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Background Adalimumab is used to treat ulcerative colitis, but additional effectiveness and safety data are needed. Patients and methods This retrospective study considered adults with ulcerative colitis treated with adalimumab at 19 hospitals. Clinical data were collected from the start of treatment, after 2, 6 and 12 months, and at the last visit. Outcome measures of effectiveness were treatment duration, reasons for discontinuation and colectomy. Results We studied 381 patients treated with adalimumab for a median of 12.1 months. Disease activity at the start of treatment was moderate to severe in 262 cases (68.8%) and endoscopic activity was moderate to severe in 339 cases (89.0%). At week 8, clinical responses were observed in 177 cases (46.5%) and clinical remission in 136 cases (35.7%). At 12 months, remission was observed in 128 cases (33.6%). Overall, 44 patients required colectomy, and 170 patients (44.6%) were still taking adalimumab when data were collected. Variables associated with adalimumab discontinuation were concomitant steroid treatment, severe clinical-endoscopic activity at baseline, need for adalimumab intensification and drug-related adverse events. Variables associated with colectomy were concomitant steroid treatment and high baseline C-reactive protein. Conclusion Adalimumab is safe and effective for the treatment of ulcerative colitis.

Nitric oxide is thought to play an important role in modulating the inflammatory process. Recently an increase in the inducible form of nitric oxide synthase (iNOS) has been found in the rat trinitrobenzene sulfonic acid model of experimental colitis, and inhibition of nitric oxide synthase activity resulted in an amelioration of tissue injury. The aim of our study was to evaluate in vivo intracolonic release of nitric oxide in this model of colitis. Experimental colitis was induced in male Sprague-Dawley rats by a single intracolonic administration of trinitrobenzene sulfonic acid. Nitrite levels were determined in rectal dialysates by HPLC. The tissue myeloperoxidase and iNOS and the luminal leukotriene B4 were also measured. Nitrite levels were significantly increased in rectal dialysates during colitis and correlated significantly with tissue myeloperoxidase and iNOS activity. The correlation between nitrite dialysate levels and wall iNOS activity confirms that nitrite in dialysates is produced by inflammatory cells and not by colonic bacterial flora. Determination of nitrite levels in rectal dialysates seems a valuable method to monitor colonic inflammation in rat trinitrobenzene sulfonic acid colitis.

Pouchitis is the major long-term complication after ileal pouch-anal anastomosis for ulcerative colitis. About 15% of patients have a chronic, treatment-resistant disease.To evaluate the efficacy of an antibiotic combination for chronic active, treatment-resistant pouchitis.Eighteen patients were treated orally with rifaximin 1 g b.d. + ciprofloxacin 500 mg b.d. for 15 days. Symptoms assessment, endoscopic and histological evaluations were performed at screening and after 15 days using the Pouchitis Disease Activity Index (PDAI). Improvement was defined as a decrease of at least 3 points in PDAI score, and remission as a PDAI score of 0. Systemic absorption of rifaximin was determined by high performance liquid chromatography. Faecal samples were collected before and after antibiotic treatment for stool culture.Sixteen out of 18 patients (88.8%) either improved (n=10) or went into remission (n=6); the median PDAI scores before and after therapy were 11 (range 9-17) and 4 (range 0-16), respectively (P0.002). No side-effects were reported. Rifaximin plasma levels and urinary excretion were negligible, confirming its mainly topical activity. A significant decrease in total anaerobes and aerobes, enterococci, lactobacilli, bifidobacteria and bacteroides in faecal samples was observed, while the reduction in number of coliforms and Clostridium perfringens did not reach a statistical significance.A combination of rifaximin and ciprofloxacin was effective in patients with active chronic, treatment-resistant pouchitis, suggesting the need, in these patients, for treatment using antibiotic agents with wide antibacterial spectrum of activity.

Pouchitis is a non-specific inflammation of the ileal reservoir and the most common complication of proctocolectomy with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis. Its frequency is related to the duration of the follow up, occurring in up to 50% of patients 10 years after IPAA in large series from major referral centers. Treatment of pouchitis is largely empirical and only small placebo-controlled trials have been conducted. The rationale for using probiotics and antibiotics in pouchitis is based on convincing evidence that implicates intestinal bacteria in the pathogenesis of this disease. Probiotics are living organisms, which, upon ingestion in certain numbers, exert health benefits beyond inherent basic nutrition. VSL#3, a highly concentrated cocktail of probiotics has been shown to be effective in the prevention of pouchitis onset and relapses. Antibiotics are the mainstay of treatment of pouchitis, and metronidazole and ciprofloxacin are the most common initial approaches, often with a rapid response. The use of antibiotics in pouchitis is largely justified although proper controlled trials have not been conducted.

Perianal fistulizing Crohn's disease (PFCD) is a common, disabling and aggressive phenotype that negatively impacts on the quality of life of affected patients. Its successful treatment is still a struggle for both physicians and patients. Significant advances in the management of this condition have occurred in the last two decades holding promise for a better future. This culminated into the concept of a collaborative multidisciplinary approach using the latest medical therapies combined with modern surgical and endoscopic techniques. Despite this, PFCD management and treatment have not been standardized yet. Thus the gastroenterologist and surgeon have to be familiar with several approaches and/or techniques. The positioning of each therapeutic option will certainly evolve with new data, but for the time being it should be driven by patient's characteristics, physician's preference and/or experience, costs and availability in local practice. Additionally, patient's perception of benefits and risks of treatment may differ from those of physicians and recognition of this difference is a starting point for difficult clinical decision-making. In this paper, a multidisciplinary group of Italian IBD experts explore and discuss current medical and surgical therapeutic options, highlighting areas of unmet needs in PFCD, with particular focus on the optimal patient flow within the Italian clinical reality.

BACKGROUND AND AIMS: The widespread use of anti-tumour necrosis factor alpha antibody (Infliximab) in Crohn's disease (CD) raises concerns about a possible cancer risk in the long term. In a matched pair study, we assessed whether Infliximab is associated with an increased risk of neoplasia. METHODS: In a multicentre matched pair study, 404 CD patients treated with Infliximab (CD-IFX) were matched with 404 CD patients who had never received Infliximab (CD-C). Cases and controls were matched for sex, age (+/-5 years), site of CD, age at diagnosis (+/-5 years), immunosuppressant use, and follow up. New diagnoses of neoplasia from April 1999 to October 2004 were recorded. RESULTS: Among the 404 CD-IFX, neoplasia was diagnosed in nine patients (2.22%) while among the 404 CD-C, seven patients developed neoplasia (1.73%) (odds ratio 1.33 (95% confidence interval 0.46-3.84); p=0.40). The survival curve adjusted for patient year of follow up showed no differences between CD-IFX and CD-C (p=0.90; log rank test). In the CD-IFX group, there was one cholangiocarcinoma, three breast cancers, one skin cancer, one leukaemia, one laryngeal cancer, and two anal carcinomas. Among the 7/404 (1.73%) CD-C, there were three intestinal adenocarcinomas (two caecum, one rectum), one basalioma, one spinalioma, one non-Hodgkin's lymphoma, and one breast cancer. Age at diagnosis of neoplasia did not differ between groups (CD-IFX v CD-C: median 50 (range 40-70 years) v 45 (27-72); p=0.50). CONCLUSION: In our multicentre matched pair study, the frequency of a new diagnosis of neoplasia in CD patients treated with Infliximab was comparable with CD patients who had never received Infliximab.

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.

Introduction : The incidence of endoscopic recurrence (ER) in Crohn's disease following curative resection is up to 75% at 1 year. Endoscopy is the most sensitive method to detect the earliest mucosal changes and the severe ER at 1 year seems to predict a clinical relapse. Methods : The aim of this prospective study was to evaluate the incidence of early ER 6 months after curative resection. Secondary outcome was to evaluate the role of 5-aminosalicylic acid (5-ASA) in the prevention of ER at 6 months. A total of 170 patients were included in the study. They were carried-out from the evaluation of the appearance of ER during a trial performed to assess the role of azathioprine vs. 5-ASA as early treatment of severe ER. All the patients started 5-ASA treatment 2 weeks after surgery. Results : Six months after surgery ER was observed in 105 patients (62%). The endoscopic score was reported as severe in 78.1% of them (82 out of 105). At univariable analysis only ileo-colonic disease influenced the final outcome associating to a lower risk of severe ER (p = 0.04; OR 0.52, 95% CI 0.277–0.974). Conclusion: In this prospective Italian multicenter IG-IBD study a great proportion of ER occur within 6 months from ileo-colonic resection, with a significant rate of severe ER. Furthermore this study confirms the marginal role of 5-ASA in the prevention of ER. This suggests that post-surgical endoscopic evaluation should be performed at 6 months instead of 1 year to allow an adequate early treatment.

The coronavirus disease 2019 (COVID-19) pandemic has not finished yet, and the most promising option towards its ending is widespread vaccination. Because patients with inflammatory bowel diseases (IBDs), namely Crohn’s disease (CD) and ulcerative colitis (UC), often require immune-modifying treatment, which might increase the risk of opportunistic infection,1 their vaccination history for several infectious diseases is routinely checked, and when inadequate, vaccination is performed at diagnosis or ideally before immune suppressive treatment is started.1 However, IBD patients were not found to be at an increased risk of developing COVID-19 or of experiencing a more severe disease course.2

Background: Crohn's disease represents a heterogeneous entity, but its location tends to be relatively stable overtime. For extensive refractory Crohn's colitis, ileorectal anastomosis after colectomy is an engaging option, since the necessity of a permanent ileostomy is avoided. Aims: In our study, the long-term outcome of two groups of patients with Crohn's colitis who underwent colectomy and ileorectal anastomosis was compared. The first group had isolated colonic Crohn's disease without rectal involvement and perianal disease, while the second group included patients who had rectal and/or ileal involvement, with or without perianal disease. Methods: Between 1996 and 2016, in a single IBD tertiary center, 80 patients with a history of colectomy and ileorectal anastomosis for refractory Crohn's colitis were retrospectively identified. Results: Recurrence of disease was diagnosed in 57/64 of patients with Crohn's colitis with rectal and/or ileal and/or perianal involvement compared with 1/16 of patients with isolated Crohn's colitis without rectal and perianal disease in a median time of recurrence of 2 years (IQR 1–6 years, minimum to maximum, 1–18 years, p < 0.001). Only 6 patients (7,5%) underwent definitive end ileostomy without proctectomy (1 in the noIRP group and 5 in the IRP group). Conclusion: Our data suggest that colectomy with ileorectal anastomosis may represent a curative option in patients with refractory isolated colitis without rectal and perianal involvement.

Background - Antineutrophil cytoplasmic antibodies (ANCAs) from patients with vasculitidis can induce neutrophils to release oxygen radicals in vitro. ANCAs with a perinuclear pattern of immunofluorescence are found in most patients with ulcerative colitis, but several findings are against ANCAs having a pathogenetic role in this disease. Aims - To evaluate the influence of ANCAs associated with ulcerative colitis on the respiratory burst activity of neutrophils. Patients - Serum samples were obtained from 14 patients with ulcerative colitis, seven of whom showed positivity for p-ANCAs, three patients with vasculitidis, two with positivity for p-ANCAs, and one for c-ANCAs, and seven healthy volunteers. Methods - A positive ANCA serology was determined with a standard indirect immunofluroescence assay. Purified immunoglobulins (IgGs) were prepared from serum samples by DEAE-Affigel blue chromatography. Human neutrophils were prepared by dextran-Ficoll-Hypaque separation. Superoxide anion (O2-. generation was measured by following the superoxide dismutase inhibitable reduction of ferricytochrome. Results - There were no significant differences among samples from ulcerative colitis IgG p-ANCA positive, ulcerative colitis IgG p-ANCA negative patients, and controls on O2-6. production, whereas ANCA positive IgG from vasculitidis significantly enhanced O2-. release (p < 0.001). Conclusions - p-ANCAs associated with ulcerative colitis have no effect on the respiratory burst activity of normal human neutrophils in vitro. These results reinforce the hypotheses that ANCAs are unlikely to contribute to the pathogenesis of ulcerative colitis.

Aims To evaluate the prevalence of clinical and ultrasonographic musculoskeletal involvement in Italian patients with inflammatory bowel disease (IBD). Methods In this cross-sectional multicenter study, 148 consecutive patients with IBD were evaluated by a gastroenterologist and a rheumatologist. All patients underwent a B-mode and power Doppler ultrasonographic examination of 6 pairs of entheses and of knee and ankle joints. Results A positive history for at least one musculoskeletal manifestation was reported by 40.5% of patients, more frequently in ulcerative colitis (UC) (p = 0.033). Inflammatory back pain was reported by 13.5% of patients, and a past history of peripheral arthritis by 14.9%, entheseal inflammation by 14.2% and dactylitis by 2.7%. At clinical examination, arthritis was observed in 19.6% of patients and enthesitis in 33%. Oligoarthritis and enthesitis at clinical examination were more frequently observed in UC than in Crohn disease (CD). 37.8% of total IBD patients fulfilled ASAS classification criteria for axial and/or peripheral spondyloarthritis, 8.1% ASAS classification criteria for axial spondyloarthritis, and 29.7% ASAS classification criteria for peripheral spondyloarthritis. With ultrasonographic examination, signs of entheseal involvement were observed in 87.8% of patients, while at power Doppler, ≥1 abnormality was observed in 27.1%. ASAS+ patients compared to those ASAS- had a significantly higher frequency at ultrasonography of acute entheseal abnormalities, power Doppler entheseal positivity and joint involvement. These abnormalities at ultrasonography were also observed in 34%, 13% and 12% of ASAS- patients. Conclusions Musculoskeletal manifestations occur frequently in patients with IBD. Ultrasonographic entheseal and joint involvement were also observed in asymptomatic patients.

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 39.5years, range 18–76years). 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 96months and 62.5months respectively. The site-specific recurrence rate was 12.2% at 5years and 25.7% at 10years. 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.

Introduction: Ulcerative colitis is an idiopathic, chronic inflammatory disease of the colonic mucosa. Its clinical course is unpredictable, marked by alternating periods of exacerbation and remission. Traditional oral corticosteroids are still the mainstay treatment for the induction of ulcerative colitis remission in patients failing or intolerant to aminosalicylates, but the risk of side effects and complications limits their usefulness. Based on these considerations, new steroids with low systemic bioavailability, such as Beclomethasone dipropionate and Budesonide, have been developed. Areas covered: We reviewed the current literature about the efficacy, safety and the role of budesonide MMX in the treatment of ulcerative colitis. The evidence reviewed in this article is a summation of relevant scientific publications, expert opinion statements, and current practice guidelines. Expert opinion: Budesonide MMX is a novel formulation that uses a Multi‐Matrix System (MMX) technology to facilitat e the release of high concentrations of active drug into the colon. Budesonide MMX at the dose of 9 mg/day for 8 weeks is effective and safe in inducing clinical and endoscopic remission in patients with mild to moderate UC, who had an inadequate response or were intolerant to either first line conventional therapy with topical and oral 5-aminosalicylic acid.

Introduction: Ulcerative colitis (UC) is a chronic inflammatory condition that causes continuous mucosal inflammation of the colon. New biological drugs have been developed in order to avoid colectomy, but corticosteroids still play a crucial role in management of active UC. Areas covered: We reviewed the current literature about the importance of corticosteroid use in the treatment of ulcerative colitis. The evidence reviewed in this article is a summation of relevant scientific publications, expert opinion statements, and current practice guidelines. This review is a summary of expert opinion in the field without a formal systematic review of evidence. Expert opinion: Corticosteroids represent the mainstay of treatment in patients with severe UC and are very effective in inducing remission in mild to moderate flares not responding to combined oral and topical mesalazine. A valid alternative to systemic corticosteroids is represented by poorly absorbed steroids, such as Beclomethasone dipropionate and Budesonide MMX. In mild-moderate distal disease topical administration of corticosteroids (both systemic and BDP) is an effective alternative to topical mesalazine. However, corticosteroids do not represent a therapeutic option as a maintenance treatment since they are associated with multiple adverse effects.

The study exploited autologous microfragmented fat to treat refractory complex Crohn’s perianal fistula, obtaining 66.7% of combined remission at 6 months in patients already treated without success using combined biosurgical approaches and multiple repair surgeries following the failure of biological therapy., Background Complex perianal fistulas represent one of the most challenging manifestations of Crohn’s disease. Combined surgical and medical therapy with biologic drugs today represent the first-line treatment option, but its efficacy does not exceed 60%. Recently, new therapeutic approaches, such as the use of mesenchymal stromal cells, have shown promising results. The adipose tissue is an abundant and easy to access source. The effectiveness, safety, and feasibility of local injections of microfragmented adipose tissue in patients with refractory complex fistulizing perianal Crohn’s disease (PCD) were evaluated. Methods Fifteen patients with persistent complex fistulizing PCD after biosurgical approach and subsequent surgical “rescue” repair were treated in S. Orsola-Malpighi Hospital with a single-local administration of microfragmented adipose tissue prepared using a minimal manipulation technique (Lipogems) in a closed system. Clinical outcomes were determined at 24-week follow-ups assessing success rate, defined as combined clinical and radiological remission. Results Upon clinical examination at 24 weeks, 10 patients had combined remission (clinical and radiographic), 4 patients showed improvements, and 1 patient failed. The results were confirmed in all patients by pelvic MRI. No relevant postoperative complications nor adverse events were reported. Conclusion These results suggest that the local injection of autologous microfragmented adipose tissue is a safe and promising “rescue therapy” for patients with multiresistant complex fistulizing PCD. This approach might be proposed as routine because it is affordable, is minimally invasive, has no risk of sphincteric damage, and can be carried out in a day-surgery setting.

Paolo Gionchetti, Carlo Calabrese, Silvio Laureti, Gilberto Poggioli, Fernando Rizzello IRCCS Azienda Ospedaliero-Universitaria di Bologna, Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Bologna, ItaliaCorrespondence: Paolo GionchettiDIMEC, Via Massarenti 9, Bologna, 40138, ItaliaEmail paolo.gionchetti@unibo.itAbstract: Procto-colectomy with an ileal pouch anal anastomosis is the procedure of choice for ulcerative colitis patients that require colectomy. Pouchitis is a non-specific inflammation of the ileal reservoir, and the most common, inflammatory and long-term, complication after pouch surgery for ulcerative colitis. The aetiology is still unknown, but many risk factors have been individuated. Pouchitis can be classified based on aetiology, duration, clinical course, and response to antibiotic therapy. Accurate diagnosis and classification is the key factor for an adequate management, and exclusion of secondary causes of pouchitis is pivotal. Most of the patients consistently respond to antibiotic therapy, but management of the subgroup of patients with chronic-antibiotic-resistant-pouchitis is still challenging, being this entity one of the major causes of pouch failure.Keywords: pouchitis, chronic antibiotic refractory pouchitis, classification, diagnosis, management