A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease.

BACKGROUND: In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. METHODS: In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life). RESULTS: Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group. CONCLUSIONS: In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).

Abdominal pain in patients with inflammatory bowel disease: association with single-nucleotide polymorphisms prevalent in irritable bowel syndrome and clinical management.

BACKGROUND: Abdominal pain is a frequent symptom in patients with inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC). Pain can result from ongoing inflammation or functional disorders imitating irritable bowel syndrome (IBS). Several single-nucleotide polymorphisms (SNPs) have been associated with IBS. However, the impact of IBS genetics on the clinical course of IBD, especially pain levels of patients remains unclear. METHODS: Data of 857 UC and 1206 CD patients from the Swiss IBD Cohort Study were analysed. We tested the association of the maximum of the abdominal pain item of disease activity indices in UC and CD over the study period with 16 IBS-associated SNPs, using multivariate ANOVA models. RESULTS: In UC patients, the SNPs rs1042713 (located on the ADRB2 gene) and rs4663866 (close to the HES6 gene) were associated with higher abdominal pain levels (P = 0.044; P = 0.037, respectively). Abdominal pain was not associated with any markers of patient management in a model adjusted for confounders. In CD patients, higher levels of abdominal pain correlated with the number of physician contacts (P < 10-15), examinations (P < 10-12), medical therapies (P = 0.023) and weeks of hospitalisation (P = 0.0013) in a multivariate model. CONCLUSIONS: We detected an association between maximal abdominal pain in UC patients and two IBS-associated SNPs. Abdominal pain levels had a pronounced impact on diagnostic and therapeutic procedures in CD but not in UC patients.

Therapies in Inflammatory Bowel Disease Patients with Extraintestinal Manifestations.

Extraintestinal manifestations (EIM) have become an important source of morbidity and disability as well as an identified risk factor for an unfavorably course of disease in inflammatory bowel diseases (IBD). Therefore, efforts have been put into a more global and interdisciplinary management of IBD patients in collaboration with rheumatologists, dermatologists, and ophthalmologists. A real therapeutic success has also been obtained with a more "systemic" IBD treatment associated with the development of monoclonal antibodies against TNF alpha and biological agents derived from the treatment of rheumatological disease (also called biological Disease-Modifying Antirheumatic Drugs). The prevalence of these EIM remains too low to undergo randomized controlled trials with this specific focus and therefore the evidence relies on case series and experts' opinions, which lowers the level of evidence. After a careful review of the most recent literature, this paper aims to update the reader on the latest therapeutic management of IBD patients with EIM.

Lower Risk of B1-to-pB3-Stage Migration in Crohn's Disease Upon Immunosuppressive and Anti-TNF Treatment in the Swiss IBD Cohort Study.

BACKGROUND: While the long-term evolution of disease behavior in Crohn's disease has been well described in the pre-anti-TNF era, our knowledge thereon remains scarce after the introduction of anti-TNF. AIMS: Our investigation examined the long-term evolution of disease concerning Montreal classification's B-stages over time in patients enrolled into the Swiss IBD Cohort Study between 2006 and 2017. METHODS: We analyzed prospectively collected SIBDCS data using a Markov model and multivariate testing for effects of treatment and other confounders on B-stage migration over time. The primary outcome was a transition in disease behavior from B1 to either B2 or pB3, or from B2 to pB3, respectively. RESULTS: The 10- and 15-year probability of remaining in B1 was 0.61 and 0.48, as opposed to a probability to migrate to B2 or B3 of 0.25 or 0.14, and 0.32 or 0.2, after 10 and 15 years, respectively. In multivariate testing, the hazard ratio for migrating from B1 to pB3 (HR 0.27) and from B2 to pB3 (HR 0.12) was lower in patients > 40 years compared to patients < 17 years. We found that immunosuppression (HR 0.38) and treatment with anti-TNF for > 1 year (HR 0.30) were associated with a decreased likelihood of transitioning from stage B1 to pB3. CONCLUSIONS: While in the anti-TNF era most patients with Crohn's disease will eventually develop stricturing and/or penetrating complications, our data indicate that immunosuppressive and anti-TNF treatment for more than 1 year reduce the risk of transitioning from stage B1 to pB3 in the long-term run.

[Extraintestinal manifestations in chronic inflammatory bowel diseases]. / Extraintestinale Manifestationen bei chronisch entzündlichen Darmkrankheiten.

Extraintestinal manifestations in chronic inflammatory bowel diseases Abstract. Chronic inflammatory bowel diseases (IBD) are inflammatory gastrointestinal disorders that are not limited to the gastrointestinal tract. Various organ systems may be involved, making IBD a systemic disease. The most common extraintestinal manifestations (EIMs) include musculoskeletal, ophthalmic, dermatological and hepato-biliary disorders. EIMs considerably contribute to the morbidity of patients with IBD and also limit their quality of life. Due to the diversity of the organ systems involved, care should be provided on an interdisciplinary basis by a medical staff trained in the treatment of IBD. Early detection of EIM allows targeted therapy and reduces the overall morbidity of the affected patients. Of importance is the fact that EIM can occur in up to 25 % of all IBD patients before the onset of the first Crohn's episode or ulcerative colitis. Therefore, dermatologists, ophthalmologists and rheumatologists should beware of this possible association in EIM and the simultaneous occurrence of intestinal symptoms.

Celiac Disease is Misdiagnosed Based on Serology Only in a Substantial Proportion of Patients.

BACKGROUND: Although the diagnostic process in celiac disease (CeD) has been addressed in several international guidelines, little is known about the actual proceeding in current clinical practice. This study investigated the initial presentation, the diagnostic process, follow-up evaluations, and adherence to a gluten-free diet in CeD patients in a real-life setting in Switzerland from a patient's perspective. METHODS: We performed a large patient survey among unselected CeD patients in Switzerland. RESULTS: A total of 1689 patients were analyzed. The vast majority complained of both gastrointestinal and nonspecific symptoms (71.5%), whereas 1.8% reported an asymptomatic disease course. A total of 35.8% CeD patients were diagnosed by a nongastroenterologist. The diagnostic process differed between nongastroenterologists and gastroenterologists, with the latter more often using duodenal biopsy alone or in combination with serology (94.7% vs. 63.0%) and nongastroenterologists more frequently establishing the diagnosis without endoscopy (37.0% vs. 5.3%, P<0.001). Follow-up serology after 6 months was performed only in half of all patients (49.4%), whereas 69.9% had at least 1 follow-up serology within the first year after diet initiation. About 39.7% had a follow-up endoscopy with duodenal biopsies (after a median of 12 mo; range, 1 to 600 mo). The likelihood of receiving any follow-up examination was higher in patients initially diagnosed by a gastroenterologist. CONCLUSIONS: A significant proportion of CeD patients are diagnosed by nongastroenterologists. Under the diagnostic lead of the latter, more than a third of the patients receive their diagnosis on the basis of a positive serology and/or genetics only, in evident violation of current diagnostic guidelines, which may lead to an overdiagnosis of this entity.

Long-Term Efficacy and Safety of Certolizumab Pegol in an Unselected Crohn's Disease Population: The FACTS III Survey.

BACKGROUND: Long-term data of certolizumab pegol (CZP) in Crohn's disease (CD) from pivotal registry trials are limited. We therefore aimed to evaluate the long-term efficacy of CZP in clinical practice in Switzerland. METHODS: In the First Approved Certolizumab Therapeutic Experience in Switzerland-III phase IV multicenter cohort, patients receiving CZP were prospectively included all over Switzerland in (non-) academic hospitals and private practice. RESULTS: We included 104 CD patients (52 male; only 22.1% anti-tumor necrosis factor (TNF) naïve, CZP as third anti-TNF agent in 46.2%) with follow-up time between 6 weeks up to 5 years. During treatment with CZP, we observed a significant decrease of the Harvey Bradshaw Index from a median of 7 at baseline (interquartile range 4-11) to 4, 5, 4, 3, 3, and 2 at weeks 6, 26, 52, 78, 104, and 156, respectively. While anti-TNF naïve patients showed a significantly better response at the end of induction, during CZP maintenance therapy response was similar as compared to anti-TNF experienced patients as well as between patients with a short (0-5 years) vs. long duration of disease (>5 years). CONCLUSIONS: CZP is an effective long-term treatment option, including CD patients with long disease duration and prior treatment with 1 or 2 anti-TNF agents.

Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease: Prevalence, Presentation, and Anti-TNF Treatment.

BACKGROUND: There is a paucity of data on extraintestinal manifestations (EIM) and their treatment in pediatric patients with inflammatory bowel disease (IBD). METHODS: Since 2008, the Pediatric Swiss IBD Cohort Study has collected data on the pediatric IBD population in Switzerland. Data on 329 patients were analyzed retrospectively. RESULTS: A total of 55 patients (16.7%) experienced 1-4 EIM (39 Crohn disease, 12 ulcerative colitis, and 4 IBD-unclassified patients). At IBD onset, presence of EIM was more frequent than in the adult population (8.5% vs 5.0%, P = 0.014). EIM were more frequent in Crohn disease when compared to ulcerative colitis/IBD-unclassified (22.5% vs 10.3%, P = 0.003). The most prevalent EIM were peripheral arthritis (26/329, 7.9%) and aphthous stomatitis (24/329, 7.3%). Approximately 27.6% of all EIM appeared before IBD diagnosis. Median time between IBD diagnosis and occurrence of first EIM was 1 month (-37.5-149.0). Thirty-one of the 55 patients (56.4%) were treated with 1 or more anti-tumor necrosis factor (TNF) agents. IBD patients with EIM were more likely to be treated with anti-TNF compared to those without (56.4% vs 35.0%, P = 0.003). Response rates to anti-TNF depended on underlying EIM and were best for peripheral arthritis (61.5%) and uveitis (66.7%). CONCLUSIONS: In a cohort of pediatric patients with IBD, EIM were frequently encountered. In up to 30%, EIM appeared before IBD diagnosis. Knowledge of these findings may translate into an increased awareness of underlying IBD, thereby decreasing diagnostic delay. Anti-TNF for the treatment of certain EIM is effective, although a substantial proportion of new EIM may present despite ongoing anti-TNF therapy.

The Search for Causative Environmental Factors in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) has become a 'prototype disease' for chronic auto-inflammatory disorders with a polygenic background and important multifaceted environmental trigger components. The environmental factors contribute both to pathogenesis and disease flares. Thus, IBD is a disease par excellence to study the interactions between host genetics, environmental factors (such as infections or smoking) and 'in-vironmental' factors - for example, our intestinal microbiota. Longitudinal intercurrent events, including the impact of long-term medication on disease progression or stabilization, can exemplarily be studied in this disease group. Whilst alterations in the human genome coding relevant variant protein products have most likely not emerged significantly over the last 50 years, the incidence of Crohn's disease and ulcerative colitis has dramatically increased in Western countries and more recently in the Asia Pacific area. An interesting concept indicates that 'Western lifestyle factors' trigger chronic intestinal inflammation or disease flares in a genetically susceptible host. To understand the disease pathogenesis as well as triggers for flares or determinants of disease courses, we must further investigate potential en(in)vironmental factors. As environmental conditions, in contrast to genetic risk factors, can be influenced, knowledge on those risk factors becomes crucial to modulate disease incidence, disease course or clinical presentation. It is obvious that prevention of environmentally triggered disease flares would be a goal most relevant for IBD patients. An increased prevalence of IBD in urban environment has been documented in Switzerland by the Swiss IBD cohort study. Several studies have attempted to identify such factors; however, only a few have been validated. The best investigated environmental factor identified in IBD cohort analyses is smoking. Other environmental factors that have been associated with clinical presentation or risk of inflammatory flares as well as increased incidence are diet and food additives. The so-called 'hygiene hypothesis' suggests that increased hygiene in childhood associated with reduced exposure to pathogens may leave the mucosal immune system insufficiently trained and thus prone to uncontrolled inflammation. Oral contraceptives and non-steroidal anti-inflammatory drugs are the 2 main classes of frequently taken drugs that have been attributed to have the potential to cause flares of the disease. What is likely to be the connection between the genetic susceptibility and the environmental triggers? There is broad evidence for a critical role of the commensal enteric microbiota as a modulator of immunologic responses relevant during onset and chronification of IBD.

Malignancies in Patients with Inflammatory Bowel Disease: A Single-Centre Experience.

BACKGROUND: Gastrointestinal and extraintestinal malignancies are long-term complications in patients with inflammatory bowel disease (IBD), likely as a result of chronic inflammation and the use of immunosuppressive medications used to control inflammation. Here, we assessed the frequency of malignancies in a large tertiary IBD centre at the University Hospital Zurich. METHODS: We performed a retrospective analysis of data from 1,026 patients from our IBD clinic treated between 2007 and 2014. RESULTS: Twenty two of the 1,026 patients developed 28 cases of malignancies, 14 patients were male and 8 patients female. The median latency between IBD diagnosis and first malignancy was 13 years (range 2-27 years). Most common malignancies were non-Hodgkin lymphoma, colorectal cancer (CRC), urothelial carcinoma, cholangiocellular carcinoma (CCC) and prostate cancer. The most common tumour type in Crohn's disease patients (13/22) was lymphoma (5 cases), in ulcerative colitis patients (9/22) CCC (2 cases) and CRC (2 cases). The observed incidence of lymphoma (32.5/100,000), bladder carcinoma (21.7/100,000) and CCC (10.8/100,000) was higher than expected and known from general population. All of the patients that developed a malignancy had received immunosuppressive therapy. Compared to a cohort of 927 IBD patients without malignancies there were no statistical differences regarding gender, antibodies targeting tumour necrosis factor and thiopurine use. CONCLUSION: Our data support the assumption that a long-standing disease course and immunosuppressive therapy increase the risk for developing malignancies in IBD patients.

The Clinical Relevance of the IBD-Associated Variation within the Risk Gene Locus Encoding Protein Tyrosine Phosphatase Non-Receptor Type 2 in Patients of the Swiss IBD Cohort.

BACKGROUND/AIMS: The single nucleotide polymorphism (SNP) rs1893217 within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) results in a dysfunctional PTPN2 protein is associated with Crohn's disease (CD) and exists in perfect linkage disequilibrium with the CD- and ulcerative colitis (UC)-associated PTPN2 SNP rs2542151. We investigated associations of PTPN2 SNP rs1893217 and clinical characteristics of inflammatory bowel disease (IBD) patients. METHODS: One thousand seventy three patients with CD and 734 patients with UC from the Swiss IBD Cohort Study (SIBDCS) were included. Epidemiologic, disease and treatment characteristics were analysed for an association with the presence of one of the rs1893217 genotypes 'homozygous wild-type' (TT), 'heterozygous' (CT) and 'homozygous variant' (CC). RESULTS: About 2.88% of IBD patients were identified with CC, 26.8% with CT and 70.4% with TT genotype. The CC-genotype was associated with the existence of gallstones in CD and pancolitis in UC patients. The presence of the C-allele (i.e. either CC or CT genotype) was associated with the onset of uveitis, but protected from aphthous oral ulcers in CD patients. UC patients carrying a C-allele were diagnosed at an older age but required intestinal surgery more often. The presence of the C-allele was associated with a successful treatment with anti-TNF antibodies in both CD and UC patients. CONCLUSION: IBD patients carrying the C-allele of PTPN2 SNP rs1893217 are at greater risk for developing a severe disease course but are more likely to respond to treatment with anti-TNF antibodies. These findings demonstrate a clinical relevance of this PTPN2 risk variant in IBD patients.

Childlessness in Patients with Inflammatory Bowel Disease - Data from the Prospective Multi-center Swiss IBD Cohort Study.

BACKGROUND AND AIMS: Childlessness and infertility represent a frequent and important issue in inflammatory bowel disease (IBD) patients. Nevertheless, until now epidemiological data remains scarce. Therefore, main objectives of this study were to evaluate the rate of childlessness and the cumulative probability of reproduction in female and male IBD patients within the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS), a large prospective multicenter nationwide cohort. METHODS: Prospectively collected data of SIBDCS was used, comprising more than 3,300 patients with Crohn's disease (CD) and ulcerative colitis (UC). We analyzed the following groups of patients: 1) female IBD patients aged ≥40 years and diagnosed before age of 30 years with at least one follow-up, 2) female IBD patients who reported actively trying to conceive, with IBD diagnosed <35 years and with age at enrolment <45 years (longitudinal observation), with at least one follow-up, and 3) childless males who actively tried to conceive. RESULTS: A total of 1,412 female patients from the SIBDCS [843 CD, 539 UC, 30 indeterminate colitis (IC)] with available data were included in our analyses. Out of those 184 females (70.1% CD and 29.9 % UC) were aged ≥ 40 years and have been diagnosed with IBD before the age of 30 years. Among these, 184 women 32.1% were childless. The portion of childless females (36.4%) was significantly higher in CD vs. UC (36.4% vs. 21.8%; p=0.026), equaling a relative risk of childlessness of 1.7 in CD vs. UC. and higher than in the Swiss general population (21%). The mean number of children per female patient was 1.32 (median 1, min 0, max 6), per female with CD 1.12 (median 1, min 0, max 4), per female with UC/IC 1.78 (median 2, min 0, max 6; P=0.001). The longitudinal analysis of female IBD patients trying to conceive revealed that one out of two women neither were pregnant nor had born a child five years after first trying to conceive. CONCLUSIONS: The rate of childlessness in females with CD is higher compared to the general Swiss population, whereas it is similar in women with UC. Moreover, the mean number of children is lower in CD than in UC. Females with CD remain more often childless compared to their UC counterparts. Although the exact underlying mechanisms are largely unknown, this discrepancy should alert healthcare professionals treating CD patients to actively address this topic.

Follow-Up of Celiac Disease in Adults: "When, What, Who, and Where".

For patients with celiac disease (CeD), a lifelong gluten-free diet is not a voluntary lifestyle choice-it is a necessity. The key end points in clinical follow-up are symptom resolution, the normalization of weight, prevention of overweight, seroconversion, and negation or minimization of increased long-term morbidity. For the latter, a surrogate endpoint is mucosal healing, which means the normalization of histology to Marsh 0-1. Ideally, celiac follow-up care includes a multidisciplinary approach, effective referral processes, improved access that leverages technological advances, and following guidelines with the identification of measurable quality indicators, ideally informed by evidence-based research. Face-to-face CeD care and telemedicine are considered the standards for this process, although published data are insufficient. Guidelines and statements on diagnosis are readily available. However, data are lacking on optimal clinic visit intervals and outcomes and quality indicators such as improvement of symptoms, function and quality of life, survival and disease control, and how to most effectively use healthcare resources. The results of future research should provide the basis for general recommendations for evidence-based standards of quality of care in CeD.

Because I'm happy - positive affect and its predictive value for future disease activity in patients with inflammatory bowel diseases: a retrospective cohort study.

Background: While the detrimental impact of negative emotions on the clinical course of inflammatory bowel disease (IBD) and quality of life has been extensively investigated, evidence for a potential impact of positive emotions is scarce. Objectives: We aim to analyse contributing factors of positive affect and their predictive value for disease course in IBD patients. Design: In this retrospective cohort study, epidemiological, psychosocial and IBD disease characteristics of Swiss IBD cohort study patients were analysed longitudinally. Methods: Epidemiological, psychosocial and disease characteristics were extracted from the database of the Swiss IBD cohort study. Participants' positive emotions were assessed cross-sectionally with the seven-item Marburg questionnaire (range 1-6) addressing positive affect in different aspects of daily life. Predictors of positive emotions were identified by linear regression. The quantitative longitudinal impact of positive emotions on the further disease course was analysed using a multivariable Cox proportional hazards model. Results: Among 702 IBD patients, those reporting more positive emotions were found to have significantly less intense medical treatment, less pain and fewer depressive symptoms (p < 0.05). A higher percentage of variability in positive emotions was explained by pain (36%) and depressive symptoms (13%) than by epidemiological characteristics (0.3%), or characteristics of IBD and its treatment (2.4%). Patients with higher levels of positive emotions (score > 3.5) experienced longer flare-free survival, also after adjusting for confounders (adjusted hazard ratio: 0.39, p < 0.05). Conclusions: The absence of pain and depressive symptoms were the strongest drivers for high positive affect. Higher scores of positive affect were associated with longer disease-free survival in IBD patients.

Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort.

OBJECTIVES: Data on the frequency of extraintestinal manifestations (EIMs) in Crohn's disease (CD) and ulcerative colitis (UC) and analyses of their risk factors are scarce. We evaluated their prevalence and risk factors in a large nationwide cohort of inflammatory bowel disease (IBD) patients. METHODS: IBD patients from an adult clinical cohort in Switzerland (Swiss IBD cohort study) were prospectively included. Data from validated physician enrolment questionnaires were analyzed. RESULTS: A total of 950 patients were included, 580 (61%) with CD (mean age 41 years) and 370 (39%) with UC (mean age 42 years). Of these, 249 (43%) of CD and 113 (31%) of UC patients had one to five EIMs. The following EIMs were found: arthritis (CD 33%, UC 21%), aphthous stomatitis (CD 10%, UC 4%), uveitis (CD 6%, UC 4%), erythema nodosum (CD 6%, UC 3%), ankylosing spondylitis (CD 6%, UC 2%), psoriasis (CD 2%, UC 1%), pyoderma gangrenosum (CD and UC each 2%), and primary sclerosing cholangitis (CD 1%, UC 4%). Multiple logistic regression identified the following risk factors for ongoing EIM in CD: active disease (odds ratio (OR)=1.95, 95% confidence interval (CI)=1.17-3.23, P=0.01), and positive IBD family history (OR=1.77, 95% CI=1.07-2.92, P=0.025). No risk factors were identified in UC patients. CONCLUSIONS: EIMs are a frequent problem in CD and UC patients. Active disease and positive IBD family history are associated with ongoing EIM in CD patients. Identification of EIM prevalence and associated risk factors may result in increased awareness for this problem and thereby facilitating their diagnosis and therapeutic management.

Knock-out of ß-glucosidase 2 has no influence on dextran sulfate sodium-induced colitis.

BACKGROUND/AIMS: The non-lysosomal glucosylceramidase, ß-glucosidase (Gba2), hydrolyzes glucosylceramide to glucose and ceramide (Cer). Cer is a potent second-messenger lipid that plays an important role in signaling cascades involved in apoptosis. The aim of this study was to investigate whether Gba2 knock-out (Gba2(-/-)) affects the extent of dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: Acute colitis was induced in wild-type (WT) and Gba2(-/-) mice by administration of 2% DSS in drinking water. After 7 days, mice underwent colonoscopy and were sacrificed. RESULTS: Both DSS-treated WT (n = 10) and Gba2(-/-) (n = 12) mice showed elevated histological and endoscopic scores compared to respective H(2)O controls (n = 9 each). However, no significant differences between the DSS groups were detected. Flow cytometric analysis of propidium iodide staining, cleavage of caspases-3 and -8, indicative for apoptosis, as well as Cer levels were not altered in DSS-treated WT or Gba2(-/-) mice. Gba2(-/-) resulted in slightly decreased expression of glucocerebrosidase (Gba1) as well as in upregulation of proteins being involved in cellular regeneration, such as STAT3 (signal transducer and activator of transcription), JNK and iNOS, upon DSS treatment. CONCLUSION: We demonstrate that Gba2(-/-) does not affect the extent of DSS-induced inflammation in mice, however, it might be involved in tissue regeneration in response to toxic agents.

The impact of colectomy on the course of extraintestinal manifestations in Swiss inflammatory bowel disease cohort study patients.

BACKGROUND AND AIMS: Extraintestinal manifestations are reported to occur in up to 45% of inflammatory bowel disease (IBD) patients during the course of disease. It is unknown whether colectomy reduces the rate of de novo extraintestinal manifestations (EIMs) or impacts on severity of EIMs following a parallel versus independent disease course from underlying IBD. METHODS: Using data from the Swiss Inflammatory Bowel Disease Cohort Study we aimed to analyse the course of EIMs in ulcerative colitis (UC) and Crohn's disease (CD) patients undergoing colectomy during the cohort's prospective follow-up. RESULTS: One hundred and twenty-one IBD patients (33 CD, 81 UC and seven unclassified) underwent colectomy during prospective follow-up in the Swiss Inflammatory Bowel Disease Cohort Study. Within the 114 patients with UC or CD any EIM was reported in 40 (nine CD and 31 UC) patients. Activity of EIMs ceased entirely after colectomy in 21 patients (52.5%). Complete cessation of EIM after colectomy was higher in patients with UC versus CD with 58.1% versus 33.3%. After colectomy, 29 out of the 114 patients (25.4%) experienced any EIM. Two thirds of these (19 patients) represented persisting EIMs, while in one third (10 patients) EIM represented a de-novo event after colectomy. Overall, 13.5% of IBD patients developed a de-novo EIM after colectomy. CONCLUSIONS: In IBD patients undergoing colectomy, EIMs present prior to surgery will persist in about half of patients. Complete cessation of EIM after colectomy may be less common in CD than in UC. In patients who never experienced EIMs prior to colectomy de-novo manifestations thereafter should be expected in up to one in seven patients.

Hypoxia Reduces the Transcription of Fibrotic Markers in the Intestinal Mucosa.

INTRODUCTION: Intestinal fibrosis, characterized by excessive deposition of extracellular matrix proteins, is a common and severe clinical complication of inflammatory bowel disease (IBD). However, the mechanisms underlying fibrosis remain elusive, and currently, there are limited effective pharmacologic treatments that target the development of fibrosis. Hypoxia is one of the key microenvironmental factors influencing intestinal inflammation and has been linked to fibrosis. OBJECTIVE: In the present study, we sought to elucidate the impact of hypoxia on fibrotic gene expression in the intestinal mucosa. METHODS: Human volunteers, IBD patients, and dextran sulphate sodium-treated mice were exposed to hypoxia, and colonic biopsies were collected. The human intestinal epithelial cell line Caco-2, human THP-1 macrophages, and primary human gut fibroblasts were subjected to hypoxia, and changes in fibrotic gene expression were assessed. RESULTS: Human volunteers subjected to hypoxia presented reduced transcriptional levels of fibrotic and epithelial-mesenchymal transition markers in the intestinal mucosa. IBD patients showed a trend towards a decrease in tissue inhibitor of metalloproteinase 1 protein expression. In mice, hypoxic conditions reduced the colonic expression of several collagens and matrix metalloproteinases. Hypoxic Caco-2 cells, THP-1 cells, and primary gut fibroblasts showed a significant downregulation in the expression of fibrotic and tissue remodelling factors. CONCLUSIONS: Stabilization of hypoxia-inducible factors might represent a novel therapeutic approach for the treatment of IBD-associated fibrosis.

Effect of distance to specialist care for the diagnosis and disease outcome of inflammatory bowel disease in the Swiss inflammatory bowel disease cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) needs early interventions and an individual specialist-patient relationship. Distance from a tertiary IBD center might affect patient's disease course and outcome. We investigated whether the patient-to-specialist distance has an impact on the disease course using the well-defined patient collective of the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS). METHODS: Patient's home address at diagnosis (postal zip code) was extracted from the SIBDCS database. Distance between each zip code and the nearest located IBD specialist center was calculated and classified into the following three sections based on proximity: <10 km (group 1); 10-35 km (group 2); >35 km (group 3). RESULTS: Our study included in total 408 IBD patients [234 Crohn's disease (CD), 154 ulcerative colitis (UC), 20 IBD unclassified (IBDU)]. Median age was lowest in group 2 at diagnosis (G1: 28 years; G2: 21 years, G3: 26 years, p < 0.01). The diagnostic delay did not differ between groups. CD patients in group 1 were treated more often with anti-tumor necrosis factor (TNF) agents (72% versus 56%, p = 0.04) and 5-aminosalicylates (44% versus 28%, p = 0.04) than in group 3. UC/IBDU patients in group 1 were treated more often with corticosteroids than patients in group 3 (83% versus 58%, p < 0.01). The occurrence of IBD-related surgeries did not differ between groups. CONCLUSIONS: Patient-to-specialist distance might affect drug treatment. However, disease course and the need for IBD-related surgery does not seem to be associated with a longer distance to specialist care in Switzerland.

[From Axial Spondyloarthritis to Osteoporosis - Spectrum of Skeletal Involvement in Inflammatory Bowel Diseases]. / Von Spondyloarthritis bis Osteoporose ­ Beteiligung des Skelettsystems bei chronisch entzündlichen Darmerkrankungen.

From Axial Spondyloarthritis to Osteoporosis - Spectrum of Skeletal Involvement in Inflammatory Bowel Diseases Abstract. Inflammatory bowel diseases (IBD) are frequently accompanied by non-inflammatory joint pain and inflammatory spondyloarthritides. Spondyloarthritides can restrict joint function and typically manifest with inflammatory back pain with nightly pain and morning stiffness that improves upon exercising. In other patients, small or large peripheral joints are predominantly involved. Treatment comprises pain medication including COX-II selective non-steroidal anti-inflammatory drugs (NSAID), since non-selective NSAID can aggravate IBD. For axial manifestations, physiotherapy and tumor necrosis factor (TNF) inhibitors are effective, while for peripheral manifestations steroid injections, sulfasalazine and TNF inhibitors are useful. Osteopenia and osteoporosis may result from inflammation, malabsorption and/or steroids. Long-lasting disease activity or steroid treatment should prompt osteoporosis screening. Adequate calcium and vitamin D intake must be ensured and treatment with bisphosphonates evaluated.