HHV-6 antigen and HHV-6 DNA expression in sporadic adenomatous polyps of the colon.

BACKGROUND. Human herpesvirus-6B (HHV-6B) antigens are commonly found in the intestinal mucosa of patients with immunosuppression. In a series of immunocompetent patients with adenomatous, polyp HHV-6B antigen expression from mucosal biopsies was more intense than in biopsies taken from patients receiving immunosuppressive drugs because of kidney transplantation or inflammatory bowel disease. METHODS. HHV-6B and cytomegalovirus (CMV) antigen expression was determined from mucosal biopsy samples by immunohistochemistry. HHV-6-DNA content was studied in adenomatous polyps (seven tubular adenomas and one tubulovillous adenoma) taken from eight immunocompetent patients and in three mucosal biopsy samples taken from immunocompetent patients without adenomas using in situ hybridization (ISH) method. RESULTS. HHV-6B antigen expression on mucosal biopsies was strongly positive in five of eight patients with adenomas and negative in all patients without adenoma. CMV antigen expression on mucosal biopsies was faintly positive in three of adenoma patients. HHV-6 ISH was positive in seven of eight adenomatous polyps, most intense in the tubulovillous adenoma and negative in all three mucosal biopsies of patients without adenomas. CONCLUSION. Intensive HHV-6-DNA expression was found in adenomatous polyps of the colon. Further studies on involvement of HHV-6 in the development of gastrointestinal polyps are warranted.

Mucosal healing at 3 months predicts long-term endoscopic remission in anti-TNF-treated luminal Crohn's disease.

BACKGROUND AND AIMS: Studies performed on patient and disease characteristics predicting the treatment response in tumor necrosis factor alpha antibody (anti-TNF)-treated Crohn's disease (CD) have generally been based on clinical data. Only a few studies have assessed the role of endoscopy as a predictor for long-term response for anti-TNF therapy. Our aim was to evaluate the role of early endoscopy in predicting the long-term endoscopic response to anti-TNF in active luminal CD in a clinical setting. PATIENTS AND METHODS: Forty-two patients with active luminal CD, treated for at least 3 months with anti-TNF, either adalimumab (52%) or infliximab (48%), were included in this prospective study. Data on the simple endoscopic score for Crohn's disease (SES-CD) at 3 months after therapy commencement, and either data on the SES-CD or surgery after 1 year, were available for all patients. Endoscopic remission was defined as SES-CD 0-2. RESULTS: At 3 months after commencing anti-TNF therapy, 10 patients (24%) were in endoscopic remission. Thirty-three patients continued anti-TNF as maintenance therapy. At 1 year, endoscopic remission (11/33, 33%) was significantly more common in those patients who had been in endoscopic remission at 3 months, compared with those with endoscopically active disease at 3 months (7/10, 70% vs. 4/23, 17%, p = 0.01). The 3-month SES-CD had a sensitivity of 88%, and specificity of 64%, to predict 1-year endoscopic remission in patients who received anti-TNF maintenance therapy. CONCLUSIONS: In anti-TNF-treated active luminal CD mucosal healing at 3 months is a strong predictor for long-term endoscopic response.

Medication use among inflammatory bowel disease patients: excessive consumption of antidepressants and analgesics.

OBJECTIVE: Little is known about differences in the use of medications between inflammatory bowel disease (IBD) patients and the general population. The aims of this study were to observe those differences and to discuss reasons for them. The relation between medication use and HRQoL of IBD patients was examined. MATERIAL AND METHODS: The use of prescribed medication of 2831 IBD patients and 5662 control subjects were scrutinized and compared by utilizing a national reimbursement register. Annual costs and number of defined daily doses (DDD) of medications were calculated. The relationship between medications and health-related quality of life (HRQoL) of IBD patients was examined by using a postal questionnaire including a generic (15D) and a disease-specific (IBDQ) HRQoL tool. The questionnaire also included demographic questions and questions about IBD patients' use of biological medications. RESULTS: Use of antidepressants (OR: 1.44, 95% CI: 1.28-1.61), anxiolytics (OR: 1.52, 95% CI: 1.31-1.78), oral bisphosphonates (OR: 6.08, 95% CI: 4.56-8.11), cardiovascular medications (OR: 1.38, 95% CI: 1.24-1.54), antibiotics (OR: 4.01, 95% CI: 3.57-4.51), proton pump inhibitors (OR: 3.90, 95% CI: 3.48-4.36), and nonsteroidal anti-inflammatory analgesics (OR: 1.17, 95% CI: 1.07-1.28) was significantly more common in IBD than among the controls. Those who used antidepressants, anxiolytics, or analgesics had significantly impaired HRQoL (p < 0.001). CONCLUSIONS: IBD patients and general population differ in terms of their medicine use in many respects, and especially use of analgesics and antidepressants is more common among IBD patients. Use of antidepressants, anxiolytics, and analgesics was related to impaired HRQoL.

Detection of muramyl dipeptide-sensing pathway defects in monocytes of patients with Crohn's disease using phospho-specific whole blood flow cytometry.

Peripheral blood mononuclear cells of Crohn's disease (CD) patients with the common 1007fs mutation of the caspase recruitment domain-containing 15/nucleotide-binding oligomerization domain-containing 2 (CARD15/NOD2) gene show impaired nuclear factor kappa B (NF-κB) activation in response to muramyl dipeptide (MDP), as determined by Western blotting. We applied phospho-specific flow cytometry to examine NF-κB and p38 activation in whole blood monocytes of 16 CD patients with or without the 1007fs and previously described rare mutations of the CARD15 gene, and healthy reference subjects. Aliquots of whole blood were supplemented with MDP (0-1000 ng/mL), incubated for 10-40 min and processed for flow cytometry. Bacterial lipopolysaccharide (LPS) was used as a positive control agonist. We found that NF-κB and p38 phosphorylation induced by MDP was not detectable in monocytes of patients homozygous for the CARD15 1007fs mutation, while those induced by LPS were normal. We also determined MDP-induced NF-κB phosphorylation levels in nuclear extracts of mononuclear cells separated from blood using enzyme-linked immunosorbent assay (ELISA), and observed that the levels decreased in a 1007fs mutation-dose dependent manner. We conclude that phospho-specific whole blood flow cytometry provides a means to study phosphorylation of NF-κB and p38 in clinical samples and can be applied to screening of CD patients homozygous for the CARD15 1007fs mutation.

Surrogate markers and clinical indices, alone or combined, as indicators for endoscopic remission in anti-TNF-treated luminal Crohn's disease.

OBJECTIVE: Endoscopically confirmed mucosal healing has become an important therapeutic goal in the treatment of Crohn's disease (CD). The role of clinical indices, such as the Crohn's disease activity index (CDAI) and the Harvey-Bradshaw index (HBI), and surrogate markers, such as C-reactive protein (CRP) and fecal calprotectin, to indicate remission determined by endoscopy needs to be clarified. We analyzed the role of surrogate markers and clinical indices, separately and in combination, by comparing them with endoscopically scored disease activity in biologically treated CD patients. MATERIAL AND METHODS: Prospectively collected data of all patients with inflammatory bowel disease treated with tumor necrosis factor alpha antibodies in a tertiary center between 2007 and 2010. Altogether 210 endoscopies in 64 CD patients were analyzed. The simple endoscopic score for Crohn's disease (SES-CD) was used for scoring disease activity and compared with available data on concurrent CDAI, HBI, CRP, and calprotectin. RESULTS: Endoscopic activity demonstrated a stronger correlation with calprotectin and CRP than with the clinical indices. Neither the clinical indices nor CRP was reliable at identifying endoscopic remission. However, calprotectin alone identified endoscopic remission with a sensitivity of 84% and specificity of 74%, but was beaten, although not statistically significantly, by a combined index, based on calprotectin and the HBI. CONCLUSIONS: Clinical scores commonly used in the assessment of disease activity are unreliable at differentiating endoscopic remission from active CD. Despite this, a score based on a combination of fecal calprotectin and the HBI is a new promising tool for identifying endoscopic remission.

Human herpesvirus 6 and cytomegalovirus in ileocolonic mucosa in inflammatory bowel disease.

OBJECTIVES: Reactivation of a latent cytomegalovirus (CMV) may occur in inflammatory bowel disease (IBD). Data of human herpesvirus 6 (HHV-6)--a close relative to CMV--in active IBD are scarce. The aim of this study was to detect HHV-6 and CMV antigens in the mucosa of active and inactive IBD. MATERIAL AND METHODS: 79 IBD patients (47 ulcerative colitis (UC) and 32 Crohn's disease (CD)) were recruited and endoscopic and histological disease activity was scored. Control group consisted of 15 non-IBD patients with normal colonoscopy. Immunohistochemical stainings for HHV-6B and CMV antigens were performed on biopsy specimens from the ileum and colorectum. The intensity of HHV-6B and CMV expression was graded as negative, mild, moderate, or intense. RESULTS: HHV-6B antigen was positive in 35 (44%) and CMV in 64 (81%). Of controls, 6 (40%) were mildly positive for HHV-6 and 6 (40%) for CMV. In IBD, both CMV and HHV-6B intensity correlated with endoscopic disease severity (CMV p = 0.010 and HHV-6 p = 0.048). Simultaneous HHV-6B and CMV antigen expression occurred in 29 (37%) and associated with endoscopic activity (p = 0.006) and to a number of immunosuppressives (p = 0.033). A significant difference in HHV-6B positivity was found between endoscopically active and inactive UC (p = 0.040). Both CMV and HHV-6B intensity correlated with histological severity in the rectal biopsy specimens (for CMV p = 0.040 and for HHV-6B p = 0.027). CONCLUSIONS: Both viruses occurred ubiquitously in the IBD mucosa. Coexistence of viruses was common and associated with disease activity and use of immunosuppressives. HHV-6B intensity correlated with endoscopic severity in UC.

Health-related quality of life in inflammatory bowel disease measured with the generic 15D instrument.

OBJECTIVES: In many surveys, inflammatory bowel disease (IBD) has been shown to have a negative impact on health-related quality of life (HRQoL), especially when the disease is active. The purpose of this study was to compare a disease-specific HRQoL tool (Inflammatory Bowel Disease Questionnaire, IBDQ) and a generic HRQoL tool (15D) in a large cohort of IBD patients, to assess the ability of the 15D to detect differences in HRQoL between disease states and to compare the HRQoL of IBD patients with that of the general population. METHODS: The study population comprised 2,931 IBD patients over 18 picked from a national Social Insurance Institute register and from a patient organization register. The 15D data for the general population came from the National Health 2000 Health Examination Survey. RESULTS: For patients with IBD, the 15D tool was feasible and had good discriminatory power. The total 15D score was significantly higher among patients with less active disease estimated by frequency of IBD symptoms and was strongly correlated with total IBDQ score. The general population scored significantly higher than did the study subjects on most of the 15D dimensions. CONCLUSIONS: The 15D was a fast and easy-to-apply method for the examination of HRQoL in IBD patients. In addition to HRQoL studies it could be used in everyday practice as well. Patients with IBD have worse HRQoL than do gender- and age-standardized controls.

IL23R in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease.

BACKGROUND: Association of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may be an important candidate for many chronic inflammatory diseases. METHODS: We studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohn's disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease. RESULTS: Association of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples. CONCLUSION: Our study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated.

CMV findings in the gastrointestinal tract in kidney transplantation patients, patients with end-stage kidney disease and immunocompetent patients.

AIM: Cytomegalovirus (CMV) is the most common viral pathogen affecting organ transplant recipients. The objective was to determine to what extent CMV can be found in the gastrointestinal tract in kidney transplant recipients and to compare them with patients in dialysis and randomly chosen otherwise healthy patients who were referred for oesophagogastroduodenoscopy (OEGD) or colonoscopy. PATIENTS AND METHODS: Biopsies for CMV examinations were obtained from 130 oesophagogastroduodenoscopies and 54 colonoscopies performed on 82 kidney transplant recipients, 49 dialysis patients with chronic end-stage kidney disease and 53 immunocompetent patients because of clinical indications. CMV was demonstrated by immunohistochemistry, both in frozen sections using a monoclonal antibody against CMV-specific antigens (pp65 matrix protein) and in paraffin sections by means of a monoclonal antibody against the delayed early protein (p52). RESULTS: CMV-positive cells were found in the gastroduodenal mucosa in 46 (68%) out of 82 kidney transplant recipients, in 9 (31%) of 49 dialysis patients and in 15 (45%) of 53 immunocompetent patients, in the colorectal mucosa in 7 (50%), in 6 (30%) and in 9 (45%) of the patient groups, respectively. In the transplant recipient group, 4 patients had severe and 10 patients moderate CMV infection in the gastroduodenal mucosa. CMV disease was diagnosed in two patients with severe infection and in one patient with moderate infection. All dialysis and immunocompetent patients had only moderate or mild CMV involvement. CONCLUSION: It appears that CMV-positive cells were present in all groups studied, suggesting that CMV-infected cells alone are not sufficient to make the diagnosis of CMV disease in the transplanted host. Moreover, the clinical symptoms and the intensity of the histologic CMV findings did not correlate with the symptoms the patients were having. In kidney transplant recipients, it emerges that CMV is activated more easily in the upper rather than in the lower gastrointestinal tract.

Impact of demographic factors, medication and symptoms on disease-specific quality of life in inflammatory bowel disease.

OBJECTIVES: To investigate the relation of demographic factors, medication and symptoms to health-related quality of life in patients with inflammatory bowel disease, and to identify patients in need of special support. METHODS: A questionnaire packet comprising the Inflammatory Bowel Disease Questionnaire (IBDQ) and the European Federation of Crohn's and Colitis Associations' (EFCCA) Survey Questionnaire was sent to 3,852 adult members of the Crohn and Colitis Association of Finland. IBDQ was used for measuring health-related quality of life (HRQoL), and the EFCCA questionnaire gave information about demographics, symptoms and medication. RESULTS: Altogether 2,386 questionnaires (62%) were available for analysis. Patients reporting symptoms affecting leisure activities or work had significantly lower total IBDQ scores (indicating worse HRQoL) than patients with less disturbing symptoms. Satisfaction with current therapy, female gender and age affected the scores. Subjects who had undergone surgery scored lower than those who had not. Patients currently receiving corticosteroids and newly diagnosed patients had lower scores than other patients. CONCLUSIONS: In everyday practice, paying attention to and reducing patients' symptoms and their impact on daily life is important when aiming at improving HRQoL. Special attention should be given to patients who have undergone surgery, and to newly diagnosed patients.

Crohn's disease activity assessed by fecal calprotectin and lactoferrin: correlation with Crohn's disease activity index and endoscopic findings.

BACKGROUND: Correlation of endoscopic Crohn's disease activity with fecal calprotectin and lactoferrin is insufficiently studied. We evaluated the clinical significance of these neutrofil-derived proteins in assessment of Crohn's disease activity by comparing them with endoscopic disease activity and with Crohn's disease activity index (CDAI) and serum CRP. METHODS: A total of 77 CD patients underwent one or more ileocolonoscopies (n = 106) with scoring of Crohn's disease index of severity (CDEIS). Patients provided stool samples for calprotectin and lactoferrin measurements and blood samples for CRP. Clinical activity was based on the CDAI. RESULTS: Both fecal calprotectin and lactoferrin correlated significantly with CDEIS (Spearman's r 0.729 and 0.773, P < 0.001). With a cutoff level of 200 microg/g for a raised fecal calprotectin concentration, sensitivity was 70%, specificity 92%, positive predictive value (PPV) 94%, and negative predictive value (NPV) 61% in predicting endoscopically active disease (CDEIS >/= 3). A fecal lactoferrin concentration of 10 microg/g as the cutoff value gave a sensitivity, specificity, PPV, and NPV of 66%, 92%, 94%, and 59%. Sensitivity of CDAI >/= 150 to detect endoscopically active disease was only 27%, specificity 94%, PPV 91%, and NPV 40%. A raised serum CRP (> 5 mg/l) gave a sensitivity, specificity, PPV, and NPV of 48%, 91%, 91%, and 48%. CONCLUSIONS: For evaluation of Crohn's disease activity, based on endoscopic findings, more sensitive surrogate markers than is CDAI or CRP are fecal calprotectin and lactoferrin. These prove to be useful tools for estimation of disease activity in Crohn's disease.

Novel CARD15/NOD2 mutations in Finnish patients with Crohn's disease and their relation to phenotypic variation in vitro and in vivo.

BACKGROUND: Three mutations (R702W, G908R, and 1007fs) of the CARD15/NOD2 gene associate with Crohn's disease (CD). Despite a strong linkage of CD to the inflammatory bowel disease (IBD) 1 region, only 16% of the Finnish CD patients carry 1 of these 3 mutations, pointing to the possibility of yet undetected founder mutations in the genetically isolated Finns. The aim of this study was to screen for CARD15 mutations in Finnish CD patients and to assess their functional consequences and relation to clinical phenotype. METHODS: We performed CARD15 mutation screening in 240 CD probands. For functional studies, blood mononuclear cells were cultured alone or with muramyl dipeptide (MDP) and IL-8 levels were determined. RESULTS: We identified 30 different variants, including 12 new ones. Allele frequencies for the R702W, G908R, and 1007fs mutations were 3.3%, 0.4%, and 4.8%, respectively. The 1007fs variant was the only 1 associated significantly with CD. Five novel variants (R38M, W355X, P727L, W907R, R1019X) were found in 5 patients. The biochemical nature of these new mutations, data obtained by cross-species comparisons, as well as low IL-8 production favors their pathogenic role. All 5 patients with novel mutations presented a complicated form of ileal or ileocolonic disease. CONCLUSIONS: In conclusion, we identified 5 novel CARD15 mutations with an apparent pathophysiological role, but could not identify a putative Finnish founder mutation. It is still possible that regulatory mutations present in the flanking or intronic areas of the CARD15 gene contribute to the genetic susceptibility of CD. Homozygosity or compound heterozygosity for CARD15 gene mutations must be considered especially in complicated CD patients.

Finnish patients with inflammatory bowel disease have fewer symptoms and are more satisfied with their treatment than patients in the previous European survey.

OBJECTIVE: Symptoms associated with inflammatory bowel diseases (IBD) have a negative impact on quality of life. The purpose of this study was to assess the quality of life in a large group of Finnish IBD patients and to compare it with that observed in a recent survey covering several other European countries. MATERIAL AND METHODS: The European Federation of Crohn's and Ulcerative Colitis Associations (EFCCA) questionnaire, comprising questions about IBD symptoms, diagnosis, therapy, extraintestinal manifestations and their impact on patients' quality of life, was sent to 3852 members of the Finnish Crohn and Colitis Association. The response rate was 63%. RESULTS: IBD was diagnosed by a specialist in over 96% of cases and 94% of patients were continuously followed-up by a specialist. Fifty-eight percent of the patients had had IBD symptoms for over a year before consulting a specialist. The frequency of symptoms was lower in the Finnish patients and 93% of patients were satisfied with their current treatment compared with 76% in the European survey. For Crohn's disease, the rate of surgery was lower than that in the European survey (43% versus 52%). The patients reported improved quality of life after surgery, but 67% of patients with Crohn's disease and 34% with ulcerative colitis reported recurrence of symptoms. Comorbidity with ankylosing spondylitis was 22 times more common than in the general Finnish population and 49% of the patients suffered from joint pain. CONCLUSIONS: Finnish IBD patients are more satisfied with their treatment than those studied in the European survey. In Finland, gastroenterologists are usually responsible for the care, but the delay before the diagnosis remains long.

Family and twin studies in inflammatory bowel disease.

Studies examining the inheritance of inflammatory bowel disease (IBD) within different family groups have been the basis for recent molecular advances in the genetics of IBD. The derived heritability in Crohn's disease (CD) is higher than in many other complex diseases. The risk of IBD is highest in first-degree relatives of a CD proband, but first-degree relatives of a proband suffering from ulcerative colitis (UC) and more distant relatives are also at increased risk. Disease concordance rates in IBD have been examined in multiplex families and in three large European twin studies.

Genome-wide search in Finnish families with inflammatory bowel disease provides evidence for novel susceptibility loci.

Epidemiological and genetic linkage studies have indicated a strong genetic basis for development of inflammatory bowel disease (IBD) which was recently supported by discovery of the Crohn's disease (CD) susceptibility gene termed NOD2/CARD15. We carried out a genome-wide linkage study in Finnish IBD families, providing a particular advantage to map susceptibility genes for ulcerative colitis (UC) within a genetic isolate. Initially, 92 IBD families with 138 affected sib-pairs (ASPs), were genotyped for 429 markers spaced at approximately 10 cM intervals. Next, the loci on chromosomes 2p13-11, 11p12-q13, and 12p13-12 were high-density mapped in the extended family cohort of 130 families with 173 ASPs. In this study, the most significant lod scores were observed for the UC families on chromosome 2p11 (D2S2333), in the vicinity of the REG gene cluster which is strikingly overexpressed in the IBD mucosa. The maximum two-point lod score was 3.34 (dominant model), and the corresponding NPL score 2.61. For UC, the second highest two-point NPL score of 2.00 was observed at proximal 12p13, where also some evidence for linkage disequilibrium emerged (P=0.07 and P=0.007 for the basic and extended IBD cohorts, respectively). The highest two-point NPL score for the CD families was 2.34 at D12S78 (12q23) with significant evidence for linkage disequilibrium (P=0.004), and for the mixed (MX) families 2.07 at D4S406 near the linkage peak reported previously. This study confirmed several of the IBD loci that have previously been reported and gives evidence for new IBD loci on chromosomes 2p11, 11p12-q13, 12p13-12, 12q23, and 19q13.

Endoscopic monitoring of infliximab therapy in Crohn's disease.

BACKGROUND: So far, infliximab (IFX) therapy for the treatment of Crohn's disease (CD) has generally been guided by clinical symptoms. Data on treatment response as ascertained by endoscopy in IFX therapy are scarce. The aims of this study were to measure the endoscopic response rate during IFX induction and maintenance therapy in luminal CD, and also evaluate the role of endoscopy in monitoring IFX therapy. METHODS: Data obtained from 71 patients with active luminal CD and treated with IFX were analyzed retrospectively. The endoscopy findings were scored according to mucosal activity as: 0 (remission), 1-2 (mild), 3-4 (moderate), and 5-6 (severe). A positive endoscopic response was determined by a decrease in score of at least two points and mucosal healing was assigned a score of between 0-2. RESULTS: At baseline all patients presented with moderate or severe luminal inflammation. A positive endoscopic response occurred in 73% of patients at 3 months and when IFX was continued, the endoscopic response was maintained in 77% of these patients at 12 months. Mucosal healing at first follow-up endoscopy was documented in 45% of patients and was highly predictive for its persistence at 12 months, maintained in 90% of patients, when IFX was continued. CONCLUSIONS: Endoscopy at 3 months from the start of IFX therapy helps to predict responders to IFX for maintenance therapy in active luminal CD.

Increased risk for coronary heart disease, asthma, and connective tissue diseases in inflammatory bowel disease.

BACKGROUND AND AIMS: Patients with inflammatory bowel diseases (IBD) show increased risk for other immune-mediated diseases such as arthritis, ankylosing spondylitis, and some pulmonary diseases. Less is known about the prevalence of other chronic diseases in IBD, and the impact of comorbidity on health-related quality of life (HRQoL). METHODS: The study population comprised 2831 IBD patients recruited from the National Health Insurance register and from a patient-association register. Study subjects completed generic 15D and disease-specific IBDQ questionnaires. The Social Insurance Institution of Finland provided data on other chronic diseases entitling patients to reimbursed medication. For each study subject, two controls, matched for age, sex, and hospital district, were chosen. RESULTS: A significant increase existed in prevalence of connective tissue diseases, pernicious anemia and asthma. Furthermore, coronary heart disease (CHD) occurred significantly more frequently in IBD patients than in their peers (p=0.004). The difference was, however, more clearly seen in females (p=0.014 versus 0.046 in males). Active and long-lasting IBD were risk factors. Concomitant other chronic diseases appeared to impair HRQoL. Asthma, hypertension and psychological disorders had an especially strong negative impact on HRQoL, as observed with both the generic and disease-specific HRQoL tools. CONCLUSIONS: In addition to many immune-mediated diseases, CHD appeared to be more common in IBD than in control patients, especially in females. The reason is unknown, but chronic inflammation may predispose to atherosclerosis. This finding should encourage more efficacious management of underlying cardiovascular risk factors, and probably also inflammatory activity in IBD.

Endoscopic evaluation of Crohn's disease activity: comparison of the CDEIS and the SES-CD.

BACKGROUND: Few data exist of prospective parallel scoring of the validated endoscopic scores in Crohn's disease (CD), Crohn's Disease Index of Severity (CDEIS), and Simple Endoscopic Score for Crohn's Disease (SES-CD). METHODS: Both the CDEIS and the SES-D were scored immediately after each endoscopy of 86 CD patients referred for ileocolonoscopy in a cross-sectional study. Furthermore, after CD therapy, 32 CD patients underwent a follow-up endoscopy with scoring of the CDEIS and SES-CD. Endoscopic scorings were graded as inactive, mild, moderate, or severe. Clinical activity was assessed with the Crohn's Disease Activity Index (CDAI) and serum C-reactive protein (CRP) was measured. RESULTS: The SES-CD correlated with the CDEIS significantly (Spearman's r = 0.938, P < 0.0001). Weaker correlations were detected between the SES-CD and the CDAI (r = 0.473) or CRP (r = 0.525, both P < 0.0001). Grading of SES-CD from inactive to severe correlated significantly with grading of the CDEIS (r = 0.859, P < 0.0001). Changes between baseline and follow-up endoscopy scores correlated significantly (r = 0.828 between delta-CDEIS and delta-SES-CD, P < 0.001), but failed to correlate with delta-CDAI or delta-CRP (all P > 0.05). CONCLUSIONS: Both validated endoscopic scores, the CDEIS and SES-CD, and their changes during CD therapy demonstrated a close correlation. For scoring of endoscopic activity in clinical routine, the SES-CD could replace the CDEIS.

PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease.

BACKGROUND: Human polymorphisms affecting gut epithelial barrier and interactions with bacteria predispose to the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC). The intestinal transporter PepT1, encoded by the SLC15A1 gene, mediates intracellular uptake of bacterial products that can induce inflammation and NF-kappaB activation upon binding to NOD2, a protein often mutated in CD. Hence, we tested SLC15A1 polymorphisms for association with IBD. METHODS: Twelve SLC15A1 single nucleotide polymorphisms (SNPs) were genotyped in 1783 individuals from 2 cohorts of Swedish and Finnish IBD patients and controls. An in vitro system was set up to evaluate the potential impact of SLC15A1 polymorphism on PepT1 transporter function by quantification of NOD2-mediated activation of NF-kappaB. RESULTS: The common allele (C) of a coding polymorphism (rs2297322, Ser117Asn) was associated with CD susceptibility both in Sweden and in Finland, but with genetic effects in opposite directions (risk and protection, respectively). The best evidence of association was found in both populations when the analysis was performed on individuals not carrying NOD2 common risk alleles (Sweden allelic P = 0.0007, OR 1.97, 95% confidence interval [CI] 1.34-2.92; Finland genotype P = 0.0013, OR 0.63, 95% CI 0.44-0.90). The PepT1 variant encoded by the C allele (PepT1-Ser117) was associated with reduced signaling downstream of NOD2 (P < 0.0001 compared to Pept1-Asn117). CONCLUSIONS: A functional polymorphism in the SLC15A1 gene might be of relevance to inflammation and antibacterial responses in IBD. Whether this polymorphism truly contributes to disease susceptibility needs to be further addressed, and should stimulate additional studies in other populations.

Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC), 2 major forms of inflammatory bowel disease (IBD), are complex disorders with significant genetic predisposition. The first CD-associated gene, CARD15/NOD2, was recently identified and since then several reports on novel IBD candidate genes have emerged. We investigated disease phenotype association to genetic variations in IL23R, ATG16L1, DLG5, ABCB1/MDR1, TLR4, TNFRSF1A, chromosome 5 risk haplotype including SLC22A4 and SLC22A5, and HLA-DRB1*0103 allele among Finnish IBD patients. METHODS: A total of 699 IBD patients were genotyped for disease-associated variants by polymerase chain reaction (PCR) and restriction enzyme digestion or Sequenom iPLEX method. RESULTS: Five markers spanning the IL23R gene were associated with CD. The SNP (single nucleotide polymorphism) rs2201841 gave the strongest association (P = 0.002). The rare HLA-DRB1*0103 allele was found to associate with UC (P = 0.008), and the TNFRSF1A A36G variant was associated with familial UC (P = 0.007). Upon phenotypic analysis we detected association between familial UC and rare TNFRSF1A alleles 36G and IVS6+10G (P = 0.001 and P = 0.042, respectively). In addition, IL23R markers were associated with stricturing CD (P = 0.010-0.017), and ileocolonic CD was more prevalent in the carriers of the same 2 TNFRSF1A variants (P = 0.021 and P = 0.028, respectively). Less significant genotype-phenotype associations were observed for the TLR4 and HLA variants. CONCLUSIONS: We were able to replicate the association of the IL23R variants with CD as well as HLA-DRB1*0103 with UC; confirmation of TNFRSF1A association with UC needs additional studies. Our findings also suggest that polymorphisms at IL23R and TNFRSF1A, and possibly HLA and TLR4, loci may account for phenotypic variation in IBD.