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Background The long-term outcome of patients after antitumour necrosis factor alpha (anti-TNF) discontinuation is not well known. Aims To assess the risk of relapse in the long-term after anti-TNF discontinuation. Methods This was an extension of the evolution after anti-TNF discontinuation in patients with inflammatory bowel disease (EVODIS) study (Crohn's disease or ulcerative colitis patients treated with anti-TNFs in whom these drugs were withdrawn after achieving clinical remission) based in the same cohort of patients whose outcome was updated. Clinical remission was defined as a Harvey-Bradshaw index

OBJECTIVES:Immunosuppressant therapies (IMTs; thiopurines, anti-tumor necrosis factor agents) may influence the immunologic control of cancer and might facilitate the spread and recurrence of cancer. This study assesses the impact of the use of IMTs on the development of incident cancers (recurrent or new) in patients with inflammatory bowel disease (IBD) and a history of malignancy.METHODS:Patients with IBD included in the ENEIDA registry with a history of cancer without being exposed to IMTs were identified and retrospectively reviewed and compared regarding further treatment with IMTs or not by means of a log-rank test.RESULTS:Overall, 520 patients with previous extracolonic cancer naive to IMTs before the diagnosis of cancer were identified. Of these, 146 were subsequently treated with IMTs (exposed), whereas 374 were not (nonexposed). The proportion of patients with incident cancers was similar in both exposed (16%) and nonexposed (18%) patients (P = 0.53); however, there was more than a 10-year difference in the age at index cancer between these 2 groups. Cancer-free survival was 99%, 98%, and 97% at 1, 2, and 5 years in exposed patients, and 97%, 96%, and 92% at 1, 2, and 5 years in non-exposed patients, respectively (P = 0.03). No differences in incident cancer rates were observed between exposed and nonexposed patients when including only those who were exposed within the first 5 years after cancer diagnosis.DISCUSSION:In patients with IBD and a history of cancer not related to immunosuppression, the use of IMTs is not associated with an increased risk of new or recurrent cancers even when IMTs are started early after cancer diagnosis.

Background Cohort studies comparing the characteristics of childhood-onset and adulthood-onset inflammatory bowel disease (IBD) in the biologics era are scarce. Aim To compare disease characteristics, the use of immunomodulators and biologic agents and the need for surgery between childhood- and adulthood-onset IBD. Methods Inflammatory bowel disease patients from the ENEIDA registry diagnosed between 2007 and 2017 were included. The childhood-onset cohort comprised patients diagnosed at 16 years. The cumulative incidences of immunosuppressive therapy, biologic therapy and surgery were estimated using Kaplan-Meier curves, compared by the log-rank test. Cox regression analysis was performed to identify potential predictive factors of treatment with immunosuppressants, biologic agents or surgery. Results The adulthood-onset cohort comprised 21 200 patients out of 20 354 (96%) and the childhood-onset cohort 846 (4%). Median follow-up was 54 months in the childhood-onset cohort and 38 months in the adulthood-onset cohort (P < 0.01). Proportions of Crohn's disease, ileocolonic involvement and inflammatory behaviour at diagnosis were higher in the childhood-onset cohort. In the multivariate analysis, after adjusting for sex, type of IBD, extraintestinal manifestations, family history and smoking habit, childhood-onset IBD was associated with higher risk of immunomodulator use (hazard ratio [HR] = 1.2, 95% confidence interval [95% CI] = 1.1-1.2) and higher probability of receiving biologic treatment (HR = 1.2, 95% CI = 1.1-1.3). However, childhood-onset IBD was not associated with higher risk of surgery (HR = 0.9, 95% CI = 0.8-1.2). Conclusions Childhood-onset IBD has differential characteristics and higher risk of treatment with immunomodulators and biologic agents, compared with adulthood-onset IBD. Nevertheless, paediatric IBD is not associated with higher risk of surgery.

Background and Aims: To evaluate the clinical outcomes in patients with IBD after switching from Remicade (R) to CT-P13 in comparison with patients who maintain Remicade (R). Methods: Patients under Remicade (R) who were in clinical remission with standard dosage at study entry were included. The 'switch cohort' [SC] comprised patients who made the switch from Remicade (R) to CT-P13, and the 'non-switch' cohort [NC] patients remained under Remicade (R). Results: A total of 476 patients were included: 199 [42%] in the SC and 277 [58%] in the NC. The median follow-up was 18 months in the SC and 23 months in the NC [p < 0.01]. Twenty-four out of 277 patients relapsed in the NC; the incidence of relapse was 5% per patient-year. The cumulative incidence of relapse was 2% at 6 months and 10% at 24 months in this group. Thirty-eight out of 199 patients relapsed in the SC; the incidence rate of relapse was 14% per patient-year. The cumulative incidence of relapse was 5% at 6 months and 28% at 24 months. In the multivariate analysis, the switch to CT-P13 was associated with a higher risk of relapse (HR = 3.5, 95% confidence interval [CI] = 2-6). Thirteen percent of patients had adverse events in the NC, compared with 6% in the SC [p < 0.05]. Conclusions: Switching from Remicade (R) to CT-P13 might be associated with a higher risk of clinical relapse, although this fact was not supported in our study by an increase in objective markers of inflammation. The nocebo effect might have influenced this result. Switching from Remicade (R) to CT-P13 was safe.

Background Thiopurines are the most widely used immunosuppressants in IBD although drug-related adverse events (AE) occur in 20%-30% of cases. Aim To evaluate the safety of thiopurines in elderly IBD patients Methods Cohort study including all adult patients in the ENEIDA registry who received thiopurines. Patients were grouped in terms of age at the beginning of thiopurine treatment, specifically in those who started thiopurines over 60 years or between 18 and 50 years of age. Thiopurine-related AEs registered in the ENEIDA database were compared. Results Out of 48 752 patients, 1888 thiopurines when over 60 years of age and 15 477 under 50 years of age. Median treatment duration was significantly shorter for those who started thiopurines >60 years (13 [IQR 2-55] vs 32 [IQR 5-82] months; P < .001). Patients starting >60 years had higher rates of all types of myelotoxicity, digestive intolerance and hepatotoxicity. Thiopurines were discontinued due to AEs (excluding malignancies and infections) in more patients starting >60 years (67.2% vs 63.1%; P < .001). Elderly age and female sex were independent risk factors for most AEs. Conclusion In elderly IBD patients, thiopurines are associated with an increased risk of non-infectious, non-neoplastic, AEs.

PurposeNivolumab, a monoclonal antibody-targeting programmed cell death protein-1, is being increasingly used for the treatment of some advanced neoplasms. Several of its adverse effects are a result of the upregulation of T cells, with colitis as one of the most severe, and a challenging differential diagnosis with ulcerative colitis. However, few real-life clinical practice cases have been reported beyond trials. Our aim was to report a series of new cases, reviewing previously communicated endoscopic-proven nivolumab-induced colitis.MethodAll patients treated with nivolumab in three university centers were identified and those who developed immune-mediated colitis (defined as the presence of diarrhea and evidence of colitis demonstrated by colonoscopy) were described. Additionally, a review of case reports of nivolumab-induced colitis reported in the literature up to March 2018 was performed.ResultsSix new cases of nivolumab-induced colitis and 13 previously reported cases out of randomized clinical trials are described. Colonoscopy showed a mucosal pattern mimicking ulcerative colitis in a large proportion of patients. Clostridium difficile superinfection was observed in two out of 19 cases. All but three patients definitively discontinued nivolumab therapy. Most patients were initially managed with oral or intravenous corticosteroids, but five of them required rescue therapy with infliximab.ConclusionsNivolumab-induced colitis may mimic ulcerative colitis. Steroid therapy (oral or intravenously) is often efficient, but one-fourth of patients need rescue therapy with anti-TNF. Intestinal superinfection with Clostridium difficile or cytomegalovirus should be ruled out before starting immunosuppressive therapy.

Background: Fecal calprotectin (FC) correlates with clinical and endoscopic activity in ulcerative colitis (UC), and it is a good predictor of relapse. However, its use in clinical practice is constrained by the need for the patient to deliver stool samples, and for their handling and processing in the laboratory. The availability of hand held devices might spread the use of FC in clinical practice.Objectives: To evaluate the usefulness of a rapid semi-quantitative test of FC in predicting relapse in patients with UC in remission.Materials and methods: Prospective, multicenter study that included UC patients in clinical remission for 6 months on maintenance treatment with mesalamine. Patients were evaluated clinically and semi-quantitative FC was measured using a monoclonal immunochromatography rapid test at baseline and every three months until relapse or 12 months of follow-up.Results: One hundred and ninety-one patients had at least one determination of FC. At the end of follow-up, 33 patients (17%) experienced clinical relapse. Endoscopic activity at baseline (p=.043) and having had at least one FC>60g/g during the study period (p=.03) were associated with a higher risk of relapse during follow-up. We obtained a total of 636 semi-quantitative FC determinations matched with a three-month follow-up clinical assessment. Having undetectable FC was inversely associated with early relapse (within three months), with a negative predictive value of 98.6% and a sensitivity of 93.9%.Conclusions: Serial, rapid semi-quantitative measurement of FC may be a useful, easy and cheap monitoring tool for patients with UC in remission.

Background: Patients with ulcerative colitis (UC) have an increased risk of colorectal cancer. Scarce data regarding the development of adenomas in these patients are available both for normal and colitic mucosa. Objective: The objective of this article is to evaluate the prevalence of adenomatous polyps and associated risk factors in patients with UC. Methods: Patients with UC were identified from the databases of two tertiary referral centers. Medical, endoscopic and histologic reports were reviewed. Results: A total of 403 patients were included (53% male; 33% extensive colitis) and 1065 colonoscopies (median per patient, 2) were recorded and analyzed. Seventy-four adenomas in 47 patients (11.7%) and three cases of colorectal cancer were found during a median follow-up of 6.3 years. The cumulative risk of colorectal adenoma was 4.7%, 16.7%, 23.6% and 34.4% at 10, 20, 30 and 40 years from UC diagnosis, respectively. The cumulative risk of developing metachronous colorectal adenoma was 66.7%, 87.9%, and 90.9% at 5, 10, and 15 years from first adenoma detection. Older age at UC diagnosis and longer disease duration were independent risk factors for colorectal adenoma development. Conclusions: The prevalence of colorectal adenomas among UC patients seems to be higher than previously reported, although lower than in the background population.

Background: The convoluted relationship between obesity, bariatric surgery and inflammatory bowel disease (IBD) is of increasing interest. Aim: To analyse evidence regarding the role of bariatric surgery in the development of de novo IBD and its impact on clinical outcomes and safety in patients with established IBD. Methods: A PubMed/Medline search was performed to identify studies reporting the development of IBD after bariatric surgery and the outcomes of IBD patients after bariatric surgery. Results: Eighty patients were reported to have developed de novo IBD after bariatric surgery (21% ulcerative colitis [UC], 75% Crohn's disease [CD]), mostly females. Roux-en-Y gastric bypass was the most frequent bariatric technique (80%). Symptoms related to IBD occurred within 1 month and 16 years after surgery. Regarding patients with known IBD undergoing bariatric surgery, 60 patients (35 CD, 24 UC, and 1 unclassified colitis) have been reported. Sleeve gastrectomy was the most frequent bariatric procedure, particularly in CD patients. Acute flares after surgery were observed in only four UC patients. In addition, two retrospective population-based studies described perioperative outcomes of bariatric surgery on IBD patients, demonstrating only a significant increase in small bowel obstruction in these patients. Conclusions: Bariatric surgery in carefully selected patients with established IBD is technically feasible and probably safe. Development of de novo IBD should be taken into account in individuals with previous bariatric surgery who develop diarrhoea, anaemia or excessive weight loss.

Background: Onset during old age has been reported in upto 10% of total cases of inflammatory bowel disease (IBD). Aim: To evaluate phenotypic characteristics and the use of therapeutic resources in patients with elderly onset IBD. Methods: Case-control study including all those patients diagnosed with IBD over the age of 60 years since 2000 who were followed-up for >12 months, identified from the IBD databases. Elderly onset cases were compared with IBD patients aged 18 to 40 years at diagnosis, matched by year of diagnosis, gender and type of IBD (adult-onset). Results: One thousand three hundred and seventy-four elderly onset and 1374 adult-onset cases were included (62% ulcerative colitis (UC), 38% Crohn's disease (CD)). Among UC patients, elderly onset cases had a lower proportion of extensive disease (33% vs 39%; P < 0.0001). In CD, elderly onset cases showed an increased rate of stenosing pattern (24% vs 13%; P < 0.0001) and exclusive colonic location (28% vs 16%; P < 0.0001), whereas penetrating pattern (12% vs 19%; P < 0.0001) was significantly less frequent. Regarding the use of therapeutic resources, there was a significantly lower use of corticosteroids (P < 0.0001), immunosuppressants (P < 0.0001) and anti-TNFs agents (P < 0.0001) in elderly onset cases. Regarding surgery, we found a significantly higher surgery rate among elderly onset UC cases (8.3% vs 5.1%; P < 0.009). Finally, elderly onset cases were characterised by a higher rate of hospitalisations (66% vs 49%; P < 0.0001) and neoplasms (14% vs 0.5%; P < 0.0001). Conclusions: Elderly onset IBD shows specific characteristics and they are managed differently, with a lower use of immunosuppressants and a higher rate of surgery in UC.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a little known entity that can affect the oropharyngeal mucosa, the gastrointestinal tract and the skin. The main risk factor for the development of this lesion is immunosuppression. Because its features are similar to other Epstein-Barr virus-associated lymphoproliferative disorders, a differential diagnosis can sometimes prove challenging. Here, we report the case of a man diagnosed with Crohn's disease and treated with azathioprine and infliximab who developed ulceration at the rectum that was refractory to conventional medical treatment. Although the histological characteristics were suggestive of an EBVMCU, lymphoproliferative disease could not be ruled out. The patient did not improve after discontinuation of the treatment, a proctectomy was performed and the diagnosis of this disease was confirmed. Although very few cases of EBVMCU affecting the colon have been reported, its diagnosis should be always considered in refractory cases of inflammatory bowel disease with patients undergoing immunosuppressive treatment. (C) 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background: Psoriasis induced by anti-tumor necrosis factor-alpha (TNF) therapy has been described as a paradoxical side effect. Aim: To determine the incidence, clinical characteristics, and management of psoriasis induced by anti-TNF therapy in a large nationwide cohort of inflammatory bowel disease patients. Methods: Patients with inflammatory bowel disease were identified from the Spanish prospectively maintained Estudio Nacional en Enfermedad Inflamatoria Intestinal sobre Determinantes geneticos y Ambientales registry of Grupo Espanol de Trabajo en Enfermedad de Croh y Colitis Ulcerosa. Patients who developed psoriasis by anti-TNF drugs were the cases, whereas patients treated with anti-TNFs without psoriasis were controls. Cox regression analysis was performed to identify predictive factors. Results: Anti-TNF-induced psoriasis was reported in 125 of 7415 patients treated with anti-TNFs (1.7%; 95% CI, 1.4-2). The incidence rate of psoriasis is 0.5% (95% CI, 0.4-0.6) per patient-year. In the multivariate analysis, the female sex (HR 1.9; 95% CI, 1.3-2.9) and being a smoker/former smoker (HR 2.1; 95% CI, 1.4-3.3) were associated with an increased risk of psoriasis. The age at start of anti-TNF therapy, type of inflammatory bowel disease, Montreal Classification, and first anti-TNF drug used were not associated with the risk of psoriasis. Topical steroids were the most frequent treatment (70%), achieving clinical response in 78% of patients. Patients switching to another anti-TNF agent resulted in 60% presenting recurrence of psoriasis. In 45 patients (37%), the anti-TNF therapy had to be definitely withdrawn. Conclusions: The incidence rate of psoriasis induced by anti-TNF therapy is higher in women and in smokers/former smokers. In most patients, skin lesions were controlled with topical steroids. More than half of patients switching to another anti-TNF agent had recurrence of psoriasis. In most patients, the anti-TNF therapy could be maintained.

OBJECTIVES: The safety of thiopurines and anti-tumor necrosis factor-alpha (TNF-alpha) drugs during pregnancy remains controversial, as the experience with these drugs in this situation is limited. Our aim is to assess the safety of thiopurines and anti-TNF-alpha drugs for the treatment of inflammatory bowel disease (IBD) during pregnancy. METHODS: Retrospective, multicenter study in IBD patients. Pregnancies were classified according to the therapeutic regimens during pregnancy or during the 3 months before the conception: non-exposed group, pregnancies exposed to thiopurines alone (group A), and pregnancies exposed to anti-TNF-alpha drugs (group B). An unfavorable Global Pregnancy Outcome (GPO) was considered if pregnancy developed with obstetric complications in the mother and in the newborn. RESULTS: A total of 187 pregnancies in the group A, 66 pregnancies in the group B, and 318 pregnancies in the non-exposed group were included. The rate of unfavorable GPO was different among the three groups (31.8% in non-exposed group, 21.9% in group A, and 34.8% in group B), being lower in pregnancies under thiopurines than among non-exposed (P=0.01). The rate of pregnancy complications was similar among the three groups (27.7% in non-exposed, 20.9% in group A, and 30.3% in group B). The rate of neonatal complications was different among the three groups (23.3% in non-exposed group, 13.9% in group A, and 21.2% in group B), being lower in pregnancies under thiopurines than among non-exposed (P=0.01). In the multivariate analysis, the treatment with thiopurines (odds ratio=0.6; 95% confidence interval=0.4-0.9, P=0.02) was the only predictor of favorable GPO, whereas maternal age >35 years at conception was the only predictor of unfavorable GPO. The treatment with anti-TNF-alpha drugs was not associated with an unfavorable GPO. CONCLUSION: The treatment with thiopurines and anti-TNF-alpha drugs does not seem to increase the risk of complications during pregnancy and does seem to be safe for the newborn. Am J Gastroenterol 2013;108:433-440; doi:10.1038/ajg.2012.430; published online 15 January 2013

Sexuality is important when assessing quality of life (QoL), which is often disturbed in inflammatory bowel disease (IBD). However, sexuality is not addressed in most QoL questionnaires. To evaluate the prevalence and predisposing factors of sexual dysfunction among IBD patients, and their own perception. A postal survey was conducted in IBD patients 25-65 years of age from two tertiary centres. Patients were asked to provide a control of the same gender and age without IBD. The questionnaire assessed patient perception of the impact of IBD on their sexuality, and also allowed calculation of the Erectile Function International Index or the Female Sexual Function Index. A total of 355 patients and 200 controls were available for the final analysis. Both groups were comparable except for a higher proportion of individuals who had been treated for depression among patients. Half of the female and one-third of the male patients considered that both sexual desire and satisfaction worsened after IBD diagnosis. As compared to controls, both men and women with IBD showed significantly lower scores in sexual function indexes, but a higher prevalence of sexual dysfunction was only noticed among women. Independent predictors of sexual dysfunction among IBD patients were the use of corticosteroids in women, and the use of biological agents, depression and diabetes in men. Sexuality is often disturbed in IBD patients, particularly among women. Many factors seem to contribute to worsened intimacy. Sexuality should be considered when QoL is assessed in these patients.

P>Background Infliximab (IFX) could change the course of Crohn's disease (CD) by reducing steroid use, surgery or prompting earlier introduction of immunomodulators (IMM). Aim To evaluate the impact of IFX availability on the course of early CD. Methods Two cohorts of newly diagnosed CD patients were identified: The first cohort included patients diagnosed from January 1994 to December 1997 and the second from January 2000 to December 2003. All patients were diagnosed, treated and followed up in the same centre until December 1999 (first cohort) or December 2005 (second cohort). Development of disease-related complications, steroid, IMM or IFX requirements and intestinal resections during follow-up were registered. Results A total of 328 patients were included (146 first cohort, 182 second cohort). A similar proportion of patients in both cohorts received steroids, but steroid exposure resulted significantly more intense in the first cohort (P = 0.001). In the second cohort, 14% of patients received IFX. Thiopurines were used more (P = 0.001) and earlier (P = 0.012) in the second cohort. No differences in surgical requirements or the development of disease-related complications were found. Conclusions Following a step-up therapeutic algorithm, IFX availability did not reduce surgical requirements or the development of disease-related complications. Aliment Pharmacol Ther 31, 233-239.