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Cyclosporine A and tacrolimus are potent immunosuppressive drugs that inhibit calcineurin, thereby resulting in profound suppression of T-cell activation. Randomized controlled trials demonstrated their efficacy in inducing remission in steroid-refractory and -dependent ulcerative colitis and both cyclosporine A and tacrolimus are considered medical rescue options for patients with acute severe ulcerative colitis resistant to corticosteroids, who otherwise would have to undergo colectomy. In contrast, calcineurin inhibitors are of limited value in the maintenance of remission, but rather act as bridging agents until maintenance therapy with other agents such as thiopurines becomes effective. Whereas cyclosporine A therapy is usually initiated as continuous intravenous infusion, tacrolimus can be given orally; however, both drugs display a narrow therapeutic window and frequent monitoring of drug levels is pivotal for both compounds. The advent of biological drugs expanded the therapeutic options in acute severe steroid resistant colitis and the choice of therapy should be guided by physician experience and consider patient characteristics and different adverse event profiles associated with both classes of compounds.

The role of non-steroidal anti-inflammatory drugs in inflammatory bowel disease is controversial, as they have been implicated in disease aggravation. Different from other cyclooxygenase inhibitors, acetylsalicylic acid (ASA) enhances the formation of anti-inflammatory and proresolution lipoxins derived from arachidonic acid as well as resolvins from omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). In this study, we examined the effect of ASA on murine dextran sodium sulfate colitis. A mouse magnetic resonance imaging (MRI) protocol and post mortem assessment were used to assess disease severity, and lipid metabolites were measured using liquid chromatography-coupled tandem mass spectrometry. Decreased colitis activity was demonstrated by phenotype and MRI assessment in mice treated with ASA, and confirmed in postmortem analysis. Analysis of lipid mediators showed sustained formation of lipoxin A4 and an increase of DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA) after treatment with ASA. Furthermore,in vitroexperiments in RAW264.7 murine macrophages demonstrated significantly increased phagocytosis activity after incubation with 17-HDHA, supporting its proresolution effect. These results show a protective effect of ASA in a murine colitis model and could give a rationale for a careful reassessment of ASA therapy in patients with inflammatory bowel disease and particularly ulcerative colitis, possibly combined with DHA supplementation.

SummaryUlcerative colitis is an idiopathic, chronic inflammatory disorder of the colonic mucosa, which starts in the rectum and generally extends proximally in a continuous manner through part of, or the entire, colon; however, some patients with proctitis or left-sided colitis might have a caecal patch of inflammation. Bloody diarrhoea is the characteristic symptom of the disease. The clinical course is unpredictable, marked by alternating periods of exacerbation and remission. In this Seminar we discuss the epidemiology, pathophysiology, diagnostic approach, natural history, medical and surgical management, and main disease-related complications of ulcerative colitis, and briefly outline novel treatment options. Enhanced understanding of how the interaction between environmental factors, genetics, and the immune system results in mucosal inflammation has increased knowledge of disease pathophysiology. We provide practical therapeutic algorithms that are easily applicable in daily clinical practice, emphasising present controversies in treatment management and novel therapies.

Background: A disturbed epithelial barrier could play a pivotal role in ulcerative colitis (UC). We performed a family-based study analyzing in vivo gastrointestinal permeability in patients with UC, their healthy relatives, spouses, and controls. Methods: In total, 89 patients with UC in remission, 35 first-degree relatives (UC-R), 24 nonrelated spouses (UC-NR), and 99 healthy controls (HC) were studied. Permeability was assessed by a sugar-drink test using sucrose (gastroduodenal permeability), lactulose/mannitol (intestinal permeability), and sucralose (colonic permeability). Data were correlated with clinical characteristics including medical treatment. Results: Increased intestinal permeability was detected significantly more often in UC patients in remission (25/89, 28.1%) compared with HC (6/99, 6.1%; P < 0.001). Similar results were obtained in UC-R (7/35, 20.0%; P = 0.01 compared with HC) regardless of sharing the same household with the patients or not. No difference was found between UC-NR (3/24, 12.5%) and HC. Notably, in UC patients increased intestinal permeability was found in 12/28 patients (42.9%) with pancolitis, 7/30 (23.3%) patients with left-sided colitis, and in 2/19 (10.5%) patients with proctitis (P = 0.04). Gastroduodenal and colonic permeability were similar in all groups. Among patients on azathioprine, increased intestinal permeability was only seen in 1/18 (5.6%) patients. In contrast, in 24/70 (34.3%) patients without azathioprine, an increased intestinal permeability was found (P = 0.005). Conclusions: An increased intestinal but not colonic permeability was found in UC patients in clinical remission that could mark a new risk factor for extensive disease location. Similar findings in healthy relatives but not spouses suggest that this barrier defect is genetically determined. (Inflamm Bowel Dis 2012)

Innovative ideas are required to improve the management of inflammatory bowel disease and to share best practice that can be implemented into clinical practice today. The use of biomarkers such as calprotectin to monitor disease progression and treatment response could help to improve management of inflammatory bowel disease, but several strategies need to be implemented to make this a reality in clinical practice. The use of calprotectin as a biomarker and the manipulation of the thiopurine pathway to extend the use of current therapies are examples of how basic research can translate into patient benefit. Translational research into the use of microbiota and predictive factors for response and toxicity to drugs, may provide future clinical applications. Global improvement in care in inflammatory bowel disease could also be advanced by improving service provision. For example, the establishment of 'Centres of Excellence', a global interactive inflammatory disease map, and the alignment of processes and standards of care within treatment centres may help to achieve better outcomes for patients with inflammatory bowel disease. Realization of this goal, as well as a better understanding of the aetiology of the disease, may be furthered by collaborative efforts between organizations involved in inflammatory bowel disease as well as wider collaboration across countries and globally.

Crohn's disease and ulcerative colitis are two chronic inflammatory bowel diseases. Current biologic therapies are limited to blocking tumor necrosis factor alpha. However, some patients are primary non-responders, experience a loss of response, intolerance or side effects defining the urgent unmet need for novel treatments. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. We discuss the immunological mechanisms of leukocyte homing and adhesion in the gut mucosa. The interaction of lymphocytes (CD4+ T-cells, CD8+ T-cells, T(REG), T(H)1, T(H)17, B-cells), monocytes, macrophages, dendritic cells and granulocytes with endothelial and epithelial cells through integrins [α4β7 (LPAM-1), α(E)β₇ (HML1 Human Mucosal Lymphocyte Antigen 1), α₄β₁ (VLA-4), α(L)β₇, (LFA-1)] and their ligands immunoglobulin superfamily cellular adhesion molecules (CAM) (MAdCAM-1 Mucosal Addressin Cellular Adhesion Molecule 1, ICAM-1 Intercellular Cell Adhesion Molecule, VCAM-1 Vascular Cell Adhesion Molecule), fibronectin as well as chemokine receptors (CCR2, CCR4, CCR5, CCR7, CCR9, CCR10, CXCR3, CX3CR1) and chemokines [CCL5, CCL25 (TECK Thymus Expressed Chemokine), CCL28, CX3CL1, CXCL10, CXCL12] in the process of gut homing is critically reviewed and summarized in scientific cartoons. Moreover, we discuss the clinical trial results of approved and investigational antibodies and small molecules including natalizumab (anti-α₄ Tysabri®, Antegren®), AJM300 (anti-α4), etrolizumab (anti-β7, rhuMAb-Beta7), vedolizumab (anti-α4β7, LDP-02, MLN-02, MLN0002), PF-00547659 (anti-MAdCAM), Alicaforsen (anti-ICAM-1), and CCX282-B (anti-CCR9, GSK-1605786, Traficet-EN™) and their risks such as PML reported for natalizumab. Hopefully, the newer gut specific drug designs discussed in this article will have an impact on both efficacy and safety.

The aetiology of intestinal barrier dysfunction in Crohn's disease (CD) is poorly understood. Associations in relatives of CD families suggest a genetic basis, but the relevant variants are still unknown. We hypothesized that variants in genes occurring in pathways such as autophagy and IL23 signalling might contribute to CD by altering intestinal permeability.We analysed five variants (rs10758669 within JAK2, rs744166 within STAT3, rs4958847, rs11747270 and rs13361189 within IRGM) in adult German inflammatory bowel disease patients (CD, n = 464; ulcerative colitis (UC), n = 292) and matched healthy controls (n = 508). These data were correlated with gastrointestinal permeability as assessed by lactulose/mannitol ratio in CD patients (n = 141) in remission.Our data confirm the association between JAK2 rs10758669 (p = 0.026, OR = 1.25, 95% CI = 1.04-1.50) and STAT3 rs744166 (p = 0.04, OR = 0.83, 95% CI = 0.688-0.998) with CD, but not UC. With respect to all the analysed IRGM variants, no association was found to either CD or UC. Among CD patients, an increased intestinal permeability was detected in 65 out of 141 patients (46.1%). Most importantly, patients carrying the C risk allele within JAK2 rs10758669 displayed an increased permeability more often compared with patients without the C allele (p = 0.004). No association with intestinal permeability was found for STAT3 rs744166 and all IRGM variants.JAK2 rs10758669 and STAT3 rs744166 increase susceptibility for CD. We show that the AC substitution in rs10758669 of the JAK2 gene is associated with increased intestinal permeability. Altering intestinal barrier function might thus be one mechanism how JAK2 contributes to CD pathogenesis.

Every May 29th the World Gastroenterology Organization (WGO) celebrates World Digestive Health Day (WDHD) and initiates a worldwide public health campaign through its 110 national societies and 50,000 members. Each year focuses on a particular digestive disorder in order to increase general public awareness of prevention and therapy. 2010 is dedicated to inflammatory bowel disease (IBD). Upon this occasion a WGO IBD task force was compiled from leading international specialists and researchers. The task force also included members of the American Gastroenterological Association (AGA), International Organization for the Study of Inflammatory Diseases (IOIBD) and the European Crohn's and Colitis Organization (ECCO) of the United European Gastroenterology Federation (UEGF). The goal of the task force was to bring together IBD specialists from around the world to discuss the epidemiology, diagnosis, and management of IBD within different regions. This is a summary of the WGO task force meeting at the American Gastroenterological Association's (AGA) Digestive Disease Week, held in New Orleans, Louisiana, USA, May, 2010. The expert panel identified the most pressing issues in IBD worldwide: reliable epidemiological data, global collaboration in clinical and basic research, the approach to distinguishing intestinal tuberculosis from Crohn's disease, access to specialist care and access to the latest diagnostic and therapeutic strategies. (Inflamm Bowel Dis 2011;)

Crohn’s disease and ulcerative colitis are chronic inflammatory diseases resulting from an inappropriate innate and adaptive immune response towards commensal microbiota. Patients with Crohn’s disease and ulcerative colitis carry an increased risk of developing colon cancer and/or small bowel carcinoma, respectively. The colorectal cancer risks of ulcerative colitis and Crohn’s disease with comparable surface area involvement and disease duration are very similar. Early disease onset, disease extent, severity of inflammation, a family history of sporadic colorectal cancer, efficacy and duration of medical therapy, coexisting primary cholangitis and mucosal dysplasia are all risk factors for colorectal cancer. Regular endoscopic surveillance is endorsed by leading professional societies and outlined in guidelines and consensus statements. The yield of endoscopic surveillance, particularly to detect dysplasia, can be improved with chromoendoscopy with methylene blue dye spray-targeted biopsies, autofluorescence plus high-resolution endoscopy, chromoendoscopy-guided confocal laser microscopy and confocal laser microscopy in combination with narrow band imaging and high-resolution endoscopy. Proper bowel preparation, complete, careful inspection of the entire colon, a minimum withdrawal time and adherence to recommended management guidelines ensure a high-quality study and improve surveillance. Dysplasia can be graded by the Vienna or Riddell classification. Colectomy is recommended for patients with flat high-grade dysplasia confirmed by an expert gastrointestinal pathologist.

BACKGROUND: Ustekinumab (UST) has been approved for moderate to severe Crohn’s Disease (CD) in adult patients (pts). While no adverse developmental outcomes (pre-& postnatal) were observed in animal studies of UST, limited data exist, including previously reported outcomes in psoriasis (PsO) pts, concerning the effects of UST on human pregnancies(1). AIMS: To characterize pregnancy outcomes in women exposed to UST during pregnancy, data from the UST CD clinical development program (CDP) are presented. METHODS: Pregnancies reported with maternal use of UST (typical terminal half-life of approx 3 weeks) from 5 CD studies were evaluated: 2 Phase 2 (C0379T07:n=131; CERTIFI:n=526) & 3 Phase 3 (UNITI-1:n=769 & UNITI-2:n=640, from which 1,281 continued on maintenance in IM-UNITI). RESULTS: 877 female pts received ≥1 IV or SC dose of UST, and 26 maternal pregnancies were reported (despite agreeing to adequate birth control). UST treatment was discontinued upon the report of pregnancy in all cases. Mean maternal age was 27.6 years (range 19–43) and mean duration of UST exposure prior to the reported pregnancy was 76 ± 62.1 weeks. Pregnancy outcomes were reported for 24 of 26 pregnancies, including 15 (62.5%) live births (LBs), 4 (16.7%) spontaneous abortions (SAs), and 5 (20.8%) elective abortions. All 4 SAs occurred in the 1(st) trimester. Mean maternal age was older for pts who had SAs (33.0 ± 2.94 years) vs. LBs (27.6 ± 3.75 years) and median UST treatment duration was longer for pts who had SAs (80 weeks) vs. LBs (56 weeks). Among the LBs, there were no congenital anomalies; 1 infant had a single episode of transient hypoglycaemia treated with oral supplement. No safety signals emerged with neonatal outcomes with gestational age of 38.2 ± 1.3 weeks (n=12), mean 5 min-APGAR of 9.8 ± 0.45 (n=5), and mean birth weight of 6.6 ± 1.6 pounds (n=13). CONCLUSIONS: While the rate of SA’s was generally comparable to the rate previously reported in PsO data, the small number of pregnancies among women with CD with prenatal exposure to UST precludes definitive interpretation of the data. In this case series, SAs were associated with older maternal age, and longer duration of UST exposure prior to the reported pregnancy was not associated with adverse outcomes. However, the limited available data from the UST CD program requires additional research to determine pregnancy and newborn safety. (1)Cather JC, Rahawi KW, Schaufelberger BW, Chan D, Horn EJ, Goyal K. Pregnancy outcomes in women exposed to ustekinumab in the psoriasis clinical development program. Journal of the American Academy of Dermatology. 2014;70(5). FUNDING AGENCIES: Janssen Research & Development, LLC funded this study

Endocytoscopy (EC) is a novel technique that allows magnified live inspection of the intestinal mucosa.To evaluate EC for the detection of key pathological findings in patients with celiac sprue.A total of 166 EC recordings were prospectively acquired. Matched videos, images, and biopsy specimens were obtained by duodenal argon beamer labeling of the respective sites.Academic tertiary referral center.Forty patients (mean age 51.5 years, 70% women) with established (n = 32) or suspected (n = 8) celiac disease (CD).A validated scoring system (Marsh classification) was used to assess disease activity. EC criteria were independently evaluated by 2 gastroenterologists and 1 pathologist.The primary endpoint was to examine EC correlation with conventional CD histology.Of 166 duodenal biopsy sites, 23% were classified as Marsh III (moderate to severe), 10% as Marsh I (mild), and 67% as Marsh 0 (normal). Using the 450x magnification, we found that identification of crypts was diagnostic for celiac pathology. Four criteria were significant predictors of Marsh III pathology when adjusted by multivariate analysis: low number of villi per visual field (3; odds ratio [OR] 9.1; 95% CI, 1.3-62.0), confluence of villi (OR 37.1; 95% CI, 1.3-1021.2), irregular epithelial lining (OR 10.9; 95% CI, 2.5-46.7), and inability to delineate loop capillaries (OR 14.9; 95% CI, 3.3-67.0). None was a good predictor of Marsh I pathology.Single-center experience. No prospective validation of the criteria in an independent patient population.EC at 450x magnification accurately identifies mucosal histopathology of advanced CD, but not early morphological changes.

Summary Inflammatory bowel disease (IBD) results from a breakdown of tolerance towards the indigenous flora in genetically susceptible hosts. Failure of dendritic cells (DC) to interpret molecular microbial patterns appropriately when directing innate and adaptive immune responses is conceivable. Primary (conventional, non-monocyte generated) CD1c+CD11c+CD14-CD16-CD19- myeloid blood or mucosal dendritic cells (mDC) from 76 patients with Crohn’s disease (CD) or ulcerative colitis (UC) in remission, during flare-ups (FU) and 76 healthy or non-IBD controls were analysed by fluorescence activated cell sorter (FACS) flow cytometry and real-time polymerase chain reaction. Cytokine secretion of freshly isolated, cultured and lipopolysaccharide (LPS)-stimulated highly purified mDC (purity >95%) was assessed using cytometric bead arrays (CBA). More cultured and stimulated circulating mDC express CD40 in IBD patients. Stimulated circulating mDC from IBD patients secrete significantly more tumour necrosis factor (TNF)-α and interleukin (IL)-8. Toll-like receptor (TLR)-4 expression by mDC was higher in remission and increased significantly in flaring UC and CD patients compared with remission (P

Monoclonal antibodies to CD3 and CD4 T-cell receptors are evolving for Crohn's disease (CD) and ulcerative colitis. Their administration is often associated with a cytokine release syndrome (CRS).We evaluated data from two prospective clinical trials (NCT00267709 and NCT00267722) of visilizumab (HuM291), a novel humanized anti-CD3 antibody, in 34 patients with CD who received 10 microg/kg intravenously on 2 consecutive days. Serum hepatic tests including bilirubin, alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), visilizumab concentrations, and a panel of 16 cytokines were measured pre- and postadministration of visilizumab.Patients experienced CRS symptoms at a median of 45 min postinfusion. The cytokine profile was characterized by interferon-inducible protein-10 (IP-10), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, monocyte chemotactic protein 1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-2 (IL-2), and interleukin 1 receptor antagonist (IL-1Ra), which were elevated between 6 (IL-1Ra) and 870 (IP-10) times their baseline concentrations. TNF-alpha and IL-2 peaked at the first day 1 h post infusion, whereas all others peaked at 6 h post infusion. Eighty-six percent of patients experienced an elevation above the upper limit of normal in hepatic enzymes (GGT 73%, AST 73%, ALT 64%, and AP 42% of patients), but not bilirubin, within 6 h postinfusion.Transient elevation of hepatic enzymes occurred frequently in patients with CD treated with visilizumab and was associated with CRS. CD patients could be predisposed due to an aberrant expression of adhesion molecules in the liver that promotes CRS upon engagement of the T-cell receptor and may relate to extraintestinal disease manifestations such as primary sclerosing cholangitis.

Summary Saccharomyces boulardii (Sb) is a probiotic yeast preparation that has demonstrated efficacy in inflammatory and infectious disorders of the gastrointestinal tract in controlled clinical trials. Although patients clearly benefit from treatment with Sb, little is known on how Sb unfolds its anti-inflammatory properties in humans. Dendritic cells (DC) balance tolerance and immunity and are involved critically in the control of T cell activation. Thus, they are believed to have a pivotal role in the initiation and perpetuation of chronic inflammatory disorders, not only in the gut. We therefore decided to investigate if Sb modulates DC function. Culture of primary (native, non-monocyte-derived) human myeloid CD1c+CD11c+CD123– DC (mDC) in the presence of Sb culture supernatant (active component molecular weight

The immune system is a significant determinant of epithelial tumorigenesis, but its role in colorectal cancer pathogenesis is not well understood. The function of the immune system depends upon the integrity of the protein network environment, and thus, we performed MELC immunofluorescence microscopy focusing on the lamina propria. By analyzing structurally intact tissues from colorectal cancer, ulcerative colitis, and healthy colonic mucosa, we used this unique and novel highly multiplexed robotic-imaging technology, which allows visualizing dozens of proteins simultaneously, and explored the toponome in colorectal cancer mucosa for the first time. We identified 1,930 motifs that distinguish control from colorectal cancer tissue. In colorectal cancer, the number of activated T cells is increased, explained by a lack of bax, caspase-3, and caspase-8. Whereas CD4+CD25+ T cells are decreased and are, other than in ulcerative colitis, not activated, cytotoxic T cells are significantly increased in colorectal cancer. Furthermore, the number of activated human lymphocyte antigen (HLA)-DR+ T-cells is increased in colorectal cancer, pointing to an altered antigen presentation. In colorectal cancer, CD3+CD29+ expression and assembly of the LFA-1 and LFA-3 receptor are differentially changed, indicating a distinct regulation of T-cell adhesion in colorectal cancer. We also identified increased numbers of natural killer and CD44+ cells in the colorectal cancer mucosa and nuclear factor-κB as regulator of apoptosis in these cell populations. High-content proteomic analysis showed that colorectal cancer induces a tremendous modification of protein expression profiles in the lamina propria. Thus, topological proteomic analysis may help to unravel the role of the adaptive immune system in colorectal cancer and aid the development of new antitumor immunotherapy approaches. [Cancer Res 2008;68(3):880–8]

The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor kappaB (NF-kappaB)-dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-kappaB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-gamma, IL-2, and tumor necrosis factor-alpha, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.

Inflammation in inflammatory bowel diseases (IBD) has been linked to a loss of tolerance to self-antigens suggesting the existence of autoantibodies in specific disease phenotypes. However, the lack of clearly defined autoantigenic targets has slowed down research. Genome-wide association studies have identified an impressive number of immune-related susceptibility loci for IBD with no clearly discernible pattern among them. Growing evidence supports the hypothesis that innate immune responses to a low-diversity and impaired gut microbiota may be of key importance in initiating and perpetuating chronic inflammation in IBD. Increasing evidence suggests that reduced microbial diversity and microbial-mucosal epithelium interaction (including adhesion and clearance) are critically involved in IBD pathogenesis. Along these lines the discovery of autoantigenic targets in Crohn's disease (CD) has refocused research in IBD on the possible role of autoimmune responses. The identification of the major zymogen granule membrane glycoprotein 2 (GP2) as an autoantigen in CD patients and its proposed role in the sensing of the microbiota lends credence to this trend. Loss of tolerance to GP2 occurs in up to 40% of patients with CD. Corresponding autoantibodies appear to be associated with distinct disease courses (types or phenotypes) in CD. Here, we critically review autoantibodies in CD for their impact on clinical practice and future IBD research. The immunomodulatory role of GP2 in innate and adaptive intestinal immunity is also discussed.

Background Crohn’s disease (CD) and ulcerative colitis (UC) challenge economies worldwide. Detailed health economic data of DRG based academic inpatient care for inflammatory bowel disease (IBD) patients in Europe is unavailable. Methods IBD was identified through ICD-10 K50 and K51 code groups. We took an actual costing approach, compared expenditures to G-DRG and non-DRG proceeds and performed detailed cost center and type accounting to identify coverage determinants. Results Of all 3093 hospitalized cases at our department, 164 were CD and 157 UC inpatients in 2012. On average, they were 44.1 (CD 44.9 UC 43.3 all 58) years old, stayed 10.1 (CD 11.8 UC 8.4 vs. all 8) days, carried 5.8 (CD 6.4 UC 5.2 vs. all 6.8) secondary diagnoses, received 7.4 (CD 7.7 UC 7 vs. all 6.2) procedures, had a higher cost weight (CD 2.8 UC 2.4 vs. all 1.6) and required more intense nursing. Their care was more costly (means: total cost IBD 8477€ CD 9051€ UC 7903€ vs. all 5078€). However, expenditures were not fully recovered by DRG proceeds (means: IBD 7413€, CD 8441€, UC 6384€ vs all 4758€). We discovered substantial disease specific mismatches in cost centers and types and identified the medical ward personnel and materials budgets to be most imbalanced. Non-DRG proceeds were almost double (IBD 16.1% vs. all 8.2%), but did not balance deficits at total coverage analysis, that found medications (antimicrobials, biologics and blood products), medical materials (mostly endoscopy items) to contribute most to the deficit. Conclusions DRGs challenge sophisticated IBD care.

Background and aims A recent study reported that a nonsynonymous SNP rs2241880 (c.898A>G, p.Thr300Ala) within ATG16L1 confers susceptibility to Crohn's disease (CD). We analyzed ATG16L1 c.898A>G in three independent European inflammatory bowel disease (IBD) cohorts from Germany, Hungary and the Netherlands. Methods In total, we included 910 European IBD patients and compared the ATG16L1 c.898A>G genotype frequency with 707 ethnically matched healthy controls. We included patients from 3 populations originating from Germany (CD n =310; ulcerative colitis [UC] n =179), Hungary (CD n =147; UC n =117), and the Netherlands (CD n =157). Subtyping analysis was performed in respect to CARD15 alterations and clinical characteristics. Results We found a highly significant association of c.898A>G to CD. The association was significant ( p =0.0005) for the total CD cohort but also for the individual populations from Germany ( p =0.02) and Netherlands ( p =0.02) whereas in the Hungarian CD patients a clear trend was observed ( p =0.19; OR 1.227, 95% CI 0.910; 1.654). No association was found between c.898A>G and UC. No statistical interactions were observed between ATG16L1 c.898A>G and C ARD15 variants. Furthermore no association to a CD subphenotype was detected. Conclusions We confirm that ATG16L1 variant c898A>G confers a risk variant for CD but is not associated with a distinct CD phenotype.

BACKGROUND: A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease. AIM: To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour. METHODS: We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn's disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics. RESULTS: The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts (P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes. CONCLUSIONS: The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype.

Crohn's disease and ulcerative colitis are idiopathic inflammatory bowel disorders. In this paper, we discuss how environmental factors (eg, geography, cigarette smoking, sanitation and hygiene), infectious microbes, ethnic origin, genetic susceptibility, and a dysregulated immune system can result in mucosal inflammation. After describing the symbiotic interaction of the commensal microbiota with the host, oral tolerance, epithelial barrier function, antigen recognition, and immunoregulation by the innate and adaptive immune system, we examine the initiating and perpetuating events of mucosal inflammation. We pay special attention to pattern-recognition receptors, such as toll-like receptors and nucleotide-binding-oligomerisation-domains (NOD), NOD-like receptors and their mutual interaction on epithelial cells and antigen-presenting cells. We also discuss the important role of dendritic cells in directing tolerance and immunity by modulation of subpopulations of effector T cells, regulatory T cells, Th17 cells, natural killer T cells, natural killer cells, and monocyte-macrophages in mucosal inflammation. Implications for novel therapies, which are discussed in detail in the second paper in this Series, are covered briefly.

Summary Crohn's disease and ulcerative colitis are two idiopathic inflammatory bowel disorders. In this paper we discuss the current diagnostic approach, their pathology, natural course, and common complications, the assessment of disease activity, extraintestinal manifestations, and medical and surgical management, and provide diagnostic and therapeutic algorithms. We critically review the evidence for established (5-aminosalicylic acid compounds, corticosteroids, immunomodulators, calcineurin inhibitors) and emerging novel therapies—including biological therapies—directed at cytokines (eg, infliximab, adalimumab, certolizumab pegol) and receptors (eg, visilizumab, abatacept) involved in T-cell activation, selective adhesion molecule blockers (eg, natalizumab, MLN-02, alicaforsen), anti-inflammatory cytokines (eg, interleukin 10), modulation of the intestinal flora (eg, antibiotics, prebiotics, probiotics), leucocyte apheresis and many more monoclonal antibodies, small molecules, recombinant growth factors, and MAP kinase inhibitors targeting various inflammatory cells and pathways. Finally, we summarise the practical aspects of standard therapies including dosing, precautions, and side-effects.

Research into the human microbiome will substantially enhance our understanding of inflammatory, metabolic and malignant diseases. The complexity of this research area can only be addressed by an interdisciplinary translational approach including bioinformatics. Data derived from pure in silico analyses and statistical associations will not automatically translate into sound clinical concepts, as we have learned previously in genetics. Potential targets for future treatment strategies include the proven impact of nutrition and medication on microbial diversity and therapeutic effects of microbial metabolic processes and metabolites. Fecal microbial transplantation (FMT) beyond its indication in refractory Clostridium difficile infection (CDI) should be held against the same standards and regulated by the same procedures that are applied to all investigational compounds and treatments prior to their approval. Donor fidelity, sample processing and recipient safety (including the role of fecal pathogens and toxins) need thorough scientific investigation and evaluation in clinical trials with objective outcome parameters prior to any recommendations for clinical practice.

We read with interest the paper by Ekkelenkamp et al ,1 who found that the early use of validated simulators during endoscopy training expedites the learning of procedural skills. Indeed, traditional teaching concepts do not take full advantage of advanced technology. We therefore prospectively investigated the impact of our self-developed custom wireless-enabled tablet PC-based multimedia training and test system on gastrointestinal endoscopy self-assessment program (GESAP®) exam performance. Control and the tablet groups were tested at the beginning and the end of their rotation by administration of all 200 random generator selected, equally distributed questions from all 11 categories (biliary, colorectal, oesophagus, intestines, nutrition, pancreas, patient preparation, paediatrics, surgery) parsed from the current GESAP® pool. Medical students and residents doing an inpatient service rotation were alternatingly assigned to either the active test (tablet PC) or traditional education (control) group, respectively. The multimedia training package included access to the institutional collaborative online course management systems (Moodle and Blackboard), eBooks, eJournals, educational slide kits, podcasts, videos, animations, images from major biomedical and scientific publishers or professional societies, as well as twitter …

Toll-like receptors (TLRs) are key components of the innate immune system that trigger antimicrobial host defense responses. The aim of the present study was to analyze the effects of probiotic Escherichia coli Nissle strain 1917 in experimental colitis induced in TLR-2 and TLR-4 knockout mice. Colitis was induced in wild-type (wt), TLR-2 knockout, and TLR-4 knockout mice via administration of 5% dextran sodium sulfate (DSS). Mice were treated with either 0.9% NaCl or 10 7 E. coli Nissle 1917 twice daily, followed by the determination of disease activity, mucosal damage, and cytokine secretion. wt and TLR-2 knockout mice exposed to DSS developed acute colitis, whereas TLR-4 knockout mice developed significantly less inflammation. In wt mice, but not TLR-2 or TLR-4 knockout mice, E. coli Nissle 1917 ameliorated colitis and decreased proinflammatory cytokine secretion. In TLR-2 knockout mice a selective reduction of gamma interferon secretion was observed after E. coli Nissle 1917 treatment. In TLR-4 knockout mice, cytokine secretion was almost undetectable and not modulated by E. coli Nissle 1917, indicating that TLR-4 knockout mice do not develop colitis similar to the wt mice. Coculture of E. coli Nissle 1917 and human T cells increased TLR-2 and TLR-4 protein expression in T cells and increased NF-κB activity via TLR-2 and TLR-4. In conclusion, our data provide evidence that E. coli Nissle 1917 ameliorates experimental induced colitis in mice via TLR-2- and TLR-4-dependent pathways.

We and others have reported the use of tacrolimus in refractory inflammatory bowel disease (IBD). Little is known about its long-term efficacy and safety.In this retrospective, observational single center study the charts of 53 adult patients with steroid-dependent (n = 18) or steroid-refractory (n = 35) IBD, Crohn's disease (CD) (n = 11), ulcerative colitis (UC) (n = 40), or pouchitis (PC) (n = 2) were reviewed. Tacrolimus (0.1 mg/kg body weight per day) was administered orally in all and initially intravenously in 2 patients (0.01 mg/kg body weight per day), aiming for serum trough levels of 4-8 ng/mL. Forty-one of 53 (77.1%) patients were receiving concomitant azathioprine. The mean treatment duration was 25.2 +/- 4.6 SD months (0.43-164 months). Patients were followed for a mean of 39 +/- 4.1 SD months (5-164 months). Response was evaluated using a modified clinical activity index (M-CAI).Thirty-one UC (78%), 10 CD (90.1%), and both PC (100%) patients experienced an immediate clinical response or went into remission at 30 days. A statistically significant drop on the M-CAI was documented for UC and CD patients. Nine UC patients (22.5%) underwent colectomy between 1.6 and 41.3 months following initiation. Mean colectomy-free survival was 104.8 +/- 15.5 (95% CI 74.4-135.2) months (limited to 164.4 months). Cumulative colectomy-free survival was estimated 56.5% at 43.8 months. Steroids were reduced or discontinued in 40 of 45 UC and CD patients (90%) taking steroids. Side effects included a temporary rise of creatinine (n = 4, 7.6%), tremor or paresthesias (n = 5, 9.4%), hyperkalemia (n = 1, 1.9%), hypertension (n = 1, 1.9%), and opportunistic infections (n = 2, 3.8%).Long-term tacrolimus therapy appears safe and effective in refractory IBD.

Physicians and other health-care professionals are rapidly adopting personal digital assistants (PDA). Palm pilots and other hand-held computers are also increasingly popular among medical students. PDAs can be used for medical student education and physician training, daily clinical practice, and research. PDAs and their increasing integration with information technology in hospitals could change the way health care is delivered in the future. But despite the increasing use of PDAs, evidence from well-designed research studies is still needed to show how much these devices can improve the quality of care, save patients' lives, and ultimately reduce health-care expenses. In this Review of PDA use in health care, the operating systems, basic functionality, security and safety, limitations, and future implications of PDAs are examined. A personal perspective and an introduction to medical PDA applications, software, guidelines, and programmes for health-care professionals is also provided.

Although the probioticEscherichia colistrain Nissle 1917 has been proven to be efficacious for the treatment of inflammatory bowel diseases, the underlying mechanisms of action still remain elusive. The aim of the present study was to analyze the effects ofE. coliNissle 1917 on cell cycling and apoptosis of peripheral blood and lamina propria T cells (PBT and LPT, respectively). Anti-CD3-stimulated PBT and LPT were treated withE. coliNissle 1917-conditioned medium (E. coliNissle 1917-CM) or heat-inactivatedE. coliNissle 1917. Cyclin B1, DNA content, and caspase 3 expression were measured by flow cytometry to assess cell cycle kinetics and apoptosis. Protein levels of several cell cycle and apoptosis modulators were determined by immunoblotting, and cytokine profiles were determined by cytometric bead array.E. coliNissle 1917-CM inhibits cell cycling and expansion of peripheral blood but not mucosal T cells. Bacterial lipoproteins mimicked the effect ofE. coliNissle 1917-CM; in contrast, heat-inactivatedE. coliNissle 1917, lipopolysaccharide, or CpG DNA did not alter PBT cell cycling.E. coliNissle 1917-CM decreased cyclin D2, B1, and retinoblastoma protein expression, contributing to the reduction of T-cell proliferation.E. coliNissle 1917 significantly inhibited the expression of interleukin-2 (IL-2), tumor necrosis factor α, and gamma interferon but increased IL-10 production in PBT. Using Toll-like receptor 2 (TLR-2) knockout mice, we further demonstrate that the inhibition of PBT proliferation byE. coliNissle 1917-CM is TLR-2 dependent. The differential reaction of circulating and tissue-bound T cells towardsE. coliNissle 1917 may explain the beneficial effect ofE. coliNissle 1917 in intestinal inflammation.E. coliNissle 1917 may downregulate the expansion of newly recruited T cells into the mucosa and limit intestinal inflammation, while already activated tissue-bound T cells may eliminate deleterious antigens in order to maintain immunological homeostasis.

Objective Vedolizumab is a gut-selective antibody to α4β7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab. Design Safety data (May 2009–June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model. Results In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1–1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p

Current biological therapies for inflammatory bowel disease reflect the exponential advancement in understanding the human intestinal immune system and particularly the biology of intestinal inflammation over the past decade. The better understanding of the mechanisms of inflammatory bowel disease has evolved from descriptive clinical data and genetically engineered animal models. It led to great interest in a variety of new therapeutic agents and procedures with novel actions. This review will discuss the mechanisms of biologics (antibodies against pro-inflammatory cytokines, T-cell antibodies, anti-inflammatory cytokines, adhesion molecule blockers, growth factors, colony stimulating factors, fusion proteins, anti-sense oligonucleotides, hormones, immunostimulatory DNA (ISS-DNA, CpG Oligodeoxynucleotides) and parasites (Trichuris suis eggs), used in inflammatory bowel disease and summarize the available data on investigational and approved agents, and briefly touch on probiotics and extracorporeal immunomodulation (leukocyte apheresis and photoapheresis). Based on the data discussed, it appears that biologics may play an increasing role in managing inflammatory bowel disease in the near future.

Although the aetiopathogenesis of Crohn's disease and ulcerative colitis, remains unsolved, current evidence indicates that defective T-cell apoptosis and impairment of intestinal epithelial barrier function play important roles in the pathogenesis of both conditions. Without appropriate control of T-cell proliferation and death during an immune response, an inappropriate accumulation of T cells and subsequent intestinal inflammation may occur. Differences in T-cell responses between Crohn's disease and ulcerative colitis have been identified, with mucosal T-cell apoptosis being defective in Crohn's disease, but not in ulcerative colitis. Furthermore, cell cycling is considerably faster, with a vigorous clonal expansion, in Crohn's disease, whereas, in ulcerative colitis, T cells cycle normally, but have a remarkably reduced capacity to divide and expand. The elimination of excessive T cells therefore seems to be a reasonable approach to restore the gut to a physiological state or, at least, a controlled state of inflammation. The tumour necrosis factor-alpha blocker, infliximab, exerts its beneficial effects, at least in part, by the induction of apoptosis in lamina propria T cells and monocytes. In addition, repeated damage and injury of the intestinal surface is a hallmark of inflammatory bowel disease and may facilitate the entry of luminal antigens into the mammalian organism and the initiation and perpetuation of both nonspecific and specific immune responses. A better understanding of and enhancement of intestinal repair mechanisms may thus provide future approaches for the treatment of inflammatory bowel disease.

Summary Background : Oral tacrolimus, approved for the prophylaxis of organ rejection in liver or kidney transplants, has been reported to be effective in anecdotal cases of refractory inflammatory bowel disease. Aim : To evaluate the usefulness of low-dose oral tacrolimus in refractory inflammatory bowel disease. Methods: Thirty-one adult Caucasian patients with steroid-dependent (n = 15) or steroid-refractory (n = 16) inflammatory bowel disease (Crohn's disease, n = 6; ulcerative colitis, n = 23; pouchitis, n = 2) were enrolled. Tacrolimus (0.1 mg/kg body weight per day) was administered orally in 30 patients and initially intravenously in one patient (0.01 mg/kg body weight per day), aiming for serum trough levels of 4–6 ng/mL. The median treatment duration was 12 months (range, 1–137 months). Results : Twenty-eight patients (90.3%) experienced a clinical and laboratory response and 20 (64.5%) went into remission. One ulcerative colitis patient and two Crohn's disease patients did not improve. Three ulcerative colitis patients (9.7%) were colectomized at 1, 12 and 24 months after tacrolimus initiation. In 19 of 23 patients (82.6%) taking steroids, steroids were reduced or discontinued. Side-effects included a temporary rise of creatinine (n = 3, 9.7%), tremor or paraesthesias (n = 3, 9.7%), hyperkalaemia (n = 1, 3.2%), hypertension (n = 1, 3.2%) and an opportunistic infection (n = 1, 3.2%). Conclusion : Oral tacrolimus is safe and effective in refractory inflammatory bowel disease.