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Background and aims Treatment of inflammatory bowel diseases (IBD) is only aimed to block or inhibit the pathogenetic steps of the inflammatory cascade. Side effects of systemic therapies, poor targeting of orally administered topical drug and low adherence to prescription represent frequent therapeutic challenges. Recent observations suggest that nanotechnology could provide amazing advantage in this field since particles having dimension in the nanometer scale (nanoparticles) can modify pharmacokinetic step of biologic and conventional therapeutic agents with a better delivery of drugs within the intestinal inflammatory cells. The aim of this review was to provide the clinician with an insight into the potential role of nanotechnology in the treatment of IBD. Methods A systematic search (PubMed) for experimental studies on the treatment of intestinal inflammation using nanotechnology for the delivery of drugs. Results and conclusions The size of the pharmaceutical formulation is inversely related to specificity for inflammation. Nanoparticles can penetrate epithelial and inflammatory cells resulting in much higher, effective and long-acting concentrations than can be obtained using conventional delivery systems. From a practical point of view, this should lead to improvements in both efficacy and adherence to treatment, providing patients with the prospect of stable and prolonged remissions with reduced drug loadings. Reduced systemic side effects could also be expected.

Inflammatory bowel diseases (IBDs), encompassing ulcerative colitis (UC) and Crohn's disease (CD) are chronic, progressive and relapsing pathologic conditions caused by a dysregulation of the immune system.1 IBDs are characterised by inflammation and ulceration of the intestinal mucosa.2 The main symptoms, such as abdominal pain, altered bowel functions and rectal bleeding, significantly alter a patient's quality of life (QOL). In the absence of any aetiological therapy, clinical improvement is the main treatment goal. Clinical improvement is typically associated with a gradual reduction in the severity of intestinal lesions; however, it is common for symptoms to recur.3 Mucosal healing (MH) offers a potential end point for IBDs treatment but until recently the aim of UC and CD treatment was to improve symptoms and prevent relapse episodes with no consideration of mucosal restitution. Improved disease prognosis is possible through the achievement of both clinical (resolution of symptoms) and endoscopic (healing of intestinal mucosa) remission, which represents the best case scenario for patients with IBDs, therefore efforts should be maximised to achieve these endpoints. MH in the rectum has been reported in UC patients following topical treatment with 5-aminosalicylic acid (5-ASA); however, this observation was used as a diagnostic tool rather than a therapeutic goal.4 MH has also been reported in a small proportion of CD patients achieving clinical remission following corticosteroid treatment.5 In CD, healing of endoscopic lesions was first reported in patients treated with methotrexate,6 azathioprine7,8 and infliximab.9,10 Existing data showed that persistent MH, following treatment with infliximab, in patients with CD resulted in the need for fewer hospitalisations, surgeries and intensive care unit stays.11 The recent availability of biological therapies has provided an invaluable addition to the therapeutic options available for IBDs. In particular, biological therapies offer …

Several old and new observations suggest the existence in Crohn's disease of a phagocytic disorder of macrophages related to impaired bactericidal activity of host cells or to the presence of invasive bacteria that have developed strategies to counteract macrophage killing. It was recently reported that disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. Secretion of proinflammatory cytokines by CD macrophages was impaired in response to E. coli or specific Toll-like receptor agonists. In addition, major advances in the etiology of Crohn's disease came from the existence of polymorphism in NOD2 and autophagy-related susceptibility genes (ATG16L1 and IRGM) in patients and from the identification of the presence of adherent-invasive E. coli (AIEC) colonizing the CD ileal mucosa and able to resist to macrophage killing. The role of impaired autophagy in Crohn's disease patients has been recently reinforced by the observation that the peptidoglycan receptor NOD2, in addition to sense intracellular bacteria, can induce autophagy by recruiting the critical autophagy protein ATG16L1 to the plasma membrane during bacterial internalization. Defects in autophagy might be the key element of the pathogenic pathway that lead to defective microbial killing, increased exposure to commensal and pathogenic intestinal bacteria and T cell activation. Defects in Paneth cells secreting lysozyme and antimicrobial peptides are observed in patients with ATG16L1 risk allele. Thus, the induction of autophagy or administration of preparations that mirrors the secretion of Paneth cells or both may be regarded as new therapeutic avenues for the treatment of Crohn's disease.

The advent of salicylates in the treatment of ulcerative colitis started in 1938 with the discovery of Salazopyrin by Nanna Svartz. This drug offered for the first time a therapeutic chance to patients with ulcerative colitis. In this paper we describe the fascinating history of Salazopyrin and salicylates from the first serendipitous observations to the last randomized clinical trials. Attention was paid to the pharmacokinetics and the mechanism of action of 5-aminosalicylates and, in particular, to the issue of the mucosal concentrations of 5-aminosalicylates and its therapeutic efficacy. Moreover a look at the new oral mesalazine formulations that allow the homogenous distribution of 5-aminosalicylate through all the large bowel was taken. Lastly, the possible use of mesalazine in the prevention of colorectal cancer was reviewed.

Crohn's disease can affect any part of the gastrointestinal tract, but terminal ileum is the most frequent localization. The reason why Crohn's disease is primarily located in the distal part of the ileum remains unexplained. In this article it has been attempted to provide a compelling explanation why Crohn's disease usually occurs in terminal ileum. Recent data indicate that some individuals are genetically predisposed to develop ileal Crohn's disease. Two genetic alterations, the polymorphism of Caspase Associated Recruitment Domain (CARD15) and Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACM6), favour the colonization of terminal ileum by entero adherent-invasive Escherichia coli (AIEC). The adhesion of these bacteria to epithelial intestinal cells depends on Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 expression in ileal epithelial cells and on the reduced ileal defensins expressed in a CARD15 dependent manner. Genetic defects in Authophagy-related 16-like gene (ATG16L1) and Immunity-related Guanosine Triphospatase (IRGM) recently found in ileal CD patients lead to a reduction of bacterial killing by macrophages and consequent continuous immunological upstimulation, cytokine secretion, chronic inflammation of the ileum and tissue injury. On the basis of all these data Crohn's disease of the ileum seems to be a subset of the disease mainly genetically determined.

Summary 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.

Summary Background Variants of myosin IXB (MYO9B) gene, encoding for a motor protein implicated in epithelial permeability, have been recently associated with inflammatory bowel disease. Aims To investigate the contribution of three polymorphisms of MYO9B gene for predisposition to Crohn’s disease and ulcerative colitis, their association with clinical phenotypes, particularly intestinal permeability, and possible interaction with the CARD15 gene. Methods 549 Crohn’s disease patients, 658 ulcerative colitis patients and 674 controls were genotyped for the rs962917, rs1545620 and rs2305764 single nucleotide polymorphisms. Results Highly significant genotypic association with Crohn’s disease and ulcerative colitis was shown for all three single nucleotide polymorphisms, with odds ratio ranging from 1.5 to 1.7 (P-value

At the “4th International Meeting on Inflammatory Bowel Diseases: on the Way to New Therapies,” Capri, 2006, genetics, bacteria–host interactions, immunomodulation, and tissue response were discussed deeply in order to understand, rationalize, and develop novel therapies. About genetics, the importance of a better understanding of the nature of known loci and of the putative associations was stressed. It was confirmed that genotype–phenotype associations in inflammatory bowel disease (IBD) have important clinical and therapeutic implications. The importance of the search for dominant bacterial antigens in chronic immune-mediated intestinal inflammation emerged, as well as knowledge of cellular and molecular mechanisms of bacterial–host interactions. It was discussed how innate and adaptive immunity signaling events can perpetuate chronic inflammation. Signal transduction pathways provide an intracellular mechanism by which cells respond and adapt to environmental stress. The identification of these signals have led to a greater understanding of the pathogenesis of IBD and pointed to potential therapeutic targets. It was shown that immune homeostasis is lost in IBD, resulting in a complex tissue response involving the action of immune and nonimmune cells. The nonimmune tissue response in IBD could be regarded as a new target for control of chronic intestinal inflammation. The changing role of biotherapy in IBD was widely discussed and in particular the anti-TNF-α monoclonal antibodies. Granulocyte-colony stimulating factor (GM-CSF) and stem cells therapies were also discussed. The risk-to-benefit ratio of the novel therapies was analyzed in detail. Finally, future directions for basic science and the unmet needs for clinical practice were presented. (Inflamm Bowel Dis 2007)

METHODS A multicentre randomized controlled trial was conducted to evaluate the efficacy of oral mesalazine (5-aminosalicylic acid) for the prevention of post-operative recurrence in 110 patients operated on for Crohn's disease by first intestinal resection. Patients were randomly allocated to receive 2.4 g/day of mesalazine, or no treatment at all. The protocol included colonoscopy with ileoscopy at 6 months and yearly thereafter. Recurrence was defined on the basis of endoscopic criteria and classified as mild or severe. RESULTS The demographic and pre-trial characteristics were very similar in the two groups of patients. The cumulative proportion of recurrence at 6, 12 and 24 months was significantly lower in the mesalazine group than in untreated group (P = 0.002). At 24 months the cumulative proportions of endoscopic recurrence were 0.52 +/- 0.12 (+/- S.E.M.) and 0.85 (+/- 0.07), respectively. At the same time the cumulative proportions of symptomatic recurrence were 0.18 +/- 0.09 and 0.41 +/- 0.09 (P = 0.006). The cumulative proportions of the severe recurrence was also significantly lower in the mesalazine group (0.17 +/- 0.09 vs. 0.38 +/- 0.09; P = 0.021). CONCLUSIONS The preliminary results of this study show that administration of oral mesalazine soon after surgery is effective in preventing post-operative endoscopic recurrence in Crohn's disease over a 2-year period. It is estimated that this treatment prevents 39% of all recurrences and 55% of the severe recurrences.

The emergency of effective biological therapy in the treatment of Crohn’s disease (CD) has led to a clinical debate about ‘step-up versus top-down strategy’. Step-up refers to the classic therapeutic approach, namely progressive intensification of treatment as disease severity increases. Top-down refers to the early introduction, in all CD patients, of intensive therapies, including biological agents and immunosuppressive drugs, with the aim of avoiding complications and improving quality of life, starting from the assumption that these drugs may interfere with the natural history of the disease. Very recently the Belgian IBD research group together with the Gut Club of North Holland designed ‘the Step Up versus Top Down Trial’. Combination of infliximab with immunosuppressives at onset was better than the current standard approach in terms of both induction and maintenance of remission. However, several observations still limit the use of infliximab as first-line treatment in adult CD patients. In particular, the epidemiological observation that over 50% of CD patients have a mild disease over time and will never require aggressive therapies is against the indiscriminate use of top-down strategy. Lack of markers able to identify high-risk patients, discussions about long-term safety and the high costs of infliximab are further factors supporting a more careful approach to the management of CD.

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. © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Over the last few years, much light has been shed on the pathogenesis of Crohn's disease. Further knowledge in this field has provided a firm basis not only in the understanding of current treatment but also for the development of new therapeutic strategies. Aim of these new agents is primarily to selectively interact with the key processes of intestinal inflammation. At present, only anti-tumour necrosis factor-alpha antibodies namely infliximab, is licensed for clinical practice but it is feasible to foresee that, in the near future, a larger range of these agents will become available. Herein, the most promising biological agents in the treatment of Crohn's disease are outlined, which patients would benefit from these agents and when they should be administered. Attention is focused on the early (top–down) or late (step-up) use of biological agents, which for their very targeted mechanism of action may be compared to guided missiles. As yet, early use of biological agents remains to be supported by convincing evidence, nevertheless it may be advocated as first-line therapy for newly diagnosed severe Crohn's disease patients, both adults and children.

Background. In cross-sectional studies, it was demonstrated that the therapeutic effect of mesalazine is closely related to its mucosal concentration. Aim. This study was carried out to verify in a longitudinal study if it was possible to improve the clinical course of ulcerative colitis at high risk of recurrence by increasing mucosal mesalazine concentration. Methods. Eighteen consecutive ulcerative colitis patients on continuous oral 5-ASA treatment (2.4–3.2 g/day) in clinical remission who had had at least four moderate to severe relapses in the preceding 2 years (referred period) were assigned to assume oral (3.2–4.8 g/day) and topical (4 g/day) mesalazine in order to increase mucosal drug concentration and were followed up for 2 years (study period). The localisation of disease was 12 pancolitis, six left colitis. The number and severity of recurrences, number of visits and endoscopies, courses of steroids and days of hospitalisation were compared with those of the previous 2 years. Rank signed test for paired data was used for statistical analysis. Results. The total number of recurrences was significantly lower during the study period in comparison with that of referred period (8 versus 80, respectively, p

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn’s disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

The introduction and rapid diffusion of biological agents in the treatment of inflammatory bowel disease had led us to believe that the old immunosuppressive drugs were destined to disappear. However, despite a decade of clinical experience in the use of biological agents, the old immunosuppressive drugs continue to play a pivotal role in the management of inflammatory bowel disease. Various factors may account for this change of view. Aim of the present review was to summarise key information currently available regarding the use of immunosuppressive drugs in the treatment of inflammatory bowel disease.

Summary Aim: To determine the efficacy of infliximab in the treatment of chronic refractory pouchitis complicated by fistulae following ileal pouch-anal anastomosis for ulcerative colitis. Methods: This open study included seven patients (four females, three males) with chronic refractory pouchitis complicated by fistulae. Pouchitis was diagnosed by clinical, endoscopic and histological criteria. The sites of the fistulae were as follows: pouch-bladder in one, vaginal in three, perianal in two, and both vaginal and perianal in one. Extra-intestinal manifestations (erythema nodosum, arthralgia) were present in four patients. Crohn's disease was carefully excluded in all patients after re-evaluation of the history, re-examination of the original proctocolectomy specimen and examination of the proximal small bowel. All patients had been treated with antibiotics and three with steroids. Patients received infliximab, 5 mg/kg, at 0, 2 and 6 weeks. Azathioprine (2.5 mg/kg) was also started for all patients as bridge therapy. Clinical response was classified as complete, partial or no response. Fistulae closure was classified as complete (cessation of fistulae drainage and total closure of all fistulae), partial (a reduction in the number, size, drainage or discomfort associated with fistulae) or no closure. The pouchitis disease activity index and quality of life were also used as outcome measures. Results: Clinically, all patients improved. At the 10-week follow-up, six of the seven patients had a complete clinical response, and five had complete fistulae closure. At the 10-week follow-up, the median pouchitis disease activity index decreased from 12 (baseline) (range, 10–15) to 5 (range, 3–8); the median quality of life decreased from 37 points (range, 33–40) to 14 (range, 9–18). Erythema nodosum and arthralgia showed complete remission soon after the first infusion of infliximab. Conclusions: These preliminary results indicate that infliximab may be recommended for the treatment of refractory pouchitis complicated by fistulae following ileal pouch-anal anastomosis for ulcerative colitis.

A case of abdominal tuberculosis with pancreatic involvement is described. A 27-year-old Italian male, with no known cause of immunodeficiency and with no evidence of pulmonary tuberculosis, was admitted to our division because of acute pancreatitis. Abdominal imaging revealed a large ‘tumour-like’ mass in the pancreas head compressing the distal choledochous, and multiple adenopathy. Histological examination of multiple specimens removed during explorative laparotomy revealed granulomas with giant cells, caseous necrosis, and positive Ziehl-Neelsen staining. Tissue culture was positive for Mycobacterium tuberculosis. Once specific medical treatment was started, the pancreatic damage completely resolved.

Background The treatment of distal ulcerative colitis, refractory to conventional 5-ASA/steroid treatment, is still a matter of debate. The present study aimed at confirming, with adequate statistical power, previous data indicating the usefulness of topical butyrate and 5-ASA in the treatment of this condition. Design Double-blind, placebo-controlled, multicentre study. A total of 51 patients with distal (

Summary Background : The role of mesalazine in preventing the clinical recurrence of Crohn's disease after surgery has been shown in a meta-analysis of all published studies. No clear relationship, however, has been shown between dosage and response. Aim : To evaluate whether 4.0 g/day of mesalazine may offer therapeutic advantages over 2.4 g/day in the prevention of both endoscopic and clinical post-operative recurrence of Crohn's disease. Methods : The study was a double-blind, randomized, multi-centre, prospective, controlled clinical trial. Two hundred and six patients, submitted to first or second intestinal resection for Crohn's disease limited to the terminal ileum, with or without involvement of the caecum/ascending colon, were enrolled. Of these, 101 were randomly allocated to receive 4.0 g/day of mesalazine (Asacol, Giuliani SpA, Milan, Italy) and 105 to receive 2.4 g/day, starting 2 weeks after surgery. The primary outcome was endoscopic recurrence, at 12 months after surgery. Three different degrees of endoscopic recurrence were evaluated (endoscopic scores: > 0, > 1 and > 2). The secondary outcome was clinical recurrence, defined as a Crohn's disease activity index of more than 150 points or an increase in the Crohn's disease activity index of 100 points or more. For statistical analysis, chi-square, Wilcoxon and Cox regression model tests were used, when appropriate. Results : Eighty-four patients in the 4.0 g/day group and 81 patients in the 2.4 g/day group were evaluable by endoscopy. Endoscopic recurrence of > 0 was significantly higher in the 2.4 g/day group than in the 4.0 g/day group (62% vs. 46%; P 1 and > 2) or clinical recurrence. Conclusions : A 4.0 g/day regimen of mesalazine does not offer a clinically significant advantage over a 2.4 g/day regimen in the prevention of post-operative endoscopic and clinical recurrence of Crohn's disease at 1 year of follow-up.

Crohn's disease (CD) is a chronic inflammatory bowel disease that may involve the whole gut. Marked intestinal T cell and macrophage activation is a key feature of the disease. Polymorphonuclear cell infiltration is also observed in the diseased gut, mainly during active inflammation. Scintigraphic detection of granulocytes and activated lymphocytes infiltrating the gut wall may be useful in identifying a subgroup of patients with clinically inactive CD who are undergoing early clinical relapse. The aims of the present study were (a) to compare the effectiveness of scintigraphy with (99m)Tc-labelled interleukin-2 ((99m)Tc-IL2) and with (99m)Tc-HMPAO labelled granulocytes ((99m)Tc-WBC) in detecting the presence and extent of bowel inflammation in patients with long-term inactive CD (12 months) and (b) to assess the accuracy of these techniques in predicting future disease relapse. We studied 29 patients with ileal and/or colonic CD in stable clinical remission (Crohn's Disease Activity Index150 for at least 12 months) using both (99m)Tc-IL2 and (99m)Tc-WBC scintigraphy in order to evaluate the extent of acute and chronic inflammation in the bowel. Planar and single-photon emission tomography images were acquired in each patient at 1 h p.i. For quantitative analysis of (99m)Tc-IL2 uptake, the abdomen was divided into 32 regions of interest. Despite the absence of symptoms, 18 patients (62%) showed a positive (99m)Tc-IL2 and 18 (62%) a positive (99m)Tc-WBC scan. Only 12 patients (41.4% of the total group) were positive on both scans, and the sites of IL2 and granulocyte bowel uptake were usually located in different segments, indicating that in CD, acute and chronic inflammation can be present in different sites. As far as the prognostic role of the two scans in predicting future disease relapse is concerned, both (99m)Tc-IL2 and (99m)Tc-WBC scintigraphy showed a high negative predictive value (1.00 and 0.91, respectively) but a weak positive predictive value (0.44 and 0.39, respectively). Nevertheless, Kaplan-Meier curves generated between scintigraphic findings and time free from disease relapse were statistically different only for (99m)Tc-IL2 scintigraphy (log-rank test, P=0.013). These results indicate that (99m)Tc-IL2 scintigraphy can be useful in selecting CD patients in clinical remission who could benefit from preventive therapy to avoid disease relapse.

The main aim of the management of Crohn's disease is to reduce inflammation. Current approaches with corticosteroids, immunosuppressive agents, mesalazine and antibiotics have limited therapeutic benefit for many patients. Considerable progress has been made with regard to our knowledge of the basic mechanisms of the disease, which is associated with immunological imbalance characterized by an excess of pro-inflammatory cytokines. Recent advances in bio-technology have led to the development of many new therapeutic agents, so-called biological agents, which selectively target single key processes involved in the pathogenesis of the disease. A growing number of biological agents are under investigation in both randomized controlled trials and uncontrolled studies. The aim of this review is to provide the clinician with an insight into the randomized controlled trials published in the literature on the use of biological agents in the treatment of Crohn's disease.

OBJECTIVES: In previous retrospective studies in patients with severe ulcerative colitis (UC), small bowel distension was found to characterize a subgroup of patients at higher risk for both toxic megacolon (TMC) and multiple organ dysfunction syndrome (MODS). In this study we prospectively evaluated the prevalence of GI distension and its relationship to clinical outcome in patients with severe UC. METHODS: Of 109 consecutive inpatients with acute UC (admitted to the GI Unit of the University of Rome during the period 1995–2000), 45 had severe colitis. Routine blood tests and acid-base balance and plain abdominal film evaluations were performed upon admission and repeated every 1–3 days. The gas content of the stomach and small and large intestines was evaluated on plain abdominal films. All patients were submitted to the standard Oxford intensive medical regimen; clinical improvement, occurrence of major complications, need for surgery, and mortality were evaluated. Statistical analysis was carried out using Student’s t, χ2, Fisher’s exact, Mann-Whitney, and Wilcoxon rank sum tests, when appropriate. RESULTS: Of 45 patients with severe UC, 24 (53%) had GI distension. Three of these 24 patients had TMC on admission (all underwent surgery and survived), 21 showed increased GI gas content (four developed TMC 1–4 days after the detection of GI distension and were operated on, two developed MODS and died, and eight did not improve but were submitted to surgery and survived). None of the 21 patients with normal GI gas content had complications; all survived (five did not improve and required surgery). CONCLUSIONS: In severe UC, persistent GI distension characterized a subgroup of patients with poor response to medical therapy and at higher risk for TMC and of need for surgery. The development of MODS was the most important predicting factor for fatal outcome.

We have evaluated morphologic alterations and epithelial cell apoptosis and proliferation of colonic mucosa in the acute and chronic phases of DSS-induced colitis. Colitis was induced in Sprague-Dawley rats by 7 days of 4% DSS oral administration followed by 7 days of tap water for one, two, and three cycles. Control rats receved tap water only. Morphological changes in colonic mucosa were evaluated and scored by light and scanning electron microscopy. Apoptosis was studied by TUNEL assay and cell proliferation by Ki-67 immunoreaction. The expression of both proapoptotic (Fas, FasL, Bax, p53) and antiapoptotic (Bcl2) cellular proteins was determined by immunohistochemistry. Morphologic assessment showed the most severe colonic epithelial lesions and inflammation in the distal colon with a trend to increasing severity from the first to the third DSS cycle. In DSS rats, the epithelial apoptotic index increased 20-fold after the first cycle and 120-fold after the second and third cycles compared with the controls; in the same way, the expression index of proapoptotic proteins (Fas, FasL, Bax, p53) dramatically increased. The proliferative index increased about 40 to 60-fold compared to controls, with no difference among the three DSS cycles. In conclusion, DSS-induced colitis in rats, which has many structural and ultrastructural features similar to those seen in human ulcerative colitis, is a suitable model for studying increased epithelial apoptosis and proliferation. Further studies employing this model will permitt two hypotheses to be tested. (1) Increased apoptosis may lead to a breakdown of the epithelial barrier function and facilitate the mucosal invasion of intraluminal microorganisms and/or antigens. (2) Abnormal and persistent epithelial hyperproliferation could be causally related to the development of colorectal cancers in the setting of chronic colonic inflammation.

OBJECTIVE Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn's disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families. METHODS In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year ( or = 1 yr). Statistical analysis was performed with chi2, Fisher's, Mann-Whitney U, and binomial probability tests, when appropriate. RESULTS A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization (p < 0.4) in CD families and extensive colitis (p < 0.05) in UC families was demonstrated. A generation difference of 15-20 yr in mean ages at onset of symptoms and at diagnosis was recorded. No features of more aggressive disease in subsequent generations and no differences in gender of transmitting parents and relatives were found. CONCLUSIONS Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15-20 yr earlier than in previous generations without features of increased severity.

OBJECTIVE: Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn’s disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families. METHODS: In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year ( RESULTS: A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization (p CONCLUSIONS: Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15–20 yr earlier than in previous generations without features of increased severity.

Summary Background No available therapy has, as yet, proven effective to treat acute radiation proctitis (ARP) following radiation therapy for malignant pelvic disease. We assessed whether sodium butyrate enemas, at a dose of 80 mmol/L (80 mL/24 h), might offer effective treatment for this condition. Methods 20 patients presenting with ARP after completing a cycle of 35-52 Gy external-beam radiation therapy for pelvic malignant disease, were treated for 3 weeks with topical sodium butyrate and saline enemas according to a randomised, double-blind, crossover protocol. Clinical, endoscopic, and histololical findings were assessed at enrolment, at week 3, and then at the end of the study. Data were analysed by two-tailed t test for paired data (continuous variables) and a logistic-regression model with variable multiple response for ordered categorical data. Findings Topical butyrate, but not saline, led to remission of symptoms (clinical score from 8·2 [SE 1·6] to 1·5 [0·7] vs 7·9 [1·8] to 8·1 [3·4]). When the treatment regimen was switched, eight out of nine of the previously placebo-treated patients went into remission, whereas three patients relapsed when switched to saline. The advantage of butyrate over placebo, expressed as CI, odds ratio, and p value was significant for almost all the clinical, endoscopic and histological factors taken into consideration. Interpretation Topical sodium butyrate, unlike other therapeutic regimens used so far, proved effective in the treatment of ARP.

Recent studies suggest that PUFAs may have a role in both duodenal ulcer incidence and H. pylori growth in vitro. This study investigated the effect of dietary PUFA supplementation on H. pylori in vivo. Fifteen H. pylori positive patients with mild functional dyspepsia were enrolled. H. pylori was histologically detected using both rapid urease test and histology by a blinded observer. Two grams of a dietary mixture of fish oil and blackcurrant seed oil (v/v) were fed daily for eight weeks and magnitude H. pylori infection determined both at the end of treatment and six months later. H. pylori clearance was obtained in eight out fifteen patients (53%). No migration of bacterium from antrum to fundus was observed. H. pylori eradication was obtained in 20% of these patients. The oil mixture used in this study produced good bacterial clearance, but poor H. pylori eradication. The effect of PUFA on H. pylori clearance may be due to modification of cellular membranes of both bacterium and host. These changes may reduce H. pylori virulence by interfering with bacterial adhesion to gastric epithelial cells or through a direct bactericidal effect on the micro-organism. If these data are confirmed, PUFA may be considered has adjuvant treatment for drugs usually employed for H. pylori eradication.

Butyrate represents the main source of energy for colonic epithelial cells; however, its availabilty/utilization is impaired in ulcerative colitis (UC). In the present randomized, double-blind, placebo-controlled pilot study, the safety and efficacy of colonic targeted oral sodium butyrate tablets, coated with a pH-dependent soluble polymer, have been evaluated in ulcerative colitis. Thirty patients with mild to moderate colitis underwent a six-week course of oral sodium butyrate (4 g/day) plus oral mesalazine (2.4 g/day), (Group A) or of oral mesalazine plus placebo (Group B). Clinical, endoscopic, and histologic data were collected at the beginning and the end of the study. Twenty-five patients completed the study (12 in group A, 13 in group B). No untoward side effects were reported. In group A, seven patients underwent remission and four improved; in Group B the numbers were 5 and 5, respectively. After treatment, all clinical parameters had significantly improved in both treatment arms compared to pretreatment findings. The UC disease activity index (UCDAI) score decreased from 7.27 ± 2.02 to 2.58 ± 2.19 (P < 0.05) in the combined treatment group and from 6.07 ± 1.60 to 3.46 ± 1.98 (P < 0.05) in group B. The endoscopic and histologic scores also significantly improved after treatment in both groups (P < 0.05). The difference between the two treatment arms was not significant, but a significantly better improvement vs baseline values (P < 0.05) was observed in the combined treatment group vs the mesalazine group, when considering both the clinical index (Δ9.58 ± 4.19 vs 5.92 ± 3.48) and the UCDAI score (Δ4.67 ± 2.19 vs 2.54 ± 2.18). A more favorable trend, although not significant, was observed for all individual parameters in group A. In conclusion, results of the present pilot study indicate that oral butyrate is safe and well tolerated. These data also suggest that oral butyrate may improve the efficacy of oral mesalazine in active ulcerative colitis and prompt the need of a large scale investigation to confirm the present findings.

Aim : To measure mucosal concentrations of mesalazine in ulcerative colitis patients treated with oral mesalazine alone, compared to patients treated with both topical and oral mesalazine. Methods : Twenty-two patients with mild to moderate ulcerative colitis were randomized to receive 2.4 g/day of oral mesalazine (11 patients) or 2.4 g/day oral plus 4 g/day of topical mesalazine (11 patients). After 2 weeks of treatment, endoscopic biopsies specimens were taken from the rectum and in descending colon just distal of the splenic flexure and stored to –80 °C for later assay (HPLC). Wilcoxon’s rank sum test for unpaired data was used for the statistical analysis. Results : Mucosal levels of mesalazine in the rectum were significantly higher in patients who received oral plus topical treatment than in those who had oral treatment alone (52.1 ng/mg, range: 13.6–122.1 vs. 0.2 ng/mg, range: 0.2–9.7, respectively; P

Background : Surgical resection of Crohn’s disease is followed by early recurrence in a high percentage of patients. Mesalazine has been shown to be effective in the prevention of post-operative recurrence, but some 50% of patients under treatment recur at 3 years of follow-up. Aim : To establish whether the mucosal concentration of mesalazine might affect the development of post-operative recurrence. Methods : Colon-ileoscopy was performed in 25 consecutive patients resected for Crohn’s disease. The mean time from surgery was 14 months. After the operation, all patients were taking oral mesalazine (Asacol, 2.4 g/day). Ten patients showed signs of endoscopic recurrence (apthae, ulcers, narrowing of the lumen) in the neoterminal ileum, five of whom also showed juxta-anastomotic colonic involvement. Fifteen patients were free of recurrence. At endoscopy, four biopsies were taken from the perianastomotic area (two specimens at the ileal site and two specimens at the colonic site of the anastomosis). The specimens were weighed and immediately frozen at −80 °C. Mesalazine concentration (ng/mg) was measured in tissue homogenates by high- performance liquid chromatography with electrochemical detection. Fisher’s exact test was used for the statistical analysis. Results : The mean value of mucosal mesalazine concentration, expressed as ng/mg of tissue, was significantly lower in patients with recurrence than in those without recurrence both in the ileum (mean ± s.d.: 21.6 ± 28.3 vs. 70.9 ± 47.4; P = 0.007) and in the colon (25.8 ± 26.4 vs. 60.3 ± 32.5; P = 0.010). Conclusions : The mucosal conentration of mesalazine in the juxta-anastomatic area is significantly lower in patients with recurrence than in those free of recurrence. These data could suggest an association between mucosal mesalazine concentrations and the clinical effectiveness of the drug.

SUMMARYThis study was performed in order to assess the cytotoxic activity, both natural (NK) and antibody-dependent (ADCC), of PBMC from 38 IBD patients and correlate it with their clinical features. Cytotoxicity assays were performed using sensitive target cells for NK and ADCC activities. In some experiments, highly purified NK cells, obtained both by Percoll density gradient and by co-culturing non-adherent PBMC with RPMI 8866 feeder cells, were used as effector cells. Furthermore, we evaluated NK cell parameters such as number, surface expression of adhesion molecules (CD11a/CD18, CD49d and CD54) and response to different stimuli. We observed a decreased NK cytotoxicity of PBMC from IBD patients, both in ulcerative colitis (UC) and Crohn's disease (CD), independently of the clinical activity of disease. In contrast, the ADCC lytic activity was within normal range. The lower NK cytotoxic activity observed in our IBD patients cannot be related to a decreased number of NK cells, surface expression of adhesion molecules, defective response to IL-2 and maturative defect. Decreased NK activity was induced in PBMC of controls when serum of patients was added and this was unrelated to monocyte-derived modulating factor(s). Our data show a decreased natural killing by fresh PBMC from IBD patients. This lower activity seems to be unrelated to a primary NK cell defect, since purified NK cells exhibited normal levels of killing. It might be hypothesized that serum factors, possibly derived from lymphocytes, with inhibitory properties on NK activity, might be functionally active in the blood of IBD patients, thus modulating NK activity.

Aim of this study was to assess the structural,ultrastructural, immunohistochemical, and clinicalaspects in Sprague-Dawley rats with dextrane sulfatesodium (DSS)-induced colitis. Colitis was induced in Sprague-Dawley rats by seven days of DSSoral administration followed by seven days of tap wateronly (for one, two and three cycles). Controls were fedwith water only. Segments of proximal, mid-, and distal colon of each animal were adequatelyprepared for light and scanning electron microscopeobservations. The severity of the lesions was scoredhistologically. For immunohistochemical study, acocktail of S-100, NSE, and antineurofilament antibodieswas used. Symptoms such as weight, feces consistency,diarrhea, hematochezia were recorded daily. From aclinical point of view symptoms appeared significantly later after the first cycle than after thesecond and third cycles and lasted significantly longerin the second and third cycles. Treated rats showed aslower weight gain rate by 20% compared to controls, and the whole colon length appeared to besignificantly shorter after colitis induction comparedto controls. Structural observations by light microscopyshowed prominent involvement of the distal colon. Immunohistochemical study of both submucosaland myoenteric nerve plexuses was similar to controls.Scanning electron microscope observations of the colonicmucosal surface in colitis rats showed a complete subversion of its architecture, characterizedby dilatations of gland crypt openings, dropout ofgoblet cells, and inhomogeneous distribution or lack ofmicrovilli. These were most evident after the third cycle. In conclusion, experimental DSS colitisin SD rats appeared to be highly reproducible and sharedmost features with human UC, not only from a structuraland clinical but also from an ultrastructural point of view.

Colitis following colonoscopy is an acute, self-limited condition characterized by tenesmus and bloody diarrhea appearing within 48 hours of colonoscopy or sigmoidoscopy. Glutaraldehyde used for disinfection of the endoscopes is considered to be the main etiological agent. Three cases of severe acute self-limited colitis are described in this report. All three were observed within one week, and showed the typical anamnestic, clinical, endoscopic, histological, and radiological features of glutaraldehyde-induced colitis. The main characteristics in these cases were the time relationship with colonoscopy and the severity of the clinical presentation, with symptoms of systemic reaction and intense and diffuse edema of the colonic mucosa. The clinical and morphological features may mimic those of colonic ischemia. All three patients recovered completely within a few days, one spontaneously and two after treatment with steroids, antibiotics, and mesalazine. Acute colitis following colonoscopy should be regarded as one of the complications related to colonoscopy, and it should be taken into account in the differential diagnosis of acute colitis.

Background and Methods: Four hundred and eighty-four patients with inflammatory bowel disease underwent clinical examination, ultrasonography, and biochemical liver function tests, to estimate the prevalence of hepatobiliary alterations. The patient group included patients without a history of liver disease. Controls were recruited from patients with functional symptoms. Results: More patients with ulcerative colitis than controls had liver steatosis and increased alkaline phosphatase levels. Factors increasing the probability of liver damage were long-standing disease, the presence of moderate/severe disease activity, and treatment with steroids and mesalazine. A significant association was found between biliary disease and long-standing colitis and also therapy with steroids and mesalazine. Alkaline phosphatase and aminotransferase levels were significantly higher in Crohn's disease patients than in controls. Hepatic and biliary damage was found more commonly in the 1st year after diagnosis. Conclusions...

Ulcerative colitis (UC) is associated with low intracolonic pH and unbalanced transmucosal ionic exchanges. Along the gastrointestinal tract carbonic anhydrase isoenzyme I (CA-I) is specifically expressed in colon epithelium and is involved in mucosal control of ion, fluid, and acid-base balance. Since altered CA-I expression may play some role in UC, CA-I was measured at the mRNA and protein level and carbonic anhydrase (CA) enzyme activity was determined in colon biopsies of 14 UC patients (6 remission, 4 mild, 4 moderate UC) and of 12 healthy subjects. Patients with mild or moderate UC showed a significant reduction of CA-I mRNA and protein and of total CA activity in the inflamed mucosa compared to controls. Patients with UC in remission showed a pattern of CA-I expression and CA activity similar to controls. This is the first report showing a reduction in the expression of CA-I in active UC.

Prognostic factors for postoperative recurrence of Crohn's disease (CD) have been widely investigated but not yet clearly identified. PURPOSE: Aim of this study was, therefore, to analyze the association between demographic, clinical, laboratory, and surgical characteristics of patients and the cumulative probability of endoscopic postoperative recurrence. METHODS: The study was performed in 110 patients who were enrolled in the Italian multicenter, randomized, controlled trial on the effectiveness of 5-aminosalicylic acid (5-ASA) in the prevention of postoperative recurrence in CD. Patients had undergone their first intestinal resection for CD of the terminal ileum with or without involvement of cecum ascending colon. Recurrence was defined on the basis of endoscopy. The following variables were evaluated as potential prognostic factors: gender, age, years since diagnosis, clinical course (perforative and nonperforative), Crohn's Disease Activity Index score, white blood count, erythrocyte sedimentation rate, C-reactive protein, and orosomucoids assessed before the operation. Timing of operation (elective or urgent), type of anastomosis (end-to-end, end-to-side, side-to-end, side-to-side), and prophylactic treatment were also evaluated. Colon ileoscopy was performed at 6, 12, 24, and 36 months after operation. The association between variables and the cumulative proportion of recurrence was analyzed both by univariate analysis (life table method, log-rank test) and multivariate regression analysis (Cox's model, stepwise procedure). RESULTS: Results of this study indicate that, of the features considered before surgery, only leukocytosis (white blood count, >9,000 ml) was significantly associated with an increased risk of recurrence (P

Mature goblet cells filled with mucin ready for secretion represent about one third of the cells in primary cultures of human colonocytes. In the present study characterization of the mucins produced by cultured human colonocytes was made by histochemical methods by lectin and monoclonal antibody binding. Two monoclonal antibodies and three lectins (Dolichos biflorus (DBA), Helix pomatia (HPA) and Arachis hypogea (PNA) recognizing epitopes or sugar haptens characteristic of different stages of mucin glycoprotein maturation, were employed. The reactivity to these probes was tested both on cultured colonocytes and on tissue sections of the normal colon mucosa. The results show that the mucins produced in culture are glycosylated to the mature form, as they show the same reactivity to lectins and antibodies of the mucins expressed in tissue sections of the normal colon mucosa. In addition, it is demonstrated that cultured human colonocytes do not express mucins reactive to PNA, which are characteristic of tumors. Since the cultured colonocytes maintain the expression of differentiated functions for at least three days, they may offer a useful model to study metabolism, function and regulation of colon mucins in health and disease.

Background. The epidemiology of inflammatory bowel disease (IBD) in Southern Europe is still unclear. Sporadic reports suggest a lower incidence of IBD in Italy than in other Western Countries and the USA. Methods. A nationwide population-based study was carried out to estimate IBD incidence rates in eight Italian cities. All new cases of IBD diagnosed over 4 years in the target populations were collected from multiple information sources. Results. From 1989 to 1992, 509 ulcerative colitis (UC), 222 Crohn's disease (CD) and 10 undefined IBD cases were collected, giving age-adjusted incidence rates (per 100 000 per year) of 5.2 for UC and 2.3 for CD. Using the capture-recapture method, an estimated completeness of 0.81 was obtained for case archives, without appreciable and significant differences between areas. The rates computed after correcting underestimation were 6.8 for UC and 2.8 for CD. The sex ratio M/F was 1.7 for UC and 1.0 for CD. The highest age-specific incidence rates were between 30 and 39 years for UC and between 20 and 29 years for CD. Conclusions. The incidence rate of CD in Italy is homogeneous between the cities investigated and lower than those reported for other Mediterranean countries. In contrast, the UC incidence rate is within the range of those reported in European studies. A wide variability in the UC rates between the cities was also observed. These results could be related to different environmental factors or the genetic background of the populations, or both.

A 45-year-old man with an eight-year history of ulcerative colitis was evaluated for severe, nonbloody diarrhea. Symptoms, which began two years earlier, were characterized by 15 bowel movements per day, accompanied by urgency and incontinence. A reduced rectal compliance was measured at manometry. All conventional treatments were not able to modify the symptoms despite improvement of inflammatory colonic lesions. PURPOSE: The aim was to reduce bowel movements and incontinence by increasing rectal compliance. METHODS: Gradual pneumatic dilations of the rectum were performed three times per week for three weeks. RESULTS: The patient's diarrhea improved dramatically, decreasing in frequency from approximately 15 to only 3 bowel movements per day, while contemporaneously increasing rectal compliance. Such effect, still evident 15 months after discontinuation of dilation, was probably obtained by improvement of viscoelastic features of the intestinal wall. CONCLUSIONS: Rectal pneumatic dilation may be a successful attempt in some forms of intractable diarrhea in long-lasting ulcerative colitis.

One of the results of gastric cytoprotection is the generation of a juxtamucosal stable pH, maintained close to neutrality by several factors among which bicarbonate secretion and mucus layer. Since &

Crohn's disease (CD) is a chronic relapsing inflammatory bowel disease (IBD) most frequently affecting the terminal ileum and right colon, with a high rate of stricturing or penetrating complications.1 Twenty years ago, the surgeon was often the main actor in the management of CD, but today's physicians (and consequently their patients) are tempted to see surgery as ‘the end of the road’ rather than part of a management strategy. The question is whether this displacement of surgery is appropriate, or necessarily in the best interests of patients. Although the mortality attributable to CD is relatively low, the chronic and relapsing course of the disease often results in substantial morbidity, poor quality of life, frequent use of health services and high direct and indirect costs of care.2–4 Surgery is an almost inevitable event in the natural history of ileal or ileocolic disease. The challenge facing physicians treating CD is, of course, not just to alleviate symptoms and prolong periods of remission, but also to reduce the need for surgery. Nevertheless, gastroenterologists have to recognise that no current medical approach has been shown to reduce the need for surgery in the long term. 70–90% of patients with ileocolic CD require an intestinal resection, at least once within 15 years of diagnosis, with a 20–40% probability of surgery during the first year of the disease.1–3,5–9 There are encouraging short-term data on reducing the need for abdominal surgery for CD within 1 year10,11 after treatment with anti-tumour neerosis factor alpha (anti-TNFα) antibody therapy, but it is long term follow up that is needed. However, surgery is not curative, because lesions and symptoms almost inexorably recur after resection.5,6,12 Mesalazine prophylaxis may reduce the postoperative recurrence rate, …

Several old and new observations suggest the existence in Crohn's disease of a phagocytic disorder of macrophages related to impaired bactericidal activity of host cells or to the presence of invasive bacteria that have developed strategies to counteract macrophage killing. It was recently reported that disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. Secretion of proinflammatory cytokines by CD macrophages was impaired in response to E. coli or specific Toll-like receptor agonists. In addition, major advances in the etiology of Crohn's disease came from the existence of polymorphism in NOD2 and autophagy-related susceptibility genes (ATG16L1 and IRGM) in patients and from the identification of the presence of adherent-invasive E. coli (AIEC) colonizing the CD ileal mucosa and able to resist to macrophage killing. The role of impaired autophagy in Crohn's disease patients has been recently reinforced by the observation that the peptidoglycan receptor NOD2, in addition to sense intracellular bacteria, can induce autophagy by recruiting the critical autophagy protein ATG16L1 to the plasma membrane during bacterial internalization. Defects in autophagy might be the key element of the pathogenic pathway that lead to defective microbial killing, increased exposure to commensal and pathogenic intestinal bacteria and T cell activation. Defects in Paneth cells secreting lysozyme and antimicrobial peptides are observed in patients with ATG16L1 risk allele. Thus, the induction of autophagy or administration of preparations that mirrors the secretion of Paneth cells or both may be regarded as new therapeutic avenues for the treatment of Crohn's disease.

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.

Dear Sir , We read with great interest the paper of Leuven group which appeared on JCC.1 The authors described the long term clinical outcome in a consecutive cohort of 121 outpatients retrospectively studied who received Infliximab for refractory moderate-to-severe ulcerative colitis (UC). They found that over a median follow-up period of 33 months, 17% of patients needed colectomy. As 67% …

Alterations in autophagy leading to a defective intracellular response to low-level invasive bacteria are considered a major recent advance in the pathogenesis of Crohn's disease. A genome-wide association study has shown an association of Crohn's disease with the autophagy related 16-like 1 gene. A second autophagy gene, the immunity-related Guanosine triphosfatase, has also been found to be significantly associated with Crohn's disease. The enteric flora of Crohn's disease patients includes, more commonly than controls, strains of adherent/invasive E. coli. The high level of adherent/invasive E. coli colonizing the intestinal mucosa of patients with Crohn's disease strongly suggests that it may play an important role in the aetiopathogenesis of the disease. E. coli strains are able to cross the mucosal barrier, survive within macrophages and induce the secretion of TNFalpha and the formation of granuloma. Recently it has been clearly shown that Crohn's disease patients have a defective mucosal macrophage killing activity resulting in increased exposure to commensal bacteria and activation of T cells. However, the hypothesis of macrophages dysfunction in the pathogenesis of Crohn's disease was already suggested in 1977 by M. Ward, who introduced the concept of the "dyspeptic macrophage", consisting of an inability to degrade a variety of phagocytosed normal gut dietary and microbial luminal constituents. Defective autophagy and dyspeptic macrophages seems therefore indicate the same pathogenetic mechanism. What is really new is the demonstration that this impaired macrophage function is genetically determined.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colonic mucosa. Over the last decade, the increasing knowledge on the pathogenic mechanisms underlying intestinal inflammation has led to the development of a number of biological agents, mainly addressed to molecules and/or pathways demonstrated to have a pathogenic role in UC. In UC, clinical course and therapeutic decisions mainly depend on disease activity and extent. While therapeutic approach to mild-to-moderate UC by using aminosalicylates and corticosteroids has been well established, treatment of severe UC is far from being satisfactory. A severe attack of UC remains a challenge to be managed jointly by gastroenterology, surgery, and intensive care units. However, the recent introduction of biological therapies has led to promising changes in the management of UC patients. Aim of this paper is to review the recent advances and future perspectives for the use of biological agents in UC. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 2, 201–218, 2008