Irene Modesto

Meta-Analysis of the Placebo Rates of Clinical Relapse and Severe Endoscopic Recurrence in Postoperative Crohn's Disease

BACKGROUNDS & AIMS The benefit of therapy for prevention of postoperative recurrence of Crohns disease (CD) is limited. Clinical relapse and severe endoscopic recurrence are the main outcomes in the evaluation of trials on prevention of recurrence. The aim of this meta-analysis was to focus on knowledge of the placebo rates of relapse and recurrence in postoperative CD and to identify factors influencing these rates. METHODS We performed a meta-analysis of placebo-controlled, randomized clinical trials, evaluating therapies for postoperative maintenance of CD identified on MEDLINE from 1990 to 2006. Primary outcomes were clinical relapse and severe endoscopic recurrence. RESULTS The pooled estimate of the placebo relapse rate was 23.7% (95% confidence interval [CI], 13-35; range 0-78). There was a statistically significant heterogeneity among studies (P < .0001). Heterogeneity in clinical relapse was present even if the trials were stratified according to the time of outcome. The pooled estimate of the severe endoscopic recurrence rate was 50.2% (95% CI, 28-73; range, 30-79). There was significant heterogeneity among the studies (P = .00038). This heterogeneity was less apparent in studies carried out within 12 months. The logistic analysis identified only duration of follow-up as a variable associated with different placebo relapse rates. No variable was identified as a predictor of a placebo endoscopic recurrence rate. CONCLUSIONS There is significant heterogeneity among placebo rates in postoperative CD. No single design variable was identified that explained the heterogeneity in placebo outcomes for clinical or endoscopic recurrence.

The Role of CARD15 Mutations and Smoking in the Course of Crohn's Disease in a Mediterranean Area

AIM:To evaluate the role of CARD15 mutations and smoking in the main events of Crohns disease (CD).PATIENTS AND METHODS:A total of 182 patients with CD were included in a prospective study in order to evaluate the role of CARD15 mutations and smoking in the main outcomes of disease course: first operation and surgical recurrence. The following variables were evaluated in a univariable and multivariable analysis: age, sex, site of disease, pattern, smoking habit, extraintestinal manifestations, duration of disease, and CARD15 mutation. The Kaplan–Meier method for survival curves and Cox model for multivariable analysis were, respectively, used.RESULTS:A total of 110 patients were operated on and 32 were reoperated on. The 7-yr cumulative free rate of surgery was 42% (95% CI 34–51%). At multivariate analysis only stricturing and penetrating pattern were predictors of surgery (HR 1.7, 95% CI 1–2.8; HR 3.2, CI 1.8–5.5, respectively). The 7-yr cumulative free rate of reoperation was 75% (95% CI 0.52–0.88). At multivariable analysis in the model with any CARD15 mutation, only smoking habit at diagnosis (HR 3.6, 95% CI 1.4–9.1) was predictive of surgical recurrence. When single mutations were considered in the model smoking (HR 4.2, 95% CI 1.8–10.1) and L1007fs mutation (HR 2.9, 95% CI 1.1–7.3) were predictive of reoperation.CONCLUSIONS:In CD, smoking predicts recurrence after surgery. The role of CARD15 mutations in the clinical course of CD remains undefined.

Incidence of Crohn’s disease and CARD15 mutation in a small township in Sicily

Background: The incidence of Crohn’s disease (CD) has been shown to be lower in Southern than in Northern Europe. Data on the frequency of the NOD2/CARD15 mutations for Mediterranean area are very scant.Aim: To determine the incidence of CD from 1979 to 2002 in a township in Sicily together with the allele frequency of NOD2/CARD15 mutations in patients, family members and controls, and to determine the allele frequency of these mutations in sporadic CD from other areas of Sicily in comparison with a control population.Methods: Casteltermini is a small town close to Agrigento (Sicily) with a population of 9,130 inhabitants. All the diagnoses of inflammatory bowel disease (IBD) made from 1979 to 2002 were obtained through the local health authority. NOD2/CARD15 mutations were studied in 23 out of the 29 patients with CD in Casteltermini, in 60 family members and in 64 controls. NOD2/CARD15 was also studied in 80 sporadic cases of CD disease among Sicilians outside Casteltermini and 118 healthy controls.Results: From 1979 to 2002, 29 patients with CD and 13 patients with ulcerative colitis (UC) were registered. The 6-year mean incidence of CD ranged from 8.0 to 17 new cases for every 100,000 inhabitants, whereas the mean incidence of UC ranged from five new cases to 7.8 for every 100,000 inhabitants. The allele frequencies of NOD2/CARD15 mutations (L1007finsC, G908R, R702W) were 8.7, 4.3 and 8.7%, respectively, in CD cases; 5.0, 4.2 and 3.1% in family members; 1.6, 2.3 and 3.1% in controls. In sporadic Sicilian CD patients outside Casteltermini the allele frequency was 7.5, 8.1, 6.2% whereas in control population it was 3.3, 1.6, 1.6%.Conclusions: A high incidence of CD compared with UC was observed in this small town in Southern Italy. The frequency of NOD2/CARD15 mutations in CD is similar to other Caucasian population studied so far.

Postoperative maintenance therapy for inflammatory bowel disease.

Purpose of review This review will highlight the knowledge gained from studies published in the year 2005 on maintenance treatment after surgery for inflammatory bowel diseases. Recent findings In Crohns disease the role of smoking in increasing the risk of relapse and recurrence after surgery is confirmed. Ornidazole seems effective in reducing endoscopic recurrence and clinical relapse after surgery. Probiotics do not appear to be effective in preventing endoscopic recurrence and clinical relapse: a controlled placebo trial showed that Lactobacillus johnsonii is not effective in preventing endoscopic recurrence. A retrospective study suggested that enteral nutrition after surgery may reduce the clinical relapse. Pathophysiological studies underlined the value of probiotics in pouchitis. Summary In Crohns disease postoperative maintenance treatment is disappointing. Giving up smoking is still the only effective measure. Mesalamine remains the drug that has been widely studied with large trials and meta-analysis. Encouraging results come from small trials on antibiotics. Azathioprine and 6-mercaptopurine must be evaluated in better designed controlled trials. There is no evidence in favour of probiotics as an effective therapy to prevent recurrence. Enteral nutrition after surgery is a candidate new therapy, but further controlled trials are needed. Pathophysiological studies confirm the beneficial role of probiotics in pouchitis.

Infliximab and ulcerative colitis.

Tumour necrosis factor (TNF)-α is an inflammatory cytokine that plays a main role in the inflammatory process underlying inflammatory bowel disease (IBD). Despite the fact that the cytokine profiles associated with ulcerative colitis (UC) and Crohn’s disease (CD) are classically considered different (a Th2 pattern in UC and a Th1 pattern in CD), there are several evidences in vitro and in vivo that TNF-α has an important role in UC. For this reason, infliximab, the chimeric monoclonal antibody to TNF-α, has been evaluated in the therapy of UC. The drug has been evaluated in different clinical settings both in adults and in children: in moderate–severe steroid-dependent UC, in severe refractory UC as rescue therapy, in active non-steroid-refractory UC, in resistant pouchitis and in maintenance of moderate–severe UC responsive to infliximab. On the basis of the randomised controlled trials (RCTs), it is possible to draw the following conclusions for adults: infliximab seems active in severe steroid-refractory UC, allowing colectomy to be spared even if further controlled trials are needed with a larger sample of patients adopting strict and well-defined inclusion criteria. The drug seems active in inducing remission after 8 weeks in steroid-refractory patients, in patients taking steroids (even if it is not clear at which dosage of steroid dependence the drug is more active) and also in patients failing aminosalicylates therapy. The long-term response of infliximab in comparison to placebo in these subgroups of patients is not clinically impressive even if it is statistically significant. Further trials are warranted in order to establish the role of infliximab in steroid-dependent UC (defined with clear criteria), in maintaining remission after severe UC, in non-steroid-dependent moderate–severe UC and in refractory pouchitis. For children it is not possible to draw the same conclusions, due to a lack of RCTs, despite the encouraging data coming from open studies, mainly in steroid-refractory UC.

Mesalazine for the treatment of inflammatory bowel disease

Introduction: Ulcerative colitis (UC) and Crohns disease (CD) represent a chronic inflammatory condition of the bowel that often require lifelong medical therapy for the induction and maintenance of the remission. Mesalazine therapies are available both as oral delayed-release and sustained-release formulation, topical formulations and as prodrug. Areas covered: Available literature regarding mesalazine is extensively reviewed in this article, covering its mechanism of action, pharmaceutics and pharmacokinetics, clinical efficacy, safety and tolerability in different settings. Expert opinion: Mesalazine has a well-established role in the management of UC. It is the treatment of choice in active and inactive mild-to-moderate UC combining oral and topical drug. No clear role of mesalazine in prevention of colon cancer has been demonstrated because of the contradictory results coming from case–control and prospective studies. The role of mesalazine in the management of CD is less clear; some studies suggest a potential efficacy of 5-ASA in preventing relapse of CD after surgical resection but more convincing results are needed.

Is 5-ASA still the treatment of choice for ulcerative colitis?

5-Amino-salacylic acid (5-ASA) is up to now the treatment of choice in the induction and maintenance of remission of mild-to-moderate ulcerative colitis (UC). Sulfasalazine, despite similar efficacy, is hampered by more side effects, but in presence of peripheral arthopaties it remains the treatment of choice. The new delayed release MMX formulation seems to be promising in reducing compliance problems, but further studies are warranted to show the superiority of new MMX formulation compared with the older formulations of 5-ASA. Some trials evaluated also the efficacy and safety of once-daily dosing of older 5-ASA formulations in maintenance of remission, finding a greater adherence to therapy in the group given the once daily regimen, compared with the classic twice daily groups. Regarding the efficacy of alternative treatment such us probiotics and antibiotics, the current data are not sufficient to promote their use in clinical practice. Clinical evidence supports the use of topical 5-ASA in active mild to moderate distal UC showing superior efficacy to placebo, topical corticosteroids, and oral 5-ASA. A combination of oral and rectal 5-ASA produces additional efficacy in both limited and extensive UC. Topical 5-ASA formulations are effective also for the maintenance of remission, however long term treatment may not be acceptable to many patients. Other topical drugs (E. Coli Nissle, propionyl-L-carnitine, butyrate, tacrolimus, rosiglitazone) have been investigated with conflicting results. The possible chemopreventive role of long term treatment with 5-ASA strengthens the indication to the long term use of 5-ASA.

The Role of Portal Vein Thrombosis in the Clinical Course of Inflammatory Bowel Diseases: Report on Three Cases and Review of the Literature

Inflammatory bowel diseases are associated with an increased risk of vascular complications. The most important are arterial and venous thromboembolisms, which are considered as specific extraintestinal manifestations of inflammatory bowel diseases. Among venous thromboembolism events, portal vein thrombosis has been described in inflammatory bowel diseases. We report three cases of portal vein thrombosis occurring in patients with active inflammatory bowel disease. In two of them, hepatic abscess was present. Furthermore, we performed a systematic review based on the clinical literature published on this topic.

Methodology for high-quality studies on course and prognosis of inflammatory bowel disease

Inflammatory bowel diseases (IBDs) are characterized by a chronic course with an alternation of relapses and remissions. Questions about prognosis are important for the patient who wants to know how the disease will affect his/her life and also for clinicians to make management decisions. Correct selection of the patients is the basis for good methodological studies on the course of IBD. A great proportion of data on the course of IBD is derived from a limited number of cohort studies. Studies help to define the endpoints for clinical trials and to identify subsets of patients in whom the prognosis of the disease can be stratified according to clinical features. Specific scientific requirements for high-quality studies on prognosis are the following: use of inception cohort, description of referral patterns, completeness of follow-up, objective outcome criteria, blind outcome assessment, adjustment for extraneous prognostic factors and statistical issues. We analyzed each of these requirements in studies on IBDs. To date, prospective and population-based cohort studies are the standard for an unbiased assessment of prognosis. A better knowledge of the course of disease of chronic disorders ideally requires: (1) data from population-based studies, to avoid selection bias from referral centers in which patients with a more severe disease are usually treated; (2) inclusion of patients seen at the onset of the disease excluding misdiagnosed cases; and (3) follow-up from the onset of the disease to the end without dropouts.

Methodological Problems in RCTs on IBD

Randomized controlled trials (RCTs) are the gold standard method for developing evidence-based medicine in inflammatory bowel disease (IBD). Methodological problems in RCTs in IBD concern different aspects such as the definition of the study population due to the extreme variability of patients with IBD, the indices of disease activity, a clearly defined outcome, the environmental risk factors (i.e smoking behaviour) that may influence the randomization, the heterogeneous placebo rate of remission and the different statistical methods used to analyze the results. It is important that trials are designed efficiently, done well and complement clinical practice with a careful subject selection, standardization of disease activity indices, and precise outcome measurement in order to continue the improvement of the IBD research process.