Ulrich Böcker

Inflammatory bowel disease and smoking. A review of epidemiology, pathophysiology, and therapeutic implications

The relationship between smoking behavior and inflammatory bowel disease (IBD) is complex. While Crohn’s disease (CD) is associated with smoking and smoking has detrimental effects on the clinical course of the disease, ulcerative colitis (UC) is largely a disease of nonsmokers and former smokers. Furthermore, cigarette smoking may even result in a beneficial influence on the course of ulcerative colitis. The potential mechanisms involved in this dual relationship include changes in humoral and cellular immunity, cytokine and eicosanoid levels, gut motility, permeability, and blood flow, colonic mucus, and oxygen free radicals. Nicotine is assumed to be the active moiety. The differential therapeutic consequences comprise the cessation of smoking in CD and, so far, clinical trials using nicotine in different forms of application for UC. In this article, we review the relationship between cigarette smoking and IBD, considering epidemiological, pathogenetic, and clinical aspects.

Predictors of disease-related concerns and other aspects of health-related quality of life in outpatients with inflammatory bowel disease.

Objective Disease-related concerns are a major dimension of health-related quality of life in inflammatory bowel disease (IBD). The aim of this study was to assess the concerns of IBD patients in an outpatient sample, and to determine the impact of psychological and disease factors on concerns and on other variables of health-related quality of life. Methods Seventy-two outpatients with IBD were assessed with regard to disease-related concerns [with the Rating Form of IBD Patients’ Concerns (RFIPC)], psychological symptoms and somatic complaints non-specific to IBD as dependent variables. Coping with illness, health locus of control, and disease variables were assessed as predictor variables. Multiple regression analyses determined the independent contribution of each predictor on the dependent variables. Results Women reported more intense concerns than men. No difference in concerns was found between patients with Crohns disease and ulcerative colitis. The highest predictive value for the RFIPC total score was found for depressive coping. It explained a greater proportion of variance on the RFIPC total score (23%) than demographic (10%) and disease variables (7%), and comparably impinged on RFIPC subscores. Furthermore, depressive coping was significantly associated with psychological distress, the self-rated health status and somatic complaints non-specific to IBD. Conclusions Our findings suggest that in IBD psychological variables, particularly depressive coping, are more predictive than medical variables for disease-related concerns and other variables of health-related quality of life. Further studies are needed to examine the effects that the way of coping with disease have on long-term outcome in IBD.

Long-Term Effectiveness of Azathioprine in IBD Beyond 4 Years: A European Multicenter Study in 1176 Patients

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.

Reducing Psychological Distress in Patients with Inflammatory Bowel Disease by Cognitive-Behavioural Treatment: Exploratory Study of Effectiveness

BACKGROUND This prospective study aimed to determine whether cognitive-behavioural group treatment accompanying medical standard care is effective in reducing psychological distress in patients with inflammatory bowel disease. METHODS Twenty-eight outpatients with Crohn disease or ulcerative colitis completed the treatment programme. Psychological treatment consisting of 12 weekly sessions was conducted in a group setting. Medical and psychometric assessments were taken at the beginning of the 3-month pretreatment waiting period, at pretreatment, at post-treatment and at the 3, 6 and 9-month follow-ups. RESULTS During baseline, no change was observed in psychological distress. Disease-related worries and concerns decreased significantly from pretreatment to the follow-ups. The disease groups differed in the decline of concerns between pre- and post-treatment, with a significant reduction of concerns in patients with ulcerative colitis but not Crohn disease. This difference did not occur at the follow-ups, indicating long-term improvement for both disease groups. Depressive coping decreased significantly in women and remained stable at the follow-ups, whereas depressive coping did not change in men. The same gender difference was found for depressive symptoms. CONCLUSIONS The exploratory findings suggest that psychological group treatment for outpatients is a feasible and effective approach for the short- and long-term reduction of psychological distress for patients with inflammatory bowel disease. However, the revealed gender differences on coping and depression might indicate the necessity to consider gender-specific aspects of inflammatory bowel disease when designing and evaluating psychological interventions.Background: This prospective study aimed to determine whether cognitive-behavioural group treatment accompanying medical standard care is effective in reducing psychological distress in patients with inflammatory bowel disease. Methods: Twenty-eight outpatients with Crohn disease or ulcerative colitis completed the treatment programme. Psychological treatment consisting of 12 weekly sessions was conducted in a group setting. Medical and psychometric assessments were taken at the beginning of the 3-month pretreatment waiting period, at pretreatment, at post-treatment and at the 3, 6 and 9-month follow-ups. Results: During baseline, no change was observed in psychological distress. Disease-related worries and concerns decreased significantly from pretreatment to the follow-ups. The disease groups differed in the decline of concerns between pre- and post-treatment, with a significant reduction of concerns in patients with ulcerative colitis but not Crohn disease. This difference did not occur at the follow-ups, indicating long-term improvement for both disease groups. Depressive coping decreased significantly in women and remained stable at the follow-ups, whereas depressive coping did not change in men. The same gender difference was found for depressive symptoms. Conclusions: The exploratory findings suggest that psychological group treatment for outpatients is a feasible and effective approach for the short- and long-term reduction of psychological distress for patients with inflammatory bowel disease. However, the revealed gender differences on coping and depression might indicate the necessity to consider gender-specific aspects of inflammatory bowel disease when designing and evaluating psychological interventions.

Enhanced production of IL-18 in butyrate-treated intestinal epithelium by stimulation of the proximal promoter region

Expression of IL‐18 in intestinal epithelial cells (IEC) has been implicated in Th1 cell‐mediated chronic intestinal inflammation and anti‐tumor immunity. However, physiological regulatory factors have not been identified. Besides their effects on proliferation and restitution, immunomodulatory functions have been attributed to short chain fatty acids (SCFA). We investigated the effect of SCFA (butyrate, propionate, acetate) on expression of IL‐18 in IEC in vitro and in vivo. Expression of IL‐18 mRNA and protein in human carcinoma‐derived HT‐29 and Caco‐2 cells was analyzed by reverse transcription‐PCR and Western blot. Transcriptional regulation of IL‐18 gene expression was determined by transient transfection of wild‐type and mutated IL‐18 promoter. Further, in vivo expression of IL‐18 in the intestine from butyrate‐treated and untreated mice was assessed by immunohistochemistry. IL‐18 mRNA and the IL‐18 protein were expressed in IEC, while IL‐18 secretion was not observed. Butyrate and acetate increased intracellular IL‐18 content in a time‐ and dose‐dependent fashion. In contrast to proinflammatory stimuli butyrate potently activated the IL‐18 promoter, indicating that IL‐18 is regulated at the transcriptional level by SCFA. Furthermore, a 108‐bp sequence in the proximal region was identified to be essential for IL‐18 promoter activation by butyrate. As proof of principle butyrate effects were confirmed in vivo by demonstration of increased IL‐18 protein expression in IEC from butyrate‐treated mice. In conclusion, SCFAup‐regulate IL‐18 protein expression in IEC, suggesting a potential regulatory contribution of these luminal constituents to T cell mediated inflammatory and neoplastic intestinal conditions.

White-Light or Narrow-Band Imaging Colonoscopy in Surveillance of Ulcerative Colitis: A Prospective Multicenter Study

BACKGROUND & AIMS Early detection of neoplastic lesions is essential in patients with long-standing ulcerative colitis but the best technique of colonoscopy still is controversial. METHODS We performed a prospective multicenter study in patients with long-standing ulcerative colitis. Two colonoscopies were performed in each patient within 3 weeks to 3 months. In white-light (WL) colonoscopy, stepwise random biopsy specimens (4 biopsy specimens every 10 cm), segmental random biopsies (2 biopsy specimens in 5 segments), and targeted biopsy specimens were taken. In NBI colonoscopy, segmental and targeted biopsy specimens were taken. The sequence of WL and NBI colonoscopy was randomized. RESULTS In 36 of 159 patients enrolled (22.6%), 54 lesions with intraepithelial neoplasia (IN) were found (51 low-grade, 3 high-grade). In WL colonoscopy we found 11 IN in stepwise biopsy specimens, 4 in segmental biopsy specimens, and 15 in targeted biopsy specimens. In NBI colonoscopy 7 IN were detected in segmental biopsy specimens and 24 IN were detected in targeted biopsy specimens. Almost all IN were found with one technique alone (κ value of WL vs NBI, -0.86; P < .001). Statistically equivalent numbers of IN were found in NBI colonoscopy with targeted and segmental biopsy specimens as in WL colonoscopy with targeted and stepwise biopsy specimens, but with fewer biopsy specimens (11.9 vs 38.6 biopsy specimens, respectively; P < .001), and less withdrawal time was necessary (23 vs 13 min, respectively; P < .001). CONCLUSIONS Stepwise biopsy specimens are indispensable in WL colonoscopy. The combination of targeted and segmental biopsy specimens in the NBI technique is as sensitive as targeted together with stepwise biopsy specimens in WL colonoscopy, but requires fewer biopsy specimens and less time. The highest sensitivity should be reached by combining the WL and NBI techniques by switching between the modes.

Comparison of magnetic resonance imaging and video capsule enteroscopy in diagnosing small-bowel pathology: localization-dependent diagnostic yield.

Abstract Objective. New technology has considerably advanced the diagnosis of small-bowel pathology. However, its significance in clinical algorithms has not yet been fully assessed. The aim of the present analysis was to compare the diagnostic utility and yield of video-capsule enteroscopy (VCE) to that of magnetic resonance imaging (MRI) in patients with suspected or established Crohns disease (Group I), obscure gastrointestinal blood loss (Group II), or suspected tumors (Group III). Material and methods. Forty-six out of 182 patients who underwent both modalities were included: 21 in Group I, 20 in Group II, and five in Group III. Pathology was assessed in three predetermined sections of the small bowel (upper, middle, and lower). The McNemar and Wilcoxon tests were used for statistical analysis. Results. In Group I, lesions were found by VCE in nine of the 21 patients and by MRI in six. In five patients, both modalities showed pathology. In Group II, pathological changes were detected in 11 of the 20 patients by VCE and in eight patients by MRI. In five cases, pathology was found with both modalities. In Group III, neither modality showed small-bowel pathology. For the patient groups combined, diagnostic yield was 43% with VCE and 30% with MRI. The diagnostic yield of VCE was superior to that of MRI in the upper small bowel in both Groups I and II. Conclusion. VCE is superior to MRI for the detection of lesions related to Crohns disease or obscure gastrointestinal bleeding in the upper small bowel.

Interleukin 18 Promoter Variants (−137G>C and −607C>A) in Patients with Chronic Hepatitis C: Association with Treatment Response

BackgroundRecently, two functional IL18 promoter variants, −607C>A (rs1946518) and −137G>C (rs187238), were associated with viral clearance in patients with hepatitis C. The present study focused on their relevance for treatment response.MethodsSeven hundred fifty-seven chronically infected European patients and 791 controls were enrolled in the study. IL18 genotyping was performed by allele-specific PCR. Liver histology was available in 67.9%.ResultsGenotype and allele frequencies were equally distributed in patients and controls. No significant association with various disease characteristics was observed. However, when comparing patients with sustained virological response (SR) and non-SR, statistically significant associations were found for both variants (p = 0.0416 and p = 0.0274, respectively). In viral genotype 1, the −607A allele was positively associated with treatment response (p = 0.0190; OR 1.537; 95% CI, 1.072–2.205) and the −137G allele with a higher rate of nonresponse (p = 0.0302; OR 1.524; 95% CI, 1.040–2.233).ConclusionsThe association of IL18 variants with treatment response in genotype 1 hepatitis C patients implies a predictive and modifying role of these genetic variants.

Endoscopy and magnetic resonance imaging in patients with Crohn's disease: A retrospective single-centre comparative study

Objective. There is ongoing debate about which imaging modality is best for patients with inflammatory bowel diseases. Magnetic resonance imaging (MRI) has been successfully used to evaluate the jejunum and the ileum. Because virtual colonoscopy by MRI requires bowel cleansing and/or rectal filling, endoscopy is preferred for assessment of the colon. However, hydro-MRI without special bowel preparation may be sufficient as a diagnostic tool if specifically targeted in the course of a known disease. The aim of this study was retrospectively to assess the correlation of endoscopy, histology and MRI findings for the terminal ileum and the colon in a cohort of patients with Crohns disease. Material andmethods. In all, 60 patients with a confirmed diagnosis of Crohns disease were included in the study. Here, 412 anatomical segments of the colon were analysed by MRI, 401 by endoscopy and 374 by histology. Results. Presence or absence of inflammation was concordantly diagnosed in 310 segments (77.3%). The highest concordance was found for the terminal ileum and, in patients with previous surgery, the anastomosis. Sensitivity and specificity for MRI versus endoscopy, MRI versus histology and endoscopy versus histology were 64.4%/81.1%, 62.1%/86.2% and 78.2%/80.3%, respectively. Conclusions. In a retrospective analysis of patients with Crohns disease, hydro-MRI assessment of inflammation in anatomical segments of the colon reaches acceptable concordance rates with endoscopy and histology without prior preparation of the bowel. The data justify a prospective controlled trial.

IL-1β transcript stability in monocytes is linked to cytoskeletal reorganization and the availability of mRNA degradation factors

Monocyte extravasation initiates reorganization of the cytoskeleton (CSK) and adhesion‐dependent cytokine gene transcription. The actin CSK is thought to be crucial for compartmentalization and translation of mRNA, many of which contain AU‐rich (ARE) instability motifs in the 3′ untranslated region. We investigated regulation of adhesion‐induced IL‐1β expression by the monocyte CSK. In serum‐free adherent monocytes, the induced IL‐1β mRNA was stable and did not coextract with actin filaments. In contrast, in cells adherent in autologous serum, IL‐1β transcripts were unstable, coextracted with actin filaments and were associated with only transient activation of the mitogen‐activated protein kinases (MAPK). Under both conditions of adherence, the ARE‐binding protein AUF1/hnRNP D was readily extracted in the cytosolic fraction. Electro‐injection with AUF1/hnRNP D modified the actin CSK and, surprisingly, stabilized IL‐1β transcripts. These data suggest that the control of mRNA degradation is linked with changes in the CSK. Mitogen‐activated protein kinase activation or alterations in the availability of mRNA degradation factors may mediate these effects.