BACKGROUND AND AIMS:Real-world studies on vedolizumab in inflammatory bowel disease (IBD) are often limited by small sample size and short follow-up. In this study, we investigated the 2-year effectiveness and safety of vedolizumab in patients with IBD, and applied eXplainable Artificial Intelligence (XAI) to identify predictors of both. METHODS:The Long-term Italian Vedolizumab Effectiveness (LIVE) study is multicentric, ambispective, observational study enrolling 1111 IBD patients (563 Crohn's disease, CD, 542 ulcerative colitis, UC). Steroid-free clinical remission (SFCR) at 24 months was the primary endpoint. A XAI model (eXtreme Gradient Boosting, XGB) was applied to identify the main clinical predictors of SFCR and development of adverse events (AEs). RESULTS:Rates of SFCR at 24 months were 31.6 % and 39.7 % in CD and UC patients, and 0.14 AEs per patient-year was recorded. On XGB analysis, previous exposure to anti-TNFα and older age were the most important drivers for the prediction of SFCR; lower baseline CRP levels and fewer comorbidities were the most important features associated with no development of AEs. CONCLUSIONS:Vedolizumab is effective and safe in IBD patients. XAI yielded promising results in identifying the most important predictors of SFCR and development of AEs.

SummaryBackgroundFew data are available addressing the impact of post‐operative management of Crohn's disease (CD) on long‐term clinical course.AimTo assess the evolution of post‐operative management strategies over the last 40 years and their impact on the re‐operation rate of CD.MethodsWe 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.ResultsImmunosuppressants, (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.ConclusionDespite 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.

Tofacitinib is an oral Janus kinase inhibitor recently approved to induce and maintain remission in ulcerative colitis (UC). Considering the number of anti-TNF non-responders, this study aims to assess the effectiveness and safety of tofacitinib in a cohort of multi-failure patients with moderate-to-severe UC at 52 weeks. From January 2021 to March 2023, we performed a prospective multicenter study observing adult patients with moderate-to-severe UC starting tofacitinib after an anti-TNF failure for a 52-week-long period. Effectiveness and safety were assessed in terms of colectomy rate, clinical remission and response, endoscopic remission, steroid-free clinical remission, and rate of adverse events. We included 58 patients with UC with an age of 42 ± 14.4 years, 59

Background The RIDART I study found a 13.6% prevalence of anemia in Italian patients with inflammatory bowel disease (IBD); most cases were due to iron-deficiency anemia (IDA). Aims To evaluate changes in hemoglobin concentration during a 24-week follow-up of anemic patients with IBD. Methods Follow-up laboratory and clinical data were obtained from RIDART I study patients with anemia. Factors affecting hemoglobin concentration, the impact of anemia on fatigue and quality of life (QoL), and its relationship with treatment, disease activity and disease complications were investigated. Results Hemoglobin was 108 g/L at baseline, increased to 121 g/L at follow-up week 12 (p < 0.001) and then stabilized until week 24, but most patients remained anemic, with IDA, throughout the study. Hemoglobin improvement was greater in patients receiving either oral or parenteral iron supplementation. Following hemoglobin normalization, anemia relapse rate during follow-up was 30%. Oral iron did not cause disease reactivation. Lower follow-up hemoglobin was associated with a higher probability of having active disease, clinical complications, increased fatigue and reduced QoL. Conclusions In anemic patients with IBD, anemia represents a long-lasting problem, in most cases persisting for up to 24 weeks, with high relapse rate and a negative impact on fatigue and QoL.

Abstract Background Tofacitinib is an oral janus kinase inhibitor (JAK) approved for patients with moderate to severe ulcerative colitis (UC) and either inadequate response or loss of response or intolerance to conventional or biologic therapy. The 5-year and 10-year cumulative risk of colectomy in UC is 10%–15%.1 Due to the increasing number of anti tumor necrosis factor (TNF)-alfa non responders, tofacitinib seems a valuable therapeutic alternative. This study aims to assess the effectiveness of tofacitinib in preventing colectomy in patients with moderate-to-severe UC refractory to anti TNF-alfa agents. Methods We performed an observational retrospective and prospective multicenter study in five Italian IBD referral units including adult patients with confirmed diagnosis of moderate-to-severe UC (defined by a total Mayo score ≥ 6), treated with tofacitinib because of response failure or intolerance to anti TNF-alfa agents. Primary aim was the effectiveness of tofacitinib in preventing colectomy during a follow-up of 52 weeks. Secondary aims were: survival without colectomy, survival without tofacitinib discontinuation, clinical remission (defined as Mayo partial score ≤ 2) at week 8, 24 and 52, endoscopic remission (defined as Mayo endoscopic score ≤ 1) and steroid-free clinical remission (Mayo Partial score ≤ 2 without steroid) at week 52; adverse events (AE) to tofacitinib. Descriptive statistics and Kaplan Meier analyses of survival were performed. Results From January 2021 to October 2022 45 patients were included. During the follow-up, 6 patients (13%) underwent colectomy and all of them before week 24. Survival without colectomy and survival without tofacitinib discontinuation are represented in Figs.1-2. Clinical remission was reached by 17 patients (37.7%) at week 8, by 20 (44.4%) at week 24, and by 22 patients (48.8%) at week 52. Among the 11 patients with an endoscopic evaluation available after completing 52-week treatment, 9 (82%) achieved endoscopic remission. At week 52, 22 patients (49%) maintained steroid-free clinical remission. In eighteen patients (40%) tofacitinib was interrupted, because of failure in 15 and because of a severe AE in 3. AE occurred in 9 patients (20%), but in 3 only (6.7%) were severe and entailed treatment interruption. Conclusion These data confirm effectiveness and safety of tofacitinib in preventing colectomy in moderate-to-severe UC refractory to anti TNF-alfa agents.

BACKGROUND Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD), with a 6% to 74% prevalence and a negative impact on patient survival and quality of life, although the prevalence is apparently declining due to improved disease treatment. We aimed to investigate the prevalence, pathogenesis, and clinical correlates of anemia in Italian patients with IBD. METHODS A multicenter, prospective, observational study, involving 28 Italian gastroenterology centers, was conducted to investigate the epidemiology and consequences of IBD-associated anemia. Clinical and laboratory data of anemic patients were obtained at study enrolment. RESULTS Anemia was diagnosed in 737 of 5416 adult IBD outpatients (prevalence 13.6%); females were more commonly affected than males (odds ratio, 1.5; 95% confidence interval [CI], 1.2-1.7) and had more severe anemia. In the majority of cases, anemia was due to iron deficiency (62.5% of cases; 95% CI, 58.3%-66.6%), either isolated or in association with inflammation and/or vitamin deficiencies; anemia of inflammation accounted for only 8.3% of cases. More severe anemia was associated with increasing fatigue and worse quality of life. Only 68.9% of anemic patients with iron deficiency (95% CI, 63.4%-73.8%) and 34.6% of those with vitamin deficiencies (95% CI, 26.2%-44.2%) were properly treated with supplementation therapy. CONCLUSIONS In Italy, the prevalence of IBD-associated anemia is lower than previously reported. Anemia of IBD is most commonly due to iron deficiency and contributes to fatigue and poor quality of life, but remains untreated in a large proportion of patients with iron and/or vitamin deficiencies. This study is registered at clinicaltrials.gov as NCT02872376.

LINKED CONTENT This article is linked to Zisman‐Ilani et al paper. To view this article, visit https://doi.org/10.1111/apt.17286

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a complex, immune-mediated, disorder which leads to several gastrointestinal and systemic manifestations determining a poor quality of life, disability, and other negative health outcomes. Our knowledge of this condition has greatly improved over the last few decades, and a comprehensive management should take into account both biological (i.e., disease-related, patient-related) and non-biological (i.e., socioeconomic, cultural, environmental, behavioral) factors which contribute to the disease phenotype. From this point of view, the so called 4P medicine framework, including personalization, prediction, prevention, and participation could be useful for tailoring ad hoc interventions in IBD patients. In this review, we discuss the cutting-edge issues regarding personalization in special settings (i.e., pregnancy, oncology, infectious diseases), patient participation (i.e., how to communicate, disability, tackling stigma and resilience, quality of care), disease prediction (i.e., faecal markers, response to treatments), and prevention (i.e., dysplasia through endoscopy, infections through vaccinations, and post-surgical recurrence). Finally, we provide an outlook discussing the unmet needs for implementing this conceptual framework in clinical practice.

Inflammatory bowel diseases, namely ulcerative colitis and Crohn's disease, occur worldwide and affect people of all ages, with a high impact on their quality of life. Sex differences in incidence and prevalence have been reported, and there are also gender-specific issues that physicians should recognize. For women, there are multiple, important concerns regarding issues of body image and sexuality, menstruation, contraception, fertility, pregnancy, breastfeeding and menopause. This practice-based review focuses on the main themes that run through the life of women with inflammatory bowel diseases from puberty to menopause. Gastroenterologists who specialize in inflammatory bowel diseases and other physicians who see female patients with inflammatory bowel diseases should provide support for these problems and offer adequate therapy to ensure that their patients achieve the same overall well-being and health as do women without inflammatory bowel diseases.

Colorectal cancer (CRC) risk is increased in Inflammatory Bowel Disease (IBD) and surveillance needs to be tailored according to individual risk. The open issues include the role of the characteristics of IBD and CRC in determining the long-term outcome. These issues were assessed in our multicenter study, including a cohort of 56 IBD patients with incident CRC. The clinical and histopathological features of IBD patients and of CRC were recorded. Incident CRC in IBD occurred at a young age (≤40 years) in 25% of patients (median age 55.5 (22–76)). Mucinous signet-ring carcinoma was detected in 6 out of the 56 (10.7%) patients, including 4 with Ulcerative Colitis (UC) and 2 with Crohn’s disease (CD). CRC was more frequently diagnosed by colonoscopy in UC (85.4% vs. 50%; p = 0.01) and by imaging in Crohn’s Disease CD (5.8% vs. 31.8%; p = 0.02). At onset, CRC-related symptoms occurred in 29 (51.9%) IBD patients. The time interval from the diagnosis of IBD to CRC was shorter in UC and CD patients with >40 years (p = 0.002; p = 0.01). CRC-related death occurred in 10 (29.4%) UC and in 6 (27.2%) CD patients (p = 0.89), with a short time interval from CRC to death (UC vs. CD: 6.5 (1–68) vs. 14.5 (8–40); p = 0.85; IBD: 12 months (1–68)). CRC occurring at a young age, a short time interval from the diagnosis of IBD to CRC-related death in the elderly, CRC-symptoms often mimicking IBD relapse and the observed high mortality rate may support the need of closer surveillance intervals in subgroups of patients.

Abstract Background Several observations suggest that immunomodulators (IMMs) and anti-TNFα agents can affect long-term clinical course of Crohn’s disease (CD). However, no convincing surgery-sparing direct effect of these medications has been demonstrated in large population-based studies. Failure to optimize these treatments, particularly a limited use in early disease course, may explain the underperformance of these strategies in the clinical practice setting. Early introduction of IMMs/anti-TNFα in CD after surgery, either as prevention of recurrence or as treatment of early endoscopic recurrence, has become a common clinical practice and may represent a surrogate model of early treatment. The aim of the present study was to evaluate the impact of IMMs/anti-TNFα on the long-term post-operative course after ileocaecal resection in CD patients. Methods All adult CD patients who underwent their first ileocaecal resection at three major referral Centers in Rome were retrospectively reviewed. Demographic and clinical characteristics were recorded: gender, age at the time of surgery, CD behaviour (penetrating or non-penetrating), previous treatment with IMMs/anti-TNFα, and time to prescription of IMMs/anti-TNFα after surgery. The primary endpoint was the need for second resection. Statistical analysis. The Kaplan–Meier survival method was used to estimate the cumulative probability of first prescription of IMMs/anti-TNFα after surgery and to estimate the post-operative course free from reoperation. Cox proportional hazards regression model was used to assess the association of clinical variables with time to reoperation. Results surgery: cohort 1 (1980–1998; n.198); cohort 2 (1999–2009; n.218); cohort 3 (2010–2020; n.241). The mean follow-up after surgery was 83 + 41 months. The cumulative probability of receiving IMMs/anti-TNFα after surgery was significantly different between the three cohorts but the probability of a postoperative course free from reoperation was not (figure). In the multivariate analysis, treatment with IMMs/anti-TNFα prior to the first resection (HR 9.15; 95%CI 2.77–30.21) and post-operative therapy with IMMs/anti-TNFα (HR: 0.24; 95%CI 0.07–0.74) were associated to the risk of reoperation. However, these associations had a time-varying effect and become not significant after 5 and 2 years after surgery respectively. Overall, 283 patients received IMMs/anti-TNFα at any time after surgery. Comparing early treatment (within 1, 2 or 3 years after surgery) with late treatment, no difference was observed in the cumulative risk of reoperation within 10 years Conclusion The increasing use of IMMs/anti-TNFα agents in the post-operative setting may have little impact on the long-term reoperation rate.

SummaryBackgroundVedolizumab registration trials were the first to include elderly patients with moderate‐to‐severe ulcerative colitis (UC) or Crohn’s disease (CD), but few real‐life data have been reported in this population.AimsWe investigated the effectiveness and safety of vedolizumab in matched cohorts of elderly and nonelderly UC and CD patients.MethodsThe Long‐term Italian Vedolizumab Effectiveness (LIVE) study is a retrospective‐prospective study including UC and CD patients who started vedolizumab from April 2016 to June 2017. Elderly patients (≥65 years) were matched clinically 1:2 to nonelderly patients (18–64 years); the 2 groups were followed until drug discontinuation or June 2019.ResultsThe study included 198 elderly (108 UC, 90 CD) and 396 matched nonelderly patients (205 UC, 191 CD). Nonelderly UC patients had a significantly higher persistence on vedolizumab compared to elderly patients (67.6% vs. 51.4%, p = 0.02). No significant difference in effectiveness was observed between elderly and nonelderly CD patients (59.4% vs. 52.4%, p = 0.32). Age ≥65 years was associated with lower persistence in UC; for CD, previous exposure to anti‐TNF‐α agents, Charlson comorbidity index >2 and moderate‐to‐severe clinical activity at baseline were associated with lower persistence. There were recorded 130 adverse events, with comparable rates between the two groups. A Charlson comorbidity index >2 was associated with an increased risk of adverse events.ConclusionVedolizumab can be considered a safe option in elderly IBD patients. Its effectiveness in elderly UC patients may be reduced, while no age‐dependent effect on effectiveness was observed in CD.

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.

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.

Abstract Background Ustekinumab (UST) is increasingly used in Italy for the treatment of refractory Crohn’s disease (CD), however very few data concerning real-life experience has been reported. Therefore, the aim of this study was to assess the long-term effectiveness of UST in refractory CD patients treated in a large Italian cohort. Methods A retrospective study was conducted in 5 Italian tertiary centers. All adult CD patients who started UST because of anti-tumor necrosis factor (TNF) failure were included. The co-primary outcomes were steroid-free clinical remission (defined as Harvey Bradshaw Index, HBI ≤4) at weeks 26 and 52. Secondary outcomes were changes in HBI score, changes in C-reactive protein (CRP) values, normalization of CRP (≤0.5 mg/dl) at weeks 8, 26, and 52, and adverse events. Categorical variables were expressed as frequency and percentage. Unpaired t-test was used to compare variables. A p-value <0.05 indicated statistical significance. Continuous variables were expressed as mean and standard deviation (SD), and median with interquartile range (IQR). Results Between Nov 2018 and Feb 2020,140 patients (51.4% male; median age 45.0 years, IQR 36.3-54.0; median disease duration 16.0 years, IQR 8.0-22.0) were included. The majority of patients had ileocolonic disease (L1, 38.6%; L2, 11.4%; L3, 50.0%) and an inflammatory phenotype (B1, 50.7%; B2, 31.0%; B3, 18.3%). All patients had previously been exposed to at least one anti-TNF agent, 27.1% to 2 anti-TNF agents, and 20.0% to vedolizumab . At inclusion 15.7% of patients received corticosteroids and 8.6% immunomodulators. All patients received an intravenous dose of 6 mg/kg, followed by subcutaneous administration of 90 mg every 8 (90%) or 12 weeks (10%) according to clinical judgment. The proportion of patients achieving steroid-free clinical remission was 61.0% and 64.2% at weeks 26 and 52 respectively. A significant decrease in the mean HBI was reported from baseline to week 8 (6.8 ± 3.6 vs 4.5 ± 3.1; p <0.001), week 26 (3.5 ± 2.9; p <0.001), and week 52 (3.1 ± 2.4; p <0.001). The mean CRP values was also significantly decreased from baseline to week 8 (4.6 ± 7.3 vs 2.8 ± 7.1; p <0.001), week 26 (1.7 ± 3.8; p <0.001), and week 52 (1.1 ± 2.2; p<0.001). At baseline 93 of 119 patients had high CRP value: a normal CRP value was observed in 34.9%, 37.8%, and 49.3% of patients at weeks 8, 26, and 52 respectively. Overall, 11 patients (7.9%) discontinued UST within 1 year: primary failure (n=2), secondary failure (n=6), adverse events (n=3: 2 allergic reactions, and 1 arthralgia). Conclusion To our knowledge this is one of the largest Italian cohort followed up to 1 year, and the results confirm that UST is an effective and safe treatment in refractory CD patients.

AbstractBackgroundThe 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.ObjectiveThe 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.MethodsThis 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.ResultsFrom 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%).ConclusionsPatients 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.

In the last decades, the comprehension of the pathophysiology of bone metabolism and its interconnections with multiple homeostatic processes has been consistently expanded. The branch of osteoimmunology specifically investigating the link between bone and immune system has been developed. Among molecular mediators potentially relevant in this field, vitamin D has been recently pointed out, and abnormalities of the vitamin D axis have been described in both in vitro and in vivo models of inflammatory bowel diseases (IBD) and arthritis. Furthermore, vitamin D deficiency has been reported in patients affected by IBD and chronic inflammatory arthritis, thus suggesting the intriguing possibility of impacting the disease activity by the administration vitamin D supplements. In the present review, the complex interwoven link between vitamin D signaling, gut barrier integrity, microbiota composition, and the immune system was examined. Potential clinical application exploiting vitamin D pathway in the context of IBD and arthritis is presented and critically discussed. A more detailed comprehension of the vitamin D effects and interactions at molecular level would allow one to achieve a novel therapeutic approach in gastro-rheumatologic inflammatory diseases through the design of specific trials and the optimization of treatment protocols.