Ulcerative Colitis: Feagan BG

Panaccione R, Fedorak RN, Aumais G, Bernard EJ, Bernstein CN, Bitton A, Croitoru K, Dieleman LA, Enns R, Feagan BG, Franchimont D, Greenberg GR, Griffiths AM, Marshall JK, Pare P, Patel S, Penner R, Render C, Seidman E, Steinhart AH. · University of Calgary, Calgary, Canada. · Can J Gastroenterol. · Pubmed #18354755 links to  free full text

Abstract: Infliximab is a chimeric, monoclonal anti-tumour necrosis factor-alpha antibody. It has been previously demonstrated to be an effective treatment for patients with Crohn's disease who do not achieve the desired response with conventional treatments. Although the etiology of ulcerative colitis (UC) differs from that of Crohn's disease, randomized controlled trials have demonstrated that infliximab is also beneficial for the treatment of moderate to severe UC in patients who are either intolerant of or refractory to immunosuppressant agents or steroids, or those who are steroid-dependent. A review of the literature is followed by practical recommendations regarding infliximab that address the needs of clinicians and UC patients. Where there is a lack of evidence-based information, the expert panel provides its combined opinion derived from the members' clinical experiences.

D'Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ, Lémann M, Marteau P, Rutgeerts P, Schölmerich J, Sutherland LR. · University Hospital Gasthuisberg, Leuven, Belgium. · Gastroenterology. · Pubmed #17258735 No free full text.

This publication has no abstract.

Feagan BG. · Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada. · Am J Gastroenterol. · Pubmed #14697913 No free full text.

Abstract: Crohn's disease and ulcerative colitis frequently recur after effective induction therapy. Accordingly, improved maintenance therapy remains the greatest unmet medical need in treating these disorders. Although 5-aminosalicylate compounds are widely used to maintain remission in Crohn's disease, the scientific evidence supporting this practice is poor. Antimetabolites (azathioprine, 6-mercaptopurine, and methotrexate) and infliximab are moderately effective in high-risk patients; however, these drugs might cause significant adverse effects. For patients with ulcerative colitis, maintenance therapy with 5-aminosalicylate compounds is a mainstay of treatment, being both effective and safe. However, this approach is not effective in a minority of patients. Although the purine metabolites can be used to treat these patients, strong scientific evidence that supports this practice is lacking. An initial experience with probiotic bacteria for maintenance of remission in ulcerative colitis seems promising. This article reviews the data from randomized, controlled trials of maintenance therapy in inflammatory bowel disease.

Feagan BG. · London Health Science Centre, University of Western Ontario, London, Ontario, Canada. · Acta Gastroenterol Belg. · Pubmed #11475131 No free full text.

This publication has no abstract.

Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JW, Dubé R, Cohen A, Steinhart AH, Landau S, Aguzzi RA, Fox IH, Vandervoort MK. · Robarts Research Institute, London, ON N6A 5K8, Canada. · N Engl J Med. · Pubmed #15958805 links to  free full text

Abstract: BACKGROUND: Selective blockade of interactions between leukocytes and vascular endothelium in the gut is a promising strategy for the treatment of inflammatory bowel diseases. METHODS: We conducted a multicenter, double-blind, placebo-controlled trial of MLN02, a humanized antibody to the alpha4beta7 integrin, in patients with active ulcerative colitis. We randomly assigned 181 patients to receive 0.5 mg of MLN02 per kilogram of body weight, 2.0 mg per kilogram, or an identical-appearing placebo intravenously on day 1 and day 29. Eligible patients also received concomitant mesalamine or no other treatment for colitis. Ulcerative colitis clinical scores and sigmoidoscopic assessments were evaluated six weeks after randomization. RESULTS: Clinical remission rates at week 6 were 33 percent, 32 percent, and 14 percent for the group receiving 0.5 mg of MLN02 per kilogram, the group receiving 2.0 mg per kilogram, and the placebo group, respectively (P=0.03). The corresponding proportions of patients who improved by at least 3 points on the ulcerative colitis clinical score were 66 percent, 53 percent, and 33 percent (P=0.002). Twenty-eight percent of patients receiving 0.5 mg per kilogram and 12 percent of those receiving 2.0 mg per kilogram had endoscopically evident remission, as compared with 8 percent of those receiving placebo (P=0.007). For the minority of patients in whom an MLN02 antibody titer greater than 1:125 developed, incomplete saturation of the alpha4beta7 receptor on circulating lymphocytes was observed and no benefit of treatment was identifiable. CONCLUSIONS: In this short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis.

Reinisch W, Sandborn WJ, Bala M, Yan S, Feagan BG, Rutgeerts P, Radford-Smith G, Xu S, Eisenberg D, Olson A, Colombel JF. · Univ Klinik Innere Medizin IV, AKH Wien, Vienna, Austria, and Division of Gastroenterology, Hospital Leuven, Belgium. · Inflamm Bowel Dis. · Pubmed #17476675 links to  free full text

Abstract: BACKGROUND: Impairment of health-related quality of life, employment, and productivity has been documented in patients with moderate to severe ulcerative colitis. METHODS: Using prospectively collected data from the Active Ulcerative Colitis Trials 1 and 2, we examined the impact of clinical response or remission, as defined using the Mayo score, on health-related quality of life, employment, disability, productivity, and hours worked per week. These analyses were based on observed data and included all 728 patients, regardless of their randomized treatment group (i.e., placebo and infliximab patients were grouped for analysis). Changes in Inflammatory Bowel Disease Questionnaire (IBDQ) and Medical Outcomes Study 36-Item Short Form (SF-36) scores among nonresponders, responders, and patients in remission were compared. In addition, changes in employment, disability status, productivity, and hours worked per week of patients in clinical remission and patients not in clinical remission were compared. RESULTS: Ulcerative colitis patients in clinical response or remission had significantly improved IBDQ and SF-36 scores at week 30 compared with those of nonresponders (P<0.001). Among those not employed at baseline, including those receiving disability compensation, greater percentages of patients in remission at week 30 were employed (20.6%) and not receiving disability compensation (58.8%) than were those not in remission (8.3% and 20.0%, respectively; P<0.05 for both comparisons). At week 30, improvements from baseline in productivity and both actual and fully productive hours worked per week were greater for patients in remission compared with those not in remission (P<0.05 for all three comparisons). CONCLUSIONS: These results confirm the validity of response and remission as defined using the Mayo score.

Feagan BG, Reinisch W, Rutgeerts P, Sandborn WJ, Yan S, Eisenberg D, Bala M, Johanns J, Olson A, Hanauer SB. · Robarts Research Institute, University of Western Ontario, London, Canada. · Am J Gastroenterol. · Pubmed #17324131 No free full text.

Abstract: OBJECTIVES: The impact of infliximab induction and maintenance therapy on health-related quality of life (HRQL) was evaluated in patients with ulcerative colitis (UC). METHODS: In two placebo-controlled, double-blind studies (the Active Ulcerative Colitis Trials 1 and 2 [ACT 1 and 2]), 728 patients were randomized to placebo or infliximab 5 mg/kg or 10 mg/kg. Infusions were administered at weeks 0, 2, 6, and every 8 wk thereafter, up to week 22 (ACT 2) or 46 (ACT 1). Changes in Inflammatory Bowel Disease Questionnaire (IBDQ) and Medical Outcomes Study 36-Item Short Form Health Survey physical and mental component summary (PCS and MCS, respectively) scores were analyzed. RESULTS: Baseline scores for the pooled patient population indicated substantial impairment in HRQL. Improvement at week 8 in the total IBDQ score was significantly greater in the infliximab 5-mg/kg (40, P < 0.001) and 10-mg/kg (36, P < 0.001) groups compared with the placebo group (28). Improvement at week 8 was also significantly greater in the infliximab 5- and 10-mg/kg groups for the PCS (6.8 and 5.9, respectively) and MCS (5.9 and 6.4, respectively) compared with placebo (PCS = 3.7, MCS = 3.0, P < 0.01 for all comparisons). Continued benefit was seen at weeks 30 and 54 with infliximab maintenance therapy (P < 0.001 for all comparisons). Improvement in total IBDQ score correlated significantly (P < 0.001) with improvement in both PCS and MCS scores, and Mayo score. CONCLUSIONS: Infliximab therapy substantially improved HRQL in patients with UC. This benefit was sustained through 1 yr with maintenance infliximab therapy.

Van Assche G, Sandborn WJ, Feagan BG, Salzberg BA, Silvers D, Monroe PS, Pandak WM, Anderson FH, Valentine JF, Wild GE, Geenen DJ, Sprague R, Targan SR, Rutgeerts P, Vexler V, Young D, Shames RS. · Universitaire Ziekenhuizen Leuven, Inwendige Geneeskunde, UZ Gasthuisberg, Herestraat 49-B-3000, Leuven, Belgium. · Gut. · Pubmed #16603634 No free full text.

Abstract: BACKGROUND: An uncontrolled pilot study demonstrated that daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), might be effective for the treatment of active ulcerative colitis. METHODS: A randomised, double blind, placebo controlled trial was conducted to evaluate the efficacy of daclizumab induction therapy in patients with active ulcerative colitis. A total of 159 patients with moderate ulcerative colitis were randomised to receive induction therapy with daclizumab 1 mg/kg intravenously at weeks 0 and 4, or 2 mg/kg intravenously at weeks 0, 2, 4, and 6, or placebo. The primary end point was induction of remission at week 8. Remission was defined as a Mayo score of 0 on both endoscopy and rectal bleeding components and a score of 0 or 1 on stool frequency and physician's global assessment components. Response was defined as a decrease from baseline in the Mayo score of at least 3 points. RESULTS: Two per cent of patients receiving daclizumab 1 mg/kg (p = 0.11 v placebo) and 7% of patients receiving 2 mg/kg (p = 0.73) were in remission at week 8, compared with 10% of those who received placebo. Response occurred at week 8 in 25% of patients receiving daclizumab 1 mg/kg (p = 0.04) and in 33% of patients receiving 2 mg/kg (p = 0.30) versus 44% of those receiving placebo. Daclizumab was well tolerated. The most frequently reported adverse events in daclizumab treated patients compared with placebo treated patients were nasopharyngitis (14.6%) and pyrexia (10.7%). CONCLUSION: Patients with moderate ulcerative colitis who are treated with daclizumab are not more likely to be in remission or response at eight weeks than patients treated with placebo.

Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. · University Hospital Gasthuisberg, Leuven, Belgium. · N Engl J Med. · Pubmed #16339095 links to  free full text

Abstract: BACKGROUND: Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis. METHODS: Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. RESULTS: In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons). CONCLUSIONS: Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.)