Ulcerative Colitis: Stallmach A

Stallmach A, Schmidt C. · Abteilung für Gastroenterologie, Hepatologie und Infektiologie, Friedrich-Schiller-Universität, Erlanger Allee 101, 07740 Jena, Germany. · Internist (Berl). · Pubmed #17393129 No free full text.

Abstract: Restorative proctocolectomy with an ileal pouch-anal anastomosis is the treatment of choice in patients with ulcerative colitis (UC) and familial adenomatous polyposis requiring surgical therapy. Pouchitis is the most frequent complication, occurring in up to 50% of patients with underlying UC. Clinical symptoms of the disease are non-specific. Moreover, surgical complications must be differentiated from idiopathic pouchitis using pouchoscopy, endoscopic ultrasound or MRI of the pelvis in certain cases. The therapy for idiopathic pouchitis, its etiology and pathophysiology being unclear, is based on antibiotic treatment, usually with metronidazole or ciprofloxacin. Probiotics such as VSL#3 can be used to prevent relapse. In summary, the clinical and functional outcomes are excellent and stable for 20 years after surgery.

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.

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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Plotz G, Raedle J, Spina A, Welsch C, Stallmach A, Zeuzem S, Schmidt C. · Medizinische Klinik I, Johann Wolfgang Goethe-Universität, Frankfurt, Germany. · Inflamm Bowel Dis. · Pubmed #18200512 links to  free full text

Abstract: BACKGROUND: Inflammatory bowel diseases (IBDs; ulcerative colitis, UC, and Crohn's disease, CD) show familial clustering suggestive of a genetic background. A linkage susceptibility region for these diseases (IBD9) lies on chromosome 3p and includes the DNA mismatch repair gene MLH1. Loss of MLH1 confers the characteristic microsatellite instability (MSI) phenotype which is also frequently found in the mucosa of IBD patients. A common germline alteration of MLH1 (655A>G) results in the amino acid exchange MLH1 I219V. Conflicting data exist on its effect on the function of the protein and it has recently been reported to cosegregate with refractory UC, suggesting that this alteration may impair mismatch repair activity and thereby contribute to certain forms of UC. METHODS: We analyzed the MLH1 I219V alteration using in silico and biochemical analyses and assessed its appearance in 67 well-classified UC patients in comparison to 40 healthy individuals. RESULTS: The analyses showed that I219 is a conserved, buried hydrophobic residue, and that I219V is unlikely to abolish MLH1 function but may modulate it. Quantitative biochemical evaluation showed identical stability and activity of the protein. Furthermore, the alteration occurred equally frequently in analyzed patients and healthy volunteers. CONCLUSIONS: The MLH1 I219V alteration does not directly contribute to the etiology of UC through an impairment of mismatch repair. A putative linkage disequilibrium of MLH1 I219V with the causative gene(s) of the IBD9 locus is rather distant.

Schmidt C, Häuser W, Giese T, Stallmach A. · Department of Gastroenterology, Hepatology and Infectology, Friedrich Schiller University Jena, Germany. · Inflamm Bowel Dis. · Pubmed #17712839 links to  free full text

Abstract: BACKGROUND: Pouchitis and irritable pouch syndrome (IPS) are 2 of the most frequent sequelae of ileal pouch-anal anastomosis (IPAA) after restorative proctocolectomy in patients with ulcerative colitis. These complications can compromise the gain in health-related quality of life (HRQOL) substantially. The pathophysiological mechanisms underlying IPS and the predictors of HRQOL in IPS have not been studied so far. METHODS: In IPAA patients in remission (n = 10), patients with pouchitis (n = 18) and patients with IPS (n = 15) symptoms, endoscopical and histological patterns, anxiety and depressiveness (Hospital Anxiety and Depression Scale HADS), and HRQOL scores (Inflammatory Bowel Disease Questionnaire, IBDQ-D) were assessed. Mucosal expression of 5 proinflammatory gene transcripts (MRP-14, IL-1beta, IL-8, MIP-2alpha, and MMP-1) were quantified using real-time polymerase chain reaction. RESULTS: Clinical symptoms and HRQOL differed significantly (P < 0.01) between patients in remission on the one hand and those with pouchitis or IPS on the other. However, between IPS and pouchitis no such differences could be found. Depressiveness scores differed between IPS and patients in remission (P = 0.05). HRQOL in IPS was predicted by depressiveness (P < 0.001). Cytokine transcripts discriminated between pouchitis and IPS (P < 0.01), whereas between IPS patients and asymptomatic patients no such differences were observed. CONCLUSIONS: Patients with IPS and pouchitis cannot be differentiated by clinical symptoms or HRQOL, which is associated with depressiveness in IPS patients. IPS is a noninflammatory sequela in IPAA patients that shares clinical features with IBD. Quantification of mucosal proinflammatory gene transcripts differentiates objectively and simply between IPS and pouchitis.

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.

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.

Heuschen G, Leowardi C, Hinz U, Autschbach F, Stallmach A, Herfarth C, Heuschen UA. · Department of Surgery, St-Vincenz-Krankenhaus, Limburg, Germany. · Int J Colorectal Dis. · Pubmed #16770571 No free full text.

Abstract: BACKGROUND AND AIMS: The pathogenesis of pouchitis, major complication after restorative proctocolectomy, and ileal J pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC) is still unclear. Changes in intraluminal bacterial colonization and correlated changes of pouch mucosa are thought to play an important role. Toll-like receptors (TLRs) as part of the innate immune system are capable of recognizing bacterial antigens. Their activation can lead to secretion of proinflammatory mediators. In this study, TLR2, 3, 4, and 5 expression profiles in the pouch mucosa of patients with UC and IPAA were analyzed and correlated with pouchitis. MATERIALS AND METHODS: Clinical symptoms, endoscopy, and histology were assessed in 35 patients using the Heidelberg Pouchitis Activity Score to classify patients as either having pouchitis or not. TLR mRNA expression in normal ileal mucosa and pouch mucosa was investigated by performing semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). The results of RT-PCR were associated with the pouchitis score. RESULTS: In the analysis of all patients, TLR3 expression was decreased significantly whereas TLR5 expression was increased significantly in pouch mucosa compared to normal ileal mucosa (p-values 0.0076 and 0.016, respectively). A more detailed analysis upon dividing the patients into patients with and without pouchitis showed decreased TLR3 expression in the pouch mucosa only of patients without pouchitis (p-value=0.0067). TLR5 expression was increased in the pouch mucosa only of patients with pouchitis (p-value=0.023). No differences in TLR2 and 4 expression were found in either group. CONCLUSION: Differential expression of TLR3 and 5 suggests bacterial involvement in the pathogenesis of pouchitis in patients with UC.

Schmidt C, Giese T, Ludwig B, Menges M, Schilling M, Meuer SC, Zeuzem S, Stallmach A. · Department of Internal Medicine II, Saarland University Hospital, Homburg/Saar, Germany. · Int J Colorectal Dis. · Pubmed #16133004 No free full text.

Abstract: BACKGROUND AND AIMS: After ileopouch anal anastomosis (IPAA), 10-40% of patients with ulcerative colitis (UC) but only 5% of patients with familial adenomatous polyposis (FAP) develop pouchitis. Immunoregulatory abnormalities might be of importance in the pathogenesis of the disease. Therefore, we characterized cytokine and chemokine transcripts in inflamed and non-inflamed pouches in patients with UC compared to those with FAP and Crohn's disease (CD). PATIENTS AND METHODS: Mucosal biopsies were taken from 87 patients with IPAA [UC (n=70), CD (n=8) or FAP (n=9)]. Patients with active ileal CD (n=14), active UC (n=17) and non-inflammatory conditions (n=12) served as controls. The expression of 20 gene transcripts was quantified using real-time polymerase chain reaction. RESULTS AND FINDINGS: Pro-inflammatory cytokines and chemokines are significantly increased in IPAA patients with acute pouchitis. This increase is independent of the underlying disease (UC or CD) and reflects the degree of inflammation. A good correlation between pouchitis activity (using the Pouchitis Disease Activity Index) and the MRP-14, interleukin-8, macrophage inflammatory protein-2alpha and matrix metalloproteinase-1 transcripts was observed. INTERPRETATIONS AND CONCLUSIONS: Our data support the view that pouchitis reflects an inflammatory process that is different from that of underlying inflammatory bowel diseases, as the cytokine and chemokine patterns in pouchitis are neither typical of CD nor of UC, but maybe due to bacterial intestinal microflora overgrowth in the pouch lumen. Quantification of transcript levels allows an estimation of the extent of mucosal inflammation and may become helpful in the evaluation of the disease, especially in clinical trials.

Häuser W, Janke KH, Stallmach A. · Department of Internal Medicine I, Klinikum Saarbrücken, D-66119 Saarbrücken, Germany. · Dis Colon Rectum. · Pubmed #15785887 No free full text.

Abstract: PURPOSE: The aim of this study was to determine if ileal pouch-anal anastomosis in patients with ulcerative colitis is a psychologic burden for patients, the frequency of mental disorders, the amount of psychologic distress, and their possible disease-related determinants. These factors were studied in patients with ulcerative colitis after ileal pouch anal anastomosis and were compared with ulcerative colitis patients without ileal pouch-anal anastomosis and the general German population. METHODS: A total of 37 patients with ulcerative colitis after ileal pouch-anal anastomosis (age 46.8 +/- 11.8 years; 35 percent female) and 62 patients with ulcerative colitis without ileal pouch-anal anastomosis (age 44.4 +/- 13.9 years; 37 percent female) completed the following questionnaires: medical and sociodemographic questionnaire of the German Competence Network "Inflammatory Bowel Diseases" and the German version of the Hospital Anxiety and Depression Scale. Disease activity was measured in patients with ileal pouch-anal anastomosis by the Pouch Disease Activity Index and in patients without ileal pouch-anal anastomosis by the German Inflammatory Bowel Disease Activity Index. Psychologic distress was assessed by the subscale scores of the Hospital Anxiety and Depression Scale. A probable mental disorder was identified if a patient scored 11 or higher in at least one subscale of the Hospital Anxiety and Depression Scale. RESULTS: The frequency of a probable psychiatric disorder in patients with ileal pouch-anal anastomosis (16 percent) and without ileal pouch-anal anastomosis (23 percent) did not differ from that in the general German population (17 percent). Ulcerative colitis patients with or without ileal pouch-anal anastomosis did not differ in the amount of psychologic distress. Ileal pouch-anal anastomosis patients had higher levels of anxiety than the general population (P < 0.01). Regression models of disease-related factors predicting mental disorder and psychologic distress showed no significant results. CONCLUSIONS: Ileal pouch-anal anastomosis neither increases nor decreases the frequency of mental disorders or the amount of psychologic distress in ulcerative colitis patients.

Jüngling B, Kindermann I, Moser C, Püschel W, Ecker KW, Schäfers HJ, Böhm M, Zeuzem S, Giese T, Stallmach A. · Department of Internal Medicine II, Saarland University, Germany. · Z Gastroenterol. · Pubmed #15700214 No free full text.

Abstract: BACKGROUND: Cardiac transplantation has become an accepted treatment modality for end-stage heart failure. Immunosuppressive agents, which are used after transplantation, are considered as therapeutic options for inflammatory bowel disease. CASE REPORT: We report on a 53-year-old patient who was treated for 2 years with cyclosporine A, azathioprine and prednisolone after heart transplantation. He developed a distal colitis with all features of ulcerative colitis. An infectious or ischemic etiology was carefully excluded. In spite of high-dose treatment with prednisolone the patient's abdominal symptoms worsened and he developed a progression of the inflammation in the entire colon and a colectomy with ileostomy was necessary. The histology was consistent with ulcerative colitis. After colectomy he recovered and remained in a good state of health. CONCLUSIONS: This report supports the concept that new onset inflammatory bowel disease can develop in a heart transplantation recipient in spite of immunosuppression.

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.

Häuser W, Dietz N, Steder-Neukamm U, Janke KH, Stallmach A. · Department of Internal Medicine I, Klinikum Saarbrücken, D-66119 Saarbrücken, Germany. · Inflamm Bowel Dis. · Pubmed #15475748 No free full text.

Abstract: BACKGROUND: In patients with ileal pouch anal anastomosis (IPAA) the influences of psychosocial variables and of extraintestinal manifestations of ulcerative colitis (UC) on health-related quality of life (HRQOL) have not been studied so far. METHODS: 61 patients with UC (age 52.7+/-13.9 years; 47% female) completed the German version of the Inflammatory Bowel Disease Questionnaire (IBDQ-D), the Short Form Health Survey (SF - 36), the German version of the Hospital Anxiety and Depression Scale (HADS-D) and the Giessener Symptom List (GBB 24). Independent of their current clinical activity 37 patients underwent endoscopies. Pouchitis was defined by the Pouch Disease Activity Score (PDAI) > or = 7. Where possible, IPAA-patients were compared with the data for the German general population and with a clinical sample of patients with UC and no IPAA. RESULTS: Patients with IPAA complained more about fatigue and arthralgia and a reduced physical and mental health (SF-36) than the German general population (P < 0.01). The IBDQ-total score could be predicted (adjusted R2 = 29.1, P < 0.01) by the number of operations due to IPAA-related complications (beta = -18.8) and HADS-D-Anxiety scores > or = 11 (beta = -29.1). The IBDQ-subscale score "Bowel" could be predicted (adjusted R2 = 13.7, P = 0.04) by PDAI > or = 7 (beta = -9.2) and the subscale score "Systemic" (adjusted R2 = 13.3, P = 0.04) by the number of extraintestinal manifestations (beta = -1.9). CONCLUSIONS: HRQOL of patients with UC and IPAA is determined not only by IPAA-related factors but also by anxiety and extraintestinal manifestations with associated musculoskeletal pain.

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, 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, 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.

Pfister K, Wittig BM, Jüngling B, Ecker KW, Barth S, Huhn M, Sasse S, Engert A, Mueller-Molaian I, Diehl V, Zeitz M, Stallmach A. · Department of Internal Medicine II, Saarland University, Homburg/Saar, Germany. · Int J Colorectal Dis. · Pubmed #12014425 No free full text.

Abstract: BACKGROUND AND AIMS: In chronic inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis an aberrant mucosal immune regulation is observed accompanied by upregulation of proinflammatory cytokines. Lamina propria T cells of inflamed mucosa have an activated phenotype characterized by increased expression of surface markers such as CD25. We therefore determined the anti-inflammatory effect of a recombinant immunotoxin consisting of an anti-CD25 single chain variable fragment (scFv) fused to a deletion mutant of Pseudomonas exotoxin A [RFT5(scFv)ETA'] on isolated lamina propria lymphocytes of patients with IBD and in the murine model of trinitrobenzene sulfonic acid (TNBS) induced colitis. PATIENTS AND/METHODS: Lamina propria lymphocytes of 25 patients with IBD and 19 control patients were stimulated in absence or presence of RFT5(scFv)ETA'. Interferon-gamma production was determined in the supernatant by ELISA and the induction of apoptosis by flow cytometry after propidium iodide staining. BALB/c mice received TNBS intrarectally and were treated with RFT5(scFv)ETA'. RESULTS: In vitro the administration of RFT5(scFv)ETA' significantly reduced interferon-gamma production and increased apoptosis in lamina propria lymphocytes isolated of inflamed mucosa. However, this contrainflammatory regulation did not result in gain of weight or increased life span in experimental colitis in vivo. CONCLUSION: In addition to the downregulation of the proinflammatory cytokine in vitro, RFT5(scFv)ETA' induced neither a direct nor a bystander effect in an in vivo model of colitis. Therefore our data do not support potential therapeutic implications of targeting CD25 by RFT5(scFv)ETA' in chronic IBD.

Pfister K, Wittig BM, Mueller-Molaian I, Remberger K, Zeitz M, Stallmach A. · Department of Internal Medicine II, Saarland University, Homburg, Germany. · Exp Mol Pathol. · Pubmed #11733944 No free full text.

Abstract: Splice variants of the glycoprotein CD44 are transiently expressed on lymphocytes during T cell activation. Increased expression of CD44v6 on peripheral blood lymphocytes (PBL) of patients with inflammatory bowel disease (IBD) was described recently. The aim of this study was therefore to characterize CD44v6 expression on CD4(+) lamina propria lymphocytes (LPL) of patients with active IBD in comparison to controls. CD44v6 expression on CD4(+) LPL (n = 19) of controls and patients with active IBD (Crohn's disease n = 14, ulcerative colitis n = 15) was analyzed by flow cytometry and compared to that on autologous PBL. Thereby, in vitro regulation of CD44v6 on LPL and PBL via CD3 and CD2 and the costimulatory signal B7-1 was examined. In addition, the role of protein kinase C (PKC) in CD44v6 expression was tested. CD44v6 expression was increased in CD4(+) LPL (median, 45%) compared to PBL (median, 38%). Surprisingly, in IBD CD44v6 was downregulated on CD4(+) lamina propria T cells, irrespective of their state of inflammation (median, 28%). CD44v6 expression on LPL was not upregulated upon CD3 activation alone but following costimulation with B7-1. However, CD2-mediated T cell activation sufficiently induced upregulation of CD44v6 on LPL and PBL. In our study, downregulation of CD44v6 on LPL of patients with IBD was not due to defective PKC activation. Taken together, these data indicate that decreased CD44v6 expression on LPL in IBD might be a feature of an inappropriate costimulatory signal in T cell activation.

Stallmach A, Chan CC, Ecker KW, Feifel G, Herbst H, Schuppan D, Zeitz M. · Department of Internal Medicine II, Saarland University, Saar, Germany. · Gut. · Pubmed #10940281 links to  free full text

Abstract: BACKGROUND AND AIMS: Matrix metalloproteinases (MMPs) are implicated in the tissue destruction associated with inflammatory diseases. Proctocolectomy with ileo-anal pouch (IAP) anastomosis is associated with pouchitis, particularly in patients with ulcerative colitis (UC). The aim of this study was to quantify MMP-1 and MMP-2 in inflamed and uninflamed pouches of patients with UC compared with those with active UC. IAP patients with familial adenomatous polyposis (FAP) served as controls. METHODS: Biopsies were taken from 33 patients with IAP (UC, n=25; FAP, n=8) and from 10 UC patients. MMP-1 and MMP-2 were quantified using sandwich enzyme linked immunosorbent assays. In addition, northern and western blotting and in situ hybridisation experiments were performed. RESULTS: In pouchitis (n=11), MMP-1 and MMP-2 concentrations were increased compared with uninflamed pouches of patients with UC (n=14) or FAP (n=8) (MMP-1 17.7 ng/mg protein v 7.8 (UC) v 7.6 (FAP), p</=0.05; MMP-2 16.4 v 9.5 (UC) v 6.3 (FAP), p</=0.05). Western and northern blots revealed increased MMP-1 and MMP-2 protein and transcript concentrations in inflamed pouches. Mesenchymal cells were identified as major producers of MMP-1 and MMP-2 in pouchitis. A similar increase in MMPs was observed in tissues of patients with active UC. CONCLUSIONS: Our results support the hypothesis that MMPs are involved in mucosal destruction and crypt hyperplasia, as seen in pouchitis.

Stallmach A, Moser C, Hero-Gross R, Müller-Molaian I, Ecker KW, Feifel G, Zeitz M. · Department of Internal Medicine II, Saarland University, Homburg, Germany. · Dis Colon Rectum. · Pubmed #10528770 No free full text.

Abstract: PURPOSE: Variant pathological changes have been observed in ileoanal pouches, including inflammation, villous atrophy, and crypt hyperplasia. Therefore, we investigated the type and degree of mucosal adaptation in patients with ulcerative colitis and familial adenomatous polyposis. METHODS: Forty-two patients with ulcerative colitis and 14 patients with familial adenomatous polyposis with ileoanal pouches were assessed. Samples were taken from three months to eight years after creation of an ileoanal pouch. Mucosal architecture was examined by morphometry after microdissection. RESULTS: Structural changes of the mucosa can be categorized into three groups. Compared with preoperative values, patients without pouchitis (73 percent) has only minor decrease of villous length (402 microm vs. 540 microm) and increase in crypt depth (274.5 microm vs. 177 microm). In patients with acute pouchitis (20 percent), a slight increase in villous length (477 microm vs. 402 microm) and pronounced crypt hyperplasia (376 microm vs. 274.5 microm) was observed compared with noninflamed ileoanal pouches. In contrast, in patients with chronic pouchitis (7 percent), severe villous atrophy (62.5 microm) and crypt hyperplasia (543 microm) was found. CONCLUSIONS: Minor structural changes of ileoanal pouch mucosa develop early as an adaptive response to a new environment. Only in a small group of patients with chronic pouchitis does severe villous atrophy and crypt hyperplasia of the ileoanal pouch mucosa develop, most likely as a consequence of mucosal inflammation.

Stallmach A, van Look M, Scheiffele F, Ecker KW, Feifel G, Duchmann R, Zeitz M. · Clinic for Internal Medicine II, Saarland University, Homburg/Saar, Germany. · Int J Colorectal Dis. · Pubmed #10207728 No free full text.

Abstract: Pouchitis is the most significant long-term complication in patients with ileoanal pouch anastomosis (IAP) and is especially frequent in patients with ulcerative colitis. There is an urgent need for simple and objective parameters to assess the presence and activity of pouchitis. Whole-gut lavage fluid (WGLF) was collected from 34 patients [8 with pouchitis (PDAI > or = 7 points) and 26 without pouchitis (Pouchitis Disease Activity Index, PDAI, < 7)]. Patients with active ulcerative colitis (n = 8) served as controls. Concentrations of IgG and sCD44 in WGLF were measured by enzyme-linked immunosorbent assays and those of albumin by immunoturbidimetry. Similar to the case in active ulcerative colitis, concentrations of IgG, albumin, and sCD44 in WGLF were significantly increased in acute pouchitis and reached high specificity (IgG 96%, albumin 96%, sCD44 100%) and acceptable sensitivity (75%) for the diagnosis of acute pouchitis. These parameters were also closely correlated with disease activity as determined by PDAI and endoscopic scoring indices. Assay of protein concentrations in WGLF is thus a simple and objective means for grading inflammation of the pouch and may be useful as a quantitative index of disease activity in clinical studies.