113067 No free full text.

Abstract: BACKGROUND & AIMS: Interleukin (IL)-10 is a cytokine with potent anti-inflammatory properties. We investigated the safety and efficacy of different doses of human recombinant (rhu)IL-10 in patients with Crohn's disease (CD). METHODS: A prospective, multicenter, double-blind, placebo-controlled study was conducted in 329 therapy-refractory patients with CD. Clinical improvement was defined by a reduction of the Crohn's Disease Activity Index (CDAI) by 100 points or more and clinical remission by a decrease of the CDAI to <150 points. At selected centers, patients underwent ileocolonoscopies and activation of the nuclear factor-kappa B (NF-kappa B) system was assessed in biopsy specimens. RESULTS: Subcutaneous treatment with rhuIL-10 over 28 days induced a fully reversible, dose-dependent decrease in hemoglobin and thrombocyte counts but no clinically significant side effects. No differences in the induction of remission were observed between rhuIL-10 groups (1 microg, 18% [9.6-29.2]; 4 microg, 20% [11.3-32.2]; 8 microg, 20% [11.1-31.8]; 20 microg, 28% [18-40.7]; and placebo, 18% [9.6-29.6]). Clinical improvement was observed in 46% (33.7-59) in the 8-microg/kg rhuIL-10 group in comparison with 27% (17-39.6) in patients taking placebo. Responders to rhuIL-10 showed inhibition of NF-kappaB p65 activation in contrast to nonresponders. CONCLUSIONS: Up to 8 microg/kg of rhuIL-10 was well tolerated. A tendency toward clinical improvement but not remission was observed in the 8-microg/kg dose group. Further studies should delineate which subgroups of patients with CD benefit from rhuIL-10 therapy.

Feagan BG, Fedorak RN, Irvine EJ, Wild G, Sutherland L, Steinhart AH, Greenberg GR, Koval J, Wong CJ, Hopkins M, Hanauer SB, McDonald JW. · London Clinical Trials Research Group, the John P. Robarts Research Institute, London, Ont, Canada. · N Engl J Med. · Pubmed #10833208 links to  free full text

Abstract: BACKGROUND: Patients with Crohn's disease often have relapses. Better treatments are needed for the maintenance of remission. Although methotrexate is an effective short-term treatment for Crohn's disease, its role in maintaining remissions is not known. METHODS: We conducted a double-blind, placebo-controlled, multicenter study of patients with chronically active Crohn's disease who had entered remission after 16 to 24 weeks of treatment with 25 mg of methotrexate given intramuscularly once weekly. Patients were randomly assigned to receive either methotrexate at a dose of 15 mg intramuscularly once weekly or placebo for 40 weeks. No other treatments for Crohn's disease were permitted. We compared the efficacy of treatment by analyzing the proportion of patients who remained in remission at week 40. Remission was defined as a score of 150 or less on the Crohn's Disease Activity Index. RESULTS: Forty patients received methotrexate, and 36 received placebo. At week 40, 26 patients (65 percent) were in remission in the methotrexate group, as compared with 14 (39 percent) in the placebo group (P=0.04; absolute reduction in the risk of relapse, 26.1 percent; 95 percent confidence interval, 4.4 percent to 47.8 percent). Fewer patients in the methotrexate group than in the placebo group required prednisone for relapse (11 of 40 [28 percent] vs. 21 of 36 [58 percent], P=0.01). None of the patients who received methotrexate had a severe adverse event; one patient in this group withdrew because of nausea. CONCLUSIONS: In patients with Crohn's disease who enter remission after treatment with methotrexate, a low dose of methotrexate maintains remission.

Sandborn WJ, Tremaine WJ, Wolf DC, Targan SR, Sninsky CA, Sutherland LR, Hanauer SB, McDonald JW, Feagan BG, Fedorak RN, Isaacs KL, Pike MG, Mays DC, Lipsky JJ, Gordon S, Kleoudis CS, Murdock RH. · Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA. · Gastroenterology. · Pubmed #10464128 No free full text.

Abstract: BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS: At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. CONCLUSIONS: A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Teshima CW, Thompson A, Dhanoa L, Dieleman LA, Fedorak RN. · University of Alberta, Edmonton, Alberta, Canada. · Can J Gastroenterol. · Pubmed #19440565 No free full text.

Abstract: BACKGROUND: Infliximab's efficacy in the induction and maintenance of remission in luminal Crohn's disease has been confirmed by randomized, controlled trials. Less clearly described are long-term outcomes in the clinical practice setting since the establishment of regularly scheduled, every eight-week maintenance infliximab infusions. Existing reports describing clinical practice outcomes are limited by short durations of follow-up or by the use of episodic dosing, or focus on safety data rather than clinical outcomes. OBJECTIVE: To examine induction and maintenance responses to infliximab in an outpatient inflammatory bowel disease clinic. METHODS: A retrospective chart review was performed. Clinical outcomes were infliximab induction and maintenance responses, defined as the ability to stop and remain off corticosteroids while not requiring additional therapy for active disease. RESULTS: One hundred thirty-three patients were identified with records sufficiently detailed to be analyzed. Of these, 117 patients (88%) demonstrated a clinical response to induction; 104 of 117 (89%) were on concomitant immunosuppressive therapy; 80 of 104 on azathioprine/6-mercaptopurine (77%); and 24 of 104 on methotrexate (23%). The mean duration of clinical response was 94 weeks (95% CI 78.8 to 109.2). The proportion of patients who maintained response at 30 weeks was 83.2%, at 54 weeks was 63.6% and at 108 weeks was 44.9%. Adverse events occurred for 15 of 117 patients (12.8%), consisting of nine infusion reactions, four serum sickness-like reactions, one rash and one infection. CONCLUSION: Patients treated with infliximab therapy for luminal Crohn's disease in our outpatient clinic achieved excellent induction and maintenance of response rates, confirming the real-life efficacy of maintenance infliximab established in clinical trials.

Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JW, Cohen A, Bitton A, Baker J, Dubé R, Landau SB, Vandervoort MK, Parikh A. · Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada. · Clin Gastroenterol Hepatol. · Pubmed #18829392 No free full text.

Abstract: BACKGROUND & AIMS: Selective blockade of lymphocyte-vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the alpha4beta7 integrin, in patients with active Crohn's disease. METHODS: Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (>or=70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score <or=150) and with an enhanced clinical response (>or=100-point decrement in CDAI). Human anti-human antibody levels were measured. RESULTS: Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease. CONCLUSIONS: This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.

Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, Johanns J, Blank M, Rutgeerts P, Anonymous00454. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA. · Gastroenterology. · Pubmed #18706417 No free full text.

Abstract: BACKGROUND & AIMS: Interleukin-12 and interleukin-23 are inflammatory cytokines implicated in Crohn's disease pathophysiology. Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin-12/23. METHODS: We performed a double-blind, cross-over trial of the clinical effects of ustekinumab in 104 patients with moderate-to-severe Crohn's disease (population 1). Patients were given subcutaneous placebo at weeks 0-3, then ustekinumab at weeks 8-11; subcutaneous ustekinumab at weeks 0-3, then placebo at weeks 8-11; intravenous placebo at week 0, then ustekinumab at week 8; or intravenous ustekinumab at week 0, then placebo at week 8. Furthermore, an open-label trial evaluated the effects of 4 weekly subcutaneous injections or 1 intravenous infusion of ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab (population 2). RESULTS: In population 1, clinical response rates for the combined groups given ustekinumab and placebo were 53% and 30% (P = .02), respectively at weeks 4 and 6, and 49% and 40% (P = .34), respectively at week 8. In a subgroup of 49 patients who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than the group given placebo (P < .05) through week 8. In population 2, the clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43% and 54%, respectively. There was no increase in the number of adverse or serious adverse events in patients given ustekinumab through week 8 compared with placebo. CONCLUSIONS: Ustekinumab induced a clinical response in patients with moderate-to-severe Crohn's disease, especially in patients previously given infliximab.

Rutgeerts P, Schreiber S, Feagan B, Keininger DL, O'Neil L, Fedorak RN, Anonymous00100. · Division of gastroenterology, University Hospital Leuven, Leuven, Belgium. · Int J Colorectal Dis. · Pubmed #18071721 links to  free full text

Abstract: BACKGROUND AND AIMS: Certolizumab pegol, a polyethylene glycolated Fc-free Fab' was efficacious and well tolerated in patients with moderate-to-severe Crohn's disease in a previously reported randomized, placebo-controlled study. In this paper, we report the effect of certolizumab pegol on health-related quality of life (HRQoL). MATERIALS AND METHODS: Patients with moderate-to-severe active Crohn's disease (n = 292) received subcutaneous certolizumab pegol 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. A post hoc analysis of the intent-to-treat population (290 patients with HRQoL data) assessed HRQoL by evaluating patients' responses to the self-administered inflammatory bowel disease questionnaire (IBDQ) at baseline and weeks 2, 4, 6, 8, 10, and 12. RESULTS: Patients receiving certolizumab pegol 400 mg at weeks 0, 4, and 8 demonstrated, via their IBDQ total score, significantly (P <or= 0.05) greater improvement in HRQoL from baseline to week 12 and at all other time points compared with placebo. Moreover, HRQoL improved over time in all certolizumab pegol groups, irrespective of baseline C-reactive protein levels. Emotional well-being (IBDQ Emotional Function domain) improved throughout the study for patients receiving certolizumab pegol 400 mg. This improvement was significantly (P <or= 0.05) greater than for patients receiving placebo at all time points. In addition, systemic symptoms (IBDQ Systemic Symptoms domain) improved significantly more in patients receiving certolizumab pegol 400 mg than in those receiving placebo at weeks 4, 8, 10, and 12 (P <or= 0.05) and approached statistical significance at week 2 (P = 0.054). CONCLUSION: This analysis suggests that certolizumab pegol 400 mg improves HRQoL in patients with moderate-to-severe Crohn's disease.

Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, Spehlmann ME, Rutgeerts PJ, Tulassay Z, Volfova M, Wolf DC, Hernandez C, Bornstein J, Sandborn WJ, Anonymous00007. · Inflammatory Bowel Disease Center and Division of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California 90048, USA. · Gastroenterology. · Pubmed #17484865 No free full text.

Abstract: BACKGROUND & AIMS: A randomized placebo-controlled trial evaluated the efficacy of natalizumab induction therapy in patients with Crohn's disease. METHODS: Patients (N = 509) with moderately to severely active Crohn's disease and active inflammation characterized by elevated C-reactive protein concentrations were randomized (1:1) to receive natalizumab 300 mg or placebo intravenously at Weeks 0, 4, and 8. The primary end point was induction of response (> or =70-point decrease from baseline in the Crohn's Disease Activity Index score at Week 8 sustained through Week 12). Additional efficacy end points included the proportion of patients with sustained remission (Crohn's Disease Activity Index score <150 points) and response or remission over time. RESULTS: Response at Week 8 sustained through Week 12 occurred in 48% of natalizumab-treated patients and 32% of patients receiving placebo (P < .001). Sustained remission occurred in 26% of natalizumab-treated patients and 16% of patients receiving placebo (P = .002). Week 4 response rates were 51% for natalizumab and 37% for placebo (P = .001). Responses remained significantly higher at subsequent assessments (P < .001) in natalizumab-treated patients. Natalizumab-treated patients also had significantly higher remission rates at Weeks 4, 8, and 12 (P < or = .009). The frequency and types of adverse events were similar between treatment groups. CONCLUSIONS: Natalizumab induced response and remission at Week 8 that was sustained through Week 12. Response and remission rates for natalizumab were superior to those for placebo at Weeks 4, 8, and 12, demonstrating the early and sustained efficacy of natalizumab as induction therapy in patients with elevated C-reactive protein and active Crohn's disease. Natalizumab was well tolerated in this study.

Siffledeen JS, Siminoski K, Jen H, Fedorak RN. · Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada. · Clin Gastroenterol Hepatol. · Pubmed #17482522 No free full text.

Abstract: BACKGROUND & AIMS: Vertebral fractures in Crohn's (CD) patients with low bone mineral density (BMD) have been documented as between 14%-22%. Vertebral fractures in CD patients with normal BMD have not been reported. The objectives were to identify the prevalence of vertebral fractures in CD patients and associated predictive factors. METHODS: Two hundred twenty-four CD patients underwent vertebral BMD analysis and radiographs. Fractures were identified by using quantitative height reduction morphometry, and severity was assessed by spinal fracture index. RESULTS: Mean age was 40.6 +/- 11.0 years. Sixty percent reported corticosteroid use during the preceding year. Forty-five of 224 (20.0%) patients had 88 vertebral fractures. Sixteen of 45 patients with vertebral fractures had normal BMD (19.0% of all patients with normal BMD). Analysis of patients with or without vertebral fractures did not demonstrate significant differences in BMD or in corticosteroid use. Linear regression analysis demonstrated that elevations in body mass index, C-reactive protein, and parathyroid hormone were significantly predictive of vertebral fractures (r = 0.415, P < .05), and height reduction was >20% (r = 0.417, P < .05). CONCLUSIONS: This study demonstrates that vertebral fractures in CD patients occur with an equal frequency in those with low and with normal BMD, regardless of corticosteroid use. The mean age of CD patients with vertebral fractures was much lower than that reported in the general population for these fractures. Elevations in body mass index and C-reactive protein and parathyroid hormone levels were predictive of vertebral fractures.