Clemens Dejaco

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 ≥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.

Temporal Bacterial Community Dynamics Vary Among Ulcerative Colitis Patients After Fecal Microbiota Transplantation

OBJECTIVES:Fecal microbiota transplantation (FMT) from healthy donors, which is an effective alternative for treatment of Clostridium difficile–associated disease, is being considered for several disorders such as inflammatory bowel disease, irritable bowel syndrome, and metabolic syndrome. Disease remission upon FMT is thought to be facilitated by an efficient colonization of healthy donor microbiota, but knowledge of the composition and temporal stability of patient microbiota after FMT is lacking.METHODS:Five patients with moderately to severely active ulcerative colitis (Mayo score ≥6) and refractory to standard therapy received FMT via nasojejunal tube and enema. In addition to clinical activity and adverse events, the patients’ fecal bacterial communities were monitored at multiple time points for up to 12 weeks using 16S rRNA gene-targeted pyrosequencing.RESULTS:FMT elicited fever and a temporary increase of C-reactive protein. Abundant bacteria from donors established in recipients, but the efficiency and stability of donor microbiota colonization varied greatly. A positive clinical response was observed after 12 weeks in one patient whose microbiota had been effectively augmented by FMT. This augmentation was marked by successive colonization of donor-derived phylotypes including the anti-inflammatory and/or short-chain fatty acid–producing Faecalibacterium prausnitzii, Rosebura faecis, and Bacteroides ovatus. Disease severity (as measured by the Mayo score) was associated with an overrepresentation of Enterobacteriaceae and an underrepresentation of Lachnospiraceae.CONCLUSIONS:This study highlights the value of characterizing temporally resolved microbiota dynamics for a better understanding of FMT efficacy and provides potentially useful diagnostic indicators for monitoring FMT success in the treatment of ulcerative colitis.

Endoscopic Ultrasound Guided Therapy of Benign and Malignant Biliary Obstruction: A Case Series

OBJECTIVES:Endoscopic retrograde cholangiography is an established method for treatment of common bile duct stones as well as for palliation of patients with malignant pancreaticobiliary strictures. It may be unsuccessful in the presence of a complex peripapillary diverticulum, prior surgery, obstructing tumor, papillary stenosis, or impacted stones. Percutaneous transhepatic biliary drainage and surgery are alternative methods with a higher morbidity and mortality in these cases. Recently, endoscopic ultrasound (EUS) guided biliary stent placement has been described in patients with malignant biliary obstruction. We describe our experience with this method that was also used for the treatment of cholangiolithiasis for the first time.METHODS:The EUS guided transduodenal puncture of the common bile duct with stent placement was performed in 5 patients. In 2 of these patients, the stents were removed after several weeks and common bile duct stones were extracted. In another patient with gastrectomy, the left intrahepatic bile duct was punctured transjejunally and a metal stent was introduced transhepatically to bridge a distal common bile duct stenosis.RESULTS:Biliary decompression was successful in all 6 patients. No immediate complications occurred. One patient developed a subacute phlegmonous cholecystitis.CONCLUSIONS:Interventional EUS guided biliary drainage is a new technique that allows drainage of the biliary system in benign and malignant diseases when the bile duct is inaccessible by conventional ERCP.

Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn's disease

Background : Antibiotics and thiopurines have been employed in the management of fistulizing Crohns disease, although evidence of their efficacy is rare.

Intravenous Iron and Erythropoietin for Anemia Associated with Crohn Disease: A Randomized, Controlled Trial

The cause of Crohn disease is still unclear, and therapeutic interventions for this condition are therefore designed to alleviate symptoms and improve quality of life [1]. Along with diarrhea and abdominal pain, anemia is an important symptom of Crohn disease. It occurs in about one third of patients; in approximately 15% of patients, it is severe (hemoglobin concentration 10.5 g/dL [to convert g/dL to g/L, multiply by 10]). It is associated with a decrease in quality of life and an increase in rates of hospitalization and death [2, 3], which suggests that it should be effectively treated. Anemia in patients with Crohn disease results primarily from iron deficiency due to chronic intestinal blood loss [4]. Furthermore, intestinal inflammation is mediated by overproduction of cytokines (including interferon-, interleukin-1, or tumor necrosis factor-) [5, 6], which may contribute to the generation of the anemia of chronic disease [7], accompanied by inadequate erythropoietin production [4]. Since it was first used in chronic renal failure [8], recombinant human erythropoietin has been shown to be effective for treating the anemia that accompanies several chronic diseases [9]. After it was used successfully in three selected cases of anemia associated with inflammatory bowel disease [10], recombinant human erythropoietin was studied in a controlled trial of patients with anemia refractory to oral iron treatment [11]. The therapeutic effectiveness of erythropoietin, however, was limited by concomitant iron deficiency. Because erythropoietin therapy is costly, its therapeutic potency should be maximized. Our primary objective was to test the efficacy of intravenous iron alone and supplemented with erythropoietin for the treatment of anemia associated with Crohn disease. A second objective was to investigate the effect of the treatment of anemia on quality of life. Methods Patients Forty patients with Crohn disease and severe anemia (hemoglobin concentration 10.5 g/dL) were randomly assigned to receive erythropoietin or placebo after giving informed consent. All patients had been unresponsive to oral iron therapy (100 mg/d) for at least 2 months (n = 14) or had been unable to tolerate oral iron therapy because of gastrointestinal side effects (n = 26). Patients who were younger than 18 years of age; who were unable to comply with the protocol; who needed surgery; or who had recently had myelosuppressive or immunosuppressive therapy, cancer, hemolysis, deficiencies in folic acid or cobalamin, creatinine concentrations greater than 2 mg/dL (152 mol/L), hypertension, thrombosis, or iron overload were excluded. The protocol was approved by the local ethics committee of our faculty. Study Design Blinded Phase Patients were randomly assigned to receive erythropoietin or placebo in a 1:1 ratio using the minimization method described by White and Freedman [12]. This method was used to balance the two study groups for the following prognostic variables: hemoglobin concentration (group boundary, 9.0 g/dL), Crohns disease activity index (group boundary, 200 points), and sex. Individual allocations to treatment group were done at a central location in a blinded manner. All patients received iron saccharate as an intravenous infusion for 16 weeks. During the first 8 weeks, all patients received either erythropoietin or placebo in a double-blind manner. A response was defined as an increase in hemoglobin concentration of 2 g/dL or more within 8 weeks. Treatment was stopped early in patients who reached a hemoglobin concentration greater than 14.0 g/dL before the end of the blinded phase. Open Phase During the second 8 weeks of the study (the open-label phase), the erythropoietin dose was increased in nonresponders in the erythropoietin group and erythropoietin therapy was started in nonresponders in the placebo group. All patients continued to receive intravenous iron saccharate. Laboratory data on hemoglobin concentration (normal value, 14 to 18 g/dL for men, 12 to 16 g/dL for women), reticulocyte count (normal, 0.5% to 2.0%), transferrin level (normal, 2.00 to 3.80 g/L), transferrin saturation (normal, 16% to 45%), ferritin level (normal, 55 to 440 g/L), and C-reactive protein level (normal, < 0.5 mg/dL) were obtained every second week. The Crohns disease activity index (a composite of 8 items: number of liquid or very soft stools, abdominal pain, general well-being, extraintestinal manifestations, use of opiates, abdominal mass, hematocrit, and body weight [range, 0 to >500 points (no upper limit), with 200 points indicating active disease]) [13] was also assessed every second week. Serum concentrations of erythropoietin (normal value, 5 to 29 mU/mL) were analyzed at study entry by using radioimmunoassay (Incstar, Stillwater, Minnesota) [14]. Quality of life was determined at study entry, after the blinded phase, and at the end of the open phase by using a previously validated questionnaire that contained nine items (feeling of well-being, mood, level of activity, pain, nausea, appetite, physical ability, social activities, and anxiety [range, 9 to 45 points, 45 indicating lowest quality of life]) [15]. Medication Ten milliliters of iron saccharate, corresponding to 200 mg Fe3+ (Ferrum Hausmann, Vifor AG, St. Gallen, Switzerland), diluted in 250 mL of 0.9% sodium chloride solution, was given intravenously to all patients throughout the trial. Infusions were given twice weekly during the first 2 weeks and once weekly thereafter until the end of the trial. To avoid iron overload, iron supplementation was withheld when transferrin saturation exceeded 50% and was restarted when saturation decreased to less than 30%. In the blinded phase, 150 IU of erythropoietin per kg of body weight (Erypo, Janssen & Cilag Pharma, Vienna, Austria) or placebo were injected subcutaneously three times a week by each participant. The drug and the placebo were similar in appearance and were supplied in vials that contained a white sterile powder, which was clear and colorless when reconstituted with 1 mL sterile water. In the open phase, nonresponders in the erythropoietin group received erythropoietin, 300 IU/kg, and nonresponders in the placebo group received erythropoietin, 150 IU/kg. Statistical Analysis The sample size necessary to detect an increase from an assumed success rate of 60% in the placebo group to 95% in the erythropoietin group with a power of 80% and at a level of 5% was estimated as 20 for each group (two-sided). The Fisher exact test, paired and unpaired Wilcoxon tests, the Kaplan-Meier estimation, the Mantel-Cox test, and the Spearman rank correlation were used for statistical evaluation. Baseline values are expressed as the mean SD. Results Baseline Data Forty patients receiving intravenous iron therapy were randomly assigned to receive either erythropoietin (n = 20) or placebo (n = 20). Four patients had isolated small bowel disease, 4 had colonic disease, 27 had ileocolonic disease, and 5 had additional stomach or esophageal disease. The patients ranged in age from 18 to 68 years (mean, 32 years). Nine patients had received blood transfusions during the previous year. At baseline, the groups were similar with respect to all characteristics except for sex: There were 3 men in the erythropoietin group (15%) and 10 men in the placebo group (50%). The baseline hemoglobin level was 8.7 1.4 g/dL in the erythropoietin group and 8.5 1.5 g/dL in the placebo group. Both groups had substantial reductions in ferritin level (erythropoietin group, 32 50 g/L; placebo group, 15 23 g/L; P = 0.176) and transferrin saturation (erythropoietin group, 4% 3%; placebo group, 4% 6%; P = 0.152), indicating iron deficiency. Serum erythropoietin concentrations were moderately elevated (erythropoietin group, 82 88 mU/mL; placebo group, 129 171 mU/mL; P > 0.2), and an inverse relation between the logarithm of erythropoietin and hemoglobin levels was seen: Equation 1 Outcome of the Blinded Phase Twenty patients in the placebo group and 19 patients in the erythropoietin group completed the trial. One patient in the erythropoietin group was lost because of noncompliance. Fifteen patients in the placebo group (75% [95% CI, 51% to 91%]) and 18 patients in the erythropoietin group (95% [CI, 74% to 100%]) responded to intravenous iron therapy (P = 0.20). The cumulative response rate was higher in the erythropoietin group (P = 0.036) (Figure 1). The mean increase in hemoglobin concentration was 4.9 g/dL in the erythropoietin group and 3.3 g/dL in the placebo group, a difference of 1.6 g/dL (CI, 0.6 g/dL to 2.5 g/dL) (P = 0.004). Figure 1. Kaplan-Meier estimation of the cumulative response to erythropoietin and iron saccharate or placebo and iron saccharate. The increases in serum ferritin levels (116 g/L [CI, 83 g/L to 171 g/L] in the erythropoietin group compared with 282 g/L [CI, 205 g/L to 360 g/L] in the placebo group; P < 0.001) and transferrin saturation (5% [CI, 3% to 7%] in the erythropoietin group compared with 10% [CI, 6% to 13%]; P = 0.032) were significantly less in the erythropoietin group than in the placebo group. C-reactive protein levels did not change. The patients who did not respond to treatment (1 in the erythropoietin group and 5 in the placebo group) had normal ferritin levels (mean, 298 g/L [range, 61 g/L to 495 g/L]) and low transferrin saturation (mean, 9% [range, 2% to 17%]) at the end of this phase of the trial. The increase in hemoglobin concentration was associated with positive changes in the quality-of-life score (Spearman rank correlation coefficient: r = 0.372; P = 0.020) and the Crohns disease activity index (r = 0.356; P = 0.026). The feeling of well-being, mood, physical ability, and social activities accounted for most of the improvement in quality of life. Improvement in the Crohns disease activity index was derived primarily from changes in two items: hematocrit and general well-being. Outcome of the Open Phase A total

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.

Sequential Treatment of Anemia in Ulcerative Colitis with Intravenous Iron and Erythropoietin

Background: Intravenous iron and erythropoietin have been shown to be effective in Crohn’s disease-associated anemia. The aim of this study was to test the sequential treatment of anemia in ulcerative colitis with intravenous iron in the first phase and erythropoietin in the second. Patients and Methods: Twenty patients with ulcerative colitis-associated anemia (hemoglobin ≤10.5 g/dl) entered this open-label trial. In the first phase all patients received intravenous iron saccharate for 8 weeks. A response was defined as an increase in hemoglobin ≥2.0 g/dl; a final hemoglobin >10.5 g/dl was regarded as full response, ≤10.5 g/dl as partial response. A hemoglobin increase <2.0 g/dl was regarded as nonresponse. In the second phase (n = 4) erythropoietin was initiated in patients without response. Patients with partial response were continued on iron saccharate for another 8 weeks. Results: During the first phase the hemoglobin increased from 8.3 to 11.9 g/dl (mean hemoglobin difference 3.6 ± 2.3 g/dl, p < 0.001). Fifteen patients (75%) showed a full response (mean hemoglobin difference 4.5 ± 1.5 g/dl), 1 (5%) a partial response (hemoglobin difference 2.1 g/dl) and 4 no response (mean hemoglobin difference 0.4 ± 1.8 g/dl) with a need for blood transfusions in a single patient. In the second study phase erythropoietin was highly effective in previous nonresponders (mean hemoglobin difference 3.3 ± 1.9 g/dl). The single patient with partial response had a minor hemoglobin increase (hemoglobin difference 1.0 g/dl). Conclusion: Most patients with ulcerative colitis-associated anemia improve on intravenous iron alone. Erythropoietin is effective in those who do not respond.

Clinical relevance of serum interleukin-6 in Crohn's disease: single point measurements, therapy monitoring, and prediction of clinical relapse

OBJECTIVE:To investigate the clinical relevance of interleukin-6 (IL-6) serum levels in patients with Crohns disease (CD), single point IL-6 measurements in sera from consecutive CD patients and healthy donors (HD), as well as longitudinal measurements during the course of steroid therapy for active CD were performed. Patients with steroid-induced remission were followed until clinical relapse.METHODS:One hundred thirty-six CD patients without steroid or other immunosuppressive treatment within 2 months and surgical procedures within 3 months before study entry were investigated; 63 patients with active CD were enrolled into the follow-up program. Clinical activity was evaluated by the Crohns disease activity index (CDAI) and serum IL-6 levels measured by enzyme-linked immunosorbent assay.RESULTS:IL-6 serum levels were significantly elevated in CD patients compared to HD (p < 0.001). In individual patients serum IL-6 levels correlated with corresponding CDAI scores in a subgroup referred to as primarily inflammatory patients presenting without bowel stenosis, previous intestinal resection, or concomitant inflammatory disorders (r = 0.72, p < 0.001). Primarily inflammatory patients displayed higher serum IL-6 levels (median: 6.0 pg/ml; range: 1.3–25) than CD patients with bowel stenosis (median: 2.0; range: 1.3–4.9; p < 0.01) or extensive intestinal resection (median: 1.5; range: 1.3–13.7; p < 0.001). Longitudinally measured serum IL-6 levels reflected the clinical response during steroid therapy and predicted clinical relapse after steroid-induced remission at week 9 of the treatment protocol.CONCLUSIONS:Serum IL-6 is a clinically relevant parameter for CD that correlates with inflammatory activity and implies a prognostic value after steroid-induced remission.

IL-10 secretion and sensitivity in normal human intestine and inflammatory bowel disease.

Interleukin-10 (IL-10) deficiency in gene knockout mice causes chronic enterocolitis. We hypothesized that inflammation in human inflammatory bowel disease might result from innate alterations in the IL-10 pathway. Serum, supernatants, and mRNA of peripheral blood mononuclear cells (PBMC) and lamina propria mononuclear cells (LPMC) derived from inflamed (LPMC-i) and noninflamed colonic mucosa (LPMC-ni) were collected from patients with Crohns colitis, ulcerative colitis, and controls. IL-10 protein concentrations and IL-10 mRNA were examined in response to PMA/CD3 or PHA stimulation. The response to rhIL-10 was assessed by inhibition of tumor necrosis factor-alpha (TNF-α), IL-6, and interferon-gamma (IFN-γ) production. Serum IL-10 levels of inflammatory bowel disease (IBD) patients were within the normal range. IL-10 concentrations in supernatants from LPMC-i were significantly lower than from LPMC-ni or PBMC. No difference was seen between samples from ulcerative colitis and Crohns disease. IL-10 mRNA was detected in 0/4 LPMC-i samples compared to 1/6 LPMC-ni and 6/6 PBMC. RhIL-10 inhibited TNF-α, IL-6, and IFN-γ synthesis in PBMC. This effect was strongly diminished in LPMC. Disease-specific alterations were not detected. Our data suggest that LPMC derived from inflamed colonic mucosa have a reduced ability to produce and to respond to rhIL-10. A disease-specific alteration in the IL-10 pathway, however, was not found.

Rapid recurrence of IBD-associated anemia and iron deficiency after intravenous iron sucrose and erythropoietin treatment.

OBJECTIVES:Anemia is a common complication of inflammatory bowel disease (IBD) and iron deficiency (ID) is its predominant cause. Therefore, oral and intravenous iron replacements are widely used. This study was performed to evaluate the frequency and timing of anemia and ID recurrence after a successful treatment cycle.METHODS:Medical records of patients who had received iron sucrose with or without erythropoietin (EPO) in one of three prospective clinical trials that had been conducted at our center (Ann Intern Med 1997, Digestion 1999, and Am J Gastroenterol 2001) were analyzed for a 5-year follow-up period. The risk for recurrence of anemia (hemoglobin (Hb)<12/13 g per 100 ml) and ID (ferritin <30 μg/l) was evaluated by Kaplan–Meier analysis using the log-rank test.RESULTS:Eighty-eight patients were available for analysis. Patients had received a mean iron dose of 2,500 mg (range 600–3,600 mg); 33 (37.1%) patients had also received EPO. Anemia recurred in a median of 10 months (95% confidence interval (CI) 8–12) and ID recurred within 19 months (95% CI 11–28). The iron dose had no influence on recurrence of ID or anemia. ID (but not anemia) recurred faster in patients with a post-treatment ferritin level <100 μg/l (median 4 months, 95% CI 1–7) than in patients with ferritin level between 100 and 400 μg/l (median 11 months, 95% CI 6–16) and >400 μg/l (median 49 months, 95% CI 32–66; P<0.001).CONCLUSIONS:IBD-associated ID and anemia recur surprisingly fast, indicating that maintenance treatment may be needed in a portion of the patient population. Recurrence of ID (but not anemia) can be delayed by aiming for high post-treatment ferritin levels.