1Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy. Correspondence: S.L. (email: [email protected])

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.

We read with interest the article by Hou et al1Hou J.K. et al.Clin Gastroenterol Hepatol. 2014; 12: 1592-1600Google Scholar describing nonmedical dietary recommendations that patients with inflammatory bowel disease (IBD) encounter on the Web, and their possible scientific basis. The authors should be congratulated for their effort to come to grips with the complex interconnections between food and IBD. On the one hand, alimentary antigens may be involved in IBD pathogenesis and disease flares, especially in Crohn’s disease (CD). On the other hand, food probably can exacerbate irritable bowel syndrome–like symptoms in many patients. We have published the results of a randomized trial of a low-fiber diet in Crohn's disease2Levenstein S. et al.Gut. 1985; 26: 989-993Google Scholar that CD patients might find helpful. Over a mean of 29 months, 30 patients randomized to a very low fiber diet, consuming fruit and vegetables only as centrifuged extracts, had identical outcomes in terms of symptoms, need for hospitalization, need for surgery, new complications, nutritional status, and postoperative recurrence to 28 patients assigned to an ad libitum Italian diet. Oral diet histories to assess compliance showed that the ad libitum patients ate more than 3 times as many portions a week of fiber-containing foods than did low-fiber controls (27 vs 8; P < .0005). In diet diaries, some patients reported symptoms of pain and diarrhea after consuming milk, specific fruits, legumes, or spinach, even in puree form. Other foods reportedly associated with symptoms included coffee, chocolate, whisky, biscuits, clear broth, spices, fish, honey, and carrot juice. This would seem to confirm that CD patients can have individual food intolerances similar to those reported by IBS patients. On these grounds, patients with CD—and possibly by extension ulcerative colitis—can be reassured that consumption of fruit and vegetables will not induce inflammation or deterioration of their condition, although these foods may trigger nonspecific gastrointestinal symptoms. We did not specifically analyze cruciferous vegetables, citrus fruits, nuts, or legumes, which we see many lay Web sites frown on, but all are abundant in the traditional Italian diet that was consumed without ill effect by our ad libitum patients. IBD can have a marked negative impact on patients' quality of life. It is important that we do not further erode their lifestyle, or deprive them of otherwise beneficial foodstuffs, by imposing unnecessary dietary restrictions. Diet and Inflammatory Bowel Disease: Review of Patient-Targeted RecommendationsClinical Gastroenterology and HepatologyVol. 12Issue 10PreviewPatients have strong beliefs about the role of diet in the cause of inflammatory bowel disease (IBD) and in exacerbating or alleviating ongoing symptoms from IBD. The rapid increase in the incidence and prevalence of IBD in recent decades strongly suggests an environmental trigger for IBD, one of which may be dietary patterns. There are several pathways where diet may influence intestinal inflammation, such as direct dietary antigens, altering the gut microbiome, and affecting gastrointestinal permeability. Full-Text PDF

1Gastroenterology Department, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy Correspondence: Susan Levenstein, MD, Aventino Medical Group, Via Sant’Alberto Magno, 5, Rome 00153, Italy. E-mail: [email protected] The authors declare no conflict of interest.

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.

DOP099 Five-year safety results from the ENCORE registry: Malignancies in patients with Crohn’s disease treated with infliximab, standard therapy, or switched from standard therapy to infliximab G. D’Haens1 *, W. Reinisch2, J.-F. Colombel3, J. Panes4, S. Ghosh5, C. Prantera6, S. Lindgren7, D.W. Hommes8, Z. Huang9, S. Huyck10, D.K. Chitkara11. 1Academic Medical Center, Inflammatory Bowel Disease Centre, Amsterdam, Netherlands, 2Medical University, Department of Internal Medicine III, Vienna, Austria, 3Icahn School of Medicine at Mount Sinai, Department of Gastroenterology, New York, United States, 4Hospital Clinic I Provincial, Department of Inflammatory Disease, Barcelona, Spain, 5University of Calgary, Department of Medicine, Calgary, Canada, 6AO San Camillo Forlianini, Gastroenterology Operative Unit, Rome, Italy, 7University Hospital MAS, Department of Gastroenterology, Malmo, Sweden, 8University of California Los Angeles, Center for Inflammatory Bowel Diseases, Los Angeles, United States, 9Merck Sharp & Dohme, Department of Epidemiology, Kenilworth, United States, 10Merck Sharp & Dohme, Department of Statistics, Merck Research Laboratories, Kenilworth, United States, 11Merck Sharp & Dohme, Department of Clinical Research, Kenilworth, United States

Poster presentations features, therapeutic approaches and effects were analyzed.A multivariate logistic regression was performed to identify risk factors of refractory CD.Results: (1) The rates of steroid-dependent and ineffective to thiopurines were 27.5% (117/425) and 21.9% (93/425) respectively.(2) Univariate analysis showed that perianal disease (P = 0.035), abdominal pain (P = 0.027), diarrhea (P = 0.011), bloody stool (P = 0.003), fever (P = 0.000), higher white blood cell (P = 0.031), lower haemoglobin (Hb) (P = 0.002), lower hematokrit (P = 0.028) and lower albumin level (P = 0.007) were risk factors for steroid-dependant CD patients.Multivariate logistic regression showed that only fever (OR = 3.646, 95% CI: 1.849 7.191, P = 0.000) and low Hb (OR = 1.016, 95% CI: 1.001 1.031, P = 0.004) were independent risk factors related to steroid-dependent.(3) Univariate analysis showed that perianal disease (P = 0.033), abdominal pain (P = 0.009), diarrhea (P = 0.046), fever (P = 0.011), lower haemoglobin (P = 0.003), high erythrocyte sedimentation rate (ESR) (P = 0.032) and higher hypersensitivity C-reactive protein (HsCRP) (P = 0.006) are risk factors of ineffective or intolerant to thiopurines CD patients.Multivariate logistic regression showed that only abdominal pain (OR = 4.875, 95% CI: 1.389 17.116, P = 0.013) and higher HsCRP (OR = 0.976, 95% CI: 0.952 1.000, P = 0.049) were independent risk factors related to ineffective or intolerate to thiopurines.Conclusions: Around one quarter of CD patients in South China became refractory during the course of disease.Fever and low Hb were independent risk factors for CD patients developed steroid-dependant.Abdominal pain and high HsCRP were independent risk factors related to ineffective to thiopurines.

I read with interest the article by Danese et al. regarding the use of budesonide MMX (Santarus Inc., San Diego, CA, USA) in ulcerative colitis.1 We have recently written an editorial on this compound and our conclusion is quite different from that of the Danese review.2 In one of the two pivotal trials, in which budesonide MMX was compared to Asacol 2.4 g (Warner Chilcott plc, Dublin, Ireland), the therapeutic advantage of budesonide MMX 9 mg over Asacol was only 5.8% and there was no therapeutic advantage over 5-ASA when clinical improvement was taken into account.3 Asacol, in this study, was a nonpowered reference arm, suggested as active control by the regulatory authorities. We must take into account that 65.3% of the patients in the 2.4 g Asacol arm had a moderate activity and that a recent Cochrane review suggests that patients with moderate activity may benefit from an initial dosage of 4–4.8 g of mesalazine instead of 2.4 g.4 Moreover, in case of oral 5-ASA failure, adding 5-ASA enema to treatment increases the success rate.5 In the second pivotal study, budesonide MMX was compared with placebo and Entocort (Entocort; AstraZeneca, Wilmington, DE, USA).6 The MMX delivery system should ensure in UC a superior efficacy over Entocort, which is a budesonide preparation mainly delivered in the terminal ileum and right colon. However, in this study the advantage of budesonide MMX over Entocort at 8 weeks was only 4.8%. Moreover, the delivery system MMX, as expected, seems to influence the different efficacy of treatment following the disease location: the better results of budesonide MMX in the two studies were obtained in the left-sided colitis while, when the inflammation was extended over the splenic flexure, the advantage over placebo was not more statistically significant. For this reason the comparison with Asacol, which has a different delivery system, could have been misleading, given that two different drugs and two different delivery systems were compared. In our Editorial, other uncertain points, mainly regarding the maintenance treatment and the dose to be employed were mentioned but I think that a letter has to be relatively short. My opinion is that at the present time, before adopting this new drug in the therapeutic armamentarium of UC resistant to mesalazines, more data must be obtained from controlled studies in which budesonide MMX should be compared with 4.8 g of 5-ASA MMX in patients with moderate activity resistant to 2.4 g of 5-ASA. Declaration of personal interests: The author has been a consultant for Giuliani spa Italy and Alfa Wasserman spa Italy in 2013. Declaration of funding interests: None.

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.

The cause of inflammatory bowel disease is not completely understood. However, there is now a strong evidence that resident intestinal bacteria, which are normally considered to be commensal, can initiate the pathological inflammation in a susceptible host. Although this may be a good rationale for antibiotic use in the treatment of these diseases, previous trials with different antibiotics have given controversial results while their long-term use is accompanied by an elevated number of adverse events. Rifaximin is an oral, minimally absorbed (<1% of the ingested dose), antimicrobial agent that exerts its bactericidal activity in the intestinal lumen, and is apparently free of systemic side effects. The efficacy of a new gastroresistant formulation of rifaximin (rifaximin-extended intestinal release) in moderately active Crohn’s disease has been recently shown in a multicenter, randomized, double-blind trial. In open-label studies promising results have also been obtained in ulcerative colitis and pouchi...

Summary On the assumption that bacteria in the gut may be a cause of symptoms and/or complications of Crohn’s disease, various antibiotics are efficaciously employed in some affected patients. However, we do not know exactly why and how they are helpful. A possible explanation is that one or several bacterial species may have a primary role in the aetiology of Crohn’s disease, but this is not supported by the data in our possession. Another hypothesis is that intestinal bacteria may cause flare-up of the disorder, either by inducing intestinal lesions or by an interaction with the immune system, but we know today that specific pathogens can cause flares only in a minority of cases. On the contrary, there is considerable evidence that the intestinal microflora and its products may amplify and perpetuate inflammation in Crohn’s disease. Despite the fact that few controlled trials have been conducted, and have shown inconclusive results, antibiotics are widely employed for improving symptoms and for inducing remission of active phases. At present, a combination of metronidazole and ciprofloxacin, active against many enteric bacteria, has proved to be effective in the treatment of Crohn’s disease complications. This therapy also seems to be effective in acute flares as an alternative to, or in combination with, corticosteroids.

Introduction. Results from clinical trials often employ the odds ratio or relative risk to compare the proportion of subjects responding to experimental treatment to the proportion responding to control treatment. These measures have the advantage of using a single index to summarize the study results, but neither measure provides information that is intuitively meaningful to clinicians, and both can vary in different ways depending on the response to control treatment. Methods. We calculated the odds ratio and relative risk for responses to control treatment varying from 5% to 75% with a fixed difference of 20% between experimental and control responses. We then compared these values to those for two measures of effect size: number-needed-to-treat (NNT; N Engl J Med 1988; 318:1728-1733) and Probabilistic Index (Statist Med 2006; 25:591-602). Results. The Figure illustrates that with a fixed difference between responses to control and experimental treatment, as the response to control treatment increases, the odds ratio decreases to a plateau and then increases, whereas the relative risk decreases progressively. Since NNT and Probabilistic Index depend only on the difference between response to control and experimental treatment, values for these measures do not change with changing response to control treatment. That is, for a 20% difference between control and experimental responses, the NNT of 5 gives the number of experimental subjects needed to obtain one more success than treating the same number of control subjects. The Probabilistic Index for these same data is 0.6, and gives the probability that a randomly selected experimental subject has an outcome preferable to that from a randomly selected control subject. Conclusion. The NNT and Probabilistic Index depend only on the difference between responses to control and experimental treatment and can help clinicians assess the potential clinical significance of different values of the odds ratio and relative risk.

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. (C) 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

A 32-year-old man presented with a two-week history of lower abdominal pain, diarrhea without blood or mucus, and progressive abdominal swelling. He had no fever or recent weight loss, but he had experienced recurrent epigastric pain, nausea and episodic diarrhea for about one year. As a teenager,

90%) samples were positive while two were negative compared with 15 (75%) positive and five negatives when the bridge ELISA assay was used.The three patients who were positive for HACA in the homogenous assay also had low levels of IFX in their serum.Conclusions: A novel non-radiolabeled liquid-phase homogeneous assay with high sensitivity, accuracy and reproducibility has been developed to measure the IFX and HACA levels in serum from patients treated with IFX.This automated assay provides an important tool for clinicians to monitor and relate the clinical status of patients with their HACA and drug levels at any time during the course of treatment.