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Max Reinshagen

Publications and source records attributed to Max Reinshagen.

At least 19 recordsLinked to original sources
PubMed2006

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.

Adult↗
PubMed2006

Proinflammatory cytokines induce neurotrophic factor expression in enteric glia: a key to the regulation of epithelial apoptosis in Crohn's disease.

OBJECTIVES: Imbalanced apoptosis of enterocytes is likely to be 1 of the mechanisms underlying Crohn's disease (CD). Apoptosis of enterocytes is regulated by glial-derived neurotrophic factor (GDNF), which is increased in CD. The cellular source of GDNF during gut inflammation is unclear. The aim of the study was to identify the source of GDNF in CD during gut inflammation. MATERIALS AND METHODS: Glial fibrillary acidic protein (GFAP), GDNF, and smooth muscle actin (SMA) was detected in the gut from patients with CD by immunohistochemistry. Cultured enteric glia cells (EGC) were labeled with anti-GFAP, anti-GDNF, and antibodies and a Golgi marker (anti-58K antibodies) after blocking Golgi export with monensin. Cultured EGCs were treated with interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, and lipopolysaccharides. Secretion of neurotrophic factors was detected by enzyme-linked immunosorbent assay. RESULTS: Mucosal GFAP-positive EGCs are increased in the colon of patients with CD. This type of glia but not subepithelial myofibroblasts expresses significant amounts of GDNF. In vitro GDNF is continuously secreted from cultured EGCs. The neurotrophic factor secretion could be stimulated by IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharides in a time- and dose-dependent manner. The increased GDNF secretion by EGCs sustained for>12 hours after withdrawal of the proinflammatory cytokines. CONCLUSIONS: A mucosal GFAP expressing EGC population is dramatically increased in CD. This population is a major cellular source of the upregulated GDNF in the inflamed gut. Therefore, mucosal EGC may play a key role in protecting the gut epithelium and may contribute to reestablish the integrity of the injured epithelium.

Animals↗
PubMed2005

Open label trial of granulocyte apheresis suggests therapeutic efficacy in chronically active steroid refractory ulcerative colitis.

AIM: To study the efficacy, safety, and feasibility of a granulocyte adsorptive type apheresis system for the treatment of patients with chronically active ulcerative colitis despite standard therapy. METHODS: An open label multicenter study was carried out in 39 patients with active ulcerative colitis (CAI 6-8) despite continuous use of steroids (a minimum total dose of 400 mg prednisone within the last 4 wk). Patients received a total of five aphereses using a granulocyte adsorptive technique (Adacolumn (reg), Otsuka Pharmaceutical Europe, UK). Assessments at wk 6 and during follow-up until 4 mo comprised clinical (CAI) and endoscopic (EI) activity index, histology, quality of life (IBDQ), and laboratory tests. RESULTS: Thirty-five out of thirty-nine patients were qualified for intent-to-treat analysis. After the apheresis treatment at wk 6, 13/35 (37.1%) patients achieved clinical remission and 10/35 (28.6%) patients had endoscopic remission (CAI<4, EI<4). Quality of life (IBDQ) increased significantly (24 points, P<0.01) at wk 6. Apheresis could be performed in all but one patient. Aphereses were well tolerated, only one patient experienced anemia. CONCLUSION: In patients with steroid refractory ulcerative colitis, five aphereses with a granulocyte/monocyte depleting filter show potential short-term efficacy. Tolerability and technical feasibility of the procedure are excellent.

Adult↗
PubMed2005

Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study.

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.

Adult↗
PubMed2005

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 <or=20% and/or serum ferritin concentrations <or=20 microg/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.

Abdominal Pain↗
PubMed2004

Cost of outpatient care in patients with inflammatory bowel disease in a German University Hospital.

BACKGROUND AND AIM: Because of its long duration, inflammatory bowel disease (IBD) causes high use of health services and high lifetime costs for medical care. The aim of the present study was to measure the costs of outpatient care in patients with IBD in a German University Hospital and to identify potentially relevant determinants of costs. METHODS: The use of resources of 599 outpatient patients treated at a German University Hospital (65% Crohn's disease [CD] and 26% ulcerative colitis [UC]) was measured using a routine database. Costs of medical services (diagnostics and treatment) were considered as well as costs of medication. Resource use was valued using fee schedules for hospital services and pharmacy prices for drugs. RESULTS: The mean cost of one outpatient visit was Euros 162, including physician costs, laboratory costs, and costs of diagnostic procedures following the visit. For a subgroup of 272 patients, the mean annual cost for outpatient care was Euros 3171. Medication accounted for 85% of the total annual costs. Potential determinants, such as main diagnosis (CD or UC), sex, age, localization of disease, and occurrence of anemia, had no influence on costs, whereas complications of IBD and use of corticosteroids showed an impact on annual costs. CONCLUSIONS: This is the first time that the structure and range of outpatient treatment costs for IBD have been demonstrated for a German hospital.

Adolescent↗
PubMed2003

Quantitative ultrasound of the proximal phalanges and dual-energy X-ray absorptiometry in Crohn's disease patients with osteopenia.

BACKGROUND: Osteopenia and osteoporosis are frequent complications in Crohn's disease, and these features are associated with an increased risk of vertebral and appendicular fractures. Bone mineral density (BMD) measurements are widely accepted to assess the fracture risk in postmenopausal osteoporosis. In recent years, quantitative ultrasound (QUS) has become attractive for the diagnosis of osteopenia as a nonionizing method. The aim of the present study was to investigate QUS and BMD measurements in osteopenic patients with Crohn's disease. METHODS: BMD of the lumbar spine and femoral neck and QUS of proximal phalanges II-V (DBM Sonic 1200; IGEA) were performed prospectively in 171 patients with Crohn's disease. The amplitude-dependent sound-of-speed (AD-SoS) and the ultrasound bone profile score (UBPS) were calculated using the WinSonic PRO 1.1 software program. X-ray examination of the spine was performed in 131 patients. Vertebral deformity was morphometrically defined according to the published methods of McCloskey and Eastell. RESULTS: BMD of the lumbar spine and femoral neck correlated significantly (r = 0.62), but no correlation between BMD and QUS could be demonstrated. Vertebral deformities (VD) were detected in 28/131 (21.4%) patients. Two patients had a history of femoral fracture (FF). Lumbar BMD was lower in patients with either VD or FF than in those patients with no preexisting fractures (T-score: -2.46 vs -2.04; P = 0.0233). QUS parameters correlated negatively to patients' age but could not be used to discriminate between patients with and without VD/FF. CONCLUSIONS: Osteoporosis-related fractures are associated with a low lumbar bone density in Crohn's disease patients. QUS of the proximal phalanges cannot detect manifest osteoporosis in Crohn's disease patients and is therefore not valuable as a screening tool for these patients.

Absorptiometry, Photon↗
PubMed2003

Glial-derived neurotrophic factor regulates apoptosis in colonic epithelial cells.

BACKGROUND & AIMS: Ablation of the enteric glia leads to a fulminant hemorrhagic jejunoileitis. We hypothesized that glial-derived neurotrophic factor (GDNF) may be involved in mucosal protection of the gut. Therefore, we examined the regulation of GDNF and its receptor (GFR-alpha1) in colonic inflammation and its effects on colonic epithelial cell apoptosis. METHODS: The expression of GDNF and GFR-alpha1 was investigated in experimental colitis of rats and in human inflammatory bowel disease (IBD). GDNF-induced activation of Akt (protein kinase B [PKB]) and mitogen-activated protein kinase (MAPK) in the colonic epithelial cell lines HT-29 and SW480 was studied. Furthermore, the antiapoptotic potency of GDNF in SW480 cells was evaluated. RESULTS: GDNF was specifically up-regulated in experimental rat colitis and in IBD. In contrast, GFR-alpha1 was constitutively expressed in rat and human colonic epithelium. GDNF potently activated MAPK and Akt (PKB) in colonic epithelial cells. Moreover, GDNF strongly prevented apoptosis in SW480 cells. Our data show that GDNF-mediated protection against apoptosis depends on activation of the MAPK and phosphatidylinositol 3-kinase/Akt (PKB) pathways. CONCLUSIONS: GDNF is up-regulated in IBD and has strong antiapoptotic properties in colonic epithelial cells. This points to a novel role of the neurotrophic factor GDNF for mucosal protection and regeneration in IBD.

Apoptosis↗
PubMed2003

Management of osteoporosis in patients with gastrointestinal diseases.

Osteoporosis is a frequent complication in the course of various gastrointestinal disorders. Since its pathogenesis is complex, and incompletely understood in comparison to the well-known pathomechanism of postmenopausal osteoporosis, adequate management is difficult. We first summarize those therapeutic options which have strong evidence in postmenopausal osteoporosis and, thereafter, we review those in the context of different gastrointestinal diseases. Treatment of the underlying intestinal disorder seems to be most important to normalise altered bone metabolism and to prevent osteoporosis in patients with coeliac disease. In patients with osteoporosis associated with Crohn's disease, various treatment strategies (such as vitamin D, sodium fluoride, bisphosphonates) are discussed. In contrast to postmenopausal osteoporosis, interventional studies in secondary osteoporosis are often limited by the small study population and data about the efficacy of any treatment in prevention of fractures are therefore lacking. Well-conducted, controlled studies with the endpoint of preventing fractures are therefore required to optimise the treatment of osteoporosis in these patients.

Bone and Bones↗
PubMed2003

Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn's disease.

BACKGROUND AND AIMS: Osteoporosis may occur in 25-30% of patients with Crohn's disease. Its pathogenesis is not completely understood. Both systemic inflammation in acute disease and treatment with systemic glucocorticoids have been implicated. The aim of the present study was to investigate changes in bone density and biochemical markers of bone metabolism before and during a 3-month period of high-dose glucocorticoid treatment for acute flare-up of Crohn's disease. METHODS: Twenty-five patients with active Crohn's disease requiring systemic glucocorticoid treatment (prednisolone, 60 mg/day) were investigated. Lumbar spine and femoral neck bone mineral densitometry was performed at baseline and again after 3 months. Clinical examinations including evaluation of the Crohn's disease activity index and measurement of the biochemical markers osteocalcin, deoxypyridinoline, osteoprotegerin and the soluble receptor activator of NF-kappaB ligand were performed prior to, and at 1, 2 and 12 weeks following steroid administration. RESULTS Median lumbar bone mineral density decreased significantly during the observation period by 1.04% from -0.84 (t score; range, -2.8 to +0.57) to -0.95 (range, -3.1 to +0.40; P = 0.022), while bone density of the total femur decreased by 2.9% from -0.83 (range, -2.61 to +1.86) to -0.90 (range, -2.65 to +0.19; P = 0.01). Serum levels of osteocalcin, a bone formation marker, and osteoprotegerin, an anti-resorptive cytokine produced by osteoblasts, decreased after the first 2 weeks of treatment and reached baseline levels after 3 months. No significant change was found for the bone resorption marker deoxypyridinoline, while soluble receptor activator of NF-kappaB ligand, a cytokine promoting bone resorption, tended to increase during steroid treatment. CONCLUSION: A decrease in bone mineral density in patients with Crohn's disease appears to result, at least in part, from a short-term effect of systemic glucocorticoid. Modulation of osteoclastogenesis by the receptor activator of NF-kappaB ligand/osteoprotegerin cytokine system and decreased osteoblastic function may be the underlying molecular basis.

Acute Disease↗
PubMed2002

[Measurement of outpatient treatment costs of chronic inflammatory bowel diseases at a German university hospital].

OBJECTIVE: To create a concept for measuring and valuating resource utilization of outpatient treatment of patients with inflammatory bowel disease in a German university hospital. MATERIAL AND METHODS: The measurement of health services was achieved using a computer-based routinely administered data base of the Medical Department. Measuring costs was performed in three steps: 1. identification of the categories of resource utilization, 2. quantitative measurement of resource use, 3. monetary valuation of the utilization of resources using German fee schedules and prices for drugs. RESULTS: The resource utilization of 272 patients with a treatment period of more than 1 year could be identified in a structured form. Categories of resource use could be identified and quantitatively measured as follows: anamnesis and physical examination by a physician in 100% of the visits, laboratory tests in 87.1%, endoscopic or sonographic services in 36.9%, and radiologic procedures in 14.1%. In 93.6% of the visits a medication was prescribed. Annual costs of outpatient care provided by the hospital were 3,171 [symbol: see text] per patient. Medication accounted for 85% of total costs. Analyzing the costs of medical treatment, mesalazine was the major cost component (48%), followed by budesonide (15%). CONCLUSION: The presented concept offers a good access to measure costs of outpatient treatment of patients with inflammatory bowel disease. It is suitable for measuring costs in the economic evaluation of alternative treatments or diagnostic strategies in an outpatient setting. It furthermore may be used as a component in cost-of-illness studies. For transferring the concept to other hospitals, the availability of a routine documentation of services should be checked. For economic analysis, a further data management is required.

Adult↗
PubMed2002

Enteric nervous plasticity and development: dependence on neurotrophic factors.

The enteric nervous system in the mammalian gut is histologically and to some extent functionally similar to the central nervous system. Thus, structural and functional similarities between these systems are evident. As shown for the central nervous system, differentiation of neural crest-derived precursor cells of the enteric nervous system also depends essentially on different neurotrophic factors. Moreover, recent studies have revealed that these trophic factors also play a critical role throughout life by regulating neurotransmitter and neuropeptide synthesis, and by influencing neuronal morphology and synaptic functions. Consequently, our understanding of these complex interactions of the enteric nervous system and neurotrophic factors requires synergistic efforts from neurophysiology, biochemistry, and pharmacology in order to understand the complex phenomena of enteric nervous development and plasticity in the gut. Knowledge of these mechanisms might help to develop strategies for therapy of neuronal abnormalities, which cause different gastrointestinal diseases.

Animals↗
PubMed2002

Lactose intolerance in active Crohn's disease: clinical value of duodenal lactase analysis.

BACKGROUND: Patients with active Crohn's disease (CD) often report having abdominal symptoms after ingestion of milk products, but the pathomechanism for lactose malabsorption seems to be complex. GOALS: To investigate the prevalence of clinical milk intolerance and to objectify symptoms with hydrogen (H 2 ) breath testing, analysis of lactase protein, and enzyme activity in the duodenal mucosa in patients with CD and in healthy controls. STUDY: In 49 patients with CD and 24 controls, H 2 breath testing was performed. All individuals underwent endoscopy of the upper gastrointestinal tract, in which multiple pinch samples were taken from the distal duodenum. Lactase activity was measured using the method of Dahlquist. The lactase protein expression was analyzed by gel electrophoresis using the monoclonal antibody mlac 10 and by immunochemistry using the monoclonal antibody mlac 4. RESULTS: Prevalence of milk intolerance in healthy controls was 16.6% versus 46.9% in patients with CD, with a high frequency (83.3%) in patients with active disease (CD activity index >150). Milk intolerance was correlated to the duration of inflammatory bowel disease ( p = 0.023) but not to the location or previous bowel resection. Hydrogen breath testing had a moderate sensitivity in detecting lactose maldigestion (70.4%) and a high specificity (95.6%). Duodenal lactase levels were also correlated to disease activity, whereas correlations to clinical symptoms remained poor. Patients with milk intolerance had a significantly reduced bone density at the lumbar spine (z-score, -1.33 +/- 0.92 vs. -0.19 +/- 0.95 [mean +/- SD]; p = 0.002) CONCLUSIONS: Milk intolerance is a frequent problem in active CD, which can be objectified accurately by H 2 lactose breath testing. Decreased lactase levels in the duodenal mucosa may be found during an acute flare but are not the predominant cause of milk intolerance in CD.

Adult↗
PubMed2002

Screening for p53 and K-ras mutations in whole-gut lavage in chronic inflammatory bowel disease.

OBJECTIVES: Molecular screening for frequently mutated genes may increase the likelihood of identifying cancer risk groups, such as patients with longstanding inflammatory bowel disease. This study investigated the prevalence and time course of p53 and K-ras mutations in colonic lavage fluid of patients with inflammatory bowel disease. METHODS: Colonic lavage fluid from 190 patients with ulcerative colitis (73), Crohn's disease (58) or controls (49 non-tumour, 10 colorectal cancer) was studied by oligomer-specific hybridization for K-ras mutations and single-strand conformation polymorphism (SSCP) for p53 mutations. Follow-up investigations were carried out after 1-3 years. RESULTS: Mutations were most frequent in carcinomas (5/10, 50%) and rare in non-tumour controls (1/49, 2.0%). They were found in Crohn's colitis in 15.4%, in extensive ulcerative colitis in 18.6%, in left-sided ulcerative colitis in 13.3%, and in distal ulcerative colitis in 6.7% (P > 0.05). There was a positive association with disease duration (> or =11 years, P < 0.05). Follow-up investigations detected the same mutation in four patients and revealed new mutations in three patients. CONCLUSIONS: In our large series of patients with inflammatory bowel disease, K-ras and p53 mutations could be detected with reasonable frequency and confirmed at follow-up in at least some patients. Our data encourage the use of molecular screening for the detection of malignant precursor lesions in at-risk patients.

Adult↗
PubMed2002

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 Crohn's 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 Crohn's Disease Activity Index (CDAI) and by Rachmilewitz's 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 r = -0.65/r = -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.

Adolescent↗