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Objectives: Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting., Materials and Methods: This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore ≥2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by ≥3 points or 30% from baseline) and remission (defined as a Mayo score of ≤2 with no individual subscores >1)., Results: Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6-9) at baseline to 1 (0-5) at 52 weeks ( p  < .01) and the faecal calprotectin decreased from 862 (335-1759) µg/g to 90 (34-169) µg/g ( p  < .01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5‒1188.9)., Conclusions: The majority of golimumab treated patients represented a treatment refractory patient-group. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis.

Objectives: Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness., Materials and Methods: Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn's disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC)., Results: Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone ≥1 surgical resection. After a median follow-up of 17 (IQR: 14-20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96-16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10-4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16-6.48)., Conclusion: Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment.

Background and Aims: Ulcerative colitis patients display increased numbers of circulating pro-inflammatory monocyte human leukocyte antigen-DR [HLA-DRhi] monocytes expressing high levels of the gut-homing C-C chemokine receptor 9 [CCR9] and tumour necrosis factor [TNF]-α. The aim of this first-in-human, double-blind, randomised, placebo-controlled trial was to evaluate selective removal of circulating CCR9-expressing monocytes by leukapheresis in patients with moderate to severe ulcerative colitis, with regards to safety, tolerability, and immunological response., Methods: Patients with ulcerative colitis were treated every second day with leukapheresis during five sessions with a C-C chemokine ligand 25 [CCL25; CCR9 ligand] column or a placebo column., Results: No major safety concerns were raised and the procedure was well tolerated. Pro-inflammatory HLA-DRhi cells decreased significantly in the active treatment group [p = 0.0391] whereas no statistically significant change was seen in the placebo group [p = 0.4688]. There was a significant decrease of HLA-DRhi monocytes in the active group compared with the placebo group when corrected for the imbalance in weight between the groups [p = 0.0105]. Mayo score decreased in the active group [p = 0.0156] whereas the change in the placebo group was not significant [p = 0.1250]. Mayo score ≤ 3 was observed in five out of 14 patients [35.7%] in the active group compared with one out of eight [12.5%] receiving placebo. The number of responders in the active treatment group was eight out of 14 patients [57.1%], whereas in the corresponding placebo group three out of eight patients [37.5%] responded to placebo. A dose-response correlation was observed between the blood volume processed and clinical outcome., Conclusion: This clinical induction trial using CCL25-tailored leukapheresis demonstrates a safe and effective removal of activated monocytes with a clinical effect in patients with ulcerative colitis., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background: In previous studies, adaptive immune responses involving T-helper cells have been shown to play an important role in inflammatory bowel diseases (IBDs)., Methods: The aim of this study was to investigate any correlation between the degree of mucosal inflammation and the phenotype of gut-infiltrating T-helper cells. Biopsies from intestinal mucosa were obtained and intestinal T cells were analyzed with regard to activity and maturation markers. Patients with active colitis (39 with Crohn's disease and 47 with ulcerative colitis) were included and treated with corticosteroids, biologicals or leukocytapheresis. Flow cytometry was used to analyze activation marker expression on gut-infiltrating T-helper cells., Results: Mucosal healing was reflected by almost 100% increase of CD62L expression in mucosal T cells in patients in remission compared to those with active inflammation (p < 0.01). The frequency of mucosal-naïve CD4(+)CD45RA(+) T cells was reduced by 50% in mucosa displaying remission (5.3% compared to 12% of the total amount and CD4(+) T cells, p < 0.001). Surprisingly, the proportion of early activated T-helper cells (CD4(+)CD69(+)) did not differ between mucosa in remission and non-remission (43% and 42%, respectively). Moreover, no change in memory T-helper cells (CD4(+)CD45RO(+)) was observed (64% compared to 66%). The findings were independent of diagnosis (Crohn's disease or ulcerative colitis) or mode of treatment., Conclusion: This study suggests that a reduced recruitment of naïve T-helper cells and increased frequency of T-helper cells with lymph node homing marker expression reflect mucosal healing in IBD. Surprisingly, the degree of activation of mucosal T-helper cells did not correlate with disease remission.

Background: Rescue therapy with infliximab (IFX) has been proven effective in a steroid-refractory attack of ulcerative colitis (UC). The long-term efficacy is not well described., Aim: To present a retrospective study of IFX as rescue therapy in UC. Primary end points were colectomy-free survival at 3 and 12 months., Methods: In this multicentre study, 211 adult patients hospitalised between 1999 and 2010 received IFX 5 mg/kg as rescue therapy due to a steroid-refractory, moderate-to-severe attack of UC. Exclusion criteria were duration of current flare for >12 weeks, corticosteroid treatment for >8 weeks before hospitalisation, previous IFX therapy or Crohn's disease., Results: Probability of colectomy-free survival at 3 months was 0.71 (95% CI, 0.64-0.77), at 12 months 0.64 (95% CI, 0.57-0.70), at 3 years 0.59 (95% CI, 0.52-0.66) and at 5 years 0.53 (95% CI, 0.44-0.61). Steroid-free, clinical remission was achieved in 105/211 (50%) and 112/209 (54%) patients at 3 and 12 months respectively. Of 75 colectomies during the first year, 48 (64%) were carried out during the first 14 days, 13 (17%) on days 15-90 and 14 (19%) between 3 and 12 months. There were three (1.4%) deaths during the first 3 months., Conclusions: Infliximab is an effective rescue treatment, both short- and long-term, in a steroid-refractory attack of UC. Most IFX failures underwent surgery during the first 14 days, which calls for studies on how to optimise induction treatment with IFX. Serious complications, including mortality, were rare., (© 2013 John Wiley & Sons Ltd.)

Background: The long-term efficacy of infliximab as rescue therapy in steroid-refractory ulcerative colitis is not well described., Aim: To examine the long-term efficacy of infliximab as a rescue therapy through a 3-year follow-up of a previous placebo-controlled trial of infliximab in acute steroid-refractory ulcerative colitis., Method: In the original study, 45 patients were randomized to a single infusion of infliximab 5 mg/kg or placebo, and at 3 months, 7/24 patients given infliximab were operated vs. 14/21 patients given placebo. Three years or later, patients were asked to participate in a clinical follow-up., Results: Another seven patients underwent colectomy during follow-up: five in the infliximab group and two in the placebo group. After 3 years, a total of 12/24 (50%) patients given infliximab and 16/21 (76%) given placebo (P = 0.012) had a colectomy. None of eight patients in endoscopic remission at 3 months later had a colectomy compared with 7/14 (50%) patients who were not in remission (P=0.02). There was no mortality., Conclusion: The benefit of rescue therapy with infliximab in steroid-refractory acute ulcerative colitis remained after 3 years. The main advantage of infliximab treatment occurred during the first 3 months, whereas subsequent colectomy rates were similar in the two groups. Mucosal healing at 3 months influenced later risk of colectomy., (© 2010 Blackwell Publishing Ltd.)

The immunosurveillance theory argues that the immune system recognizes tumour-specific antigens expressed by transformed cells, which results in the destruction of cancer precursors before they become clinically manifest. As a model for the development of cancer, we set out to study premalignant lesions and immune responses in sentinel lymph nodes from patients with long-standing ulcerative colitis and progression of mucosal dysplasia. Mesenteric lymph nodes draining dysplastic and normal intestinal segments were identified by sentinel node technique during surgery in 13 patients with ulcerative colitis who were subjected to colectomy because of intestinal dysplasia. T cells were extracted from the lymph nodes and analysed by flow cytometry, and lymphocyte proliferation assays were set up in the presence of extracts from dysplastic and normal intestinal mucosa. Increase in CD4/CD8 ratio was observed in sentinel lymph nodes draining dysplastic epithelium compared to normal mucosa. The increase in CD4(+) T cells in relation to CD8(+) T cells correlated with the degree of dysplasia reflected by a significant increase in the ratio against low-grade dysplasia compared to indefinite dysplastic lesions. The T-cell response was specific to antigens from dysplastic epithelial lining as seen in proliferation assays. The observation suggests an important surveillance role for the immune system against premalignant intestinal lesions in patients with long-standing ulcerative colitis.

Background & Aims: Despite treatment with corticosteroids, severe to moderately severe attacks of ulcerative colitis have a high colectomy rate. We intended to find a rescue therapy other than cyclosporin A, which imposes a high risk of side effects and cyclosporine-related mortality., Methods: This was a randomized double-blind trial of infliximab or placebo in severe to moderately severe ulcerative colitis not responding to conventional treatment. Patients were randomized to infliximab/placebo either on day 4 after the initiation of corticosteroid treatment if they fulfilled the index criteria for fulminant ulcerative colitis on day 3 or on day 6-8 if they fulfilled index criteria on day 5-7 for a severe or moderately severe acute attack of ulcerative colitis. Results were analyzed according to the intention-to-treat principle. The primary end point was colectomy or death 3 months after randomization. Secondary end points were clinical and endoscopic remission at that time in patients who did not undergo operation., Results: Forty-five patients were included (24 infliximab and 21 placebo). No patient died. Seven patients in the infliximab group and 14 in the placebo group had a colectomy (P = .017; odds ratio, 4.9; 95% confidence interval, 1.4-17) within 3 months after randomization. No serious side effects occurred. Three patients in the placebo group required operation for septic complications., Conclusions: Infliximab 4-5 mg/kg is an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of ulcerative colitis not responding to conventional treatment.

Background: Several placebo controlled studies have demonstrated the efficacy of infliximab in inflammatory bowel disease (IBD) but the potential toxicity of this new biological compound has been less studied., Aim: To assess the use of infliximab in IBD in a population based cohort, with special emphasis on the occurrence of severe adverse events and mortality., Patients: All patients with IBD treated with infliximab between 1999 and 2001 in Stockholm County were evaluated., Methods: Prospective registration of clinical data was carried out. Retrospective analyses were made of possible adverse events occurring in relation to infliximab treatment. Adverse events requiring pharmacological treatment or hospitalisation were defined as severe. Clinical response was assessed as remission, response, or failure., Results: A cohort comprising 217 patients was assembled: 191 patients had Crohn's disease (CD), and infliximab was used off label for ulcerative colitis (UC) in 22 patients. Four patients were treated for indeterminate colitis (IC). Mean age was 37.6 (0.9) years (range 8-79). The mean number of infliximab infusions was 2.6 (0.1) (range 1-11). Forty two severe adverse events were registered in 41 patients (CD, n = 35). Eleven of the severe adverse events occurred postoperatively (CD, n = 6). Three patients with CD developed lymphoma (of which two were fatal), opportunistic infections occurred in two patients (one with UC, fatal), and two patients with severe attacks of IBD died due to sepsis (one with CD, one postoperatively with UC). One additional patient with UC died from pulmonary embolism after colectomy. Mean age in the group with fatal outcome was 62.7 years (range 25-79). The overall response rate was 75% and did not differ between the patient groups., Conclusions: Infliximab was efficacious as an anti-inflammatory treatment when assessed in a population based cohort of patients with IBD. However, there appear to be a significant risk of deleterious and fatal adverse events, particularly in elderly patients with severe attacks of IBD. Off label use of infliximab in UC and IC should be avoided until efficacy is proven in randomised controlled trials. The underlying risk of developing malignancies among patients with severe or chronically active CD in need of infliximab treatment is not known but the finding of a 1.5% annual incidence of lymphoma emphasises the need for vigilant surveillance with respect to this malignant complication.

Objective: There is an increased risk of colorectal cancer among patients with ulcerative colitis (UC). However, the overall and site specific cancer risks in these patients have been investigated to a limited extent. To study the association between UC and cancer, a population-based study of 1547 patients with UC in Stockholm diagnosed between 1955 and 1984 was carried out., Methods: The patients were followed in both the National Cancer Register and the National Cause of Death Register until 1989. For comparisons, regional cancer incidence rates in Stockholm County were used together with individually computed person-years at risk in the UC disease cohort., Results: A total of 121 malignancies occurred among 97 individuals as compared with 89.8 expected (standardized morbidity ratio [SMR] = 1.4; 95% confidence interval (CI), 1.1-1.6). Overall, an excess number of colorectal cancers (SMR, 4.1; 95% CI, 2.7-5.8), and hepatobiliary cancers in men (SMR = 6.0; 95% CI, 2.8-11.1) associated with primary sclerosing cholangitis, was observed. The risk of pulmonary cancer was decreased (SMR = 0.3; 95% CI, 0.1-0.9). In all, 91 extracolonic malignancies were observed, compared with the 82.3 expected (SMR = 1.11; 95% CI, 0.9-1.3)., Conclusions: In UC patients, the overall cancer incidence is increased mainly because of an increased incidence of colorectal and hepatobiliary cancer. This increase is partly counterbalanced by a decreased risk of pulmonary cancer compared with that in the general population.

Background & Aims: Expression of the mucin-associated carbohydrate antigen sialyl-Tn (STn) and DNA aneuploidy has each been shown to correlate with malignant transformation in patients with sporadic colon cancer and in those with ulcerative colitis (UC). This study aimed to determine how STn expression topographically and temporally relates to aneuploidy and neoplasia in patients with long-standing UC., Methods: Twenty-six patients enrolled in a cancer surveillance program were studied, and 1691 mucosal specimens from repeated colonoscopies and colectomies were assessed in a standardized, prospective fashion for the presence of dysplasia, aneuploidy, and STn antigen., Results: STn was expressed in 47% of specimens from 6 patients who underwent colectomy for dysplasia and 7% of specimens from 6 well-matched patients who underwent surgery for medical intractability. Seven other patients who never developed dysplasia or aneuploidy expressed STn in 6% of biopsy specimens. STn expression was independent of aneuploidy in colons both with and without dysplasia. Of 5 patients with aneuploidy but without dysplasia, 4 expressed STn earlier than aneuploidy., Conclusions: In UC, STn antigen and DNA aneuploidy are independent markers of neoplastic transformation. Determination of STn expression may complement dysplasia and aneuploidy for identification of risk for colonic neoplasia in UC.

Background: Colonoscopic surveillance is a standard procedure in many patients with long standing, extensive ulcerative colitis (UC), in order to avoid death from colorectal cancer. No conclusive proof of its benefits has been presented however., Aims: To evaluate the association between colonoscopic surveillance and colorectal cancer mortality in patients with UC., Patients: A population based, nested case control study comprising 142 patients with a definite UC diagnosis, derived from a study population of 4664 patients with UC, was conducted., Methods: Colonoscopic surveillance in all patients with UC who had died from colorectal cancer after 1975 was compared with that in controls matched for age, sex, extent, and duration of the disease. Information on colonoscopic surveillance was obtained from the medical records., Results: Two of 40 patients with UC and 18 of 102 controls had undergone at least one surveillance colonoscopy (relative risk (RR) 0.29, 95% confidence interval 0.06 to 1.31). Twelve controls but only one patient with UC had undergone two or more surveillance colonoscopies (RR 0.22, 95% confidence interval 0.03 to 1.74), indicating a protective dose response relation., Conclusion: Colonoscopic surveillance may be associated with a decreased risk of death from colorectal cancer in patients with long standing UC.

Fifty-nine patients with longstanding, total ulcerative colitis were followed up in a prospective colonoscopic surveillance program. Biopsy specimens were sampled from predetermined locations of the colon and rectum at regular intervals. All specimens were assessed for histological dysplasia and, by flow cytometry, for detection of DNA aneuploidy during 8 years of follow-up. Special emphasis was made to correlate the findings of DNA aneuploidy with findings of dysplasia at colonoscopy or, in case proctocolectomy was performed, in the surgical specimen. Fifteen patients (25.4%) had DNA aneuploidy detected at least once during the follow-up. Eight of 10 patients with repeated findings had consistent ploidy level of the aneuploid peaks from one examination to another. Ten patients had multiple peaks. DNA aneuploidy tended to become more widespread in the bowel during the follow-up but persisted in the same part(s) of the colon and rectum. DNA aneuploidy occurred before development of definite dysplasia in 6 patients, simultaneously with development of dysplasia in 6 patients, and after the development of dysplasia in 1 patient only. In 2 patients, single aneuploid peaks were detected once but could not be found again at subsequent examinations. Dysplasia correlated closely topographically to DNA aneuploidy, but the latter finding was more common without concomitant dysplasia. Only in 1 patient, and at one examination, definite dysplasia was recorded without findings of DNA aneuploidy. Detection of DNA aneuploidy in patients with ulcerative colitis is persistent and reproducible and closely correlated to dysplasia. Widespread changes indicate that the entire colorectal mucosa is at increased risk of malignant transformation. Changes in nuclear DNA content appear to be an earlier phenomenon than dysplasia in the malignant transformation of the colorectal mucosa in ulcerative colitis, and the use of flow cytometry in surveillance programs may be of value for selection of patients at high risk of developing colorectal carcinoma.

In a 15-year surveillance program composed of 72 patients with total ulcerative colitis, 12 patients developed definite dysplasia. At endoscopy, low-grade dysplasia was detected in seven patients, high-grade in four, and a carcinoma (Dukes' stage A at operation) in one. One of the patients with high-grade dysplasia and macroscopical lesions at colonoscopy had a carcinoma (Dukes' A) detected at operation. A sequential development of dysplasia was found in seven patients. The cumulative risk of developing at least low-grade dysplasia was 14% after 25 years of disease duration. Using flow cytometric analyses, abnormal, aneuploid DNA content was detected in biopsies of 12 of 59 patients (20.3%); this correlated significantly with low-grade and high-grade dysplasia. Aneuploidy preceded dysplasia in two patients and was also detected in two dysplasia-free patients. The long-term use of colonoscopic surveillance in ulcerative colitis is a reliable way to select patients, in whom dysplasia is developing, for prophylactic surgery. Additionally, flow cytometric DNA analyses may help in the selection. The risk of missing a carcinoma until it becomes incurable appears to be low.