Azathioprine for prevention of clinical recurrence in Crohn's disease patients with severe endoscopic recurrence: an IG-IBD randomized double-blind trial.

OBJECTIVE: The recurrence of Crohn's Disease after ileo-colonic resection is a crucial issue. Severe endoscopic lesions increase the risk of developing early symptoms. Prevention and treatment of post-operative Endoscopic Recurrence (ER) have been studied with conflicting results. We compare effi cacy of azathioprine (AZA) vs. high-dose 5-aminosalicylic acid (5-ASA) in preventing clinical recurrence and treating severe post-operative ER. PATIENTS AND METHODS: We performed a 1-year multicenter randomized double-blind double-dummy trial. Primary end-points were endoscopic improvement and therapeutic failure (clinical recurrence or drug discontinuation due to lack of efficacy or adverse events) 12 months after randomization. We also performed a post-trial analysis on symptomatic and endoscopic outcomes 10 years after the beginning of the trial, with a median follow-up of 60 months. RESULTS: Therapeutic failure occurred in 8 patients (17.4%) within 12 months from randomization, with no significant difference between patients treated with 5-ASA (20.8%, 5 patients) and those with AZA (13.6%, 3 patients). Therapeutic failure was due to clinical recurrence in the 5-ASA group and to adverse events in the AZA group. Endoscopic improvement at 12 months was observed in 8 patients, 2 (11.8%) in the 5-ASA group and 6 (30%) in the AZA group. No serious adverse event was recorded. At the post-trial analysis (median follow-up 60 months), 47.8% (22/46) of patients experienced clinical recurrence: 54.2% (13/24) in the 5-ASA group and 40.9% (9/22) in the AZA group, p=0.546. Patients treated with AZA had lower risk of drug escalation. Clinical recurrence was associated with smoking (p=0.031) and previous surgery (p=0.003). CONCLUSIONS: Our trial indicates that there was no difference in terms of treatment failure between 5-ASA and AZA in patients with severe ER. The main limit of AZA is its less favorable safety profile.

Long term course of ulcerative colitis in the prebiologic era. A retrospective study in a tertiary referral center.

AIM: Several population-based studies have shown that long term prognosis of ulcerative colitis (UC) may be better than previously reported. The aim of this study was to evaluate the course of UC in a referral center cohort in the pre-biologic era and to identify possible prognostic factors. METHODS: All patients with established diagnosis of UC have been extracted from our GI Unit IBD Database. Clinical and demographic characteristics of all patients were recorded at the time of diagnosis. The disease course was retrospectively evaluated considering four primary end points: change in disease extension, need of corticosteroids, need of immunomodulators, and need of colectomy. The Kaplan-Meier survival method was used to estimate the cumulative probability of a course free of the outcome of interest. RESULTS: Eight hundred and seven UC patients diagnosed between 1984 and 2008 have been included: 21.8% had proctitis, 47.6% had distal colitis and 30.6% had extensive colitis. The median follow up after diagnosis was 91 months (range 12-596). The probability of extension of proctitis within 10 years was 39.7%. In the whole cohort, the 10 years probability of receiving corticosteroids and immunomodulators was 46.7% and 12.4%, respectively. The 10-year probability of colectomy was 6.5%. Extensive colitis was associated with a higher probability of receiving corticosteroids, immunomodulators and surgery. CONCLUSION: Long-term prognosis of UC is favourable for the majority of patients. Extensive colitis is the most relevant negative prognostic factor. Results from our referral center study are similar to that reported in population-based studies. Further studies are required to assess the possible impact of biologics and new treatment strategies on long term outcomes.

[Role of rifaximin in the treatment of colonic diverticular disease]. / Ruolo della rifaximina nel trattamento della malattia diverticolare del colon.

Diverticular disease of the colon is the fifth most important gastrointestinal disease in terms of direct and indirect healthcare costs in western countries. Although most patients with colonic diverticula remain asymptomatic for their whole life, in 20-25% of cases will develop symptoms. Antibiotics are commonly used in the treatment of inflammatory complication of diverticular disease. Several clinical observation suggest a role of rifaximin in the management of symptomatic uncomplicated diverticular disease of the colon. This is a critical review of clinical studies addressing the role of long term administration of rifaximin for the treatment of symptomatic colonic diverticular disease. The evidence from prospective controlled trials suggests that rifaximin is effective for obtaining symptomatic relief in patients with uncomplicated diverticular disease. The therapeutic gain compared with fiber supplementation only is approximately 30%. No definitive conclusion can be drawn regard a possible role of rifaximin for preventing diverticulitis.

Natural history of ileo-caecal Crohn's disease after surgical resection. A long term study.

AIM: Surgery is an almost inevitable event in Crohn's disease (CD) but is not curative; postoperative recurrence follows a predictable course. Several factors potentially affecting the risk of recurrence have been investigated but results are largely inconclusive. The aim of the present study was to evaluate the long-term course of ileo-caecal CD after surgery and to identify possible predictors of clinical and surgical recurrence. METHODS: Patients with ileo-caecal CD who had undergone surgical resection and with at least one year of post-operative follow-up were studied. The postoperative course was retrospectively evaluated. The primary end-points were clinical recurrence (defined as reappearance of symptoms requiring steroid treatment in the presence of endoscopic and/or radiologic recurrence) and surgical recurrence, defined as need for reoperation. RESULTS: Two hundred and twelve patients were included in the study. Median follow-up after surgery was 117 months (interquartile range 51-216). The cumulative probability of a post-operative course without clinical and surgical recurrence after 30, 60, 90, 120 months was 78.2%, 69.4%, 58.0%, 50.6% and 97.0%, 96.4%, 85.6%, 72% respectively. Early surgery (within three years from diagnosis) was associated with a longer postoperative course without clinical recurrence compared with late surgery (performed after three years from diagnosis). None of the other clinical variables considered (gender, age, family history for IBD, smoking habits, pattern of CD, and postoperative prophylactic treatment) was associated with the risk of clinical and surgical recurrence. CONCLUSION: Surgery is an excellent treatment for patients with isolated ileo-caecal CD. The overall long-term outcome is good: by 10 years after operation approximately 50% of patients are free of clinical recurrence and over 70% do not require further surgery. Surgery, therefore, continues to play an important role in ileo-caecal CD and should therefore not be considered only a failure of medical treatment.

Cardiac involvement in inflammatory bowel disease: role of acylcarnitine esters.

OBJECTIVES: Cardiovascular complications have been frequently described in Inflammatory Bowel Disease (IBD). Both Crohn disease and Ulcerative Colitis are characterized by malabsorption of some micronutrients, such as carnitine, which is a very important element for myocardial metabolism, being demonstrated that its deficiency correlates with heart involvement in coeliac disease. Aims of this study are to evaluate cardiac function in IBD patients asymptomatic for cardiovascular diseases and to correlate the cardiac data with the profile of carnitine esters plasma levels. MATERIALS AND METHODS: The study was carried out on 20 IBD patients by comparison with 18 sex- and age-matched clinically healthy controls. Personal and familial history, physical examination, standard electrocardiogram and echocardiogram were performed in all subjects. Complete panel of nutritional status parameters and serum levels of free carnitine and its esters were evaluated both in IBD patients and control subjects. RESULTS: Isovaleryl-carnitine, Tiglyl-carnitine, Octenoylcarnitine and Decanoyl-carnitine, were found to be significantly lower in IBD patients. Significant correlations were found between some carnitine esters and echocardiographic parameters although total and free carnitine were meanly more elevated in IBD. No statistically significant differences in echocardiographic parameters were found between IBD patients and control subjects. CONCLUSIONS: Deficiency of some isoforms of carnitine, especially those esterified with short chain fatty acids, may play an important role in cardiac involvement in course of IBD and could lead, over time, to dilated cardiomiopathy.

Long-term prevention of post-operative recurrence in Crohn's disease cannot be affected by mesalazine.

BACKGROUND: Prevention of post-operative recurrence has a central role in the management of Crohn's Disease (CD). Many drugs have been evaluated in prospective randomised controlled trials (RCTs) but the results are disappointing. Mesalazine, the drug more extensively investigated, has been shown to be effective for preventing recurrence in the short-term; however, the overall benefit is small and no data are available on the long-term effectiveness. AIM: To compare the long-term occurrence of post-operative recurrence in patients who received regular prophylactic treatment with mesalazine with patients who did not receive prophylaxis after the first radical resection for ileo-caecal CD. PATIENTS AND METHODS: The records of 216 patients with ileo-caecal CD at their first resection were reviewed: 146 patients (67.6%) received post-operative prophylaxis with mesalazine while 70 patients (32.4%) received no prophylaxis. Allocation of patients in the two groups was determined by patients' preferences and by different policies in the post-operative prophylactic approach. The mean follow-up after surgery was 153.7 months (range 12-544). The co-primary endpoints were post-operative clinical and surgical recurrence. STATISTICAL ANALYSIS: Kaplan-Meier survival method, Chi-square, Student t-test. RESULTS: The two groups were comparable with regard to gender, age at surgery, smoking habits, pattern of CD (perforating/not perforating), and disease duration before surgery. One year after surgery, a small, not statistically significant, risk reduction in clinical recurrence was observed in mesalazine treated group (-7.6%; 95% CI -18.0% to 2.8%). Within 10 years after surgery, the cumulative probability of clinical recurrence and surgical recurrence were similar in the two groups (Log Rank test p=0.9 and p=0.1 respectively). CONCLUSION: Mesalazine prophylaxis is not effective for preventing the long-term post-operative recurrence in ileo-caecal Crohn's disease.

Colectomy rate in acute severe ulcerative colitis in the infliximab era.

BACKGROUND: Severe ulcerative colitis is a potentially life-threatening condition. Due to advances in medical therapy, the mortality rate has dropped to <2% over the past 30 years, but the colectomy rate reaches 30%. Recently, infliximab has been shown to be effective as rescue therapy but little is known about long-term benefits. AIM: To evaluate short-and long-term colectomy rates for severe ulcerative colitis in the era of biological treatment and to identify predictive factors of long-term colectomy. PATIENTS AND METHODS: From 2001 to 2006 all in-patients with severe ulcerative colitis, according to Truelove and Witts criteria, were retrospectively reviewed. All patients had received intravenous steroid treatment; infliximab (5 mg/kg at 0, 2 and 6 weeks) was used as rescue therapy in steroid-refractory patients; colectomy was performed in patients who deteriorated whilst on steroid treatment or failed to respond to infliximab. RESULTS: Of the 314 ulcerative colitis patients hospitalized during the study period, 52 (16.5%) met the criteria of severe ulcerative colitis. After median 7 days (range 4-15) on intravenous steroids, 37/52 (71%) patients showed a clinical response, while 15/52 (29%) were steroid-refractory. Of these, four underwent urgent colectomy and 11 received infliximab. A clinical response was observed in all infliximab-treated patients. In the long-term, another six patients underwent elective colectomy. The overall colectomy rate, following the acute attack, was 19%; the cumulative probability of a course without colectomy was 90%, 86%, 84%, 81%, after 6, 12, 18 and 24 months, respectively. No deaths occurred. The long-term colectomy risk was comparable in patients treated with infliximab and in steroid-responsive patients (18% vs. 11% respectively; OR 1.9; 95% CI 0.26-14.5). No predictive factors of colectomy, in the long-term, were identified. CONCLUSIONS: Surgery continues to play an important role in acute severe ulcerative colitis. Infliximab can avoid urgent colectomy in steroid-refractory patients but the risk of elective colectomy, in the long-term, is not modified.

Is early endoscopic retrograde cholangiopancreatography useful in the management of acute biliary pancreatitis? A meta-analysis of randomized controlled trials.

AIMS: To compare early endoscopic retrograde cholangiopancreatography with conservative management for the treatment of acute biliary pancreatitis: a meta-analysis of prospective randomized trials. METHOD: Pertinent studies were selected from the Medline, Embase, and the Cochrane Library Databases, references from published articles and reviews. Conventional meta-analysis according to DerSimonian and Laird method was used for the pooling of the results. The rate difference (95% CI) and the number needed to treat were used as a measure of the therapeutic effect. RESULTS: Five prospective randomized trials including 702 patients were selected. Overall complications and mortality rates were 31% and 6%, respectively. In predicted severe pancreatitis the pooled rate difference for complications in early endoscopic retrograde cholangiopancreatography was 38.5% (95% CI -53% to -23.9%); p < 0.0001; number needed to treat = 3. In predicted mild pancreatitis the pooled rate difference for complications in early endoscopic retrograde cholangiopancreatography was 1.8% (95% CI -5.6% to 9.3%); p = 0.6. No mortality was observed in predicted mild pancreatitis. In predicted severe pancreatitis the pooled rate difference for mortality in the early endoscopic retrograde cholangiopancreatography group was 4.3% (95% CI -16% to 7.5%); p < 0.24. CONCLUSIONS: Early endoscopic retrograde cholangiopancreatography reduces pancreatits-related complications in patients with predicted severe pancreatitis although mortality rate is not affected. In predicted mild pancreatitis early endoscopic retrograde cholangiopancreatography has no advantage compared to conservative management.

Early versus late surgery for ileo-caecal Crohn's disease.

BACKGROUND: Surgical resection is almost inevitable in Crohn's disease. Surgery is usually performed for refractory or complicated disease: no studies appear to have been carried out, so far, to evaluate the potential benefits of performing surgery early in the course of the disease. AIM: To compare the long-term course of Crohn's disease following ileo-caecal resection performed at the time of diagnosis (early surgery) or during the course of the disease (late surgery). Patients and methods Overall 207 patients with ileo-caecal Crohn's disease at their first resection were reviewed: 83 patients underwent surgery at the time of diagnosis (early surgery), while 124 underwent surgery 54.2 months (range 1-438) after diagnosis (late surgery). The mean follow-up after surgery was 147 months (range 12-534). The primary endpoint was clinical recurrence, defined as need for corticosteroids for symptomatic disease in the presence of endoscopic and/or radiologic recurrence. Secondary endpoints were need for immunosuppressants and surgical recurrence. STATISTICAL ANALYSIS: Kaplan-Meier survival method and Cox proportional hazards regression model. RESULTS: Within 10 years after surgery, the cumulative probability of clinical recurrence was significantly lower in the early surgery group (Log Rank test P = 0.01). A trend was observed regarding the need for immunosuppressants (P = 0.05). No difference was observed regarding surgical recurrence. At multivariate analysis, early surgery was the only independent variable associated with a reduced risk of clinical recurrence (Hazard ratio, HR = 0.57; 95% CI 0.35 to 0.92, P = 0.02), but not with need for immunosuppressants and surgical recurrence (HR = 0.51; 95% CI 0.20 to 1.30, P = 0.15; HR = 0.66; 95% CI 0.33 to 1.35, P = 0.25, respectively). CONCLUSION: Early surgery prolongs clinical remission compared to surgery performed during the course of the disease, but the natural history of disease is not modified.

Use of a 99mTc labeled anti-TNFalpha monoclonal antibody in Crohn's disease: in vitro and in vivo studies.

AIM: Crohn's disease (CD) is a chronic inflammatory bowel disease characterized by a cellular-mediated immune response driven by cytokines secreted mainly by T helper 1 cells (Th1). In active phases of the disease, an increased production and release of tumor necrosis factor a (TNFalpha) by macrophages and monocytes of the lamina propria has been described. The aim of this study was to detect the presence of TNFalpha within the gut mucosa in patients with active CD by using (99m)Tc-labelled chimeric human/mouse monoclonal antibody anti-TNFalpha (Infliximab, Remicade). METHODS: Infliximab has been labeled with (99m)Tc after reduction of disulfide bound by 2-ME method. In vitro binding assay and biodistribution in animal of [(99m)Tc]Infliximab has been performed to evaluate the retention of its biological activity. Ten patients with active CD refractory to conventional medical therapies were studied. Images of the abdomen were acquired at 6 to 20 h after i.v. injection of about 10 mCi of [(99m)Tc]Infliximab and a week later, all patients were also studied with [(99m)Tc]HMPAO-labeled autologous white blood cells (WBC). RESULTS: A product with high labeling efficiency (>95%) and stability has been obtained. In vitro tests with stimulated T-cells expressing TNFalphalpha indicated that [(99m)Tc] Infliximab retains its binding activity to cell bound TNFalpha as compared to unlabelled Infliximab. The degree of [(99m)Tc]Infliximab uptake by the inflamed bowel evaluated at 20 h postinjection was much less than that seen with labeled WBC and with a different distribution. Three of these patients received anti-TNFalpha (Infliximab) for therapeutic purposes with good clinical results despite the scintigraphy with (99m)Tc-Infliximab was negative in 2 of them. CONCLUSION: Scintigraphy with [(99m)Tc]Infliximab shows the presence of little TNFalpha in the affected bowel of patients with active CD. Therefore, the clinical benefit that patients have from Infliximab therapy is unlikely the consequence of a local a reduction of TNFalpha and the mechanism of action of Infliximab, in therapeutic doses, deserves further investigations.

Mucosal features and granulocyte-monocyte-apheresis in steroid-dependent/refractory ulcerative colitis.

BACKGROUND: Mucosa-infiltrated granulocyte neutrophils are an early characteristic of inflammation and the main histological feature of active ulcerative colitis. Mucosal healing has recently been indicated as an important tool in the evaluation of response to treatment. While several studies have stressed the efficacy of granulocyte-monocyte-apheresis in inducing clinical remission in active ulcerative colitis, few data are available on mucosal features. AIM: Aim of this study was to assess the effects of granulocyte-monocyte-apheresis on clinical and mucosal features in patients with ulcerative colitis, dependent upon or refractory to steroids. MATERIAL AND METHODS: From April 2004 to April 2005, 12 patients (5 females, 7 males, mean age 49 years, range 33-71 years), with mild-moderate ulcerative colitis (six left colitis, six pancolitis) dependent/refractory upon steroids were enrolled. Each patient was treated for a 5-week period with five cycles of granulocyte-monocyte-apheresis. Patients were evaluated at baseline and 1 week after the last apheresis by means of Global Physician Assessment, quality of life features, laboratory tests (erythrocyte sedimentation rate, CRP, full blood count, faecal calprotectine), endoscopy and histology. RESULTS: At week 6 of follow-up, complete mucosal healing was observed in 3 out of 12 patients, partial mucosal healing in 8 patients and no change in 1 patient. Clinical response was complete in 8 out of 12 patients. CONCLUSIONS: These data suggest that granulocyte-monocyte-apheresis induces an improvement both in clinical and mucosal lesions in steroid-dependent/refractory ulcerative colitis. Of note, the reduction in granulocyte infiltration and the improvement in mucosal lesions are accompanied by a reduction in faecal calprotectine.

Seasonal variations in onset of symptoms in Crohn's disease.

BACKGROUND: Seasonal variations in onset of symptoms have been reported in ulcerative colitis but not in Crohn's disease. AIM.: To investigate whether our inflammatory bowel diseases patients presented seasonal variations in onset of symptoms. PATIENTS AND METHODS: Patients with a diagnosis of inflammatory bowel diseases established between 1995 and May 2004, and consecutively observed from June 2003 to May 2004, were included in the study. Onset of symptoms (year, season and month) was recorded. Expected onsets with a uniform distribution during the year were calculated and compared to observed onsets. STATISTICAL ANALYSIS: chi-square test, odds ratio (95% confidence interval). RESULTS: Overall 425 inflammatory bowel diseases patients were enrolled. Onset of symptoms (year and season) was established in 353/425 patients (83%; 150 Crohn's disease; 203 ulcerative colitis). Onset of symptoms in inflammatory bowel diseases patients as a whole occurred more frequently in spring-summer compared to autumn-winter (odds ratio 1.39; 95% confidence interval 1.03-1.87; p<0.03). This variation was observed in Crohn's disease (odds ratio 1.59; 95% confidence interval 1.00-2.51; p<0.05) and a similar trend, although not significant, was observed in ulcerative colitis (odds ratio 1.27; 95% confidence interval 0.86-1.88; p=0.27). CONCLUSIONS: These data indicate that onset of Crohn's disease symptoms occurred more frequently during spring-summer. A similar trend was observed in ulcerative colitis. Environmental factors, such as associated infections, smoking, use of drugs and seasonal changes in immune function may be responsible for triggering the clinical onset of inflammatory bowel diseases.