IOIBD Recommendations for Clinical Trials in Ulcerative Proctitis: The PROCTRIAL Consensus.

BACKGROUND & AIMS: Clinical trials evaluating biologics and small molecules in patients with ulcerative colitis are predominantly excluding ulcerative proctitis. The objective of the Definition and endpoints for ulcerative PROCtitis in clinical TRIALs initiative was to develop consensus statements for definitions, inclusion criteria, and endpoints for the evaluation of ulcerative proctitis in adults. METHODS: Thirty-five international experts held a consensus meeting to define ulcerative proctitis, and the endpoints to use in clinical trials. Based on a systematic review of the literature, statements were generated, discussed, and approved by the working group participants using a modified Delphi method. Consensus was defined as at least 75% agreement among voters. RESULTS: The group agreed that the diagnosis of ulcerative proctitis should be made by ileocolonoscopy and confirmed by histopathology, with the exclusion of infections, drug-induced causes, radiation, trauma, and Crohn's disease. Ulcerative proctitis was defined as macroscopic extent of lesions limited to 15 cm distance from the anal verge in adults. Primary and secondary endpoints were identified to capture response of ulcerative proctitis to therapy. A combined clinical and endoscopic primary endpoint for the evaluation of ulcerative proctitis disease activity was proposed. Secondary endpoints that should be evaluated include endoscopic remission, histologic remission, mucosal healing, histologic endoscopic mucosal improvement, disability, fecal incontinence, urgency, constipation, and health-related quality of life. CONCLUSIONS: In response to the need for guidance on the design of clinical trials in patients with ulcerative proctitis, the Definition and end points for ulcerative PROCtitis in clinical TRIALs consensus provides recommendations on the definition and endpoints for ulcerative proctitis clinical trials.

Mortality in patients with Crohn's disease in Örebro, Sweden 1963-2010.

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 Örebro 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.

Development of an index to define overall disease severity in IBD.

BACKGROUND AND AIM: Disease 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. METHODS: Using 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. RESULTS: For 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. CONCLUSIONS: Based 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.

Microscopic colitis in patients with ulcerative colitis or Crohn's disease: a retrospective observational study and review of the literature.

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.

Low-dose budesonide for maintenance of clinical remission in collagenous colitis: a randomised, placebo-controlled, 12-month trial.

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%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious. CONCLUSIONS: 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).

The changing face of Crohn's disease: a population-based study of the natural history of Crohn's disease in Örebro, Sweden 1963-2005.

OBJECTIVE: Changes in medical therapy and surgery might have influenced the natural history of 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 behavior, 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 behavior five 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 behavior 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 < 0.001). The reduction in surgery preceded an increased use of immunomodulators and was explained by a decrease in surgery within three months from diagnosis (p = 0.001). CONCLUSIONS: We observed a striking decrease in complicated disease behavior and surgery five years after CD diagnosis, the latter largely due to a decrease in early surgery. Our findings suggest that the introduction of new treatments alone does not explain the reduction in surgery rates, the increasing proportion of patients with inflammatory disease at diagnosis also play an important role.

Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment.

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.

An in vitro model to evaluate the impact of the soluble factors from the colonic mucosa of collagenous colitis patients on T cells: enhanced production of IL-17A and IL-10 from peripheral CD4⁺ T cells.

Soluble factors from intestinal mucosal cells contribute to immune homeostasis in the gut. We have established an in vitro model 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-1ß and 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, our in vitro model reveals implications of soluble factors from CC colonic mucosa on peripheral T cells, enhancing their production of both pro- and anti-inflammatory cytokines.

Geographical variability and environmental risk factors in inflammatory bowel disease.

The changing epidemiology of inflammatory bowel disease (IBD) across time and geography suggests that environmental factors play a major role in modifying disease expression. Disease emergence in developing nations suggests that epidemiological evolution is related to westernisation of lifestyle and industrialisation. The strongest environmental associations identified are cigarette smoking and appendectomy, although neither alone explains the variation in incidence of IBD worldwide. Urbanisation of societies, associated with changes in diet, antibiotic use, hygiene status, microbial exposures and pollution have been implicated as potential environmental risk factors for IBD. Changes in socioeconomic status might occur differently in different geographical areas and populations and, consequently, it is important to consider the heterogeneity of risk factors applicable to the individual patient. Environmental risk factors of individual, familial, community-based, country-based and regionally based origin may all contribute to the pathogenesis of IBD. The geographical variation of IBD provides clues for researchers to investigate possible environmental aetiological factors. The present review aims to provide an update of the literature exploring geographical variability in IBD and to explore the environmental risk factors that may account for this variability.

Celiac disease and other autoimmune diseases in patients with collagenous colitis.

BACKGROUND AND AIMS: 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. METHODS: Patients with CC answered questionnaires about demographic data and disease activity. The patient's files were scrutinized for information about autoimmune diseases. RESULTS: 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. CONCLUSION: 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.

Increased prevalence of antibodies against dietary proteins in children and young adults with cerebral palsy.

OBJECTIVES: Undernourishment is common in children with cerebral palsy (CP), but the reasons are unknown. We previously reported elevated levels of immunoglobulin (Ig) A and IgG antibodies against gliadin (AGA) and tissue transglutaminase (tTG) in 99 children and young adults with CP without characteristic findings of gluten enteropathy in small bowel biopsies. Our aim was to perform a case-control study of IgG antibodies against other dietary antigens, AGA, anti-tTG, and IgE antibodies against wheat and gluten. METHODS: Sera from 99 cases with CP and 99 healthy, age- and sex-matched controls were analysed with fluorescence enzyme-linked immunosorbent assay for detection of IgG antibodies against ß-lactoglobulin, casein, egg white, IgG- and IgA-AGA, IgA-anti-tTG, and IgE antibodies against gluten and wheat. RESULTS: Compared with controls, the odds ratio in cases with CP for having elevated levels of IgG antibodies against ß-lactoglobulin was 17.0 (95% confidence interval [CI] 2.3-128), against casein 11.0 (95% CI 2.6-46.8), and against egg white 7.0 (95% CI 1.6-30.8). The IgE responses for wheat/gluten were generally low. The tetraplegic and dyskinetic CP subtypes had significantly higher frequencies of elevated levels for all of the tested antibodies except IgG against egg white, and IgA-anti-tTG. A significantly lower weight was seen in cases with CP with positive versus negative serology. CONCLUSIONS: Elevated levels of IgG against dietary antigens were more frequent in the CP group compared with controls, and particularly in the tetraplegic and dyskinetic CP subtypes with the most severe neurologic handicap and undernourishment. Hypothetically, malnourishment may cause increased intestinal permeability and thus immunization against dietary antigens.

Endpoints for extraintestinal manifestations in inflammatory bowel disease trials: the EXTRA consensus from the International Organization for the Study of Inflammatory Bowel Diseases.

Extraintestinal manifestations occur frequently in patients with inflammatory bowel disease (IBD) and remain a diagnostic and therapeutic challenge. The aim of the Endpoints for Extraintestinal Manifestations in Inflammatory Bowel Disease Trials (EXTRA) initiative was to achieve international expert consensus on how to assess these manifestations in IBD trials. A systematic literature review was done to identify methods to diagnose extraintestinal manifestations in patients with IBD and measure treatment outcomes. A consensus meeting involving a panel of 41 attendees, including gastroenterologists and referral specialists, was held on March 31, 2021, as part of an International Organization for the Study of Inflammatory Bowel Diseases initiative. The panel agreed that a specialist's expertise is needed to confirm the diagnosis of extraintestinal manifestations before the inclusion of a patient in IBD trials, except for axial spondyloarthritis, for which typical symptoms and MRI can be sufficient. Easy-to-measure endpoints were identified to assess the response of extraintestinal manifestations to treatment without needing specialist involvement. For uveitis, peripheral spondyloarthritis, and arthralgia, endpoint measurements need specialist expertise. The timing of endpoint measurements was discussed for individual extraintestinal manifestations. The EXTRA consensus proposes guidelines on how to thoroughly evaluate extraintestinal manifestations within IBD trials, and recommends that these guidelines are implemented in future trials to enable prospective assessment of these manifestations and comparison between studies.

A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes.

BACKGROUND & AIMS: The composition of the gastrointestinal microbiota is thought to have an important role in the etiology of inflammatory bowel diseases (IBDs) such as Crohn's disease (CD) and ulcerative colitis (UC). Interindividual variation and an inability to detect less abundant bacteria have made it difficult to correlate specific bacteria with disease. METHODS: We used 454 pyrotag sequencing to determine the compositions of microbial communities in feces samples collected from a cohort of 40 twin pairs who were concordant or discordant for CD or UC, and in mucosal samples from a subset of the cohort. The cohort primarily comprised patients who were in remission, but also some with active disease. RESULTS: The profiles of the microbial community differed with disease phenotypes; relative amounts of bacterial populations correlated with IBD phenotypes. The microbial compositions of individuals with CD differed from those of healthy individuals, but were similar between healthy individuals and individuals with UC. Profiles from individuals with CD that predominantly involved the ileum differed from those with CD that predominantly involved the colon; several bacterial populations increased or decreased with disease type. Changes specific to patients with ileal CD included the disappearance of core bacteria, such as Faecalibacterium and Roseburia, and increased amounts of Enterobacteriaceae and Ruminococcus gnavus. CONCLUSIONS: Bacterial populations differ in abundance among individuals with different phenotypes of CD. Specific species of bacteria are associated with ileal CD; further studies should investigate their role in pathogenesis.

Is smoking a risk factor for collagenous colitis?

OBJECTIVE: The association between smoking and idiopathic inflammatory bowel disease is well known; smoking seems to have a diverse effect. Crohn's disease is associated with smoking, while ulcerative colitis is associated with non-smoking. Data on smoking in microscopic colitis of the collagenous type (CC) are lacking. The aim of this investigation was to study smoking habits in CC and to observe whether smoking had any impact on the course of the disease. MATERIALS AND METHODS: 116 patients (92 women) with median age of 62 years (interquartile range 55-73) answered questionnaires covering demographic data, smoking habits and disease activity. As control group we used data from the general population in Sweden retrieved from Statistics Sweden, the central bureau for national socioeconomic information. RESULTS: Of the 116 CC patients, 37% were smokers compared with 17% of controls (p < 0.001, odds ratio (OR) 2.95). In the age group 16-44 years, 75% of CC patients were smokers compared with 15% of controls (p < 0.001, OR 16.54). All CC smoker patients started smoking before the onset of disease. Furthermore, smokers developed the disease earlier than non-smokers--at 42 years of age (median) compared with 56 years in non-smokers (p < 0.003). Although the proportion with active disease did not differ between smokers and non-smokers, there was a trend indicating that more smokers received active treatment (42% vs. 17%, p = 0.078). CONCLUSIONS: Smoking is a risk factor for CC. Smokers develop their disease more than 10 years earlier than non-smokers.

What Are the Most Challenging Aspects of Inflammatory Bowel Disease? An International Survey of Gastroenterologists Comparing Developed and Developing Countries.

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.

Worries and concerns in a large unselected cohort of patients with Crohn's disease.

OBJECTIVE: Disease-related worries constitute an important dimension of patient-reported perception of health status in inflammatory bowel disease (IBD). The Rating Form of IBD Patient Concerns (RFIPC) questionnaire is purported to measure IBD-related worries. This study evaluated the psychometric properties of a Swedish translation of RFIPC in an unselected population of Crohn's disease (CD) patients. The degree and nature of the worries were characterized and predictive factors for outcome of RFIPC and underlying dimensions were identified. MATERIAL AND METHODS: The RFIPC was completed by 447 CD patients in conjunction with regular visits. A physician global assessment of disease activity and four other health-related quality of life (HRQL) questionnaires were used for construct validity. Reliability and responsiveness were evaluated with follow-up visits. Underlying dimension and predictive factors were identified with factor analysis and multiple linear regression analysis. RESULTS: Test-retest reliability was 0.90, correlation with corresponding HRQL measures 0.60-0.80 and responsiveness ratio 0.84. Median RFIPC sum score was lower than in previous studies. Top three concerns were ostomy, energy level and bowel control. Four dimensions were identified in descending order of concern: disease-related complications, daily-life achievements, intimacy, and stigmatization. Predictors of RFIPC score were disease activity, gender, and BMI (p < 0.001-0.008). CONCLUSIONS: The Swedish version of RFIPC exhibited an adequate psychometric performance in CD patients, but was less sensitive to change in disease activity. The patients were more concerned about complications and achievement than intimacy and stigmatization. The strongest predictors of more worry were active disease, female gender and higher BMI.

Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn's disease in Swedish men.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

The Gut Microbiota in Collagenous Colitis Shares Characteristics With Inflammatory Bowel Disease-Associated Dysbiosis.

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.

Short health scale: a valid, reliable, and responsive instrument for subjective health assessment in Crohn's disease.

BACKGROUND: 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). METHODS: 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. RESULTS: Patients in remission scored better on all 4 questions than those with active disease (P < 0.001). 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 (P < 0.005). CONCLUSIONS: 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.

Diagnosis and management of microscopic colitis.

Microscopic colitis, comprising collagenous and lymphocytic colitis, is characterized clinically by chronic watery diarrhea, and a macroscopically normal colonic mucosa where diagnostic histopathological features are seen on microscopic examination. The annual incidence of each disorder is 4-6/100,000 inhabitants, with a peak incidence in 60-70-year-old individuals and a noticeable female predominance for collagenous colitis. The etiology is unknown. Chronic diarrhea, abdominal pain, weight loss, fatigue and fecal incontinence are common symptoms, which impair the health-related quality of life of the patient. There is an association with other autoimmune disorders such as celiac disease, diabetes mellitus, thyroid disorders and arthritis. Budesonide is the best-documented short-term treatment, but the optimal long-term strategy needs further study. The long-term prognosis is good and the risk of complications including colonic cancer is low.