A propensity score weighted comparison of vedolizumab and adalimumab in Crohn's disease.

BACKGROUND AND AIM: There are no head-to-head randomized controlled trials between biologics in Crohn's disease (CD). We aimed to perform a multicenter, real-life comparison of the effectiveness of vedolizumab (VDZ) and adalimumab (ADA) in CD. METHODS: Data of consecutive patients with CD treated with VDZ and ADA from January 2016 to April 2019 were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease. The effectiveness was evaluated at 12, 52 weeks, and as failure-free survival at the end of follow up. Propensity score analysis was performed using the inverse probability of treatment weighting method. RESULTS: Five hundred eighty-five treatments (VDZ: n = 277; ADA: n = 308) were included (median follow-up: 56.0 weeks). After 12 weeks, a clinical response was achieved in 64.3% patients treated with VDZ and in 83.1% patients treated with ADA (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.38-1.10, P = 0.107), while at 52 weeks, a clinical response was observed in 54.0% patients treated with VDZ and in 69.1% patients treated with ADA (OR 0.77, 95% CI 0.45-1.31, P = 0.336). Cox survival analysis weighted for propensity score showed no significant difference in the probability of failure-free survival between the two drugs (hazard ratio = 1.20, 95% CI 0.83-1.74, P = 0.340). Post-treatment endoscopic response and mucosal healing rates were similar between the two groups (endoscopic response: 35.3% for VDZ and 25.5% for ADA, P = 0.15; mucosal healing: 31.8% for VDZ and 33.8% for ADA, P = 0.85). CONCLUSIONS: In the first study comparing VDZ and ADA in CD via propensity score analysis, the drugs showed comparable effectiveness and a similar safety profile.

A propensity score weighted comparison of Vedolizumab, Adalimumab, and Golimumab in patients with ulcerative colitis.

BACKGROUND: No real-life study on the comparative effectiveness of Vedolizumab (VDZ), Adalimumab (ADA), and Golimumab (GOL) in ulcerative colitis (UC) is currently available. AIMS: To compare the effectiveness of the three biologics in consecutive patients with UC. METHODS: A three-arms propensity score-adjusted analysis was performed using the Inverse Probability of Treatment Weighting method. RESULTS: 463 treatments (VDZ: n = 187; ADA: n = 168; GOL: n = 108) were included (median follow-up: 47.6 weeks). At 12 weeks (n = 463), a steroid-free remission was reported in 24.1% patients in the VDZ group, in 33.3% patients in the ADA group, and in 30.6% patients in the GOL group (p = n.s. for all comparisons). At 52 weeks (n = 377), a steroid-free remission was reported in 51.5% patients in the VDZ group, in 31.2% patients in the ADA group, and in 29.4% patients in the GOL group (p = 0.002 for VDZ vs. ADA, p = 0.001 for VDZ vs. GOL, p = n.s. for ADA vs. GOL). Cox survival analysis demonstrated that patients treated with VDZ had reduced probability of treatment discontinuation compared to those treated with ADA (HR: 0.42, 95% CI 0.28-0.64, p < 0.001) and GOL (HR: 0.30, 95% CI 0.19-0.46, p < 0.001), while patients treated with ADA had reduced risk of treatment discontinuation compared to those treated with GOL (HR: 0.71, 95% CI 0.50-1.00, p = 0.048). CONCLUSIONS: VDZ was superior to ADA and GOL at 52 weeks and as treatment persistence, while ADA showed a superior treatment persistence compared to GOL.

Persistence on Anti-Tumour Necrosis Factor Therapy in Older Patients with Inflammatory Bowel Disease Compared with Younger Patients: Data from the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD).

BACKGROUND AND OBJECTIVE: Older people with inflammatory bowel disease (IBD) appear to have a lower response to anti-tumour necrosis factor (TNF) therapy, with more frequent complications than younger patients. The objective of this study was to assess persistence on therapy and the safety of anti-TNF therapy in older patients (aged ≥ 60 years). METHODS: We retrospectively reviewed the database of the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD), extracting data regarding IBD patients aged ≥ 60 years and controls < 60 years of age at their first course of anti-TNF treatment. Data concerning persistence on therapy over the first year of treatment (primary objective) together with data on reasons for treatment withdrawal, concomitant diseases and treatments were collected. RESULTS: We identified 114 anti-TNF-naϊve patients aged ≥ 60 years (median age 64 years, range 60-80 years; 47 males) compared with 330 younger controls aged < 60 years (median age 39 years, range 18-59 years; 57 males). Older patients with Crohn's disease (n = 73) showed a significantly lower persistence with every kind of anti-TNF therapy (whether analysed together [p < 0.001] or separately for intravenous and subcutaneous [SC] therapy) than younger controls, whereas older patients with ulcerative colitis (n = 41) showed a lower persistence when combining all kinds of anti-TNF treatment (p = 0.004) and for SC therapy. Secondary failures, infections, and neoplasias, but not primary failure, occurred more frequently in older IBD patients than in younger controls. CONCLUSION: Despite a comparable number of primary failures, older IBD patients treated for the first time with anti-TNF agents showed lower treatment persistence due to higher rates of secondary failure, adverse events, infections, and tumours than younger patients in the first year of follow-up. The reasons for this difference still remain unclear.

Effectiveness and safety of biologics in pediatric inflammatory boweldisease: Real-life data from the Sicilian Network.

BACKGROUND: Biological therapies have modified the disease course of pediatric inflammatory bowel disease (IBD) and are routinely used in clinical practice. Our observational study aims to evaluate effectiveness and safety of biologics in IBD. METHOD: Clinical benefit and safety data of 93 children with IBD, receiving biologics (Infliximab - IFX, Adalimumab - ADA, Golimumab - GOL) from January 2013 to December 2017, were extracted from the cohort of the Sicilian Network of IBD. RESULTS: Among 87 children aged 7-17 years (63 Crohn's disease [CD], 24 Ulcerative colitis [UC]), 101 out of 108 biologic treatments were considered. Evaluation of 74 biologic treatments in CD patients at 26, 52, 104 weeks showed clinical benefit rates of 84.2%, 93.3%, 66.7% with IFX (n= 38) and 88.9%, 84.4%, 65.2% with ADA (n= 36). Biologic treatments (n=27) evaluated in the UC group at 26, 52, 104 weeks, led to clinical benefit rates of 85.7%, 83.3%, 50% in IFX subgroup (n=21) and 40%, 50%, 33% in the ADA subgroup (n=5), respectively. One patient treated with GOL showed 100% clinical benefit at 26 and 52 weeks. Overall adverse events (AEs) rate was 9.25%. Six younger children, <6 years, receiving 8 treatments (4 ADA, 4 IFX) presented a clinical remission rate of 75% at 12 weeks and 25% at 52 weeks. AEs rate was 25% in this group. CONCLUSION: Our data show that biologic therapy in children, even at a younger age, is effective in allowing long-term remission with a good safety profile.

Physicians' Knowledge and Application of Immunization Strategies in Patients with Inflammatory Bowel Disease: A Survey of the Italian Group for the Study of Inflammatory Bowel Disease.

BACKGROUND: No data on European countries about knowledge and application of immunization strategies in patients with inflammatory bowel disease (IBD) are available. OBJECTIVES: We designed a questionnaire aimed at exploring these issues among Italian gastroenterologists dealing with adult and paediatric IBD. METHODS: An anonymous, 24-item, questionnaire was sent via e-mail to all members of the Italian Group for the study of Inflammatory Bowel Disease. Three sets of questions were formulated: (1) Characteristics of respondents; (2) General opinions on the role of vaccines in IBD patients; (3) Immunizations of IBD patients in clinical practice. RESULTS: Of the 455 total surveys sent, there were 198 respondents (response rate: 43.5%). The great majority of respondents (82.9%) reputed as "very important" to perform the vaccinations recommended by the guidelines in patients with IBD. The indication to immunization is given at the diagnosis of the disease by 55.6% of the respondents. The most frequently recommended vaccine in IBD patients is the annual flu vaccine, while the recommendation rate for the other vaccines is variable depending on the different pathogens. CONCLUSIONS: Efforts carried out by the scientific societies are required to increase the awareness of this relevant topic among physicians.

Effectiveness and safety of Ustekinumab for the treatment of Crohn's disease in real-life experiences: a meta-analysis of observational studies.

Background: The aim of this meta-analysis was to estimate the effectiveness and safety of Ustekinumab in Crohn's disease (CD) reported by observational studies.Research design and methods: PubMed/Medline and Embase were systematically searched through September 2019. Only real-life observational studies were included.Results: Thirteen studies comprising 1450 patients met the inclusion criteria. Ustekinumab was administered subcutaneously at induction among 7 studies, while in 6 studies the intravenous formulation was used. At induction (8-16 weeks), the pooled estimate rates of clinical response and remission were 56% (95% CI: 43-68%; range: 16-94%; I2 = 94%) and 34% (95% CI: 25-45%; range: 15-58%; I2 = 90%), respectively. The rate of clinical response was higher among studies which employed the subcutaneous compared with the intravenous induction (68% vs. 38%, p = 0.01). At maintenance, the pooled estimate rates of clinical response, clinical remission, endoscopic response, and endoscopic remission were 62% (95% CI: 50-73%; range: 42-89%; I2 = 89%), 40% (95% CI: 28-54%; range: 26-73%; I2 = 90%), 56% (95% CI: 37-73%; range: 20-77%; I2 = 87%), and 19% (95% CI: 11-30%; range: 7-31%; I2 = 67%), respectively.Conclusions: Ustekinumab is an effective treatment in patients with CD with a reassuring safety profile. The subcutaneous induction seems to be superior to the intravenous one.

Lupus-like reactions in patients with inflammatory bowel disease treated with anti-TNFs are insidious adverse events: data from a large single-center cohort.

Objectives: Very few data on the incidence, predictors, and clinical outcomes of lupus-like reactions (LLRs) in patients with inflammatory bowel disease (IBD) treated with anti-TNFs have been reported. Materials and methods: All records of consecutive IBD patients who started a treatment with an anti-TNF from January 2006 to June 2018 were retrospectively reviewed. Patients were defined as having LLR by the presence of immunologic abnormalities (positivity for ANA and/or anti-ds-DNA), along with clinical features that included at least two of the following: arthralgia, fatigue, fever, cutaneous manifestations, or serositis, which had a clear temporal association with exposure to the anti-TNFs, and resolved without recurrence once the drug was discontinued. Results: 760 patients (1059 total treatments with anti-TNFs) were included. Participants contributed a total of 2863.5 person-years of follow-up, during which 16 cases of LLRs (2.1% of patients) were reported, accounting for an incidence rate of 5.6 per 1000 person-years. Female gender and being former smokers were more prevalent in the LLR group (75.0% versus 44.1%, p = .02; and 18.8% versus 5.4%, p = .037, respectively), with a hazard ratio of 4.40 (95% CI: 1.40-13.81; p = .011) and 4.87 (95% CI: 1.37-17.38; p = .015), respectively, at Cox regression analysis. All LLRs resolved following discontinuation of the drug after a mean of 8.1 ± 4.2 weeks. Ten patients required corticosteroids to control severe symptoms. Conclusions: In this large cohort of patients treated with anti-TNFs with long follow-up, LLRs were rare adverse events, more common in women and former smokers, occurring with nonspecific and insidious clinical features.

Prevalence and incidence of inflammatory bowel disease in two Italian islands, Sicily and Sardinia: A report based on health information systems.

BACKGROUND: Few epidemiological data about inflammatory bowel disease (IBD) in Italy are available. AIMS: To estimate IBD prevalence and incidence in two Italian regions - Sicily and Sardinia - using regional health information systems. METHODS: Data from hospital discharges and disease-specific payment exemptions register were retrieved and underwent record-linkage procedures. Standardized prevalence and incidence were calculated as rates per 100,000 inhabitants. RESULTS: In Sicily, during the year 2013, the overall IBD incidence rate was 27 per 100,000 inhabitants, while the incidence rate of Crohn's disease (CD) was 16 for males and 13 for females, and the incidence of ulcerative colitis (UC) was 15 and 11 for males and females, respectively. At the date of December 31st, 2013, the standardized prevalence rate of IBD was estimated at 300 cases per 100,000 inhabitants. In Sardinia, during the period 2008-2010, the average IBD incidence rate per 100,000 was 15, with an incidence rate of 5 per 100,000 for CD, and 10 per 100,000 for UC, while the standardized prevalence rate of IBD was estimated at 187 cases per 100,000 inhabitants. CONCLUSIONS: The particularly high incidence of CD in Sicily, and the marked difference of IBD occurrence between the two islands deserve future investigations.

Psoriasis and Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) and psoriasis (PS) are associated conditions. The reason for this association lies in the sharing of predisposition genes and common immunological mechanisms. SUMMARY: This review will focus on the interplay between IBD and PS, with details on prevalence and phenotype of PS in IBD, genetics, pathogenetic pathways, and therapy. Key Messages: Microbiome seems relevant in both conditions: a reduction of beneficial bacteria has been observed. IBD and PS have in common some comorbidities like cardiovascular disease, similar risk of cancer and psychiatric problems. Many biological therapies such as anti-tumour necrosis factor (TNF) and anti-interleukin 23 are effective in both conditions, underlining the common immunological mechanisms. Paradoxical PS has been mainly observed after anti-TNF therapies, but preliminary reports show that it can also occur with other biologics. Genetic predisposition to this phenomenon has been reported.

A Propensity Score-matched Comparison of Infliximab and Adalimumab in Tumour Necrosis Factor-α Inhibitor-naïve and Non-naïve Patients With Crohn's Disease: Real-Life Data From the Sicilian Network for Inflammatory Bowel Disease.

BACKGROUND AND AIMS: There is an unmet need to better understand the effectiveness of different biologics in inflammatory bowel diseases. We aimed at performing a multicentre, real-life comparison of the effectiveness of infliximab [IFX] and adalimumab [ADA] in Crohn's disease [CD]. METHODS: Data of consecutive patients with CD treated with IFX and ADA from January 2013 to May 2017 were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease. We used propensity score-matching accounting for the main baseline characteristics in TNF-α inhibitor-naïve and non-naïve patients. RESULTS: A total of 632 patients [735 total treatments] were included. Among naïve patients, a clinical benefit [the sum of steroid-free remission plus clinical response] was achieved in 81.8% patients treated with ADA and in 77.6% patients treated with IFX (adjusted odds ratio [OR]: 1.23, 95% CI 0.63-2-44, p = 0.547] at 12 weeks; after 1 year, a clinical benefit was achieved in 69.2% of patients treated with ADA and in 64.5% patients treated with IFX [adjusted OR: 1.10, 95% CI 0.61-1.96, p = 0.766]. Among non-naïve patients, a clinical benefit was achieved in 61.7% of patients treated with ADA and in 68.1% of patients treated with IFX [adjusted OR: 0.72, 95% CI 0.21-2.44, p = 0.600] at 12 weeks; after 1 year, a clinical benefit was achieved in 48.9% of patients treated with ADA and in 40.4% patients treated with IFX [adjusted OR: 1.23, 95% CI 0.54-2.86, p = 0.620]. CONCLUSIONS: In this propensity score-matched comparison of ADA and IFX in CD, both drugs showed high rates of clinical benefit, without significant differences between them.

Factors Affecting Clinical and Endoscopic Outcomes of Placebo Arm in Trials of Biologics and Small Molecule Drugs in Ulcerative Colitis: A Meta-Analysis.

BACKGROUND: Previous systematic cumulative analyses of the placebo arm in ulcerative colitis (UC) were limited by the wide heterogeneity in the scores and definitions of response. We aimed at estimating the placebo rates of remission, response, and mucosal healing (MH) in phase 2 and 3 randomized placebo-controlled trials of biologics and small molecule drugs that used homogeneous criteria for the assessment of outcomes. METHODS: PubMed Central, Embase, and reference lists of articles were systematically searched through July 2017. Only studies that employed the Mayo score were included. RESULTS: Thirty-one randomized placebo-controlled trials consisting of 2702 patients met the inclusion criteria. At induction, the pooled estimates of the placebo rates of remission, response, and MH were 9% (95% confidence interval [CI], 7%-12%; range: 0%-29%; I2 = 75.0%), 34% (95% CI, 31%-38%; range: 12%-75%; I2 = 61.3%), and 26% (95% CI, 22%-30%; range: 2%-65%; I2 = 77.7%), respectively. At maintenance, the pooled estimates of the placebo rates of remission, response, and MH were 14% (95% CI, 10%-18%; range: 6%-30%; I2 = 73.0%), 23% (95% CI, 20%-27%; range: 18%-36%; I2 = 53.0%), and 19% (95% CI, 15%-23%; range: 12%-30%; I2 = 65.0%), respectively. Among the variables assessed by logistic regression analysis, multiple factors influenced the outcomes of placebo arms, including concomitant systemic steroids at baseline, endoscopic central reading, being naïve or non-naïve to anti-TNFs, and disease duration. CONCLUSIONS: Despite the wide use of homogeneous criteria for the assessment of clinical and endoscopic outcomes, a high heterogeneity among placebo arms of modern trials in UC still exists.

Anti-interleukin-12 and anti-interleukin-23 agents in Crohn's disease.

INTRODUCTION: Blockers of IL-12/23, as well as specific blockers of IL-23, have been investigated as options for medical therapy in inflammatory bowel disease. These biological agents include ustekinumab - the first agent of this pharmacological class which has shown clinical efficacy in psoriasis, psoriatic arthritis, and moderate-to-severe Crohn's disease (CD) - and other monoclonal antibodies under investigation, including brazikumab, risankizumab, mirikizumab, and guselkumab. AREAS COVERED: This review will focus on the rationale of the blockade of IL-12/23 axis in CD, efficacy and safety data of ustekinumab derived from randomized controlled trials and real-life observational studies, and the preliminary data of the highly promising selective IL-23 inhibitors. EXPERT OPINION: Data from literature have demonstrated that ustekinumab holds the potential to deserve a relevant role in the management of patients with CD thanks to several properties, including the fast onset of action, the long duration of efficacy, the favorable safety profile, the systemic anti-inflammatory effect, and the peculiar way of administration. Nonetheless, additional research is warranted to determine the real value of ustekinumab, as current data are not able to answer all the questions about its effectiveness in real-life practice, and the external validity of the available results is not absolute.

A real life comparison of the effectiveness of adalimumab and golimumab in moderate-to-severe ulcerative colitis, supported by propensity score analysis.

BACKGROUND: Adalimumab and golimumab are effective in the treatment of moderate to severe ulcerative colitis. AIMS: We reported the comparative effectiveness of adalimumab and golimumab in ulcerative colitis. METHODS: 118 patients treated with adalimumab and 79 treated with golimumab were included and evaluated at 8 weeks and at the end of follow up. RESULTS: Overall clinical benefit was 72.6% at 8 weeks and 58.9% at the end of follow up. Patients with longer disease duration and those treated with adalimumab had a better outcome. Clinical benefit was 78.8% in adalimumab patients and 63.3% in golimumab patients (p = 0.026) after 8 weeks; it was 66.9% in adalimumab patients and 46.8% in golimumab patients (p = 0.008) at the end of follow up. These data were confirmed by propensity score analysis. A further analysis considering adalimumab optimization as treatment failure showed that the difference between adalimumab and golimumab was not significant. CONCLUSION: Adalimumab and golimumab are effective in the treatment of ulcerative colitis. Adalimumab seems to be more effective than golimumab. This difference is probably affected by the impossibility of golimumab to be optimized in Italy while adalimumab is.

The real-world effectiveness of vedolizumab on intestinal and articular outcomes in inflammatory bowel diseases.

BACKGROUND: The effectiveness of vedolizumab in real-world practice is under evaluation, while its role in inflammatory bowel disease-associated spondyloarthritis is still unclear. AIMS: To report real-world data about the effectiveness of vedolizumab on intestinal and articular symptoms after 10 and 22 weeks of treatment. METHODS: Web-based data from the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD) were extracted to perform a prospective multicentre observational study. RESULTS: 163 patients (84 with Crohn's disease and 79 with ulcerative colitis) were included. At week 10, a steroid-free remission was achieved in 71 patients (43.6%), while at week 22 a steroid-free remission was obtained in 40.8% of patients. A response on articular symptoms was reported after 10 weeks of treatment in 17 out of 43 (39.5%) patients with active spondyloarthritis at baseline, and in 10 out of 22 (45.4%) patients at week 22. The only factor associated with articular response was the coexistence of clinical benefit on intestinal symptoms (at week 10: OR 8.471, p = 0.05; at week 22: OR 5.600, p = 0.08). CONCLUSIONS: Vedolizumab showed good effectiveness after 10 and 22 weeks of treatment. A subset of patients reported improvement also on articular symptoms, probably as a consequence of the concomitant control of gut inflammation.

The Addition of an Immunosuppressant After Loss of Response to Anti-TNFα Monotherapy in Inflammatory Bowel Disease: A 2-Year Study.

Background: The addition of an immunosuppressant (IM) after loss of response to anti-TNFα monotherapy is an emerging strategy of therapeutic optimization in patients with inflammatory bowel disease (IBD). However, few clinical data have been reported to date. We aimed to evaluate the efficacy and safety of this selective combination therapy in patients with IBD. Methods: All consecutive patients with loss of response to anti-TNFα monotherapy despite an intensive dose optimization who added an IM from October 2014 to October 2016 were entered into a prospective database. Results: Among 630 patients treated with anti-TNFα agents during the study period, 46 (7.3%) added an IM. A total of 31 patients (67.4%) were treated with an intravenous anti-TNFα (infliximab, as originator or biosimilar), while 15 (32.6%) were treated with a subcutaneous anti-TNFα agent (10 adalimumab and 5 golimumab). The mean duration of follow-up was 12.8 ± 7.3 months. Twenty-one patients (45.7%) remained on combination therapy at the end of follow-up: 15 (32.6%) maintained a steroid-free remission, and 6 (13.0%) achieved a clinical response. In patients who experienced treatment success, the median value of C-reactive protein decreased from baseline to the end of follow-up (13.2 vs 3.0, P = 0.01; normal values <5 mg/L). Adverse events leading to treatment discontinuation were reported in 8 out of 46 patients (17.4%). Conclusions: In the largest cohort on this argument reported to date, the addition of an IM was an effective and safe optimization strategy after loss of response to anti-TNFα monotherapy. Low doses of IM were sufficient to achieve a clinical response.

Is Epstein-Barr virus infection associated with the pathogenesis of microscopic colitis?

BACKGROUND: Epstein-Barr virus (EBV) has been associated with inflammation in the colon, particularly in patients with inflammatory bowel disease (IBD). Even if a relevant plasmocytosis, similar to IBD, is present in microscopic colitis (MC), the frequency of EBV infection in this setting is unknown. OBJECTIVES: We aimed to compare the frequency of colonic EBV infection in patients with MC, ulcerative colitis (UC), and irritable bowel syndrome (IBS). STUDY DESIGN: The frequency of colonic EBV infection in biopsies of 30 patients with MC, 30 patients with UC, and 30 controls with IBS was retrospectively assessed. PCR was performed to detect viral EBV DNA in colonic biopsies. In situ hybridization was also performed to identify and localize EBV-encoded small RNA1 and 2 (EBERs) within cells. RESULTS: The presence of EBV DNA was detected in 27 out of 30 MC patients, in 20 out of 30 UC cases, and in none of IBS group. The frequency of EBV DNA in MC was significantly higher compared with that reported in UC (90.0% vs. 66.7%, p=0.03). EBERs+ cells were observed in 18 out of 30 MC patients, in only 3 out of 30 UC patients (60.0% vs. 10.0%, p<0.001), and in none of IBS group. CONCLUSIONS: EBV infection is almost always detectable in the colonic mucosa of patients with MC. Further studies are necessary to confirm this association and to clarify the role of EBV in MC and, more generally, in colonic inflammation.

Tolerability profile of thiopurines in inflammatory bowel disease: a prospective experience.

OBJECTIVES: The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting. MATERIALS AND METHODS: All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported. RESULTS: Two hundred and fifty three patients were included. Median total follow-up was 32 months (range: 0.2-75 months). At the end of the study, AZA was discontinued in 160 patients (63.2%). The main reason leading to drug withdrawal was the occurrence of AEs (109/160 patients [68.1%]; cumulative incidence among the entire cohort: 43.1%). Overall, the most frequent AEs leading to treatment withdrawal were nausea (31/253 patients, 12.3%) and subjective symptoms, i.e., poorly defined side effects such as fatigue, headache and muscle pain (20/253 patients, 7.9%). Among the 109 AZA-intolerant patients, a switch to 6-mercaptopurine (6-MP) was performed in 44 cases (40.4%). At the end of follow-up, 6-MP was discontinued in 35/44 patients (79.5%), mostly due to AEs (29/35 patients, 82.8%). Azathioprine-induced hepatic and pancreatic toxicity was associated with male gender (p = .01 and p = .03, respectively), and occurrence of nausea with Crohn's disease (p = .04). CONCLUSIONS: Our real-life prospective cohort showed the higher cumulative incidence of thiopurine withdrawal due to AEs reported to date. Switching from AZA to 6-MP was often ineffective.