[Current position on Vedolizumab for ulcerative colitis and Crohn's disease]. / Vedolizumab bei Colitis ulcerosa und Morbus Crohn: eine Standortbestimmung.

Vedolizumab, the first drug in the class of anti-integrin molecules, is newly approved for ulcerative colitis and Crohn's disease and can be prescribed in Germany since mid-2014. By a specific receptor binding a relatively gut-selective mode of action was achieved without the known side effects of the systemic immunosuppression of the anti-TNF-alpha antibodies. According to the present data the safety profile of Vedolizumab appears to be more favorable than that of the anti-TNF- alpha therapy. Vedolizumab is suitable for induction therapy in patients with ulcerative colitis and Crohn's disease, however the kinetic of response compared with the anti-TNF-alpha antibodies seems to be slower. For maintenance therapy the Vedolizumab data show a deep and sustained remission in patients initially responding to induction therapy with a lower loss of efficacy in the long-term treatment known from the anti-TNF-alpha therapy. On the basis of currently available data the efficacy of Vedolizumab in ulcerative colitis appears to be slightly better than in Crohn's disease.

[Rational and efficient diagnosis in different stages of Crohn's disease]. / Rationale und rationelle Diagnostik in unterschiedlichen Krankheitsphasen des Morbus Crohn.

The treatment of patients with inflammatory bowel disease has become more complex in recent years through the introduction of various immunosuppressive agents as well as the approval of monoclonal antibodies. Patients receiving such treatment must be carefully monitored. National and international guidelines define a diagnostic and therapeutic context for the practitioner, but can only partially respond to specific questions on the procedure for individual patients. Within the framework of a project initiated by Abbott entitled "IBD ahead" 34 German IBD experts have elaborated concrete proposals for the utility of clinical symptom assessment, endoscopy and the use of laboratory parameters including foecal markers of inflammation. Furthermore, we discuss the significance of conventional X-rays, computed tomography, ultrasound and magnetic resonance tomography. These recommendations are illustrated by case studies from everyday practice in the participating centres.

Clinical trial: five or ten cycles of granulocyte-monocyte apheresis show equivalent efficacy and safety in ulcerative colitis.

BACKGROUND: Ulcerative colitis is characterized by leucocyte infiltration into the colonic mucosa. Granulocyte-monocyte apheresis depletes these cells. AIM: To assess the non-inferiority of 5-10 apheresis treatments in patients with steroid-dependent or steroid-refractory ulcerative colitis. METHODS: A total of 196 adults with moderate-severe ulcerative colitis were randomized 1:1 to 5 (n = 96) or 10 (n = 90) open label apheresis treatments. The primary endpoint was non-inferiority of clinical activity index score after 12 weeks. RESULTS: The intent-to-treat population comprised 82 and 80 patients for the 5- and 10-treatment groups, respectively. The difference between the two groups in mean clinical activity index was 0.24 with an upper 95% confidence interval of 1.17, which was below a predefined non-inferiority threshold of 1.33. Clinical activity index score improved from baseline in both groups (from 8.7 to 5.6 with 5 treatments, and from 8.8 to 5.4 with 10), with no significant difference between the groups (P = 0.200). Outcomes for the 5- and 10-treatment groups were similar--clinical remission: 44% and 40%, respectively (P = 0.636); clinical response: 56% and 59%, respectively (P = 0.753). The treatment was well tolerated in both groups. CONCLUSIONS: This prospective study comparing apheresis regimens in ulcerative colitis demonstrates that 5 treatments were not inferior to 10 treatments in steroid-refractory or -dependent ulcerative colitis.

[Are there gender-related differences in the therapeutic management of patients suffering from inflammatory bowel disease? Subgroup analysis of a prospective multicentre online-based trial]. / Gibt es geschlechtsspezifische Behandlungsunterschiede bei Patienten mit chronisch entzündlichen Darmerkrankungen? Eine Subgruppenanalyse einer prospektiven, multizentrischen, online-basierten Studie.

INTRODUCTION: The most frequently prescribed medications for patients suffering from inflammatory bowel disease (IBD) in the Rhein-Main region of Germany are aminosalicylates and corticosteroids irrespective of the disease activity. In contrast, immunomodulators only play a marginal role. As anti-TNF therapy is very costly, it is prescribed in outpatient services of hospitals rather than in gastroenterological practices. AIM: The aim of this study was to evaluate possible gender-related differences in the therapeutic management of IBD patients treated in the Rhein-Main region of Germany. METHODS: Data records about past medical history, disease status, laboratory values and medical treatment of outpatients of 10 gastroenterological practices and 3 hospitals were collected from November 1st 2005 to July 31st 2007 and analysed with regard to gender-related differences in therapy and disease management. RESULTS: Overall, no statistically significant difference in gender-specific medical treatment could be observed in the study cohort. However, detailed analyses revealed, that 1. women suffering from IBD, who are treated in outpatient services of hospitals, are more often under immunosuppressants, irrespective of disease activity, 2. in gastroenterological practices less than 3 % of patients are prescribed any immunosuppressive therapy (vs. 17 % [men] und 42 % [women] in hospital outpatient services), and 3. anti-TNF therapy is applied more frequently in men as compared to women in hospital outpatient services in both remission and active disease. CONCLUSION: This study discloses the gender-specific differences in the therapeutic management of IBD patients in a congested urban area in Germany. Further studies are required to confirm the tendencies detected.

[Pathophysiological-based diagnosis and therapy of iron-deficient anaemia in inflammatory bowel disease]. / Pathophysiologisch-orientierte Diagnostik und Therapie der Eisenmangelanämie bei chronisch entzündlichen Darmerkrankungen.

Anaemia is the most frequent extraenteric complication of inflammatory bowel disease (IBD, Crohn's disease and ulcerative colitis). A disabling complication of IBD, anaemia worsens the patient's general condition and quality of life, and increases hospitalization rates. The main types of anemia in IBD are iron deficiency anemia and anemia of chronic disease. The combination of the serum transferrin receptor with ferritin concentrations and inflammatory markers allows a reliable assessment of the iron status. Iron deficiency is usually treated with oral iron supplements. However, it is less effective in IBD and may lead to an increased inflammatory activity through the generation of reactive oxygen species. A systematic review of anemia in IBD, its pathogenetic features, epidemiology, diagnosis and therapy based on the evidence from recent studies will be the focus of this article.

Escherichia coli strain Nissle 1917 ameliorates experimental colitis via toll-like receptor 2- and toll-like receptor 4-dependent pathways.

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-kappaB 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.

Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells.

BACKGROUND: Breakdown of tolerance against the commensal microflora is believed to be a major factor in the pathogenesis of inflammatory bowel disease (IBD). Dendritic cells (DC) have been implicated in this process in various animal models, but data on human DC in IBD are very limited. AIM: To characterise plasmacytoid DC (PDC) and myeloid DC (MDC) in patients with active versus inactive IBD and healthy controls. PATIENTS AND METHODS: Peripheral blood was obtained from 106 patients (Crohn's disease (CD) n=49, ulcerative colitis (UC) n=57) and healthy controls (n=19). Disease activity was scored using the modified Truelove Witts (MTWSI) for UC and the Harvey Bradshaw severity indices (HBSI) for CD. Four colour flow cytometric analysis was used to identify, enumerate, and phenotype DC. DC from patients with acute flare ups and healthy controls were cultured and stimulated with CpG ODN 2006 or lipopolysaccharide (LPS). RESULTS: IBD patients in remission (PDC UC, 0.39%; CD, 0.35%; MDC-1 UC, 0.23%; CD, 0.22% of PBMC) have slightly lower numbers of circulating DC compared with healthy controls (PDC 0.41%, MDC-1 0.25% of PBMC). In acute flare ups IBD patients experience a significant drop of DC (PDC UC, 0.04%; CD, 0.11%; MDC-1 UC, 0.11%; CD, 0.14% of PBMC) that correlates with disease activity (correlation coefficients: PDC MTWSI, 0.93; HBSI, 0.79; MDC-1 MTWSI, 0.75; HBSI, 0.81). Moreover, both express alpha4beta7 integrin and display an immature phenotype. Freshly isolated PDC and MDC-1 from untreated flaring IBD patients express higher baseline levels of CD86 which increases further in culture and upon stimulation compared with healthy controls. CONCLUSION: IBD patients lack immature blood DC during flare ups which possibly migrate to the gut. An aberrant response to microbial surrogate stimuli suggests a disturbed interaction with commensals.

Clinical relevance of transabdominal ultrasonography and magnetic resonance imaging in patients with inflammatory bowel disease of the terminal ileum and large bowel.

BACKGROUND: Ileocolonoscopy represents the diagnostic standard in the work-up of patients with inflammatory bowel diseases (IBD). Patients are often reluctant to be colonoscoped because of the invasiveness and pain sensation during colonoscopy. AIMS: To compare the usefulness oftransabdominal ultrasound (US) and magnetic resonance imaging (MRI) in assessing disease extension and activity in patients with IBD restricted to the terminal ileum and large bowel. PATIENTS AND METHODS: 61 patients with IBD [37 Crohn's disease (CD) and 24 ulcerative colitis (UC)] were prospectively studied. All patients underwent clinical and laboratory assessment, ileocolonoscopy, transabdominal sonography, and MRI within 5 days. Involved bowel segments were defined as those with bowel wall thickness >3 mm and increased Doppler signal on US or contrast enhancement of the bowel wall on MRI. To compare disease activity endoscopic, MRI and US findings were graded with newly developed scores. RESULTS: The segment-by-segment analysis revealed an overall accuracy of 89% for US and 73% for MRI in identifying active IBD. The accuracy was better in patients with UC than in patients with CD for both US and MRI. The endoscopic activity index (EAI) correlated stronger with the US activity index (r = 0.884) than with the MRI activity index (r = 0.344). The correlation of US and MRI activity indices with EAI was better in patients with UC compared with patients with CD. All three imaging methods showed a significant correlation with clinical disease activity in patients with UC but not in patients with CD. CONCLUSION: This study provides strong evidence that US should be considered as a first-choice method for follow-up of patients with IBD of the terminal ileum and large bowel.

Review article: the aetiopathogenesis of inflammatory bowel disease--immunology and repair mechanisms.

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.

A study for the evaluation of safety and tolerability of intravenous high-dose iron sucrose in patients with iron deficiency anemia due to gastrointestinal bleeding.

INTRODUCTION: The provision of adequate iron to support erythropoiesis in iron deficient patients is a time-consuming process which may present compliance problems for patients in the outpatient setting. The aim of the present study was to evaluate the safety and tolerability of intravenous high-dose iron sucrose therapy specifically in patients with iron deficiency anemia (IDA) due to gastrointestinal blood loss. METHODS: A single dose of iron sucrose of 7 mg iron/kg body weight (not exceeding 500 mg) was infused over 3.5 hours in 31 consecutive patients with IDA due to gastrointestinal blood loss. Safety and tolerability of the therapy was assessed by the occurrence of adverse events under therapy and up to one week after completion of the study. Further examinations comprised vital parameters, ECG, and clinical chemistry including iron indices. RESULTS: A total of 14 adverse events were observed in 10 patients, of which two adverse events in two patients were considered as being definitely related to drug administration. None of the patients had to be withdrawn from therapy. Significant changes in vital parameters and ECG during therapy and follow-up were not observed and clinical chemistry remained unchanged. DISCUSSION: A single intravenous high-dose iron sucrose therapy in patients with IDA due to gastrointestinal blood loss appears to be safe and therefore is a therapeutic option which may save time and improve patient compliance.

[Biologic therapy of inflammatory bowel disease]. / Biologische Therapie chronisch-entzündlicher Darmerkrankungen.

Biological therapies in inflammatory bowel disease reflect the exponential advancement in understanding the human intestinal immune system and particularly the biology of intestinal inflammation during the past decade. The better understanding of the mechanisms of inflammatory bowel disease has evolved from desriptive clinical data and genetically engineered animal models. It led to great interest in the evaluation of a variety of new therapeutic agents with novel actions. This review will discuss the mechanisms of biologicals (antibodies against pro-inflammatory cytokines, T cell antibodies, anti-inflammtory cytokines, adhesion molecule blockers, growth factors, hormones, colony stimulating factors, fusion proteins, anti-sense oligonucleotides, trefoil peptides, immunostimulatory [ISS] DNA) used in the treatment of inflammatory bowel disease and summarizes the available data on established biologic therapies as well as investigational agents and briefly touch on probiotics. Based on the data discussed, it seems that biologicals will play an important role in managing inflammatory bowel disease in the near future.

Rescue therapy with tacrolimus is effective in patients with severe and refractory inflammatory bowel disease.

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.

Functional relevance of activin A in the intestinal epithelium.

BACKGROUND: Activin A modulates inflammation and repair in various tissues. The aim of this study was to characterize the effects of activin A on intestinal epithelial cell function and to evaluate a potential role in intestinal epithelial wound repair and inflammation. METHODS: The expression of activin A and its receptors ActRI and ActRII in intestinal epithelial IEC-6 cells and in tissues from IBD patients and non-inflamed controls was evaluated using RT-PCR and immunohistochemistry. Functional effects of activin A on intestinal epithelial cell migration and proliferation were assessed using an in vitro wounding model and colorimetric MTT assays. RESULTS: Expression of the activin betaA subunit and the activin receptors ActRI and ActRII in IEC-6 cells was demonstrated using RT-PCR. Activin A (50 ng/ml) caused a significant, on average 2.8-fold enhancement of epithelial cell migration and a significant on average 4.1-fold inhibition of IEC-6 cell proliferation. Expression of ActRI and ActRII was observed in all intestinal tissues from patients with IBD and in all controls. In contrast, no expression of the activin betaA-subunit was observed in controls, while betaA expression was found in intestinal tissues from IBD patients. CONCLUSIONS: Activin A may play an important role in the modulation of intestinal epithelial cell function, thus providing a new approach to modulate intestinal wound repair.