TNFSF15 polymorphisms are associated with susceptibility to inflammatory bowel disease in a new European cohort.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.

Systematic review: microscopic colitis.

BACKGROUND: Collagenous and lymphocytic colitis are fairly common causes of chronic non-bloody diarrhoea, especially in elderly female. AIM: To present a systematic review of microscopic colitis. METHODS: A PubMed search using the MeSH terms microscopic colitis, collagenous colitis, lymphocytic colitis and chronic diarrhoea was performed. RESULTS: Annual incidence of each disorder is 4-6/100,000 inhabitants. The aetiology is unknown. Clinical characteristics are well described and there is an association with autoimmune diseases. Budesonide is the best-documented short-term treatment of collagenous colitis. In meta-analysis pooled odds ratio for clinical response after 6-8 weeks of treatment was 12.3 (95% CI: 5.5-27.5) in comparison with placebo. The evidence for bismuth subsalicylate is weaker and the effectiveness of other alternatives such as loperamide, cholestyramine, aminosalicylates, probiotics, or Boswellia serrata extract is unknown. Although unproven, in unresponsive severe disease azathioprine or methotrexate may be tried. No controlled trials have been carried out in lymphocytic colitis. The long-term prognosis of microscopic colitis is good, serious complications are rare and there is no increased mortality. CONCLUSIONS: Clinical and epidemiological aspects of microscopic colitis are well described. Budesonide is the best-documented short-term therapy in collagenous colitis, but the optimal long-term strategy needs further study. Controlled treatment data of lymphocytic colitis are awaited for.

The prognostic significance of faecal calprotectin in patients with inactive inflammatory bowel disease.

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.

CARD15/NOD2 polymorphisms do not explain concordance of Crohn's disease in Swedish monozygotic twins.

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.

Genetic refinement and physical mapping of a chromosome 16q candidate region for inflammatory bowel disease.

Crohn's disease (CD) is a complex genetic disorder for which a susceptibility gene, IBD1, has been mapped within the pericentromeric region of chromosome 16. In order to refine the location of IBD1, 77 multiplex CD families were genotyped for 26 microsatellite markers evenly spaced by approximately 1 cM. Nonparametric linkage analyses exhibited a maximum NPL score of 3.49 (P=2.37x10(-4)) in a region centred by markers D16S3136, D16S3117 and D16S770. Simulation studies showed that the probability for IBD1 to be located in a 5 cM region around these markers was 70%. A 2.5 Mb YAC and BAC contig map spanning this genetic region on chromosome band 16q12 was built. TDT analyses demonstrated suggestive association between the 207 bp allele of D16S3136 (P<0.05) and a new biallellic marker hb27g11f-end (P=0.01). These markers were located in the hb27g11 and hb87b10 BAC clones from the contig. Taken together, the present results provide a crucial preliminary step before an exhaustive linkage disequilibrium mapping of putatively transcribed regions to identify IBD1.

Smoking habits in patients with ulcerative colitis: evaluation of retrospective questionnaires.

: We evaluated retrospective smoking data reported by 221 patients with ulcerative colitis in 1984 and repeated in an identical questionnaire in 1989. Reported years of smoking initiation or smoking cessation agreed to a high extent; the difference between the two questionnaires was in mean (± SD) -0.1 ± 1.5 (median, 0) years, and 96% of the differences were <±2 SD. Data on smoking habits and amount of cigarette consumption at the time of diagnosis were also consistent in the two questionnaires. In 197 cases (89.1%), the two questionnaires agreed completely, and in only five cases (2.3%), smoking reports disagreed. In nine cases (4.1%), reported smoking habits agreed, but reported number of cigarettes differed. In 10 cases (4.5%), the amount of consumption was incompletely reported in one of the two questionnaires, whereas reported smoking habits agreed.

Serum Procollagen III Propeptide Is Not of Diagnostic Predictive Value in Collagenous Colitis.

SUMMARY: : The thickened collagen layer found subepithelially in colorectal biopsies from patients with collagenous colitis consists partly of collagen type III. Procollagen III propeptide (P-III-NP) is a product of collagen III metabolism. We analyzed serum levels of this propeptide to assess its diagnostic value in collagenous colitis. Serum from 38 patients with collagenous colitis and 38 age- and sex-matched controls were analyzed for P-III-NP. Data on the patients included duration and severity of symptoms, treatment, and thickness of the collagen layer. There was no significant difference between P-III-NP in patients (3.8 ± 2.0 µg/L) and controls (3.7 ± 1.3 µg/L), and P-III-NP did not correlate with clinical activity. There was a significant correlation, however, between P-III-NP and age both in patients (r = 0.57, p = 0.0009) and controls (r = 0.64, p = 0.0001). This study shows that P-III-NP is not useful as a diagnostic or prognostic tool in collagenous colitis, and a colonoscopy with biopsy is still the only diagnostic method available. Key Words: Collagenous colitis-Procollagen III propeptide-P-III-NP.

Antineutrophil Cytoplasmic Antibodies in Inflammatory Bowel Disease and Collagenous Colitis: No Association with Lactoferrin, ß-Glucuronidase, Myeloperoxidase, or Proteinase 3.

: Perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) occur frequently in ulcerative colitis (UC) but not in Crohn's disease (CD). Their pathogenetic importance is unknown, and studies of associated antigens have been inconsistent. Indirect immunofluorescence technique was used to screen the occurrence of antineutrophil cytoplasmic antibodies in 36 patients with UC, in 37 patients with CD, in 38 patients with collagenous colitis (CC), and in 190 controls. Enzyme immunoassays (EIAs) were used to detect the target antigen(s) by using lactoferrin (Lf), ß-glucuronidase (ß-Glc), myeloperoxidase (MPO), and proteinase 3 (PR3) as the substrates. P-ANCA was found in 23 (63.9%) of 36 of the patients with UC, in two (5.4%) of 37 with CD, in four (10.5%) of 38 with CC, and in four (2.1%) of 190 of healthy controls. No case of cytoplasmic staining pattern (C-ANCA) was found. With EIA, P-ANCA in IBD or CC was not found to be associated with reactivity to Lf, ß-Glc, MPO, or PR3, which confirms findings reported by others. P-ANCA was found in a higher frequency in UC than in CD or CC. The antigens of P-ANCA remain unidentified.

Collagenous and lymphocytic colitis: a clinical and histopathological review.

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.

Crohn's disease presenting as life-threatening ileal bleeding.

We report a case of Crohn's disease in a 32-year old Saudi male. The disease presented with severe, life-threatening ileal bleeding necessitating an urgent laparotomy and 100 cm of ileum and ascending colon was resected. The bleeding source was several ulcers in an inflamed ileum and histopathologic examination revealed typical findings of Crohn's disease with a chronic, transmural inflammation, non-caseating granuloma and the Ziehl-Neelsen stain was negative. The postoperative course was uneventful. On follow-up he is doing well on medical treatment with mesalamine and substitution therapy with vitamin B12.

[Drug-induced enterocolitis. Important differential diagnosis in the investigation of diarrhea and intestinal hemorrhage]. / Läkemedelsutlöst enterokolit. Viktig differentialdiagnos vid utredning av diarré och tarmblödning.

This article is a review of the side-effects of drugs affecting the small and large intestines. Pseudomembranous colitis is caused by antibiotics facilitating an overgrowth of Clostridium difficile. A hemorrhagic colitis, generally self-limiting, can be caused by penicillin, amoxycillin and ampicillin. Toxicity of NSAID may induce intestinal ulcers, diaphragm-like strictures, perforation, colitis and relapse of inflammatory bowel disease. Drug-induced lymphocytic colitis has been reported due to ticlopidine, Cyclo 3 Fort, and occasionally by ranitidine, carbamazepine, vinburnine, tardyferon, and flutamide. Sulphasalazine and 5-ASA can cause relapse of ulcerative colitis. Neutropenic enterocolitis is a severe complication to cytotoxic therapy for cancer. Ischemic colitis can be caused by drugs inducing mesenteric vasoconstriction.

[New knowledge of heredity in inflammatory bowel disease. Specific gene mapping in a EU-project]. / Nytt om arftligheten vid inflammatorisk tarmsjukdom. Specifika gener kartläggs i EU-projekt.

Chronic inflammatory bowel diseases, ulcerative colitis and Crohn's disease, are steadily increasing in prevalence, and one half to one per cent of the Swedish population are currently estimated to be affected. The aetiology remains unknown, but is probably multifactorial. Both dietary, microbiological and immunological causes have been discussed. Clinical studies, including several Swedish studies, have also shown genetic factors to be crucially involved. Findings in sophisticated molecular biological studies suggest certain specific genes to be involved, and a current EU project in which Sweden is participating has been launched to map the mode of inheritance in detail.

Long-term treatment with olsalazine for ulcerative colitis: safety and relapse prevention: a follow-up study.

In a published placebo-controlled study comprising 101 patients, olsalazine was shown to possess relapse-preventing properties superior to placebo and similar to those of sulphasalazine. This is a retrospective follow-up of the 76 patients who continued olsalazine treatment on an open basis. The relapse pattern is similar to that of patients on sulphasalazine treatment, and the long-term tolerance and safety are encouraging.

Long-term prognosis of clinical symptoms and health-related quality of life in microscopic colitis: a case-control study.

BACKGROUND: 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. AIM: To study outcome of symptoms and health-related quality of life (HRQoL). METHODS: 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 of <3 stools/day, were evaluated separately (CC; n = 72, LC; n = 60). RESULTS: 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. CONCLUSIONS: 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.

Smoking is a risk factor for recurrence of intestinal stricture after endoscopic dilation in Crohn's disease.

BACKGROUND: Endoscopic balloon dilation is an efficacious and safe alternative to surgery as treatment of short intestinal strictures in Crohn's disease (CD). Factors predicting outcome of the procedure are not well described. AIM: To evaluate whether smoking at diagnosis, treatment with azathioprine, or other clinical variables may affect clinical outcome after endoscopic dilation. The endpoint was requirement of a new intervention such as dilation or surgery with intestinal resection or strictureplasty. METHODS: Retrospective study of 83 patients with CD who underwent endoscopic balloon dilation of an intestinal stricture between 1987 and 2009. RESULTS: After index dilation 55/83 patients underwent a new intervention. Among current smokers, 31/32 (97%) underwent another intervention compared to 18/33 (55%) among never smokers (adjusted HR: 2.50, 95% CI: 1.14-5.50, P = 0.022). After 5 years, cumulative probability of new intervention was 0.81 in smokers compared to 0.52 in never smokers; difference 0.29 (95% CI: 0.07-0.52, P = 0.01). In 16 patients, therapy with azathioprine was initiated before or shortly after the index dilation; 7/16 underwent a new intervention compared to 48/67 of those without azathioprine (HR: 0.46, 95% CI: 0.21-1.03, P = 0.06). After adjustment for other variables, the association was even weaker (HR: 0.80, 95% CI: 0.29-2.18, P = 0.668). Sex, age at diagnosis, age at first dilation, balloon size, location of stricture, and treatment period did not influence outcome. CONCLUSIONS: Smoking doubles the risk of recurrent stricture formation requiring a new intervention after index dilation. Maintenance therapy with azathioprine did not influence the subsequent course and need for a new intervention.

Immunohistochemical characterization of lymphocytes in microscopic colitis.

BACKGROUND AND AIMS: Microscopic colitis (MC), encompassing the subgroups collagenous colitis (CC) and lymphocytic colitis (LC), is characterized by macroscopically normal or near-normal colonic mucosa, and an increased number of intraepithelial lymphocytes (IELs) and mononuclear cell infiltration in the underlying lamina propria (LP), in addition to an increased collagen layer in CC. This study aimed to characterize the inflammatory cells involved in mucosal inflammation, using immunohistochemistry. METHODS: Paraffin-embedded biopsies from 23 untreated patients with MC (CC=13, LC=10) and 17 controls were stained with antibodies against CD3, CD4, CD8, CD20, CD30, Foxp3, CD45RO and Ki67. Computerized image analysis was used to calculate areas of stained lymphocytes in the surface and crypt epithelia as well as in the LP. RESULTS: In CC and LC, an increase of predominantly CD8(+) lymphocytes was seen in both the epithelium and the lamina propria, whereas a decreased amount of CD4(+) lymphocytes was found in the lamina propria. CD45RO(+) and Foxp3(+) cells were more abundant in all areas in both patient groups compared to controls, as were CD20(+) areas, although more scarce. Ki67(+) areas were only more abundant in the epithelium, whereas CD30(+) areas were more abundant in the lamina propria of both patient groups compared to controls. CONCLUSIONS: This study confirms an increased amount of CD8(+) lymphocytes in the epithelium. Lymphocytic proliferation and activation markers were more abundant, whereas a decreased amount of CD4(+) lymphocytes was seen in the LP. Further studies are needed to reveal the underlying mechanism(s).

Infliximab as rescue therapy in hospitalised patients with steroid-refractory acute ulcerative colitis: a long-term follow-up of 211 Swedish patients.

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

Endoscopic dilation is an efficacious and safe treatment of intestinal strictures in Crohn's disease.

BACKGROUND: Bowel strictures are a major cause of morbidity, hospitalisation and surgery in Crohn's disease. AIM: We report short- and long-term efficacy and safety of endoscopic balloon dilation of strictures due to Crohn's disease. METHODS: Retrospective study of patients who underwent endoscopic balloon dilation between 1987 and 2009. RESULTS: 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, with >5-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. CONCLUSIONS: 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.

Microscopic colitis: Current status, present and future challenges: statements of the European Microscopic Colitis Group.

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.