Wolfgang Kreisel

Budesonide Induces Remission More Effectively Than Prednisone in a Controlled Trial of Patients With Autoimmune Hepatitis

BACKGROUND & AIMS Autoimmune hepatitis (AIH) is a chronic liver disease associated with cirrhosis and liver failure. Corticosteroid therapy induces long-term remission but has many side effects. We compared the effects of budesonide (a steroid that is rapidly metabolized, with low systemic exposure) and prednisone, both in combination with azathioprine. METHODS We performed a 6-month, prospective, double-blind, randomized, active-controlled, multicenter, phase IIb trial of patients with AIH without evidence of cirrhosis who were given budesonide (3 mg, three times daily or twice daily) or prednisone (40 mg/d, tapered to 10 mg/d); patients also received azathioprine (1-2 mg/kg/d). Treatment was followed by a 6-month, open-label phase during which all patients received budesonide in addition to azathioprine. The primary end point was complete biochemical remission, defined as normal serum levels of aspartate aminotransferase and alanine aminotransferase, without predefined steroid-specific side effects, at 6 months. RESULTS The primary end point was achieved in 47/100 patients given budesonide (47.0%) and in 19/103 patients given prednisone (18.4%) (P < .001; 97.5% 1-side confidence interval [CI] = 16.2). At 6 months, complete biochemical remission occurred in 60% of the patients given budesonide versus 38.8% of those given prednisone (P = .001; CI: 7.7); 72.0% of those in the budesonide group did not develop steroid-specific side effects versus 46.6% in the prednisone group (P < .001; CI = 12.3). Among 87 patients who were initially given prednisone and then received budesonide after 6 months, steroid-specific side effects decreased from 44.8% to 26.4% at month 12 (P < .002). CONCLUSIONS Oral budesonide, in combination with azathioprine, induces and maintains remission in patients with noncirrhotic AIH, with a low rate of steroid-specific side effects.

Budesonide in previously untreated autoimmune hepatitis

Abstract: Background: Autoimmune hepatitis (AIH) is a chronic liver disease that is effectively treated with immunosuppressive therapy. Predniso(lo)ne, often in combination with azathioprine, is the basic therapeutic option to induce remission. However, this regimen can cause numerous side effects. The aim of the present study was to evaluate budesonide as a treatment option in the induction of remission in patients with previously untreated AIH.

Complete remission of Crohn's disease after high-dose cyclophosphamide and autologous stem cell transplantation.

Summary:In a 36-year-old male with ileocolic Crohns disease (CD) no long-lasting remission was obtained by treatment with corticosteroids, mesalazine, azathioprine and antibiotics. Surgical interventions due to relapsing fistulae and abscesses resulted in the removal of >1.5 m of small bowel and left only 40 cm of large bowel. In July 2000, a new fistula and abscess developed. The combination of corticosteroids, mesalazine, ciprofloxacin, metronidazol, azathioprine, formula diet and anti-TNF-α antibody largely reduced clinical activity, and resection of fistula and abscess were successful. Despite clinical remission, histology showed activity in the small bowel and the colon. In March 2001, stem cell mobilization chemotherapy with cyclophosphamide was performed. It induced an endoscopic remission for 9 months, which was maintained on azathioprine and corticosteroids. After relapse, in March 2002, high-dose chemotherapy with cyclophosphamide and reinfusion of T-cell-depleted autologous peripheral CD34+ blood stem cells were performed. This led to a complete clinical, endoscopical and histological remission for 9 months without any treatment. Thereafter, endoscopy showed initial aphthous lesions with minimal histological signs of inflammation. The patient is asymptomatic, but low-dose prednisolone and methotrexate are prophylactically given. Immunoablative chemotherapy followed by autologous peripheral blood stem cell transplantation may be a beneficial therapeutic option in complicated refractory CD.

6-Thioguanine — efficacy and safety in chronic active Crohn's disease

Background : Azathioprine and mercaptopurine are commonly used in chronic active Crohns disease. They share the disadvantage of a delayed onset of action and potentially serious side‐effects, and are metabolized to thioguanine nucleotides which are thought to be the active metabolites. The direct use of 6‐thioguanine may offer a more rapid and safer alternative. We conducted an open prospective study to investigate the efficacy and safety of 6‐thioguanine in chronic active Crohns disease.

Endoscopic diagnosis of acute intestinal GVHD following allogeneic hematopoietic SCT: a retrospective analysis in 175 patients

Diagnosis of acute intestinal GVHD (aGVHD) following allogeneic hematopoietic cell transplantation is based on clinical symptoms and histological lesions. This retrospective analysis aimed to validate the ‘Freiburg Criteria’ for the endoscopic grading of intestinal aGVHD. Grade 1: no clear-cut criteria; grade 2: spotted erythema; grade 3: aphthous lesions; and grade 4: confluent defects, ulcers, denudation of the mucosa. Having excluded patients with infectious diarrhea, we evaluated 175 consecutive patients between January 2001 and June 2009. Setting a cutoff between grade 1 (no change in therapy) and grade 2 (intensification of immunosuppression), macroscopy had a sensitivity of 89.2% (95% confidence interval (CI): 80.4–94.9%), a specificity of 79.4% (95% CI: 69.6–87.1%), a positive-predictive value of 79.6% (95% CI: 70.0–87.2%) and a negative-predictive value of 89.0% (95% CI: 80.2–94.9%). In all, 20% of patients with aGVHD in the lower gastrointestinal tract (GIT) had lesions only in the terminal ileum. In all patients with aGVHD ⩾2 of the upper GIT, typical lesions were also found in the lower GIT. Ileo-colonoscopy showed the highest diagnostic yield for aGVHD. In conclusion, the ‘Freiburg Criteria’ for macroscopic diagnosis of intestinal aGVHD provide high accuracy for identifying aGVHD ⩾2.

Identification of the 110 000 Mr glycoprotein isolated from rat liver plasma membrane as dipeptidylaminopeptidase IV

We have described a dissociated turnover of terminal carbohydrates and protein component of a 110 000 M, glycoprotein isolated from rat liver plasma membrane: fucose, N-acetylneuraminic acid and galactose turn over several times on the intact polypeptide [l], whereas mannose and Nacetylglucosamine (core sugars in N-glycosidically bound carbohydrate chains) turn over coordinatedly to the protein [2]. Here, we describe the identification of the isolated glycoprotein as the monomer of dipeptidylaminopeptidase IV (EC 3.4.14.X) a dimeric glycoprotein of the plasma membrane. Our results suggest differently glycosylated forms of this enzyme within the cell. photometer. Alternatively, the following method was used (modified according to [4]): 0.05 ml glycyl-prolyl-p-nitroanilide tosylate solution (10 mg/ml H20), 0.005-o. 1 ml enzyme-containing solution, add 1.0 ml with 0.1 mol/l Tris buffer (pH 8.0). E was measured at 405 nm using a Gilford UV/VIS photometer. For routine measurements the latter method was taken. Protein was determined as in [5]. Rat liver plasma membranes were isolated by the method in [6] with some modifications [7] and checked for purity as described. Fractionation of plasma membrane glycoproteins and isolation of the 110 000 Mr glycoprotein were performed as in [l]. SDS gel electrophoresis was performed as in [8].

Normal and Altered Three-dimensional Portal Venous Hemodynamics in Patients with Liver Cirrhosis

PURPOSE To compare time-resolved three-dimensional (3D) phase-contrast magnetic resonance (MR) imaging with three-directional velocity encoding (flow-sensitive four-dimensional [4D] MR imaging), with Doppler ultrasonography (US) as standard of reference, for investigating alterations in 3D portal venous hemodynamics in patients with liver cirrhosis compared with healthy age-matched control subjects and healthy young volunteers. MATERIAL & METHODS This prospective study was approved by the local ethics committee, and written informed consent was obtained from all participants. Three-dimensional portal venous hemodynamics was assessed, employing flow-sensitive 4D MR imaging with a 3-T MR system (spatial resolution, approximately 2 mm(3); temporal resolution, approximately 45 msec) in 20 patients with hepatic cirrhosis, 20 healthy age-matched control subjects, and 21 healthy young volunteers. Flow characteristics were analyzed by using 3D streamlines and time-resolved particle traces. Quantitative analyses were performed by retrospectively evaluating regional peak and mean velocities, flow volume, and vessel area. Doppler US was used as standard of reference. Independent-sample t tests or Wilcoxon-Mann-Whitney tests were applied for comparing each subject group. Paired-sample t tests or Wilcoxon tests were applied when comparing MR imaging and US. RESULTS Three-dimensional visualization of portal venous hemodynamics was successful, with complete visualization of the vessels in 18 patients and 35 volunteers, with limitations in the left intrahepatic branches (87%, reader A; 89%, reader B). A moderate but significant correlation was observed between 4D MR imaging and Doppler US in nearly all maximum and mean velocities, flow volumes, and vessel areas (r = 0.24-0.64, P = .001-.044). With MR imaging, significant underestimation was observed of intrahepatic flow velocities and flow volumes, except vessel area, which Doppler US represented as even lower (P < .001 to P = .045). Six patients had collateralization with reopened umbilical vein, while one had flow reversal in the superior mesenteric vein visible at MR imaging only. CONCLUSION Flow-sensitive 4D MR imaging may constitute a promising, alternative technique to Doppler US for evaluating hemodynamics in the portal venous system of patients with liver cirrhosis and may be a means of assessing pathologic changes in flow characteristics.

Feasibility and response to budesonide as topical corticosteroid therapy for acute intestinal GVHD

Therapy of acute intestinal GVHD is still one of the main challenges after allogeneic transplantation. Increasing systemic immunosuppression (IS) is the first choice and includes corticosteroids and lymphocyte antibodies, often associated with severe side-effects. In inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, topical steroid therapy is used very successfully. Because of the similarity between these and acute intestinal GVHD we conducted a trial with oral budesonide (Budenofalk), a new topically active glucocorticoid, to treat patients with acute GVHD ⩾ grade II. After a diagnosis of aGVHD ⩾ grade II, 22 patients received increased IS, mainly systemic corticosteroids, and additionally budesonide 9 mg/day divided into three doses. Improvement in aGVHD, infectious side-effects, reduction of systemic IS and outcome were documented. Results were compared with the results of 19 control patients, who were treated only by increasing IS dose. In 17/22 patients (70%), treated with budesonide, the acute intestinal GVHD resolved and no relapse occurred after decreasing the systemic IS, while continuing budesonide. In only 8/19 patients in the control group did the acute intestinal GVHD resolve and 2/8 patients had a relapse of intestinal GVHD after decreasing IS, with an overall response of 33%. No severe intestinal infections occurred. We conclude that budesonide may be effective in acute intestinal GVHD as a topical corticosteroid and prospective, randomized studies should demonstrate its efficacy in allowing reduction of systemic immunosuppressive therapy, and its side-effects.

Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn's disease.

Background : 6‐Thioguanine‐nucleotides seem to be the active metabolites of thiopurine therapy, and their monitoring has been considered a useful tool for optimizing response in inflammatory bowel diseases. Tioguanine (thioguanine) therapy results in much higher levels of 6‐thioguanine‐nucleotide levels when compared with azathioprine or mercaptopurine.

Remission maintenance by tioguanine in chronic active Crohn's disease

Background: Tioguanine may offer an alternative for immunosuppression in chronic active Crohns disease. Recently, we have shown that tioguanine is effective in inducing rapid remission.