Sieglinde Angelberger

Publications of Sieglinde Angelberger

• Simultaneous quantification of eleven thiopurine nucleotides by liquid chromatography-tandem mass spectrometry.

  Authors: Ute Hofmann, Georg Heinkele, Sieglinde Angelberger, Elke Schaeffeler, Cornelia Lichtenberger, Simon Jaeger, Walter Reinisch, Matthias Schwab

  Analytical chemistry. 02/2012; 84(3):1294-301.

  The prodrugs azathioprine and 6-mercaptopurine, which are well-established anticancer and immunosuppressive agents, are extensively metabolized by activating and inactivating enzymes. Whereas theThe prodrugs azathioprine and 6-mercaptopurine, which are well-established anticancer and immunosuppressive agents, are extensively metabolized by activating and inactivating enzymes. Whereas the 6-thioguanine nucleotides (TGN) are currently being considered as major active metabolites, methylthioinosine nucleotides seem to contribute to the cytotoxic effect as well. Thiopurine-related adverse drug reactions and thiopurine failure are frequent. Thus, therapeutic monitoring of TGN and methylthioinosine derivatives has been suggested to improve thiopurine therapy, however with limited success. To elucidate systematically underlying molecular mechanisms as potential explanation for interindividual variability of thiopurine response, we developed a novel highly specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantitation of eleven mono-, di-, and triphosphates of thioguanosine, methylthioinosine, methylthioguanosine, and thioinosine. Using stable isotope-labeled analogues as internal standards obtained by chemical synthesis, an intra- and interassay variability below 8% and an accuracy of 92% to 107% were achieved in spiked quality control samples with known standards. All eleven metabolites could be determined in red blood cells from patients with inflammatory bowel diseases and long-term azathioprine therapy. Thus, our novel method opens a new avenue for the understanding of the thiopurine metabolism by quantitation of all important thiopurine nucleotide metabolites in one run.

• Long-term follow-up of babies exposed to azathioprine in utero and via breastfeeding.

  Authors: Sieglinde Angelberger, Walter Reinisch, Agnes Messerschmidt, Wolfgang Miehsler, Gottfried Novacek, Harald Vogelsang, Clemens Dejaco

  Journal of Crohn's & colitis. 04/2011; 5(2):95-100.

  Recommendations on breastfeeding under thiopurines are inconsistent due to limited data. To assess the risk of infections in offspring breastfed by mothers receiving azathioprine (AZA) forRecommendations on breastfeeding under thiopurines are inconsistent due to limited data. To assess the risk of infections in offspring breastfed by mothers receiving azathioprine (AZA) for inflammatory bowel disease (IBD). Babies, who were breastfed from their mothers treated either with or without AZA were included from a local pregnancy-registry. Women were asked by structured personal interview on general development, infections, hospitalisations and vaccinations of their offspring. A group of 11 mothers taking AZA (median 150 mg/d) during pregnancy and lactation and another of 12 patients without using any immunosuppressive therapy breastfed 15 babies each for median 6 months and 8 months, respectively. Median age of children at time of interview was 3.3 and 4.7 years, respectively. All offspring showed age-appropriate mental and physical development. Infections were commonly seen childhood diseases. Similar rates were observed for most of the various infections between offspring with and without azathioprine exposure during breastfeeding. However, common cold more than two episodes/year and conjunctivitis were numerically more often reported in the group without AZA exposure. In an exploratory analysis no difference in the rate of hospitalisations was seen between exposed (0.06 hospitalisations/patient year) versus non-exposed children (0.12 hospitalisations/patient year, p=0.8) Our study which reports the largest number of babies breastfed with exposure to AZA suggests that breastfeeding does not increase the risk of infections.

• Predictors of indeterminate IFN-γ release assay in screening for latent TB in inflammatory bowel diseases.

  Authors: Pavol Papay, Alexander Eser, Stefan Winkler, Sophie Frantal, Christian Primas, Wolfgang Miehsler, Sieglinde Angelberger, Gottfried Novacek, Andrea Mikulits, Harald Vogelsang, Walter Reinisch

  European journal of clinical investigation. 03/2011; 41(10):1071-6.

  IFN-γ release assays (IGRA), widely used for latent tuberculosis screening prior to anti-TNF-α treatment, are limited by indeterminate results in patients under immunomodulatory (IM) therapy. The aimIFN-γ release assays (IGRA), widely used for latent tuberculosis screening prior to anti-TNF-α treatment, are limited by indeterminate results in patients under immunomodulatory (IM) therapy. The aim of our observational study was to delineate factors associated with indeterminate IGRA results. A total of 190 patients with inflammatory bowel disease were included. IGRA was indeterminate if the result of IFN-γ concentration was < 0·35 IU mL(-1) for tuberculosis-specific antigens and < 0·5 IU mL(-1) for the positive control. Predictors for indeterminate results were delineated from multivariate logistic regression. IFN-γ release assays was indeterminate in 26/190 (13·7%) patients. Indeterminate IGRA were associated with lower serum albumin levels (odds ratio [OR] 0·88, 95% confidence interval [CI] 0·79-0·96), lower absolute lymphocyte count (OR 0·39, 95% CI 0·18-0·75) and double IM therapy (OR 2·98, 95% CI 0·95-8·90). Sub-analysis of IM therapy revealed an association of steroid therapy with indeterminate IGRA (OR 3·19, 95% CI 1·35-7·70). Hypoalbuminaemia increased the risk of indeterminate IGRA by (OR 2·97, 95% CI 1·03-8·61) and lymphopaenia by (OR 3·28, 95% CI 1·41-7·65). After a mean of 18·5 ± 14·4 days, retesting of IGRA in 18 patients with indeterminate results yielded 9 negative vs. 9 indeterminate results. Our results reveal associations of indeterminate IGRA with low serum albumin levels and absolute lymphocyte count and double IM therapy. IGRA testing appears best to be performed prior to initiation of IM therapy in patients with inflammatory bowel disease.

• Infliximab or cyclosporine as rescue therapy in hospitalized patients with steroid-refractory ulcerative colitis: a retrospective observational study.

  Authors: Mats Sjöberg, Andrea Walch, Mina Meshkat, Anders Gustavsson, Gunnar Järnerot, Harald Vogelsang, Erik Hertervig, Gottfried Novacek, Ingalill Friis-Liby, Lars Blomquist [......] Christer Grännö, Mogens Vilien, Magnus Ström, Hans Verbaan, Per M Hellström, Clemens Dejaco, Anders Magnuson, Jonas Halfvarson, Walter Reinisch, Curt Tysk

  Inflammatory bowel diseases. 03/2011; 18(2):212-8.

  Cyclosporine (CsA) or infliximab (IFX) are used as rescue therapies in steroid-refractory, severe attacks of ulcerative colitis (UC). There are no data comparing the efficacy of these twoCyclosporine (CsA) or infliximab (IFX) are used as rescue therapies in steroid-refractory, severe attacks of ulcerative colitis (UC). There are no data comparing the efficacy of these two alternatives. Outcome of rescue therapy was retrospectively studied in two cohorts of patients hospitalized due to steroid-refractory moderate to severe UC: 1) a Swedish-Danish cohort (n = 49) treated with a single infusion of IFX; 2) an Austrian cohort (n = 43) treated with intravenous CsA. After successful rescue therapy, maintenance immunomodulator treatment was given to 27/33 (82%) of IFX patients and to 31/40 (78%) of CsA patients. Endpoints were colectomy-free survival at 3 and 12 months. Kaplan-Meier and Cox regression models were used to evaluate the association between treatment groups and colectomy. At 15 days, colectomy-free survival in the IFX cohort was 36/49 (73%) versus 41/43 (95%) in the CsA cohort (P = 0.005), at 3 months 33/49 (67%) versus 40/43 (93%) (P = 0.002), and at 12 months 28/49 (57%) versus 33/43 (77%) (P = 0.034). After adjusting for potential confounding factors, Cox regression analysis yielded adjusted hazard ratios for risk of colectomy in IFX-treated patients of 11.2 (95% confidence interval [CI] 2.4-53.1, P = 0.002) at 3 months and of 3.0 (95% CI 1.1-8.2, P = 0.030) at 12 months in comparison with CsA-treated patients. There were no opportunistic infections or mortality. Colectomy frequencies were significantly lower after rescue therapy with CsA than with a single infusion of IFX both at 3 and 12 months' follow-up. The superiority of CsA was seen principally during the first 15 days.

• Long-term outcome in patients with ulcerative colitis treated with intravenous cyclosporine A is determined by previous exposure to thiopurines.

  Authors: Andrea Walch, Miena Meshkat, Harald Vogelsang, Gottfried Novacek, Clemens Dejaco, Sieglinde Angelberger, Andrea Mikulits, Wolfgang Miehsler, Alfred Gangl, Walter Reinisch

  Journal of Crohn's & colitis. 10/2010; 4(4):398-404.

  Rescue therapy with intravenous cyclosporine A (CsA) helps to avoid colectomy in a substantial proportion of patients with severe ulcerative colitis (UC) but the impact on long-term outcome remainsRescue therapy with intravenous cyclosporine A (CsA) helps to avoid colectomy in a substantial proportion of patients with severe ulcerative colitis (UC) but the impact on long-term outcome remains unclear. Therefore, we aimed to define predictive factors for colectomy in patients treated with intravenous CsA for severely active UC. A retrospective, single-center study with a minimum follow-up of 18 months was performed. A total of 64 patients were evaluable (median age 33 years [range 17-80 years], female 54.7%). Median intravenous CsA dose was 4 mg/kg/day (range 2-5mg/kg/day). After a median follow-up of 65 months (range 2-160 months), 19 patients (29.7%) underwent colectomy, 15 within 18 months. Of the various baseline parameters tested, only previous non-response to thiopurine treatment (p=0.006) was associated with an increased risk of colectomy. During 18 months follow-up, thiopurine-naïve patients receiving thiopurine maintenance therapy after intravenous CsA (32/64, 50.0%) underwent colectomy in 12.5% of cases. The colectomy rate was 27.3% among 22 patients previously non-responsive to thiopurines who continued treatment after intravenous CsA, compared to 50.0% in the 10 patients who discontinued thiopurines prior to intravenous CsA or who never received thiopurines (p=0.037). The long-term colectomy rate after intravenous CsA in patients with severely active UC was relatively low in our series compared to the literature. Concomitant treatment with thiopurines was the only predictor for a reduced risk of colectomy.

• Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn's disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy, multicentre trial.

  Authors: Walter Reinisch, Sieglinde Angelberger, Wolfgang Petritsch, Olga Shonova, Milan Lukas, Simon Bar-Meir, Alexander Teml, Elke Schaeffeler, Matthias Schwab, Karin Dilger, Roland Greinwald, Ralph Mueller, Eduard F Stange, Klaus R Herrlinger

  Gut. 06/2010; 59(6):752-9.

  The aim of the study was to compare azathioprine versus mesalazine tablets for the prevention of clinical recurrence in patients with postoperative Crohn's disease (CD) with moderate or severeThe aim of the study was to compare azathioprine versus mesalazine tablets for the prevention of clinical recurrence in patients with postoperative Crohn's disease (CD) with moderate or severe endoscopic recurrence. This was a 1 year, double-blind, double-dummy, randomised study which took place in 21 gastroenterology centres in Austria, the Czech Republic, Germany and Israel. The study participants were 78 adults with CD who had undergone resection with ileocolonic anastomosis in the preceding 6-24 months without subsequent clinical recurrence and with a Crohn's disease activity index (CDAI) score <200, but with moderate or severe endoscopic recurrence. The study drugs were azathioprine 2.0-2.5 mg/kg/day or mesalazine 4 g/day over 1 year. The primary end point was therapeutic failure during 1 year, defined as a CDAI score > or = 200 and an increase of > or = 60 points from baseline, or study drug discontinuation due to lack of efficacy or intolerable adverse drug reaction. Treatment failure occurred in 22.0% (9/41) of azathioprine-treated patients and 10.8% (4/37) of mesalazine-treated patients, a difference of 11.1% (95% CI -5.0% to 27.3%, p=0.19). Clinical recurrence was significantly less frequent with azathioprine versus mesalazine (0/41 (0%) vs 4/37 (10.8%), p=0.031), whereas study drug discontinuation due to adverse drug reactions only occurred in azathioprine-treated patients (9/41 (22.0%) vs 0%, p=0.002). The proportion of patients showing > or = 1 point reduction in Rutgeerts score between baseline and month 12 was 63.3% (19/30) and 34.4% (11/32) in the azathioprine and mesalazine groups, respectively (p=0.023). In this population of patients with postoperative CD at high risk of clinical recurrence, superiority for azathioprine versus mesalazine could not be demonstrated for therapeutic failure.

• Public awareness of Crohn's disease and ulcerative colitis: A national survey.

  Authors: Sieglinde Angelberger, Harald Vogelsang, Gottfried Novacek, Wolfgang Miehsler, Clemens Dejaco, Alfred Gangl, Walter Reinisch

  Journal of Crohn's & colitis. 09/2009; 3(3):157-61.

  Crohn's disease (CD) and ulcerative colitis (UC) are lifelong inflammatory bowel diseases (IBD) progressing over time. Lack of public awareness may contribute to tardy consultation of primary careCrohn's disease (CD) and ulcerative colitis (UC) are lifelong inflammatory bowel diseases (IBD) progressing over time. Lack of public awareness may contribute to tardy consultation of primary care physicians, late diagnosis and development of potentially preventable complications of disease. A public opinion poll has been performed to assess the awareness of CD and UC in the Austrian population. In March/April 2006, 122 interviewers of an international polling institute asked 1001 Austrians aged 16 and over about their knowledge of CD and UC. People interviewed were selected using a quota sampling scheme representing the Austrian population. CD and UC were never heard/read in 68% and 79% (group 1), respectively, whereas 23% and 14% had already heard/read these terms (group 2). Only 9% and 7% of participants gained information on or were familiar with CD and UC (group3), respectively. Among provided choices of potentially afflicted organs interviewees of group 3 associated the terms "CD" and "UC" with an intestinal disease in 86% each. Among those of group 2+3 the corresponding figures were 53% and 60% for CD and UC, respectively. Overall, 7% and 4% of the participants stated to be aware and/or informed on CD and UC and correctly associated these terms with an intestinal disease. This is the first study on public awareness of the terms "Crohn's disease" and "ulcerative colitis". Poor knowledge in the public is reported which may vastly impact outcome and health economic consequences of IBD.

• Colonic involvement does not predispose to thrombosis in IBD.

  Authors: Sieglinde Angelberger, Wolfgang Miehsler, Gottfried Novacek

  Inflammatory bowel diseases. 08/2008;

• NOD2/CARD15 gene variants are linked to failure of antibiotic treatment in perianal fistulating Crohn's disease.

  Authors: Sieglinde Angelberger, Walter Reinisch, Clemens Dejaco, Wolfgang Miehsler, Thomas Waldhoer, Jan Wehkamp, Cornelia Lichtenberger, Elke Schaeffeler, Harald Vogelsang, Matthias Schwab, Alexander Teml

  The American journal of gastroenterology. 06/2008; 103(5):1197-202.

  OBJECTIVES: The Crohn's disease (CD) susceptibility gene, nucleotide-binding oligomerizetion domain 2 (NOD2)/caspase recruitment domain 15 (CARD15), is linked to the innate immune response associatedOBJECTIVES: The Crohn's disease (CD) susceptibility gene, nucleotide-binding oligomerizetion domain 2 (NOD2)/caspase recruitment domain 15 (CARD15), is linked to the innate immune response associated with altered epithelial bacterial defense. Its relevance in antibiotic therapy of perianal fistulating CD remains elusive. The aim of the study was to explore systematically the association between NOD2/CARD15 variants and clinical response of perianal fistulas in patients using antibiotic therapy. METHODS: Fifty-two patients (median age 36 yr) with draining perianal fistulas were treated with ciprofloxacin (N = 49) or metronidazole (N = 3) for a median duration of 7 wk. Complete response was defined as the absence of any draining fistula despite gentle finger compression. Genotyping for NOD2/CARD15 variants and human beta (beta)-defensin 2 (HBD-2) copies was performed by 5' nuclease assays (Applied Biosystems, Foster City, CA). The examiners and laboratory investigators were blinded. The Fisher exact test and Wilcoxon signed rank test were used for statistical analysis. RESULTS: Ciprofloxacin was discontinued in one patient due to diarrhea after 2 wk. Complete fistula response was observed in 13 of 39 patients with NOD2/CARD15 wild-type (33.3%) compared with none in patients carrying NOD2/CARD15 variants (0%, P= 0.02). The median number of HBD-2 gene copies between responders and partial/nonresponders was similar. CONCLUSIONS: The study result suggests a substantial contribution of NOD2/CARD15 to the antibiotic treatment outcome of perianal fistulating CD. NOD2/CARD15 variants may predispose to an altered intestinal microflora in perianal fistulas that is less responsive to antibiotic treatment.

• Complications in Crohn's disease: right-sided ureteric stenosis and hydronephrosis.

  Authors: Sieglinde Angelberger, Klaus G Fink, Wolfgang Schima, Roland Szlauer, Harald Vogelsang, Walter Reinisch, Alfred Gangl, Gottfried Novacek

  Inflammatory bowel diseases. 09/2007; 13(8):1056-7.