Max Reinshagen

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations.

Principal changes with respect to the 2004 ECCO guidelines Ileocolonoscopy is recommended within the first year after surgery where treatment decisions may be affected (Statement 8C). Thiopurines are more effective than mesalazine or imidazole antibiotics alone in post-operative prophylaxis (Statement 8F). ### 8.1 Epidemiology of post-operative Crohns disease In the natural history of CD, intestinal resection is almost unavoidable since about 80% of patients require surgery at some stage. Surgery is unfortunately not curative as the disease inexorably recurs in many patients. The post-operative recurrence rate varies according to the definition used: clinical, endoscopic, radiological, or surgical. It is lowest when the repeat resection rate is considered, intermediate when clinical indices are used and highest when endoscopy is employed as the diagnostic tool.1–10 Data from endoscopic follow-up of patients after resection of ileo-caecal disease have shown that in the absence of treatment, the post-operative recurrence rate is around 65–90% within 12 months and 80–100% within 3 years of the operation. The clinical recurrence without therapy is about 20–25%/year.1,10 It has been demonstrated that the post-operative clinical course of CD is best predicted by the severity of endoscopic lesions. Symptoms, in fact, appear only when severe lesions are present and it is not uncommon to observe patients with fairly advanced recurrent lesions at endoscopy who remain asymptomatic.1 For these reasons, clinical indices such as the CDAI have low sensitivity at discriminating between patients with or without post-operative recurrence.11 These data mandate strategies aimed at interrupting or delaying the natural course of post-operative recurrence. Several medications have been tried in an attempt to prevent post-operative recurrence, mostly with disappointing results. The aim of this Consensus was therefore critically to evaluate the optimal strategies for the management of post-operative recurrence in CD. Most, if not all, of the evidence available deals with …

Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel disease--a randomized, controlled, open-label, multicenter study.

OBJECTIVES:Anemia is a frequent complication in patients with inflammatory bowel disease (IBD). The optimal route for iron supplementation to replenish iron stores has not been determined so far. We therefore evaluated the efficacy and safety of intravenous iron sucrose as compared with oral iron sulfate for the treatment of iron deficiency anemia (IDA) in patients with IBD.METHODS:A randomized, prospective, open-label, multicenter study was performed in 46 patients with anemia and transferrin saturation ≤20% and/or serum ferritin concentrations ≤20 μg/L. The intravenous group received a single dose of iron sucrose of 7 mg iron/kg body weight, followed by five 200 mg infusions for the following 5 wks. The oral group received iron sulfate 100–200 mg per day for 6 wks.RESULTS:While a comparable increase in hemoglobin was observed for both administration routes (median increase 0.25 g/L in the intravenous group vs 0.21 g/L in the oral group), only iron sucrose led to a rise in serum ferritin concentrations. Intractable gastrointestinal adverse events caused permanent study drug discontinuation in five patients (20.8%) receiving iron sulfate, whereas only one patient (4.5%) had to be withdrawn because of side effects due to iron sucrose.CONCLUSIONS:Although being equal in short-term efficacy and overall tolerability our results suggest a better gastrointestinal tolerability for iron sucrose. Larger trials are mandatory to prove a possible advantage of iron sucrose in short- and long-term efficacy as well as in tolerability over iron sulfate in the management of IDA in IBD.

Nerve Growth Factor and Its High-Affinity Receptor in Chronic Pancreatitis

OBJECTIVE To study the mechanisms that are involved in nerve growth and contribute to pain generation in chronic pancreatitis (CP). SUMMARY BACKGROUND DATA Chronic pancreatitis is a painful disease associated with characteristic nerve changes, including an increase in nerve number and diameter. The mechanisms that influence nerve growth are not known. Nerve growth factor (NGF) and its high-affinity tyrosine kinase receptor A (TrkA) are involved in neural development and survival and growth of central and peripheral nerves. METHODS Nerve growth factor and TrkA were investigated by Northern blot analysis, in situ hybridization, and immunohistochemical staining in the pancreases of 24 patients with CP, and the findings were correlated with clinical parameters. RESULTS By Northern blot analysis, NGF and TrkA mRNA expression were increased in 42% (13.1-fold) and 54% (5.5-fold) of the CP samples (p < 0.01), respectively. In situ hybridization revealed that in CP, enhanced NGF mRNA expression was present in metaplastic ductal cells, in degenerating acinar cells, and in acinar cells dedifferentiating into tubular structures. TrkA mRNA was intensely present in the perineurium. Further, enhanced NGF and TrkA mRNA signals were also present in intrapancreatic ganglia cells in CP samples. Immunohistochemistry confirmed the in situ hybridization findings. Analysis of the molecular findings with clinical parameters revealed a significant relation (p < 0.05) between NGF mRNA levels and pancreatic fibrosis (r = 0.64) and acinar cell damage (r = 0.74) and between TrkA mRNA and pain intensity (r = 0.84). CONCLUSION Activation of the NGF/TrkA pathway occurs in CP. It might influence neural morphologic changes and the pain syndrome in this disorder.

Updated German Guideline on Diagnosis and Treatment of Ulcerative Colitis, 2011

! Hintergrund Die Colitis ulcerosa (CU) ist neben dem Morbus Crohn die wichtigste chronisch-entzundliche Darmerkrankung (CED). Die Inzidenz fur die Colitis ulcerosa liegt in Deutschland bei bei 3,0–3,9 pro 100000 Einwohner [1, 2]. Die Pravalenz durfte in der westlichen Welt derzeit bei 160– 250 pro 100000 Einwohner liegen [3, 4]. Der hochste Gipfel der alterspezifischen Inzidenz liegt bei den 16bis 25-Jahrigen, wenn auch die Verteilung uber die Altersdekaden weit gleichmasiger ist als fruher beschrieben wurde [2]. Somit beginnt fur die meisten Patienten ihre Erkrankung wahrend der Schulzeit oder der Berufausbildung und dauert wahrend ihres gesamten beruflichen Lebens an. Daraus folgt, dass durch die Erkrankung nicht nur direkte Kosten (Medikamente, Arztbesuche, Operationen, Krankenhausaufenthalte etc.), sondern auch umfangreiche indirekte Kosten (Rente, Arbeitsausfalle etc.) entstehen. Es ist davon auszugehen, dass bei Patienten mit CU ca. die Halfte der Gesamtkosten den indirekten Kosten zuzuordnen sind [5]. An direkten medizinischen Kosten wurden dabei zuletzt zwischen 2500 und 5000€ pro Inhaltsverzeichnis! Hintergrund Die Colitis ulcerosa (CU) ist neben dem Morbus Crohn die wichtigste chronisch-entzündliche Darmerkrankung (CED). Die Inzidenz für die Colitis ulcerosa liegt in Deutschland bei bei 3,0–3,9 pro 100000 Einwohner [1, 2]. Die Prävalenz dürfte in der westlichen Welt derzeit bei 160– 250 pro 100000 Einwohner liegen [3, 4]. Der höchste Gipfel der alterspezifischen Inzidenz liegt bei den 16bis 25-Jährigen, wenn auch die Verteilung über die Altersdekaden weit gleichmäßiger ist als früher beschrieben wurde [2]. Somit beginnt für die meisten Patienten ihre Erkrankung während der Schulzeit oder der Berufausbildung und dauert während ihres gesamten beruflichen Lebens an. Daraus folgt, dass durch die Erkrankung nicht nur direkte Kosten (Medikamente, Arztbesuche, Operationen, Krankenhausaufenthalte etc.), sondern auch umfangreiche indirekte Kosten (Rente, Arbeitsausfälle etc.) entstehen. Es ist davon auszugehen, dass bei Patienten mit CU ca. die Hälfte der Gesamtkosten den indirekten Kosten zuzuordnen sind [5]. An direkten medizinischen Kosten wurden dabei zuletzt zwischen 2500 und 5000€ pro Inhaltsverzeichnis

Proinflammatory cytokines increase glial fibrillary acidic protein expression in enteric glia

Background: Enteric glia protect the integrity of the gut, as loss of enteric glial fibrillary acidic protein (GFAP) positive (+) glia leads to a haemorrhagic jejunoileitis. Crohn’s disease (CD) and necrotising enterocolitis (NEC) show pathological changes in enteric glia. Therefore, factors controlling GFAP+ enteric glia are of great interest. The aim of the present study was to characterise enteric glia and determine the effect of interleukin 1β (IL-1β), interleukin 4 (IL-4), tumour necrosis factor α (TNF-α), and lipopolysaccharides (LPS) on cultured enteric glia. Methods: Dissected rat colon and cultured enteric glia cells were double labelled with anti-GFAP and anti-S-100 antibodies. For regulatory studies, enteric glia cells were treated with cytokines and LPS. Proliferation was assayed using bromodeoxyuridine (BrdU) and mitosis of enteric glia was blocked by demecolcine. Results: We were able to distinguish GFAP negative (−) from GFAP+ glia subtypes in situ and in primary cultures. Incubation of cells with IL-1β, TNF-α, and LPS led to a significant increase in GFAP+ enteric glia while IL-4 had no effect on GFAP expression. After incubation with IL-1β, total intracellular GFAP of enteric glia cells was increased. Upregulation of GFAP+ enteric glia could also be observed after stimulation with IL-1β on blocking mitosis. BrdU uptake in stimulated enteric glia showed no increased proliferation rate. Conclusions: Two different types of enteric glia based on GFAP expression exist in the gut. Proinflammatory cytokines and LPS cause a dramatic increase in GFAP+ enteric glia. This suggests that cytokines play an important role in controlling GFAP+ enteric glia which might in turn be involved in modulating the integrity of the bowel during inflammation.

Diagnostic imaging in Crohn's disease: comparison of magnetic resonance imaging and conventional imaging methods.

Abstract Conventional enteroclysis remains the method of choice in the diagnosis of inflammatory small bowel disease. The reported sensitivity rates, however, for the diagnosis of extraintestinal processes, such as fistulae and abscesses, are moderate. Computed tomography (CT) is the method of choice for the diagnosis of extraintestinal complications. The anatomical designation of the affected bowel segment may, however, prove difficult due to axial slices, and the applied radiation dose is high. The use of magnetic resonance imaging (MRI) in the diagnosis of inflammatory small bowel disease is a relatively new indication for the method; prerequisites were the development of breathhold sequences and phased array coils. Optimized magnetic resonance tomographic imaging requires a combined method of enteroclysis and MRI, which guarantees an optimal filling and distension of the small bowel. The high filling volume leads to a secondary paralysis of the small bowel and avoids motion artifacts. In a trial of 84 patients with histological and endoscopic correlation the sensitivity in diagnosing inflammatory bowel disease was 85.4% for enteroclysis and 95.2% for MRI, and the specificity was 76.9% for enteroclysis and 92.6% for MRI. As none of the abscesses was diagnosed with enteroclysis, the sensitivity was 0% for enteroclysis, but 77.8% for MRI. The sensitivity in diagnosing fistulae was 17.7% for enteroclysis and 70.6% for MRI. In summary, MRI can detect the most relevant findings in patients with inflammatory small bowel disease with an accuracy superior to that of enteroclysis.

Protective effect of epidermal growth factor in an experimental model of colitis in rats

BACKGROUND/AIMS The role of epidermal growth factor (EGF) in the maintenance of mucosal integrity in the lower gastrointestinal tract is unknown. The aim of this study was to determine the effect of EGF in experimental colitis. METHODS Colitis was induced with 2,4,6-trinitrobenzenesulfonic acid/ethanol enemas. Rats were pretreated with intraperitoneal administration of recombinant human EGF (600 micrograms/kg) or vehicle 1 hour before induction of colitis and daily thereafter until killed at 8 hours, 48 hours, and 1 week. A separate group received an identical dosage and administration of EGF or vehicle for 1 week with treatment initiated 24 hours after the induction of colitis. Colonic tissue was evaluated macroscopically, histologically, and for myeloperoxidase activity. RESULTS Pretreatment with EGF reduced microscopic erosions at 8 and 48 hours by 74% and 54%, respectively (P < 0.05). At 1 week, microscopic ulcerations and myeloperoxidase activity were reduced by 65% in the EGF-pretreated group (P < 0.05). No significant difference in macroscopic injury, histological damage, or myeloperoxidase activity was noted when EGF treatment was initiated after the induction of colitis. CONCLUSIONS Systemic EGF administration reduces mucosal damage and inflammation in a trinitrobenzenesulfonic acid/ethanol model of colitis in rats through a mechanism involving mucosal protection.

Interaction of the cholinergic system and cholecystokinin in the regulation of endogenous and exogenous stimulation of pancreatic secretion in humans

Pancreatic enzyme secretion is regulated in humans by the cholinergic system and by cholecystokinin (CCK). The interaction between both regulatory systems in response to exogenous and endogenous stimulation was analyzed in the present study using the cholinergic antagonist atropine and the CCK antagonist loxiglumide. A dose-dependent stimulation of pancreatic enzyme output was achieved either by duodenal perfusion of graded caloric loads or by IV infusion of increasing doses of cerulein. Prestimulated pancreatic secretion was inhibited by atropine and loxiglumide. Atropine furthermore almost completely blocked meal-stimulated pancreatic secretion, whereas loxiglumide caused 60% inhibition. The enzyme response to graded doses of exogenous CCK was significantly inhibited by atropine and loxiglumide. Plasma levels of CCK were not altered by atropine but increased with infusion of loxiglumide. This study supports the concept that pancreatic enzyme secretion is predominantly dependent on a cholinergic tone and that CCK modulates the enzyme-secretory response.

Validation of the EuroQol questionnaire in patients with inflammatory bowel disease.

Objective The EuroQol EQ-5D is a generic questionnaire for describing and valuing patients’ health-related quality of life. The purpose of the study was to analyse the construct validity, criterion validity, test–retest reliability and responsiveness of the EQ-5D in patients with inflammatory bowel disease. Methods 152 consecutive patients with inflammatory bowel disease (123 with Crohns disease and 29 with ulcerative colitis) completed the EQ-5D, the SF-36 and the Inflammatory Bowel Disease Questionnaire (IBDQ). Of the study group, 66 patients filled in the EQ-5D a second time after a 2-week gap, including a transition question. Disease activity was measured by the Crohns Disease Activity Index (CDAI) and by Rachmilewitzs Clinical Activity Index (CAI). Results The EQ-5D showed a moderate ceiling effect. Correlation between the EQ-5D visual analogue scale (EQ VAS) score and CDAI/CAI was rs = −0.65/rs = −0.71 (both P < 0.001). Levels of responses to EQ-5D items and the EQ VAS score were significantly better for patients in remission than for patients with active disease (all P < 0.01). For the total sample, coefficients of correlation between the EQ VAS score and SF-36 and IBDQ scores ranged between 0.37 and 0.73 (all P < 0.0001). When repeated, the EQ-5D was reliable in stable patients (intraclass correlation coefficient for EQ VAS = 0.77, kappa statistic for items 0.39 to 1.00); the EQ VAS was responsive in patients who, in the transition question, indicated an improvement in health state (effect size 0.79). Conclusions The EQ-5D is reasonably valid, reliable and responsive in patients with inflammatory bowel disease. It can be used to generate preference-based valuations of health-related quality of life in inflammatory bowel disease.

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.