Systematic evaluation of clinical predictors of aggressive ulcerative colitis

Background: Studies evaluating risk factors associated with an "aggressive" disease course in ulcerative colitis (UC) are scarce. A recent definition of "aggressive" UC incorporated the following characteristics: 1) high relapse rate, 2) need for surgery, 3) development of colorectal cancer, and 4) presence of extraintestinal manifestations (EIM). The following factors for an aggressive / disabling disease course in UC have been identified so far: age < 40 years at S140 Poster presentations UC diagnosis, pancolitis, concomitant primary sclerosing cholangitis, and deep ulcerations of the colonic mucosa. We aimed to evaluate risk factors for an "aggressive" disease course in UC patients. Methods: Data from the Swiss IBD cohort study were analyzed. Patients were recruited from university centers (80%), regional hospitals (19%), and private practices (1%). We applied the following definition for "aggressive" UC: 1) patients ever treated with TNFantagonists or calcineurin inhibitors (tacrolimus / cyclosporine), and 2) need for (procto)-colectomy. Non-normal data are presented as median and interquartile range [IQR]

Prevalence of extraintestinal manifestations in paediatric patients with Inflammatory Bowel Disease : results from the Swiss IBD Cohort Study

Background: There is a paucity of data from large cohort studies on the prevalence and type of extraintestinal manifestations in pediatric patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to assess the prevalence and type of EIM in pediatric patients with inflammatory bowel disease (IBD). Methods: Data from patients enrolled in the Pediatric Swiss IBD Cohort Study (P-SIBDCS) were analyzed. Since 2008 the P-SIBDCS collects data on patients aged 2-17 from hospitals and private practices across Switzerland. Results of continuous data are reported as median and interquartile range

Associations between fruit and vegetable intake and quality of life

Abstract Dysregulation of the immune response to microbiota is associated with inflammatory bowel disease (IBD), which can trigger intestinal fibrosis. MyD88 is a key component of microbiota signalling but its influence on intestinal fibrosis has not been clarified. Small bowel resections from donor-mice were transplanted subcutaneously into the neck of recipients C57BL/6 B6-MyD88tm1 Aki (MyD88−/−) and C57BL/6-Tg(UBC-green fluorescence protein (GFP))30Scha/J (GFP-Tg). Grafts were explanted up to 21 days after transplantation. Collagen layer thickness was determined using Sirius Red stained slides. In the mouse model of fibrosis collagen deposition and transforming growth factor-beta 1 (TGF-β1) expression was equal in MyD88+/+ and MyD88−/−, indicating that MyD88 was not essential for fibrogenesis. Matrix metalloproteinase (Mmp)9 expression was significantly decreased in grafts transplanted into MyD88−/− recipients compared to MyD88+/+ recipients (0.2 ± 0.1 vs. 153.0 ± 23.1, respectively, p < 0.05), similarly recruitment of neutrophils was significantly reduced (16.3 ± 4.5 vs. 25.4 ± 3.1, respectively, p < 0.05). Development of intestinal fibrosis appears to be independent of MyD88 signalling indicating a minor role of bacterial wall compounds in the process which is in contrast to published concepts and theories. Development of fibrosis appears to be uncoupled from acute inflammation

Prevalence and risk factors for therapy escalation in ulcerative colitis in the Swiss IBD Cohort Study

BACKGROUND: Physicians traditionally treat ulcerative colitis (UC) using a step-up approach. Given the paucity of data, we aimed to assess the cumulative probability of UC-related need for step-up therapy and to identify escalation-associated risk factors. METHODS: Patients with UC enrolled into the Swiss IBD Cohort Study were analyzed. The following steps from the bottom to the top of the therapeutic pyramid were examined: (1) 5-aminosalicylic acid and/or rectal corticosteroids, (2) systemic corticosteroids, (3) immunomodulators (IM) (azathioprine, 6-mercaptopurine, methotrexate), (4) TNF antagonists, (5) calcineurin inhibitors, and (6) colectomy. RESULTS: Data on 996 patients with UC with a median disease duration of 9 years were examined. The point estimates of cumulative use of different treatments at years 1, 5, 10, and 20 after UC diagnosis were 91%, 96%, 96%, and 97%, respectively, for 5-ASA and/or rectal corticosteroids, 63%, 69%, 72%, and 79%, respectively, for systemic corticosteroids, 43%, 57%, 59%, and 64%, respectively, for IM, 15%, 28%, and 35% (up to year 10 only), respectively, for TNF antagonists, 5%, 9%, 11%, and 12%, respectively, for calcineurin inhibitors, 1%, 5%, 9%, and 18%, respectively, for colectomy. The presence of extraintestinal manifestations and extended disease location (at least left-sided colitis) were identified as risk factors for step-up in therapy with systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and surgery. Cigarette smoking at diagnosis was protective against surgery. CONCLUSIONS: The presence of extraintestinal manifestations, left-sided colitis, and extensive colitis/pancolitis at the time of diagnosis were associated with use of systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and colectomy during the disease course

Expression Patterns of TNFα, MAdCAM1, and STAT3 in Intestinal and Skin Manifestations of Inflammatory Bowel Disease.

Pathogenesis of cutaneous extraintestinal manifestations [EIM] in inflammatory bowel disease [IBD] remains elusive. Efficacy of anti-TNF agents suggests TNF-dependent mechanisms. The role of other biologics, such as anti-integrins or JAK-inhibitors, is not yet clear. We performed immunohistochemistry for TNFα, NFκB, STAT1/STAT3, MAdCAM1, CD20/68, caspase 3/9, IFNγ, and Hsp-27/70 on 240 intestinal [55 controls, 185 IBD] and 64 skin biopsies [11 controls, 18 erythema nodosum [EN], 13 pyoderma gangenosum [PG], 22 psoriasis]. A semiquantitative score [0-100%] was used for evaluation. TNFα was upregulated in intestinal biopsies from active Crohn`s disease [CD] vs controls [36.2 vs 12.1, p &lt; 0.001], but not ulcerative colitis [UC: 17.9]. NFκB, however, was upregulated in intestinal biopsies from both active CD and UC [43.2 and 34.5 vs 21.8, p &lt; 0.001 and p = 0.017, respectively]. TNFα and NFκB were overexpressed in skin biopsies from EN, PG, and psoriasis. No MAdCAM1 overexpression was seen in skin tissues, whereas it was upregulated in active UC vs controls [57.5 vs 35.4, p = 0.003]. STAT3 was overexpressed in the intestinal mucosa of active and non-active IBD, and a similar upregulation was seen in skin biopsies from EN [84.7 vs 22.3, p &lt; 0.001] and PG [60.5 vs 22.3, p = 0.011], but not in psoriasis. Caspase 3 and CD68 overexpression in skin biopsies distinguished EN/PG from psoriasis and controls. Upregulation of TNFα/NFκB in EN and PG is compatible with the efficacy of anti-TNF in EIM management. Data on overexpressed STAT3, but not MAdCAM1, support a rationale for JAK-inhibitors in EN and PG, while questioning the role of vedolizumab

The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis

Intestinal fibrosis and stenosis are common complications of Crohn's disease [CD], frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H] converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and oxidative stress. In human intestinal samples from CD patients, we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate [DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis

Low serum zinc levels predict presence of depression symptoms, but not overall disease outcome, regardless of ATG16L1 genotype in Crohn's disease patients.

Zinc deficiency (ZD) in Crohn's disease (CD) is considered a frequent finding and may exacerbate CD activity. ZD is associated with depression in non-CD patients. We aimed to assess the prevalence of ZD in CD patients in clinical remission, its association with mood disturbances and to analyze a potential impact on future disease course. Zinc levels from CD patients in clinical remission at baseline and an uncomplicated disease course within the next 3 years ( &lt;i&gt;n&lt;/i&gt; = 47) were compared with those from patients developing complications ( &lt;i&gt;n&lt;/i&gt; = 50). Baseline symptoms of depression and anxiety were measured with the Hospital Anxiety and Depression scale. Mean zinc level in the 97 patients (40.4 ± 15.7 years, 44.3% males) was 18.0 ± 4.7 μmol/l. While no ZD (&lt;11 μmol/l) was observed, we found low zinc levels (&lt;15.1 μmol/l) in 28 patients (28.9%). Males had higher zinc levels compared with females (19.4 ± 5.7 &lt;i&gt;versus&lt;/i&gt; 16.8 ± 3.3, &lt;i&gt;p&lt;/i&gt; = 0.006). Patients with low zinc levels more often reported depression symptoms compared with patients with higher levels (27.3 &lt;i&gt;versus&lt;/i&gt; 9.4%, &lt;i&gt;p&lt;/i&gt; = 0.047). In a multivariate analysis, zinc levels were an independent negative predictor for depression symptoms [odds ratio (OR) 0.727, 95% confidence interval (CI) 0.532-0.993, &lt;i&gt;p&lt;/i&gt; = 0.045]. Zinc levels of patients with a complicated disease course were not different from those of patients without (17.7 ± 4.3 &lt;i&gt;versus&lt;/i&gt; 18.3 ± 5.1, n.s.). Baseline zinc levels did not predict disease outcome regardless of ATG16L1 genotype. Low-normal zinc levels were an independent predictor for the presence of depression symptoms in CD patients. Zinc levels at baseline did not predict a complicated disease course, neither in CD patients overall, nor ATG16L1 &lt;sup&gt;T300A&lt;/sup&gt; carriers