Crohn's disease after surgery: Changes in post-operative management strategies over time and their impact on long-term re-operation rate-A retrospective multicentre real-world study.

BACKGROUND: Few data are available addressing the impact of post-operative management of Crohn's disease (CD) on long-term clinical course. AIM: To assess the evolution of post-operative management strategies over the last 40 years and their impact on the re-operation rate of CD. METHODS: We included 657 patients with CD who had undergone their first radical ileo-caecal resection between 1980 and 2020. Three cohorts were defined according to year of surgery: cohort 1 (1980-1998; n = 198), cohort 2 (1999-2009; n = 218) and cohort 3 (2010-2020; n = 241). We estimated exposure to immunomodulators and anti-TNFα agents after surgery and rates of re-operation using Kaplan-Meier survival analyses. We used Cox proportional hazards regression to assess the association of clinical variables with time to re-operation. RESULTS: Immunosuppressants, (IMMs) and anti-TNFα exposure within 5 years after surgery increased significantly from cohort 1 to cohort 2 and cohort 3 (IMMs: 1.6%, 38.2% and 28.0%, respectively, p < 0.001; anti-TNFα: 0.0%, 20.7% and 52.0%, respectively, p < 0.001). There was no significant difference across cohorts regarding the cumulative probability of re-operation within 5 and 10 years. Multivariate analysis identified IMMs/anti-TNFα exposure before the first surgery (HR 9.15; 95% CI 2.77-30.21) and post-operatively (HR: 0.24; 95% CI 0.07-0.74) as variables associated with the risk of re-operation. However, these associations had a time-varying effect and become non-significant after 5 and 2 years after surgery, respectively. CONCLUSION: Despite increased post-operative use of IMMs and anti-TNFα agents in the last two decades, the impact of these strategies on the risk of long-term re-operation rate has been modest.

Switching from VEDOlizumab intravenous to subcutaneous formulation in ulcerative colitis patients in clinical remission: The SVEDO Study, an IG-IBD study.

BACKGROUND: The administration of biological drugs in inflammatory bowel diseases (IBD) is increasingly moving from intravenous to subcutaneous formulations. AIMS: To evaluate the efficacy and safety of vedolizumab subcutaneous administration after switching from intravenous administration in ulcerative colitis (UC) patients in corticosteroid-free clinical remission. METHODS: An observational, multicentre, prospective study was conducted by the Italian Group for the study of IBD (IG-IBD). UC patients in clinical remission (pMAYO < 2) not receiving steroids for > 8 months before the switch, and with at least 6 months of follow-up were included. Switch from intravenous to subcutaneous vedolizumab was defined as successful in patients not experiencing a disease flare (pMAYO ≥ 2) or needing oral steroids or stopping subcutaneous vedolizumab during the 6 months of follow-up after the switch. RESULTS: Overall, 168 patients were included. The switch was a success in 134 patients (79.8%). Vedolizumab retention rate was 88.7% at month six. C-reactive protein and faecal calprotectin values did not change after the switch (p = 0.07 and p = 0.28, respectively). Ten of the 19 patients who stopped subcutaneous formulation switched back to intravenous formulation recapturing clinical remission in 80%. Side effects were observed in 22 patients (13.1%). CONCLUSION: Effectiveness of switching from intravenous to subcutaneous vedolizumab formulation in UC patients in steroid-free clinical remission is confirmed in a real-world setting.

Stricturing Crohn's disease: what is the role of endoscopic stenting? A systematic review.

BACKGROUND/AIMS: Endoscopic stenting for stricturing Crohn's disease (CD) is an emerging treatment that achieves more persistent dilatation of the stricture over time than endoscopic balloon dilatation (EBD). We aimed to explore the efficacy and safety of stenting for the treatment of CD strictures. METHODS: A systematic electronic literature search was performed (PROSPERO; no. CRD42022308033). The primary outcomes were technical success, efficacy, complication rate, and the need for further interventions due to reobstruction. The outcomes of partially covered self-expanding metal stents (PCSEMS) with scheduled retrieval after seven days were also analyzed. RESULTS: Eleven eligible studies were included in the review. Overall, 173 patients with CD were included in this study. Mean percentage of technical success was 95% (range, 80%-100%), short-term efficacy was 100% in all studies, and long-term efficacy was 56% (range, 25%-90%). In patients with a scheduled PCSEMS retrieval, the long-term efficacy was 76% (range, 59%-90%), the mean complication rate was 35% (range, 15%-57%), and the major complication rate was 11% (range, 0%-29%). CONCLUSION: Endoscopic stenting with scheduled PCSEMS retrieval may be considered a feasible second-line treatment for short CD strictures to postpone surgery. However, larger head-to-head prospective studies are needed to understand the role of stenting as an alternative or additional treatment to EBD in CD.

Comparison of two strategies for the management of postoperative recurrence in Crohn's disease patients with one clinical risk factor: A multicentre IG-IBD study.

BACKGROUND: The management of postoperative recurrence (POR) in Crohn's disease (CD) after ileo-colonic resection is a highly debated topic. Prophylactic immunosuppression after surgery is currently recommended in the presence of at least one clinical risk factor. OBJECTIVE: Our aim was to determine whether early immunosuppression can be avoided and guided by endoscopy in CD patients with only one risk factor. METHODS: CD patients with only one risk factor for POR, including previous intestinal resection, extensive small intestine resection (>50 cm), fistulising phenotype, history of perianal disease, and active smoking, were retrospectively included. Two groups were formed based on whether immunosuppression was started immediately after surgery ("prophylaxis group") or guided by endoscopy ("endoscopy-driven group"). Primary endpoints were rates of any endoscopic recurrence (Rutgeerts ≥ i2a) and severe endoscopic recurrence (i4) within 12 months after surgery. Secondary outcomes were clinical recurrence rates at 6, 12 and 24 months after surgery. RESULTS: A total of 195 patients were enroled, of whom 61 (31.3%) received immunoprophylaxis. No differences between immunoprophylaxis and the endoscopy-driven approach were found regarding any endoscopic recurrence (36.1% vs. 45.5%, respectively, p = 0.10) and severe endoscopic recurrence (9.8% vs. 15.7%, respectively, p = 0.15) at the first endoscopic evaluation. Clinical recurrence rates were also not statistically different (p = 0.43, p = 0.09, and p = 0.63 at 6, 12, and 24 months, respectively). CONCLUSIONS: In operated CD patients with only one risk factor for POR, immediate immunoprophylaxis does not decrease the rate of early clinical and endoscopic recurrence. Prospective studies are needed to confirm our results.

Non-hepatic Solid Organ Transplant in Patients with Inflammatory Bowel Disease: An ECCO CONFER Multicentre Case Series.

BACKGROUND AND AIMS: Solid organ transplantation, with the exception of liver, has rarely been reported in patients affected by inflammatory bowel diseases [IBD]. METHODS: This is an ECCO-CONFER project collecting cases of solid organ transplants [with the exclusion of liver] that were performed in IBD patients. We evaluated the change in the IBD therapy, need for bowel resection due to medically refractory IBD, or need for hospitalisation due to IBD relapse ['severe IBD course'] before and after transplantation. RESULTS: in total, 34 organ transplantations [28 kidney, five heart, one lung] in 33 IBD patients were collected [67% male, 55% Crohn's disease, mean age 53 ±â€…16 years]. The median follow-up was 4.3 years (interquartile range [IQR] 3.2-10.7); 29 patients [87.9%] were treated with tacrolimus, 25 [76%] with systemic steroids, 22 [67%] with mycophenolate mofetil, 11 [33%] with everolimus, six with cyclosporine [18%]. One patient was treated with infliximab, two patients with adalimumab, two patients with vedolizumab, one patient with ustekinumab. Overall, a severe IBD course was observed in three [9.3%] patients before transplantation and in four [11.7%] in the post-transplant setting [p = 0.26]. Three cases of cancer [excluding skin non-melanoma] [9.1%] were recorded in the post-transplantation period versus two in the pre-transplantation period [6.1%, p = 0.04]. Six patients [18.2%] died during the period of observation. No deaths were associated with IBD or complications of the transplant. CONCLUSIONS: In IBD patients, solid organ transplantation does not seem to impact on the IBD severity. However, the risk of malignancy needs further investigation.

Noninvasive Assessment of Postoperative Disease Recurrence in Crohn's Disease: A Multicenter, Prospective Cohort Study on Behalf of the Italian Group for Inflammatory Bowel Disease.

BACKGROUND & AIMS: Colonoscopy (CS) is the gold standard to assess postoperative recurrence (POR) in Crohn's disease (CD). However, CS is invasive and may be poorly tolerated by patients. The aim of this study was to prospectively assess the diagnostic accuracy of a noninvasive approach in detecting POR, using the endoscopic Rutgeerts' score (RS) as the reference standard. METHODS: Consecutive patients with CD who underwent ileo-cecal resection were prospectively enrolled in 3 referral Italian centers. Patients underwent CS and bowel ultrasound within 1 year of surgery. Uni- and multivariable analyses were used to assess the correlation between noninvasive parameters and endoscopic recurrence, defined by a RS ≥2. RESULTS: Ninety-one patients were enrolled. Sixty patients (66%) experienced endoscopic POR. The multivariable analysis identified bowel wall thickness (BWT) per 1-mm increase (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.21-4.89; P = .012), the presence of mesenteric lymph nodes (OR, 15.63; 95% CI, 1.48-164.54; P = .022), and fecal calprotectin (FC) values ≥50 mcg/g (OR, 8.58; 95% CI, 2.45-29.99; P < .001) as independent predictors for endoscopic recurrence. The presence of lymph nodes or the combination of BWT ≥3 mm and FC values ≥50 mcg/g correctly classified 56% and 75% of patients, with less than 5% of patients falsely classified as having endoscopic recurrence. Conversely, the combination of BWT <3 mm and FC <50 mcg/g correctly classified 74% of patients with only 4.5% of patients falsely classified as not having endoscopic recurrence. CONCLUSIONS: A noninvasive approach combining bowel ultrasound and FC can be used with confidence for detecting POR in patients with CD without the requirement for CS.

An Objective Comparison of Vedolizumab and Ustekinumab Effectiveness in Crohn's Disease Patients' Failure to TNF-Alpha Inhibitors.

INTRODUCTION: The use of ustekinumab and vedolizumab as second-line therapies in patients with Crohn's disease (CD) in which tumour necrosis factor alpha inhibitors (TNFi) failed is still debated. The aim of this study was to compare, in a large multicenter observational retrospective cohort, the effectiveness of ustekinumab and vedolizumab as second-line therapies, as assessed by clinical and objective outcomes including endoscopy and gastrointestinal imaging. METHODS: Clinical response, remission, and steroid-free remission at weeks 26 and 52 were evaluated in a retrospective propensity score-weighted and propensity score-matched cohort of patients in which TNFi failed. Objective response and remission were evaluated by 1 or more techniques among endoscopy, magnetic resonance/computed tomography enteroclysis, and small bowel ultrasound. RESULTS: A total of 470 patients with CD (239 treated with ustekinumab and 231 treated with vedolizumab) were included in the study. At week 26, clinical outcomes were similar between the 2 groups. At week 52, clinical remission (ustekinumab 42.5% vs vedolizumab 55.5%, P = 0.01) and steroid-free remission (ustekinumab 40.6% vs vedolizumab 51.1%, P = 0.038) rates were significantly higher in vedolizumab-treated patients. Three hundred two patients (hundred thirty-five treated with ustekinumab and hundred sixty-seven treated with vedolizumab) had an objective evaluation of disease activity at baseline and week 52. At week 52, objective response and remission rates were similar between the 2 groups. Clinical response at week 26 predicted steroid-free remission at week 52 in both ustekinumab-treated and vedolizumab-treated patients. Safety profiles were similar between the 2 groups. DISCUSSION: In patients with CD in which TNFi failed, both ustekinumab and vedolizumab showed similar clinical effectiveness after 26 weeks of treatment. At 1 year, vedolizumab was associated with a higher rate of clinical remission when compared with ustekinumab. However, no difference was observed between the 2 groups when objective outcomes were investigated at this time point.

Effectiveness of ustekinumab in patients with refractory Crohn's disease: a multicentre real-life study in Italy.

BACKGROUND: The effectiveness of ustekinumab in patients with refractory Crohn's disease (CD) has been investigated in several real-world studies. However, very few data concerning the real-life experience in Italy have been reported. Therefore, this study assessed the effectiveness of ustekinumab in a large cohort of Italian patients with refractory CD. METHODS: All patients who had started on ustekinumab after failure of or intolerance to antitumour necrosis factor-α (TNF-α) treatment at five tertiary centres between November 2018 and February 2020 were retrospectively enrolled. The coprimary outcome was corticosteroid-free clinical remission, defined as a Harvey-Bradshaw Index (HBI) score of ⩽4, at weeks 26 and 52. The secondary outcomes were changes in the HBI and C-reactive protein (CRP) values at weeks 8, 26, and 52 from baseline and the normalization of CRP in patients with initially abnormal values. RESULTS: Totally, 140 patients who had previously received at least one anti-TNF-α agent were enrolled; 40.0% received two anti-TNF-α agents and 20.0% received vedolizumab. At baseline, 108 patients (77.1%) had HBI scores of >4; of these, 56.5% and 58.3% achieved corticosteroid-free clinical remission at weeks 26 and 52, respectively. Significant decreases in HBI and CRP values were observed at weeks 8, 26, and 52 in the entire study cohort (all p < 0.0001). The CRP values were normalized in 34.9%, 37.8%, and 49.3% of the patients by weeks 8, 26, and 52, respectively. The baseline HBI score of ⩾8 was a negative predictor of corticosteroid-free clinical remission at week 52 (odds ratio: 0.21, 95% confidence interval: 0.08-0.56, p = 0.002). The probability of remaining on ustekinumab after 52 weeks was 92.1%. Eleven (7.9%) patients discontinued ustekinumab (three for adverse events). CONCLUSION: Our study findings confirm the effectiveness and safety of ustekinumab in patients with CD after failure of or intolerance to anti-TNF-α therapy.

Gastroenteropancreatic Neuroendocrine Neoplasms in Patients with Inflammatory Bowel Disease: An ECCO CONFER Multicentre Case Series.

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms [GEP-NENs] have rarely been reported in association with inflammatory bowel diseases [IBDs]. METHODS: An ECCO COllaborative Network For Exceptionally Rare case reports project [ECCO-CONFER] collects cases of GEP-NENs diagnosed in patients with IBD. RESULTS: GEP-NEN was diagnosed in 100 IBD patients; 61% female, 55% Crohn's disease, median age 48 years (interquartile range [IQR] 38-59]). The most common location was the appendix [39%] followed by the colon [22%]. Comprehensive IBD-related data were available for 50 individuals with a median follow-up of 30 months [IQR 11-70] following NEN diagnosis. Median duration of IBD at NEN diagnosis was 84 months [IQR 10-151], and in 18% of cases NEN and IBD were diagnosed concomitantly. At diagnosis, 20/50 were stage-I [T1N0M0], and 28/50 were graded G1 [ki67 ≤2%]. Incidental diagnosis of NEN and concomitantly IBD diagnosis were associated with an earlier NEN stage [p = 0.01 and p = 0.02, respectively]. Exposure to immunomodulatory or biologic therapy was not associated with advanced NEN stage or grade. Primary GEP-NEN were more frequently found in the segment affected by IBD [62% vs 38%]. At the last follow-up data, 47/50 patients were alive, and only two deaths were related to NEN. CONCLUSIONS: In the largest case series to date, prognosis of patients with GEP-NEN and IBD seems favourable. Incidental NEN diagnosis correlates with an earlier NEN stage, and IBD-related therapies are probably independent of NEN stage and grade. The association of GEP-NEN location and the segment affected by IBD may suggest a possible role of inflammation in NEN tumorigenesis.

Should the Mediterranean diet be recommended for inflammatory bowel diseases patients? A narrative review.

Inflammatory bowel diseases (IBD) are chronic, progressive and relapsing inflammatory disorders of unknown etiology that may cause disability over time. Data from epidemiologic studies indicate that diet may play a role in the risk of developing and the course of IBD. It is known that the group of beneficial bacteria was reduced in the IBD and that the Mediterranean diet (MD)-which is defined as eating habits characterized by high consumption of plant foods, mainly cereals, vegetables, fruit as well as olive oil, and small portions of dairy products, sweets, sugar and meat products-affects gut microbiota, enriching beneficial bacteria, which support gut barrier function and reduce inflammation. Although several studies support different favorable effects of MD on IBD, adherence to MD by IBD patients is generally low, including patients from the Mediterranean Basin. Patients avoid many products which are elements of MD because there cause gastrointestinal symptoms. Patients should be encouraged to have a healthy and well-balanced diet according to individual tolerance of products. A good option seems to be good modified MD, changing hard-to-digest products to easy digest.

What are the challenges in selecting pharmacotherapy for pregnant women with inflammatory bowel disease?

The peak of incidence of inflammatory bowel disease (IBD) overlaps with the peak of reproductive age. Moreover, women affected by IBD are often concerned with the possible negative effects of their disease and medications on pregnancy and birth outcomes. From a physician point of view, managing IBD in pregnancy is challenging. Disease activity is the major cause of poor pregnancy outcomes and, therefore, achieving and maintaining IBD remission for the whole duration of pregnancy is the main therapeutic goal. The challenges in selecting therapy lie in balancing the proven efficacy of each drug with the level of safety uncertainty. Except for methotrexate and thalidomide, for which it exits an absolute contraindication in pregnancy, the evidence actually available suggest that most medications can be safely used during pregnancy if appropriately prescribed. The risks associated with drug withdrawal may be higher than the known risks of the medications themselves on pregnancy outcomes. However, all the decisions should be shared with the patient, all available information should be discussed and any therapeutic strategy must be tailored according to patient's context, including disease pattern, activity, severity and acceptance of risk.

Long-term outcomes of acute severe ulcerative colitis in the rescue therapy era: A multicentre cohort study.

BACKGROUND: The long-term course of ulcerative colitis after a severe attack is poorly understood. Second-line rescue therapy with cyclosporine or infliximab is effective for reducing short-term colectomy but the impact in the long-term is controversial. OBJECTIVE: The purpose of this study was to evaluate the long-term course of acute severe ulcerative colitis patients who avoid early colectomy either because of response to steroids or rescue therapy. METHODS: This was a multicentre retrospective cohort study of adult patients with acute severe ulcerative colitis admitted to Italian inflammatory bowel disease referral centres from 2005 to 2017. All patients received intravenous steroids, and those who did not respond received either rescue therapy or colectomy. For patients who avoided early colectomy (within 3 months from the index attack), we recorded the date of colectomy, last follow-up visit or death. The primary end-point was long-term colectomy rate in patients avoiding early colectomy. RESULTS: From the included 372 patients with acute severe ulcerative colitis, 337 (90.6%) avoided early colectomy. From those, 60.5% were responsive to steroids and 39.5% to the rescue therapy. Median follow-up was 44 months (interquartile range, 21-85). Colectomy-free survival probability was 93.5%, 81.5% and 79.4% at 1, 3 and 5 years, respectively. Colectomy risk was higher among rescue therapy users than in steroid-responders (log-rank test, p = 0.02). At multivariate analysis response to steroids was independently associated with a lower risk of long-term colectomy (adjusted odds ratio = 0.5; 95% confidence interval, 0.2-0.8), while previous exposure to antitumour necrosis factor-α agents was associated with an increased risk (adjusted odds ratio = 3.0; 95% confidence interval, 1.5-5.7). Approximately 50% of patients required additional therapy or new hospitalisation within 5 years due to a recurrent flare. Death occurred in three patients (0.9%). CONCLUSIONS: Patients with acute severe ulcerative colitis avoiding early colectomy are at risk of long-term colectomy, especially if previously exposed to antitumour necrosis factor-α agents or if rescue therapy during the acute attack was required because of steroid refractoriness.

Late-onset Crohn's disease: a comparison of disease behaviour and therapy with younger adult patients: the Italian Group for the Study of Inflammatory Bowel Disease 'AGED' study.

BACKGROUND: Disease phenotype and outcome of late-onset Crohn's disease are still poorly defined. METHODS: In this Italian nationwide multicentre retrospective study, patients diagnosed ≥65 years (late-onset) were compared with young adult-onset with 16-39 years and adult-onset Crohn's disease 40-64 years. Data were collected for 3 years following diagnosis. RESULTS: A total of 631 patients (late-onset 153, adult-onset 161, young adult-onset 317) were included. Colonic disease was more frequent in late-onset (P < 0005), stenosing behaviour was more frequent than in adult-onset (P < 0003), but fistulising disease was uncommon. Surgery rates were not different between the three age groups. Systemic steroids were prescribed more frequently in young adult-onset in the first year, but low bioavailability steroids were used more frequently in late-onset in the first 2 years after diagnosis (P < 0.036, P < 0.041, respectively). The use of immunomodulators and anti-TNF's even in patients with more complicated disease, that is, B2 or B3 behaviour (Montreal classification), remained significantly inferior (P < 0.0001) in late-onset compared to young adult-onset. Age at diagnosis, Charlson comorbidity index, and steroid used in the first year were negatively associated with the use of immunomodulators and biologics. Comorbidities, related medications and hospitalizations were more frequent in late-onset. Polypharmacy was present in 56% of elderly Crohn's disease patients. CONCLUSION: Thirty-two percent of late-onset Crohn's disease presented with complicated disease behaviour. Despite a comparable use of steroids and surgery, immunomodulators and biologics were used in a small number of patients.

[The advantages of patient's active involvement in the management of chronic Inflammatory Bowel Diseases.] / L'importanza del coinvolgimento attivo del paziente nella gestione delle malattie infiammatorie croniche dell'intestino.

The patient's active involvement is an emerging hot-topic, which can be applied in to the management of chronic inflammatory bowel diseases (IBD). Since in this field most of the therapeutic strategies are not based on sturdy scientific evidences, the patient's role has become central and it is believed essential for any patients to have an active cognitive, behavioural and emotive profile. Moreover different patient's aspects should be considered, such as the patient's activation, the patient's engagement and the patient's disease knowledge. The initial evidences available on this topic within IBD context have showed how a higher patient's active profile and a deeper disease knowledge have had a positive effect on compliance, perceived health-care satisfaction, self-management and health costs. Therefore, considering the favourable outcomes so far highlighted, we hope that the evaluation of patient's involvement may become a standard procedure, allowing patients who need it to undergo active programmes which have proved to be effective in improving patient's degree of activation.

Sustained Clinical Efficacy and Mucosal Healing of Thiopurine Maintenance Treatment in Ulcerative Colitis: A Real-Life Study.

BACKGROUND AND AIMS: Thiopurines are commonly used for treating ulcerative colitis (UC), despite the fact that controlled evidence supporting their efficacy is limited. The aim of this study was to evaluate the long-term outcome of thiopurines as maintenance therapy in a large cohort of UC patients. METHODS: All UC patients receiving thiopurine monotherapy at three tertiary IBD centers from 1995 to 2015 were identified. The primary endpoint was steroid-free clinical remission. Secondary endpoints were mucosal healing (MH), defined as Mayo endoscopic subscore 0, long-term safety, and predictors of sustained clinical remission. RESULTS: We identified 192 patients, contributing a total of 747 person-years of follow-up (median follow-up 36 months, range 1-210 months). Steroid dependency was the most common indication for thiopurine treatment (58%). Steroid-free remission occurred in 45.3% of patients; 36.3% stopped thiopurines because of treatment failure and 18.2% for adverse events or intolerance. The cumulative probability of maintaining steroid-free remission while on thiopurine treatment was 87%, 76%, 67.6%, and 53.4% at 12, 24, 36, and 60 months, respectively. MH occurred in 57.9% of patients after a median of 18 months (range 5-96). No independent predictors of sustained clinical remission could be identified. CONCLUSIONS: Thiopurines represent an effective and safe long-term maintenance therapy for UC patients.