Strictureplasty for Crohn's disease of the small bowel in the biologic era: long-term outcomes and risk factors for recurrence.

BACKGROUND: The number of indications for strictureplasty for Crohn's disease has been greatly reduced since the widespread use of biologics, although the risk of intestinal failure remains. The aim of the study was to analyze the outcomes of strictureplasty and to identify risk factors for site-specific recurrence in the era of biologics. METHODS: Consecutive patients treated with strictureplasty for Crohn's disease between 2002 and 2018 were retrospectively included. Univariate analysis was carried out. Risk factors for recurrence were identified through a multilevel logistic regression analysis. RESULTS: Two hundred sixty-six patients were included in the study ( 171 males, median age 39.5 years, range 18-76 years). The majority of the 718 strictures requiring surgery in these patients were located in the ileum (61%), treated with conventional strictureplasty (89.6%) and required an additional resection (73.7%). Median follow-up time and time to recurrence were 96 months and 62.5 months respectively. The site-specific recurrence rate was 12.2% at 5 years and 25.7% at 10 years. Smoking was associated with a higher risk of recurrence in patients with milder disease. The 10-year recurrence rate was significantly higher for strictureplasties performed in the terminal ileum (30.9%, p = 0.0019) as compared to the ileum (21.8%) and the jejunum (8.4%). Multilevel logistic regression analysis showed that postoperative exposure to biologics (OR 4.74, p 0.001), nonconventional strictureplasty (OR 3.57, p 0.008) and a strictureplasty performed on a previous anastomosis (OR 13.58, p 0.002) were associated with site-specific recurrence. CONCLUSIONS: Strictureplasty is associated with optimal long-term outcomes in the biologic era and should be performed when feasible, to reduce the risk of intestinal failure in Crohn's disease patients.

Red flags for appropriate referral to the gastroenterologist and the rheumatologist of patients with inflammatory bowel disease and spondyloarthritis.

Collaboration between gastroenterologists and rheumatologists is recommended for the correct management of patients with associated spondyloarthritis (SpA) and inflammatory bowel disease (IBD). We aimed to establish the appropriateness of several red flags for a prompt specialist referral. A systematic review of the literature was performed using the GRADE method to describe the prevalence of co-existing IBD-SpA and the diagnostic accuracy of red flags proposed by a steering committee. Then, a consensus among expert gastroenterologists and rheumatologists (10 in the steering committee and 13 in the expert panel) was obtained using the RAND method to confirm the appropriateness of each red flag as 'major' (one sufficient for patient referral) or 'minor' (at least three needed for patient referral) criteria for specialist referral. The review of the literature confirmed the high prevalence of co-existing IBD-SpA. Positive and negative predictive values of red flags were not calculated, given the lack of available data. A consensus among gastroenterology and rheumatology specialists was used to confirm the appropriateness of each red flag. Major criteria to refer patients with SpA to the gastroenterologist included: rectal bleeding, chronic abdominal pain, perianal fistula or abscess, chronic diarrhoea and nocturnal symptoms. Major criteria to refer patients with IBD to the rheumatologist included: chronic low back pain, dactylitis, enthesitis and pain/swelling of peripheral joints. Several major and minor red flags have been identified for the diagnosis of co-existing IBD-SpA. The use of red flags in routine clinical practice may avoid diagnostic delay and reduce clinic overload.

The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases.

Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthropathies, Crohn's disease, ulcerative colitis and juvenile idiopathic arthritis, comprise a group of chronic disorders characterized by an immune-mediated pathogenesis. Although at clinical presentation these diseases appear unrelated, they have been recognized to share similar pathogenic mechanisms. Data from epidemiological and genetic studies further support the concept that IMIDs are interrelated, as they can co-occur in the same patient and share a similar genetic susceptibility. The specific aetiologies of IMIDs remain unknown, but all are known to involve dysregulation of the immune system, including an over-expression of the pro-inflammatory cytokine tumour necrosis factor (TNF). The pivotal role played by TNF in the pathogenesis and pathophysiology of IMIDs has been documented by extensive preclinical and clinical investigations, and confirmed by the efficacy of anti-TNF biotechnological drugs, such as etanercept, infliximab and adalimumab, in the therapeutic management of these disorders. In this narrative review, we discuss the available data on the TNF-dependent pathogenesis of IMIDs and associations among the different disorders. Although much remains to be discovered about the pathogenesis and aetiology of IMIDs, their common inflammatory pathological features may explain why they can be successfully targeted by anti-TNF drugs. Among these, adalimumab, a fully human monoclonal antibody, has been approved for treatment of nine distinct IMID indications and it is likely to become a valuable therapeutic tool for this complex cluster of chronic inflammatory disorders.

anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab.

The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF) has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long-term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs.

Adalimumab in the treatment of immune-mediated diseases.

Tumour necrosis factor (TNF) plays an important role in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). TNF inhibition results in down-regulation of abnormal and progressive inflammatory processes, resulting in rapid and sustained clinical remission, improved quality of life and prevention of target organ damage. Adalimumab is the first fully human monoclonal antibody directed against TNF. In this article, we review the role and cost effectiveness of adalimumab in the treatment of IMIDs in adults and children. The efficacy and tolerability of adalimumab has been demonstrated in patients with a wide range of inflammatory conditions, leading to regulatory approval in rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis, paediatric Crohn's disease, and intestinal Behçet's disease), ankylosing spondylitis (AS), axial spondyloarthritis (SpA) and juvenile idiopathic arthritis. The major tolerability issues with adalimumab are class effects, such as injection site reactions and increased risk of infection and lymphoma. As with all anti-TNF agents, adalimumab is immunogenic, although less than infliximab, and some patients receiving long-term adalimumab will develop anti-drug antibodies, causing a loss of response. Comparisons of its clinical utility and cost effectiveness have shown it to be a valid treatment choice in a wide range of patients. Recent data from Italian economic studies show the cost effectiveness of adalimumab to be below the threshold value for health care interventions for most indications. In addition, analysis of indirect costs shows that adalimumab significantly reduces social costs associated with RA, PsA, AS, Crohn's disease and psoriasis. The fact that adalimumab has the widest range of approved indications, many often presenting together in the same patient due to the common pathogenesis, may further improve the utility of adalimumab. Current clinical evidence shows adalimumab to be a valuable resource in the management of IMIDs. Further research, designed to identify patients who may benefit most from this drug, will better highlight the role and cost-effectiveness of this versatile TNF inhibitor.

The course of inflammatory bowel disease during pregnancy and postpartum: a prospective European ECCO-EpiCom Study of 209 pregnant women.

BACKGROUND: The impact of pregnancy on the course of IBD is still controversial. AIM: To investigate the impact of pregnancy on IBD and to search for factors with potential impact on remission. METHODS: Pregnant IBD women from 12 European countries were enrolled between January 2003 and December 2006 and compared at conception (1:1) with nonpregnant IBD women. Data on disease course were prospectively collected at each trimester during pregnancy and in the postpartum (6 months) using a standardised questionnaire. RESULTS: A total of 209 pregnant IBD women were included: 92 with Crohn's disease (CD; median age 31 years, range 17-40) and 117 with ulcerative colitis (UC; median age 32 years, range 19-42). No statistically significant difference in disease course during pregnancy and postpartum was observed between pregnant and nonpregnant CD women. Longer disease duration in CD and immunosuppressive therapy were found to be risk factors for activity during pregnancy. Pregnant UC women were more likely than nonpregnant UC women to relapse both during pregnancy (RR 2.19; 95% CI: 1.25-3.97, 0.004) and postpartum (RR 6.22; 95% CI: 2.05-79.3, P = 0.0004). During pregnancy, relapse was mainly observed in the first (RR 8.80; 95% CI 2.05-79.3, P < 0.0004) and the second trimester (RR 2.84, 95% CI 1.2-7.45, P = 0.0098). CONCLUSIONS: Pregnant women with Crohn's disease had a similar disease course both during pregnancy and after delivery as the nonpregnant women. In contrast, pregnant women with ulcerative colitis were at higher risk of relapse during pregnancy and in the postpartum than nonpregnant ulcerative colitis women.

Risk of permanent stoma in extensive Crohn's colitis: the impact of biological drugs.

AIM: The overall risk of permanent stoma was determined in patients with extensive Crohn's colitis. An attempt was made to analyse whether biological drugs have modified the surgical approach in patients with anorectal involvement. METHOD: In all, 233 patients with Crohn's disease colitis operated on between 1995 and 2010 were reviewed retrospectively. Fifty-one were treated before 2002 (prebiological era) and 182 after 2002 (biological era). The relationship was determined between the use of immunosuppressors, biological drugs, the presence of perianal disease and anorectal stenosis and the rate of permanent stoma formation. RESULTS: In the prebiological era 23 (45.1%) patients without anorectal involvement underwent colectomy and ileorectal anastomosis, 17 (33.3%) with severe anorectal disease had proctocolectomy and 11 (21.6%) with anorectal involvement had abdominal colectomy with permanent ileostomy. In the biological era 73 (40.1%) patients without anorectal involvement underwent colectomy and ileorectal anastomosis, nine (5%) with severe anorectal involvement had proctocolectomy and 100 (54.9%) with anorectal involvement had colectomy with terminal ileostomy. Of these 100, 75 have subsequently been treated with biological drugs with full regression of anorectal lesions in 81.3%. Rates of permanent stoma in the prebiological and biological era were 60.8% and 19.2% (P < 0.001). Univariate and multivariate analysis showed that only the use of biological drugs was significantly associated with an increased rate of rectal preservation (P < 0.05). CONCLUSION: The risk of a permanent stoma in patients with Crohn's colitis and anorectal involvement is significantly reduced with combined surgical and biological treatment.

New insights into the brain involvement in patients with Crohn's disease: a voxel-based morphometry study.

BACKGROUND: Crohn's disease (CD) is a chronic intestinal disorder characterized by overproduction of inflammatory cytokines and recurrent abdominal pain. Recently, brain morphological abnormalities in the pain matrix were found in patients with chronic pain disorders including irritable bowel syndrome. To investigate potential structural brain changes associated with CD, we used magnetic resonance imaging (MRI). Furthermore, we tested whether in patients gray matter (GM) volumes correlated with disease duration. METHODS: Eighteen CD patients in remission and 18 healthy controls underwent structural MRI. Voxel-based morphometry (VBM) is a fully automated technique allowing identification of regional differences in the amount of GM enabling an objective analysis of the whole brain between groups of subjects. VBM was used for comparisons and correlation analysis. KEY RESULTS: With respect to controls, CD patients exhibited decreased GM volumes in portion of the frontal cortex and in the anterior midcingulate cortex. Disease duration was negatively correlated with GM volumes of several brain regions including neocortical and limbic areas. CONCLUSIONS & INFERENCES: Crohn's disease is associated with brain morphological changes in cortical and subcortical structures involved in nociception, emotional, and cognitive processes. Our findings provide new insight into the brain involvement in chronic inflammatory bowel disorders.

Randomized controlled trials in pouchitis.

Pouchitis is the most common complication of Proctocolectomy with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). The diagnosis of pouchitis requires the presence of symptoms, together with characteristic endoscopic and histological abnormalities. The exact cause of pouchitis is not known. Whereas 'acute' pouchitis can be treated rapidly and successfully in the majority of patients, "refractory" and 'chronic pouchitis' remain therapeutic challenges to patients and physicians. Metronidazole and Ciprofloxacin budesonide enemas and oral probiotic therapy with VSL#3 all appear to be effective therapies for acute and/or chronic pouchitis. The medical therapy of pouchitis remains largely empiric, and additional multicenter, randomized, double-blind, placebo-con- trolled, dose-ranging trials are needed. In future trials, treatment indications such as active acute or chronic pouchitis and maintenance of remission for acute or chronic pouchitis should be clearly defined.

Folate in gastrointestinal health and disease.

OBJECTIVE: Folate has heterogeneous functions and is involved in several activities in both animal and human body. It is an important constituent of our organism, and its bioavailability is mainly dependent from the correct function of our gastrointestinal tract. Our aim is to describe what happens to folate homeostasis in gastrointestinal health and disease, analyzing the alterations of folate metabolism in some specific conditions of intestinal and liver impairment. DISCUSSION: Folate absorption and metabolization involve the small intestine and the liver; in conditions of gastrointestinal tract disease (i.e. celiac disease, liver disease) folate function may be compromised with important consequences on the whole organism. Moreover, folate deficiency may produce gastrointestinal alterations too. For this reason, the gastrointestinal tract could be the responsible but also the victim of folate deficiency. CONCLUSIONS: The presence of folate deficiency should always be assessed in patients with a gastrointestinal disease. Further studies are needed to assess the role of folates in gastrointestinal tract diseases and in other gynecologic, neurologic, psychiatric, cardiovascular, ophthalmic and neoplastic diseases. Folates supplementation could be considered, in the future, as an effective complimentary therapy in several pathologic conditions.

Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-EpiCom study, 2003-2006.

BACKGROUND: Inflammatory bowel disease (IBD) frequently affects women during their reproductive years. Pregnancy outcome in women with IBD is well described, particularly in retrospective studies. AIM: To evaluate the pregnancy outcome in patients with IBD in a prospective European multicentre case-control study. METHODS: Inflammatory bowel disease pregnant women from 12 European countries were enrolled between January 2003 and December 2006 and matched (1:1) to non-IBD pregnant controls by age at conception and number of previous pregnancies. Data on pregnancy and newborn outcome, disease activity and therapy were prospectively collected every third month using a standard questionnaire. Logistic regression analysis with odds ratio was used for statistical analyses. P value<0.05 was considered significant. RESULTS: A total of 332 pregnant women with IBD were included: 145 with Crohn's disease (CD) and 187 with ulcerative colitis (UC). Median age (range) at conception was 31 years (15-40) in CD and 31 (19-42) in UC patients. No statistically significant differences in frequency of abortions, preterm deliveries, caesarean sections, congenital abnormalities and birth weight were observed comparing CD and UC women with their non-IBD controls. In CD, older age was associated with congenital abnormalities and preterm delivery; smoking increased the risk of preterm delivery. For UC, older age and active disease were associated with low birth weight; while older age and combination therapy were risk factors for preterm delivery. CONCLUSION: In this prospective case-control study, women with either Crohn's disease or ulcerative colitis have a similar pregnancy outcome when compared with a population of non-inflammatory bowel disease pregnant women.

Distinct proteomic profiles characterise non-erosive from erosive reflux disease.

BACKGROUND: Erosive reflux disease (ERD) and non-erosive reflux disease (NERD) are often regarded as part of the spectrum of the same disease. AIM: To elucidate molecular features that characterise NERD and ERD at the protein level. METHODS: A total of 56 consecutive subjects were enrolled: 10 healthy subjects, 24 with NERD and 22 with ERD. Eight specimens were taken from macroscopically normal mucosa at 5 cm of gastro-oesophageal junction. Four were processed for the proteins extraction and four for evaluation using haematoxylin-eosin and immunohistochemistry. We used shotgun proteomics to identify tentative disease molecular features for ERD or NERD. Candidate distinctive proteins were verified using immunohistochemistry. RESULTS: Shotgun proteomics analysis revealed 33 differentially expressed proteins in NERD vs. ERD samples, involved in cellular proliferation, keratinisation, stress responses and sugar metabolism. Based on a gene ontology meta-analysis, seven of them were further analysed using Western blotting (WB) and four also using immunohistochemistry. We identified novel candidate disease molecular features for GERD and few distinctive proteins to discriminate NERD and ERD. In particular, Transitional Endoplasmic Reticulum ATPase (TER ATPase), GAPDH, Alpha 1 Acid Glycoprotein 1, Annexin A1, Calmodulin and 14-3-3 proteins were confirmed at WB analysis. CONCLUSIONS: Non-erosive reflux disease and ERD are distinct disease entities at the protein level. This study proposes an array of candidate biomarkers possibly useful to discriminate between NERD and ERD.

Potential role of the cannabinoid receptor CB in the pathogenesis of erosive and non-erosive gastro-oesophageal reflux disease.

BACKGROUND: Cannabinoid (CB) receptors have been located in brain areas involved in the triggering of TLESRs as well as in the nodose ganglion from which vagal afferents emanate. The distribution of CB(1) receptors has been investigated in the human gastrointestinal mucosa, as expression of inflammatory process. AIM: To evaluate the CB(1) expression in oesophageal mucosa. METHODS: A total of 87 consecutive subjects were enrolled: 10 controls, 39 NERD and 38 erosive oesophagitis. Eight specimens were taken from macroscopically normal mucosa. Five were processed by haematoxylin-eosin, MIB1/CB(1) evaluation and three for the RNA and proteins extraction. RESULTS: The mean MIB1-LI value was 31% and 22% in NERD and ERD patients, respectively, compared to 68% in the healthy subjects. Mean CB(1)mRNA/GUSB mRNA value of the controls was 0.66, while in GERD patients, it was 0.28. In NERD and ERD, the mean values of CB(1)/GUSB were 0.38 and 0.17, respectively, with highly significant differences between the NERD vs. ERD groups. Semi-quantitative analysis of CB(1) expression, performed with WB, shows in NERD patients a higher CB(1) receptor expression than ERD patients. CONCLUSIONS: With this study, we showed for the first time the presence of CB(1) receptors in the human oesophageal epithelium.

Implications of antioxidant enzymes in human gastric neoplasms.

The present study is the first to evaluate the expression and activity of MnSOD, Cu/ZnSOD and catalase in human gastric samples, since ROS play a significant role in the pathogenesis of different forms of malignancy inducing mutations and various diseases such as gastric cancer. Biopsies and surgical samples from 53 patients (male/female 22/31, mean age 56.5+/-15.8 years) consisted of 15 healthy, 12 autoimmune atrophic gastritis, 10 Helicobacter pylori (HP) infection, 8 HP-negative chronic gastritis (CG) and 8 adenocarcinoma cases. Enzyme activity and expression were evaluated by spectrophotometry and immunoblotting after specific extraction in phosphate buffer. We found that MnSOD activity was increased in adenocarcinoma, CG and HP tissues (p<0.05-0.001), while Cu/ZnSOD was significantly lower in adenocarcinoma and HP tissues (p<0.001) when compared to the healthy control. MnSOD and Cu/ZnSOD were expressed to a significantly higher degree in adenocarcinoma and HP tissues (p<0.05 and <0.001 respectively) and to a significantly lower degree in CG tissues with respect to the healthy patients (p<0.05 and <0.001). A significant decrease in CAT activity in adenocarcinoma and HP tissues was observed (p<0.01 and <0.05). Gastric human neoplasms showed significant changes in antioxidant enzymes, that represent the first line in antioxidant protection against radical attack. The difficulties in correlating the antioxidant enzyme with the neoplasms was related to the complexity of the biochemical pathways that regulate the cellular redox balance. Our results are important in enhancing the understanding of the role that these enzymes play in the promotion/suppression of the carcinogenesis cascade in human gastric mucosa.

Medical treatment and management of severe ulcerative colitis.

Severe colitis is a life-threatening complication of ulcerative colitis. Early recognition of the severity of the colitis and intensive treatment and monitoring have all contributed to improved outcome. Since their introduction in the 1950s, corticosteroids are the first line therapy for severe active ulcerative colitis (UC). Several prognostic parameters (such as stools movement per day, C-reactive protein, increased amount of intestinal gas or small bowel dilation, hypoalbuminemia, fever, etc.) help the physician to quickly introduce infliximab or cyclosporine or to refer the patient to the surgeon. This decision requires a careful evaluation of the patient and a medical/surgical team.

Interaction of probiotic Lactobacillus and Bifidobacterium strains with human intestinal epithelial cells: adhesion properties, competition against enteropathogens and modulation of IL-8 production.

The human intestinal microbiota plays a pivotal role in human nutrition and health by promoting the supply of nutrients, preventing pathogen colonization and shaping and maintaining normal mucosal immunity. The depletion of the individual microbiota can result in a higher susceptibility to enteropathogenic bacteria infection. In order to reduce this risk, the use of food supplements containing probiotic bacteria has been recently addressed. In this paper, we investigate the protective role toward enteropathogen infection of probiotic strains belonging to Lactobacillus and Bifidobacterium. According to our experimental data, Lactobacillus acidophilus Bar13, L. plantarum Bar10, Bifidobacterium longum Bar33 and B. lactis Bar30 were effective in displacing the enteropathogens Salmonella typhimurium and Escherichia coli H10407 from a Caco-2 cell layer. Moreover, L. acidophilus Bar13 and B. longum Bar33 have been assessed for their immunomodulatory activity on IL-8 production by HT29 cells. Both strains showed the potential to protect enterocytes from an acute inflammatory response. These probiotic strains are potential candidates for the development of new functional foods helpful in counteracting enteropathogen infections.

Ninety-six-hour wireless oesophageal pH monitoring following proton pump inhibitor administration in NERD patients.

BACKGROUND: Comparative studies of proton pump inhibitors (PPIs) have revealed that acid reflux is influenced by PPI treatment, formulations and dosing regimens. Wireless pH capsules have circumvented some of the limitations of conventional catheter-based pH testing with the additional advantage of 96-h recording periods. AIM: To clarify the effectiveness of intra-oesophageal acid suppression by omeprazole, pantoprazole and lansoprazole in non-erosive reflux disease patients through a 4-day monitoring of oesophageal pH and related symptoms. METHODS: Twenty-four patients with typical symptoms of gastro-oesophageal reflux disease were enrolled and administered upper endoscopy and placement of a wireless pH capsule. Patients randomly received omeprazole, pantoprazole or lansoprazole for 3 days after the first 24 h. Symptom-reflux associations were expressed using the symptom index (SI). RESULTS: All patients completed the study. Significant decrease in acid exposure occurred on day 2 and in each successive day in all groups. Pantoprazole and omeprazole are more effective than lansoprazole at inducing a normalization of intra-oesophageal acid exposure at days 2 and 3. Significant reduction in SI at day 2 was observed. CONCLUSIONS: Four-day ambulatory oesophageal pH monitoring is feasible and safe. Omeprazole, pantoprazole and lansoprazole have an equivalent potency for normalizing intra-oesophageal acid exposure after 3 days of treatment in non-erosive reflux disease patients.