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Background Some studies have suggested a reduced life expectancy in patients with Crohn's disease (CD) compared with the general population. The evidence, however, is inconsistent. Aims Prompted by such studies, we studied survival of CD patients in Orebro county, Sweden. Methods From the medical records, we identified all patients diagnosed with CD during 1963-2010 with follow-up to the end of 2011. We estimated: overall survival, net and crude probabilities of dying from CD, relative survival ratio (RSR), and excess mortality rate ratios (EMRR) at 10-year follow-up. Results The study included 492 patients (226 males, 266 females). Median age at diagnosis was 32 years (3-87). Net and crude probabilities of dying from CD increased with increasing age and were higher for women. Net survival of patients aged ≥60 at diagnosis was worse for patients diagnosed during 1963-1985 (54%) than for patients diagnosed during 1986-1999 (88%) or 2000-2010 (93%). Overall, CD patients' survival was comparable to that in the general population [RSR = 0.98; 95% CI: (0.95-1.00)]. However, significantly lower than expected survival was suggested for female patients aged ≥60 diagnosed during the 1963-1985 [RSR = 0.47 (0.07-0.95)]. The adjusted model suggested that, compared with diagnostic period 1963-1985, disease-related excess mortality declined during 2000-2010 [EMRR = 0.36 (0.07-1.96)]; and age ≥60 at diagnosis [EMRR = 7.99 (1.64-39.00), reference: age 40-59], female sex [EMRR = 4.16 (0.62-27.85)], colonic localization [EMRR = 4.20 (0.81-21.88), reference: ileal localization], and stricturing/penetrating disease [EMRR = 2.56 (0.52-12.58), reference: inflammatory disease behaviour] were associated with poorer survival. Conclusion CD-related excess mortality may vary with diagnostic period, age, sex and disease phenotype.Key summaryThere is inconsistent evidence on life expectancy of patients with Crohn's diseaseCrohn's disease-specific survival improved over time.Earlier diagnosis period, older age at diagnosis, female sex, colonic disease and complicated disease behaviour seems to be associated with excess Crohn's disease-related mortality.

Background and Aims: As inflammatory bowel disease (IBD) becomes more prevalent, the challenges that gastroenterologists face in managing these patients evolve. We aimed to describe the most important challenges facing gastroenterologists from around the world and compare these between those working in developed and developing countries. Methods: An online questionnaire was developed, and a link distributed to gastroenterologists. Data were analyzed descriptively using Friedman and Wilcoxon matched-pair signed rank tests to compare rankings for responses. Mann-Whitney U tests were used to compare rankings between responses from gastroenterologists from developed and developing countries. Lower scores reflected greater challenges. Results: Of 872 who started, 397 gastroenterologists (45.5%) completed the survey. Respondents represented 65 countries (226 [56.9%] from developed countries). Overall, the challenge ranked most important (smallest number) was increasing IBD prevalence (13.6%). There were significant differences in mean ranking scores for many simple aspects of care for those from developing countries compared to providers from developed countries, such as access to simple IBD treatments (5.52 vs. 6.02, p = 0.01), access to anti-TNF drugs including dose escalation (3.33 vs. 3.93, p < 0.01), access to good stoma care (2.57 vs. 3.03, p < 0.001), access to therapeutic drug monitoring (1.47 vs. 1.84, p < 0.001), and access to care for people from low socioeconomic status (2.77 vs. 3.37, p < 0.001). Conclusions: Increasing IBD prevalence is seen by gastroenterologists as the greatest challenge facing them. There are significant differences between the IBD challenges facing gastroenterologists from developed and developing countries that reflect inequities in access to health care.

Summary Background The incidence and short‐term outcome of anaemia in inflammatory bowel disease (IBD) are largely unknown. Aim To determine the incidence, prevalence and clinical outcome of anaemia in terms of resolution of anaemia within 12 months. We also planned to assess risk factors for anaemia in IBD. Methods A random sample of 342 patients was obtained from the population‐based IBD cohort of Örebro University Hospital, Sweden, consisting of 1405 patients diagnosed between 1963 and 2010. Haemoglobin measurements recorded from 1 January 2011 to 31 December 2013 were extracted from the Clinical Chemistry data system. Results In Crohn's disease, the incidence rate of anaemia was 19.3 (95% CI: 15.4‐23.7) per 100 person‐years and the prevalence was 28.7% (CI: 22.0‐36.2), compared with 12.9 (CI: 9.8‐16.5) and 16.5% (CI: 11.2‐22.9) for ulcerative colitis. Crohn's disease was associated with an increased incidence (OR = 1.60; CI: 1.02‐2.51) and prevalence of anaemia (OR = 2.04; CI: 1.20‐3.46) compared to ulcerative colitis. Stricturing disease phenotype in Crohn's disease (HR = 2.59; CI: 1.00‐6.79) and extensive disease in ulcerative colitis (HR = 2.40; CI: 1.10‐5.36) were associated with an increased risk of anaemia. Despite a higher probability of receiving specific therapy within 3 months from the diagnosis of anaemia, Crohn's disease patients had a worse outcome in terms of resolution of anaemia within 12 months (56% vs 75%; P = 0.03). Conclusions Anaemia is a common manifestation of IBD even beyond the first years after the diagnosis of IBD. Crohn's disease is associated with both an increased risk and a worse outcome.

Background Endoscopic balloon dilation (EBD) is widely used to manage Crohn's disease-associated strictures. However, most studies of the safety and efficacy are small and heterogenous. We performed a combined analysis of published studies and evaluated 676 comprehensive individual participant data sets to determine the overall effects of EBD. Methods Citations from the Embase, MEDLINE, and the Cochrane library from 1991 through 2013 were systematically reviewed, and references of cited articles were assessed for relevant publications. We collected data from studies including ≥15 patients and additionally generated a unique individual patient database containing 676 individual data sets derived from 12 studies. Technical feasibility, short-term and long-term efficacies, and safety were evaluated. Results In 1463 patients with Crohn's disease who underwent 3213 EBD procedures, 98.6% of strictures were ileal and 62% anastomotic. The technical success rate of the EBDs was 89.1% with a clinical efficacy of 80.8%. Complications occurred in 2.8% per procedure. After 24 months of follow-up, 73.5% of subjects underwent redilation and 42.9% surgical resection. In a multivariate analysis of 676 individual patients, a stricture length of ≤5 cm was associated with a surgery-free outcome; every 1 cm increase of stricture length increased the hazard of need for surgery by 8% (P = 0.008). Inflammation did not affect outcomes or rate of complications. Conclusions Based on a systematic literature review and analysis of data sets from 676 patients, EBD has a high rate of short-term technical and clinical efficacies, with substantial long-term efficacy and acceptable rates of complication.

Background and aimDisease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC.MethodsUsing a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute.ResultsFor CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities.ConclusionsBased on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.

Background and Aims: An adaptive immunological response to microbial antigens has been observed in Crohn’s disease (CD). Intriguingly, this serological response precedes the diagnosis in some patients and has also been observed in healthy relatives. We aimed to determine whether genetic factors are implicated in this response in a CD twin cohort. Methods: In total, 82 twin pairs (Leuven n = 13, Maastricht n = 8, Orebro n = 61) took part: 81 pairs with CD (concordant monozygotic n = 16, discordant monozygotic n = 22, concordant dizygotic n = 3, discordant dizygotic n = 40) and 1 monozygotic pair with both CD and ulcerative colitis. Serology for Pseudomonas fluorescens -related protein (anti-I2), Escherichia coli outer membrane porin C (anti-OmpC), CBir1flagellin (anti-CBir1) and antibodies to oligomannan (anti- Saccharomyces cerevisiae antibody [ASCA]) was determined by standardized enzyme-linked immunoassay. Results: All markers were more often present in CD twins than in their healthy twin siblings. Using the intraclass correlation coefficient (ICC), agreements in concentrations of anti-OmpC and anti-I2 were observed in discordant monozygotic but not in discordant dizygotic twin pairs with CD (anti-OmpC, ICC 0.80 and −0.02, respectively) and (anti-I2, ICC 0.56 and 0.05, respectively). In contrast, no agreements were found in anti-CBir, immunoglobulin (Ig) G ASCA and ASCA IgA. Conclusions: We show that anti-I2 and anti-CBir1 statuses have specificity for CD and confirm previous reported specificities for anti-OmpC and ASCA. Based on quantitative analyses and observed ICCs, genetics seems to predispose to the anti-OmpC and anti-I2 response but less to ASCA and anti-CBir1 responses.

OBJECTIVES Onset of microscopic colitis (MC) in patients with ulcerative colitis (UC) or Crohn's disease (CD), or vice versa, has been reported occasionally but the subject is not well described. We therefore report a retrospective observational study of such patients and review the literature. METHODS Forty-six Swedish gastroenterology clinics were contacted about patients with diagnoses of both inflammatory bowel disease (IBD) and MC. Publications were searched on PubMed. RESULTS We identified 31 patients with onset of MC after a median (range) of 20 (2-52) years after diagnosis of IBD, or vice versa; 21 UC patients developed collagenous colitis (CC) (n = 16) or lymphocytic colitis (LC) (n = 5); nine CD patients developed CC (n = 5) or LC (n = 4); one CC patient developed CD. Of the 21 UC patients, 18 had extensive disease, whereas no consistent phenotype occurred in CD. Literature review revealed 27 comprehensive case reports of patients with diagnoses of both IBD and MC. Thirteen MC patients developed IBD, of which four required colectomy. Fourteen IBD patients later developed MC. There were incomplete clinical data in 115 additional reported patients. CONCLUSIONS Altogether 173 patients with occurrence of both IBD and MC were found. The most common finding in our patients was onset of CC in a patient with UC. Although these are likely random associations of two different disorders, MC should be considered in the patient with UC or CD if there is onset of chronic watery diarrhoea without endoscopic relapse of IBD.

INTRODUCTION: In inflammatory bowel disease (IBD), an aberrant immune response to gut microbiota is important, but the role of the microbiota in collagenous colitis (CC) is largely unknown. We aimed to characterize the microbiota of patients with CC compared with that of healthy control and patients with IBD. METHODS: Fecal samples were collected from patients with CC (n = 29), age- and sex-matched healthy controls (n = 29), patients with Crohn's disease (n = 32), and patients with ulcerative colitis (n = 32). Sequence data were obtained by 454 sequencing of 16S rRNA gene amplicons, and the obtained sequences were subsequently taxonomically classified. RESULTS: Analysis of similarity statistics showed a segregation between patients with CC and healthy controls with increasing taxonomic resolution, becoming significant comparing operational taxonomic unit data (P = 0.006). CC had a lower abundance of 10 different taxa. Taxa-specific analyses revealed a consistent lower abundance of several operational taxonomic units belonging to the Ruminococcaceae family in patients with CC, q < 0.05 after false discovery rate correction. Loss of these taxa was seen in patients with CC with active disease and/or corticosteroid treatment only and resembled the findings in patients with IBD. DISCUSSION: CC is associated with a specific fecal microbiome seen primarily in patients with active disease or ongoing corticosteroid treatment, whereas the microbiome of CC patients in remission resembled that of healthy controls. Notably, the shift in key taxa, including the Ruminococcaceae family, was also observed in IBD. There may be common mechanisms in the pathogenesis of CC and IBD.

Soluble factors from intestinal mucosal cells contribute to immune homeostasis in the gut. We have established anin vitromodel to investigate the regulatory role of soluble factors from inflamed intestinal mucosa of collagenous colitis (CC) patients in the differentiation of T cells. Peripheral blood CD4+T cells from healthy donors were polyclonally activated in the presence of conditioned medium (CM) generated from denuded biopsies (DNB) or isolated lamina propria mononuclear cells (LPMCs) from mucosal biopsies from CC patients compared to noninflamed controls, to determine proliferation and secretion of cytokines involved in T-cell differentiation. Compared to controls, we observed significantly increased production of the proinflammatory cytokines IFN-γ, IL-17A, IL-6, and IL-1βand the anti-inflammatory cytokines IL-4 and IL-10 in the presence of CC-DNB-CM. The most pronounced effect of CC-LPMC-CM on peripheral CD4+T cells was a trend towards increased production of IL-17A and IL-10. A trend towards reduced inhibition of T-cell proliferation was noted in the presence of CC-DNB-CM. In conclusion, ourin vitromodel reveals implications of soluble factors from CC colonic mucosa on peripheral T cells, enhancing their production of both pro- and anti-inflammatory cytokines.

Andreas Münch,1,* Johan Bohr,2,3,* Lina Vigren,4 Curt Tysk,2,3,* Magnus Ström1,* 1Division of Gastroenterology and Hepatology, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping, 2Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro University, Örebro, 3School of Health and Medical Science, Örebro University, Örebro, 4Division of Gastroenterology, Department of Clinical Science, Lund University, Malmö, Sweden *These authors are members of the Swedish Organization for the study of Inflammatory Bowel Disease (SOIBD), a national organization for gastroenterologists, colorectal surgeons, and basic scientists Background: In most cases, collagenous colitis can be treated effectively with budesonide. However, some patients develop side effects or have chronic symptoms refractory to budesonide. This paper reports an open case series of patients intolerant or refractory to budesonide who were treated with methotrexate (MTX). Methods and patients: Nine patients (seven women) with a median (range) age of 62 (44–77) years were studied. Bowel movements were registered during 1 week prior to baseline and after 6 and 12 weeks’ treatment, enabling calculation of the mean bowel movements/day. All patients underwent colonoscopy with biopsies before inclusion to confirm diagnosis. Open treatment with MTX was given 15 mg subcutaneously weekly for 6 weeks and was increased to 25 mg for a further 6 weeks if symptoms were unresponsive to the first 6 weeks’ treatment. The endpoint was clinical remission, which was defined as a mean

Background: The mechanisms behind increased fecal calprotectin (FC) in healthy relatives of patients with inflammatory bowel disease (IBD) are unknown. Our aims were to explore if there is a subclinical inflammation with increased neutrophil activity in healthy twin siblings in discordant twin pairs with IBD and to assess the influence of genetics in this context. Methods: Nuclear factor kappa B (NF-B) and neutrophil activity, based on myeloperoxidase (MPO) and FC, were analyzed in healthy twin siblings in discordant twin pairs with IBD and compared with healthy controls. NF-B and MPO were assessed by immunohistochemistry and FC by enzyme-linked immunosorbent assay. Results: In total, 33 of 34 healthy twin siblings were histologically normal. Increased NF-B was more often observed in healthy twin siblings in discordant twin pairs with Crohn's disease (13/18 [73%]) and with ulcerative colitis (12/16 [75%]) than in healthy controls (8/45 [18%]). MPO was more often increased in healthy twin siblings in discordant pairs with Crohn's disease (12/18 [67%]) than in healthy controls (11/45 [24%]) and FC more often in healthy twin siblings in discordant pairs with ulcerative colitis (14/21 [67%]) than in healthy controls (6/31 [19%]). Interestingly, the observed differences remained when healthy monozygotic and dizygotic twin siblings were analyzed separately. Conclusions:We observed increased NF-B, MPO, and FC in healthy twins in both monozygotic and dizygotic discordant pairs with IBD. These novel findings speak for an ongoing subclinical inflammation with increased neutrophil activity in healthy first-degree relatives., Funding Agencies:Bengt Ihre's foundation Nanna Svartz' foundation Orebro University Hospital Research Foundation Orebro County Research Foundation Swedish Foundation for Gastrointestinal research

Collagenous colitis (CC) is associated with autoimmune disorders. The aim of the present study was to investigate the relationship between CC and autoimmune disorders in a Swedish multicenter study.Patients with CC answered questionnaires about demographic data and disease activity. The patient's files were scrutinized for information about autoimmune diseases.A total number of 116 CC patients were included; 92 women, 24 men, median age 62 years (IQR 55-73). In total, 30.2% had one or more autoimmune disorder. Most common were celiac disease (CeD; 12.9%) and autoimmune thyroid disease (ATD, 10.3%), but they also had Sjögren's syndrome (3.4%), diabetes mellitus (1.7%) and conditions in skin and joints (6.0%). Patients with associated autoimmune disease had more often nocturnal stools. The majority of the patients with associated CeD or ATD got these diagnoses before the colitis diagnosis.Autoimmune disorders occurred in one-third of these patients, especially CeD. In classic inflammatory bowel disease (IBD), liver disease is described in contrast to CC where no cases occurred. Instead, CeD was prevalent, a condition not reported in classic IBD. Patients with an associated autoimmune disease had more symptoms. Patients with CC and CeD had an earlier onset of their colitis. The majority of the patients with both CC and CeD were smokers. Associated autoimmune disease should be contemplated in the follow-up of these patients.

BackgroundRescue 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. AimTo present a retrospective study of IFX as rescue therapy in UC. Primary end points were colectomy-free survival at 3 and 12months. MethodsIn this multicentre study, 211 adult patients hospitalised between 1999 and 2010 received IFX 5mg/kg as rescue therapy due to a steroid-refractory, moderate-to-severe attack of UC. Exclusion criteria were duration of current flare for >12weeks, corticosteroid treatment for >8weeks before hospitalisation, previous IFX therapy or Crohn's disease. ResultsProbability of colectomy-free survival at 3months was 0.71 (95% CI, 0.64-0.77), at 12months 0.64 (95% CI, 0.57-0.70), at 3years 0.59 (95% CI, 0.52-0.66) and at 5years 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 12months respectively. Of 75 colectomies during the first year, 48 (64%) were carried out during the first 14days, 13 (17%) on days 15-90 and 14 (19%) between 3 and 12months. There were three (1.4%) deaths during the first 3months. ConclusionsInfliximab 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 14days, which calls for studies on how to optimise induction treatment with IFX. Serious complications, including mortality, were rare.

To evaluate the optimum dose of olsalazine for maintaining remission in ulcerative colitis, 198 patients in remission for more than three months were randomly assigned to receive 0.5 g, 1.0 g, or 2.0 g/day for 12 months. A dose-ranging effect was detected in the per protocol analysis, with remission rates of 60% (0.5 g), 70% (1.0 g), and 78% (2.0 g) (p = 0.03, trend in proportions). The higher dose was most effective in patients with proctitis (90% remission on 2 g/day, p = 0.03) or those in remission for less than 12 months before the trial (88% remission on 2 g/day, p = 0.0006). There was little dose-ranging effect in patients with extensive colitis or those in remission for more than 12 months. Diarrhoea necessitated treatment withdrawal in 12%. The optimal dose of olsalazine for maintaining remission in ulcerative colitis is 1 g/day. For patients with proctitis or recent relapse, 2 g/day may be preferable, although the dose seems to be less important in patients with more extensive disease or those in long term remission.

Microscopic colitis (MC) is an inflammatory bowel disease presenting with chronic, non-bloody watery diarrhoea and few or no endoscopic abnormalities. The histological examination reveals mainly two subtypes of MC, lymphocytic or collagenous colitis. Despite the fact that the incidence in MC has been rising over the last decades, research has been sparse and our knowledge about MC remains limited. Specialists in the field have initiated the European Microscopic Colitis Group (EMCG) with the primary goal to create awareness on MC. The EMCG is furthermore a forum with the intention to promote clinical and basic research. In this article statements and comments are given that all members of the EMCG have considered being of importance for a better understanding of MC. The paper focuses on the newest updates in epidemiology, symptoms and diagnostic criteria, pathophysiology and highlights some unsolved problems. Moreover, a new treatment algorithm is proposed on the basis of new evidence from well-designed, randomized control trials.

Bowel strictures are a major cause of morbidity, hospitalisation and surgery in Crohn's disease.We report short- and long-term efficacy and safety of endoscopic balloon dilation of strictures due to Crohn's disease.Retrospective study of patients who underwent endoscopic balloon dilation between 1987 and 2009.We performed 776 dilations, of which 621 (80%) were on anastomotic strictures, in 178 patients (94 women) with Crohn's disease. At first dilation, median (IQR) age of patients was 45 (37-56) years and disease duration 16 (8-22) years. Technical success rate was 689/776 (89%). A subset of 75 patients from the primary catchment area, with5-year follow-up, underwent a total of 246 dilations. At 1-year follow-up, 60/75 (80%) patients had undergone no further intervention or one additional dilation only. At 3 and 5 years, corresponding figures were 43/75 (57%) and 39/75 (52%). Cumulative proportions of patients undergoing surgery at 1, 3 and 5 years were 13%, 28% and 36%. Complication rate per procedure for all 178 patients was 41/776 (5.3%), bowel perforation (n = 11, 1.4%), major bleeding requiring blood transfusion (n = 8, 1.0%), minor bleeding (n = 10, 1.3%) and abdominal pain or fever (n = 12, 1.5%). Ten patients underwent surgery due to complications (perforation n = 8, bleeding n = 2). There was no procedure-related mortality.Endoscopic balloon dilation is an efficacious and safe alternative to surgical resection of intestinal strictures in Crohn's disease. At 5-year follow-up, 52% of patients required no further or one additional dilation only, whereas 36% had undergone surgical resection. Complication frequency was low.

Background: Cyclosporine (CsA) or infliximab (IFX) are used as rescue therapies in steroid-refractory, severe attacks of ulcerative colitis (UC). There are no data comparing the efficacy of these two alternatives. Methods: Outcome of rescue therapy was retrospectively studied in two cohorts of patients hospitalized due to steroid-refractory moderate to severe UC: 1) a Swedish-Danish cohort (n 49) treated with a single infusion of IFX; 2) an Austrian cohort (n 43) treated with intravenous CsA. After successful rescue therapy, maintenance immunomodulator treatment was given to 27/33 (82%) of IFX patients and to 31/40 (78%) of CsA patients. Endpoints were colectomy-free survival at 3 and 12 months. Kaplan-Meier and Cox regression models were used to evaluate the association between treatment groups and colectomy. Results: At 15 days, colectomy-free survival in the IFX cohort was 36/49 (73%) versus 41/43 (95%) in the CsA cohort (P = 0.005), at 3 months 33/49 (67%) versus 40/43 (93%) (P = 0.002), and at 12 months 28/49 (57%) versus 33/43 (77%) (P = 0.034). After adjusting for potential confounding factors, Cox regression analysis yielded adjusted hazard ratios for risk of colectomy in IFX-treated patients of 11.2 (95% confidence interval [CI] 2.4-53.1, P = 0.002) at 3 months and of 3.0 (95% CI 1.1-8.2, P = 0.030) at 12 months in comparison with CsA-treated patients. There were no opportunistic infections or mortality. Conclusions: Colectomy frequencies were significantly lower after rescue therapy with CsA than with a single infusion of IFX both at 3 and 12 months' follow-up. The superiority of CsA was seen principally during the first 15 days.

Objectives: The characteristic clinical symptoms of collagenous colitis are non-bloody diarrhoea, urgency and abdominal pain. Treatment is aimed at reducing the symptom burden and the disease impact on patients' health-related quality of life. The objective of this study was to analyse health-related quality of life in patients with collagenous colitis. Methods: In a cross-sectional, postal HRQL survey, 116 patients with collagenous colitis at four Swedish hospitals completed four health-related quality of life questionnaires, two disease-specific (Inflammatory Bowel Disease Questionnaire and Rating Form of IBD Patient Concerns), and two generic (Short Form 36, SF-36, and Psychological General Well-Being, PGWB), and a one-week symptom diary. Demographic and disease-related data were collected. Results for the collagenous colitis population were compared with a background population controlled for age and gender (n = 8931). Results: Compared with a Swedish background population, patients with collagenous colitis scored significantly worse in all Short Form 36 dimensions (p < 0.01), except physical function. Patients with active disease scored worse health-related quality of life than patients in remission. Co-existing disease had an impact on health-related quality of life measured with the generic measures. Lower education level and shorter disease duration were associated with decreased well-being. Conclusion: Health-related quality of life was impaired in patients with collagenous colitis compared with a background population. Disease activity is the most important factor associated with impairment of health-related quality of life. Patients in remission have a health-related quality of life similar to a background population. (C) 2010 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

P>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.

Crohn's disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1beta. Production of mature IL-1beta is dependent on a caspase-1-activating protein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required for bacteria-induced IL-1beta secretion. The combination of the polymorphisms CARD8 (C10X)and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis.Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD.The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping.Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32-8.76); P = 0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44-1.77); P = 0.74).We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.

Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD.A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied.The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A.This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.

Health-related quality of life (HRQoL) is an essential part of inflammatory bowel disease (IBD) assessment. The Short Health Scale (SHS), an HRQoL questionnaire in which the patients rate the disease impact on 4 important aspects of subjective health (symptoms, function, worry, and general well-being) was demonstrated in a previous study to be valid, reliable, and responsive in patients with ulcerative colitis. The present study evaluates the SHS in patients with Crohn's disease (CD).In all, 367 CD patients completed the SHS and 4 other HRQoL questionnaires (IBDQ, SF-36, RFIPC, and PGWB) at their regular outpatient visits. Then 330 patients completed the questionnaires at a second visit 6 months later. In addition, reliability data were obtained from repeat measurements 4 weeks after the first visit in 40 patients stable in remission.Patients in remission scored better on all 4 questions than those with active disease (P0.001). All 4 questions were strongly correlated with the corresponding dimensions of the other HRQoL questionnaires (r(s) = 0.74-0.83). Reliability was confirmed with strong test-retest correlations (r(s) = 0.69-0.82) and intraclass correlation coefficients (0.66-0.77). Patients who changed from remission to active disease or vice versa showed a significant change in all 4 SHS scores (P0.005).SHS is a valid, reliable and responsive HRQoL instrument also in patients with CD. It is easily completed by the patient and requires no further calculation by the investigator. SHS gives a comprehensive overview of the main aspects of the patient's subjective health perception and is a useful tool in both clinical practice and clinical studies.

Background: Faecal calprotectin, an established biomarker used to assess mucosal inflammation, has been shown to correlate with endoscopic activity in inflammatory bowel disease (IBD). Longitudinal monitoring of faecal calprotectin, however, has rarely been employed beyond assessment of therapy response and post hoc analyses of clinical trials. Aim: To study whether consecutive measurements of faecal calprotectin every third month are useful for monitoring patients with IBD in clinical remission. Methods: Patients aged 18 years or older, with a known diagnosis of IBD in clinical remission, were prospectively studied. Patients provided faecal samples every third month and were prospectively followed until the first clinical relapse or the end of the 2-year follow-up period. Measurements (EK-CAL, Bühlmann Lab. AG, Switzerland) were done at the end of the study. A Cox model with time-dependent covariates was used for analysis. Results: Among 104 patients, Crohn's disease (n = 49) and ulcerative colitis (n = 55), 37 had a relapse. A doubling of faecal calprotectin level between two consecutively collected samples was associated with a 101% increased risk of relapse (HR: 2.01; 95% CI: 1.53-2.65; P < 0.001). The relative risk of relapse attenuated with time (HR: 0.80; 95% CI: 0.75-0.86; P < 0.001), by a 20% decrease in risk of relapse per 3-month period since the sample was obtained. Conclusions: By consecutively measuring faecal calprotectin every third month, we quantified the risk of relapse related to faecal calprotectin change and observed attenuation of the risk across time. Our data suggest that longitudinal monitoring of faecal calprotectin is informative in predicting relapse in IBD., Funding Agencies:Örebro University Hospital Research Foundation OLL-333321Swedish Foundation For Strategic Research RB13-0160Uppsala-Örebro Regional Research Foundation RFR-314671Örebro County Research Foundation OLL-290301 OLL-172601 OLL-93671 OLL-122871

OBJECTIVE: This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis.DESIGN: A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase.RESULTS: Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5 days (95% CI (9.0 to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), pCONCLUSIONS: Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation.TRIAL REGISTRATION NUMBERS: http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31).

Corticosteroids are a cornerstone in the treatment of a severe attack of ulcerative colitis (UC). The long-term prognosis in this patient group is not well described. We studied the long-term colectomy and relapse rates in patients given intensive intravenous corticosteroid treatment (IIVT) for acute UC.A retrospective clinical study of 158 patients with UC treated in 1975-1982 with IIVT. Patients were followed-up to death, colectomy or last visit.A total of 11 patients were excluded due to change of diagnosis (N = 10) or lost to follow-up (N = 1). The indication for index IIVT in the remaining 147 patients was a severe attack (N = 61), a moderately severe attack (N = 45), a mild attack (N = 29) or chronic continuous disease (N = 12). The median (range) duration of follow-up was 173 (4-271) months in patients escaping colectomy during the first 3 months. Three months after IIVT, the colectomy rates were 28/61 (46%) in a severe attack, 4/45 (9%) in a moderately severe, and 1/29 (3%) in a mild attack. After 10 yr, the colectomy rates were 39/61 (64%), 22/45 (49%), and 8/29 (28%), respectively. During follow-up, neither colectomy incidence beyond 3 months, time to first relapse nor relapse incidence was influenced by severity of initial attack, except for a lower relapse incidence after a severe attack.In patients escaping colectomy during the first 3 months after IIVT, the future prognosis was similar irrespective of initial disease severity.

OBJECTIVE: Adult-type hypolactasia (AtH) can be diagnosed by genotyping in addition to functional tests or intestinal biopsy. The aims of this study were to estimate the prevalence of AtH by genotyping and to investigate whether AtH prevalence has changed in Sweden during the 20th century. MATERIAL AND METHODS: Schoolchildren (n=690) born in 1983 and 1989, and elderly individuals (n=392) born between 1920 and 1932 were genotyped for AtH using Pyrosequencing technology. RESULTS: The overall prevalence of AtH among children was 14.1%. The majority of children (92%, n=635) were Caucasians with genotype prevalences: CC, 61 (10%); CT, 259 (41%); TT, 307 (49%). The frequency of the mutated allele q was 0.300 in this cohort. The prevalence of AtH estimated from the Hardy-Weinberg equilibrium (HWE) (q 2), was 9.0% (95% CI: 6.7-11.2%). Eight percent (n=55) of the children were non-Caucasian; genotype prevalences were CC, 36 (66%); CT, 15 (27%); TT, 4 (7%). The prevalence of AtH in these children estimated from HWE was 62.5% (95% CI: 49.7-75.3%). The elderly subjects were all Caucasians. Their genotype prevalences were: CC, 20 (5%); CT, 166 (42%); TT, 206 (53%); the frequency of the mutated allele q was 0.262 and their AtH prevalence estimated from HWE was 6.8% (95% CI: 4.3-9.2%). CONCLUSIONS: The overall prevalence of AtH in children (14%) was higher than previously thought. Among Caucasians, higher figures were seen in children than in the elderly (9% versus 6.8%). The prevalence thus seems to be increasing and this may be due to the immigration of both non-Caucasian and Caucasian groups with a higher prevalence of AtH.

Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with active ulcerative colitis and Crohn's disease. Preliminary data have indicated that this type of therapy is safe and efficacious, and large sham-controlled studies are currently in progress. In Scandinavia, a substantial number of patients with chronic inflammatory bowel disease have already received leukocyte apheresis on a compassionate use basis and the aim of this study was to report the clinical outcome and adverse events in the first patients treated.Clinical details of the first consecutive 100 patients with inflammatory bowel disease treated with granulocyte, monocyte/macrophage (Adacolumn) apheresis in Scandinavia were prospectively registered. Median length of follow-up was 17 months, (range 5-30).The study population comprised 52 patients with ulcerative colitis, 44 patients with Crohn's disease and 4 patients with indeterminate colitis. In 97 patients the indication for Adacolumn treatment was steroid-refractory or steroid-dependent disease. Clinical remission was attained in 48% of the patients with ulcerative colitis, and an additional 27% had a clinical response to the apheresis treatment. The corresponding figures for patients with Crohn's disease were 41% and 23%, respectively. Complete steroid withdrawal was achieved in 27 out of the 50 patients taking corticosteroids at baseline. Adverse events were reported in 15 patients and headache was most frequently reported (n=7).Granulocyte, monocyte/macrophage apheresis treatment seems to be a valuable adjuvant therapy in selected patients with refractory inflammatory bowel disease. The risk for toxicity or severe adverse events appears to be low.

Background: The relationship between clinical and histological parameters in collagenous colitis (CC) is poorly understood. Smoking is a risk factor for CC, whereas its impact on clinical activity and outcome is not well known. Methods: In a post hoc analysis of pooled data from two randomized controlled trials we assessed the association between demographic data (gender, age, smoking habits, family history of inflammatory bowel disease), clinical variables (duration of symptoms, mean number of stools/watery stools per day, abdominal pain, clinical remission) and histological data (thickness of the collagen band, inflammation of the lamina propria, total numbers of intraepithelial lymphocytes, degeneration). Moreover, we analysed the predictive value of baseline parameters for clinical outcome in a logistic regression model. Results: Pooled data were available from 202 patients with active CC, of whom 36% were current smokers, 29% former smokers and 35% non-smokers. Smoking status was associated with decreased ability to achieve clinical remission (current smokers vs non-smokers: odds ratio [OR] 0.31, 95% confidence interval [CI] 0.10–0.98, p = 0.045; former smokers vs non-smokers: OR 0.19, 95% CI 0.05–0.73, p = 0.016). Current smokers had an increased mean number of watery stools at baseline compared with non-smokers ( p = 0.051) and increased mean number of watery stools per se was associated with decreased likelihood of obtaining clinical remission (OR 0.63, 95% CI 0.47–0.86, p = 0.003). Patient characteristics and histology at baseline had no association with clinical parameters and no predictive value for clinical outcome. Conclusion: Smoking worsens clinical symptoms in CC and is associated with an increased number of watery stools and decreased likelihood of achieving clinical remission. There is no significant association between histology and clinical data.

Genetics and environmental factors are implicated in the etiology of inflammatory bowel disease (IBD). We studied environmental factors in a population-based Swedish-Danish twin cohort using the co-twin control method.A questionnaire was sent to 317 twin pairs regarding markers of exposures in the following areas: infections/colonization and diet as well as smoking, appendectomy, and oral contraceptives. Odds ratios (OR) were calculated by conditional logistic regression. When confounding appeared plausible, multivariate conditional logistic regression was added. The questions were also divided into topic groups, and adjustment was made for multiple testing within each of the groups.The response rate to the questionnaire was 83%. In consideration of the study design, only discordant pairs were included (Crohn's disease [CD], n = 102; ulcerative colitis [UC], n = 125). Recurrent gastrointestinal infections were associated with both UC (OR, 8.0; 95% confidence interval [CI], 1.0-64) and CD (OR, 5.5; 95% CI, 1.2-25). Hospitalization for gastrointestinal infections was associated with CD (OR, 12; 95% CI, 1.6-92). Smoking was inversely associated with UC (OR, 0.4; 95% CI, 0.2-0.9) and associated with CD (OR, 2.9; 95% CI, 1.2-7.1).The observed associations indicate that markers of possible infectious events may influence the risk of IBD. Some of these effects might be mediated by long-term changes in gut flora or alterations in reactivity to the flora. The influence of smoking in IBD was confirmed.

Previous chromatographic analysis of colonic mucins from monozygotic twins with inflammatory bowel disease (IBD) suggested a genetic mucin alteration in ulcerative colitis (UC). This study explores this further by assessing mucosal expression of the oncofetal carbohydrate antigen TF (galactose beta1, 3 N-acetylgalactosamine alpha-), among the same IBD twins.Formalin fixed paraffin embedded rectal biopsies were studied from 22 monozygotic twin pairs with IBD. These included eight UC twin pairs and 14 Crohn's disease (CD) twin pairs, with six pairs concordant for disease and 16 unaffected twin siblings. Closely adjacent sections were assessed by peanut lectin histochemistry for TF expression and immunohistochemically for nuclear factor kappaB (NFkappaB) activation with investigators blinded to the diagnosis.Unaffected twins were almost all TF positive (15/16) compared with 5/29 histologically normal controls (p0.0001). Unaffected UC (7/8) and CD twins (8/8) were similarly TF positive. TF positivity was confined mainly to the superficial epithelium and absent from the stem cell compartment of the lower crypts, suggesting that glycosylation changes are acquired rather than genetically determined. Activated NFkappaB was present in the surface epithelium of mucosal biopsies from 13/14 unaffected IBD twins but in only 6/22 histologically normal controls (p=0.0004). All 22 affected IBD twins were TF positive and 18 were positive for activated NFkappaB.Altered mucosal glycosylation in unaffected identical twins of IBD patients was confirmed in this study. This occurred in both UC and CD twins. The changes are probably acquired rather than congenital and may reflect "preinflammatory" NFkappaB activation.

Background. CARD15/NOD2 polymorphisms are associated with Crohn's disease. There is a high concordance for disease and disease phenotype in monozygotic twin pairs with Crohn's disease. Aim. We studied CARD15/NOD2 polymorphisms in a Swedish, population-based cohort of monozygotic twins with Crohn's disease to assess whether these variants explain disease concordance. Subjects and methods. Twenty-nine monozygotic twin pairs (concordant n = 9, discordant n = 20) with Crohn's disease and 192 healthy controls were investigated for the CARD15/NOD2 variants Arg702Trp, Gly908Arg and Leu1007fsinsC. Results. CARD15/NOD2 mutations were found in 5/38 (13%) twins with Crohn's disease, corresponding to a total allele frequency of 6.6%. Only 2/9 concordant twin pairs carried any of the variants and the remaining seven were wild type genotype. The total allele frequency was 4.4 times higher (95% confidence interval 1.0–21.5, p = 0.06) in concordant twins than in discordant ones, 11.1% versus 2.5%. In healthy controls the total allele frequency was 2.6%. Conclusions. CARD15/NOD2 polymorphisms contribute but do not alone explain concordance of Crohn's disease in monozygotic twins and, at least in a Swedish population, other polymorphisms are required. The low occurrence of CARD15/NOD2 mutations in the study and other Northern European populations suggests that these variants are of less importance in Northern Europe.

Background and aims: An increased occurrence of anti- Saccharomyces cerevisiae antibodies (ASCA) is reported in unaffected members of families with Crohn’s disease. Whether ASCA is a familial trait due to genetic factors or is caused by exposure to environmental factors is unknown. To assess the genetic influence of ASCA we studied its occurrence in a twin population. Patients and methods: ASCA were analysed in 98 twin pairs with inflammatory bowel disease and were related to clinical phenotype and CARD15/NOD2 genotype. Results: ASCA were more common in Crohn’s disease than in ulcerative colitis (40/70 (57%) twins v 5/43 (12%) twins). Associations with ileal Crohn’s disease, stricturing/penetrating behaviour, and young age, but not CARD15/NOD2 were confirmed. ASCA were found in 1/20 (5%) healthy siblings in discordant monozygotic pairs with Crohn’s disease compared with 7/27 (26%) in discordant dizygotic pairs. Using the intraclass correlation coefficient (ICC), no agreement in ASCA titres was observed in discordant twin pairs with Crohn’s disease, in monozygotic (ICC = −0.02) or dizygotic (ICC = −0.26) pairs. In contrast, strong agreement was seen within concordant monozygotic twin pairs with Crohn’s disease (ICC = 0.76). Conclusions: These findings question the concept of ASCA as a marker of genetic susceptibility for Crohn’s disease. The agreement in ASCA titres within concordant monozygotic twin pairs with Crohn’s disease, suggests that the level of increase is genetically determined. We propose that ASCA are a marker of a response to an environmental antigen and that a specific gene(s) other than CARD15/NOD2 determines the level of response and perhaps also specific phenotypic characteristics.

Collagenous colitis is generally regarded as a benign disease with few serious complications. We report two women with collagenous colitis who presented with colonic perforation, one spontaneously and one 7 days after a barium enema, and a review of the literature. Including the present cases, 13 patients with collagenous colitis and colonic perforation have been reported, in two patients spontaneously and in 11 patients after a colonoscopy or barium enema. All were operated on except one patient who recovered after medical treatment. The pathogenesis of this complication is unknown. We propose that there might be a connection between mucosal tears and colonic perforation in collagenous colitis.

Background: Microscopic colitis, including collagenous colitis and lymphocytic colitis, mainly affects middle aged and older subjects, with a female predominance in collagenous colitis. The diseases have previously been regarded as rare. We present an epidemiological study of microscopic colitis in a well defined Swedish population. Methods: Patients were retrospectively searched for in colonoscopy reports of those who had a colonoscopy in the period 1993–1998 for non-bloody diarrhoea. All colonic mucosal biopsies were reassessed using strict diagnostic criteria. Results: Biopsies from 1018 patients were reassessed. Fifty one (45 female) collagenous colitis patients and 46 (31 female) lymphocytic colitis patients were diagnosed. Median age at diagnosis was 64 years in collagenous colitis and 59 years in lymphocytic colitis. The mean annual incidence of collagenous colitis was 4.9/105 inhabitants (95% confidence interval (CI) 3.6–6.2/105) and of lymphocytic colitis 4.4/105 inhabitants (95% CI 3.1–5.7/105). The annual incidence of collagenous colitis increased from 3.7/105 in 1993–1995 to 6.1/105 in 1996–1998 (difference 2.4/105 (95% CI −0.3–5.1/105)) whereas the incidence of lymphocytic colitis increased from 3.1/105 to 5.7/105 (difference 2.6/105 (95% CI 0.1–5.2/105)). Conclusions: The annual incidences of collagenous colitis and lymphocytic colitis are higher than considered previously and are now equal to the incidence of Crohn’s disease in Sweden, and combined rates approach the incidence of ulcerative colitis. Microscopic colitis was diagnosed in 10% of all patients with non-bloody diarrhoea referred for colonoscopy and in almost 20% of those older than 70 years.

Faecal calprotectin for the prediction of relapse in inactive inflammatory bowel disease : - authors' reply

Crohn's disease (CD) is a complex genetic disorder for which aetiology is unknown. Recently, genetic factors for susceptibility have been described. Several genetic loci have been mapped and partially explain the familial aggregations of the disease. However, environmental factors may also contribute to these aggregations. We considered that if the role of non-genetic factors was negligible, CD patients would be randomly distributed in sibships with multiple affected siblings. On the other hand if there was a significant environmental contribution, the siblings would be affected non-randomly over exposure status. In order to test this hypothesis, we studied 102 sibships with two or more affected siblings. A statistical test, named Cluster of Affected Sibling Test or CAST, was developed, based on the exact calculation of the probability of observing a given number of clusters of affected siblings in multiplex families. The null hypothesis of a random distribution of affected siblings was rejected (P=0.005). The observed excess of affected sibling clusters indicates that birth order influences the disease status. Considering that an adjacent order of birth is a global estimate of environmental sharing, this observation strongly suggests that environmental factors contribute to the observed familial aggregations of the disease. This observation provides evidence that familial CD is a relevant tool for further studies of environmental factors and gene-environment interaction. More generally, the CAST statistics may be widely applicable to estimate the involvement of environmental factors in the aetiology of other binary traits which may be observed in multiple members of the same sibship.

Appendectomy is associated with a low risk of subsequent ulcerative colitis. This study analyzes the risk of Crohn's disease after appendectomy.We followed-up 212,218 patients with appendectomy before age 50 years and a cohort of matched controls, identified from the Swedish Inpatient Register and the nationwide Census, for any subsequent diagnosis of Crohn's disease.An increased risk of Crohn's disease was found for more than 20 years after appendectomy, with incidence rate ratio 2.11 (95% confidence interval [CI], 1.21-3.79) after perforated appendicitis, 1.85 (95% CI, 1.10-3.18) after nonspecific abdominal pain, 2.15 (95% CI, 1.25-3.80) after mesenteric lymphadenitis, 2.52 (95% CI, 1.43-4.63) after other diagnoses. After nonperforated appendicitis, there was an increased risk among women but not among men (incidence rate ratio 1.37; 95% CI, 1.03-1.85, respectively, 0.89, 95% CI, 0.64-1.24). Patients operated on before age 10 years had a low risk (incidence rate ratio 0.48, 95% CI, 0.23-0.97). Crohn's disease patients with a history of perforated appendicitis had a worse prognosis.Appendectomy is associated with an increased risk of Crohn's disease that is dependent on the patient's sex, age, and the diagnosis at operation. The pattern of associations suggests a biologic cause.

Objective: Changes in medical therapy and surgery might have influenced the natural history Crohn’s disease (CD). Our aim was to explore the short-term outcome of CD and to specifically assess trends in disease phenotype, medications and surgery in the first five years from diagnosis. Material and Methods: A population-based cohort comprising 472 CD patients diagnosed within the primary catchment area of Örebro University Hospital 1963-2005 were identified retrospectively and described. Data on medication, surgery, progression in disease location and behaviour, were extracted from the medical records. Patients were divided into three cohorts based on year of diagnosis. Results: The proportion of patients with complicated disease behaviour 5 years after diagnosis decreased from 54.4% (95%CI, 43.9-65.6) to 33.3% (27.4-40.0) in patients diagnosed 1963-1975 and 1991-2005, respectively (p=0.002), whereas the proportion of patients progressing to complicated disease behaviour was stable among those with non-stricturing, non-penetrating disease at diagnosis (p=0.435). The proportion of patients undergoing surgery decreased from 65.8% (55.4-76.0) to 34.6% (28.6-41.5) in patients diagnosed 1963-1975 and 1991-2005, respectively (p, Funding Agencies:Örebro University Hospital Research Foundation OLL-256371Örebro County Research Foundation OLL-403371 OLL-457731

Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX3CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX3CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.

Background/Aim: Diarrhoea in collagenous colitis has been considered as secretory though the pathophysiology has been studied thoroughly in only a few patients. The result of fasting is one way to distinguish between secretory and osmotic diarrhoea. Our aim was to investigate the effect of fasting on diarrhoea in collagenous colitis. Methods: Fourteen patients with collagenous colitis were admitted to the hospital for investigation. All were female. Five of these did not have diarrhoea during admission and were excluded. Stools were examined for weight, electrolytes, pH, fat and osmolality during a period on a normal diet and during fasting. Results: During the fasting period the faecal weight was significantly reduced from median 757 (440–3,198) to 191 (22– 2,197) g. The faecal sodium concentration was also reduced, though not significantly, during fasting from median 65 (29–85) to 45 (19–88) mmol/l. The osmotic gaps varied according to the method of calculation applied. Conclusions: The data indicate that the cause of the diarrhoea in collagenous colitis could be multifactorial. In some patients an osmotic factor dominates and in others a secretory factor, while in some patients a combination of both seems to exist.

Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

A history of appendectomy is rare in patients with ulcerative colitis. This suggests a protective effect of appendectomy or that appendicitis and ulcerative colitis are alternative inflammatory responses. We sought to characterize this inverse relation further.We studied a cohort of 212,963 patients who underwent appendectomy before the age of 50 years between 1964 and 1993 and a cohort of matched controls who were identified from the Swedish Inpatient Register and the nationwide census. The cohort was followed until 1995 for any subsequent diagnosis of ulcerative colitis.Patients who underwent appendectomy for appendicitis and mesenteric lymphadenitis had a low risk of ulcerative colitis (for patients with perforated appendicitis, the adjusted hazard ratio was 0.58 [95 percent confidence interval, 0.38 to 0.87]; for those with nonperforated appendicitis it was 0.76 [95 percent confidence interval, 0.65 to 0.90]; and for those with mesenteric lymphadenitis it was 0.57 [95 percent confidence interval, 0.36 to 0.89]). In contrast, patients who underwent appendectomy for nonspecific abdominal pain had the same risk of ulcerative colitis as the controls (adjusted hazard ratio, 1.06; 95 percent confidence interval, 0.74 to 1.52). For the patients who had appendicitis, an inverse relation with the risk of ulcerative colitis was found only for those who underwent surgery before the age of 20 years (P0.001).Appendectomy for an inflammatory condition (appendicitis or lymphadenitis) but not for nonspecific abdominal pain is associated with a low risk of subsequent ulcerative colitis. This inverse relation is limited to patients who undergo surgery before the age of 20 years.

Collagenous colitis and lymphocytic colitis are newly described colitides that are only diagnosable microscopically; therefore, both are known under the umbrella term ’microscopic colitis’. This is a short review of the clinical findings, and epidemiological and basic observations of these relatively little described colitides belonging to the group of inflammatory bowel diseases.

BackgroundA familial defect in intestinal barrier function has been found in Crohn’s disease.AimTo investigate possible genetic and environmental influences on this barrier defect by studying intestinal permeability in both relatives and spouses of patients with Crohn’s disease.SubjectsThe study included 39 patients with Crohn’s disease, 34 healthy first degree relatives, and 22 spouses. Twenty nine healthy volunteers served as controls.MethodsIntestinal permeability was assessed as the lactulose:mannitol ratio in five hour urinary excretion after oral load, both before (baseline) and after ingestion of acetylsalicylic acid. The permeability response represents the difference between the two tests. A ratio above the 95th percentile for controls was classified as abnormal.ResultsBaseline permeability was higher in patients and spouses than in controls. An abnormal baseline permeability was seen in 36% of the patients, 23% of the spouses, 18% of the relatives, and 3% of the controls. After ingestion of acetylsalicylic acid, permeability increased significantly in all groups. Relatives were similar to patients with regard to permeability after exposure to acetylsalicylic acid, whereas spouses were similar to controls. The proportions with an abnormal permeability response to acetylsalicylic acid were 32% in patients, 14% in spouses, 41% in relatives, and 3% in controls.ConclusionThe findings suggest that baseline permeability is determined by environmental factors, whereas permeability provoked by acetylsalicylic acid is a function of the genetically determined state of the mucosal barrier, and support the notion that environmental and hereditary factors interact in the pathogenesis of Crohn’s disease.

Active Crohn's disease constitutes a major problem in gastroenterology. Symptoms vary with site, extent and local complications of the disease as well as with the absence or presence of extraintestinal manifestations. Due to the troublesome consequences of the disease new treatments have continuously been tried. However, the results have varied and no definite breakthrough has occurred in the medical treatment of active Crohn's disease during the last years. The new salicylates have shown some effect using higher doses, but have not fulfilled the expectations once connected with their development. The new steroids have compared well to, but not exceeded, the older corticosteroid preparations in terms of therapeutic efficacy but they have a better side-effect profile. The role of the purine analogs azathioprine/6-mercaptopurine has been further evaluated. The onset of their effect is slow, an intravenous loading dose might shorten this time span, and they are steroid sparing. The controlled data on methotrexate are limited and the long-term effects not well studied and there is concern about toxicity. Even the use of cyclosporine in active Crohn's disease is controversial and connected with serious adverse events. Studies on the new immune modulating therapies such as anti-TNF-alpha antibodies, anti-CD4 antibodies, interleukin-10 and interferon have been encouraging but large scale studies are still awaited before the effect and the spectra of side-effects can be fully evaluated. The aim of this chapter is to summarize the present knowledge of medical treatment of active Crohn's disease and to point towards the directions of new therapeutic options.

Background and aim: The incidence of Crohn's disease (CD) is continuing to rise in several countries and in others it appears to have already levelled off after a period of increase. We updated our previous population-based study, by re-extraction of all information on patients diagnosed with CD between 1963 and 2010. Our aim was to assess temporal trends in incidence, prevalence and disease phenotype at diagnosis. Methods: Patients of all ages with a potential diagnosis of CD were identified retrospectively by evaluation of medical notes of all current and previous patients at the colitis clinic, Örebro University Hospital amended by computerised search in the inpatient, outpatient, primary care and histopathological records. Diagnosis was confirmed by subsequent evaluation of medical notes. Disease phenotype was defined according to the Montreal classification. Results: The incidence increased over time, especially among Crohn's disease, A1 and A3. SaTScan model revealed a statistically significant high incidence during 1991-2010 (p=0.0001). The median age at diagnosis increased from 28 (3-79) years to 37 (5-87) years (p=0.0002). The point prevalence increased from 21/10(5) (14-32) in 1965 to 267/10(5) (244-291) in 2010. Non-stricturing and non-penetrating disease at diagnosis increased from 12.5% in 1963-1965 to 82.3% in 2006-2010 (p, Funding Agencies:Karlskoga Hospital Reseach Foundation AE-37256Bengt Ihre's Foundation SLS-254051Örebro University Hospital Research Foundation OLL-256371Örebro County Research Foundation OLL-93671 OLL-172601 OLL-200541 OLL-256771Swedish Foundation

Microscopic colitis, comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhoea. The long-term prognosis is not well described.To study outcome of symptoms and health-related quality of life (HRQoL).A case-control study using a postal questionnaire with three population-based controls per patient matched for age, sex and municipality. HRQoL was assessed by the Short Health Scale (SHS). Patients in clinical remission, defined as a mean of3 stools/day, were evaluated separately (CC; n = 72, LC; n = 60).The study included 212 patients and 627 matched controls. Median disease duration was 5.9 (range 0.5-27) years and 6.4 (0.3-14.8) years for CC and LC respectively. Abdominal pain, fatigue, arthralgia, myalgia, faecal incontinence and nocturnal defecation were significantly more prevalent in CC patients compared with controls. These differences persisted in CC patients in clinical remission with respect to abdominal pain (36% vs. 21%), fatigue (54% vs. 34%), arthralgia (61% vs. 41%) and myalgia (53% vs. 37%). In LC patients, abdominal pain, fatigue, faecal incontinence and nocturnal defecation were more prevalent compared with controls. In LC patients in clinical remission, fatigue was more prevalent compared with controls (54% vs. 37%). These differences were statistically significant (P 0.05). All four HRQoL dimensions (symptom burden, social function, disease-related worry, general well-being) were impaired in patients with active CC and LC.Although considered to be in clinical remission, patients with microscopic colitis suffer from persisting symptoms such as abdominal pain, fatigue, arthralgia or myalgia several years after diagnosis.