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.

Minimizing infliximab toxicity in the treatment of inflammatory bowel disease.

BACKGROUND: Infliximab is a widely used biological agent for the treatment of inflammatory bowel disease, and has a favorable risk/benefit ratio. AIM: It is useful to know that patients treated with infliximab are exposed to developing adverse events that could be reduced with a prudent and a rational clinical approach and by optimizing the treatment protocol. METHODS: PubMed (including Epub) was searched in October 2006 and again in March 2007. RESULTS: The high immunogenic potential of infliximab determines the antibodies that inhibit the effect of infliximab and the appearance of subsequent acute and delayed infusion reactions. Infliximab has an immunomodulatory effect, thus increasing the risk of serious and latent infections. Screening for tuberculosis, HBV, opportunistic or latent infections, heart failure, and haematological, neurological and hepatological disorders must be performed before infliximab therapy. There is no definitive evidence that infliximab increases the risk of neoplasia. Mortality in infliximab-treated patients does not appear increased compared to the controls. CONCLUSIONS: Infliximab safety is similar to that of conventional immunomodulators and patients treated had similar rates of mortality, neoplasm and lymphoma as patients not treated with infliximab. Patients treated with infliximab have an increased risk of serious infections but it is not related to infliximab therapy.

Clinical course of ulcerative colitis.

AIM: To provide a review of studies on prognosis in ulcerative colitis by reviewing the relevant population-based cohort studies. On the basis of incidence and population studies, ulcerative colitis has a favourable clinical course, with good quality of life, a chronic course characterized by at least one relapse, and a surgery rate of 30% after 10 years from diagnosis. Patients affected by severe ulcerative colitis have a higher risk of colectomy, and some clinical variables may predict the disease's clinical course. Most patients respond to steroids and only a low percentage become dependent, or non-responders to steroids. Patients who have a long-lasting ulcerative colitis (>10 years) or are affected by an extensive disease have an increased risk of developing colorectal cancer, while those treated with immunosuppressants for long period of time may have an increased risk of developing lymphomas. Data on mortality in ulcerative colitis patients are not homogeneous, but if a real risk exists it is in patients with extensive or severe disease. The evidence that patients with severe ulcerative colitis are often non-smokers may explain why in one study the mortality rate was lower.

Meta-analysis: remission and response from control arms of randomized trials of biological therapies for active luminal Crohn's disease.

BACKGROUND: Remission and response are the main outcomes to evaluate the efficacy of new treatments for Crohn's disease (CD). AIM: To explain variation of remission and response rates in active luminal CD. METHODS: We studied control patients from trials of biological therapies through articles retrieved by MEDLINE search (from 1997 to 2007) and by bibliography review. Thousand nine hundred and thirteen control patients from 28 trials were identified; data were extracted by three independent observers and pooled by DerSimonian and Laird random effect model; factors influencing remission and clinical response were explored by metaregression for aggregated data. RESULTS: The pooled control rates of remission and response were 17% and 33%, respectively, both with significant heterogeneity among studies (P < 0.0001). At metaregression, the time of primary outcome evaluation was associated with remission, whereas the trial's criteria for defining response and publication year were predictors of response. CDAI score, CRP levels or other clinical variables related with disease activity or concomitant medications were not significant factors. CONCLUSIONS: Populations used as 'add-on' treatment comparator in trials of biological therapies for active luminal CD are poorly characterized and outcomes are heterogeneous. Planning of future trials will require better description of patients and concomitant therapies, blinding of outcome assessors and homogeneous criteria of outcome definition.

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.

The role of calprotectin in predicting endoscopic post-surgical recurrence in asymptomatic Crohn's disease: a comparison with ultrasound.

BACKGROUND AND OBJECTIVES: Faecal calprotectin is predictive of clinical relapse in inflammatory bowel disease and ultrasound is sensitive in detecting its post-surgical recurrence. However, no data regarding the role of calprotectin in predicting post-surgical recurrence in asymptomatic Crohn's disease are available. The aim of this study was to prospectively evaluate the role of calprotectin as a predictive marker for one year post-surgical endoscopic recurrence in comparison with ultrasound in patients with asymptomatic Crohn's disease. MATERIAL AND METHODS: We consecutively enlisted 50 patients who had undergone a resection for Crohn's disease. Faecal calprotectin was analysed and ultrasound were performed at the third month, and a colonoscopy after one year. The sensitivity and specificity of these two techniques were evaluated using endoscopic findings as a golden standard. A Receiver Operator Curve (ROC) curve was plotted, in order to identify the best-cut off value for calprotectin. RESULTS: 39 out of 50 patients were evaluated by performing a colonoscopy after one year; 19 patients had an endoscopic recurrence after one year. Calprotectin sensitivity and specificity were calculated for 5 different cut-off values; the best cut-off value for calprotectin sensitivity (63%) and specificity (75%) was > 200 mg/L. The US sensitivity and specificity at the third month were 26% and 90% respectively. CONCLUSIONS: When performed three months after surgery ultrasound is more specific than calprotectin in predicting endoscopic recurrence. Faecal calprotectin at a dosage > 200 mg/L seems to have a better sensitivity than ultrasound. Values of calprotectin > 200 mg can be an indication to colonoscopy in the group of patients with negative ultrasound in order to detect early recurrence.

Infliximab in the treatment of Crohn's disease: predictors of response in an Italian multicentric open study.

BACKGROUND: Almost 20% of patients with active Crohn's disease are refractory to conventional therapy. Infliximab is a treatment of proven efficacy in this group of patients and it is not clear which variables predict a good response. AIMS.: To evaluate the role of infliximab looking at the predictors of response in a large series of patients with Crohn's disease. PATIENTS AND METHODS: Five hundred and seventy-three patients with luminal refractory Crohn's disease (Crohn's Disease Activity Index (CDAI)>220-400) (312 patients) or with fistulising disease (190 patients) or both of them (71 patients) were treated with a dose of 5 mg/kg in 12 Italian referral centres. The primary endpoints of the study were clinical response and clinical remission for luminal refractory and fistulising disease. We evaluated at univariable and multivariable analysis the following variables: number of infusions, sex, age at diagnosis, smoking habit, site of disease, previous surgery, extraintestinal manifestations and concomitant therapies, and type of fistulas. RESULTS: Patients with luminal refractory disease: 322 patients (84.1%) had a clinical response and 228 (59.5%) reached clinical remission. Patients with fistulising disease: 187 patients (72%) had a reduction of 50% of the number of fistulas and in 107 (41%) a total closure of fistulas was observed. For luminal disease, single infusion (OR 0.49, 95% CI 0.28-0.86) and previous surgery (OR 0.53, 95% CI 0.30-0.93) predicted a worse response for fistulising disease. Other fistulas responded worse than perianal fistulas (OR 0.57, 95% CI 0.303-1.097). CONCLUSION: In Crohn's disease infliximab is effective in luminal refractory and in fistulising disease. A single infusion and previous surgery predicted a worse response in luminal disease whereas perianal fistulas predicted a better response than other type of fistulas.