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Background Patients undergoing ileocecal resection for Crohn’s disease (CD) are at high risk of postoperative intra-abdominal septic complications (IASC). The associated risk factors are still debated. The aim of the study was to identify the variables associated with IASC in patients treated for primary CD of the terminal ileum. Methods Retrospective single-centre study including consecutive patients undergoing ileocecal resection for CD between 2004-2021 and managed before surgery in a multidisciplinary IBD unit. Outcomes to identify the variables associated with IASC (primary aim) and severe complications, classified as Clavien-Dindo grade 3 and higher (secondary aim). The potential independent predictors of each outcome were evaluated using logistic regression. To reduce overfitting, all models were built including only the variables that were significant at univariate analyses, except for age, gender and history of cardiovascular diseases, that were included a priori. Standard diagnostic procedures were adopted to check all models validity: influential observation analysis (Dbeta, change in Pearson chi-square), Hosmer-Lemeshow test for the goodness of fit and C statistic (area under the Receiving Operator Curve). Results A total of 853 patients were included. Overall sample characteristics are shown in Table 1. Table 2 and Table 3 reported the comparison according to the primary (IASC) and secondary (severe complications) outcomes, respectively. Table 4 showed the multivariate analyses of the potential predictors of IASC and severe complications. The onset of IASC was associated with lower serum albumin level (OR 1.81, 95% CI 1.15-2.94, p=0.011) and the use of oral budesonide at time of surgery (OR 2.07, 95% CI 1.12-3.83, p= 0.021). The risk of severe complications was associated with a history of cardiovascular disease (OR 2.91, 95% CI 1.08-7.84, p=0.03) and lower serum albumin level (OR 1.58, 95% CI 1.02-2.50, p=0.04). Conclusion The present study analysed a large population of patients affected by CD of the terminal ileum who were treated homogeneously before surgery in a multidisciplinary setting and confirmed the significant impact of preoperative nutritional status on the risk of severe postoperative complications and IASC. The latter, however, was also associated with the use of oral budesonide at the time of surgery. This finding has not been previously reported in the literature. Based on the present evidence, oral budesonide should be discontinued or tapered to the lowest dose before surgery.

Background Anastomotic leak remains one of the most relevant complications after intestinal resection for Crohn’s disease (CD). While surgery has always been considered the standard treatment for perianastomotic abscess or collection, percutaneous drainage (PD) has been proposed as a potential alternative. The aim of this study was therefore to compare the success rate of percutaneous drainage with that of surgery for the management of anastomotic leak in CD patients. Methods Retrospective, single-centre study including all consecutive patients who were diagnosed with an anastomotic leak as a complication of intestinal resection for CD between 2004 and 2022. Patients requiring emergency surgery due to generalised peritonitis or clinical instability were excluded. Anastomotic leak was defined as a perianastomotic fluid collection confirmed by radiological findings within 30 days from surgery. Patients underwent either PD or surgery as a primary treatment for the complication. The success after PD was defined as the removal of the drainage with clinical and radiological resolution of the complication. The need for further surgical treatment was considered as a failure in both groups. Primary aim: to compare the success rate of PD vs surgery. Secondary aims: to compare the outcomes at 90 days after the procedures; to identify the variables associated with the indication to PD. Results Among the 47 patients included, 25 (53%) underwent PD and 22 (47%) surgery. Table 1 shows the outcomes by the procedure. Success rate was 84% in PD and 95% in surgery group (p=0.20). The median time to success was 14 days after PD (drainage removal) and 12.5 days after surgery (discharge) (p=0.92). Similar rates of post-procedure medical (12% vs 18%, p=0.55) and surgical (24% vs 36%, p=0.62) complications were shown. An ileostomy was required in 91% of surgery cases. At 90 days, similar rates of discharges (100% vs 95%, p=0.28), readmissions (8% vs 0%, p=0.18) and reoperations (16% vs 9%, p=0.48) were observed between PD and surgery cases, respectively. In the multivariate analysis (Table 2), PD was more likely to be performed in patients whose anastomotic leak was diagnosed later after surgery (OR 1.25, 95%CI 1.03-1.53, p=0.027), in those who underwent an ileo-colic anastomosis alone (OR 3.72, 95%CI 2.29-12.45, p=0.034) and in those who were treated after 2016 (OR 6.36, 95%CI 1.04-39.03, p=0.046). Conclusion The present study confirms that PD is a safe and effective procedure to treat anastomotic leak and perianastomotic abscess in CD patients. Surgery, in particular, is associated with a high risk of stoma formation, which would require a subsequent operation. PD should be indicated in all eligible patients as an effective alternative to surgery.

Background The impact of Ileal Pouch-Anal Anastomosis (IPAA) on the fertility of women affected by ulcerative colitis (UC) is still debated in the literature. The primary aim of this study was to assess the risk factors for infertility in women undergoing IPAA. The second aim was compare the outcomes of pregnancy before and after IPAA. Methods Retrospective study including women (18–45 years) undergoing IPAA for UC (2004–2020). Univariate comparison was carried out as appropriate. Cox regression analysis was used to identify significant predictors of infertility over the follow-up (defined as the conceiving time starting one year after IPAA surgery). Results Some 149 patients answered the questionnaire and were included in the study. Table 1 shows the comparison between fertile (23, 15.5%) and infertile (20, 13.4%) women after IPAA surgery. At the cox regression analysis, only the Mayo endoscopic score of 3 was associated with the risk of postoperative infertility (OR 4.16, 95% CI 1.07–16.6, p=0.040). Table 2 shows the comparison between pregnancies before (72) and after (27) IPAA. Pregnancies after IPAA were more likely to require assisted conception treatment (25.9% vs 2.7%, p Of the 61 nulliparous women who did not try to conceive after IPAA, 11 (18%) feared physical consequences, 10 (16.4%) were afraid to transmit the disease, while 3 (4.9%) were recommended by their gynecologist. Conclusion IPAA surgery is associated with a reduction of the fertility of 46.5%, and the preoperative severity of the disease seems to be the strongest predictor of infertility. Although the pregnancy after IPAA requires a longer conceiving time, it is safe for both the mother and the child, at least when carried out through caesarean delivery. A great proportion of women of childbearing age affected by UC still refer confusion regarding the risks of complications and infertility associated with IPAA. A dedicated counsel pathway should be mandatory in all referral centres. A larger multicentric study will be required to assess the outcomes in a larger population.

Background Intestinal Ultrasound (IUS) is a non-invasive, widely available technique that can rapidly evaluate bowel wall thickness and provide direct visualization of bowel vascularisation and motility. Studies have shown high concordance between ultrasound and MR enterography and endoscopy for disease location and activity, and fewer technical difficulties associated with IUS. While more is known about the role of IUS in evaluating response to pharmacologic treatment in CD patients, data regarding the monitoring of asymptomatic patients are scarce. Our objective was to study the impact of IUS in the management of patients with CD in stable clinical remission in a real-world setting. Methods We conducted a retrospective, monocentric observational study in patients with CD in clinical remission (Harvey Bradshaw Index ≤ 4), not in treatment with immunomodulators/immunosuppressants, in whom annual monitoring via IUS was performed. Biochemical data including C-reactive protein (CRP) and relevant ultrasound parameters (bowel wall thickness, extension and vascularization via Limberg score) were recorded. Changes in treatment or the need for second-level diagnostic tests based on ultrasound findings were registered along with outcomes at 1 year follow-up. Results A total of 201 patients with CD underwent IUS at our center between March and May 2021. Of these, 86 were in clinical remission with mesalazine treatment/no treatment. In 49/86 (57%) of cases, significant ultrasound findings were reported. In 27/49 cases, ultrasound findings led to a treatment modification or a second-level diagnostic test. Specifically, 12 patients were started on a course of oral budesonide or metronidazole; of these, 6 were in remission at 1 year follow-up, 3 patients required surgery within 1 year, and 2 experienced a disease flare treated with a second course of budesonide. Of the 15 patients in which a second-level diagnostic test was performed, in 12 cases disease activity was confirmed: 6 were started on a course of budesonide or metronidazole with persistent clinical remission at 1 year, 2 were started on biologics, and 4 developed complications during the follow-up period and were referred for surgery. In the remaining 3 cases, the second level diagnostic test excluded active disease and the patients maintained clinical remission at 1 year follow-up. Conclusion The results of this study demonstrate how IUS can be a useful tool that can modify treatment strategies and stratify patients requiring more invasive second-level diagnostic exams, with the objective of reducing clinical relapses. Prospective, randomized studies with large cohorts are needed to confirm these findings.

Background COVID-19 vaccines have demonstrated excellent efficacy and safety profiles among the general population. However, studies have shown that vaccine hesitancy remains a significant problem especially in patients with chronic diseases, in part because of a lack of data regarding vaccine safety in these special populations. With this in mind, we investigated rates of vaccine-related side effects and disease flares in patients with inflammatory bowel disease (IBD). Methods We conducted an online survey of patients with Crohn’s disease (CD) and ulcerative colitis (UC) who were vaccinated from January 23 to October 15, 2021 with COVID-19 vaccines approved in Europe. We collected data regarding patient demographics, disease type, treatment and activity at the time of vaccination, patient-reported systemic side effects, and rates of disease flares and outcomes within 15 days of both vaccine doses. Results A total of 329 (179 M, 150 F) patients participated in the survey, 162 with CD and 167 with UC. Mean age was 47.1 years (range 19–80). Patients were vaccinated with Pfizer-BioNTech (46.8%), Moderna (51.7%) or Oxford/AstraZeneca (1.5%). Three patients received only one dose because of recent prior infection, and one patient received a single dose dose due to infection before vaccine cycle completion. At the time of vaccination most patients (63.8%) reported disease remission, 22.8%= mild activity, 12.8%= moderate, 0.6%= severe. Mesalazine monotherapy was reported in 174 patients, 89 were on biologics, 8 were on azathioprine, and 58 were not undergoing treatment at the time of vaccination. Nineteen were on concomitant corticosteroid treatment. After the first dose, the most common side effects were mild: fatigue (38.6%), arthromyalgia (16.7%), headache (14.3%), fever (6.7%) and nausea (1.8%). Side effects after the second dose were more frequent but similar in nature (fatigue= 54.8%, fever= 34.8%, arthromyalgia= 31.7%, headache= 22.8%, nausea= 2.5%). Fourteen patients (4.3%) reported disease flare after the first dose and 26 patients (8%) after the second dose. Characteristiscs of these patients are summarized in Table 1. Most flares were self-limiting and did not require modification in treatment. In the five cases where treatment modification was required, two already had moderate/severe disease at the time of vaccination, one had suspended biologic treatment, and two patients had autonomously suspended maintenance therapy. Conclusion Disease flares are infrequent and generally self-limiting after COVID-19 vaccination in patients with IBD. Other side effects are mild and comparable to the general population. Vaccination is strongly recommended in patients with IBD, and patients should be reassured about their safety.

Background Telemedicine is one of the major changes that clinicians have encountered over the past decade; in particular during the COVID-19 pandemic, televisits were rapidly implemented to guarantee patients’ assistance, with the intention of Health Care Providers (HCPs) to continue to use them beyond the pandemic. The aim of our national survey was to evaluate the current usage of telemedicine for IBD patients from their perspective, investigating patients’ impressions about telemedicine and factors affecting them through a Machine Learning (ML) analysis. Methods In March 2021, the Italian IBD patients’ association (AMICI Onlus) distributed to their members - through its mailing list and on social media platforms - an anonymous online questionnaire investigating the use of telemedicine. Socio-demographic and IBD characteristics were collected; the usage, patients’ satisfaction and trust of telemedicine were assessed through Likert scales. ML tools - Decision Trees (DT) and Random Forest (RF) - were applied to identify the determinants of patient’s perceptions about telemedicine; the produced RF ranking displays two indicators: %IncMSE and IncNodePurity. Results Nine hundred and seventy-eight IBD patients (women 58.9%) from every Italian region completed the questionnaire. Among the respondents, 87 (8.9%) personally had a telemedicine experience; 153 reported that their Centre performed a telemedicine service during the COVID-19 pandemic (24.2% televisits, 39.2% e-mails, 24.8% phone-calls, 3.9 % dedicated website, 7.9% others). Overall, 707 (72.3%) would trust a telemedicine service, 760 (77.7%) would like to have it also with another HCP (e.g., nutritionist, psychologist) and 778/961 (81%) would like to use telemedicine in the future (17 did not answer to this specific question); 792 (81%) stated they thought useful to have the possibility to use telemedicine and 847 (86.6%) would like their Centre to offer them this facility. Considering this last question as the output at the DT, the variable which have been found to influence the most this patients’ willingness is patient’s perception of the usefulness of telemedicine in treating their disease, since it represented the root of the tree explaining the results. The RF rankings confirmed that this variable influenced the most patients’ perception with the highest levels of %IncMSE and IncNodePurity(Figure 1). Conclusion The practice of telemedicine in the management of IBD patients has not been very relevant throughout Italy so far (less than 10%), but more than four every five respondents would like to use telemedicine. Machine learning analysis shows that the perceived usefulness of telemedicine service is the key point for patients who would like it was a part of usual clinical practice.

Background Ustekinumab (UST) and vedolizumab (VDZ) are approved biologic therapies for moderate-to-severe Crohn’s disease (CD). Data regarding their comparative efficacy in patients previously treated with anti-TNF agents are available. However, data is lacking regarding their long-term effectiveness after failure of a second or third-line biologic treatment. Our aim is to evaluate ustekinumab efficacy after swapping from vedolizumab therapy for primary or secondary failure. Methods We conducted a single-centre, retrospective study in CD patients treated with UST as third line biologic therapy who swapped from VDZ therapy upon failure between January, 2019 and October, 2021. We assessed clinical (HBI), laboratoristic (CRP), endoscopic (SES-CD) activity and use of steroids at the beginning of ustekinumab therapy and after, 12 months of treatment. We also collected data regarding previous biologic treatments. Clinical remission was defined as HBI Results Of, 43 patients treated with UST after VDZ failure, 26 had a minimum follow up of, 12 months and were included in the study. All patients had previously been treated with antiTNF agents. After, 12 months, 4 patients have suspended treatment for failure; among patients still on treatment, clinical remission was evident in, 63% (n = 14) of cases, 13 of them were also in laboratoristic remission. Endoscopy at, 12 months was available in, 11/14 patients in clinical remission; of these, 6 (55%) were in endoscopic remission. In patients who did not achieve clinical remission, 18% (n = 4) obtained clinical response. The last, 18% (n = 4) of patients persisted on therapy. Conclusion Ustekinumab seems to be a viable and effective therapeutic option in patients with failure to multiple prior biologic therapies, obtaining deep remission after, 12 months of treatment in a large proportion of patients.

To evaluate the effect of tissue harmonic imaging (THI) on the measurement of fetal nuchal translucency thickness (NT).One-hundred and three pregnant women underwent first-trimester NT measurement according to The Fetal Medicine Foundation criteria. NT was evaluated using conventional ultrasonography (CUS) and THI without modifying any other ultrasound parameter (e.g. gain). For each patient three images with CUS and three images with THI were stored and then measured independently on the ultrasound system by two different operators. The maximum measurements using CUS and THI were compared. Differences between the values of CUS and THI NT measurements were tested using the Wilcoxon signed-rank test. Bland-Altman plots were constructed, and intraobserver and interobserver variabilities were assessed by calculation of the intraclass correlation coefficient. Probability values of0.05 were considered significant.Mean maternal age was 32.8 (range, 20-42) years, mean gestational age at examination was 12 + 1 (11 + 0 to 13 + 6) weeks and mean crown-rump length (CRL) was 55.8 (SD, 7.2) mm. Median fetal NT was 1.4 (0.8-3.5) mm using CUS and 1.2 (0.6-3.3) mm using THI (P0.001) for the first operator. A second operator remeasured the first 51 cases: median fetal NT was 1.4 (0.8-3.8) mm using CUS and 1.1 (0.6-3.1) mm using THI (P0.001). Fetal NT measurements were above the expected median value according to CRL in 49 cases (47.6%) using CUS and in only 24 cases (23.3%) using THI.THI leads to a small, but significant, reduction of the NT measurement and this could reduce the sensitivity of screening for Down syndrome.

Plant cell cultures are valuable bioreactors for the production of bioactive compounds. Artemisia annua L. cell suspension cultures established for producing the antimalarial artemisinin (AN) were exploited to investigate the biosynthesis of other healthful phytochemicals. Culture supplementation with the putative elicitors ß-cyclodextrins (ß-CDs) was successful to increase intracellular and extracellular levels of AN. Other bioactive isoprenoid compounds, known for their antioxidant activity, were also investigated in the supplemented A. annua cell cultures by using metabolomic and transcriptomic analyses. In particular, the application of ß-CDs was useful to induce a considerable significant increase of lutein, quinones (Q9 and Q10) intracellular contents compared to untreated cell cultures. Moreover, the release of carotenoids and quinones into the culture medium of ß-CDs-treated cell cultures was significantly enhanced. Real Time PCR analysis revealed an up-regulation of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) gene, suggesting that the ß-CDs induced increase of isoprenoid compounds could be due to the enhancement of the plastidial isoprenoid biosynthetic route. In addition, protoplasts derived from Artemisia suspension cultures were explored to engineer subcellular compartmentalization using a modified SNARE protein as a molecular tool for biotechnological metabolite accumulation.

Biological therapies are an important step in the management of Inflammatory Bowel Diseases. In consideration of high cost and safety issues there is the need to have clear recommendations for their use. Despite the American Gastroenterological Association and the European Crohn's and Colitis Organisation have published exhaustive Inflammatory Bowel Disease guidelines, national guidelines may be necessary as cultural values, economical and legal issues may differ between countries. For these reasons the Italian Society of Gastroenterology and the Italian Group for the study of Inflammatory Bowel Disease have decided to elaborate the Italian guidelines on the use of biologics in Inflammatory Bowel Disease. The following items have been chosen: definitions of active, inactive, steroid dependent and resistant disease; measures of activity; anti-tumor necrosis factor alpha therapy use in active steroid dependent and refractory luminal Crohn's Disease, in fistulising Crohn's Disease, in steroid dependent and resistant active Ulcerative Colitis; risk of cancer; risk of infections during anti-tumor necrosis factor alpha therapy; special situations. These guidelines are based on evidence from relevant medical literature and clinical experience of a national working group.

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.

Chronic refractory pouchitis is a long-term complication after ileal pouch-anal anastomosis and it may be associated with ileal inflammation.To determine the efficacy of infliximab in treatment of chronic refractory pouchitis complicated by ileitis, using a wireless capsule endoscopy.Sixteen patients with chronic refractory pouchitis complicated by ileitis were enrolled. Pouchitis was diagnosed by clinical, endoscopic and histological criteria. Ileitis was documented using wireless capsule endoscopy. Duodenum-jejunum and proximal-middle ileum were evaluated and the presence of small lesions and large lesions were noted. Crohn's disease, intestinal infections were excluded in all patients. Patients were treated with infliximab and clinical response was recorded. Wireless capsule endoscopy was repeated at week 10 and Pouchitis Disease Activity Index score was determined.Ten patients were enrolled and completed the study. Clinical remission was achieved in nine patients. At wireless capsule endoscopy and pouch endoscopy, a complete recovery of lesions was observed in eight patients. One patient presented four small lesions of the ileum at the 6 weeks of treatment and one patient did not show any modification. Clinical and endoscopic remission was maintained in these eight patients at least 6 months.These preliminary results indicate that infliximab may be recommended for the treatment of chronic refractory pouchitis complicated by ileitis.

Pouchitis is a common long-term complication after ileal pouch anal anastomosis for ulcerative colitis. Chronic refractory pouchitis is a treatment-resistant condition that affects 5-15% of patients.To test the hypothesis of a small bowel involvement using wireless capsule endoscopy.This is a single-blind, prospective, cohort study. Twenty-four patients: 16 were patients with chronic refractory pouchitis and eight, with a macroscopically and histologically normal ileal pouch, were considered as control subjects. Diagnosis of pouchitis was confirmed using the pouchitis disease activity index. All subjects were submitted to wireless capsule endoscopy procedure. Within 2 weeks before wireless capsule endoscopy, patients underwent a pouch endoscopy and a small bowel follow-through. Re-examination of the colonic surgical and histological specimens was also performed.One patient with chronic pouchitis was excluded because of incomplete bowel cleaning. At small bowel follow-through of 16 patients, two subjects (13%) showed only a focal ectasia of the middle ileum and a substenosis of the pouch. At wireless capsule endoscopy all the 15 evaluable patients with chronic pouchitis (100%) showed diffuse lesions from duodenum to ileum consisting of aphthae, erosions, erythema, atrophy, cobblestone, deep/fissural ulcers.This enteropathy needs further research, and wireless capsule endoscopy could be useful to show involvement of small bowel in patients with chronic pouchitis.

Pouchitis is the major long-term complication after ileal-pouch nal anastomosis for ulcerative colitis. Ten to 15% of patients develop a chronic pouchitis, either treatment responsive or treatment refractory.To evaluate the efficacy of oral budesonide in inducing remission and improving quality of life in patients with chronic refractory pouchitis.Twenty consecutive patients with active pouchitis, not responding after 1 month of antibiotic treatment were treated with budesonide controlled ileal release 9 mg/day for 8 weeks. Symptomatic, endoscopic and histological evaluations were undertaken before and after treatment according to Pouchitis Disease Activity Index. Remission was defined as a combination of Pouchitis Disease Activity Index clinical score ofor = 2, endoscopic score ofor = 1 and total Pouchitis Disease Activity Index score ofor = 4. The quality of life was assessed with the Inflammatory Bowel Disease Questionnaire.Fifteen of 20 patients (75%) achieved remission. The median total Pouchitis Disease Activity Index scores before and after therapy were, respectively, 14 (range 9-16) and 3 (range 2-10) (P0.001). The median Inflammatory Bowel Disease Questionnaire score also significantly improved from 105 (range 77-175) to 180 (range 85-220) (P0.001).Eight-week treatment with oral budesonide appears effective in inducing remission in patients with active pouchitis refractory to antibiotic treatment in this open-label study.

The correct approach for endometriosis management is still unclear. This review explores recent data concerning diagnosis and treatment of endometriosis, trying to define guidelines for the most appropriate diagnostic approach and therapeutic regimen. At present, laparoscopy is still considered the gold standard in endometriosis diagnosis. The risks and the diagnostic limitations of laparoscopy and the inaccuracy of clinical examination justify the considerable efforts made to improve the diagnosis with imaging techniques. The therapeutic approach is still far from being defined as causal and focuses on management of clinical symptoms of the disease rather than on the disease itself. A first-line medical therapy should be tried in patients with pelvic pain not asking for a pregnancy. Surgical treatment is considered the best treatment for women with pain and or pelvic mass who wish to become pregnant in a short time. For infertile patients, medical therapy has a limited role. The 2 treatment options include surgery or in vitro fertilization (IVF). According to our results, it seems that correct management of infertile women with endometriosis is a combination of surgery and IVF in women who did not obtain post-surgery pregnancy spontaneously.

About two-thirds of patients with ulcerative colitis have an inflammatory involvement distal to the splenic flexure, and therefore may be effectively treated with topical treatment, allowing the delivery of the active drug directly to the site of inflammation and limiting systemic absorption and potential side-effects. Topical aminosalicylate therapy is the most effective approach, and most patients will benefit hugely, provided that the formulation reaches the upper extent of the disease. Therefore, the choice of topical preparation should be based on the proximal extent of the disease and on patient preference. Oral aminosalicylates are less effective than topical therapies; however, a combination of oral and topical aminosalicylates can be successful in refractory patients. Alternatives to aminosalicylates are the new glucocorticoids, budesonide and beclometasone dipropionate, either as enemas or oral formulations (only beclometasone dipropionate). A combination of oral or rectal new glucocorticoids with rectal aminosalicylates should be considered in patients refractory to either approach. When these measures fail, treatment with oral glucocorticoids is necessary. An intensive intravenous steroid regimen is also helpful for patients refractory to oral steroids. Alternative treatments include short-chain fatty acid enemas, nicotine enemas and patches, acetarsol suppositories, ciclosporin enemas and epidermal growth factor enemas. Several factors potentially having a negative impact on therapeutic response include concurrent enteric pathogens, coexistent irritable bowel syndrome, patient nonadherence to therapy, inadequate dosing and duration of therapy, and proximal progression of the disease. Surgical colectomy may be required in those rare patients refractory or intolerant to pharmacotherapy.

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 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 cyclosporin or to refer the patient to the surgeon. This decision requires a careful evaluation of the patient and a medical /surgical team. Infliximab seems to be a promising drug but more controlled trial are needed.

To explore the efficacy and safety of the topically acting steroid beclometasone dipropionate (BDP) in an oral controlled release formulation in the treatment of extensive or left-sided ulcerative colitis.In a multicentre, randomised, parallel-group, single-blind study, patients with active mild to moderate ulcerative colitis were randomised to a 4-week treatment with BDP 5 mg/day o.d. vs. 5-ASA 0.8 g t.d.s. The primary efficacy variable was the decrease of Disease Activity Index (DAI) (clinical symptoms and endoscopic appearance of mucosa). Safety was evaluated by monitoring adverse events, vital signs, haematochemical parameters and adrenal function.One hundred and seventy-seven patients were enrolled and randomly treated with BDP (n = 90) or 5-ASA (n = 87). Mean DAI score decreased in both treatments groups (P0.0001 vs. baseline for both groups). Clinical remission was achieved in 63.0% of patients in the BDP group vs. 62.5% in the 5-ASA group. A significant DAI score improvement (P0.05) in favour of BDP was observed in patients with extensive disease. Both treatments were well tolerated. Mean plasma cortisol levels were significantly reduced vs. baseline in BDP recipients, but without signs of pituitary-adrenal function depletion.Oral BDP gave an overall treatment result in patients with active ulcerative colitis without signs of systemic side-effects.

The meta-analyses of published trials have shown topical therapy with 5-aminosalicylic acid (5-ASA) to be the treatment of choice in active distal ulcerative colitis. Oral aminosalicylates are effective for both distal and extensive ulcerative colitis, but in distal colitis the rates of improvement and remission are usually lower than those reported for rectal 5-ASA therapy. An alternative to 5-ASA therapy is represented by the new steroids; budesonide and beclometasone dipropionate (BDP) enemas, the most extensively studied, have been shown to be as effective as conventional steroids but with a significantly lower inhibition of plasma cortisol. Patients who do not respond to 5-ASA or new steroids should be treated with oral steroids. Azathioprine or 6-mercaptopurine may be effective in patients who do not respond or cannot be weaned off steroids. Treatment of pouchitis is largely empirical and few controlled studies have been carried-out. Antibiotics are the treatment of choice and most patients make a good response to metronidazole or ciprofloxacin. Chronic refractory pouchitis may benefit from a prolonged course of a combination of antibiotics. Highly concentrated probiotics (VSL#3) are effective both for the prevention of pouchitis onset and the prevention of relapses.

The monitoring of patients with ulcerative colitis is easier than in patients with Crohn's disease for several reasons: the severity of symptoms and activity of inflammation tend to run parallel in ulcerative colitis when involvement of the large bowel is more extensive. The easy accessibility of the colonic mucosa by endoscopic and histologic examination provides further information concerning the degree of inflammation. In severe attacks, the patient must be admitted to hospital and monitored carefully. Clinical and laboratory parameters (such as daily stools, CRP, fever, haemoglobin, albumin, etc.) and plain abdominal X-ray are useful in monitoring the activity of the disease and to predict the outcome. In mild to moderate attacks, endoscopic and histologic evaluation are the best methods for choosing the appropriate treatment and for assessing response.

Refractoriness to conventional therapy is a common and intriguing problem in Crohn's disease patients. At the present time there is no agreement on its definition and several mechanisms are involved in its determination. Immunosuppressors, such as azathioprine (AZA), 6-mercaptopurine (6MP) and methotrexate (MTX) are effective drugs for controlling the inflammatory process and avoid chronic glucocorticosteroid treatment and its related side-effects. Recently, the introduction of tumour necrosis factor antibodies (infliximab) has dramatically changed the natural history of Crohn's disease and its therapeutic approach. Several studies have determined the efficacy, mechanisms and safety of infliximab. However, this molecular approach has also left several questions unanswered about the mechanisms of refractoriness, possible concomitant treatments and long-term safety and efficacy.

Preliminary data suggest that short-term antibiotic therapy with a single drug is effective for the treatment of patients with pouchitis. However, some patients are resistant to treatment.To evaluate the therapeutic efficacy of a prolonged course of a combination of two antibiotics in patients with refractory or recurrent pouchitis, as well as its impact on their quality of life.Patients with active refractory or recurrent pouchitis were recruited. This was defined as both: (i) a history of pouchitis at least twice in the last 12 months or persistent pouchitis requiring continual intake of antibiotics; and (ii) a Pouchitis Disease Activity Index score 3 7 (best to worst pouchitis=0-18) at the beginning of therapy. Treatment consisted of a combination of metronidazole, 400 or 500 mg twice daily, and ciprofloxacin, 500 mg twice daily, for 28 days. Symptomatic, endoscopic and histological evaluations were undertaken before and after antibiotic therapy using the Pouchitis Disease Activity Index score. Remission was defined as a combination of a Pouchitis Disease Activity Index clinical score ofor= 2, endoscopic score ofor= 1 and total score ofor= 4. The quality of life was assessed with the Inflammatory Bowel Disease Questionnaire, which encompasses bowel, systemic and emotional symptoms as well as social function (worst to best=32-224).Forty-four patients (24 male, 20 female; median age, 37.5 years) entered the trial and completed treatment. Thirty-six (82%) went into remission. The median Pouchitis Disease Activity Index scores before and after therapy were 12 (range, 8-17) and 3 (range, 1-10), respectively (P0.0001). The median Inflammatory Bowel Disease Questionnaire score also significantly improved from 96.5 (range, 74-183) to 175 (range, 76-215) with this therapy (P0.0001). The eight patients (five male, three female) who did not go into remission were significantly older (median 47.5 vs. 35 years; P=0.007), had a longer history of pouchitis (95.5 vs. 26 months; P=0.0008), had a greater proportion with chronic pouchitis (chronic/relapsing: 6/2 vs. 9/27; relative risk, 1.6; 95% confidence interval, 1.0-2.4) and tended to have a higher Pouchitis Disease Activity Index score before treatment (median 14.5 vs. 12; P=0.13) than those who went into remission. Even in these eight patients, the median Pouchitis Disease Activity Index score significantly improved from 14.5 (range, 8-16) to 9.5 (range, 7-10) (P=0.0078), as did the Inflammatory Bowel Disease Questionnaire score from 95.5 (range, 74-134) to 127 (range, 76-187) (P=0.039). The Inflammatory Bowel Disease Questionnaire score strongly correlated with the Pouchitis Disease Activity Index score (r=0.79, P0.0001), and was significantly related to the patients' overall assessment of satisfaction (P0.0001). No serious side-effects were noted.Four-week treatment with a combination of metronidazole and ciprofloxacin is highly effective in patients with active recurrent or refractory pouchitis, objectively improving the inflammation and quality of life. The Inflammatory Bowel Disease Questionnaire is a sensitive tool for evaluating patients with pouchitis, and correlates well with disease activity.

To evaluate efficacy and safety of oral beclometasone dipropionate (BDP) when added to 5-ASA in the treatment of patients with active ulcerative colitis.In a 4-week, placebo-controlled, double-blind study, patients with extensive or left-sided mild to moderate active ulcerative colitis were randomized to receive oral 5-ASA (3.2 g/day) plus BDP (5 mg/day) or placebo. Clinical, endoscopic and histologic features, and haematochemical parameters were recorded at baseline and at the end of the study.One hundred and nineteen patients were enrolled and randomly treated with BDP plus 5-ASA (n = 58) or placebo plus 5-ASA (n = 61). Both treatment groups showed a statistically significant decrease of disease activity index (DAI) and histology score at the end of treatment (P = 0.001, each). DAI score was lower in the BDP group than in the placebo group (P = 0.014), with more patients in clinical remission in the BDP group (58.6% vs. 34.4%, P = 0.008). Serum cortisol levels significantly decreased in BDP group vs. baseline (P = 0.002), but without signs of pituitary-adrenal function depletion. A low incidence of adverse events was observed in both groups.Oral BDP in combination with oral 5-ASA is significantly more effective than 5-ASA alone in the treatment of patients with extensive or left-sided active ulcerative colitis.

Restorative proctocolectomy with ileal pouch anal anastomosis is the first choice procedure for the treatment of ulcerative colitis and familial adenomatous polyposis. The introduction of the stapled technique has shortened the duration of the procedure and reduced the complication rates. Data on 335 consecutive patients undergoing ileal pouch anal anastomosis for ulcerative colitis (277 pts), Indeterminate colitis (20 pts) and familial adenomatous polyposis (38 pts) between 1984 and 1998 were prospectively collected. Parameters evaluated included diagnosis, surgical technique, functional outcome, early and late complications and their management and results. Twenty-nine patients (8.6%) presented with pelvic sepsis. Twelve patients (3.5%) experienced late perianal fistulas. The pouch failure rate was 3.4%. Six patients required a re-do pouch procedure, with 75.9% preservation of sphincter function. No correlation was found between complication rates and diagnosis. The mean number of stools was 5.2/24 h. The study confirmed the safety and effectiveness of the procedure. In particular, morbidity rates are comparable to those of major abdominal procedures and the long-term functional results are satisfactory. However, a number of technical aspects, such as the anastomosis technique, the need for temporary ileostomy and the treatment of indeterminate colitis, still remain controversial.

The etiology of inflammatory disease is still unknown, but a body of evidence from clinical and experimental observation indicates a role for intestinal microflora in the pathogenesis of this disease. Reduction of microflora using antibiotics, bowel rest and fecal diversion decreases activity in Crohn's disease and in ulcerative colitis. Several trials have been carried out on the use of antibiotic treatment in patients with active ulcerative colitis with contrasting results. A number of trials have been carried out using Rifaximin, a non-absorbable broad-spectrum antibiotic, confirming the absence of systemic bioavalaibility of the drug even when administered at very high doses and for prolonged periods. It may therefore be useful in treatment of ulcerative colitis and pouchitis, since its absorption through inflamed mucosa is negligible, it maintains a topical action without systemic effects and the lack of resistant bacterial strains may allow prolonged and repeated treatments.

A body of evidence from clinical and experimental observations indicates a role for intestinal microflora in the pathogenesis of inflammatory bowel disease (IBD). Probiotics are defined as ‘living organisms, which upon ingestion in certain numbers, exert health benefits beyond inherent basic nutrition’. Recent evidence supports the potential role of probiotics in IBD therapy.

Although 5-aminosalicylic acid (5-ASA) oral compounds are the standard maintenance treatment for ulcerative colitis in remission, some patients cannot use them because of side-effects. Clinical and experimental observations have suggested the potential role of probiotics in inflammatory bowel disease therapy.To evaluate the effects on intestinal microflora and the clinical efficacy of a new probiotic preparation in patients with ulcerative colitis in remission.Twenty patients with ulcerative colitis, intolerant or allergic to 5-ASA, have been treated with a new probiotic preparation (VSL#3, CSL, Milan, Italy) containing 5x10(11) cells/g of 3 strains of bifidobacteria, 4 strains of lactobacilli and 1 strain of Streptococcus salivarius ssp. thermophilus. Two doses of 3 g were administered o.d. for 12 months. Faecal samples for stool culture were obtained from the patients at the beginning of the trial and after 10, 20, 40, 60, 75, 90 days, 12 months and at 15 days after the end of the treatment. The following bacterial groups have been evaluated in the faeces: total aerobic and anaerobic bacteria, enterococci, Streptococcus thermophilus, lactobacilli, bifidobacteria, Bacteroides, clostridia, coliforms. Patients were assessed clinically every two months, and assessed endoscopically at 6 and 12 months or in relapse.Faecal concentrations of Streptococcus salivarius ssp. thermophilus, lactobacilli and bifidobacteria increased significantly in all patients, compared to their basal level, from the 20th day of treatment (P0.05) and remained stable throughout the study. Concentrations of Bacteroides, clostridia, coliforms, total aerobic and anaerobic bacteria did not change significantly during treatment (P = N.S.). Fifteen of 20 treated patients remained in remission during the study, one patient was lost to follow up, while the remaining relapsed. No significant side-effects have been reported.These results show that this probiotic preparation is able to colonize the intestine, and suggest that it may be useful in maintaining the remission in ulcerative colitis patients intolerant or allergic to 5-ASA. Controlled trials are warranted to confirm these preliminary results.

Patients with Crohn's disease may become zinc‐deficient and, in such patients, an altered metabolism of radiolabelled long‐chain fatty acids has been reported. We have investigated the possible reversal by zinc supplementation of altered long‐chain fatty acid profiles of red cells in Crohn's disease. Twenty patients with long‐standing Crohn's disease in clinical remission received 200 mg of zinc sulphate daily for 6 weeks. Phospholipid fatty acid profiles of washed red cells were analysed before and after zinc treatment and compared to those of 20 unsupplemented healthy controls. Plasma zinc levels in Crohn's were 72 ± 8 μg/dL before zinc treatment and increased to 114 ± 10 μg/dl after the therapy. Prior to zinc supplementation, the percentage of palmitic, stearic and oleic acids was significantly higher in Crohn's disease, while linoleic, arachidonic and n‐3 fatty acids were reduced in Crohn's disease compared to healthy controls. Zinc supplementation abolished these pre‐treatment differences in red‐cell long‐chain fatty acid profiles but did not affect plasma fatty acid values. Further studies are needed to clarify whether these fatty acid changes can be related to the clinical course of the disease. Copyright © 1994, Wiley Blackwell. All rights reserved

Background Few data exist regarding the long‐term effectiveness of golimumab in ulcerative colitis. No data have been reported on real‐world continuous clinical response. Objective This study aimed to describe the long‐term outcomes in a large cohort of patients on golimumab who had ulcerative colitis. Methods Consecutive patients with active ulcerative colitis, started on golimumab, were enrolled and prospectively followed up. The primary end point was to evaluate the long‐term persistence on golimumab therapy. Results A total of 173 patients with ulcerative colitis were studied. Of these, 79.2% were steroid dependent, and 46.3% were naïve to anti‐tumour necrosis factor alpha agents. The median duration of golimumab therapy was 52 weeks (range: 4–142 weeks). The cumulative probability of maintaining golimumab treatment was 47.3% and 22.5% at 54 and 108 weeks, respectively. Biological‐naïve status (odds ratio [OR] = 3.02, 95% confidence interval [CI]: 1.44–6.29; p = 0.003) and being able to discontinue steroids at Week 8 (OR = 3.32, 95% CI: 1.34–8.30; p = 0.010) and Week 14 (OR = 2.94, 95% CI: 1.08–8.02; p = 0.036) were associated with longer persistence on therapy. At Week 54, 65/124 (52.4%) postinduction responders were in continuous clinical response. A continuous clinical response was associated with a lower likelihood of golimumab discontinuation throughout the subsequent year of therapy (p

Background Crohn’s disease (CD) is a chronic, relapsing and remitting inflammatory bowel disease. The relationship of attachment to the illness is considered to be bidirectional. Objective The authors investigated aspects of this bidirectional relationship. Method A group of 102 patients with CD and 306 healthy subjects filled out the Attachment Style Questionnaire and the Parental Bonding Instrument. Results Patients with CD exhibit a predominantly insecure attachment and perceived their parents’ behaviors as characterized by low maternal care and high paternal overprotection. Discussion The evaluation of attachment style and early parental experiences in patients with CD may shed light on the bidirectional relationship between attachment and illness. These findings may confirm the bidirectional relationship between insecure attachment and chronic illness.

Background Previous studies have shown a relationship between inflammatory bowel disease (IBD) and psychological stress. Adverse parenting is recognized as an important risk factor for the development of psychiatric disorders in adulthood. Objective The authors sought to further investigate this relationship by clarifying aspects of the bonding relationship in IBD patients and control subjects. Method A group of 307 patients with IBD and a group of 307 healthy subjects filled out the questionnaire Parental Bonding Instrument. Results Patients with IBD perceived their parents’ behaviors as characterized by low care and paternal overprotection; the category Optimal Parenting differs highly in the two samples. Conclusion This study demonstrated an association between inadequate parenting and a chronic physical illness. These findings are consistent with a growing literature that links early parental experience to chronic illness.

Background: Ulcerous rectocolitis and Crohn’s disease are the best known forms of inflammatory bowel disease (IBD). Skin manifestations are not uncommon in IBD and may be divided into specific cutaneous signs, aspecific cutaneous signs, and cutaneous signs caused by drugs used for IBD therapy. The specific signs (fistulas, rhagades and ulcers) are the result of the diffusion of the intestinal inflammatory process into the skin. Aspecific cutaneous signs (stomatic aphthosis, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, vasculitis, bullous diseases) are quite frequently found in those suffering from IBD, but also in apparently healthy subjects, and may sometimes be the first sign of the intestinal disease. Cutaneous manifestations due to drugs vary in clinical aspect and are the direct consequence of the therapies adopted, which in IBD patients can be quite numerous: steroids, immunosuppressants, 5-aminosalicylic acid, biological agents, antibiotics. Objective and Methods:Due to the frequent finding of cutaneous manifestations in patients affected by IBD, a collaboration was set up between the Dermatological Clinic of the University of Bologna and the Center for the Study of IBD of the same university hospital. The aim was to diagnose the cutaneous signs appearing during IBD and to establish their etiopathogenesis in order to assess whether they were the result of epiphenomena of the IBD or side effects of the therapies adopted. Results: The cutaneous manifestations we observed can be divided into three distinct groups: signs that were specific to the basic disease, aspecific signs and finally signs attributable to the drugs used for therapy. Particular attention was given to the aspecific signs and those consequential to therapy. The aspecific cutaneous signs seen in our clinic generally reflect those reported in the literature. The cutaneous manifestations due to drugs were further divided into three groups: rosacea, acneiform dermatitis and psoriasis-like dermatitis. The most notable aspect of our series is the high number of patients presenting psoriasiform-type dermatitides with a generally widespread diffusion. Conclusion: We would like to draw attention to the fact that all patients with psoriasis had been undergoing treatment with drugs inhibiting tumor necrosis factor α (TNF-α) as part of IBD therapy. In all cases, the cutaneous reaction started after the third or fourth infusion of the biological drug. Anti-TNF-α agents have also been successfully used to treat psoriasis in the last few years. The reason for this apparently paradoxical effect of the therapy is still unclear.

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

Background and aims The effectiveness of adalimumab in the treatment of ulcerative colitis is under debate. Although controlled trials have shown that adalimumab is significantly better than placebo, the absolute clinical benefit is modest. We report data on the effectiveness of adalimumab in a cohort of ulcerative colitis patients treated in 22 Italian centres. Methods All patients with active disease treated with adalimumab were retrospectively reviewed. Co-primary endpoints were clinical remission at weeks 4, 12, 24 and 54. Secondary endpoints were sustained clinical remission, steroid discontinuation, endoscopic remission and need for colectomy. Results Eighty-eight patients were included. Most patients had received previous infliximab treatment. Clinical remission rates were 17%, 28.4%, 36.4% and 43.2% at 4, 12, 24 and 54 weeks respectively. Twenty-two patients required colectomy. Clinical remission and low C-reactive protein at week 12 predicted clinical remission at week 54 (OR 4.17, 95% CI 2.36–19.44; OR 2.63, 95% CI 2.32–14.94, respectively). Previous immunosuppressant use was associated with a lower probability of clinical remission at week 54 (OR 0.67, 95% CI 0.08–0.66) and with a higher rate of colectomy (HR 9.7, 95% CI 1.46–9.07). Conclusion In this large “real-life” experience adalimumab appears effective in patients with otherwise medically refractory ulcerative colitis. Patients achieving early remission can expect a better long-term outcome.

Purpose: Dendritic cells regulate immune responses to microbial products. We assessed effects of bacterial DNA in the clinically-effective probiotic preparation, VSL#3, on activation, cytokine production and T-cell stimulatory capacity of human dendritic cells. Methods: Whole blood and enriched dendritic cells were cultured with bacterial DNA in the presence or absence of Toll-like receptor antibodies. Expression of Toll-like receptor 9 and activation markers (CD40, CCR7) on CD11c+ (myeloid) and CD11c- (plasmacytoid) dendritic cells was analysed by flow cytometry. Cytokine production was assessed by intracellular staining and ELISA. Activation of naive allogeneic CD4+ T-cells was measured in mixed leukocyte reactions. Results: Probiotic bacterial DNA activated plasmacytoid and myeloid dendritic cells as indicated by enhanced CD40 and CCR7 expression. Probiotic bacterial DNA enhanced interleukin-10 production by myeloid dendritic cells using pathways involving Toll-like receptor 9 and inhibited dendritic cells' ability to stimulate naive T-cells. Conclusions: Probiotic bacterial DNA induces an immunoregulatory rather than a pro-inflammatory cytokine profile in dendritic cells, suggesting that beneficial effects of probiotic bacteria are mediated in part by their DNA. These results suggest that the release of bacterial DNA from the microflora as a result of physiologically occurring bacterial lysis may be involved in intestinal immune homeostasis.