Prediction of Response to Systemic Corticosteroids in Active UC by Microbial Composition-A Prospective Multicenter Study.

BACKGROUND: Corticosteroids are used for induction of remission in patients with moderately to severely active ulcerative colitis. However, up to one-third of patients fail to this therapy. We investigated if fecal microbial composition or its metabolic capacity are associated with response to systemic corticosteroids. METHODS: In this prospective, multicenter study, patients with active ulcerative colitis (Lichtiger score ≥4) receiving systemic corticosteroids were eligible. Data were assessed and fecal samples collected before and after 4 weeks of treatment. Patients were divided into responders (decrease of Lichtiger Score ≥50%) and nonresponders. The fecal microbiome was assessed by the 16S rRNA gene marker and analyzed with QIIME 2. Microbial metabolic pathways were predicted using parsimonious flux balance analysis. RESULTS: Among 93 included patients, 69 (74%) patients responded to corticosteroids after 4 weeks. At baseline, responders could not be distinguished from nonresponders by microbial diversity and composition, except for a subgroup of biologic-naïve patients. Within 4 weeks of treatment, responders experienced changes in beta diversity with enrichment of ascribed beneficial taxa, including Blautia, Anaerostipes, and Bifidobacterium, as well as an increase in predicted butyrate synthesis. Nonresponders had only minor longitudinal taxonomic changes with a significant increase of Streptococcus salivarius and a microbial composition shifting away from responders. CONCLUSION: Baseline microbial diversity and composition seem to be of limited use to predict response to systemic corticosteroids in active ulcerative colitis. Response is longitudinally associated with restoration of microbial composition and its metabolic capacity.

Factors Associated with Response to Systemic Corticosteroids in Active Ulcerative Colitis: Results from a Prospective, Multicenter Trial.

BACKGROUND: Among patients with ulcerative colitis, 30-50% receive corticosteroids within the first five years after diagnosis. We aimed to reconsider their effectiveness in the context of the biologic era. METHODS: In this prospective, multicenter study, patients with active ulcerative colitis (Lichtiger score ≥ 4) were eligible if initiating systemic corticosteroids. The primary endpoint was clinical response (decrease in the Lichtiger score of ≥50%) at week 4. Secondary endpoints included combined response defined as clinical response and any reduction in elevated biomarkers (CRP and/or calprotectin). Steroid dependence was assessed after three months. RESULTS: A total of 103 patients were included. Clinical response was achieved by 73% of patients, and combined response by 68%. A total of 15% of patients were steroid-dependent. Activity of colitis did not influence short-term response to treatment but increased the risk for steroid dependence. Biologic-naïve patients responded better than biologic-experienced patients. Past smoking history (OR 5.38 [1.71, 20.1], p = 0.003), hemoglobin levels (OR 0.76 [0.57, 0.99] for higher levels, p = 0.045), and biologic experience (OR 3.30 [1.08, 10.6], p = 0.036) were independently associated with nonresponse. CONCLUSION: Disease activity was not associated with short-term response to systemic corticosteroids but was associated with steroid dependence in patients with active ulcerative colitis. Exposure to biologics negatively affects response rates.

Inflammatory Bowel Disease and Risk of Major Bleeding During Anticoagulation for Venous Thromboembolism.

BACKGROUND: Little is known about the bleeding risk in patients with inflammatory bowel disease (IBD) and venous thromboembolism (VTE) treated with anticoagulation. Our aim was to elucidate the rate of major bleeding (MB) events in a well-defined cohort of patients with IBD during anticoagulation after VTE. METHODS: This study is a retrospective follow-up analysis of a multicenter cohort study investigating the incidence and recurrence rate of VTE in IBD. Data on MB and IBD- and VTE-related parameters were collected via telephone interview and chart review. The objective of the study was to evaluate the impact of anticoagulation for VTE on the risk of MB by comparing time periods with anticoagulation vs those without anticoagulation. A random-effects Poisson regression model was used. RESULTS: We included 107 patients (52 women, 40 with ulcerative colitis, 64 with Crohn disease, and 3 with unclassified IBD) in the study. The overall observation time was 388 patient-years with and 1445 patient-years without anticoagulation. In total, 23 MB events were registered in 21 patients, among whom 13 MB events occurred without anticoagulation and 10 occurred with anticoagulation. No fatal bleeding during anticoagulation was registered. The incidence rate for MB events was 2.6/100 patient-years during periods exposed to anticoagulation and 0.9/100 patient-years during the unexposed time. Exposure to anticoagulation (adjusted incidence rate ratio, 3.7; 95% confidence interval, 1.5-9.0; P = 0.003) and ulcerative colitis (adjusted incidence rate ratio, 3.5; 95% confidence interval, 1.5-8.1; P = 0.003) were independent risk factors for MB events. CONCLUSION: The risk of major but not fatal bleeding is increased in patients with IBD during anticoagulation. Our findings indicate that this risk may be outweighed by the high VTE recurrence rate in patients with IBD.

Use of complementary and alternative medicine and low quality of life associate with the need for psychological and psychotherapeutic interventions in inflammatory bowel disease.

INTRODUCTION: Patients with inflammatory bowel disease (IBD) suffer from various symptoms, impairing their quality of life and often affecting psychosocial issues. This may lead to the need for additional psychological care. This study investigated patients' subjective need for integrated psychosomatic support and psychotherapy and indicators for it. MATERIALS AND METHODS: This is a cross-sectional multicentre study in Austrian IBD patients who were in routine care at 18 IBD outpatient clinics. Patients filled in an anonymous, validated questionnaire (Assessment of the Demand for Additional Psychological Treatment Questionnaire [ADAPT]) assessing the need for psychological care. The ADAPT gives two separate scores: the need for integrated psychosomatic support and for psychotherapy. In addition, health-related quality of life and the use of complementary and alternative medicine as well as clinical and socio-demographic variables were queried. Multivariable regression analysis was performed to estimate the effect of the previously mentioned variables on the need for additional psychological care. RESULTS: Of 1286 patients, 29.7% expressed a need for additional psychological care, 19.6% expressed a need for integrated psychosomatic support and 20.2% expressed a need for psychotherapy. In the multivariable analysis, the two strongest indicators for the need for both types of psychological care were the use of complementary and alternative medicine (for integrated psychosomatic support: odds ratio = 1.64, 95% confidence interval 1.13-2.39, p = 0.010; for psychotherapy: odds ratio = 1.74, 95% confidence interval 1.20-2.53, p = 0.004), and a low health-related quality of life score (for integrated psychosomatic support: odds ratio = 0.95, 95% confidence interval 0.94-0.96, p < 0.001; for psychotherapy: odds ratio = 0.96, 95% confidence interval 0.94-0.97, p < 0.001). DISCUSSION: About 30% of the Austrian IBD patients expressed a need for integrated psychosomatic support and/or psychotherapy. The most important indicators for this need were the use of complementary and alternative medicine and low quality of life.

Prevalence and indicators of use of complementary and alternative medicine in Austrian patients with inflammatory bowel disease.

OBJECTIVE: Complementary and alternative medicine (CAM) seems to be frequently used among patients with inflammatory bowel disease (IBD). We aimed to determine the prevalence and indicators of CAM use in Austrian IBD patients. METHODS: In a multicentre cross-sectional study, adult patients with IBD attending 18 Austrian outpatient clinics completed a multi-item questionnaire that recorded use of CAM as well as medical and socioeconomic characteristics. Patients were recruited between June 2014 and June 2015. The study outcome was the prevalence of CAM use and its socioeconomic and disease-related associations. RESULTS: A total of 1286 patients (Crohn's disease 830, ulcerative colitis 435, IBD unclassified 21; females 651) with a median age of 40 years (interquartile range 31-52 years) and a median disease duration of 10 years (4-18 years) were analysed. The prevalence of previous and/or current CAM use was 50.7%, with similar results for Crohn's disease and ulcerative colitis. In the multivariable analysis, female gender and a university education were independent socioeconomic indicators of CAM use. IBD-related indicators were longer duration of the disease and previous and/or current treatment with steroids and TNF-α inhibitors. CONCLUSION: CAM use for IBD is frequent in Austrian IBD patients and associated with female gender, higher educational level of university degree, longer duration of the disease, and treatment with steroids and TNF-α inhibitors.

Diagnostic delay in patients with inflammatory bowel disease in Austria.

BACKGROUND: Delayed diagnosis seems to be common in inflammatory bowel diseases (IBD). The study was carried out to investigate the diagnostic delay and associated risk factors in Austrian IBD patients. METHODS: In a multicenter cross-sectional study adult patients with IBD attending 18 Austrian outpatient clinics completed a multi-item questionnaire that recorded medical and socioeconomic characteristics. The study outcome was diagnostic delay defined as the period from symptom onset to diagnosis of IBD. RESULTS: A total of 1286 patients (Crohn's disease 830, ulcerative colitis 435, inflammatory bowel disease unclassified 21; females 651) with a median age of 40 years (interquartile range 31-52 years) and a median disease duration of 10 years (4-18 years) were analyzed. The median diagnostic delay was 6 months (2-23 months) in Crohn's disease and 3 months (1-10 months) in ulcerative colitis (p < 0.001). In the multivariable regression analysis Crohn's disease, greater age at diagnosis and a high educational level (compared to middle degree level) were independently associated with longer diagnostic delay. CONCLUSION: The diagnostic delay was longer in Crohn's disease than in ulcerative colitis patients and was associated with greater age at diagnosis and a higher educational level.

Impaired counter-regulation of interleukin-1 by the soluble IL-1 receptor type II in patients with chronic liver disease.

OBJECTIVE: To assess the production of the endogenous IL-1 modulators IL-1 receptor antagonist (IL-1Ra), type I and II soluble IL-1 receptors (IL-1sRI and II) in patients with chronic liver disease (CLD). MATERIAL AND METHODS: Plasma levels of IL-1beta (IL-1beta) and IL-1 modulators were assessed in 126 CLD patients and 39 healthy controls. IL-1sRII was also measured in the supernatants of primary hepatocyte cultures. RESULTS: Plasma IL-1sRI and IL-1Ra levels were significantly higher in cirrhotic CLD patients than in non-cirrhotic CLD patients and in controls. Levels did not depend on the etiology of CLD. Likewise, plasma IL-1beta levels were elevated in CLD patients compared with those in controls. In contrast, IL-1sRII levels did not differ between CLD patients and controls. Cultures of human primary hepatocytes showed that IL-1sRII is induced by IL-1beta, but not IL-6. CONCLUSIONS: In cirrhotic CLD patients elevated plasma IL-1beta is not counteracted by endogenous levels of IL-1sRII, whereas high IL-1sRI is expected to neutralize the naturally occurring antagonist IL-1Ra, resulting in a dysregulation of the IL-1 system that might enhance pro-inflammatory activity of IL-1.

Subfulminant hepatitis B after infliximab in Crohn's disease: need for HBV-screening?

Infections are a major adverse effect during the treatment with anti-TNF-alpha. While exclusion of any bacterial infection and screening for tuberculosis are mandatory before initiating a therapy with anti-TNF-alpha-antibodies, there are no guidelines whether to screen for or how to deal with chronic viral infections such as hepatitis B. In this case report, we have described a patient with Crohn's disease who developed subfulminant hepatitis B after the fourth infusion of infliximab due to an unrecognized HBs-antigen carrier state. He recovered completely after lamivudine therapy was started, but this severe adverse event could have been prevented if screening for HBV and pre-emptive therapy with lamivudine would have been started prior to infliximab. We therefore strongly argue in favor of extended screening recommendations for infectious diseases including viral infections before considering a therapy with infliximab.

Elevated systemic levels of free interleukin-18 (IL-18) in patients with Crohn's disease.

OBJECTIVES: Interleukin 18 (IL-18) is a proinflammatory cytokine and a member of the IL-1 family. Animal models and investigations in humans point to an important role for this cytokine in inflammatory bowel diseases (IBD). IL-18 binding protein (IL-18BP) is a naturally occurring antagonist of IL-18. Methods. In this study, we measured IL-18 and IL-18BP plasma concentrations and spontaneous release in cultures of colonic explants from healthy subjects (n = 41), patients with Crohn's disease (CD, n = 135), and patients with ulcerative colitis (UC, n = 93). RESULTS: Both CD and UC patients had higher IL-18BP plasma levels than controls. Plasma levels of free, unbound IL-18 were significantly elevated in CD patients compared to healthy controls, but not in UC patients. Colonic explant cultures from inflamed areas in IBD patients released significantly higher levels of IL-18 than non-inflamed areas and controls. IL-18BP levels from the same cultures were below the detection limit over a culture period of 24 h. CONCLUSIONS: Our results confirm the importance of IL-18 in the pathogenesis of IBD and suggest that especially in CD, IL-18BP might be produced in insufficient quantities to counteract the effects of endogenous IL-18.

Increased expression of CCL20 in human inflammatory bowel disease.

Inflammatory bowel disease (IBD) constituting Crohn's disease (CD) and ulcerative colitis (UC) is related to a dysregulated T cell response. CCL20 attracts memory T lymphocytes and dendritic cells. We asked whether CCL20 expression is altered in IBD. Colonic biopsies were obtained from 114 subjects with IBD, non-IBD colitis, irritable bowel syndrome, and healthy controls. CCL20 and CCR6 mRNA expression was measured by Taqman-PCR, and protein secretion from colonic explant cultures (CEC) and its regulation by TNF-alpha by ELISA. CCL20, CCR6, and Langerin were identified by immunohistochemistry and immunofluorescence. CCL20 mRNA and protein were severalfold increased in involved CD and UC but not in non-IBD colitis. TNF-alpha increased and anti-TNF-alpha decreased CCL20 release in healthy control CEC but not in involved IBD colonic specimens. CCL20 localized to follicle-associated epithelium, and CCR6 to the adjacent mantle zone of lymphoid follicles. Furthermore, abundant numbers of Langerin(+) immature dendritic cells were identified in the subepithelial space of IBD specimens. CCL20 might regulate the attraction of T lymphocytes and dendritic cells in IBD.

Anti-inflammatory effects of hepatocyte growth factor: induction of interleukin-1 receptor antagonist.

Hepatocyte growth factor (HGF) prevents liver failure in various animal models including endotoxin-induced acute liver failure. We were interested to find out whether human HGF exerts anti-inflammatory effects by modulation of cytokine synthesis. Therefore, human HepG2 cells were cultured with increasing concentrations of HGF. HGF dose-dependently upregulated the production of interleukin-1 receptor antagonist (IL-1Ra). Incubation of HepG2 cells with interleukin-1beta (IL-1beta) caused an increase in IL-1Ra levels, while interleukin-6 (IL-6) had no effect on IL-1Ra synthesis. Co-stimulation of HepG2 cells with HGF + IL-1beta resulted in a synergistic effect on IL-1Ra mRNA and protein expression. Stimulation of freshly isolated mouse hepatocytes from male C57 BL/6 mice with HGF increased IL-1Ra mRNA and protein synthesis dose-dependently. A co-stimulation with HGF and IL-1beta had a synergistic effect on IL-1Ra mRNA expression but only a partially additive effect on IL-1Ra protein synthesis. HGF-induced IL-1Ra production was significantly decreased by the mitogen-activated protein kinase (MAPK) inhibitor PD98059. Accordingly, HGF stimulation specifically increased MAPK-dependent signalling pathway (p42/44). In contrast, in preactivated PBMC mRNA expression and protein synthesis of IL-1Ra, interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-alpha) were unaffected after stimulation with HGF. In conclusion, our data suggest that HGF exerts anti-inflammatory effects by modulating the signal transduction cascade leading to increased expression of IL-1Ra, which might explain the protective and regenerative properties of this cytokine in animal models of liver failure.

Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis.

BACKGROUND/AIMS: Severe alcoholic hepatitis (AH) is associated with high mortality. Tumor necrosis factor-alpha (TNFalpha) has been demonstrated to play an important role in its pathophysiology. METHODS: Twelve patients with biopsy-confirmed AH and a Maddrey discriminant factor >32 were treated with a single infusion of the anti-TNF monoclonal antibody Infliximab at a dose of 5mg/kg body weight. Serial measurements were made for various cytokines using specific enzyme-linked immunoassays (ELISA). In four patients, liver biopsy samples were available pretreatment and on day+28 of therapy. RESULTS: Ten of the 12 patients are alive at a median of 15 (12-20) months. Two patients died within 30 days from septicemia. Serum bilirubin levels, Maddrey score, neutrophil count and C-reactive protein fell significantly within the first month. There was an early, though not significant, decrease in plasma levels of proinflammatory cytokines (interleukins (IL)-1beta, IL-6, IL-8, interferon-gamma), whereas plasma levels of TNFalpha remained near the sensitivity limit of the assay throughout the treatment course. While TNFalpha mRNA expression in the liver did not change, expression of IL-8, a cytokine regulated mainly by TNFalpha, was almost absent on day+28. CONCLUSIONS: Our data suggest that randomized controlled trials of anti-TNF antibody in severe AH are warranted.

Plasma levels of interleukin-18 and interleukin-18 binding protein are elevated in patients with chronic liver disease.

Interleukin 18 (IL-18) is a recently described proinflammatory cytokine. In mouse models it has been shown to play a key role in the development of liver injury. IL-18 binding protein (IL-18BP) is a naturally occurring antagonist of IL-18. In this study we investigated whether IL-18/IL-18BP levels are altered in patients with chronic liver disease (CLD). We measured IL-18 and IL-18BP plasma levels in 153 patients with CLD and 41 healthy controls by a specific ELISA. Plasma levels of IL-18 were significantly higher in CLD patients than in healthy controls. Cirrhotics had higher levels than noncirrhotics. IL-18 levels increased with disease progression. IL-18BP plasma levels paralled the increase of IL-18 with disease progression, except in stage Child C cirrhosis. IL-18 and IL-18BP levels were elevated independent of the etiology of CLD. IL-18 and IL-18BP correlated with laboratory parameters of inflammation and liver injury. Plasma levels of IL-18 and its antagonist, IL-18BP, are elevated in CLD and correlate with severity of disease. IL-18BP may not be sufficient to counteract the overwhelming proinflammatory response in end stage liver disease.

Endotoxin and its binding proteins in chronic liver disease: the effect of transjugular intrahepatic portosystemic shunting.

BACKGROUND: Gut-derived endotoxin is insufficiently cleared by the diseased liver, and thus, is elevated in plasma of patients with chronic liver disease (CLD). Endotoxin action might be modified by binding to soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP), both of which have not yet been sufficiently studied in CLD. METHODS: Endotoxin, sCD14 and LBP have been determined in peripheral blood of 72 patients and 39 control subjects, and in portal and hepatic venous blood of 12 patients during transjugular intrahepatic portosystemic shunt (TIPS) implantation. RESULTS: Peripheral endotoxin (average 3-fold increased compared to controls), LBP, and sCD14 plasma levels were elevated in chronic liver disease irrespective of Child stage m, preserve/absence of cirrhosis or aetiology. LBP, and sCD14. Furthermore, endotoxin levels in the portal vein (38.1 +/- 6.1 pg/ml) were only slightly elevated compared to the hepatic vein (29.2 +/- 4.4 pg/ml), and peripheral endotoxin levels did not increase after TIPS. CONCLUSIONS: Decreased hepatocellular function rather than hepatic blood shunting might be responsible for endotoxemia. The elevation in LBP and sCD14 levels may be a consequence of endotoxemia.