Five-year Safety Data From ENCORE, a European Observational Safety Registry for Adults With Crohn's Disease Treated With Infliximab [Remicade®] or Conventional Therapy.

BACKGROUND AND AIMS: The ENCORE registry aimed at comparing the long-term safety of Crohn's disease [CD] treatment with infliximab [Remicade®] and with conventional therapies in real-world clinical practice. METHODS: The 5-year, prospective, observational ENCORE registry followed patients with CD in nine European countries, who received treatment with infliximab, conventional therapies, or switched to infliximab from conventional therapy. Adverse events [AEs] in pre-specified categories and serious AEs were recorded at least every 6 months of the 5-year observation period. Frequency of events was evaluated, and multivariable analyses using follow-up time [Cox proportion hazards model] and exposure time [Poisson regression] were used to identify risk factors for time to AEs in pre-specified categories. RESULTS: Patients who received infliximab [N = 1541], conventional therapies [N = 1121], or switched to infliximab [N = 298] were followed for medians of 60.4, 55.6, and 42.5 months, respectively. Infliximab median exposure was 18.7 and 19.3 months in the infliximab and switched-to-infliximab groups, respectively. In time-to-event Cox proportion hazards [PH] analyses adjusting for confounders, infliximab [vs conventional therapy] was associated with serious infections (hazard ratio [HR] = 1.64, 95% confidence interval [CI]: 1.17, 2.31] and haematological conditions [HR = 2.91, CI: 1.51, 5.59], and not associated with lymphoproliferative disorders/malignancy [HR = 1.44, CI: 0.86, 2.42] or death [HR = 1.22, CI: 0.63, 2.36]. Prednisone use was associated with higher mortality [HR = 3.58, CI: 1.49, 8.61]. In exposure-adjusted Poisson regression analyses, infliximab was associated with lower mortality (risk ratio [[RR] 0.39, CI: 0.17, 0.88]). CONCLUSIONS: Data from 5-year safety follow-up of patients with CD in the ENCORE registry demonstrate that infliximab [Remicade®] exposure is associated with increased risk of serious infections and haematological conditions, whereas mortality may be decreased.

Budesonide multi-matrix system formulation for treating ulcerative colitis.

Budesonide is a corticosteroid characterized by high topical activity and low systemic effect associated with fewer glucocorticoid-related adverse events than conventional steroids. Differently from Crohn's disease, no evidence suggests that oral budesonide is effective for the induction of remission of ulcerative colitis (UC). Budesonide multi-matrix (MMX) system is a new oral preparation that, by employing a MMX, provides the release of the drug throughout the entire colon. Its efficacy in inducing UC remission, at a dose of 9 mg, is based on some recent trials. However, in two studies the absolute differences between budesonide MMX and placebo were much lower than the rate of success reported in previous trials with mesalazines. In addition, the therapeutic advantage of budesonide MMX 9 mg over 5-aminosalicylic acid (5-ASA) showed by one study, and the advantage of budesonide MMX over budesonide reported in the other study, was only 5.8 and 4.8%, respectively. The evidence supporting the use of budesonide MMX at a dose of 6 mg for maintenance is weak. Therefore, the effective dosage should be 9 mg also in maintenance, but not for > 4 - 6 months, because a prolonged treatment has showed to increase the rate of side effects.

Antibiotics and inflammatory bowel diseases.

Inflammatory bowel diseases are characterized by an altered composition of gut microbiota (dysbiosis) that may contribute to their development. Antibiotics can alter the bacterial flora, and a link between antibiotic use and onset of Crohn's disease (CD), but not ulcerative colitis, has been reported. The hypothesis that Mycobacterium avium subspecies paratuberculosis (MAP) could be an etiologic agent of CD has not been confirmed by a large study on patients treated by an association of antibiotics active against MAP. The observations supporting a role of intestinal microbiota in CD pathogenesis provide the rationale for a therapeutic manipulation of the intestinal flora through the employment of antibiotics. However, current data do not strongly support a therapeutic benefit from antibiotics, and there is still controversy regarding their use as primary therapy for treatment of acute flares of CD, and for postoperative recurrence prevention. Nevertheless, clinical practice and some studies suggest that a subgroup of patients with colonic involvement, early disease, and abnormal laboratory test of inflammation may respond better to antibiotic treatment. Since their long-term use is frequently complicated by a high rate of side effects, the use of antibiotics that work locally appears to be promising.

Rifaximin and Crohn's disease.

In a recent article, Longman and Swaminath analyzed our paper on the use of rifaximin in patients with moderately active Crohn's disease (CD). Here we report some considerations concerning their article. The exploratory post-hoc subgroup analysis showed that early-stage disease and, differently from that written by Longman and Swaminath, also colonic involvement seemed to be associated with a significant higher efficacy of rifaximin-EIR 800 mg twice daily. Early-stage disease is generally considered as the more easily treatable phase of CD, and the better response to rifaximin in Crohn's colitis is in accordance with the high concentration of bacteria in the colon. In addition, patients with C reactive protein level > 5 mg/L achieved remission more significantly than patients with normal values, thus suggesting that the symptoms were probably caused by inflammation instead of by non-inflammatory causes. We also analyze the role of rifaximin against gut bacteria and the clinical situations that could obtain the best results from antibiotics.

Glucocorticosteroids in the treatment of inflammatory bowel disease and approaches to minimizing systemic activity.

Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions characterized by chronic, uncontrolled inflammation of the gastrointestinal tract. Reported prevalence is high in the United States and northern Europe, while the incidence varies greatly across the rest of Europe. Glucocorticosteroids are the standard treatment for IBD, but due to adverse events their use can be limited. However, new formulations of glucocorticosteroids have been developed to reduce systemic activation. The aim of this review was to assess and summarize the efficacy and safety of new formulations of glucocorticosteroids. A MEDLINE search identified publications focused on new formulations of nonsystemic steroid-based drugs for IBD and benefits and limitations of each of the new glucocorticosteroid formulations were identified. Budesonide has good efficacy and is an established treatment for Crohn's disease; it has been shown to be beneficial for the induction of remission in these patients, although it is not recommended for the maintenance of induced remission. Glucocorticosteroids are not recommended for the maintenance of remission in patients with IBD. However, a recent study suggested that beclomethasone dipropionate may be effective for prolonged treatment in patients in the postacute phase of Crohn's disease who were treated with a short course of systemic steroids. The efficacy of fluticasone propionate and prednisolone metasulphobenzoate in IBD is not well established given the small number of patients enrolled in the few published clinical trials. While the tolerability of these glucocorticosteroids is favourable, more research comparing these new agents with traditional systemic glucocorticosteroids is warranted.

Use of antibiotics in the treatment of Crohn's disease.

Many data coming from animal models and clinical observations support an involvement of intestinal microbiota in the pathogenesis of Crohn's disease (CD). It is hypothesized in fact, that the development of chronic intestinal inflammation is caused by an abnormal immune response to normal flora in genetically susceptible hosts. The involvement of bacteria in CD inflammation has provided the rationale for including antibiotics in the therapeutic armamentarium. However, randomized controlled trials have failed to demonstrate an efficacy of these drugs in patients with active uncomplicated CD, even if a subgroup of patients with colonic location seems to get benefit from antibiotics. Nitroimidazole compounds have been shown to be efficacious in decreasing CD recurrence rates in operated patients, and the use of metronidazole and ciprofloxacin is recommended in perianal disease. However, the appearance of systemic side effects limits antibiotic long-term employment necessary for treating a chronic relapsing disease. Rifaximin, characterized by an excellent safety profile, has provided promising results in inducing remission of CD.

Surgical and nonsurgical hospitalization rates and charges for patients with ulcerative colitis in Italy: a 10-year cohort study.

BACKGROUND: Today we are observing an increasing incidence of ulcerative colitis associated with an improved survival of patients. AIM: To analyse current rates, outcomes, and costs of inpatient care for ulcerative colitis patients of central Italy. METHODS: The cohort included 644 ulcerative colitis patients, living in the Lazio region, with diagnosis made or confirmed by the staff of a single tertiary referral centre in Rome (1997-2006). Follow-up data on hospitalization rates, costs, and colectomy rates were collected from the Regional Hospital Information System. RESULTS: Overall hospitalization rates were 3 times higher than those of the region's general population, reflecting excess admissions for digestive or infectious diseases (standardized hospitalizations rates for digestive-tract: 15.9; for infectious diseases: 3.5). The overall cumulative risk for colectomy was 7.5%. On the average, hospitalizations for ulcerative colitis lasted 10 days. The mean reimbursement for a ulcerative colitis-related hospitalization was EUR 5120 (€4609 for nonsurgical admissions, €8655 for surgical hospitalizations). CONCLUSION: Ulcerative colitis patients are 3 times more likely to be hospitalized than the general population. Colectomy rates in Italian ulcerative colitis patients resemble those of northern Europe, but most hospital admissions are for diagnostic procedures or medical therapy. Hospitalizations are almost twice as long as those reported in the United States although their mean cost is considerably lower.

Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn's disease.

BACKGROUND & AIMS: Bacteria might be involved in the development and persistence of inflammation in patients with Crohn's disease (CD), and antibiotics could be used in therapy. We performed a clinical phase 2 trial to determine whether a gastroresistant formulation of rifaximin (extended intestinal release [EIR]) induced remission in patients with moderately active CD. METHODS: We performed a multicenter, randomized, double-blind trial of the efficacy and safety of 400, 800, and 1200 mg rifaximin-EIR, given twice daily to 402 patients with moderately active CD for 12 weeks. Data from patients given rifaximin-EIR were compared with those from individuals given placebo, and collected during a 12-week follow-up period. The primary end point was remission (Crohn's Disease Activity Index <150) at the end of the treatment period. RESULTS: At the end of the 12-week treatment period, 62% of patients who received the 800-mg dosage of rifaximin-EIR (61 of 98) were in remission, compared with 43% of patients who received placebo (43 of 101) (P = .005). A difference was maintained throughout the 12-week follow-up period (45% [40 of 89] vs 29% [28 of 98]; P = .02). Remission was achieved by 54% (56 of 104) and 47% (47 of 99) of the patients given the 400-mg and 1200-mg dosages of rifaximin-EIR, respectively; these rates did not differ from those of placebo. Patients given the 400-mg and 800-mg dosages of rifaximin-EIR had low rates of withdrawal from the study because of adverse events; rates were significantly higher among patients given the 1200-mg dosage (16% [16 of 99]). CONCLUSIONS: Administration of 800 mg rifaximin-EIR twice daily for 12 weeks induced remission with few adverse events in patients with moderately active CD.

Beclomethasone dipropionate in Crohn's ileitis: a randomised, double-blind trial.

BACKGROUND: Steroids, the mainstay of Crohn's disease treatment, have been associated with systemic side effects. AIM: To evaluate the efficacy and tolerability of beclomethasone dipropionate for maintaining remission induced by a short course of systemic steroids in patients with Crohn's ileitis with or without right colonic involvement. METHODS: Patients (n=84) with active Crohn's disease who achieved remission during a 2-week prednisone run-in period were randomised to receive beclomethasone dipropionate for 24 weeks or continue prednisone for a further 2 weeks followed by placebo for 22 weeks. The primary outcome was relapse rate (Crohn's Disease Activity Index score>150 and an increase of ≥60 points from baseline) or withdrawal due to disease deterioration. RESULTS: The relapse rate was 23.3% and 53.8% in beclomethasone dipropionate and placebo groups, respectively (p=0.027). According to Kaplan-Meier analysis, the cumulative relapse rate was 38.0% in the beclomethasone dipropionate group and 56.0% in the placebo group (p=0.025). Six percent and 1.7% of all adverse events in the beclomethasone dipropionate and placebo groups, respectively, were endocrine-related. CONCLUSION: These results demonstrate that beclomethasone dipropionate significantly reduces the relapse rate in post-active Crohn's ileitis patients compared with placebo after induction of remission with a short course of systemic steroids, and is well tolerated.

The impact of endoscopy and specialist care on 30-day mortality among patients with acute non-variceal upper gastrointestinal hemorrhage: an Italian population-based study.

OBJECTIVE: To analyze the effects of endoscopy and care in a gastroenterology ward on 30-day mortality among Italian patients hospitalized for acute non-variceal upper gastrointestinal hemorrhage (UGIH). METHODS: We conducted a population-based study based on administrative data contained in the Regional Hospital Information System (RHIS) for the Lazio Region (Italy). We identified all hospitalizations with a main diagnosis of UGIH during period 2000-2005. Discharge data were analyzed for procedures performed, ward where the patient was cared for, comorbidities, vital status at discharge. Vital status 30 days after admission was cross-checked with the Regional Registry of Causes of Death. Logistic regression models were performed taking into account patients' risk factors (OR and C.I. 95%). RESULTS: A total of 13,427 hospitalizations for UGIH (mean patient age, 68 years; 60% males) were identified. The 30-day mortality was 6.9%. Significantly lower rates were observed among hospitalizations that included endoscopy (OR 0.30, 95% C.I. 0.26-0.34), specialist care (OR 0.55, 95% C.I. 0.37-0.82), or both (OR 0.12, 95% C.I. 0.07-0.22). The protective effects of endoscopy and specialist care remained strong after adjustment for potential risk factors. CONCLUSIONS: Endoscopy, per se, reduces mortality among patients hospitalized for UGIH, and care in a gastroenterology ward may offer additional protective effects.

5-ASA in ulcerative colitis: improving treatment compliance.

5-Aminosalicylic acid (5-ASA) compounds are a highly effective treatment for ulcerative colitis (UC). While UC patient compliance in clinical studies is over 90%, only 40% of patients in every day life take their prescribed therapy. Adherence to medication has been emphasized recently by a Cochrane meta-analysis that has suggested that future trials of 5-ASA in UC should look at patient compliance rather than drug efficacy. Better compliance can be obtained by reducing the number of tablets and times of administration. Given that the 5-ASA formulations have different delivery systems that split the active moiety in various regions of the intestine, it is particularly important that an adequate dose of the drug arrives at the inflamed part of the colon. 5-ASA Multi matrix (MMx) is a novel, high strength (1.2 g), oral formulation designed for once-daily dosing. It releases the active moiety throughout the colon. Different studies with this compound have shown that it is as effective as 5-ASA enema in the treatment of mild-to-moderate, left-sided UC, and is comparable to a pH-dependent, delayed release 5-ASA (Asacol), even if given once daily. Recently, the effectiveness in the acute phase of UC has been confirmed also in maintenance. In conclusion, at present, 5-ASA MMx seems theoretically the best agent for maintaining patient compliance, and consequently, treatment effectiveness.

Antibiotics and probiotics in inflammatory bowel disease: why, when, and how.

PURPOSE OF REVIEW: To summarize recent evidence on the role of intestinal bacteria in inflammatory bowel diseases, and of antibiotics and probiotics in their treatment. The implications connected with the use of antibiotics are also examined. RECENT FINDINGS: The hypothesis that Mycobacterium paratuberculosis could be a causative agent of Crohn's disease has not been confirmed by a large trial on symptomatic patients treated by a combination of antibiotics active against this bacterium. An increased number of adherent-invasive Escherichia coli have been found in the intestinal tissue of patients with Crohn's disease, but their role in the pathogenesis of this condition remains to be defined. The combination of metronidazole and azathioprine, associating the effects of a reduced bacterial load with immunosuppression, appears to be a therapeutic option to decrease the recurrence of postoperative Crohn's disease in high-risk patients. However, concerns are raised by the possibility that antibiotics may induce disease relapse due to Clostridium difficile infection. SUMMARY: Recent literature provides increasing support for the use of antibiotics in Crohn's disease, although the side effects limit their long-term use. The efficacy of antibiotics in ulcerative colitis is not confirmed by the available literature, except in severe colitis. More trials are needed to support the use of probiotics as therapy in inflammatory bowel disease.