Clinical trial: ulcerative colitis maintenance treatment with 5-ASA: a 1-year, randomized multicentre study comparing MMX with Asacol.

BACKGROUND: 5-ASA-MMX (1.2 g/tablet) is a 5-aminosalicylic acid formulation, designed for once-daily dosing in the treatment of ulcerative colitis. AIM: To evaluate the efficacy and safety of 5-ASA-MMX (2.4 g/day, once daily), compared with Asacol (2.4 g/day, twice daily) in the maintenance of left-sided UC, through a double-blind, double-dummy, parallel-group, randomized, comparator study. METHODS: In all, 331 patients with UC were randomized to receive either 5-ASA-MMX 2.4 g/day, once daily, or Asacol 2.4 g/day, twice daily, for 12 months. All patients were in remission for >or=1 month prior to the trial, with >or=1 documented relapse in the previous year. The co-primary endpoints of this study were the proportion of patients in clinical, and clinical and endoscopic remission following 12 months' treatment. RESULTS: In the intent-to-treat population, excluding those with major protocol deviations, 68.0 and 65.9% patients in the 5-ASA-MMX and Asacol groups, respectively, were in clinical remission (P = 0.69), and 60.9 and 61.7% of patients, respectively, were in clinical and endoscopic remission (P = 0.89). Diary card data revealed statistically significant treatment differences favouring 5-ASA-MMX. Both treatments were similarly tolerated. CONCLUSIONS: Once-daily 5-ASA-MMX is similarly effective with a comparable safety profile to Asacol administered twice daily, for the maintenance treatment of ulcerative colitis.

Infliximab in severe ulcerative colitis: short-term results of different infusion regimens and long-term follow-up.

BACKGROUND: Severe ulcerative colitis is a life-threatening disorder, despite i.v. glucocorticoids treatment. Infliximab has been proposed as a safe rescue therapy. AIM: To evaluate short- and long-term effectiveness and safety of infliximab in severe refractory ulcerative colitis. METHODS: Eighty-three patients with severe ulcerative colitis (i.v. glucocorticoids treatment-refractory) were treated with infliximab in 10 Italian Gastroenterology Units. Patients underwent one or more infusions according to the choice of treating physicians. Short-term outcome was colectomy/death 2 months after the first infusion. Long-term outcome was survival free from colectomy. Safety data were recorded. RESULTS: Twelve patients (15%) underwent colectomy within 2 months. One died of Legionella pneumophila infection 12 days after infliximab. Early colectomy rates were higher in patients receiving one infusion (9/26), compared with those receiving two/more infusions (3/57, P = 0.001, OR = 9.53). Seventy patients who survived colectomy and did not experience any fatal complications were followed-up for a median time of 23 months; 58 patients avoided colectomy during the follow-up. Forty-two patients were maintained on immunosuppressive drugs. No clinical features were associated with outcomes. CONCLUSIONS: Infliximab is an effective and relatively safe therapy to avoid colectomy and maintain long-term remission for patients with severe refractory ulcerative colitis. In the short term, two or more infusions seem to be more effective than one single infusion.

Antibiotic treatment of Crohn's disease: results of a multicentre, double blind, randomized, placebo-controlled trial with rifaximin.

BACKGROUND: Clinicians often employ antibiotics in Crohn's disease. Rifaximin is active against bacteria frequently found in the intestinal mucosa of Crohn's disease patients. AIM: To evaluate the difference in efficacy between once and twice/daily oral administration of rifaximin and placebo in the treatment of active Crohn's disease. METHODS: We enrolled 83 patients with mild-to-moderate Crohn's disease and randomized to three treatments for 12 weeks: Group A (rifaximin 800 mg o.d. + placebo), Group B (rifaximin 800 mg b.d.) and Group C (placebo b.d.). RESULTS: Clinical remission was achieved by 52% of Group B, 32% (A) and 33% (C). Clinical response was seen in 67% (B), 48% (A) and 41% (C), without reaching a statistically significant difference. Treatment failures were: 4% (B), 12% (A) and 33% (C), (P = 0.010). Remission and response rates of rifaximin 800 mg b.d. were significantly higher than those of placebo and rifaximin 800 mg o.d. in patients with elevated C reactive protein values (P < 0.05). CONCLUSIONS: Rifaximin 800 mg b.d. was superior to placebo in inducing clinical remission of active Crohn's disease. Although this difference was not statistically significant, the number of the failures in the placebo group was significantly higher than those who received rifaximin 800 mg b.d.

European evidence based consensus on the diagnosis and management of Crohn's disease: current management.

This second section of the European Crohn's and Colitis Organisation (ECCO) Consensus on the management of Crohn's disease concerns treatment of active disease, maintenance of medically induced remission, and surgery. The first section on definitions and diagnosis includes the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn's disease. The third section on special situations in Crohn's disease includes postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy for Crohn's disease.

Infliximab in the treatment of severe ulcerative colitis: a follow-up study.

Conventional treatment options for patients with severe steroid-refractory ulcerative colitis (UC) include intravenous cyclosporine, which is frequently burdened by toxicity, or colectomy. Preliminary data suggest a benefit of anti-tumor necrosis factor alpha (Infliximab) therapy in patients with steroid refractory UC. Thirteen patients with severe UC, refractory to therapy with methyl-prednisolone, 60 mg IV daily were treated with a single intravenous infusion of Infliximab 5 mg/kg. Ten out of 13 patients (77%) had a clinical response to therapy defined by a CAI < or = 10 on two consecutive days. Two patients (15%) underwent total colectomy because of clinical worsening; one patient refused surgery and was lost to follow-up. Infusion with Infliximab produced no significant adverse events. The mean time of follow-up was 25.6 months (range 17-24); in this period of time 8 out of 10 patients (80%) maintained clinical remission and were able to discontinue corticosteroids therapy. Infliximab appears to be an effective agent for inducing long standing remission in refractory patients with severe UC.

Review article: medical treatment of moderate to severe Crohn's disease.

The treatment for patients with Crohn's disease of moderate to severe activity includes traditional drugs, such as corticosteroids, the primary therapy for these forms of disease, able to induce the remission of symptoms in a high percentage of patients. Because of the side-effects produced by systemic steroids, a new glucocorticoid derivative, budesonide, which acts locally in the mucosa, has recently been introduced with positive results. On the assumption that intestinal bacteria play a role in the causing Crohn's disease symptoms, antibiotics are often used in the treatment of active phases, as an alternative to or in association with steroids. The most widely employed antibiotics are metronidazole and ciprofloxacin. Immunosuppressors, such as azathioprine and 6-mercaptopurine, are useful for the treatment of chronic active disease and for maintaining remission, but they have only a marginal role in the therapy of an acute flare-up of Crohn's disease. Methotrexate acts more rapidly and its use in patients with active disease resistant to standard therapy is of interest. The discovery of biological agents represents a new era in the management of patients. To date, infliximab is the more extensively studied biological therapy in the treatment of Crohn's disease and clinical studies have demonstrated its efficacy in inducing remission of refractory disease.

Probiotics and Crohn's disease.

Antibiotics are often employed in the treatment of Crohn's disease, with interesting results. However indiscriminate suppression of intestinal bacteria may be harmful and long-term use of antibiotics is burdened by side-effects and by the risk of developing bacterial resistance. Manipulation of enteric flora with probiotic compounds would be a possible and appealing alternative. First aim of our study has been to investigate the efficacy of this probiotic in reducing the endoscopic recurrence rate or in reducing the severity of recurrent lesions at 1 year after surgery. Secondary goal has been the reduction of the clinical recurrence rate. Forty-five patients have been randomised to receive Lactobacillus rhamnosus strain GG or placebo for 12 months. The results have shown no differences in endoscopic and clinical remission between the two groups.

Anti-tumour necrosis factor alpha (infliximab) in the treatment of severe ulcerative colitis: result of an open study on 13 patients.

BACKGROUND: Conventional treatment options for patients with severe steroid-refractory ulcerative colitis include intravenous cyclosporine, which is frequently burdened by toxicity, or colectomy. Preliminary data suggest a benefit from anti-tumour necrosis factor alpha (Infliximab) therapy in patients with steroid refractory ulcerative colitis. AIM: To evaluate the efficacy of Infliximab in the treatment of severe ulcerative colitis refractory to conventional therapy PATIENTS AND METHODS: A series of 13 patients with severe ulcerative colitis, refractory to therapy with methyl-prednisolone, 60 mg daily for seven or more days, were treated with a single intravenous infusion of Infliximab 5 mg/kg. RESULTS AND CONCLUSIONS: Of these 13 patients, 10 (77%) had a clinical response to therapy defined by a clinical activity index 10 on two consecutive days. In 2 patients (15%) total colectomy was necessary on account of clinical worsening whilst one patient refused surgery and was lost to follow-up. All patients who responded showed very rapid clinical improvement, within 2 to 3 days of infusion. Infusion with Infliximab produced no significant adverse events. The mean time of follow-up was 10.1 months (range 5-12; during this time, 9 out of 10 patients (90%) maintained clinical remission and were able to discontinue corticosteroid therapy. Infliximab appears to be an effective agent for inducing long-standing remission in refractory patients with severe ulcerative colitis.

Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn's disease: a randomised controlled trial with Lactobacillus GG.

BACKGROUND AND AIMS: Experimental studies have shown that luminal bacteria may be involved in Crohn's disease. Probiotics are a possible alternative to antibiotics. The aim of this randomised placebo controlled study was to determine if Lactobacillus GG, given by mouth for one year, could prevent Crohn's recurrent lesions after surgery or to reduce their severity. METHODS: Patients operated on for Crohn's disease in whom all of the diseased gut had been removed were randomly allocated to receive 12 billion colony forming units of Lactobacillus or identical placebo for one year. Ileocolonoscopy was performed at the end of the trial or at the onset of symptoms. Endoscopic recurrence was defined as grade 2 or higher of Rutgeerts scoring system. RESULTS: Eight of 45 patients were excluded from the trial (three for non-compliance and five for protocol violations). Clinical recurrence was ascertained in three (16.6%) patients who received Lactobacillus and in two (10.5%) who received placebo. Nine of 15 patients in clinical remission on Lactobacillus (60%) had endoscopic recurrence compared with six of 17 (35.3%) on placebo (p=0.297). There were no significant differences in the severity of the lesions between the two groups. CONCLUSIONS: Lactobacillus GG seems neither to prevent endoscopic recurrence at one year nor reduce the severity of recurrent lesions.

Review article: medical treatment of active Crohn's disease.

Crohn's disease, a heterogeneous inflammatory process that can affect various sites in the gut, presents an ongoing management challenge for the clinician. The treatment of active disease and complications is one of the main goals in the therapy of this disease. New therapies are aimed at delivering the active compounds to the diseased site, reduction or suppression of enteral flora and modulation of more focal targets within the immune response. The use of antibiotics in the therapy of Crohn's disease is gaining popularity, on the grounds that intestinal bacteria may play a role in the pathogenesis of Crohn's disease lesions. Metronidazole is one of the most widely used antibiotics, especially in the treatment of perianal disease. Corticosteroids are the mainstays of medical treatment in active Crohn's disease and induce the remission of symptoms in about 60-80% of patients. The use of immunosuppressive agents, such as cyclosporine and methotrexate, in patients with active disease resistant to standard therapy has gained acceptance in recent years. With new therapies the outlook for patients with Crohn's disease is more optimistic than it has been for a long time.

Oral and topical 5-aminosalicylic acid (mesalazine) in inducing and maintaining remission in mild-moderate relapse of ulcerative colitis: one-year randomised multicentre trial.

BACKGROUND: The association of oral 5-aminosalicylic acid (mesalazine) and enema is effective in treatment of mild-moderate forms of ulcerative colitis. However no study has been aimed at determining optimal duration of this association in active ulcerative colitis. AIM: To determine whether longer duration of therapy: 1. increases the rate of patients achieving remission, and 2. reduces relapse rate during the maintenance period in patients in remission. PATIENTS AND METHODS: A total of 149 patients, (89 male, 60 female), were randomly assigned to a regimen with 5-aminosalicylic acid tablets 2.4 g/day associated with 5-aminosalycilic enema 2 g/day for a 4-week (n = 73) or 8-week regimen (n = 76). After this acute therapy, patients were submitted to clinical, endoscopic and histological examinations and those in remission were assigned to a follow-up (maintenance) period with oral mesalazine alone at a dosage of 1.2 g/day. A clinical visit, including laboratory tests, at 6 months and an endoscopic-histological control at 12 months were carried out to exclude symptoms and endoscopic-histological signs of activity. Relapse of disease, i.e., presence of clinical symptoms or abnormal laboratory tests, was confirmed by endoscopy and histology. RESULTS: At end of acute phase, clinical, endoscopic and histological remission was comparable in the two groups: 42/76 (55%), in the 4-week, and 47/73 patients (64%), in the 8-week regimen. No difference was found stratifying patients according to extension of disease. Of these 89 patients in remission, 75 (34 from 4-week regimen; 41 from 8-week regimen) completed 12 months' follow-up. At end of follow-up, a similar percentage of patients in the 4-week regimen (50%) and 8-week regimen (51%) were still in remission. No significant difference between cumulative relapse rates of the two groups was found. Stratifying patients according to extension of disease, in the 8-week regimen group, those with left-sided colitis showed a higher remission rate than that of patients with diffuse colitis (66% versus 35%, p < 0.05). All regimens were well tolerated by most patients during the entire study period. CONCLUSIONS: An additional 4 weeks of topical treatment does not increase the remission rate in patients with mild-moderate active ulcerative colitis but seems to reduce the probability of relapse in patients with left-sided colitis.

Use of anti-tumour necrosis factor agents in inflammatory bowel disease. European guidelines for 2001-2003.

The introduction of novel anti-tumor necrosis factor (TNF) agents has not only led to impressive new therapeutic opportunities but also resulted in uncertainty regarding their optimal use and possible side effects. Guidelines are presented here for the use of anti-TNF agents in gastrointestinal disorders. Experts were chosen from different European countries by an algorithm to avoid bias. An expert consensus on guidelines was established using a two-stage procedure of systematic Medline and abstract search for evidence and a qualifying meeting to derive recommendations. Detailed guidelines were developed for the use and the future clinical development of anti-TNF agents in inflammatory bowel disease. Grading of available evidence and grading of recommendations were performed according to AHCPR guidelines. At present infliximab is the only registered agent for Crohn's disease. Infliximab should be always used at a dose of 5 mg/kg. The guidelines define the indications both in refractory and in fistulating disease for the readministration and before surgery. Guidelines for safety and for concomitant treatments are given. Prospects, potential clinical use, and future directions for the clinical development of other anti-TNF agents are detailed. Clinical use of anti-TNF agents will be influenced by a large number of clinical trials being concluded in 2001 and 2002. It is likely that anti-TNF therapies will become an important long-term therapy for a proportion of patients with Crohn's disease. Biological agents will be followed by smaller and more stable, orally available compounds. These guidelines will be succeeded by a formal public consensus in 2002/2003.

Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease.

OBJECTIVES: To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease. SEARCH STRATEGY: Studies were selected using the MEDLINE data base (1966 - December 1997), abstracts from major gastrointestinal meetings and references from published articles and reviews. The Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register was also searched. SELECTION CRITERIA: Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms. DATA COLLECTION AND ANALYSIS: Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel ('Odds Ratio' in MetaView). MAIN RESULTS: The odds ratio of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.36 (95% CI 1.57-3.53). This corresponded to a number needed to treat of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the odds ratio of response was 2.04 (CI 1.24 - 3.35). Treatment >/= 17 weeks increased the odds ratio of a response to 2.51 (CI 1.63-3. 88). A steroid sparing effect was seen with an odds ratio of 3.86 (CI 2.14 - 6.96), corresponding to a number needed to treat of about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased on therapy with an odds ratio of 3.01 (CI 1.30 - 6.96). The number needed to treat to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14. REVIEWER'S CONCLUSIONS: Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. The odds ratio of response increases after >/= 17 weeks of therapy, suggesting that there is a minimum length of time for a trial of azathioprine or 6-mercaptopurine therapy. Adverse events were more common among patients on therapy.

Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission.

OBJECTIVE: We sought to determine whether psychosocial factors influence the course of ulcerative colitis, hypothesizing that high perceived stress among patients with inactive disease will increase the risk of subsequent exacerbation. METHODS: Sixty-two patients with known ulcerative colitis were enrolled into a prospective cohort study while in clinical remission. Their perceived stress, depressive symptoms, and stressful life events were followed, along with potential confounders, for up to 45 months; exacerbation status was monitored for up to 68 months. RESULTS: The 27 patients who experienced an exacerbation were compared with those who remained in remission. Having a score in the upper tertile on the long-term (past 2 yr) baseline Perceived Stress Questionnaire significantly increased the actuarial risk of exacerbation (hazards ratio = 2.8, 95% confidence interval 1.1-7.2). At any given study visit, high long-term stress tripled the risk of exacerbation during the next 8 months (risk for the three tertiles, 8.3%, 16.7%, and 26.2%, p = 0.02). Shorter sleep time, briefer remission, histological activity, and use of nonsteroidal antiinflammatory drugs, antibiotics, or oral contraceptives also increased the medium- and/or long-term risk of exacerbation, but adjustment for these variables did not eliminate the associations with stress. Exacerbation was not associated with stressful life events, depressive symptoms, short-term (past month) perceived stress, smoking, disease extent or duration, or severity of recent course. CONCLUSIONS: Short-term stress does not trigger exacerbation in ulcerative colitis, but long-term perceived stress increases the risk of exacerbation over a period of months to years.