BACKGROUND & AIMS: Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy.... Show moreBACKGROUND & AIMS: Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy. Topical tacrolimus is effective and safe in patients with refractory UP. However, it is not clear how tacrolimus suppositories fit into in the treatment algorithm of UP.METHODS: We performed a randomized controlled, double-blind study at 8 hospitals in the Netherlands and Belgium from 2014 through 2017. Eighty-five patients with refractory UP (65% women) were randomly assigned to groups given once daily tacrolimus suppositories (2 mg; n = 43) or beclomethasone (3 mg; n = 42) for 4 weeks. The primary outcome was clinical response (decrease in Mayo score of 3 or more). Secondary outcomes included clinical remission, endoscopic response and remission, adverse events and quality of life. Outcomes were compared using Fisher's exact test and Mann-Whitney U test.RESULTS: Proportions of patients with clinical responses were 63% in the tacrolimus group and 59% in the beclomethasone group (P = .812); proportions of patients in clinical remission were 46% and 38%, respectively (P = .638). Proportions of patients with an endoscopic response were 68% and 60% in the tacrolimus group and in the beclomethasone group (P = .636); proportions in endoscopic remission rates were 30% and 13%, respectively (P = .092) Median increases in the inflammatory bowel disease questionnaire score were 18.0 in the tacrolimus group and 20.5 in the beclomethasone group (P = .395). Adverse event rates did not differ significantly between groups.CONCLUSIONS: In a 4-week randomized controlled trial, tacrolimus and beclomethasone suppositories induce comparable clinical and endoscopic responses in patients with UP refractory to 5-ASA. There were no significant differences in adverse events rates. Tacrolimus and beclomethasone suppositories are therefore each safe and effective treatment options for 5-ASA refractory disease. Show less
Pariente, B.; Cosnes, J.; Danese, S.; Sandborn, W.J.; Lewin, M.; Fletcher, J.G.; ... ; Lemann, M. 2011
Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative... Show moreCrohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lemann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lemann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. Show less
Background and aims Pilot studies with visilizumab, a humanised monoclonal antibody to CD3, suggest efficacy for corticosteroid-refractory ulcerative colitis (UC). A placebo-controlled trial was... Show moreBackground and aims Pilot studies with visilizumab, a humanised monoclonal antibody to CD3, suggest efficacy for corticosteroid-refractory ulcerative colitis (UC). A placebo-controlled trial was warranted. Methods A randomised, double-blind, placebo-controlled study evaluated the efficacy of visilizumab induction treatment in 127 patients with severely active UC despite treatment with >= 5 days of intravenous corticosteroids. Patients received placebo or visilizumab 5 mu g/kg intravenously on days 1 and 2. Corticosteroids were tapered according to disease activity. Patients were followed up for 90 days. The primary end point was induction of response at day 45. Secondary end points included remission and mucosal healing at day 45, symptomatic response at day 15 and colectomy. Results Response at day 45 occurred in 55% of patients receiving visilizumab compared with 47% of those who received placebo (p=0.475). Remission at day 45 occurred in 8% of patients receiving visilizumab compared with 9% of those who received placebo (p=0.704). Mucosal healing at day 45 occurred in 29% of patients receiving visilizumab compared with 26% of those who received placebo (p=0.799). Symptomatic response at day 15 occurred in 82% of patients receiving visilizumab compared with 74% of those who received placebo (p=0.244). Colectomy was performed in 18% of patients receiving visilizumab compared with 7% of those who received placebo (p=0.130). Cardiac disorders and vascular disorders occurred more frequently in the patients who received visilizumab. Conclusion Visilizumab at a dose of 5 mu g/kg for two consecutive days was not effective for severe, corticosteroid-refractory UC and was associated with increased cardiac and vascular adverse events. (Registered at http://www.clinicaltrials.govNCT00279422/). Show less
Woude, C.J. van der; Stokkers, P.; Bodegraven, A.A. van; Assche, G. van; Hebzda, Z.; Paradowski, L.; ... ; ICC 2010
Background: NI-0401 is a fully human monoclonal antibody, which binds to the CD3 subunit of the T-cell receptor, causing modulation of T-cell activity. We investigated the safety and the ability to... Show moreBackground: NI-0401 is a fully human monoclonal antibody, which binds to the CD3 subunit of the T-cell receptor, causing modulation of T-cell activity. We investigated the safety and the ability to modulate the TCR-CD3 complex of NI-0401 in patients with active Crohn's disease (CD). Methods: A double-blind, placebo-controlled, randomized, multicenter, dose-escalating trial was conducted in CD patients age 18-70 years, a Crohn's Disease Activity Index (CDAI) of 220450, and detectable levels of C-reactive protein. The primary outcome was safety and the ability of NI-0401 to modulate the TCR-CD3 complex on T cells. Efficacy parameters included the proportion of patients achieving remission (CDAI <150), clinical response (CDAI fall >= 100), and change from baseline in the CD Endoscopy Index of Severity (CDEIS). Results: Forty patients received placebo (n = 7) or NI-0401 (n 33) 0.05-10 mg daily for 5 days. NI-0401 doses <= 1 mg were well tolerated. Infusion reactions occurred at doses >= 2 mg. The extent and duration of TCR-CD3 modulation increased with dose. No differences between groups were observed in the proportions of patients achieving clinical remission or response. The mean CDEIS at week 6 differed significantly between the 1-mg and placebo group. Conclusions: NI-0401 was tolerated at doses <= 1 mg with manageable side effects. NI-0401 induced a dose-dependent modulation of the TCR-CD3 complex. No significant improvement of CDAI was observed but 1 mg NI-0401 demonstrated an improvement in CDEIS. Show less
Background: Visilizumab is a humanized IgG(2) monoclonal anti-CD3 antibody. We evaluated its safety and dose response in severe intravenous steroid-refractory ulcerative colitis (UC). Methods: In... Show moreBackground: Visilizumab is a humanized IgG(2) monoclonal anti-CD3 antibody. We evaluated its safety and dose response in severe intravenous steroid-refractory ulcerative colitis (UC). Methods: In all, 104 patients were treated. In Stage 1, 73 patients were randomly assigned to receive intravenous visilizumab 5, 7.5, 10, or 12.5 mu g/kg/day for 2 consecutive days. In Stage II, 33 patients received visilizumab at the optimal clinical dose (OCD) of 5 mu g/kg/day for 2 days. Symptomatic response and remission were defined by the modified Truelove-Witts severity index. Clinical response and remission were defined by the Mayo score. Results: The rates of symptomatic response at day 15 in the 5, 7.5, 10, or 12.5 mu g/kg dose groups were 71%, 70%, 50%, and 61%. respectively, in Stage I and in 54% in Stage II. The symptomatic remission rates were 3.5%, 5%, 22%, and 11% in Stage I and 18% in Stage II. The rates of clinical response at day 30 in the 5, 7.5, 10, or 12.5 mu g/kg dose groups were 71%, 65%, 50%, and 67%, respectively, in Stage I and 55% in Stage II. The clinical remission rates were 6%, 5%, 0%, and 11% in Stage I and 6% in Stage II. All patients experienced adverse events. Serious adverse events included abdominal abscess, cytomegalovirus infection, atrial fibrillation, herpes zoster, and esophageal candidiasis. Conclusions: Treatment with visilizumab induced symptomatic response and clinical response. Results with 5 mu g/kg/day were similar to those observed with higher doses (NCT00267306 at www.clinicaltrials.gov). Show less
Fidder, H.H.; Steen, K. van de; Assche, G. van; Rutgeerts, P.; Vermeire, S. 2010
BACKGROUND & AIMS: Few prospective data are available to support the clinical relevance of mucosal healing in patients with Crohn's disease. This study examined whether complete healing,... Show moreBACKGROUND & AIMS: Few prospective data are available to support the clinical relevance of mucosal healing in patients with Crohn's disease. This study examined whether complete healing, determined by endoscopy, predicts a better outcome in Crohn's disease. METHODS: One-hundred thirty-three newly diagnosed and treatment-naive Crohn's disease patients were given either a combination of immunosuppressive therapy (azathioprine) and 3 infusions of infliximab or treatment with conventional corticosteroids. Patients given azathioprine were given repeated doses of infliximab for relapses, patients given corticosteroids were given azathioprine in cases of corticosteroid dependency and infliximab only if azathioprine failed. A representative subset of 49 patients from the initially randomized cohort underwent ileocolonoscopy after 2 years of therapy. Correlation analysis was performed between different clinical parameters including endoscopic activity (Simple Endoscopic Score) and clinical outcome 2 years after this endoscopic examination. Data were available from 46 patients 3 and 4 years after therapy began. RESULTS: Complete mucosal healing, defined as a simple endoscopic score of 0 after 2 years of therapy, was the only factor that predicted sustained, steroid-free remission 3 and 4 years after therapy was initiated; it was observed in 17 of 24 patients (70.8%) vs 6 of 22 patients with lesions detected by endoscopy (27.3%, Simple Endoscopic Score > 0) (P = .036; odds ratio = 4.352; 95% confidence interval, 1.10-17.220). Fifteen of 17 patients with mucosal healing at year 2 maintained in remission without further infliximab infusions during years 3 and 4 (P = .032; odds ratio = 4.883; 95% confidence interval, 1.144-20.844). CONCLUSIONS: Complete mucosal healing in patients with early-stage Crohn's disease is associated with significantly higher steroid-free remission rates 4 years after therapy began. Show less
