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Background and Aims: Immunomediated adverse events [IAEs] are the most frequently reported infliximab [IFX]-related adverse events. Combination therapy may reduce their incidence, although this strategy is not recommended in elderly patients. We aimed to compare the rates of IFX-related IAEs and loss of response [LOR] in elderly and younger patients., Methods: Adult patients in the ENEIDA registry who had received a first course of IFX therapy were identified and grouped into two cohorts regarding age at the beginning of treatment [over 60 years and between 18 and 50 years]. The rates of IAEs and LOR were compared., Results: In total, 939 patients [12%] who started IFX over 60 years of age and 6844 [88%] below 50 years of age were included. Elderly patients presented a higher proportion of AEs related to IFX [23.2% vs 19%; p = 0.002], infections [7.1% vs 4.3%; p < 0.001] and neoplasms [2.2% vs 0.5%; p < 0.001]. In contrast, the rates of IAEs [14.8% vs 14.8%; p = 0.999], infusion reactions [8.1% vs 8.1%; p = 0.989], late hypersensitivity [1.3% vs 1.2%; p = 0.895], paradoxical psoriasis [1% vs 1.5%; p = 0.187] and drug-induced lupus erythematosus [0.6% vs 0.7%; p = 0.947] were similar in elderly and younger patients. LOR rates were also similar between the two groups [20.5% vs 19.3%; p = 0.438]. In the logistic regression analysis, IFX monotherapy, extraintestinal manifestations and female gender were the only risk factors for IAEs, whereas IFX monotherapy, extraintestinal manifestations and Crohn's disease were risk factors for LOR., Conclusions: Elderly patients with inflammatory bowel disease have a similar risk of developing IFX-related IAEs and LOR to that of younger patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Studies to evaluate the use of mycophenolate mofetil (MMF) in inflammatory bowel disease (IBD) are limited after the appearance of biological treatments., Aims: Our primary objective was to evaluate the effectiveness and safety of MMF in IBD., Methods: IBD patients who had received MMF were retrieved from the ENEIDA registry. Clinical activity as per the Harvey-Bradshaw Index (HBI), partial Mayo score (pMS), physician global assessment (PGA) and C-reactive protein (CRP) were reviewed at baseline, at 3 and 6 months, and at final follow-up. Adverse events and causes of treatment discontinuation were documented., Results: A total of 83 patients were included (66 Crohn's disease, 17 ulcerative colitis), 90% of whom had previously received other immunosuppressants. In 61% of patients systemic steroids were used at initiation of MMF, and in 27.3% biological agents were co-administered with MMF. Overall clinical effectiveness was observed in 64.7% of the population. At the end of treatment, 45.6% and 19.1% of subjects showed remission and clinical response, respectively. MMF treatment was maintained for a median of 28.9 months (IQR: 20.4-37.5)., Conclusion: Our study suggests, in the largest cohort to date, that MMF may be an effective alternative to thiopurines and methotrexate in IBD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The coronavirus 2019 (COVID-19) pandemic is a clinical situation that could be used as prototype for implementation of new systems of care., Methods: This was a single-center, cross-sectional study. We evaluated the feasibility of a strategy based on the conversion of face-to-face visits to telephone consultations to manage IBD outpatients during the COVID-19 pandemic. A 4-item telephone survey (3 closed questions and a 100-point numeric description scale) was conducted to evaluate satisfaction of patients with telephone consultations., Results: Between March 11 and April 8, 2020, 98% of the 216 scheduled face-to-face visits could be converted to telephone consultations, and we resolved an additional 162 urgent consultations by telephone. The rate of IBD-related hospitalization and visits to the emergency department decreased by 50% and 58%, respectively, compared with rates in the same period the previous year. The 4-item survey was conducted in 171 outpatients. In closed questions, patients reported a very high degree of satisfaction with telephone consultations, with no differences between scheduled (n = 123) and urgent consultations (n = 48; P = NS). The overall satisfaction rating with the telephone consultation evaluated with the numerical description scale was 94% and 93% for scheduled and urgent consultations, respectively (P < 0.82). Less than 20% of patients would have preferred a face-to-face visit to the telephone consultation at the time., Conclusions: A strategy based on the conversion of face-to-face visits to telephone consultations was able to guarantee a minimum standard quality of care during the COVID-19 pandemic. Patients reported a very high degree of satisfaction with telephone consultations., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Although commonly used in inflammatory bowel disease [IBD], thiopurines frequently cause intolerance, and switching to a second thiopurine has only been reported in some small series. Ours aims in this study were to evaluate the safety of switching to a second thiopurine in a large cohort, and to assess the impact of age on tolerance., Methods: Adult IBD patients from the ENEIDA registry, who were switched to a second thiopurine due to adverse events [excluding malignancies and infections], were identified. At the beginning of thiopurine treatment, patients were divided by age into two groups: 18-50 and over 60 years of age. The rate and concordance of adverse events between the first and second thiopurines, treatment intolerance, and persistence with the second thiopurine were evaluated., Results: A total of 1278 patients [13% over 60 years of age] were switched to a second thiopurine. At 12 months, the cumulative probability of switch intolerance was 43%, and persistence with treatment was 49%. Independent risk factors of switch intolerance were age over 60 years (odds ratio [OR] 1.49; 95% confidence interval [CI] 1.07-2.07; p = 0.017) , previous gastrointestinal toxicity [OR 1.4; 95% CI 1.11-1.78; p = 0.005], previous acute pancreatitis [OR 6.78; 95% CI 2.55-18.05; p <0.001], and exposure to the first thiopurine <6 months [OR 1.59; 95% CI 1.14-2.23; p = 0.007]., Conclusions: In a large series in clinical practice, switching to a second thiopurine proved to be a valid strategy. Tight monitoring of elderly IBD patients switching to a second thiopurine because of adverse events is recommended., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Data on patients with inflammatory bowel diseases (IBD) who have had 2019 novel coronavirus (SARS-CoV-2) disease (COVID-19) are needed., Aims: To report the clinical characteristics, including gastrointestinal symptoms, of COVID-19 in IBD patients, and to assess the risk of COVID-19 in IBD., Methods: This case series included consecutive IBD patients with laboratory-confirmed COVID-19. Age-adjusted cumulative incidences were compared with the general population in the Madrid region., Results: Through April 8, 12 of 1918 IBD patients were diagnosed with COVID-19. The average age was 52 years, 75% of the patients were female and 58.3% had Crohn's disease. Seven patients (58%) were on maintenance treatment with immunomodulators/biologics, of these four with combined therapy (33%). Eight patients (66%) required hospitalisation (one intensive care unit admission, and two deaths), and four patients were isolated at home. Nine patients had diarrhoea ranging between 4 and 10 loose stools per day (mean 5.4, SD 1.6). In five patients (42%) diarrhoea was a presenting symptom. In two patients, diarrhoea was the only symptom at debut. Cumulative incidence of COVID-19 was 6.2 per 1000 IBD patients. IBD patients had a lower adjusted incidence ratio of COVID-19 (OR 0.74, 95% CI 0.70-0.77; P < 0.001), and a similar associated mortality ratio (OR 0.95, 95% CI: 0.84-1.06; P = 0.36), compared with the general population., Conclusions: IBD patients do not have an increased risk of COVID-19 and associated mortality compared with the general population. In many IBD patients, diarrhoea was a presenting symptom, and sometimes, was the only symptom at onset of COVID-19., (© 2020 John Wiley & Sons Ltd.)

Background: Interstitial lung [ILD] disease and granulomatous lung disease [GLD] are rare respiratory disorders that have been associated with inflammatory bowel disease [IBD]. Clinical presentation is polymorphic and aetiology is unclear., Methods: This was an ECCO-CONFER project. Cases of concomitant ILD or GLD and IBD, or drug-induced ILD/GLD, were collected. The criteria for diagnosing ILD and GLD were based on definitions from the American Thoracic Society and the European Respiratory Society and on the discretion of reporting clinician., Results: We identified 31 patients with ILD. The majority had ulcerative colitis [UC] [n = 22]. Drug-related ILD was found in 64% of these patients, 25 patients [80.6%] required hospitalisation, and one required non-invasive ventilation. The causative drug was stopped in all drug-related ILD, and 87% of patients received systemic steroids. At follow-up, 16% of patients had no respiratory symptoms, 16% had partial improvement, 55% had ongoing symptoms, and there were no data in 13%. One patient was referred for lung transplantation, and one death from lung fibrosis was reported. We also identified 22 GLD patients: most had Crohn's disease [CD] [n = 17]. Drug-related GLD was found in 36% of patients and 10 patients [45.4%] required hospitalisation. The causative drug was stopped in all drug-related GLD, and 81% of patients received systemic steroids. Remission of both conditions was achieved in almost all patients., Conclusions: ILD and GLD, although rare, can cause significant morbidity. In our series, over half of cases were drug-related and therefore focused pharmacovigilance is needed to identify and manage these cases., (© Crown copyright 2019.)

Background: Tacrolimus is a calcineurin inhibitor commonly used for prophylaxis of rejection in renal and liver transplantation. There are limited but favourable data regarding its possible use in patients with inflammatory bowel disease (IBD)., Aims: To evaluate the efficacy and safety of tacrolimus in patients with IBD in clinical practice., Methods: We performed a retrospective, multicentre study in 22 centres in Spain. All adult patients who received oral tacrolimus for luminal or perianal IBD were included. Clinical response was assessed by Harvey-Bradshaw index and partial Mayo score after 3 months. Perianal disease was evaluated by fistula drainage assessment., Results: One hundred and forty-three patients were included (mean age 38 years; 51% male; median disease duration 110 months). In ulcerative colitis (UC) (n = 58), the partial Mayo score decreased after 3 months from median 6 to 3 (P = 0.0001), whereas in Crohn's disease (CD) (n = 85), the Harvey-Bradshaw index decreased after 3 months from median 9 to 7 (P = 0.011). In CD patients, blood tacrolimus concentrations during induction (>10 ng/mL vs <10 ng/mL; odds ratio 0.23, 95% CI 0.05-0.87) and the concomitant use of thiopurines (odds ratio 0.18, 95% CI 0.04-0.81) were associated with lower clinical disease activity at 3 months. Of 62 patients with perianal disease, complete closure was observed in 8% (n = 5) of patients with perianal fistulas, with 34% (n = 21) showing partial response. Treatment was maintained for a median of 6 months (IQR, 2-16). After a median clinical follow-up of 24 months (IQR, 15-57), the rate of treatment-related adverse events was 34%, correlating with blood drug concentrations (P = 0.021). Finally, 120 patients (84%) discontinued tacrolimus, usually due to absence or loss of response. Three patients (2%) were subsequently diagnosed with cancer. The overall rate of surgery was 39%, with a 33% colectomy rate in UC., Conclusions: Tacrolimus shows a clinical benefit in both CD and UC after 3 months of treatment, but its long-term effectiveness and frequent adverse events remain relevant issues in clinical practice., (© 2020 John Wiley & Sons Ltd.)

Background and Aims: Primary sclerosing cholangitis [PSC] is usually associated with inflammatory bowel disease [IBD]. An increased risk of malignancies, mainly colorectal cancer [CRC] and cholangiocarcinoma [CCA], has been reported in PSC-IBD patients. Our aim was to determine the clinical characteristics and management of PSC in IBD patients, and the factors associated with malignancies., Methods: PSC-IBD patients were identified from the Spanish ENEIDA registry of GETECCU. Additional data were collected using the AEG-REDCap electronic data capture tool., Results: In total, 277 PSC-IBD patients were included, with an incidence rate of 61 PSC cases per 100 000 IBD patient-years, 69.7% men, 67.5% ulcerative colitis and mean age at PSC diagnosis of 40 ± 16 years. Most patients [85.2%] were treated with ursodeoxycholic acid. Liver transplantation was required in 35 patients [12.6%] after 79 months (interquartile range [IQR] 50-139). It was more common in intra- and extrahepatic PSC compared with small-duct PSC (16.3% vs 3.3%; odds ratio [OR] 5.7: 95% confidence interval [CI] = 1.7-19.3). The incidence rate of CRC since PSC diagnosis was 3.3 cases per 1000 patient-years [95% CI = 1.9-5.6]. Having symptoms of PSC at PSC diagnosis was the only factor related to an increased risk of CRC after IBD diagnosis [hazard ratio= 3.3: 95% CI = 1.1-9.9]. CCA was detected in seven patients [2.5%] with intra- and extrahepatic PSC, with median age of 42 years [IQR 39-53], and presented a lower life expectancy compared with patients without CCA and patients with or without CRC., Conclusions: PSC-IBD patients with symptoms of PSC at PSC diagnosis have an increased risk of CRC. CCA was only diagnosed in patients with intra- and extrahepatic PSC and was associated with poor survival., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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 started 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., (© 2019 John Wiley & Sons Ltd.)

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 of age and the adulthood-onset cohort those 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., (© 2019 John Wiley & Sons Ltd.)

Aim: To assess the likelihood of detecting latent tuberculosis infection [LTBI] by the positive conversion of a serial tuberculin skin test [TST] at 1 year in inflammatory bowel disease [IBD] patients with negative baseline two-step TST., Methods: In this multicentre prospective cohort study, we evaluated rate and predictors of conversion of TST at 1 year in patients with negative baseline TST. We also evaluated management of patients who had a positive TST at baseline or a conversion at 1 year. In all patients we assessed TB cases occurring during follow-up., Results: Of the 192 IBD patients receiving anti-tumour necrosis factor [TNF] and 220 IBD controls not receiving anti-TNF, 35 [8.5%, 95% CI 5.7-11.3] had positive conversion (median TST induration 13 mm, interquartile range [IQR] 9-16). Ten anti-TNF cohort patients [5.2%, 95% CI 2.5-9.5] versus 25 controls [11.4%, 95% CI 7.5-16.3] had TST conversion [p = 0.029]. In multivariate analysis, conversion was associated with smoking habit (odds ratio [OR] 2.19, 95% CI 1.08-3.97; p = 0.028). Anti-TNF-treated patients had a lower conversion rate [OR 0.41, 95% CI 0.20-0.83; p = 0.013]. The likelihood of conversion correlates with fewer immunosuppressive therapies between baseline TST and TST at 1 year [p = 0.042]. One case of active TB [isoniazid-resistant strain] occurred in a patient with positive baseline TST receiving anti-TNF [0.05 events/100 patient-years]., Conclusions: Serial TST at 1 year can detect LTBI in IBD patients receiving anti-TNF therapy with negative baseline TST. Serial TST seems to be advisable to reduce the risk of TB cases associated with inability to detect LTBI in pre-treatment screening.

Background: Effectiveness of vedolizumab in real world clinical practice is unknown., Aim: To evaluate the short and long-term effectiveness of vedolizumab in patients with inflammatory bowel disease (IBD)., Methods: Patients who received at least 1 induction dose of vedolizumab were included. Effectiveness was defined based on Harvey-Bradshaw index (HBI) in Crohn's disease (CD) and Partial Mayo Score (PMS) in ulcerative colitis (UC). Short-term response was assessed at week 14. Variables associated with short-term remission were identified by logistic regression analysis. The Kaplan-Meier method was used to evaluate the long-term durability of vedolizumab treatment. Cox model was used to identify factors associated with discontinuation of treatment and loss of response., Results: 521 patients were included (median follow-up 10 months [interquartile range 5-18 months]). At week 14, 46.8% had remission and 15.7% clinical response. CD (vs UC), previous surgery, higher CRP concentration and disease severity at baseline were significantly associated with impaired response. The rate of vedolizumab discontinuation was 37% per patient-year of follow-up (27.6% in UC and 45.3% in CD, P < 0.01). CD (vs UC), anaemia at baseline, steroids during induction and CRP concentration were associated with lower durability of treatment. Seven per cent of patients developed adverse events, infections being the most frequent., Conclusions: Over 60% of IBD patients respond to vedolizumab. Many patients discontinue treatment over time. CD and disease burden impair both short- and long-term response. Vedolizumab seems to be safe in clinical practice., (© 2018 John Wiley & Sons Ltd.)

Objectives: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs in utero with that of children who were not exposed to the drugs., Methods: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox-regression analysis was performed to identify potential predictive factors for severe infections in the offspring., Results: The study population comprised 841 children, of whom 388 (46%) had been exposed to anti-TNFα agents. Median follow-up after delivery was 47 months in the exposed group and 68 months in the non-exposed group. Both univariate and multivariate analysis showed the incidence rate of severe infections to be similar in non-exposed and exposed children (1.6% vs. 2.8% per person-year, hazard ratio 1.2 (95% confidence interval 0.8-1.8)). In the multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (2.5% (1.5-4.3))., Conclusions: In utero exposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

Introduction: Primary eosinophilic colitis (EC) in adults is a rare and poorly studied disease, with 3 case series, 2 database-based studies and 52 case reports published to date., Methods: Retrospective study of all adult EC cases diagnosed in a large tertiary hospital (Hospital Clínico San Carlos, Madrid) between 2006 and 2016. We included all cases with a histopathological diagnosis of EC and we selected only those cases that were clinically recognized primary EC. We report their clinical, endoscopic and histopathological features and review the literature on this topic., Results: We identified 22 primary EC cases. Patients were mostly women (77%) with a mean age of 41 years. 4 patients (18%) had coexistent allergic diseases. Most patients consulted with diarrhea (86%) and 3 patients also suffered from rectal bleeding. Blood tests showed peripheral eosinophilia in 4 cases (18%). 19 patients had no endoscopic lesions, 2 had features of unspecific colitis and one showed features suggestive of IBD. Mean and maximum number of eosinophils per high power field ranged from 16 to 199 and 20 to 253 (mean: 48 and 70). They were mainly located in the lamina propria and most cases were associated with signs of eosinophil activation. Most patients were treated by corticosteroids, diet or budesonide and the result of treatment was generally good. No complications or recurrences were reported., Conclusions: EC etiology and pathogenesis is unknown. Its clinical, endoscopical and imaging features are not specific, and clear histopathological criteria are lacking. Identification of signs of eosinophilic activation could be helpful., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Background and Aim: Sensitivity of tuberculin skin test [TST] during screening for latent tuberculosis infection [LTBI] is affected by steroid and/or immunosuppressant therapy. The aim of this study was to compare performance of the two-step TST in inflammatory bowel disease patients immediately before anti-tumour necrosis factor [TNF] therapy as part of routine screening for LTBI vs control patients when the TST was carried out at an early stage., Methods: In this multicentre prospective controlled study, we evaluated the performance of two-step TST with 5-mm threshold. Factors associated with TST results were determined by logistic regression., Results: We evaluated 243 candidates for anti-TNF therapy and 337 control patients. Overall, 105 patients [18.1%] had an induration ≥ 5 mm in the first TST or in TST retest. LTBI was diagnosed in 25% of patients by TST retest. Twenty-eight [11.5%] anti-TNF group patients vs 77 [22.8%] control patients had a positive TST (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.28-0.70; P < 0.001]. In multivariate analysis, positive TST was associated with higher age [OR 2.63, 95% CI 1.21-5.72; P < 0.001] and 5-aminosalicylate therapy [OR 1.86, 95% CI 1.14-3.05; P = 0.013]. Negative TST was associated with steroid therapy [OR 0.36, 95% CI 0.16-0.83; P = 0.016], immunosuppressant therapy [OR 0.36, 95% CI 0.21-0.62; P < 0.001], or steroids + immunosuppressant therapy [OR 0.20, 95% CI 0.07-0.59; P = 0.004]., Conclusions: The sensitivity of routine TST performed just before starting anti-TNF therapy is low. TST performed at an early stage enables screening in the absence of immunosuppressive treatment and thus maximises the diagnostic yield of TST for detecting LTBI., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background and Aims: Patients with inflammatory bowel disease [IBD] are at increased risk for developing some types of neoplasia. Our aims were to determin the risk for cancer in patients with IBD and to describe the relationship with immunosuppressive therapies and clinical management after tumor diagnosis., Methods: Retrospective, multicenter, observational, 5-year follow-up, cohort study. Relative risk [RR] of cancer in the IBD cohort and the background population, therapeutic strategies, and cancer evolution were analyzed., Results: A total of 145 cancers were diagnosed in 133 of 9100 patients with IBD (global cumulative incidence 1.6% vs 2.4% in local population; RR = 0.67; 95% confidence interval [CI]: 0.57-0.78). Patients with IBD had a significantly increased RR of non-melanoma skin cancer [RR = 3.85; 2.53-5.80] and small bowel cancer [RR = 3.70; 1.23-11.13]. After cancer diagnosis, IBD treatment was maintained in 13 of 27 [48.1%] patients on thiopurines, in 2 of 3 on methotrexate [66.6%], none on anti-TNF-α monotherapy [n = 6] and 4 of 12 [33.3%] patients on combined therapy. Rate of death and cancer remission during follow-up did not differ [p > 0.05] between patients who maintained the treatment compared with patients who withdrew [5% vs 8% and 95% vs 74%, respectively]. An association between thiopurines [p = 0.20] or anti-TNF-α drugs [p = 0.77] and cancer was not found., Conclusions: Patients with IBD have an increased risk for non-melanoma skin cancer and small bowel cancer. Immunosuppresive therapy is not related to a higher overall risk for cancer or worse tumor evolution in patients who maintain these drugs after cancer diagnosis., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Tuberculosis reactivation can lead to severe complications in patients treated with anti-tumour necrosis factor-alpha., Aim: To assess the usefulness of repeat tuberculosis screening tests in inflammatory bowel disease patients on stable anti-TNF therapy., Methods: Cross-sectional study, in patients on prolonged anti-TNF treatment (≥ 12 months) and basal negative screening for latent tuberculosis. Quantiferon(®)-TB Gold In-tube test was performed and then, tuberculin skin test was administered., Results: 74 patients were included, median duration of anti-TNF treatment was 30 months (IQR 19-54); 47 patients on infliximab and 27 on adalimumab; no patient was on glucocorticoids. Previous BCG vaccination was present in 5 cases. After anti-TNF was started, 4 patients suffered from potential tuberculosis exposure and two cases travelled to endemic areas. The cumulative incidence of tuberculin skin test conversion was 2.7% (95% CI 0.3-9.4%, 2/74), and the incidence rate of tuberculin skin test conversion was 0.83% (95% CI 0.1-2.9%) per patient-year of treatment with anti-TNF drugs. All Quantiferon tests but one (a patient with an indeterminate result and a negative tuberculin skin test) were negative., Conclusions: The incidence rate of conversion of tuberculosis screening tests among patients on anti-TNF treatment seems to be low and these conversions were diagnosed based on a positive tuberculin skin test and were discordant with Quantiferon testing., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: The safety of thiopurines and anti-tumor necrosis factor-α (TNF-α) 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-α 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-α 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-α drugs was not associated with an unfavorable GPO., Conclusion: The treatment with thiopurines and anti-TNF-α drugs does not seem to increase the risk of complications during pregnancy and does seem to be safe for the newborn.

Background: Methotrexate is useful in inflammatory bowel disease (IBD), but its role is secondary because of its limited experience and a supposedly unfavorable safety profile., Aim: To describe the efficacy and safety of methotrexate in a long-term real clinical practice., Methods: Retrospectively reviewed records of IBD patients treated with methotrexate in eight hospitals of Madrid (Spain)., Results: A total of 77 patients were included (80% Crohn's disease); 94% received methotrexate because of steroid dependency. Overall, 82% of the patients initially responded (28% remission). Eighty-eight percent of the patients followed maintenance treatment for a mean of 17 (range: 1-108) months. Forty percent of the patients lost response at a mean of 57 weeks after starting methotrexate. No statistically significant differences were found in the response rates in terms of the disease type, route of administration, or the Montreal Classification category. The mean methotrexate cumulative dose was 1108 mg (range: 25-6480). The main adverse events included 10 cases of gastrointestinal symptoms, four of myelotoxicity, and 10 of abnormal liver function tests, and led to methotrexate withdrawal in four (5%) patients. Transient elastography, performed in 46 patients, detected six additional cases with significant fibrosis and normal liver function tests., Conclusion: Methotrexate is useful in inducing a response in IBD, although its efficacy decreases frequently through the follow-up. Although methotrexate seems safe in the long term, in addition to biochemical controls, a more accurate method to detect liver damage should be considered.

Aim: Anti-tumor necrosis factor (TNF)-alpha agents are widely used for the treatment of both inflammatory bowel disease (IBD) and psoriasis. Psoriatic skin lesions induced by anti-TNF have been described in patients with IBD. We report a case series of psoriasis induced by anti-TNF agents in IBD patients., Methods: Systematic analysis of cases of psoriasis induced by anti-TNF in an IBD patient cohort in tertiary hospitals of Madrid., Results: A total of 21 of 1294 patients with IBD treated with anti-TNF-alpha agents developed drug-induced psoriasis (cumulative incidence 1.62%; 95% CI 1.06%-2.47%): 14 patients with infliximab and 7 with adalimumab; seventeen with Crohn's disease, 4 with ulcerative colitis. The onset of skin lesions varied in a wide range of time (after a mean 13±8 doses). The most frequent site of skin lesions was the limbs (62%) followed by the trunk (48%) and the scalp (43%). The psoriasis phenotypes were plaque psoriasis (57%), scalp (14%), palmoplantar pustulosis (14%), pustular generalized psoriasis (5%), guttate (5%) and inverse (5%). Four patients interrupted the anti-TNF treatment, and that led to the complete regression of lesions in 1 of them. The other 17 patients were maintained on anti-TNF therapy and managed with topical steroids., Conclusion: Psoriatic lesions can be induced by anti-TNF drugs. Plaque psoriasis on the extremities and trunk were the most frequent presentations in our series. Topical steroid treatment is effective in most patients. Anti-TNF discontinuance may be reserved for patients with severe psoriasis or patients without response to topical therapy., (Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Objectives: Immunomodulators are used as maintenance treatment of inflammatory bowel disease (IBD). Data regarding their possible effects in the course of pregnancy when the father is exposed at the time of conception are limited., Methods: To evaluate the outcomes of pregnancies of which the fathers were exposed to thiopurines at the time of conception. A series of male patients followed in seven IBD clinics in Madrid, Spain, was studied. Any exposure to thiopurines during the 3 months preceding conception was considered significant. Controls were pregnancies fathered by patients who either had never been treated with thiopurines or had interrupted them >3 months before conception. Statistical comparisons and multivariate analysis were carried out with the generalized estimating equations model., Results: There were 46 conceptions in the exposed group (mercaptopurine 9, azathioprine 37) and 84 in the control group. In the exposed group, there were more Crohn's patients (82.6% vs. 53.6%), the duration of the disease was longer (median: 8 vs. 5 years), fathers were slightly older (mean: 34.2 vs. 32.7 years), and there were fewer patients on mesalamine (15.2% vs. 47.6%). Otherwise, baseline characteristics were similar in both groups. There were no significant differences regarding unsuccessful pregnancies-namely, spontaneous abortions, ectopic pregnancies, anembryonic pregnancies, or fetal deaths (10.9% exposed group vs. 13.1% control group; odds ratio (OR): 0.79, confidence interval (CI): 0.22-2.85), preterm births (4.3% vs. 2.4%; OR: 1.3, CI: 0.22-7.61), low birth weight (6.5% vs. 6%; OR: 1.06, CI: 0.25-4.54), or congenital malformations (2.2% vs. 2.4%; OR: 0.82, CI: 0.08-9). No infant neoplasms were detected. The proportion of conceptions that needed >1 year to be achieved was higher in the exposed group, but this was not statistically significant (15.2% vs. 8.3%; OR: 1.92, CI: 0.54-6.88). Multivariate analysis was carried out for unsuccessful pregnancies and fertility impairment, and it showed that, although mesalamine exposure confounded the effect of the exposure to thiopurines on these outcomes, this effect was still nonsignificant (respectively, OR: 0.49, CI: 0.17-1.44; OR: 2.82, CI: 0.7-11.38)., Conclusions: Our data do not support the practice of routinely recommending to male patients that they interrupt thiopurines when wanting to conceive.

Background: Thr300Ala polymorphism in ATG16L1 was reported as a susceptibility factor to Crohn's disease (CD). Inconsistently replicated associations with ulcerative colitis (UC) and specifically with ileal CD were also reported. Our aims were: to replicate the ATG16L1 Thr300Ala association with inflammatory bowel disease (IBD) in the Spanish population, to perform a meta-analysis to determine the risk conferred to the different IBD subgroups, and to test for the interaction with CARD15 or IL23R risk loci., Methods: Thr300Ala (rs2241880) single nucleotide polymorphism (SNP) was genotyped in 712 IBD patients and 745 controls by TaqMan technology. Genetic frequencies were compared with chi-square tests. Our findings were pooled in a meta-analysis., Results: In Spain, we observed an association of rs2241880 with CD (P = 0.008; odds ratio [OR, 95% confidence interval, CI] = 1.28 [1.06-1.54]), but not with UC. No significant differences emerged when patients were stratified by clinical features. Similarly, the meta-analysis demonstrated a significant association only with CD (P < 10(-4); OR [95% CI] = 1.33 [1.28-1.38]). A significant difference between ileal CD patients and controls was observed, but heterogeneity was found in comparisons involving colonic CD patients and definite conclusions cannot be drawn. No interaction between rs2241880 and the established CARD15 or IL23R susceptibility variants was observed., Conclusions: The Thr300Ala polymorphism is associated with CD, regardless of the CARD15 or IL23R status, but not with UC. Stratification by clinical phenotypes did not show definitive results because of the existing heterogeneity among studies.

Background: Pancreatitis is a potentially severe condition. Patients with inflammatory bowel disease (IBD) seem to be at increased risk for acute pancreatitis., Aim: To describe the incidence, main causes and possible predictive factors of acute pancreatitis in inflammatory bowel disease., Methods: Information was retrospectively extracted from the clinical records of patients followed in the IBD Units of nine hospitals in Madrid (n = 5073)., Results: A total of 82 acute pancreatitis episodes were diagnosed (cumulative incidence, 1.6%); 98% of them were mild. Recurrent acute pancreatitis developed in 13% of patients. Most cases of acute pancreatitis (63.4%) were attributed to drug exposure [azathioprine/mercaptopurine (AZA/MP) n = 46, mesalazine (mesalamine) n = 6]; 20.7% were idiopathic, and 12.2% were biliary. Incidence of acute pancreatitis in patients treated with AZA/MP was 3.1%. In patients with acute pancreatitis, female gender (OR 3.4 95% CI: 1.3-9.3; P = 0.012) and Crohn's disease (CD) (OR 5.8 95% CI: 1.6-20.6; P = 0.007) were risk factors for AZA/MP-associated acute pancreatitis, the latter also when analysed only in patients treated with AZA/MP (n = 1477) (OR 5.2 95% CI: 1.8-14; P = 0.002)., Conclusions: The incidence of acute pancreatitis in our IBD patients (1.6%) is similar to that previously described. Drugs, mainly AZA/MP, are the leading cause. AZA-induced acute pancreatitis is always mild. Patients with CD are at a higher risk for AZA/MP-associated acute pancreatitis. The frequency of idiopathic acute pancreatitis is higher than expected, suggesting that part of these cases could be extraintestinal manifestations of IBD.

Background: The pregnane X receptor gene (PXR/NR1I2) has been recently associated with an increased risk for inflammatory bowel disease (IBD), although a subsequent case-control study failed to replicate the original association in an independent population. This nuclear receptor regulates genes involved in the detoxification process in the liver and intestine, like ABCB1/MDR1. PXR expression was significantly reduced in the colon of patients with ulcerative colitis (UC), but remained unaffected in Crohn's disease (CD) patients. Considering previous results, we aimed at investigating the impact of this locus on IBD predisposition in the Spanish population., Methods: Three PXR polymorphisms, including the 1 more strongly correlated with IBD risk in the initial study at -25385C/T (rs3814055) and the 6 haplotypes conformed by them, were analyzed in 365 UC and 331 CD patients and compared with 550 ethnically matched controls., Results: The overall haplotypic distribution showed a significant difference between UC and CD patients (P = 0.05; chi(2) = 10.84). Among UC patients a significant difference was seen between those with extensive colitis and controls (P = 0.004; chi(2) = 17.04), mainly due to the presence of a risk haplotype (rs3814055*T//rs6784598*C//rs2276707*C: P = 0.001; odds ratio [OR] = 1.66, 95% confidence interval [CI] 1.20-2.30). Patients with extensive UC carrying the -25385T allele showed increased susceptibility compared with left-sided colitis patients and with healthy subjects. In patients with extensive UC a significantly different distribution of genotypes of the MDR1 G/A change located in intron 3 (rs3789243) was observed between carriers/noncarriers of the -25385T risk allele (P = 0.005)., Conclusions: Our data seem to support the association of the PXR locus with extensive UC and the interaction between PXR and MDR1 genes.

The great amount of nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS) exerts deleterious effects, and iNOS expression is raised in the colonic mucosa of inflammatory bowel disease (IBD) patients. This is the first association analysis of polymorphisms within the NOS2A extended gene with IBD susceptibility. We analyzed 336 patients of Crohn's disease (CD), 355 of ulcerative colitis (UC), and 536 healthy controls from a Spanish population. We tested a (CCTTT)n microsatellite, a (-/TAAA) insertion, and two single nucleotide polymorphisms (SNPs) flanking them (rs2779251 and rs2779248) in the NOS2A promoter, together with two SNPs in the coding region: one within exon 10, D385D (rs1137933), and another mapping to exon 16, S608L (rs2297518). Analysis of these markers evidenced differences among IBD patients and healthy controls. Allele (CCTTT) 13 is related to higher UC risk (p = 0.001; odds ratio [OR] [95% confidence interval, CI] = 1.64 [1.20-2.23]). Carriers of minor alleles of the two promoter SNPs analyzed showed an association with UC predisposition, and common allele homozygotes of the two exonic SNPs were more frequent among CD patients than among controls. Concordantly, one out of the three haplotypes carrying both exonic risk alleles was found to increase CD susceptibility (p = 0.007; OR [95%CI] = 1.74 [1.13-2.67]). Therefore, the NOS2A gene seems to be involved in IBD aetiology.

Inflammatory bowel disease (IBD), which comprises ulcerative colitis (UC) and Crohn's disease (CD), shows a multifactorial origin, with genetic and environmental factors involved. Although the genetic influence is clear for both diseases, the genetics involved is complex and epistatic interactions with other genes probably exist. The Fc receptor-like 3 gene (FCRL3) maps to the human chromosome 1q21-22 and certain single nucleotide polymorphisms (SNPs) in its promoter have been associated with some autoimmune diseases. Our aim was to study the role of two promoter SNPs of the FCRL3 gene (-169A>G, rs7528684 and -110C>T, rs11264799) in patients with IBD and their interaction with HLA-DRB1 and CARD15 in patients with UC and CD, respectively. A case-control study with 311 patients with CD, 324 patients with UC and 497 healthy controls was performed. All the individuals were White Spaniards. No significant associations were found between any FCRL3 SNP and CD or UC, but the stratification in patients with UC by human leukocyte antigen (HLA) showed a significant increase in heterozygosity at the FCRL3 locus, especially -169 AG (AG vs AA+GG, P= 0.0027, odds ratio = 3.6, 95% confidence interval 1.4-2.9), when HLA-DRB1*0103 carrier patients were compared with HLA-DRB1*0103 noncarriers. Our data suggest an epistatic interaction between genes in chromosomes 6p21 and 1q21-22, marked, respectively, by HLA-DRB1*0103 and FCRL3-169 AG.

Background The long-term efficacy of adalimumab in patients with ulcerative colitis is not well known. Aim To evaluate the short- and long-term outcomes of adalimumab in ulcerative colitis patients previously treated with infliximab. Methods Patients with active ulcerative colitis were treated with adalimumab after failure of other therapies including infliximab. Short-term clinical response and remission were assessed at weeks 4 and 12. The proportion of patients who continued on adalimumab and the proportion of patients who remained colectomy free were assessed over the long term. Results Clinical response at weeks 4 and 12 was achieved in 16 (53%) and 18 (60%) patients, respectively, and clinical remission was obtained in 3 (10%) and 8 (27%) patients, respectively. After a mean 48 weeks' follow-up, 15 patients (50%) continued on adalimumab. Six patients (20%) required colectomy. All patients who achieved clinical response at week 12 were colectomy free at long term. Conclusions Adalimumab was well tolerated and induced durable clinical response in many patients with otherwise medically refractory ulcerative colitis. Patients achieving clinical response at week 12 avoided colectomy over the long term. [ABSTRACT FROM AUTHOR]

Genome-wide studies highlighted the effect in Crohn's disease (CD) and ulcerative colitis (UC) susceptibility of single nucleotide polymorphisms (SNPs) in 3p21, where BSN (bassoon), MST1 (macrophage stimulating-1) and MST1R (MST1 Receptor) genes map. MST1R expression was significantly downregulated in multiple sclerosis (MS) compared with control brains, resembling findings in the MS mouse model. We pursued to replicate the effect of this locus on inflammatory bowel diseases and to evaluate its contribution to MS risk. Polymorphisms rs9858542, rs2131109 and rs1128535 were analysed by TaqMan assays in Spanish patients (370 CD, 405 UC and 415 MS) and 800 ethnically matched controls. Allele frequencies of these SNPs were significantly different in CD patients compared with controls [rs9858542: P=0.001, Odds ratio (OR)=1.35; rs2131109: P=0.0005, OR=1.37; rs1128535: P=0.007, OR=0.78] and, specifically, in the ileal phenotype [rs9858542: P=0.0004, OR=1.47; rs2131109: P=0.00009, OR=1.52; rs1128535: P=0.02, OR=0.69]. No differences were detected between UC or MS patients and control individuals. The effect of this locus on CD predisposition was replicated, but no influence on UC or MS predisposition could be detected. This susceptibility locus seems to affect mainly to the ileal CD subphenotype, although this point awaits further corroboration in independent cohorts. [ABSTRACT FROM AUTHOR]

To evaluate the cost-effectiveness of tofacitinib for the treatment of moderate-to-severe ulcerative colitis (UC) after conventional therapy (mesalazine, corticosteroids or thiopurines) failure or intolerance, from the Spanish National Health System (NHS) perspective. According to our results, lifetime QALY gains appear to be similar for all three comparisons while tofacitinib is the most cost-saving therapy for treating moderate-to-severe UC in biologic-naïve patients after conventional therapy failure or intolerance, from the Spanish NHS perspective. [Extracted from the article]

To evaluate the cost-effectiveness of tofacitinib for the treatment of moderate-to-severe active ulcerative colitis (UC) after failure or intolerance to a first line of biologic treatment, from the Spanish National Health System perspective. Compared to adalimumab, tofacitinib generates small QALY gains (0.09) and presents slight incremental costs (€961.68), mostly due to a lower efficacy of adalimumab (NMA) that would cause an increased treatment discontinuation and thereby reduce pharmaceutical costs. According to the analysis results, after failure or intolerance to biologic therapy, tofacitinib is a cost-saving therapy for the treatment of bio-experienced moderate-to-severe UC patients with similar QALY gains vs infliximab and vedolizumab. [Extracted from the article]