Klaus R Herrlinger

Publications of Klaus R Herrlinger

• 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.

• Determination of 6-thioguanosine diphosphate and triphosphate and nucleoside diphosphate kinase activity in erythrocytes: novel targets for thiopurine therapy?

  Authors: Susanne Karner, Shaojun Shi, Christine Fischer, Elke Schaeffeler, Markus F Neurath, Klaus R Herrlinger, Ute Hofmann, Matthias Schwab

  Therapeutic drug monitoring. 03/2010; 32(2):119-28.

  6-Thioguanine nucleotides are the sum of 6-thioguanosine 5'-monophosphate (TGMP), -diphosphate (TGDP), and -triphosphate (TGTP) representing essential metabolites involved in drug action of6-Thioguanine nucleotides are the sum of 6-thioguanosine 5'-monophosphate (TGMP), -diphosphate (TGDP), and -triphosphate (TGTP) representing essential metabolites involved in drug action of thiopurines. Elevated levels of TGDP have been associated with poor response to azathioprine therapy in patients with inflammatory bowel disease. The conversion of TGDP to TGTP is supposed to be catalyzed by nucleoside diphosphate kinase (NDPK). The aim of this work was to investigate simultaneously individual 6-thioguanosine phosphate levels and NDPK activity in red blood cells (RBCs) of patients on azathioprine therapy. Ion-pair high-performance liquid chromatography methods with fluorescence and ultraviolet detection were applied to quantify individual levels of 6-thioguanosine 5'-phosphates and NDPK activity, respectively, in RBCs. Recombinantly expressed NDPK isoforms A and B were unequivocally identified to catalyze the formation of TGTP (30.6 +/- 3.88 nmol x min x mg for NDPK A versus 41.2 +/- 1.05 nmol x min x mg for NDPK B). Comprehensive analyses on the stability of TGMP, TGDP, and TGTP and the reproducibility of NDPK activity in RBCs were performed to provide a reliable sampling protocol for clinical practice. Of note, isolation of RBCs within 6 hours followed by immediate storage at -80 degrees C is crucial for prevention of degradation of 5'-phosphates. In a clinical study of 37 patients on azathioprine, TGTP was the predominant 6-thioguanosine phosphate in RBCs. In contrast, three patients showed TGTP/(TGDP + TGTP) ratios of 57.2%, 64.3%, and 66% corresponding to elevated TGDP levels. NDPK activity ranged from 4.1 to 11.3 nmol x min x mg hemoglobin. No correlation between NDPK activity and the 6-thioguanosine phosphate levels was found. The question whether interindividual variability of NDPK activity may explain differences in 6-thioguanosine 5'-phosphates levels has to be investigated in a prospective large-scale study.

• Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease.

  Authors: Maureen J Koslowski, Irmgard Kübler, Mathias Chamaillard, Elke Schaeffeler, Walter Reinisch, Guoxing Wang, Julia Beisner, Alexander Teml, Laurent Peyrin-Biroulet, Stefan Winter, Klaus R Herrlinger, Paul Rutgeerts, Séverine Vermeire, Rachel Cooney, Klaus Fellermann, Derek Jewell, Charles L Bevins, Matthias Schwab, Eduard F Stange, Jan Wehkamp

  PLoS ONE. 02/2009; 4(2):e4496.

  Reduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathwayReduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathway transcription factor, orchestrates Paneth cell differentiation, directly regulates the expression of HD-5 and -6, and was previously associated with the decrease of these antimicrobial peptides in a subset of ileal CD. To investigate a potential genetic association of TCF-4 with ileal CD, we sequenced 2.1 kb of the 5' flanking region of TCF-4 in a small group of ileal CD patients and controls (n = 10 each). We identified eight single nucleotide polymorphisms (SNPs), of which three (rs3814570, rs10885394, rs10885395) were in linkage disequilibrium and found more frequently in patients; one (rs3814570) was thereby located in a predicted regulatory region. We carried out high-throughput analysis of this SNP in three cohorts of inflammatory bowel disease (IBD) patients and controls. Overall 1399 healthy individuals, 785 ulcerative colitis (UC) patients, 225 CD patients with colonic disease only and 784 CD patients with ileal involvement were used to determine frequency distributions. We found an association of rs3814570 with ileal CD but neither with colonic CD or UC, in a combined analysis (allele positivity: OR 1.27, 95% CI 1.07 to 1.52, p = 0.00737), which was the strongest in ileal CD patients with stricturing behaviour (allele frequency: OR 1.32, 95% CI 1.08 to1.62, p = 0.00686) or an additional involvement of the upper GIT (allele frequency: OR 1.38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis.

• Azathioprine-induced suicidal erythrocyte death.

  Authors: Corinna Geiger, Michael Föller, Klaus R Herrlinger, Florian Lang

  Inflammatory bowel diseases. 08/2008; 14(8):1027-32.

  BACKGROUND: Azathioprine is widely used as an immunosuppressive drug. The side effects of azathioprine include anemia, which has been attributed to bone marrow suppression. Alternatively, anemiaBACKGROUND: Azathioprine is widely used as an immunosuppressive drug. The side effects of azathioprine include anemia, which has been attributed to bone marrow suppression. Alternatively, anemia could result from accelerated suicidal erythrocyte death or eryptosis, which is characterized by exposure of phosphatidylserine (PS) at the erythrocyte surface and by cell shrinkage. METHODS: The present experiments explored whether azathioprine influences eryptosis. According to annexin V binding, erythrocytes from patients indeed showed a significant increase of PS exposure within 1 week of treatment with azathioprine. In a second series, cytosolic Ca2+ activity (Fluo3 fluorescence), cell volume (forward scatter), and PS-exposure (annexin V binding) were determined by FACS analysis in erythrocytes from healthy volunteers. RESULTS: Exposure to azathioprine (> or =2 microg/mL) for 48 hours increased cytosolic Ca2+ activity and annexin V binding and decreased forward scatter. The effect of azathioprine on both annexin V binding and forward scatter was significantly blunted in the nominal absence of extracellular Ca2+. CONCLUSIONS: Azathioprine triggers suicidal erythrocyte death, an effect presumably contributing to azathioprine-induced anemia.

• Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing.

  Authors: Alexander Teml, Elke Schaeffeler, Klaus R Herrlinger, Ulrich Klotz, Matthias Schwab

  Clinical pharmacokinetics. 02/2007; 46(3):187-208.

  This review summarises clinical pharmacological aspects of thiopurines in the treatment of chronic inflammatory bowel disease (IBD). Current knowledge of pharmacogenetically guided dosing isThis review summarises clinical pharmacological aspects of thiopurines in the treatment of chronic inflammatory bowel disease (IBD). Current knowledge of pharmacogenetically guided dosing is discussed for individualisation of thiopurine therapy, particularly to avoid severe adverse effects. Both azathioprine and mercaptopurine are pro-drugs that undergo extensive metabolism. The catabolic enzyme thiopurine S-methyltransferase (TPMT) is polymorphically expressed, and currently 23 genetic variants have been described. On the basis of an excellent phenotype-genotype correlation for TPMT, genotyping has become a safe and reliable tool for determination of a patient's individual phenotype. Thiopurine-related adverse drug reactions are frequent, ranging from 5% up to 40%, in both a dose-dependent and -independent manner. IBD patients with low TPMT activity are at high risk of developing severe haematotoxicity if pharmacogenetically guided dosing is not performed. Based on several cost-benefit analyses, assessment of TPMT activity is recommended prior to thiopurine therapy in patients with IBD. The underlying mechanisms of azathioprine/mercaptopurine-related hepatotoxicity, pancreatitis and azathioprine intolerance are still unknown. Although the therapeutic response appears to be related to 6-thioguanine nucleotide (6-TGN) concentrations above a threshold of 230-260 pmol per 8 x 10(8) red blood cells, at present therapeutic drug monitoring of 6-TGN can be recommended only to estimate patients' compliance.Drug-drug interactions between azathioprine/mercaptopurine and aminosalicylates, diuretics, NSAIDs, warfarin and infliximab are discussed. The concomitant use of allopurinol without dosage adjustment of azathioprine/mercaptopurine leads to clinically relevant severe haematotoxicity due to elevated thiopurine levels. Several studies indicate that thiopurine therapy in IBD during pregnancy is safe. Thus, azathioprine/mercaptopurine should not be withdrawn in strictly indicated cases of pregnant IBD patients. However, breastfeeding is contraindicated during azathioprine/mercaptopurine therapy. Use of azathioprine/mercaptopurine for induction and maintenance of remission in corticosteroid-dependent or corticosteroid-refractory IBD, particularly Crohn's disease, is evidence based. To improve response rates in thiopurine therapy of IBD, comprehensive analyses including metabolic patterns and genome-wide profiling in patients with azathioprine/mercaptopurine treatment are required to identify novel candidate genes.

• A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease.

  Authors: Alexander Teml, Matthias Schwab, Daan W Hommes, Sven Almer, Milan Lukas, Thomas Feichtenschlager, Timothy Florin, Julia Seiderer, Wolfgang Petritsch, Bernd Bokemeyer, Wolfgang Kreisel, Klaus R Herrlinger, Peter Knoflach, Bruno Bonaz, Thomas Klugmann, Hans Herfarth, Nikolaus Pedarnig, Walter Reinisch

  Wiener klinische Wochenschrift. 01/2007; 119(17-18):519-26.

  OBJECTIVE: Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) andOBJECTIVE: Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) and 6-thioguanine (6-TG) therapy. The aim of the study was to evaluate the prevalence of 6-TG-related hepatotoxicity in a large multi-centered IBD population by means of a systematic online survey. METHODS: Clinical and laboratory data, imaging techniques (sonography, CT, MRI) and histology of liver biopsies were surveyed in IBD patients treated with 6-TG. The decision on whether liver imaging and/or liver biopsy were performed was exclusively at the discretion of the investigator. RESULTS: 6-TG use was fully documented in 296 patients (median treatment duration 56 weeks, range < 1-207). Laboratory signs of drug-induced liver injury were found in 43 patients (14.5%). Liver imaging revealed pathologic results in 68/176 patients (38.6%). Liver biopsy was performed in a subset of 60 patients; using silver-reticulin staining (n = 59), NRH was considered in 16 patients (27.1%). Age was the only independent, albeit weak, risk factor for development of NRH. CONCLUSION: This large online survey confirms the strong association between 6-TG treatment and the significant risk of development of NRH in patients with IBD. The definitive diagnosis of NRH depends solely upon liver biopsy.

• Extraintestinal manifestations and complications in inflammatory bowel diseases.

  Authors: Katja S Rothfuss, Eduard F Stange, Klaus R Herrlinger

  World journal of gastroenterology : WJG. 09/2006; 12(30):4819-31.

  Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) that often involve organs other than those of the gastrointestinal tract. These nonintestinal affectionsCrohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) that often involve organs other than those of the gastrointestinal tract. These nonintestinal affections are termed extraintestinal symptoms. Differentiating the true extraintestinal manifestations of inflammatory bowel diseases from secondary extraintestinal complications, caused by malnutrition, chronic inflammation or side effects of therapy, may be difficult. This review concentrates on frequency, clinical presentation and therapeutic implications of extraintestinal symptoms in inflammatory bowel diseases. If possible, extraintestinal manifestations are differentiated from extraintestinal complications. Special attention is given to the more recently described sites of involvement; i.e. thromboembolic events, osteoporosis, pulmonary involvement and affection of the central nervous system.

• Randomized, double blind controlled trial of subcutaneous recombinant human interleukin-11 versus prednisolone in active Crohn's disease.

  Authors: Klaus R Herrlinger, Thomas Witthoeft, Andreas Raedler, Bernd Bokemeyer, Thomas Krummenerl, Jorg-Dieter Schulzke, Norbert Boerner, Bruno Kueppers, Joerg Emmrich, Axel Mescheder, Ulrich Schwertschlag, Mark Shapiro, Eduard F Stange

  The American journal of gastroenterology. 04/2006; 101(4):793-7.

  BACKGROUND: Interleukin-11 has shown benefit in animal inflammatory bowel disease models. Recently, recombinant human interleukin-11 (rhIL-11) has been observed to induce remission in a subset ofBACKGROUND: Interleukin-11 has shown benefit in animal inflammatory bowel disease models. Recently, recombinant human interleukin-11 (rhIL-11) has been observed to induce remission in a subset of patients with mild to moderate Crohn's disease (CD). The present study compared the efficacy of rhIL-11 versus prednisolone in remission induction in CD. METHODS: Patients with active CD were randomly assigned to receive either subcutaneous rhIL-11 (1 mg once weekly) and prednisolone placebo tablets, or active prednisolone (60 mg/day) and rhIL-11 placebo, for 12 weeks. Prednisolone/placebo was tapered after week 1, and patients were assessed every second week. RESULTS: Fifty-one patients received medication: 13/27 (rhIL-11) and 17/24 (prednisolone) completed 12 weeks of treatment. Remission rates (intent to treat) for rhIL-11 versus prednisolone were 4% versus 46% at week 4 (p < 0.001) and 19% versus 50% at week 6 (p < 0.05). Response to treatment (deltaCDAI > 100) was seen in 19% (rhIL-11) versus 63% (prednisolone) after 4 weeks (p < 0.002) and 37% versus 63% after 6 weeks (p = 0.1). After 12 weeks of treatment, it was observed that 22% (rhIL-11) versus 21% (prednisolone) had remained in remission. Frequent side effects of rhIL-11 included fever (n = 3), rash (4), arthralgia/arthritis (3), nausea/vomiting (3), and headache (6). CONCLUSION: rhIL-11 is well tolerated but significantly inferior when compared to prednisolone in short-term remission induction in patients with active CD. In this patient cohort, both treatments appeared to be poor in maintaining remission over a period of 3 months.

• The pharmacogenetics of methotrexate in inflammatory bowel disease.

  Authors: Klaus R Herrlinger, J R Fraser Cummings, Martin C N M Barnardo, Matthias Schwab, Tariq Ahmad, Derek P Jewell

  Pharmacogenetics and genomics. 11/2005; 15(10):705-11.

  OBJECTIVES: Methotrexate (MTX) is an effective immunosuppressive treatment in inflammatory bowel disease (IBD) but its use is limited by unpredictable toxicity and efficacy. MTX metabolism is complexOBJECTIVES: Methotrexate (MTX) is an effective immunosuppressive treatment in inflammatory bowel disease (IBD) but its use is limited by unpredictable toxicity and efficacy. MTX metabolism is complex involving a number of enzymes. An individual's response to MTX may in part be genetically determined by functional genetic variation in genes encoding these enzymes. We report a pharmacogenetic evaluation of MTX therapy in IBD. METHODS: We studied 102 IBD patients treated with MTX, and 202 patients with Crohn's disease (CD), 205 patients with ulcerative colitis (UC) and 189 healthy volunteers served as controls to assess allele frequencies in the disease and healthy populations. All subjects were genotyped for four polymorphisms: G80A in the reduced folate carrier (RFC1) gene, G452T in the gamma-glutamyl hydrolase (GGH) gene and C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene. Three non-conservative SNPs in the RFC1 and the MTHFR gene could not be detected in our patient cohort. Genotype-phenotype associations were evaluated with respect to efficacy and toxicity of MTX therapy. RESULTS: No significant differences in the allele frequencies between CD, UC and healthy controls were detected. Overall 21% of patients experienced MTX side effects. Patients homozygous for the MTHFR 1298C allele were more likely to experience one or more side effects compared to patients with the wild-type 1298AA genotype (21.0 vs. 6.3%, P < 0.05). None of the genotyped SNPs or haplotypes, either alone or in combination, was associated with short-term efficacy or sustained response. CONCLUSIONS: Side effects of MTX in IBD are associated with a SNP in the MTHFR gene but response cannot be predicted by any of the investigated SNPs.

• Mechanisms of disease: defensins in gastrointestinal diseases.

  Authors: Jan Wehkamp, Klaus Fellermann, Klaus R Herrlinger, Charles L Bevins, Eduard F Stange

  Nature clinical practice. Gastroenterology & hepatology. 10/2005; 2(9):406-15.

  Defensins are endogenous antibiotics with microbicidal activity against Gram-negative and Gram-positive bacteria, fungi, viruses and protozoa. In the gastrointestinal tract, defensins help regulateDefensins are endogenous antibiotics with microbicidal activity against Gram-negative and Gram-positive bacteria, fungi, viruses and protozoa. In the gastrointestinal tract, defensins help regulate the composition and number of colonizing microbes, and protect the host from food-borne and water-borne pathogens. In health, the normal host relationship with the commensal luminal microbiota is beneficial, but the same commensal bacteria could have a pathogenic role in inflammatory diseases. A disturbance in antimicrobial defense, as provided by Paneth cells of the small intestine, seems to be a critical factor in the pathogenesis of ileal Crohn's disease, an inflammatory disease of the intestinal tract. The disruption of the critical balance between antimicrobial peptides and luminal bacteria might also explain other gastrointestinal infections and diseases. Elucidating the underlying mechanisms involved in the regulation and biology of defensins could open up new therapeutic avenues.

• Fatal staphylococcal sepsis in Crohn's disease after infliximab.

  Authors: Klaus R Herrlinger, Annette Borutta, Gabriel Meinhardt, Eduard F Stange, Klaus Fellermann

  Inflammatory bowel diseases. 10/2004; 10(5):655-6.

  We report a case of a 40-year-old woman who had received infliximab for perianal Crohn's disease. After six infusions of infliximab, the patient developed staphylococcal pneumonia resulting in fatalWe report a case of a 40-year-old woman who had received infliximab for perianal Crohn's disease. After six infusions of infliximab, the patient developed staphylococcal pneumonia resulting in fatal adult respiratory distress syndrome. The case is discussed in the context of the toxicity profile of infliximab.

• Serum procalcitonin differentiates inflammatory bowel disease and self-limited colitis.

  Authors: Klaus R Herrlinger, Rike Dittmann, Gunther Weitz, Jan Wehkamp, Diether Ludwig, Matthias Schwab, Eduard F Stange, Klaus Fellermann

  Inflammatory bowel diseases. 06/2004; 10(3):229-33.

  BACKGROUND: The distinction between idiopathic inflammatory bowel disease (IBD) and infectious, usually self-limited enterocolitis is still a diagnostic dilemma. Procalcitonin (PCT) is the prohormoneBACKGROUND: The distinction between idiopathic inflammatory bowel disease (IBD) and infectious, usually self-limited enterocolitis is still a diagnostic dilemma. Procalcitonin (PCT) is the prohormone of calcitonin and is considered a specific marker of bacterial infection. The aim of this prospective study was to determine the value of PCT in differentiating flares of IBD from self-limited colitis. In addition, because standard laboratory inflammatory parameters are poorly correlated with disease activity in IBD, the relation between PCT levels and disease activity was investigated. METHODS: A total of 76 patients (26 Crohn's disease, CD; 25 ulcerative colitis, UC; and 25 patients with self-limited enterocolitis) were enrolled. Serum levels of PCT were measured by a sandwich immunoluminometric assay. C-reactive protein (CRP) levels, white blood cell counts, and stool cultures were obtained from all patients. Disease activity was assessed by the Crohn's disease activity index (CDAI) and the Truelove index for CD and UC, respectively. RESULTS: Patients with self-limited enterocolitis showed significantly higher PCT levels when compared with IBD patients (0.36 ng/mL, range 0.18-1.7 vs 0.10 ng/mL, range 0.08 0.5, p < 0.001). For a PCT value of > or =0.4, the sensitivity for self-limited colitis was 92% and specifity 96%. The positive predictive value (PPV) for self-limited colitis was 96%, whereas the negative predictive value (NPV) was 93%. In IBD patients, PCT levels were in the normal range although significantly higher in active disease when compared with inactive disease (0.13 ng/mL, range 0.08-0.5 vs 0.09 ng/mL, range 0.08-0.15, p < 0.001). This difference was less pronounced for CD (0.11 ng/mL, range 0.08-0.2 vs 0.09 ng/mL, range 0.08-0.15, p < 0.05) than for UC (0.14 ng/mL, range 0.08-0.5 vs 0.09 ng/mL, range 0.08-0.11, p < 0.01). In CD, PCT levels correlated significantly 0.5, p < 0.01). with the CDAI (r =0.05, p <0.01). CONCLUSIONS: The measurement of PCT offers two diagnostic options in IBD. Supranormal levels indicate self-limited enterocolitis. Furthermore, although within the normal range in IBD, PCT levels may serve as a new serological marker of disease activity.

• 6-thioguanine-buried alive?

  Authors: Klaus R Herrlinger, Matthias Schwab, Klaus Fellermann, Eduard F Stange

  Gastroenterology. 04/2004; 126(3):940-1; author reply 941-2.

• Inducible and constitutive beta-defensins are differentially expressed in Crohn's disease and ulcerative colitis.

  Authors: Jan Wehkamp, Juergen Harder, Michael Weichenthal, Oliver Mueller, Klaus R Herrlinger, Klaus Fellermann, Jens M Schroeder, Eduard F Stange

  Inflammatory bowel diseases. 08/2003; 9(4):215-23.

  Antimicrobial peptides such as defensins provide nonspecific mucosal defense against a multitude of microorganisms. Recently, it has been shown that luminal bacteria may invade the mucosa inAntimicrobial peptides such as defensins provide nonspecific mucosal defense against a multitude of microorganisms. Recently, it has been shown that luminal bacteria may invade the mucosa in inflammatory bowel diseases, suggesting a defect in innate mucosal immunity. The aim of this study was to investigate the expression of human beta-defensins (HBD) in controls, Crohn's disease (CD), ulcerative colitis (UC), and unspecific inflammation. Up to 4 biopsies were taken from 103 patients (33 controls, 24 with Crohn's disease, 36 with ulcerative colitis, 10 with unspecific colitis). Mucosal mRNA was measured using real-time fluorescence temperature cycler reverse-transcription polymerase chain reaction with primers for HBD-1, HBD-2, HBD-3, tumor necrosis factor alpha, and interleukin 8. Mucosal HBD-1 expression was marginally decreased in both CD and UC. HBD-2 was increased exclusively in UC but not in CD. The expression of the novel defensin HBD-3 was strongly correlated with HBD-2 and also raised predominantly in UC. The expression of both inducible beta-defensins was enhanced in the state of inflammation. Expression of HBD-2 showed a weak correlation with interleukin 8 only in inflamed CD biopsies but not with tumor necrosis factor alpha. The missing induction of both inducible beta-defensins in CD as compared with UC may cause a defect in barrier function that predisposes to bacterial invasion.

• Crohn's disease: a defensin deficiency syndrome?

  Authors: Klaus Fellermann, Jan Wehkamp, Klaus R Herrlinger, Eduard F Stange

  European journal of gastroenterology & hepatology. 07/2003; 15(6):627-34.

  This comprehensive review promotes the novel concept that a defensin deficiency, i.e. lack of mucosal peptide antibiotics, may play a pivotal role in the aetiopathogenesis of Crohn's disease. Such anThis comprehensive review promotes the novel concept that a defensin deficiency, i.e. lack of mucosal peptide antibiotics, may play a pivotal role in the aetiopathogenesis of Crohn's disease. Such an impaired function of this chemical barrier is consistent with the epidemiological relationship of good domestic hygiene with the incidence of inflammatory bowel diseases. The disregulated adaptive immune system, formerly believed to be the major cause in the development of Crohn's disease, may reflect only the primary break of the mucosal defence since the immune response is mostly directed against lumenal bacteria. Recent work has identified five different defensins expressed in colonic mucosa. In contrast to ulcerative colitis, Crohn's disease is characterised by an impaired induction of human beta defensins 2 and 3. This deficient induction may be due to changes in the intracellular transcription by NFkappaB and the intracellular peptidoglycan receptor NOD2, mutated in Crohn's disease. These findings are consistent with the mucosal attachment of lumenal bacteria in inflammatory bowel diseases and the frequent occurrence of other infectious agents. The hypothesis of an impaired mucosal antibacterial activity is also consistent with the benefit from antibiotic or probiotic treatment in certain inflammatory bowel disease states.

• Response of refractory colitis to intravenous or oral tacrolimus (FK506).

  Authors: Klaus Fellermann, Zita Tanko, Klaus R Herrlinger, Thomas Witthoeft, Nils Homann, Andreas Bruening, Diether Ludwig, Eduard F Stange

  Inflammatory bowel diseases. 10/2002; 8(5):317-24.

  Intravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis, whereas the experience with FK506 is limited. In this report we compareIntravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis, whereas the experience with FK506 is limited. In this report we compare intravenous to oral FK506 treatment in 38 patients with refractory ulcerative (n = 33) or indeterminate (n = 5) colitis. FK506 was started intravenously in the first group (n = 18) at a dose of 0.01 to 0.02 mg/kg up to 14 days, followed by 0.1 to 0.2 mg/kg orally, or was started orally at this dose in a second group (n = 20). Additional azathioprine/6-mercaptopurine was given and steroids were tapered in responding patients, followed by a dose reduction of FK506. Clinical disease activity and laboratory parameters were assessed to evaluate efficacy and safety. Primary objectives were the induction of remission (Truelove index of mild) and colectomy-free survival. Treatment lasted for a mean of 7.6 months, and the mean observation period was 16.2 months. Eighteen of 38 patients improved within 14 days, and a complete remission was achieved in 13 patients after 1 month. A colectomy within 1 month was performed in 3 of 38 patients. The overall colectomy rate was 34%. One-half of the patients with a minimum follow-up of 2 years required a colectomy. Intravenous and per oral administration were equally safe and effective. The most frequent adverse events included tremor, hyperglycemia, hypertension, and infection, but none were severe. Renal impairment was rare and subsided upon drug withdrawal. In conclusion. FK506 is effective in the treatment of refractory colitis with per oral dosing being equivalent to intravenous administration.

• Human beta-defensin 2 but not beta-defensin 1 is expressed preferentially in colonic mucosa of inflammatory bowel disease.

  Authors: Jan Wehkamp, Klaus Fellermann, Klaus R Herrlinger, Steffi Baxmann, Klaus Schmidt, Bettina Schwind, Michael Duchrow, Charlotte Wohlschläger, Alfred C Feller, Eduard F Stange

  European journal of gastroenterology & hepatology. 08/2002; 14(7):745-52.

  OBJECTIVE : Various antimicrobial peptides such as defensins are part of innate immunity and contribute to the intestinal barrier that may be defective in inflammatory bowel disease (IBD). This studyOBJECTIVE : Various antimicrobial peptides such as defensins are part of innate immunity and contribute to the intestinal barrier that may be defective in inflammatory bowel disease (IBD). This study investigated beta-defensin mRNA and peptide expression in the colon from controls and patients with Crohn's disease, ulcerative colitis or unspecific colitis as inflammatory controls. METHODS : Mucosal mRNA expression was measured by multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) with primers for human beta-defensin 1 (HBD-1) and human beta-defensin 2 (HBD-2) in CaCo-2 cells and in biopsies from 103 patients (33 controls, 24 Crohn's disease patients, 36 ulcerative colitis patients, 10 unspecific colitis patients). Paraffin-embedded tissue from colonic resections was tested for HBD-1 and HBD-2 peptides by immunohistochemistry. RESULTS : HBD-1 mRNA was expressed constitutively whereas HBD-2 was induced by pro-inflammatory cytokines in CaCo-2 cells. HBD-1 mRNA was detectable in 61% of control and Crohn's disease biopsies and 53% of ulcerative colitis biopsies. HBD-2 transcript was expressed differentially, with 18% of control biopsies positive as opposed to 34% in Crohn's disease and 53% in ulcerative colitis. HBD-2 mRNA but not HBD-1 mRNA was expressed preferentially in inflamed areas. Immunohistochemical investigation demonstrated the presence of defensin peptides in colonic epithelium as well as the differential induction in IBD. CONCLUSIONS : HBD-1 is expressed constitutively in colonic tissue irrespective of inflammation. HBD-2 is barely present in uninflamed colon but it is induced in inflammation. The lower expression of HBD-2 in Crohn's disease compared with ulcerative colitis indicates different responses of the mucosal innate defence. Defensins may play a crucial role in controlling pathogen invasion in IBD, although the functional significance remains to be established.