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Background: Ulcerative proctitis (UP) can have a milder, less aggressive course than left-sided colitis or extensive colitis. Therefore, immunosuppressants tend to be used less in patients with this condition. Evidence, however, is scarce because these patients are excluded from randomised controlled clinical trials. Our aim was to describe the characteristics of patients with refractory UP and their disease-related complications, and to identify the need for immunosuppressive therapies., Methods: We identified patients with UP from the prospective ENEIDA registry sponsored by the GETECCU. We evaluated socio-demographic data and complications associated with immunosuppression. We defined immunosuppression as the use of immunomodulators, biologics and/or small molecules. We used logistic regression to identify factors associated with immunosuppressive therapy., Results: From a total of 34,716 patients with ulcerative colitis, we identified 6281 (18.1%) with UP; mean ± SD age 53 ± 15 years, average disease duration of 12 ± 9 years. Immunosuppression was prescribed in 11% of patients, 4.2% needed one biologic agent and 1% needed two; 2% of patients required hospitalisation, and 0.5% underwent panproctocolectomy or subtotal colectomy. We identified 0.2% colorectal tumours and 5% extracolonic tumours. Patients with polyarthritis (OR 3.56, 95% CI 1.86-6.69; p < 0.001) required immunosuppressants., Conclusions: Among patients with refractory UP, 11% required immunosuppressant therapy, and 4.2% required at least one biologic agent., (© 2024 John Wiley & Sons Ltd.)

Background: Ustekinumab is approved for ulcerative colitis (UC)., Aims: To assess the durability of ustekinumab in patients with UC and its short-term effectiveness, durability and tolerability in clinical practice., Methods: Retrospective, multicentre study of patients who had received their first ustekinumab dose at least 16 weeks before inclusion. Patients were followed until treatment discontinuation or last visit. Only patients with active disease at the start of ustekinumab treatment were considered in the effectiveness analysis. Patients who stopped ustekinumab before their last visit were considered not to be in subsequent remission., Results: We included 620 patients; 155 (25%) discontinued ustekinumab during follow-up (median 12 months). Rate of discontinuation was 20% per patient-year of follow-up. Anaemia at baseline (hazard ratio, HR 1.5; 95% confidence interval [CI] 1.1-2.1), steroids at baseline (HR 1.5; 95% CI 1.06-2.08) and more severe clinical activity at baseline (HR 1.5; 95% CI 1.09-2.06) were associated with higher risk of discontinuation. At the end of induction, 226 (40%) patients were in steroid-free clinical remission. Moderate-severe vs mild disease activity at baseline (odds ratio [OR] 0.3; 95% CI 0.2-0.5), male sex (OR 0.5; 95% CI 0.4-0.8), and increased number of previous biologics (OR 0.6; 95% CI 0.6-0.8) were associated with lower likelihood of steroid-free clinical remission at week 16. One hundred and seventy-six patients (28%) had at least one adverse event. We observed no negative impact of ustekinumab on extraintestinal manifestations and/or immune-mediated diseases., Conclusions: Ustekinumab durability in UC was relatively high, and treatment was effective in highly refractory patients. The safety profile was consistent with previous studies., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims: Inflammatory bowel disease (IBD) is a prevalent chronic noncurable disease associated with profound metabolic changes. The discovery of novel molecular indicators for unraveling IBD etiopathogenesis and the diagnosis and prognosis of IBD is therefore pivotal. We sought to determine the distinctive metabolic signatures from the different IBD subgroups before treatment initiation., Methods: Serum and urine samples from newly diagnosed treatment-naïve IBD patients and age and sex-matched healthy control (HC) individuals were investigated using proton nuclear magnetic resonance spectroscopy. Metabolic differences were identified based on univariate and multivariate statistical analyses., Results: A total of 137 Crohn's disease patients, 202 ulcerative colitis patients, and 338 HC individuals were included. In the IBD cohort, several distinguishable metabolites were detected within each subgroup comparison. Most of the differences revealed alterations in energy and amino acid metabolism in IBD patients, with an increased demand of the body for energy mainly through the ketone bodies. As compared with HC individuals, differences in metabolites were more marked and numerous in Crohn's disease than in ulcerative colitis patients, and in serum than in urine. In addition, clustering analysis revealed 3 distinct patient profiles with notable differences among them based on the analysis of their clinical, anthropometric, and metabolomic variables. However, relevant phenotypical differences were not found among these 3 clusters., Conclusions: This study highlights the molecular alterations present within the different subgroups of newly diagnosed treatment-naïve IBD patients. The metabolomic profile of these patients may provide further understanding of pathogenic mechanisms of IBD subgroups. Serum metabotype seemed to be especially sensitive to the onset of IBD., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The objective of this study was to assess the durability, short-term and long-term effectiveness, and safety of tofacitinib in ulcerative colitis (UC) in clinical practice., Methods: This is a retrospective multicenter study including patients with UC who had received the first tofacitinib dose at least 8 weeks before the inclusion. Clinical effectiveness was based on partial Mayo score., Results: A total of 408 patients were included. Of them, 184 (45%) withdrew tofacitinib during follow-up (mean = 18 months). The probability of maintaining tofacitinib was 67% at 6 m, 58% at 12 m, and 49% at 24 m. The main reason for tofacitinib withdrawal was primary nonresponse (44%). Older age at the start of tofacitinib and a higher severity of clinical activity were associated with tofacitinib withdrawal. The proportion of patients in remission was 38% at week 4, 45% at week 8, and 47% at week 16. Having moderate-to-severe vs mild disease activity at baseline and older age at tofacitinib start were associated with a lower and higher likelihood of remission at week 8, respectively. Of 171 patients in remission at week 8, 83 (49%) relapsed. The probability of maintaining response was 66% at 6 m and 54% at 12 m. There were 93 adverse events related to tofacitinib treatment (including 2 pulmonary thromboembolisms [in patients with risk factors] and 2 peripheral vascular thrombosis), and 29 led to tofacitinib discontinuation., Discussion: Tofacitinib is effective in both short-term and long-term in patients with UC. The safety profile is similar to that previously reported., (Copyright © 2023 by The American College of Gastroenterology.)

Background: Optimal golimumab concentration thresholds for important outcomes during maintenance are lacking., Aims: To investigate the association of golimumab trough concentrations during maintenance with key outcomes, including endoscopic and histologic remission, and long-term event-free persistence with golimumab, in patients with UC., Methods: This multi-centre, cross-sectional study included patients with UC on golimumab maintenance recruited either in remission or during a flare. Colonoscopy was scheduled, and study-specific rectocolonic biopsies were taken for blind central histologic reading. Samples for golimumab trough concentrations were collected close to colonoscopy., Results: Fifty-two patients were included. Median golimumab trough concentrations (μg/ml) were significantly higher in patients who had clinical remission (2.01 vs. 0.72, p = 0.047), combined clinical-biochemical remission (PMS ≤2 + faecal calprotectin <250 μg/g) (2.21 vs. 1.47, p = 0.041), endoscopic healing (Mayo endoscopic subscore 0) (2.52 vs. 1.47, p = 0.003), histologic remission (Geboes index ≤2.0) (2.33 vs. 1.50, p = 0.02) and disease clearance (clinical remission endoscopic healing + histologic remission) (2.52 vs. 1.70, p = 0.009), compared with those not meeting these criteria. Golimumab concentrations were significantly higher in patients who avoided golimumab dose escalation/discontinuation during follow-up (2.24 vs. 0.98, p = 0.012). Receiver-operating characteristic analyses identified golimumab thresholds [area under the curve] of 0.85 [0.76], 1.90 [0.76], 2.29 [0.75], 1.79 [0.68], 2.29 [0.72] and 1.56 [0.71] μg/ml as associated with clinical remission, combined remission, endoscopic healing, histologic remission, disease clearance and long-term event-free persistence with golimumab, respectively., Conclusions: Golimumab trough concentrations during maintenance are associated with favourable treatment outcomes including endoscopic healing, histologic remission and long-term persistence on golimumab. We identified the optimal golimumab thresholds most closely associated with key outcomes., (© 2022 John Wiley & Sons Ltd.)

Background and Aims: The development programm UNIFI has shown promising results of ustekinumab in ulcerative colitis [UC] treatment which should be confirmed in clinical practice. We aimed to evaluate the durability, effectiveness, and safety of ustekinumab in UC in real life., Methods: Patients included in the prospectively maintained ENEIDA registry, who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score [PMS]>2], were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at Week 16., Results: A total of 95 patients were included. At Week 16, 53% of patients had response [including 35% of patients in remission]. In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with lower likelihood of achieving remission. Remission was achieved in 39% and 33% of patients at Weeks 24 and 52, respectively; 36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at Week 16, 63% at Week 56, and 59% at Week 72; primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection., Conclusions: Ustekinumab is effective in both the short and the long term in real life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab., (© 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.)

Aim: To evaluate the effectiveness and safety of tofacitinib in ulcerative colitis [UC] in real life., Methods: Patients from the prospectively maintained ENEIDA registry and treated with tofacitinib due to active UC were included. Clinical activity and effectiveness were defined based on Partial Mayo Score [PMS]. Short-term response/remission was assessed at Weeks 4, 8, and 16., Results: A total of 113 patients were included. They were exposed to tofacitinib for a median time of 44 weeks. Response and remission at Week 8 were 60% and 31%, respectively. In multivariate analysis, higher PMS at Week 4 (odds ratio [OR] = 0].2; 95% confidence interval [CI] = 0].1-0.4) was the only variable associated with lower likelihood of achieving remission at Week 8. Higher PMS at Week 4 [OR = 0.5; 95% CI = 0.3-0.7] and higher PMS at Week 8 [OR = 0.2; 95% CI = 0.1-0.5] were associated with lower probability of achieving remission at Week 16. A total of 45 patients [40%] discontinued tofacitinib over time. Higher PMS at Week 8 was the only factor associated with higher tofacitinib discontinuation [hazard ratio = 1.5; 95% CI = 1.3-1.6]. A total of 34 patients had remission at Week 8; of these, 65% had relapsed 52 weeks after achieving remission; the dose was increased to 10 mg/12 h in nine patients, and five of them reached remission again. Seventeen patients had adverse events., Conclusions: Tofacitinib is effective and safe in UC patients in real practice, even in a highly refractory cohort. A relevant proportion of patients discontinue the drug over time, mainly due to primary failure., (© 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: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients., Methods: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent., Results: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn's disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug., Conclusions: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Faecal calprotectin is a useful technique for detecting activity in patients with ulcerative colitis. However, there may be high levels due to factors other than the activity of ulcerative colitis. Our aim was to analyse possible false positive results of calprotectin for the activity of ulcerative colitis owing to the presence of inflammatory polyps., Patients and Methods: Retrospective, observational, descriptive study. Data was collected from patients monitored for 2 years in whom a colonoscopy had been requested within 3 months after detecting high calprotectin values (>150μg/g) and before modifying the treatment., Results: We reviewed 39 patients and in 5 of them, with previous diagnosis of extensive ulcerative colitis, inflammatory polyps were detected. Three patients were on treatment with mesalazine, one with azathioprine and other with infliximab. All of them were asymptomatic and the endoscopy did not show macroscopic activity (endoscopic Mayo score=0) or histological activity. The median values of calprotectin were 422μg/g (IQR: 298-2,408) and they remained elevated in a second measurement. In 4 of the patients the inflammatory polyps were multiple and small in size. The other patient had a polyp measuring 4cm., Discussion: In clinical practice we can find high faecal calprotectin levels not due to the presence of ulcerative colitis activity, but due to other lesions such as inflammatory polyps. This fact must be taken into account before carrying out relevant changes such as step-up therapy to immunosuppressive drugs or biological drugs in patients with confirmed high calprotectin levels., (Copyright © 2019 Elsevier España, S.L.U. All rights reserved.)

Thiopurines (azathioprine and mercaptopurine) are widely used in patients with inflammatory bowel disease. In this paper, we review the main indications for their use, as well as practical aspects on efficacy, safety and method of administration. They are mainly used to maintain remission in steroid-dependent disease or with ciclosporin to control a severe ulcerative colitis flare-up, as well as to prevent postoperative Crohn's disease recurrence, and also in combination therapy with biologics. About 30-40% of patients will not respond to treatment and 10-20% will not tolerate it due to adverse effects. Before they are prescribed, immunisation status against certain infections should be checked. Determination of thiopurine methyltransferase activity (TPMT) is not mandatory but it increases initial safety. The appropriate dose is 2.5mg/kg/day for azathioprine and 1.5mg/kg/day for mercaptopurine. Some adverse effects are idiosyncratic (digestive intolerance, pancreatitis, fever, arthromyalgia, rash and some forms of hepatotoxicity). Others are dose-dependent (myelotoxicity and other types of hepatotoxicity), and their surveillance should never be interrupted during treatment. If therapy fails or adverse effects develop, management can include switching from one thiopurine to the other, reducing the dose, combining low doses of azathioprine with allopurinol and assessing metabolites, before their use is ruled out. Non-melanoma skin cancer, lymphomas and urinary tract tumours have been linked to thiopurine therapy. Thiopurine use is safe during conception, pregnancy and breastfeeding., (Copyright © 2017 Elsevier España, S.L.U. All rights reserved.)

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 > 60 μg/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.

Objectives: To determine the efficacy and safety of cyclosporine (CyA) in a large national registry-based population of patients with steroid-refractory (SR) acute severe ulcerative colitis (ASUC) and to establish predictors of efficacy and adverse events., Methods: Multicenter study of SR-ASUC treated with CyA, based on data from the ENEIDA registry. SR-ASUC patients treated with infliximab (IFX) or sequential rescue therapy (CyA-IFX or IFX-CyA) were used as comparators., Results: Of 740 SR-ASUC patients, 377 received CyA, 131 IFX and 63 sequential rescue therapy. The cumulative colectomy rate was higher in the CyA (24.1%) and sequential therapy (32.7%) than in the IFX group (14.5%; P=0.01) at 3 months and 5 years. There were no differences in early and late colectomy between CyA and IFX in patients treated after 2005. 62% of patients receiving CyA remained colectomy-free in the long term (median 71 months). There were no differences in mortality between CyA (2.4%), IFX (1.5%) and sequential therapy (0%; P=0.771). The proportion of patients with serious adverse events (SAEs) was lower in CyA (15.4%) than in IFX treated patients (26.5%) or sequential therapy (33.4%; P<0.001). This difference in favor of CyA was maintained when only patients treated after 2005 were analyzed., Conclusions: Treatment with CyA showed a lower rate of SAE and a similar efficacy to that of IFX thereby supporting the use of either CyA or IFX in SR-ASUC. In addition, the risk-benefit of sequential CyA-IFX for CyA non-responders is acceptable.

Background: Data supporting a role of female hormones and/or their receptors in inflammatory bowel disease (IBD) are increasing, but most of them are derived from animal models. Estrogen receptors alpha (ERα) and beta (ERβ) participate in immune and inflammatory response, among a variety of biological processes. Their effects are antagonistic, and the net action of estrogens may depend on their relative proportions., Aim: To determine the possible association between the balance of circulating ERβ and ERα (ERβ/ERα) and IBD risk and activity., Methods: Serum samples from 145 patients with IBD (79 Crohn's disease [CD] and 66 ulcerative colitis [UC]) and 39 controls were retrospectively studied. Circulating ERα and ERβ were measured by ELISA. Disease activities were assessed by clinical and endoscopic indices specific for CD and UC., Results: Low values of ERβ/ERα ratio were directly associated with clinical (p = 0.019) and endoscopic (p = 0.002) disease activity. Further analyses by type of IBD confirmed a strong association between low ERβ/ERα ratio and CD clinical (p = 0.011) and endoscopic activity (p = 0.002). The receiver operating curve (ROC) analysis showed that an ERβ/ERα ratio under 0.85 was a good marker of CD endoscopic activity (area under the curve [AUC]: 0.84; p = 0.002; sensitivity: 70%; specificity: 91%). ERβ/ERα ratio was not useful to predict UC activity., Conclusions: An ERβ/ERα ratio under 0.85 indicated CD endoscopic activity. The determination of serum ERβ/ERα might be a useful noninvasive screening tool for CD endoscopic activity.

Background: The impact of prior anti-TNF use on "real-life" outcomes of adalimumab therapy in ulcerative colitis (UC) is not well known., Aim: To compare the influence of prior anti-TNF use on the outcomes of adalimumab maintenance treatment in UC patients. We also assessed the effectiveness of adalimumab dose escalation., Methods: This retrospective multicenter cohort study included consecutive UC who advanced to an adalimumab maintenance regimen. Patients in whom adalimumab was discontinued prior to week eight of treatment were excluded. The co-primary efficacy endpoints were the cumulative probabilities of adalimumab failure-free survival and colectomy-free survival. We also assessed the need for and the effectiveness of adalimumab dose escalation., Results: Of 184 UC on maintenance treatment with adalimumab, 116 (63%) had previous anti-TNF use. After a median follow-up of 23 months (interquartile range 13-49), 112 patients (60%) maintained corticosteroid-free clinical response. Sixty-nine patients (37%) had adalimumab failure, and 22 (12%) needed colectomy. Anti-TNF-naïve patients had significantly lower adjusted rates of adalimumab failure (hazard ratio [HR] 0.65; p < 0.001), adalimumab dose escalation (HR 0.35; p = 0.002), and need for colectomy (HR 0.26; p < 0.004). Seventy-six patients (41%) needed dose escalation after secondary loss of response, and 47% of these regained response after escalation. Short-term response after escalation was identified as a significant predictor of colectomy avoidance (HR 0.53; p = 0.007)., Conclusions: In this "real-life" cohort of UC patients on maintenance treatment with adalimumab, anti-TNF-naïve patients had significantly better long-term outcomes. Adalimumab dose escalation enabled recovery of response in nearly half of patients.

Objective: To describe how mesalazine (MSZ) is used in our practice in ulcerative colitis (UC), at what dose, and the success rate (regarding adherence to therapy)., Methods: Observational, transversal study, including all patients with UC and with MSZ maintenance therapy seen from September 2014 to February 2015 at two IBD units in Spain. Treatment adherence was measured by the Morisky-Green scale., Results: We included 203 patients (mean MSZ dose: 2.6 ± 1.0 g/d; median of treatment: 19.5 months [IQR: 8-48]). Doses < 2 g/d were used in 15.3% of cases, 2-2.9 g/d doses in 35.0%, 3-3.9 doses in 29.5%, and ≥ 4 g/d doses in the remaining 20.2%. A single daily dose was preferred in 51.2% of cases, two doses in 33.0% and three doses in 15.8%. A different MSZ brand had been previously used in 36.6% of patients. In 134 cases (66%), the maintenance dose had been increased during a flare-up, and in 49 (36.6% of cases) this higher dose had been kept for maintenance (dose ≥ 4 g/d in 36 patients). During the MSZ therapy, 14 patients (6.9%) suffered mild side effects (21.4% altered liver function tests). Therapy adherence was good in 81.8% of cases., Conclusions: Half of our UC patients take high MSZ doses (≥ 3 g/d) as maintenance therapy, with acceptable safety and good adherence. Half of all patients take a single daily dose, and one third needed a different commercial brand during therapy. Opting for a higher MSZ maintenance dose is a possible strategy for a satisfactory maintenance therapy.

Objectives: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed., Methods: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included., Results: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07-3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe., Conclusions: The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe.

Background: Psoriasis induced by anti-tumor necrosis factor-α (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 genéticos y Ambientales registry of Grupo Español 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.

Background: The outcomes of infliximab dose escalation in ulcerative colitis (UC) have not been well evaluated., Aims: To assess the short- and long-term outcomes of infliximab dose escalation in a cohort of patients with UC., Methods: This was a multicenter, retrospective, cohort study. All consecutive UC patients who had lost response to infliximab maintenance infusions and who underwent infliximab dose escalation were included. Post-escalation short-term clinical response and remission were evaluated. In the long term, the cumulative probabilities of infliximab failure-free survival and colectomy-free survival were calculated. Predictors of short-term response and event-free survival were estimated using logistic regression analysis and Cox proportional hazard regression analysis., Results: Seventy-nine patients were included. Fifty-four patients (68.4%) achieved short-term clinical response and 41 patients (51.9%) entered in clinical remission. After a median follow-up of 15 months [interquartile range (IQR) 8-26], 33 patients (41.8%) had infliximab failure. Patients with short-term response had a significantly lower adjusted rate of infliximab failure [hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.12-0.49; p < 0.001]. During a median follow-up of 24 months (IQR 13-34), 9 patients (11.4%) needed colectomy. Short-term response was identified as a predictor of colectomy avoidance (HR 0.14; 95% CI 0.03-0.69; p < 0.007)., Conclusions: In UC patients who lost response to infliximab during maintenance, infliximab dose escalation enabled recovery of short-term response in nearly 70% of patients. In the long term, 58% of patients maintained sustained clinical benefit, and 9 of 10 avoided colectomy. Short-term response was associated with an 86% reduction in the relative risk of colectomy.

Background: Infliximab and adalimumab effectiveness might be related with changes in angiogenic factors. The aim of the study was to compare the concentrations of angiogenic proteins in patients with inflammatory bowel disease (IBD) and healthy controls and to analyze changes in the levels during infliximab and adalimumab treatment., Methods: A prospective case-control study was conducted in 37 patients with IBD starting treatment with infliximab (16 with Crohn's disease and 6 with ulcerative colitis) or adalimumab (15 with Crohn's disease) and 40 control subjects. Four samples were taken from IBD patients, one before each of the first 3 doses of infliximab/adalimumab and one at week 14. Serum levels of vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 1 (Ang1), angiopoietin 2, and Tie2 were measured using enzyme-linked immunosorbent assay., Results: Patients with IBD had higher VEGF levels than control subjects (511.5 ± 255.6 versus 395.5 ± 256.4; P = 0.05). Patients who achieved remission at the third dose of anti-TNF-alpha had lower VEGF levels at baseline (453.5 ± 250.7 versus 667.5 ± 153.9 pg/mL) and before the second (409.7 ± 217 versus 681.3 ± 350.6 pg/mL) and third (400.5 ± 222.8 versus 630.4 ± 243.1 pg/mL) doses compared with those with no remission (P < 0.05). Ang1 levels decreased before each treatment dose in patients who achieved remission (P < 0.05). High baseline VEGF levels predicted for a poor response to anti-TNF-alpha therapy (area under the receiver operating characteristics curve = 0.8), whereas high Ang1 levels were associated with disease remission (area under the receiver operating characteristics curve = 0.7). Concentrations of angiogenic proteins did not correlate with clinical activity scores., Conclusions: Circulating VEGF and Ang1 levels decrease after anti-TNF-alpha therapy and may predict response to treatment. Whether these changes are a direct effect of anti-TNF-alpha therapy or a sign of disease improvement remains to be elucidated.

Background and Aims: While it is commonly accepted that Inflammatory bowel disease (IBD) Comprehensive Care Units (ICCUs) facilitate the delivery of quality care to Crohn's disease and ulcerative colitis patients, it remains unclear how an ICCU should be defined or evaluated. The aim of the present study was to develop a comprehensive set of Quality Indicators (QIs) of structure, process, and outcomes for defining and evaluating an ICCU., Methods: A Delphi consensus-based approach with a standardized three-step process was used to identify a core set of QIs. The process included an exhaustive search using complementary approaches to identify potential QIs, and two Delphi voting rounds to select the QIs defining the core requirements for an ICCU., Results: The consensus selected a core set of 56 QIs (12 structure, 20 process and 24 outcome). Structure and process QIs highlighted the need for multidisciplinary management and continuity of care. The minimal IBD team should include an IBD nurse, gastroenterologists, radiologists, surgeons, endoscopists and stoma management specialists. ICCUs should be able to provide both outpatient and inpatient care and admission should not break the continuity of care. Outcome QIs focused on the adequate prophylaxis of disease complication and drug adverse events, the need to monitor appropriateness of treatment and the need to reinforce patient autonomy by providing adequate information and facilitating the patients' participation in their own care., Conclusions: The present Delphi consensus identified a set of core QIs that may be useful for evaluating and certifying ICCUs., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aims: The aim of this study was to compare angiogenic factors in serum levels of active ulcerative colitis (UC) patients and in healthy controls, and to analyze these angiogenic levels depending on the achievement of remission after oral corticosteroid treatment throughout treatment, and according to the Truelove-Witts activity index., Methods: Blood samples were collected from 13 patients receiving oral corticosteroids for treatment of UC flares at three different intervals--baseline, during, and after treatment--and from 26 healthy controls. Vascular endothelial growth factor (VEGF), placental growth factor (PlGF), VEGF receptor 1 (VEGFR1), angiopoietins (Ang) 1 and 2, and its receptor Tie2 were assayed by ELISA., Results: While VEGF and Ang2 levels in UC patients were higher than in healthy controls (P < 0.05), UC patients showed lower levels of Ang1 than healthy individuals (P < 0.05). In UC patients who achieved clinical remission after corticosteroid treatment, a statistically significant higher baseline serum level of PlGF was observed (22 ± 5 vs. 18 ± 2; P < 0.05). Angiogenic factor levels varied during treatment; however, they did not show a statistically significant correlation to the activity of the disease., Conclusions: VEGF, Ang1, and Ang2 levels showed statistically significant differences between UC patients and healthy controls. Although determination of PlGF serum levels before corticosteroid treatment might be helpful to anticipate the response by UC patients, no angiogenic pattern that could accurately predict "a priori" this response to corticosteroid treatment was observed. Corticosteroids altered temporarily circulating levels of VEGF, angiopoietins and Tie2. No correlation was found between systemic levels of angiogenic factors and the clinical activity of UC.

Background: Beclometasone dipropionate (BDP) is a relatively new topically acting oral steroid to treat mild to moderately active ulcerative colitis (UC). We estimate that 20,000 patients have received oral BDP in Spain in the last two years. Our aim was to evaluate the efficacy and safety of oral BDP in clinical practice., Methods: Retrospective and multicenter study that included 434 patients with active UC treated with BDP. The partial Mayo Clinic score (pMS, 0-9) was used to measure disease activity. Remission was defined as post-treatment pMS of 0 or 1; response as a decrease in pMS of 3 points or 2 points and >30%, and failure as lack of remission or response., Results: BDP dose was 5 mg/day in 88% of patients and mean treatment duration was 6.2 weeks. BDP achieved remission in 44.4%, response in 22.3% and failed in 33.2% of patients. Mean pMS decreased from 4.9 ± 1.3 to 2.4 ± 2.3 (p<0.0001). Remission rate was higher in mild and moderate than in severe UC (p<0.043) and tended to be higher in left-sided and extensive UC than in proctitis (p<0.06). Failure was less frequent in patients treated for >4 weeks (p<0.02). Mild adverse events were reported in 7.6% of patients., Conclusion: BDP induces response or remission in two thirds of active UC patients, with a good safety profile. Patients with mild to moderate, left-sided or extensive UC, receiving BDP for more than 4 weeks are most likely to benefit from this treatment., (Copyright © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background: Azathioprine (AZA) liver toxicity arises in approximately 3% of inflammatory bowel disease patients and may result in treatment discontinuation., Aim: To describe the tolerance to mercaptopurine (MP) in patients with previous AZA-related liver injury., Methods: Retrospective description of 31 patients (14 Crohn's, 17 ulcerative colitis), in which AZA therapy was interrupted because of liver injury, with MP started as alternative therapy., Results: Mean AZA dose was 2.2 +/- 0.4 mg x kg/day. Median (interquartile range) of AZA exposure when liver injury was detected was 2 months (1-5.2). The type of AZA-related injury was cytolitic in 32%, cholestatic in 39% and mixed in 29%. After a median of 2.5 months (0.7-5.2), the therapy was switched to MP at a mean dose of 1.3 +/- 0.2 mg x kg/day. Median of follow-up of MP therapy was 32 months (8-54). In 87.1% of patients (95%CI: 70-96%), MP was tolerated without further liver injury; of these, 77.4% tolerated full MP doses and 9.7% tolerated lower doses. In a further cohort of 12.9% of patients, (95%CI: 3-29%), liver injury reappeared (two cholestasis, two mixed), 1-3 months after the onset of MP exposure., Conclusion: The administration of MP is a good alternative in patients with AZA-related liver injury, before thiopurines are definitely discarded.

Background: The aim was to evaluate the efficacy and tolerance of oral and intravenous iron treatment in anemic inflammatory bowel disease (IBD) patients, considering both hematological and quality-of-life outcomes., Methods: We performed a prospective multicenter study in IBD patients with iron deficiency anemia. Patients having hemoglobin >10 g/dL were prescribed oral ferrous sulfate. If hemoglobin <10 g/dL, intravenous (sucrose) iron was administered. Oral iron-intolerant patients were changed to intravenous treatment. Clinical (Truelove/Harvey-Bradshaw), hematological (response defined as hemoglobin normalization), and quality-of-life (shortened CCVEII-9 questionnaire) evaluations were performed at baseline and at 3 and 6 months., Results: 100 IBD patients (59 Crohn's disease, 41 ulcerative colitis) were included. Mean basal hemoglobin levels were 10.8 +/- 1.3 g/dL (range, 6.6-12.9). Seventy-eight patients received oral treatment and 22 intravenous iron. Hemoglobin normalization was achieved in 86% of patients: 89% with oral, and 77% with intravenous iron. An IBD activity increase was not demonstrated in any patient. Four patients (5.1%) showed oral iron intolerance leading to discontinuation of treatment. No adverse events were reported for intravenous iron. Hemoglobin correlated with CCVEII-9 (P < 0.001). The CCVEII-9 score increased in patients who normalized hemoglobin levels in 3 months (from 58 +/- 9 to 73 +/- 10) or 6 months (54 +/- 9, 68 +/- 12, and 74 +/- 10) (P < 0.001)., Conclusions: Oral iron treatment is effective and well tolerated in most IBD patients, and does not exacerbate the symptoms of the underlying IBD. Intravenous iron, on the other hand, is an effective and safe alternative treatment for iron deficiency anemia in more severely anemic or intolerant patients. Anemia correction with iron treatment is associated with a relevant improvement in the patients' quality of life.

Background: The purpose of the study was to determine the role of fecal calprotectin and lactoferrin in the prediction of inflammatory bowel disease relapses, both in patients with ulcerative colitis (UC) and Crohn's disease (CD), in a large, long-term, follow-up study., Methods: The prospective multicenter study included CD and UC patients who had been in clinical remission for 6 months. At baseline, patients provided a single stool sample for calprotectin and lactoferrin determination. Follow-up was 12 months in patients showing no relapse and until activity flare in relapsing patients., Results: In all, 163 patients (89 CD, 74 UC) were included. Twenty-six patients (16%) relapsed during follow-up. Calprotectin concentrations in patients who suffered a relapse were higher than in nonrelapsing patients (239 +/- 150 versus 136 +/- 158 microg/g; P < 0.001). Relapse risk was higher in patients having high (>150 microg/g) calprotectin concentrations (30% versus 7.8%; P < 0.001) or positive lactoferrin (25% versus 10%; P < 0.05). Fecal calprotectin (>150 microg/g) sensitivity and specificity to predict relapse were 69% and 69%, respectively. Corresponding values for lactoferrin were 62% and 65%, respectively. The area under the receiver operating characteristic curve to predict relapse using calprotectin determination was 0.73 (0.69 for UC and 0.77 for CD). Better results were obtained when only colonic CD disease or only relapses during the first 3 months were considered (100% sensitivity). High fecal calprotectin levels or lactoferrin positivity was associated with clinical relapse in Kaplan-Meier survival analysis, and both fecal tests were associated with relapse in the multivariate analysis., Conclusions: Fecal calprotectin and lactoferrin determination may be useful in predicting impending clinical relapse-especially during the following 3 months-in both CD and UC patients.

Aim: Infliximab can provoke acute or delayed infusion reactions (IR) leading to treatment withdrawal. Our aim was to determine the frequency of IR in patients with inflammatory bowel disease receiving intravenous infliximab and premedicated with steroids and antihistaminics., Methods: We prospectively studied 100 consecutive patients (74 with Crohn's disease, 26 with ulcerative colitis) treated with infliximab induction therapy (3 doses: weeks 0-2-6), followed or not by maintenance every 8 weeks. All patients were premedicated with 100 mg i.v. hydrocortisone and 5 mg i.v. dexchlorpheniramine 30 min before each infusion., Results: The mean age was 40.9+/-13 years (51% females, and 38% smokers). Ninety-two percent of the patients were under immunomodulator therapy (azathioprine/ mercaptopurine 85% or methotrexate 7%). A total of 560 infusions were administered, with a mean of 5.6 per patient (range, 1-21). Fifty-six percent of the patients received maintenance therapy. The mean length of follow-up was 17+/-16 months. IR occurred in 6 patients (6%) and in 1.4% of all infusions (8/560). All reactions were mild or moderate. Five IR were immediate, occurring in the second infusion. One IR was delayed (exanthema 5 days after the second infusion). Infliximab therapy was discontinued in only 3 patients (in the patient with the delayed IR and in 2 patients with immediate IR that reappeared during the third infusion)., Conclusion: In patients with inflammatory bowel disease treated with infliximab and under immunomodulator therapy, premedication with steroids and antihistaminics was associated with a low prevalence of IR. Moreover, after close follow-up, infliximab had to be discontinued in only 3% of the patients.

Background/aims: Results of randomized controlled trials showing efficacy of infliximab in ulcerative colitis (UC) should be confirmed in clinical practice. We aimed to evaluate the efficacy and safety of infliximab in UC patients of the Madrid area, looking for clinical predictors of response., Methodology: Multicenter retrospective survey of all UC patients treated with infliximab in the region of Madrid (Spain)., Results: 47 UC patients were included (45% males, mean age 44 +/- 15 yrs), mean follow up of 4.7 months (range 0.5-21), and a total number of 211 infliximab infusions. Clinical response and steroid-free remission rates were, respectively, 97/42% in the 2nd week, 93/69% in the 6th week, and 80/65% at the long-term follow up (mean 8.2 months, range 3.5-21). Colectomy rate was 10.6% (five patients). Age, gender, disease duration, indication (steroid-resistance/dependence), disease severity, C-reactive protein, concomitant thiopurinic therapy or smoking habit did not influence on efficacy. Extent of the disease was the only predictive factor (p=0.02). Only 4 cases of mild adverse events were reported., Conclusions: Infliximab is effective and safe for UC. Real life clinical practice may have better outcome than showed in randomized controlled trials. Extent of the disease was the only predictive factor for clinical response in our experience.

Background: The efficacy of azathioprine in the management of steroid-dependent ulcerative colitis is taken for granted. However, study populations frequently include together steroid-dependent and refractory patients., Aim: To assess the efficacy and safety of thiopurinic immunomodulators in strictly defined steroid-dependent ulcerative colitis., Methods: Survey of 34 patients with steroid-dependent ulcerative colitis, treated with azathioprine according to protocol. Therapeutical success: glucocorticoid withdrawal within 12 months, without steroid requirements during another year., Results: Mean age was 39.1 +/- 17 years. Pancolitis and extensive colitis accounted for 50% of cases. Therapeutic success of immunomodulator treatment reached 70.6%, intention to treat analysis (confidence interval 95%: 52-84%) and 72.7%, as per protocol (confidence interval 95%: 54-86%). Mean time to steroid withdrawal was 4.6 months. In therapy successes, mean corpuscular volume and total serum bilirubin increased with treatment time (P = 0.0001). Fifteen adverse effects were observed in 13 patients (38%). Azathioprine was withdrawn in seven cases (20.6%); in four of them (with liver toxicity), treatment with mercaptopurine was indicated., Conclusions: Therapy with thiopurinic immunomodulators (azathioprine) represents the first option in the management of steroid-dependent ulcerative colitis. Its efficacy (70%) and its acceptable safety support this view. Increasing mean corpuscular volume and serum bilirubin values may be a surrogate marker of a beneficial effect.

Pyoderma gangrenosum is an extraintestinal manifestation of inflammatory bowel disease that can be therapeutically troublesome. We comment on the case of a patient with clinically inactive ulcerative colitis who progressively developed necrotic lesions on both tibial aspects of his legs, which corresponded both clinically and histologically to pyoderma gangrenosum. Treatment with steroids and azathioprine could not control this complication. A single dose of infliximab 5 mg/kg was given, achieving an impressive response of the skin lesions followed by complete healing 3 months later. Infliximab can be useful in the management of refractory extraintestinal manifestations of inflammatory bowel disease.

Background: infliximab is a monoclonal antiTNF-ct antibody that has repeatedly shown to be effective in the management of Crohn's disease. However, data are scarce about its efficacy in ulcerative colitis., Aim: to describe the joint experience of three Spanish hospitals in the use of infliximab in patients with active refractory ulcerative colitis., Patients and Methods: we present seven cases of ulcerative colitis (6 with chronic active disease despite immunosuppressive therapy, and one with acute steroid-refractory ulcerative colitis) treated with infliximab 5 mg/kg of body weight. Clinical response was evaluated by means of the Clinical Activity Index at 2, 4 and 8 weeks after initial infusion. Biochemical (erythrocyte sedimentation rate and C-reactive protein), endoscopic, and histological changes were also assessed., Results: mean age of patients was 45.8 +/- 17 years (range 23-77); 4 were female. No adverse effects were recorded. Inflammatory activity diminished significantly in 6 of 7 patients (85.7%; CI 95%: 42-99%) both from a clinical (p = 0.01) and biochemical (p <0.05) point of view. Five out of six patients (83.3%; 36-99%) with corticosteroid-dependent disease could be successfully weaned off these drugs. Five patients were endoscopicly controlled both before and after therapy, and a positive endoscopic and histological response could be recorded in all of them., Conclusion: infliximab may be an effective and safe therapy for some patients with ulcerative colitis refractory to other forms of therapy, although controlled studies are needed to assess its role in the general management of this disease.