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Bosani M, Ardizzone S, Porro GB. Biologics: Targets and Therapy. 2009;3:77–97.This paper has been retracted after we were made aware that it contains a large amount of reused, and uncited material that was not placed within quotation marks.The following statement has been supplied by Dr Sandro Ardizzone:The review entitled "Biologic targeting in the treatment of inflammatory bowel disease" has been commissioned by this journal and published in 2009 (Matteo Bosani, Sandro Ardizzone, Gabriele Bianchi Porro. Biologics: Targets & Therapy 2009;3:77–97). The paper was written by our young coworker (Dr M Bosani). He has consulted many papers, including our previous reviews published years before. The not perfect knowledge of English language has greatly influenced the writing of the paper itself. So he saved in word file several parts of our previous papers (Ardizzone S, Bianchi Porro G. Inflammatory bowel disease: new insights into pathogenesis and treatment. J Intern Med 2002;252:475–496 – Ardizzone S, Bianchi Porro G. Biologic therapy for inflammatory bowel disease. Drugs 2005:2253–2286), and then transferred to the final paper. He was unaware as we are, of the fact that he could not reuse previously published material in other journals. The reuse of this material was made in good faith.Taking our responsibility for what happened, we intend to apologize for this inconvenience to the Editor (Dr Doris Benbrook) and Publisher (Dr Tim Hill). Moreover, for the reasons mentioned above, I consider appropriate to retract the paper itself.This retraction relates to this paper.

Background and Aim: Since the outbreak of COVID-19, concerns have been raised as to whether inflammatory bowel disease (IBD) patients under biologic therapy may be more susceptible to the disease. This study aimed to determine the incidence and outcomes of COVID-19 in a large cohort of IBD patients on biologic therapy., Methods: This observational retrospective multicenter study collected data about COVID-19 in IBD patients on biologic therapy in Italy, between February and May 2020. The main end-points were (i) to assess both the cumulative incidence and clinical outcome of COVID-19, according to different biologic agents and (ii) to compare them with the general population and a cohort IBD patients undergoing non-biologic therapies., Results: Among 1816 IBD patients, the cumulative incidence of COVID-19 was 3.9 per 1000 (7/1816) with a 57% hospitalization rate and a 29% case-fatality rate. The class of biologic agents was the only risk factor of developing COVID-19 (P = 0.01). Non-gut selective agents were associated with a lower incidence of COVID-19 cases, related symptoms, and hospitalization (P < 0.05). Compared with the general population of Lombardy, an overall lower incidence of COVID-19 was observed (3.9 vs 8.5 per 1000, P = 0.03). Compared with 565 IBD patients on non-biologic therapies, a lower rate of COVID-19 symptoms was observed in our cohort (7.5% vs 18%, P < 0.001)., Conclusions: Compared with the general population, IBD patients on biologic therapy are not exposed to a higher risk of COVID-19. Non-gut selective agents are associated with a lower incidence of symptomatic disease, supporting the decision of maintaining the ongoing treatment., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: COVID-19 patients have an increased susceptibility to develop thrombotic complications, thus thromboprophylaxis is warranted which may increase risk of upper gastrointestinal bleeding (UGIB). Our aim was to evaluate incidence of UGIB and use of upper GI endoscopy in COVID-19 inpatients., Methods: The medical and endoscopic management of UGIB in non-ICU COVID-19 patients has been retrospectively evaluated. Glasgow Blatchford score was calculated at onset of signs of GI bleeding. Timing between onset of signs of GI bleeding and execution, if performed, of upper GI endoscopy was evaluated. Endoscopic characteristics and outcome of patients were evaluated overall or according to the execution or not of an upper GI endoscopy before and after 24h., Results: Out of 4871 COVID-19 positive patients, 23 presented signs of UGIB and were included in the study (incidence 0.47%). The majority (78%) were on anticoagulant therapy or thromboprophylaxis. In 11 patients (48%) upper GI endoscopy was performed within 24h, whereas it was not performed in 5. Peptic ulcer was the most common finding (8/18). Mortality rate was 21.7% for worsening of COVID-19 infection. Mortality and rebleeding were not different between patients having upper GI endoscopy before or after 24h/not performed. Glasgow Blatchford score was similar between the two groups (13;12-16 vs 12;9-15)., Conclusion: Upper GI bleeding complicated hospital stay in almost 0.5% of COVID-19 patients and peptic ulcer disease is the most common finding. Conservative management could be an option in patients that are at high risk of respiratory complications., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Budesonide-MMX has an established role in the management of relapsing mild-to-moderate ulcerative colitis. Data regarding effectiveness and tolerability in real-life clinical practice are limited., Aim: The aim of this study was to assess the use of budesonide-MMX in ulcerative colitis, as well as short-term effectiveness and tolerability in real-life practice., Methods: We conducted a retrospective study of adult patients with mild-to-moderate ulcerative colitis treated with budesonide-MMX at four tertiary inflammatory bowel disease centres in Italy from June 2016 to February 2018. Demographic and clinical features of patients, the use of budesonide-MMX, disease course and concomitant therapy were recorded. The primary outcome assessed was clinical remission at 2 months., Results: A total of 82 patients with active mild-to-moderate ulcerative colitis were included in the study with a mean age of 45.9 years and a median partial Mayo Score of 4 (interquartile range 3-5). A total of 41 patients were male. Overall, 36 had extensive colitis, 38 left-sided colitis and eight proctitis. Treatments at the time of inclusion included 10 patients receiving biologic therapy, seven azathioprine and 54 mesalazine or salazopyrin. The main reasons for the addition of budesonide-MMX were clinical relapse (47.5%) or inadequate response to current therapy (39.0%). In total, 50% of patients achieved clinical remission, whereas 9.8% had clinical improvement. No response was noted in 40.2% of subjects. Using multivariate binary logistic regression, a moderate degree of activity was the main independent predictor of non-response. Eight significant adverse effects were reported in six patients with three discontinuing treatment., Conclusion: In real-life clinical practice, budesonide-MMX is commonly used in combination with other therapies, both for acute disease flares and for partial response to therapy., (© Author(s) 2019.)

Background and Aim: Limited data suggests that pseudomembranes are uncommon in patients with inflammatory bowel disease (IBD) and C. difficile associated disease (CDAD), but the reason for this is unknown. We aimed to evaluate the rate of pseudomembranes in this population, identify predictive factors for pseudomembranes' presence and assess its clinical impact., Methods: This was a sub-study of a retrospective European Crohn's & Colitis Organization (ECCO) multi-center study on the outcome of hospitalized IBD patients with C. difficile. The present study included only patients who underwent lower endoscopy during hospitalization, and compared demographic and clinical parameters in the group of patients with discernable pseudomembranes versus those without., Results: Out of 155 patients in the original cohort, 93 patients underwent lower endoscopy and constituted the study population. Endoscopic pseudomembranes were found in 12 (13%) of these patients. Patients with pseudomembranes presented more commonly with fever (p=0.02) compared to patients without pseudomembranes. No difference between the two groups was found with respect to the use of immunosuppressant drugs, background demographics or disease characteristics. Neither was there a difference between the group with or without pseudomembranes in the frequency of severe adverse clinical outcome or in the duration of hospitalization. On multi-variate analysis the presence of fever remained independently associated with the finding of pseudomembranes (OR 6, 95% CI 1.2-32, p=0.03)., Conclusions: This study documents that hospitalized IBD patients with CDAD have low rate of endoscopic pseudomembranes, which is not accounted for by the use of immunosuppressant drugs. IBD patients with CDAD and discernable pseudomembranes more commonly present with fever, but their clinical outcome is similar to patients without pseudomembranes., (Copyright © 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Management of Clostridium difficile infection in patients with flaring inflammatory bowel disease (IBD) has not been optimized. We investigated the effects of combination therapy with antibiotics and immunomodulators in patients with IBD and C difficile infection., Methods: We analyzed data from 155 patients (59% with ulcerative colitis [UC]) from a retrospective, European Crohn's and Colitis organization, multi-center study comparing outcome of hospitalized IBD patients with C difficile infection who were treated with antibiotics (n = 51) or antibiotics and immunomodulators (n = 104). The primary composite outcome was death or colectomy within 3 months of admission, in-hospital megacolon, bowel perforation, hemodynamic shock, or respiratory failure., Results: The primary outcome occurred in 12% of patients given the combination treatment vs none of the patients given antibiotics alone (P = .01). UC, abdominal tenderness, or severe bloody diarrhea was more common among patients that received the combined therapy. However, multivariate analysis revealed that only the combination therapy maintained a trend for an independent association with the primary outcome (likelihood ratio = 11.9; CI, 0.9-157; P = .06). Treatment with 2 or 3 immunomodulators was correlated with the primary outcome, independent of disease severity at presentation (odds ratio [OR] = 17; CI, 3.2-91; P < .01). Acid-suppressing medications increased the risk of C difficile relapse (OR = 3.8; CI, 1.1-12.9; P = .03), whereas recent hospitalization correlated with increased rate of C difficile persistence (OR = 8; CI, 2.1-29; P = .002)., Conclusions: Patients with IBD that also have C difficile infection are frequently treated with a combination of antibiotics and immunomodulators. However, this combination tends to associate with a worse outcome than antibiotic therapy alone. Prospective controlled trials are urgently needed to optimize the management of these challenging patients.

The etiology of inflammatory bowel disease (IBD) has not yet been clarified and immunosuppressive agents which nonspecifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Under normal situations, the intestinal mucosa is in a state of "controlled" inflammation regulated by a delicate balance of proinflammatory (tumor necrosis factor [TNF-alpha], interferon-gamma [IFN-gamma], interleukin-1 [IL-1], IL-6, IL-12 and anti-inflammatory cytokines IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may therefore be a logical target for inflammatory bowel disease therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, Th1 polarization, T cell activation, nuclear factor-kappaB (NF-kappaB), and other miscellaneous therapies are being evaluated as potential therapies for the treatment of inflammatory bowel disease. In this context, infliximab and adalimumab are currently the only biologic agents approved in Europe for the treatment of inflammatory Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP571, certolizumab pegol, etanercept, onercept. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanism involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutics agents to inhibit leukocyte trafficking include natalizumab (approved for use in Crohn's disease in USA), MLN-02, and ISIS 2302. Other agents being investigated for the treatment of Crohn's disease include inhibitors of T cell activation, proinflammatory cytokine receptors, Th1 polarization, growth hormone, and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned above. Controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspective on the development of therapies for inflammatory bowel disease. A review is made of the main areas of research exploring the mechanisms associated with the pathogenesis of IBD, providing advances in the agents currently in use, and identifying a host of new therapeutic biologic targets.

Background: Colonoscopy is frequently performed in ulcerative colitis (UC), but its benefit in the management of the disease is a matter of debate. The objective was to determine the clinical impact of colonoscopy in UC., Methods: Consecutive patients with UC undergoing colonoscopy were studied. The design and main outcome measurement was appropriateness of indications, evaluated according to guidelines. Endoscopic findings altering the management of the patients were registered. The endoscopist's management decisions based on patient's clinical picture were compared with those selected after endoscopy. Need for further investigations was recorded. Endpoints for colonoscopy-improving management were prospectively defined: change in medical therapy, need for adjunctive procedures, identification or exclusion of cancer, adenomatous polyps, or other conditions with clinical impact. The setting was an open access endoscopy service in a tertiary care center., Results: In all, 507 patients (268 male, 239 female, mean age 42 years) were included. Colonoscopy was indicated in 60.8% of cases. In 46% of patients endoscopy revealed a significant lesion; this rate was higher for indicated (67.2) than for not indicated procedures (13.5%, P < 0.0001). The endoscopist's decision was altered by the endoscopic finding in 7.6% of cases and was not different between appropriate and inappropriate procedures., Conclusions: Endoscopy is a potent tool in the management of UC if correctly used. However, in the majority of cases a correct therapeutic decision may be established simply on the basis of the clinical picture. Relevant endoscopic findings have a relatively low impact on the medical treatment, but may have a very important value in the prognostic assessment of the disease.

Pancreatic insufficiency (PI) may be an extraintestinal manifestation of inflammatory bowel diseases (IBD). We report the results of a cross-sectional study that was carried out to investigate both the prevalence of PI in IBD patients and its clinical course over a 6-month follow-up period. In total, 100 Crohn's disease (CD) patients, 100 ulcerative colitis (UC) patients, and 100 controls were screened for PI by the fecal elastase-1 (FE-1) test. The decision limits employed were: < or =200 microg/g stool for PI and < or =100 microg/g for severe PI. Patients with abnormal FE-1 values were re-tested after 6 months. Odds ratios (OR) for PI were estimated by unconditional logistic regression analysis. PI was found in 22 UC and 14 CD patients. The OR for the FE-1 test < or =200 microg/g was 10.5 [95% confidence interval (CI): 2.5-44.8] for IBD patients compared to the controls. The risk of PI was related to three or more bowel movements per day (OR = 25.0), the passage of loose stools (OR = 7.7), and previous surgery (OR = 3.7). At the 6-month follow-up, FE-1 values became normal in 24 patients and showed persistently low concentrations in 12. These patients had a larger number of bowel movements per day (OR = 5.4), previous surgery (OR = 5.7), and a longer duration of the disease (OR = 4.2). PI is frequently found in IBD patients, particularly in those with loose stools, a larger number of bowel movements/day and previous surgery. PI is reversible in most patients, and persistent PI is not associated with clinically active disease.

Case Report: We present the case of a 52-year-old man with steroid-dependent ulcerative colitis, needing immunosuppressive therapy with azathioprine. The drug had been started 3 years earlier, but stopped after a few months because the patient reported palpitations, lipothymia, nausea and vomiting. Given the continued steroid-dependent ulcerative colitis and the lack of clinical documentation about a reaction with a dubious relationship to azathioprine, we decided to rechallenge the patient with the drug under clinical monitoring and after informed consent. After starting 50 mg of azathioprine, the patient showed general malaise, nausea and vomiting. An ECG showed atrial fibrillation, and the patient reported that the symptoms were similar to those previously experienced., Discussion: We have found two other cases of similar onset of atrial fibrillation after azathioprine use, although some confounding elements in these episodes make the possible causal relationship between the drug and this adverse event uncertain.