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.

Monocyte human leukocyte antigen-DR expression-a tool to distinguish intestinal bacterial infections from inflammatory bowel disease?

BACKGROUND: We sought to determine the quantitative expression of human leukocyte antigen-DR (HLA-DR) on monocytes in patients with acute intestinal bacterial infections and inflammatory bowel disease (IBD). METHODS: The quantitative expression of HLA-DR on monocytes was determined by fluorescence-activated cell sorting analysis in patients with IBD, patients with acute intestinal bacterial infections (bact.), and healthy subjects (contr.). RESULTS: The quantitative expression of HLA-DR in patients with bact. (n = 20; 90,000 molecules per monocyte; confidence interval [CI], 79,000-102,000) was significantly higher than that in patients with ulcerative colitis (n = 40, 30,000; CI, 30,000-38,000; P < 0.0001), Crohn disease (n = 80, 31,000; CI, 32,000-39,000; P < 0.0001), or in contr. (n = 28, 39,000; CI, 36,000-46,000; P < 0.0001). In patients with ulcerative colitis and Crohn disease, HLA-DR expression was significantly decreased, as compared with contr. (P < 0.05 and P < 0.01, respectively). With a cutoff point of 50,000, HLA-DR showed a sensitivity of 95% and a specificity of 92% in discriminating between bact. and active IBD. CONCLUSION: The quantitative measurement of HLA-DR expression could serve as a valuable tool to discriminate between bact. and active IBD.

Clinical presentation of venous thromboembolism in inflammatory bowel disease.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) are at increased risk of venous thromboembolism (VTE), but data on frequency, site of thrombosis and risk factors are limited. We sought to determine prevalence, incidence as well as location and clinical features of first VTE among IBD patients. METHODS: We evaluated a cohort of 2811 IBD patients for a history of symptomatic, objectively confirmed first VTE, recruited from 14 referral centers. Patients with VTE before IBD diagnosis or cancer were excluded. Incidence rates were calculated based on person-years from IBD diagnosis to first VTE or end of follow-up, respectively. RESULTS: 2784 patients (total observation time 24,778 person-years) were analyzed. Overall, of 157 IBD patients with a history of VTE, 142 (90.4%) had deep vein thrombosis (DVT) and/or pulmonary embolism (PE), whereas 15 (9.6%) had cerebral, portal, mesenteric, splenic or internal jugular vein thrombosis. The prevalence and incidence rate of all VTE was 5.6% and 6.3 per 1000 person years, respectively. Patients with VTE were older at IBD diagnosis than those without VTE (34.4±14.8years vs 32.1±14.4years, p=0.045), but did not differ regarding sex, underlying IBD and disease duration. 121 (77.1%) VTE were unprovoked, 122 (77.7%) occurred in outpatients and 78 (60.9%) in patients with active disease. Medication at first VTE included corticosteroids (42.3%), thiopurines (21.2%), and infliximab (0.7%). CONCLUSION: VTE is frequent in IBD patients. Most of them are unprovoked and occur in outpatients. DVT and PE are most common and unusual sites of thrombosis are rare.

Impaired anti-inflammatory efficacy of n-butyrate in patients with IBD.

BACKGROUND: The intestinal mucosa of patients with inflammatory bowel diseases (IBD) characteristically shows a high degree of inflammation when compared to healthy subjects. This appears to be attributable to an imbalance in local reactivity of inflammatory cells. In the present study, we tested the hypothesis that immune cells from patients with IBD are less sensitive to anti-inflammatory agents in the gut as exemplified by the short-chain fatty acid (SCFA) n-butyrate. MATERIAL AND METHODS: Peripheral blood mononuclear cells (PBMC) of patients with IBD (22 Crohn`s Disease, CD; 9 Ulcerative Colitis, UC) and 20 healthy individuals were stimulated through TLR-4 and TLR-2 engagement, respectively, and the anti-inflammatory activity of n-butyrate (0·06-1 mM) on cytokine production (IL-1ß, IL-10, IL-12/23p40, TNF-α) was assessed. Inhibition curves were generated, and effective doses (ED20-ED80) were determined. RESULTS: Hyperresponsiveness to TLR-2 activation reflected by increased IL-12/23p40 and TNF-α production was observed in patients with IBD. To inhibit the release of IL-12/23p40 from PBMC after activation via TLR2-agonists, higher concentrations of n-butyrate were required in patients with IBD , when compared to healthy subjects. With regard to TLR-4 activation, PBMC from patients with IBD and controls were equally responsive to the immunoregulatory effects of n-butyrate. Further analysis revealed that the impaired sensitivity of PBMC to the anti-inflammatory action of n-butyrate was independent from hyperreactivity of immunocompetent cells. CONCLUSIONS: Impaired sensitivity to the inhibitory action of n-butyrate in IBD may constitute a determinant in the pathogenesis of these inflammatory diseases.

Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) are at increased risk of a first venous thromboembolism (VTE), yet their risk of recurrent VTE is unknown. We performed a cohort study to determine the risk for recurrent VTE among patients with IBD compared with subjects without IBD. METHODS: We assessed 2811 patients with IBD for a history of VTE, recruited from outpatient clinics at 14 referral centers (June 2006-December 2008). Patients with VTE before a diagnosis of IBD or those not confirmed to have VTE, cancer, or a VTE other than deep vein thrombosis or pulmonary embolism, were excluded. Recurrence rates were compared with 1255 prospectively followed patients without IBD that had a first unprovoked VTE (not triggered by trauma, surgery, or pregnancy). The primary end point was symptomatic, objectively confirmed, recurrent VTE after discontinuation of anticoagulation therapy after a first VTE. RESULTS: Overall, of 116 IBD patients who had a history of first VTE, 86 were unprovoked. The probability of recurrence 5 years after discontinuation of anticoagulation therapy was higher among patients with IBD than patients without IBD (33.4%; 95% confidence interval [CI]: 21.8-45.0 vs 21.7%; 95% CI: 18.8-24.6; P = .01). After adjustment for potential confounders, IBD was an independent risk factor of recurrence (hazard ratio = 2.5; 95% CI: 1.4-4.2; P = .001). CONCLUSIONS: Patients with IBD are at an increased risk of recurrent VTE compared to patients without IBD.

Expression of the high-affinity IgG receptor FcRI (CD64) in patients with inflammatory bowel disease: a new biomarker for gastroenterologic diagnostics.

OBJECTIVES: We sought to determine the quantitative expression of the high-affinity Fc receptor (CD64) on polymorphonuclear neutrophils (PMNs) in inflammatory and functional conditions of the intestine and investigated its correlation with clinical and biological parameters of inflammation. METHODS: The quantitative expression of CD64 was determined by fluorescence-activated cell sorting analysis in patients with active or inactive inflammatory bowel disease (IBD, n=76), infectious enterocolitis, lactose and/or fructose intolerance, and healthy subjects. RESULTS: The quantitative expression of CD64 in patients with active IBD (3,398+/-3,589 molecules per PMN, n=27) was significantly higher than in healthy subjects (607+/-265, n=28, P<0.001) or in patients with lactose/fructose intolerance (531+/-150, n=32, P<0.001). The expression of CD64 correlated significantly with C-reactive protein (CRP, 0.65, P<0.0001), Crohn's disease activity index (CDAI, 0.53, P<0.0001), and colitis activity index (CAI, 0.63, P<0.0001) in patients with IBD. With a cutoff point of 800, CD64 had a sensitivity of 88% and a specificity of 93% in discriminating between lactose/fructose intolerance and active IBD. The quantitative expression of CD64 in patients with infectious enterocolitis (19,190+/-8,920, n=22) was significantly higher than in patients with active IBD (P<0.001). With a cutoff point of 10,000, CD64 showed a sensitivity of 96% and a specificity of 97% in discriminating between infectious enterocolitis and active IBD. CONCLUSIONS: CD64 could serve as a valuable tool to discriminate between IBD, infectious enterocolitis, and functional intestinal disorders.

Hypertonic saline reduces neutrophil-epithelial interactions in vitro and gut tissue damage in a mouse model of colitis.

Transepithelial migration of polymorphonuclear neutrophils (PMN) plays a crucial role in inflammatory conditions of the intestine, such as inflammatory bowel diseases. Hypertonic saline (HS) exerts various inhibitory effects on PMN function. We hypothesized that HS could inhibit transepithelial migration of PMN and thereby prevent inflammatory events in experimental colitis. Isolated human PMN were treated with HS (40 mM), and their transmigration across a monolayer of T84 epithelial cells was induced by N-formyl-methionyl-leucyl-phenylalanine. Monolayer disruption was assessed by monitoring changes in transepithelial conductance in an Ussing chamber. Colitis in mice was induced by oral administration of dextran sulfate sodium (DSS). Animals were treated with 4 or 8 ml/kg of 7.5% saline intraperitoneally two times daily for 7 days. Controls received equivalent volumes of normal saline (NS, n = 6) or no intraperitoneal treatment (DSS, n = 12). The severity of inflammation was evaluated based on disease activity index and histology score. HS treatment of PMN in vitro significantly reduced cell migration and the disruption of T84 monolayers compared with untreated control cells (n = 5, P < 0.05). This effect of HS was dose dependent. HS treatment in vivo also reduced colitis-induced gut tissue damage, as indicated by an improved histology score compared with the NS and DSS groups. We conclude that HS inhibits transepithelial migration of PMN in vitro and gut tissue damage in vivo in a mouse model of colitis. Thus HS may have clinical value to reduce PMN-mediated intestinal damage.

Malnutrition and impaired muscle strength in patients with Crohn's disease and ulcerative colitis in remission.

OBJECTIVE: This prospective, controlled, and multicentric study evaluated nutritional status, body composition, muscle strength, and quality of life in patients with inflammatory bowel disease in clinical remission. In addition, possible effects of gender, malnutrition, inflammation, and previous prednisolone therapy were investigated. METHODS: Nutritional status (subjective global assessment [SGA], body mass index, albumin, trace elements), body composition (bioelectrical impedance analysis, anthropometry), handgrip strength, and quality of life were assessed in 94 patients with Crohn's disease (CD; 61 female and 33 male, Crohn's Disease Activity Index 71 +/- 47), 50 patients with ulcerative colitis (UC; 33 female and 17 male, Ulcerative Colitis Activity Index 3.1 +/- 1.5), and 61 healthy control subjects (41 female and 20 male) from centers in Berlin, Vienna, and Bari. For further analysis of body composition, 47 well-nourished patients with inflammatory bowel disease were pair-matched by body mass index, sex, and age to healthy controls. Data are presented as median (25th-75th percentile). RESULTS: Most patients with inflammatory bowel disease (74%) were well nourished according to the SGA, body mass index, and serum albumin. However, body composition analysis demonstrated a decrease in body cell mass (BCM) in patients with CD (23.1 kg, 20.8-28.7, P = 0.021) and UC (22.6 kg, 21.0-28.0, P = 0.041) compared with controls (25.0 kg, 22.0-32.5). Handgrip strength correlated with BCM (r = 0.703, P = 0.001) and was decreased in patients with CD (32.8 kg, 26.0-41.1, P = 0.005) and UC (31.0 kg, 27.3-37.8, P = 0.001) compared with controls (36.0 kg, 31.0-52.0). The alterations were seen even in patients classified as well nourished. BCM was lower in patients with moderately increased serum C-reactive protein levels compared with patients with normal levels. CONCLUSION: In CD and UC, selected micronutrient deficits and loss of BCM and muscle strength are frequent in remission and cannot be detected by standard malnutrition screening.

Altered status of antioxidant vitamins and fatty acids in patients with inactive inflammatory bowel disease.

BACKGROUND & AIMS: Data regarding the nutritional status, antioxidant compounds and plasma fatty acid (FA) composition in inactive IBD are conflicting. We compared plasma levels of antioxidants and FA of patients with inactive IBD with active IBD and controls. METHODS: Plasma levels of vitamin C, vitamin E, carotenoids, saturated, monounsaturated and polyunsaturated FA, inflammatory markers and nutritional status were determined after an overnight fast in 132 patients with quiescent IBD (40.6+/-13.2 years, 87F/45M), 35 patients with active disease (37.9+/-12.1 years, 25F/10M) and 45 age- and BMI-matched healthy controls (38.1+/-10.5 years, 39F/6M). Results are expressed as mean+/-SD or median [25th percentile;75th percentile]. RESULTS: Body mass index (BMI) was normal in inactive (23.9+/-4.7 kg/m(2)), active IBD (22.7+/-4.2 kg/m(2)) and controls (22.3+/-1.9 kg/m(2)). Compared with controls patients with quiescent IBD showed significantly decreased plasma levels of carotenoids (1.85 [1.37;2.56] vs 1.39 [0.88;1.87] micromol/L) and vitamin C (62.3 [48.7;75.0] vs 51.0 [36.4;77.6] micromol/L), increased levels of saturated FA (3879 [3380;4420] vs 3410 [3142;3989] micromol/L) and monounsaturated FA (2578 [2258;3089] vs 2044 [1836;2434] micromol/L) and similar levels of vitamin E and polyunsaturated FA. Results in active disease were similar to inactive disease. CONCLUSION: This study shows that antioxidant status and FA profile in a larger population of IBD patients are disturbed independently from disease activity and despite normal overall nutritional status.

Impact of depressive mood on relapse in patients with inflammatory bowel disease: a prospective 18-month follow-up study.

OBJECTIVE: There is evidence of an interaction between psychological factors and activity of inflammatory bowel disease (IBD). We examined the influence of depressive mood and associated anxiety on the course of IBD over a period of 18 months in a cohort of patients after an episode of active disease. METHODS: In this prospective, longitudinal, observational study, 60 patients (37 women and 23 men) with clinically inactive IBD (Crohn disease, n = 47, 78%; ulcerative colitis, n = 13, 22%) were enrolled after a flare of disease. Psychological status, health-related quality of life (HRQOL), and disease activity were evaluated at baseline and then every 3 months for a period of 18 months by means of clinical and biological parameters, the Beck Depression Inventory (BDI), the Spielberger State-Trait Anxiety Inventory, the Inflammatory Bowel Disease Questionnaire, the Perceived Stress Questionnaire, and the Rating Form of Inflammatory Bowel Disease Patients Concerns. RESULTS: At baseline, depression (BDI > or = 13 points) was found in 17 of 60 (28%) patients. Thirty-two patients (59%) experienced at least one relapse during the 18 months of follow-up. Regression analysis showed a significant correlation between BDI scores at baseline and the total number of relapses after 12 (p <.01) and 18 months (p <.01) of follow-up. Furthermore, depression scores at baseline correlated with the time until the first recurrence of the disease (p <.05). Anxiety and low HRQOL were also related with more frequent relapses during follow-up (p <.05 and p <.01, respectively). CONCLUSIONS: Psychological factors such as a depressive mood associated with anxiety and impaired HRQOL may exert a negative influence on the course of IBD. Therefore, assessment and management of psychological distress should be included in clinical treatment of patients with IBD.