Crohn Disease: Stallmach A

Hoffmann JC, Preiss JC, Autschbach F, Buhr HJ, Häuser W, Herrlinger K, Höhne W, Koletzko S, Krieglstein CF, Kruis W, Matthes H, Moser G, Reinshagen M, Rogler G, Schreiber S, Schreyer AG, Sido B, Siegmund B, Stallmach A, Bokemeyer B, Stange EF, Zeitz M. · Medizinische Klinik I, St. Marienkrankenhaus, Ludwigshafen. · Z Gastroenterol. · Pubmed #18810679 No free full text.

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Hoffmann JC, Autschbach F, Bokemeyer B, Buhr HJ, Herrlinger K, Höhne W, Krieglstein C, Kruis W, Moser G, Preiss JC, Reinshagen M, Rogler G, Schreiber S, Schreyer AG, Siegmund B, Stallmach A, Stange EF, Zeitz M. · Medizinische Klinik I, St. Marienkrankenhaus Ludwigshafen. · Dtsch Med Wochenschr. · Pubmed #18788069 No free full text.

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Schmidt C, Stallmach A. · Department of Internal Medicine II, Saarland University, Homburg, Germany. · Minerva Gastroenterol Dietol. · Pubmed #15990703 No free full text.

Abstract: Despite of scientific efforts during the last decades, etiology and pathogenesis of the two major inflammatory bowel diseases, namely Crohn's disease and ulcerative colitis, remain rather unclear. According to the results of multiple studies it is accepted that the development of either disease is the result of an exaggerated or insufficiently suppressed immune response to a hitherto undefined luminal antigen, probably derived from the microbial flora. This inflammatory process leads to the well-known mucosal damage and therefore a further disturbance of the epithelial barrier function, resulting in an increased influx of bacteria into the intestinal wall, even further accelerating the inflammatory process. However, these immunological disturbances that have been investigated extensively during the past years have to be considered on the genetic background of the individual patient and the environmental factors the patient is exposed to. In this review we will attempt to summarize the current knowledge about risk factors for inflammatory bowel diseases, genetic and environmental factors of IBD and focus on the immunological alterations of innate and acquired immune system underlying Crohn's disease and ulcerative colitis.

Wittig BM, Stallmach A, Zeitz M, Günthert U. · Medical Clinic I, Benjamin Franklin University Hospital, Free University of Berlin, Berlin, Germany. · Pathobiology. · Pubmed #12571424 No free full text.

Abstract: A major problem in inflammatory bowel disease (IBD) is the accumulation of highly activated T-helper cells that are refractory to apoptosis induction. Hence, persistent inflammatory lesions are prevalent and are the basis of chronic disease. In IBD upregulation of costimulatory molecules on lamina propria lymphocytes has been described leading to apoptosis resistance. CD44 is a cell adhesion molecule and a signalling receptor that functions as a costimulatory molecule in T-cell activation. Several variant isoforms of CD44 (CD44v) are expressed by alternative splicing of variant exons encoding extracellular regions. Particularly isoforms containing CD44v7 are expressed on T cells and macrophages in T-helper-1 (Th1)-mediated chronic inflammation and autoimmune diseases. In this review recent data on the functional involvement of CD44v7 isoforms in IBD are discussed. In a mouse model of experimental colitis blockade or deletion of CD44v7 protects mice from severe intestinal inflammation by inducing apoptosis in lamina propria mononuclear cells. Recently, we observed that in lamina propria mononuclear cells from the inflamed but not uninflamed mucosa of patients with Crohn's disease, blockade of CD44v7 isoforms also induces apoptosis. The finding that obstruction of CD44v7 isoforms can antagonize Th1-cytokine-dependent immune pathology identifies CD44v7 as a target in the treatment of inflammatory diseases such as IBD, rheumatoid arthritis, multiple sclerosis and other autoimmune diseases in which CD44v7 isoforms are upregulated.

Schmidt C, Marth T, Wittig BM, Hombach A, Abken H, Stallmach A. · Abteilung für Innere Medizin II, Universität des Saarlandes, Homburg/Saar, Deutschland. · Pathobiology. · Pubmed #12571423 No free full text.

Abstract: Inflammatory bowel diseases (IBDs; Crohn's disease (CD) and ulcerative colitis) are chronic inflammatory diseases leading to destruction of gastrointestinal tissue. They are characterized by an exaggerated immune response. In CD, an increased expression of T-helper-1 (Th1) cytokines was observed in which interleukin-12 (IL-12) seems to play a pivotal role. Different immunosuppressive agents have been used to treat patients suffering from IBD, nevertheless remarkable side effects or treatment failure are limiting factors in this regard. Therefore, studies on more specific treatment of CD have recently been published, using recombinant anti-inflammatory cytokines or inhibitors of proinflammatory cytokines and their receptors. Beyond these principles anti-IL-12 strategies seem to play a promising role because of the central position of this Th1-inducing cytokine in the inflammatory cascade. Up to now anti-IL-12 antibodies, complement receptor-3 antibodies and IL-12p40 homodimers have been evaluated in their potential to suppress the mucosal inflammation. Based on our understanding of the pathogenesis of CD, the available data and experiences concerning these principles are presented in this review.

Wittig BM, Duchmann R, Stallmach A, Zeitz M. · Innere Medizin II, Universitätskliniken des Saarlandes, 66421 Homburg/Saar. · Internist (Berl). · Pubmed #11271620 No free full text.

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von Ahsen N, Armstrong VW, Behrens C, von Tirpitz C, Stallmach A, Herfarth H, Stein J, Bias P, Adler G, Shipkova M, Oellerich M, Kruis W, Reinshagen M, Schütz E. · Department of Clinical Chemistry, University of Göttingen, Göttingen, Germany. · Clin Chem. · Pubmed #16214825 links to  free full text

Abstract: BACKGROUND: Azathioprine (aza) therapy is beneficial in the treatment of inflammatory bowel disease, but 10%-30% of patients cannot tolerate aza therapy because of adverse drug reactions. Thiopurine S-methyltransferase (TPMT) deficiency predisposes to myelotoxicity, but its association with other side effects is less clear. Inosine triphosphatase (ITPA) mutations are other pharmacogenetic polymorphisms possibly involved in thiopurine metabolism and tolerance. METHODS: We analyzed data from a 6-month prospective study including 71 patients with Crohn disease undergoing first-time aza treatment with respect to aza intolerance. Patients were genotyped for common TPMT and ITPA mutations and had pretherapy TPMT activity measured. RESULTS: Early drop-out (within 2 weeks) from aza therapy was associated with ITPA 94C > A [P = 0.020; odds ratio (OR), 4.6; 95% confidence interval (95% CI), 1.2-17.4] and low TPMT activity [<10 nmol/(mL erythrocytes . h); P = 0.007; OR = 5.5; 95% CI, 1.6-19.2]. A high-risk group defined by ITPA 94C > A or TPMT <10 nmol/(mL erythrocytes . h) showed significant association with early drop-out (P = 0.001; OR = 11.3; 95% CI, 2.5-50.0) and all drop-outs (P = 0.002; OR = 4.8; 95% CI, 1.8-13.3). For only drop-outs attributable to aza-related side effects (n = 16), there was a significant association with ITPA 94C > A (P = 0.002; OR = 7.8; 95% CI, 2.1-29.1). Time-to-event analysis over the 24-week study period revealed a significant association (P = 0.031) between the time to drop-out and ITPA 94C > A mutant allele carrier status. CONCLUSIONS: Patients with ITPA 94C > A mutations or low TPMT activity constitute a pharmacogenetic high-risk group for drop-out from aza therapy. ITPA 94C>A appears to be a promising marker indicating predisposition to aza intolerance.

Ecker KW, Stallmach A, Seitz G, Gierend M, Greinwald R, Achenbach U. · Surgical and Medical Dept., University of Saarland, Homburg/Saar, Germany. · Scand J Gastroenterol. · Pubmed #12737444 No free full text.

Abstract: BACKGROUND: In addition to their anti-inflammatory effects, steroids influence electrolyte and water transport systems in the intestinal mucosa. This study analysed the effect of the topically acting glucocorticoid budesonide on ileostomy output in patients with Crohn disease. METHODS: Oral budesonide (3 mg/three times daily for 8 days; n = 20) was compared to placebo (n = 20) in a double-blind design using matched-pair randomization according to ileal resection length in patients without detectable inflammatory activity. Under controlled hospital conditions, absolute output volumes were measured and response was defined as a reduction in intestinal output of > 25% compared to pretreatment conditions. RESULTS: In the treatment group, we observed an absolute decrease in median intestinal output from 1,240 ml to 865 ml (30.2%), compared to 0.3% under placebo (from 950 ml to 947.5 ml). Response was documented in 60% (12/20 patients) in the treatment group compared to no response under placebo (P < 0.0001). While both treatment groups showed similar absolute median reductions (400 ml with ileal resection < or = 20 cm and 405 ml with ileal resection > 20 cm), the relative reduction (response rate) was lower in the subgroup of an ileal resection > 20 cm (36%) due to the greater increase in output secondary to the loss of ileum. CONCLUSIONS: These data support the assumption that the absorptive capacity of the intestinal mucosa for water may be improved by topically acting steroids and suggest that this occurs independently of their anti-inflammatory effect.

Reinshagen M, Schütz E, Armstrong VW, Behrens C, von Tirpitz C, Stallmach A, Herfarth H, Stein J, Bias P, Adler G, Shipkova M, Kruis W, Oellerich M, von Ahsen N. · Department of Medicine I, Klinikum Braunschweig, Braunschweig, Germany. · Clin Chem. · Pubmed #17495015 links to  free full text

Abstract: BACKGROUND: A prospective randomized trial in patients with Crohn disease studied whether 6-thioguanine nucleotide (6-TGN) concentration-adapted azathioprine (AZA) therapy is clinically superior to a standard dose of 2.5 mg/kg/day AZA. METHODS: After 2 weeks of standard therapy, patients (n = 71) were randomized into standard (n = 32) or adapted-dose (n = 25) groups; 14 patients dropped out before randomization. In the adapted group, the AZA dose was adjusted to maintain 6-TGN concentrations between 250 and 400 pmol/8 x 10(8) erythrocytes (Ery). Response criteria were the number of patients in remission after 16 weeks without steroids (primary) and remission after 24 weeks, frequency of side effects, and quality of life (secondary). RESULTS: After 16 weeks, 14 of 32 (43.8%) patients in the standard group vs 11 of 25 (44%) in the adapted group were in remission without steroids (intent-to-treat analysis). After 24 weeks, 43.8% vs 40% were in remission. No significant differences were found concerning quality of life, disease activity, 6-TGN concentrations, AZA dose, or dropouts due to side effects. Sixty-six patients had a wild-type thiopurine S-methyltransferase (TPMT) genotype, with TPMT activities of 8 to 20 nmol/(mL Ery x h). Five patients (dropouts after randomization) were heterozygous, with TPMT activities <8 nmol/(mL Ery x h). 6-Methyl mercaptopurine (6-MMP) concentrations >5700 pmol/8 x 10(8) Ery were not associated with hepatotoxicity. CONCLUSION: Standard and adapted dosing with the provided dosing scheme led to identical 6-TGN concentrations and remission rates. Adapted dosing had no apparent clinical benefit for patients with TPMT activity between 8 and 20 nmol/(mL Ery x h). Additionally, 6-MMP monitoring had no predictive value for hepatotoxicity.

Hoffmann U, Heilmann K, Hayford C, Stallmach A, Wahnschaffe U, Zeitz M, Günthert U, Wittig BM. · Medical Clinic 1, Department for Gastroenterology, Infectiology and Rheumatology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin D 12200, Germany. · Cell Death Differ. · Pubmed #17479111 links to  free full text

Abstract: Deletion of exon CD44v7 abrogates experimental colitis by apoptosis induction in intestinal mononuclear cells. Here we show that CD44v7 expression was upregulated upon CD40 ligation in human mononuclear cells, and examined whether ligation of CD44v7 also affects activation and apoptosis in lamina propria mononuclear cells (LPMC) from Crohn's disease (CD) patients. Thirty five patients with chronic inflammatory bowel disease (IBD), fourteen controls and four patients with diverticulitis were evaluated. CD44v7 was upregulated predominantly in the inflamed mucosa of CD patients. Furthermore, incubation with an anti-CD44v7 antibody induced apoptosis in LPMC isolated from inflamed mucosa of CD patients, but not from non-inflamed mucosa, from patients with ulcerative colitis (UC) or from normal controls. CD40 ligation and simultaneous incubation with anti-CD44v7 significantly downregulated CD80 in dendritic cells, thus inhibiting a critical second signal for naive T-cell activation. The apoptotic signal was mediated via the intrinsic mitochondrial pathway with decreased Bcl-2 and increased 7A6 (a mitochondrial membrane protein) expression. It was Fas independent and required caspases-3 and -9 activation. The process is highly specific for macrophage activation via CD40. These findings point to a novel mechanism of apoptosis induction in CD patients mediated by CD44v7 ligation.

Schmidt C, Giese T, Goebel R, Schilling M, Marth T, Ruether A, Schreiber S, Zeuzem S, Meuer SC, Stallmach A. · Department of Internal Medicine II, Saarland University, Homburg, Germany. · Int J Colorectal Dis. · Pubmed #17318554 No free full text.

Abstract: BACKGROUND AND AIMS: It has been suggested that Crohn's Disease (CD) is associated with an elevated T helper 1 response as manifested by increased production of interleukin-18 (IL-18). Local concentrations of neutralizing IL-18 binding proteins (IL-18 bp) may counteract biological functions of mature IL-18 in mucosal inflammation. Therefore, we investigated the IL-18/IL-18 bp system in a large group of patients with active inflammatory bowel disease (IBD) to identify patients that could respond theoretically to IL-18 neutralizing treatment strategies. PATIENT/METHODS: IL-18 and IL-18 bp messenger RNA (mRNA) expression in colonic mucosa from patients with active CD (n = 72), active ulcerative colitis (UC; n = 32), and non-IBD controls (infectious colitis or diverticulitis; n = 19) and normal, non-diseased controls (n = 20) were measured by reverse-transcribed real-time polymerase chain reaction. Mature IL-18 protein and IL-18 bp expression in inflamed mucosa were assessed by Western blotting. RESULTS/FINDINGS: Although IL-18 mRNA was increased in some patients with CD, the increase was not statistically significant. Densitometric evaluation of IL-18/alpha-actin ratio in patients with active CD (n = 20) and patients with UC (n = 10) demonstrated an increased ratio of IL-18 protein in CD when compared to UC (1.04 vs 0.72 [median]). On closer inspections, only 7/20 CD patients had an increased IL-18 protein expression in inflamed areas compared to noninflamed mucosa. INTERPRETATION/CONCLUSION: IL-18 expression in active CD is heterogeneous, only a minority of patients expresses elevated levels. Further treatment strategies targeting IL-18 expression in active CD should be concentrated on this subgroup of patients.

Schmidt C, Giese T, Hermann E, Zeuzem S, Meuer SC, Stallmach A. · Department of Internal Medicine II, Friedrich Schiller-University, Jena, Germany. · Inflamm Bowel Dis. · Pubmed #17206641 links to  free full text

Abstract: BACKGROUND: Concentrations of proinflammatory cytokines are increased in the intestinal mucosa of patients with active Crohn's disease (CD). In a prospective study we investigated whether cytokines can predict long-term remission (>6 months) in patients with steroid-refractory CD receiving treatment with infliximab or cyclophosphamide, followed by azathioprine or methotrexate. METHODS: Cytokine transcripts were quantified using real-time polymerase chain reaction (PCR) in mucosal biopsies from 19 patients with active, steroid-refractory CD before and 8 weeks after initiation of therapy. Patients were treated with cyclophosphamide (monthly treatment of 750 mg cyclophosphamide intravenously) or infliximab (5 mg/kg body weight) and were followed until relapse of the disease. Statistical analysis was performed to identify predictive factors to discriminate between patients with or without long-term remission. RESULTS: Seventeen out of 19 patients achieved remission of the disease, two patients were nonresponders, while six out of 17 patients exhibited an early recurrence. Pretreatment TNF-alpha, IL-18, MRP-14, and IL-8 transcripts were significantly correlated with long-term remission. While several cytokines, most importantly MMP-1, determined after 8 weeks were able to predict patients achieving long-term remission, only a decrease of TNF-alpha levels after 8 weeks was predictive. Overall, statistical analysis identified lower pretreatment TNF-alpha levels as the strongest predictor of long-term remission among baseline variables. CONCLUSIONS: Quantification of mucosal TNF-alpha transcripts prior to therapy allows identification of patients achieving long-term remission upon immunosuppression with infliximab or cyclophosphamide. Real-time PCR might have considerable potential in the analysis of disease activity and subsequent clinical management of patients with immunosuppressive therapies.

Holtmann MH, Krummenauer F, Claas C, Kremeyer K, Lorenz D, Rainer O, Vogel I, Böcker U, Böhm S, Büning C, Duchmann R, Gerken G, Herfarth H, Lügering N, Kruis W, Reinshagen M, Schmidt J, Stallmach A, Stein J, Sturm A, Galle PR, Hommes DW, D'Haens G, Rutgeerts P, Neurath MF. · First Department of Medicine, Johannes Gutenberg University, Mainz, Germany. · Dig Dis Sci. · Pubmed #16927148 No free full text.

Abstract: In Crohn's disease the optimal duration of azathioprine treatment is still controversial and for ulcerative colitis only limited data are available to support its efficacy. Charts of 1176 patients with IBD from 16 European centers were analyzed. Flare incidences and steroid dosages were assessed for the time before and during treatment and after discontinuation. Within the first 4 years, azathioprine suppressed flare incidence and steroid consumption in both diseases (P < 0.001). While in CD discontinuation after 3-4 years did not lead to reactivation, this was the case in UC. However, continuation beyond 4 years further improved clinical activity in CD and steroid requirement in both diseases (P < 0.001). Discontinuation of azathioprine may thus be considered after 3-4 years in CD patients in complete remission without steroid requirement. In all other CD patients and for UC patients in general, continuation seems beneficial. These results support a novel differential algorithm for long-term azathioprine therapy in IBD.

Dederichs F, Pinciu F, Gerhard H, Eveld K, Stallmach A. · Abteilung für Gastroenterologie, Hepatologie und Infektologie, Universitätsklinikum Jena, Germany. · Z Gastroenterol. · Pubmed #16902896 No free full text.

Abstract: A 42-year-old man with steroid-dependent Crohn's disease developed fever, vomiting and headache after the second administration of infliximab. Extensive microbiological and biochemical work-up revealed an atypical meningitis caused by Listeria monocytogenes. After antibiotic therapy of 21 days duration, the patient could be discharged from hospital totally recovered without any further complications. As previously demonstrated, TNF-alpha plays an important role in resistance to Listeria monocytogenes. Listeria infections have been reported in 26 patients receiving TNF-alpha inhibitors. An additional therapy with other immunosuppressants increases the risk for Listeria infections. Listeria meningitis is a seldom adverse event of therapy with TNF-alpha inhibitors but is associated with a high lethality. Therefore patients should be informed about the possible adverse event of a Listeria infection during anti-TNF-alpha therapy before receiving immunosuppressive treatment. Furthermore, therapy with TNF-alpha inhibitors should only be executed within a close doctor-patient relationship and in cooperation with specialised centres.

Schmidt C, Wittig BM, Moser C, Zeitz M, Stallmach A. · Department of Internal Medicine II, Saarland University Hospital Homburg, Homburg, Germany. · Aliment Pharmacol Ther. · Pubmed #16842461 No free full text.

Abstract: BACKGROUND: In patients with steroid-refractory Crohn's disease, the therapeutic goal is to achieve both rapid remission and maintenance of clinical response. AIM: To evaluate the long-term benefit in patients treated with cyclophosphamide pulse therapy and azathioprine or methotrexate, a combination shown to be effective in a recent pilot study. METHODS: Sixteen patients with acute steroid-refractory Crohn's disease participated in a prospective open-labelled uncontrolled pilot study between December 1998 and June 2003. All had a median number of 4 monthly pulses of intravenous cyclophosphamide (750 mg) and were followed until relapse of the disease. RESULTS: Thirteen of 16 patients (81%) achieved remission within 8 weeks after two pulses of cyclophosphamide in combination with azathioprine or methotrexate, with a Crohn's Disease Activity Index decrease from 294 to 111 (median). Remission sustained for 19 months (median, range: 1-45). Moreover, eight patients with pyoderma gangrenosum and erythema nodosum who responded to cyclophosphamide have maintained their remission for up to 30 months.CONCLUSIONS: In steroid refractory patients with Crohn's disease, cyclophosphamide is highly effective to induce remission. This uncontrolled study indicates that cyclophosphamide-induced remission is long-lasting under standard immunosuppressive therapy.

Ecker KW, Stallmach A, Löffler J, Greinwald R, Achenbach U. · Department of General, Visceral and Vascular Surgery, Müritz-Hospital, Weinbergstrasse 19, D-17192 Waren, Germany. · Dis Colon Rectum. · Pubmed #15714248 No free full text.

Abstract: PURPOSE: In a previous, controlled study, it was shown that orally administered budesonide increases the absorptive capacity of the intestinal mucosa in patients with ileostomies caused by Crohn's disease. This open, nonrandomized study was designed to analyze this functional, not inflammation-dependent steroid-effect in the long-term course comparing exposure, withdrawal, and reexposure. METHODS: Phase 1: 23 patients without inflammatory activity of the disease received oral budesonide (3 mg t.i.d.) for at least four weeks (36.7 weeks; standard deviation, 45.3 weeks) because of high intestinal output syndrome. Phase 2: Medication was stopped for four weeks. Phase 3: Medication as in Phase 1. In each phase the weight of the ileostomy bags was measured with a spring balance before emptying and documented in a diary. Mean values per day and per week were calculated and the differences statistically evaluated by the Wilcoxon-(Pratt)-test. RESULTS: Comparing the last week of Phase 1 to first week of Phase 2, a significant (P < 0.0001) increase of the intestinal output (295 g; standard deviation, 313 g) was observed after omitting budesonide. In contrast, comparing the last week of Phase 2 to Phase 3, a significant (P < 0.0001) decrease of the intestinal output by 323.7 g (standard deviation, 322.2 g) was noticed reaching the same level as in Phase 1. CONCLUSIONS: These data show that the functional, inflammation-independent effect of budesonide on the intestinal mucosa is strongly correlated to the administration of the drug and may be maintained long-term. These results should be confirmed by a larger number of patients.

Schmidt C, Giese T, Ludwig B, Mueller-Molaian I, Marth T, Zeuzem S, Meuer SC, Stallmach A. · Department of Internal Medicine II , Saarland University, Homburg, Germany. · Inflamm Bowel Dis. · Pubmed #15674109 No free full text.

Abstract: BACKGROUND: It has been suggested that Crohn's disease (CD) is associated with an exaggerated T-helper 1 cytokine response manifested by increased production of interleukin (IL)-12. IL-12 is a heterodimeric protein comprising 2 disulfide-linked subunits designated p35 and p40. Recently, IL-12-related cytokines, IL-23 and IL-27, were described. Biologically active IL-23 is a heterodimer whose p40 subunit is identical to IL-12p40 whereas its p19 subunit is distantly related to IL-12p35. IL-27 consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide. AIM: We sought to determine whether mucosal expression of IL-23p19 and IL-27p28 transcripts correlate with the inflammatory activity in inflammatory bowel disease (IBD). PATIENTS/METHODS: Messenger RNA expression in colonic mucosa from patients with Crohn's disease (CD; n = 37) and ulcerative colitis (UC; n = 19), and in non-IBD control subjects (specific colitis [SC]; n = 16) and normal, nondiseased control patients (n = 12) was measured by reverse-transcribed real-time polymerase chain reaction. RESULTS: IL-23p19 was significantly increased in inflamed mucosa in CD (P = 0.0377) and to a lesser extent also in UC patients but not in SC patients. Elevation of IL-23p19 transcript levels in CD correlated with the severity of endoscopic lesions. IL-27p28 transcripts and EBI3 transcripts were significantly elevated only in active CD. DISCUSSION: IL-23p19, IL-27p28, and EBI3 transcripts are strongly up-regulated in CD. The stimulatory effects of these cytokines on naive T cells in addition to a strongly synergistic action with IL-12 to trigger interferon-gamma production may contribute to the perpetuation of the inflammatory process in patients with CD. Notably, increased expression of IL-23 and IL-27 transcripts in CD suggests a T helper 1-dominated immunologic function in this disease.

Wehkamp J, Harder J, Weichenthal M, Schwab M, Schäffeler E, Schlee M, Herrlinger KR, Stallmach A, Noack F, Fritz P, Schröder JM, Bevins CL, Fellermann K, Stange EF. · Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany. · Gut. · Pubmed #15479689 links to  free full text

Abstract: BACKGROUND: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human alpha defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease. METHODS: Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied. Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor alpha, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene). Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes. RESULTS: Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations. In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients. In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status. Immunohistochemistry identified Paneth cells as the sole source of HD-5. CONCLUSION: As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.

Stallmach A, Giese T, Schmidt C, Meuer SC, Zeuzem SS. · Department of Gastroenterology, Marienhospital Altenessen, Essen, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #15167167 No free full text.

Abstract: Treatment with the anti-tumour necrosis factor alpha chimeric monoclonal antibody infliximab is highly effective in the treatment of refractory and fistulising Crohn's disease. Infliximab has been tolerated well, with minimal and short-lived adverse effects. The likelihood of severe reactions to infliximab, such as acute and delayed hypersensitivity infusion reactions, is small; nevertheless, if they do occur, they are life-threatening. We report a case of an anaphylaxis-like reaction in a 22-year-old female with long-standing Crohn's disease. The patient was treated successfully with adalimumab, a fully human anti-tumour necrosis factor alpha monoclonal antibody. Follow-up demonstrated mucosal healing and normalisation of elevated pro-inflammatory cytokine transcripts.

Häuser W, Dietz N, Grandt D, Steder-Neukamm U, Janke KH, Stein U, Stallmach A. · Medizinische Klinik I, Klinikum Saarbrücken, Saarbrücken, Germany. · Z Gastroenterol. · Pubmed #14963785 No free full text.

Abstract: BACKGROUND AND AIMS: The inflammatory bowel disease questionnaire (IBDQ) is the standard instrument for assessment of health-related quality of life (HRQOL) in patients with inflammatory bowel diseases. It has not been validated for patients with ileal pouch anal anastomosis (IPAA) and ulcerative colitis (UC). METHODS: To determine acceptance (percentage of completed items), reliability (Cronbach's alpha of the IBDQ-D subscales) and convergent validity (correlations of the IBDQ subscales with the questionnaires used for validation) 61 patients with UC (age 52.7 +/- 13.9 years; 47 % female, 53 % male) and IPAA completed the German (Competence Network IBD) version of the Inflammatory Bowel Disease Questionnaire (IBDQ-D), the Short Form Health Survey (SF-36) the Hospital Anxiety and Depression Scale German Version (HADS-D) and the Giessener Symptom List (GBB 24). Face validity was assessed by a physicians' and patients' panel. All 37 patients underwent endoscopy making it possible to differentiate between patients with and without pouchitis (discriminant validity). RESULTS: With 97.7 % completed items the acceptance was high. Cronbach's alpha value for the subscales ranged from 0.71 to 0.93. Missing items covering extraintestinal manifestations of IBD were criticized by patients. The correlation coefficients with comparable subscales of other instruments ranged between 0.41 and 0.76. Patients with clinical pouchitis scored significantly lower in all subscales than patients without pouchitis (p < 0.001). CONCLUSION: The IBDQ-D has good acceptance, reliability, convergent and discriminant validity, but limited face and construct validity in patients with IPAA and UC.

Stallmach A, Marth T, Weiss B, Wittig BM, Hombach A, Schmidt C, Neurath M, Zeitz M, Zeuzem S, Abken H. · Department of Internal Medicine II, Saarland University, Homburg, Germany. · Gut. · Pubmed #14960512 links to  free full text

Abstract: BACKGROUND AND AIMS: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role in the immune response in Crohn's disease (CD). Since IL-12 p40 dimers act as IL-12 antagonists, we assayed p40 dimer proteins to modulate chronic intestinal inflammation. METHODS: We generated a fusion protein consisting of the IL-12(p40) subunit fused to the constant region of IgG2b. IL-12(p40)-IgG2b was tested in a murine 2,4,6,-trinitrobenzene sulphonic acid (TNBS) colitis model and in lamina propria mononuclear cells (LPMNC) from patients with CD in vitro. RESULTS: Dimeric IL-12(p40)-IgG2b fusion protein bound specifically to the IL-12 receptor. In concentrations <10(-7) M, it acted as an IL-12 antagonist as it inhibited interferon gamma (IFN-gamma) secretion, suppressed proliferation, and increased apoptosis of LPMNC from patients with CD. However, in concentrations >10(-6) M, IL-12(p40)-IgG2b increased IFN-gamma secretion and lymphocyte proliferation thereby acting as an IL-12 agonist. In TNBS colitic mice, IL-12(p40)-IgG2b decreased mortality (10% v 68%), prevented body weight loss, reduced tumour necrosis factor alpha, and increased IL-10 secretion. CONCLUSIONS: The IL-12(p40)-IgG2b fusion protein has dichotomic properties as a specific IL-12 antagonist and selective repressor of mucosal inflammation at low concentration and as an IL-12 agonist at high concentration.

Stallmach A, Giese T, Schmidt C, Ludwig B, Mueller-Molaian I, Meuer SC. · Department of Gastroenterology, Hepatology and Nutritional Medicine, Catholic Clinics Essen-Nord, 45329 Essen, Germany. · Int J Colorectal Dis. · Pubmed #14605835 No free full text.

Abstract: BACKGROUND AND AIMS: Immunoregulatory properties of cytokines may contribute to pathological immune reactions in inflammatory bowel disease. There is an urgent need for a simple and dependable means for quantitating inflammatory activity in mucosal biopsies and assessing relapse risk particularly in patients with active Crohn's disease (CD). PATIENTS AND METHODS: Cytokine and chemokine transcripts were quantified using real-time PCR in mucosal biopsy specimens from 70 patients with active inflammatory bowel disease (CD, n=45; ulcerative colitis n=25) and 16 patients with specific colitis (ischemic colitis, infectious colitis). Controls were 12 patients with noninflammatory conditions. CD patients with steroid-induced remission (n=20) were followed for up to 12 months. RESULTS: Compared to not-inflamed mucosa the vast majority of active CD tissue samples expressed significantly elevated transcript levels of IL-1beta, IL-8, IL-23, MRP-14, MIP2alpha, and MMP-1. Moreover, increased cytokine transcript levels were detected in both active ulcerative colitis and specific colitis. Importantly, TNF-alpha, IFN-gamma, CD40L, and IL-23 transcripts increased in active CD only. Transcript levels (MRP-14, IL-8, MMP-1, MIP2alpha) were correlated with clinical disease activity (CDAI) and endoscopic scoring indices. Medical treatment induced stable remission in 14 of 20 patients which was paralleled by a reduction in increased transcript levels. All six patients without normalization of MIP2alpha, MRP-14, TNF-alpha, and IL-1beta transcripts developed an early relapse (n=5) or chronic activity (n=1) during follow-up. CONCLUSION: Elevated proinflammatory cytokine transcripts in active CD may underlie disease reactivation and chronicity. Real-time PCR quantification is a simple and objective method for grading inflammation of intestinal mucosa and may be useful in identifying patients who would benefit from anti-inflammatory remission maintenance.

Stallmach A, Wittig BM, Moser C, Fischinger J, Duchmann R, Zeitz M. · Department of Internal Medicine II, Saarland University, Homburg, Germany. · Gut. · Pubmed #12584219 links to  free full text

Abstract: BACKGROUND AND AIMS: One major problem in the management of steroid refractory attacks of patients with inflammatory bowel disease (IBD) is the establishment of a rapidly acting immunosuppressive regimen. Based on its well known efficacy in systemic vasculitis, intravenous cyclophosphamide pulse therapy was used in refractory IBD patients to evaluate both its efficacy and safety. METHODS: Between December 1998 and May 2001, seven patients (Crohn's disease, n=5; indeterminate colitis, n=1) with severe steroid refractory IBD (Crohn's disease activity index (CDAI) 264-479 points) received 4-6 cycles of monthly treatment with intravenous cyclophosphamide (750 mg) in a prospective uncontrolled pilot study. RESULTS: All patients improved after two intravenous pulses of cyclophosphamide and six of seven patients achieved complete remission (CDAI <150 points). One patient with Crohn's disease of the small and large bowel showed an impressive clinical response but did not enter into remission. Tapering to low dose steroids was possible in all responders. Remission was maintained in all patients for 18 months (median) but required a second course of intravenous pulse cyclophosphamide in one patient. The drug was well tolerated except for two episodes of candida oesophagitis. CONCLUSIONS: Intravenous pulse cyclophosphamide may be a safe and effective treatment in patients with severe IBD unresponsive to steroid treatment and merits evaluation in a controlled trial.

Stallmach A, Marth T, Adrian N, Wittig BM, Ecker KW, Schilling M, Zeitz M. · Department of Internal Medicine II, Saarland University, 66421 Homburg, Germany. · Int J Colorectal Dis. · Pubmed #12172923 No free full text.

Abstract: BACKGROUND AND AIMS: Since interleukin-12 is pathogenetically involved in Crohn's disease (CD) but not in ulcerative colitis (UC), expression and mechanisms of induction of interleukin-12 receptor (IL-12R) subunits beta(1) and beta(2) were analyzed in lamina propria mononuclear cells (LPMNC) of patients with CD and UC. PATIENTS AND METHODS: LPMNC from patients with CD ( n=17), UC ( n=14), and controls ( n=19) were isolated by standard techniques. IL-12R beta(1) and IL-12R beta(2) transcripts were semiquantified by RT-PCR, and expression of IL-12R beta(2) chain was characterized by flow cytometry. LPMNC were activated by cross-linking with anti-CD3 antibodies and B7-1 costimulation. RESULTS: IL-12R beta(1) and IL-12R beta(2) transcript concentrations were higher in inflamed specimens than in noninflamed segments of patients with CD but not in UC. Increased percentage of mucosal CD4(+)/IL-12R beta(2)(+) cells was observed in active CD, but not UC. In vitro stimulation of LPMNC with anti-CD3 antibodies resulted in an increase in IL-12R beta(1) transcripts irrespective of B7-1 mediated costimulation (84% and 95%, respectively). However, increased expression of IL-12R beta(2) mRNA (110%) was detected only after B7-1 costimulation. CONCLUSION: Our data indicate that increased mucosal expression of IL-12R beta(2) on LPMNC in CD but not in UC may be the result of B7-1 costimulation. Modulation or inhibition of IL-12R beta(2) expression on LPMNC could provide a selective therapeutic approach in CD.

Stallmach A, Schmidt C, Marth T. · Innere Medizin II, Universitätskliniken des Saarlandes, Germany. · Z Gastroenterol. · Pubmed #12055668 No free full text.

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