Crohn Disease: Adler G

Adler G, Reinshagen M, Anonymous00112. · Abt. Innere Medizin I, Medizinische Universitätsklinik Ulm. · Z Gastroenterol. · Pubmed #12541176 No free full text.

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Stange EF, Schreiber S, Fölsch UR, von Herbay A, Schölmerich J, Hoffmann J, Zeitz M, Fleig WE, Buhr HJ, Kroesen AJ, Moser G, Matthes H, Adler G, Reinshagen M, Stein J, Anonymous00103. · Abteilung Innere Medizin 1, Robert-Bosch-Krankenhaus, Stuttgart. · Z Gastroenterol. · Pubmed #12541167 No free full text.

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von Herbay A, Schmid RM, Adler G. · Pathologisches Institut, Universität Heidelberg. · Dtsch Med Wochenschr. · Pubmed #10480015 No free full text.

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

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

Herfarth H, Gross V, Andus T, Caesar I, Vogelsang H, Adler G, Malchow H, Petri A, Gierend M, Schölmerich J, Anonymous00336. · Department of Internal Medicine, University of Regensburg, 93042 Regensburg, Germany. · Int J Colorectal Dis. · Pubmed #13680283 No free full text.

Abstract: BACKGROUND AND AIMS: The nonsystemic steroid budesonide has been used to treat active ileocecal and ileocolonic Crohn's disease (CD). This study investigated the optimal budesonide dose using a pH-dependent release formulation. The goal of treatment was the remission of CD (CDAI <150) within 6 weeks of treatment. PATIENTS AND METHODS: The study was of randomized, double-blind, dose-finding design. Patients with active CD ileocolitis without steroid pretreatment were treated with 3x2 mg ( n=39), 3x3 mg ( n=33), or 3x6 mg ( n=32) oral pH-modified released budesonide daily. RESULTS: The remission rates after 6 weeks were 36% with 3x2 mg, 55% with 3x3 mg, and 66% with 3x6 mg. Significantly more patients were in remission while treated with 3x6 mg than with 3x2 mg budesonide/day. Subgroup analyses revealed that patients with high disease activity (CDAI >/= 300) or ileocolonic disease with disease manifestation distal to the transverse colon responded better to the highest budesonide dose. CONCLUSION: Oral pH-modified released budesonide shows a dose-dependent effectiveness in patients with active ileocolonic CD. In the majority of patients 9 mg budesonide per day is sufficient. However, in patients with highly active disease or ileal disease with distal colonic manifestation higher doses of budesonide could increase the therapeutic response

von Tirpitz C, Klaus J, Steinkamp M, Hofbauer LC, Kratzer W, Mason R, Boehm BO, Adler G, Reinshagen M. · Department of Medicine I, University of Ulm, Ulm, Germany. · Aliment Pharmacol Ther. · Pubmed #12641503 links to  free full text

Abstract: BACKGROUND: Osteoporosis is a frequent complication in Crohn's disease. Although the efficacy of both sodium fluoride and aminobisphosphonates in postmenopausal osteoporosis has been investigated in long-term therapy studies, no long-term results are available regarding the effect of these agents in the management of osteoporosis in patients with Crohn's disease. METHODS: Eighty-four patients with Crohn's disease and pathological bone mineral density findings were randomized to receive either vitamin D3 (1000 IU) and calcium citrate (800 mg) daily (group A) or sodium fluoride (25 mg b.d., group B) or intravenous ibandronate (1 mg every 3 months, group C) in addition to daily calcium/vitamin D substitution. On admission to the study and after 12 and 27 months, patients underwent dual-energy X-ray absorptiometry and radiological examination of the spine. RESULTS: Sixty-eight patients completed the 1-year observation period and were available for the intention-to-treat analysis. No new vertebral fractures were diagnosed. In group A, lumbar bone density increased by 2.6% (P = 0.066, N.S.), in group B by 5.7% (P = 0.003) and in group C by 5.4% (P = 0.003). Therapy with sodium fluoride was associated with an increase in osteocalcin (N.S.), whereas administration of ibandronate was associated with a decrease in the resorption parameter, carboxy-terminal cross-linked type-I collagen telopeptide (P < 0.05). Both sodium fluoride and ibandronate resulted in significant decreases in the serum concentration of osteoprotegerin after 9 months (P < 0.001). CONCLUSIONS: The findings of the present study show that both sodium fluoride and ibandronate are effective in combination with calcium and vitamin D substitution in the management of osteopenia and osteoporosis in patients with Crohn's disease. Both agents are safe and well tolerated, and induce continuous increases in lumbar bone density.

Rieber A, Aschoff A, Nüssle K, Wruk D, Tomczak R, Reinshagen M, Adler G, Brambs HJ. · Department of Diagnostic Radiology, University of Ulm, Germany. · Eur Radiol. · Pubmed #10997423 No free full text.

Abstract: The aim of the study was to evaluate the additional findings of MRI following small bowel enteroclysis and to compare the efficacy of negative and positive intraluminal contrast agents. Fifty patients with inflammatory or tumorous small bowel disease were investigated by small bowel enteroclysis and consecutive MRI using breathhold protocol (T1-weighted fast low-angle shot, T2-weighted turbo spin echo). Patients were randomly assigned to either receiving a positive oral (Magnevist, Schering, Berlin, Germany) or a negative oral MR contrast media (Abdoscan, Nycomed, Oslo, Norway). The pattern of contrast distribution, the contrast effect, presence of artifacts, as well as bowel wall and extraluminal changes, were determined and compared between the contrast type using Fischer's exact test. Sensitivity, specificity, and diagnostic accuracy for MRI and enteroclysis were calculated. Twenty-seven patients had clinically proven Crohn's disease and two patients surgically proven small bowel tumours. Magnetic resonance imaging had important additional findings as abscesses and fistulae in 20 patients. Surgically compared sensitivities were 100 and 0% for MRI and enteroclysis, for the detection of abscesses, and 83.3 and 17 % for the diagnosis of fistulae, respectively. Bowel wall thickening was more reliably detected with use of positive oral contrast media without intravenous enhancement (p < 0.001), whereas postcontrast negative oral contrast media allow for a superior detection (p < 0.001). T2-weighted sequences were necessary with use of negative oral contrast media, because loop abscesses may be masked. Magnetic resonance imaging should be performed in all patients with suspicion of extraintestinal complications, because the complications are more reliably detected by MRI. Negative oral contrast media show advantages with the use of intravenous contrast but can mask loop abscesses using only T1-weighted imaging.

von Tirpitz C, Klaus J, Brückel J, Rieber A, Scholer A, Adler G, Böhm BO, Reinshagen M. · Department of Medicine I, University of Ulm, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #10656205 No free full text.

Abstract: BACKGROUND AND AIMS: Low bone density with an increased risk of vertebral fractures is a frequent complication in inflammatory bowel disease. Since the aetiology of osteopathia in these patients is different compared to postmenopausal or steroid-induced osteoporosis, no treatment strategy is established. Supplementation of calcium and vitamin D has been shown to prevent further bone loss, but no data are available showing the anabolic effect of sodium fluoride in Crohn's disease. METHODS: We carried out a one-year prospective clinical trial in 33 patients with chronic active Crohn's disease who were randomly assigned to receive either calcium (500 mg b.i.d.) and 1000 IU vitamin D3 only, or retarded-release sodium fluoride (25 mg t.i.d.) additionally. The diagnosis of Crohn's disease had been made at least two years ago, and all patients had received systemic high-dose steroid therapy during the previous year. Eleven of 15 patients who received calcium/vitamin D and 15 of 18 patients who additionally received sodium fluoride completed the study. The primary endpoint of the study was the increase of bone mineral density, measured by dual energy X-ray absorptiometry (DXA) after one year of treatment. Bone-specific alkaline phosphatase and osteocalcin were used as markers for bone turnover. RESULTS: In the calcium/vitamin D only group, bone density was not significantly changed after one year of treatment, whereas in the calcium/vitamin D/fluoride group, bone density of the lumbar spine increased from -1.39+/-0.3 (Z-score, mean +/- SEM) to -0.65+/-0.3 (P<0.05) after one year of treatment. Increase of bone density was positively correlated to the osteoblastic markers bone-specific alkaline phosphatase (r = 0.53) and osteocalcin (r = 0.43). CONCLUSIONS: Sodium fluoride in combination with vitamin D and calcium is an effective, well-tolerated and inexpensive treatment to increase lumbar bone density in patients with chronic active Crohn's disease and osteoporosis.

Lochs H, Adler G, Beglinger C, Duchmann R, Emmrich J, Ewe K, Gangl A, Gasché C, Hahn E, Hoffmann P, Kaskas B, Malchow H, Pohl C, Raedler A, Renner E, Schölmerich J, Schreiber S, Stange E, Tilg H, Vogelsang H, Weigert N, Zeitz M. · Medizinische Klinik mit Schwerpunkt Gastroenterologie, Hepatologie und Endokrinologie, Charité, Medizinische Fakultät der Humboldt-Universität zu Berlin. · Z Gastroenterol. · Pubmed #10427657 No free full text.

Abstract: The chimeric anti-TNF antibody Remicade (Infliximab) has recently been approved for human use by the FDA and is now available on the market. Since there is considerable interest in this kind of treatment among patients with Crohn's disease, an international working group has summarized the presently available information about efficacy, side effects and possible problems of this treatment. Studies show that Remicade is effective in the treatment of active Crohn's disease, maintaining remission and fistulae. The working group does not see Infliximab as a first-line treatment for Crohn's disease. It may be used in active phase recurrent disease, chronic active disease and fistulae if standard treatment was not successful. For the surveillance special attention has to be given to the unknown malignancy rate of Infliximab. Infusion should be performed in an institution, routinely performing intravenous infusions and a two-hour surveillance of the patients should be guaranteed to recognize anaphylactic reactions or acute side effects. There is presently no information indication that the combination with immunosuppressants might increase risks or side effects of this treatment. Due to the limited information available the working group would prefer to use Remicade in studies only and recommends central collection and documentation of all data on efficacy and side effects for the next year.

Klaus J, Reinshagen M, Adler G, Boehm B, von Tirpitz C. · University of Ulm, Department of Internal Medicine I, Robert Koch Str, 8, 89081 Ulm, Germany. · BMC Gastroenterol. · Pubmed #18947388 links to  free full text

Abstract: BACKGROUND: Reduced bone mineral density (BMD) and osteoporosis are frequent in Crohn's disease (CD), but the underlying mechanisms are still not fully understood. Deficiency of sex steroids, especially estradiol (E2), is an established risk factor in postmenopausal osteoporosis. AIM: To assess if hormonal deficiencies in male CD patients are frequent we investigated both, sex steroids, bone density and bone metabolism markers. METHODS: 111 male CD patients underwent osteodensitometry (DXA) of the spine (L1-L4). Disease related data were recorded. Disease activity was estimated using Crohn's disease activity index (CDAI). Testosterone (T), dihydrotestosterone (DHT), estradiol (E2), sex hormone binding globulin (SHBG), Osteocalcin and carboxyterminal cross-linked telopeptids (ICTP) were measured in 111 patients and 99 age-matched controls. RESULTS: Patients had lower T, E2 and SHBG serum levels (p < 0.001) compared to age-matched controls. E2 deficiency was seen in 30 (27.0%) and T deficiency in 3 (2.7%) patients but only in 5 (5.1%) and 1 (1%) controls. Patients with E2 deficiency had significantly decreased T and DHT serum levels. Use of corticosteroids for 3 of 12 months was associated with lower E2 levels (p < 0.05). Patients with life-time steroids >10 g had lower BMD. 32 (28.8%) patients showed osteoporosis, 55 (49.5%) osteopenia and 24 (21.6%) had normal BMD. Patients with normal or decreased BMD showed no significant difference in their hormonal status. No correlation between markers of bone turnover and sex steroids could be found. ICTP was increased in CD patients (p < 0.001), and patients with osteoporosis had higher ICTP levels than those with normal BMD. CONCLUSION: We found an altered hormonal status--i.e. E2 and, to a lesser extent T deficiency--in male CD patients but failed to show an association to bone density or markers of bone turnover. The role of E2 in the negative skeletal balance in males with CD, analogous to E2 deficiency in postmenopausal females, deserves further attention.

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

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

von Boyen GB, Steinkamp M, Geerling I, Reinshagen M, Schäfer KH, Adler G, Kirsch J. · Department of Medicine I, Gastroenterology, University of Ulm, Ulm, Germany. · Inflamm Bowel Dis. · Pubmed #16670534 links to  free full text

Abstract: 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.

Ebinger M, Leidl R, Thomas S, Von Tirpitz C, Reinshagen M, Adler G, Konig HH. · Department of Health Economics, University of Ulm, Germany. · J Gastroenterol Hepatol. · Pubmed #14731130 No free full text.

Abstract: 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.

von Tirpitz C, Epp S, Klaus J, Mason R, Hawa G, Brinskelle-Schmal N, Hofbauer LC, Adler G, Kratzer W, Reinshagen M. · Department of Medicine I, University of Ulm, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #14560148 No free full text.

Abstract: 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.

Pauls S, Kratzer W, Rieber A, Schmidt SA, Mittrach C, Adler G, Brambs HJ, Gabelmann A. · Abteilung Diagnostische Radiologie, Universitätsklinik Ulm. · Rofo. · Pubmed #12886478 No free full text.

Abstract: PURPOSE: Evaluation of dynamic contrast enhanced MRI in patients with Crohn's disease to assess local inflammatory activity. MATERIAL AND METHODS: Prospective study of 13 patients with histologically proven Crohn's disease. Axial and coronal slices were acquired by a 1.5 T MR (Magnetom Vision, Siemens, Germany): T1 flash 2 D (TR 72.5 ms, TE 4.1 ms), T2 (TR 2730 ms, TE 138 ms), turbo-flash sequences T1 (TR 94.2 ms, TE 4.1 ms) post contrast media fat saturated (Magnevist, 0.2 ml/kg, flow 4 ml/s). In area of maximal thickening of terminal ileal wall, axial dynamic T1 sequences (TR 11 ms, TE 4.2 ms) were acquired every 1.5 s post contrast media application for a total duration of 1 min. Contrast uptake was subjectively measured by semiquantitative score and computed assisted ROI evaluation. MR parameters were correlated with CDAI (Crohn's disease activity index) and SAI (severe activity index). RESULTS: Contrast uptake in the intestinal wall occurred after 18.5 s (range: 3.0 - 28.0), contrast upslope until plateau phase lasted for 16.1 s (range: 8.0 - 50.0). Maximum contrast enhancement into the bowel wall was 266 % (105 - 450 %) of baseline. After maximum contrast uptake, we observed a plateau phase in all cases for the total duration of measurement. A significant correlation existed for maximum contrast uptake to CDAI (r = 0.591; p = 0.033), for beginning of contrast upslope to the time until plateau phase (r = 0.822; p = 0.001), and for the time until plateau phase to CDAI (r = 0.562; p = 0.046). CDAI was on average 108, median 106; SAI was on average 114, median 115. SAI correlated significantly to CDAI (r = 0.874). Maximum contrast uptake, beginning of contrast upslope, and time until plateau phase were independent to creeping fat, local lymphadenitis, laboratory parameters, temperature, body mass index, heart frequency and systolic blood pressure. CONCLUSION: Dynamic MRI enables to quantify local inflammatory activity of bowel wall in patients with Crohn's disease. Larger studies are necessary to establish this method in clinical routine.

Schmidt T, Reinshagen M, Brambs HJ, Adler G, Rieber A, V Tirpitz C, Kratzer W. · Universitätsklinikum Ulm, Abteilung Innere Medizin I, Robert-Koch-Str. 8, 89081 Ulm. · Z Gastroenterol. · Pubmed #12858235 No free full text.

Abstract: BACKGROUND: Enteroclysis, intestinal wall ultrasound (IWU) and abdominal magnetic resonance imaging (MRI) are three established methods in the diagnosis of Crohn's disease (CD). To date, however, the three methods have not been compared in one patient collective. AIMS: The present prospective study compared the relative performance of IWU, MRI and enteroclysis in determining the extent of disease involvement and intestinal complications in patients with CD both at initial diagnosis and during follow-up. PATIENTS AND METHODS: Included in the present study were 48 patients with confirmed CD (age: 19-66 years) examined with all three methods between August 1999 and December 2000. IWU was performed in B-mode with a 4-7 MHz convex transducer head and a 5-12 MHz linear transducer head by an experienced examiner. At MRI, T1 and T2 weighted sequenced (Flash 2D before and after intravenous application of gadolinium DTPA or TSE) were acquired in coronal and transverse planes. Enteroclysis was performed using conventional biphasic technique. Interpretation was conducted on the basis of a standardized catalogue of findings. RESULTS: Changes in bowel segments consistent with inflammation were identified in 41 of 48 patients. All three methods returned equivalent findings with regard to the length of inflamed bowel segments (IWU, range: 3-25 cm, mean: 12 cm; MRI, range: 3-25 cm, mean: 10 cm; enteroclysis, range: 3-30 cm, mean: 11 cm) and wall thickness (IWU, range: 4-10 mm, mean: 7 mm; MRI, range: 5-10 mm, mean: 7 mm; of nine patients with stenotic change, five were correctly diagnosed with IWU (sensitivity, 55.6%; specificity, 97.4%), four with MRI (sensitivity, 44.4%; specificity, 100%) and six with enteroclysis (sensitivity, 66.7%; specificity, 100%). Fistulae were correctly identified in five patients with IWU (sensitivity, 55.6%; specificity, 97.4%), in four with MRI (sensitivity, 44.4%; specificity, 100%) and in six with enteroclysis (sensitivity, 66.7%; specificity, 100 %) of a total of nine patients with confirmed fistula formation. Abscesses were correctly identified in five patients with IWU (specificity, 66.7%; specificity, 100%), in five with MRI (sensitivity, 83.3%; specificity, 100%) and in no patients with enteroclysis (sensitivity, 0%; specificity, 100%) in six patients with abscesses. CONCLUSION: Both IWU and MRI identify extent, severity and intestinal complications with adequate diagnostic accuracy in patients with CD. Both techniques possess the potential for replacing enteroclysis in the work-up of CD. Enteroclysis should be reserved for the work-up of complex fistula systems.

von Tirpitz C, Klaus J, Steinkamp M, Mason R, Kratzer W, Adler G, Rieber A, Reinshagen M. · First Department of Medicine, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany. · J Gastroenterol. · Pubmed #12673446 No free full text.

Abstract: 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.

König HH, Ulshöfer A, Gregor M, von Tirpitz C, Reinshagen M, Adler G, Leidl R. · Department of Health Economics, University of Ulm, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #12439115 No free full text.

Abstract: 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.

Klaus J, Armbrecht G, Steinkamp M, Brückel J, Rieber A, Adler G, Reinshagen M, Felsenberg D, von Tirpitz C. · Department of Medicine I, University of Ulm, Germany. · Gut. · Pubmed #12377802 links to  free full text

Abstract: BACKGROUND AND AIMS: Osteopenia and osteoporosis are frequent in Crohn's disease. However, there are few data on related vertebral fractures. Therefore, we evaluated prospectively the prevalence of osteoporotic vertebral fractures in these patients. METHODS: A total of 293 patients were screened with dual energy x ray absorptiometry of the lumbar spine (L1-L4) and proximal right femur. In 156 patients with lumbar osteopenia or osteoporosis (T score <-1), x ray examinations of the thoracic and lumbar spine were performed. Assessment of fractures included visual reading of x rays and quantitative morphometry of the vertebral bodies (T4-L4), analogous to the criteria of the European Vertebral Osteoporosis Study. RESULTS: In 34 (21.8%; 18 female) of 156 Crohn's disease patients with reduced bone mineral density, 63 osteoporotic vertebral fractures (50 fx. (osteoporotic fracture with visible fracture line running into the vertebral body and/or change of outer shape) and 13 fxd. (osteoporotic fracture with change of outer shape but without visible fracture line)) were found, 50 fx. in 25 (16%, 15 female) patients and 13 fxd. in nine (5.8%, three female) patients. In four patients the fractures were clinically evident and associated with severe back pain. Approximately one third of patients with fractures were younger than 30 years. Lumbar bone mineral density was significantly reduced in patients with fractures compared with those without (T score -2.50 (0.88) v -2.07 (0.66); p<0.025) but not at the hip (-2.0 (1.1) v -1.81 (0.87); p=0.38). In subgroups analyses, no significant differences were observed. CONCLUSIONS: In patients with Crohn's disease and reduced bone mineral density, the prevalence of vertebral fractures-that is, manifest osteoporosis-was strikingly high at 22%, even in those aged less than 30 years, a problem deserving further clinical attention.

Potthast S, Rieber A, Von Tirpitz C, Wruk D, Adler G, Brambs HJ. · Radiologische Klinik Ulm, Abteilung Röntgendiagnostik der Universität Ulm, Steinhövelstrasse 9, 89075 Ulm, Germany. · Eur Radiol. · Pubmed #12042948 No free full text.

Abstract: The objective of this retrospective study was to compare MRI of the abdomen with ultrasound of the abdomen and gastrointestinal tract in patients with Crohn's disease. Forty-six patients were included in the study. We analyzed the localization of Crohn's lesions, the number of affected bowel segments, the number of stenoses, and the presence of abscesses, fistulae, and any additional findings. Findings were verified by means of one or more of the following: enteroclysis; surgical findings; and colonoscopy. The results show that MRI is superior to ultrasound in the localization of affected bowel segments (sensitivity: MRI 97.5%; US 76%) and in recognizing fistulae (sensitivity: MRI 87%; US 31%), stenoses (sensitivity: MRI 100%; US 58%) and abscesses (sensitivity: MRI 100%; US 89%). Magnetic resonance imaging of the abdomen should be obtained to clarify discrepant clinical and sonographic findings. In addition, despite its higher cost, MRI of the abdomen is justified in patients in whom Crohn's lesions are known or suspected in anatomic areas proximal to the terminal or neoterminal ileum and in cases with suspicion of fistulae and abscesses.

Rösch M, Leidl R, Tirpitz C, Reinshagen M, Adler G, König HH. · Abteilung Gesundheitsökonomie, Universität Ulm, Germany. · Z Gastroenterol. · Pubmed #11961730 No free full text.

Abstract: OBJECTIVE: Cost diaries administered by patients have been used as a method to measure costs for different diseases. Our aim was to test the application of a patient cost diary in patients with inflammatory bowel disease (IBD) and to measure disease specific resource utilization and costs. PATIENTS AND METHODS: A specific patient cost diary for IBD was developed and tested in a prospective pilot study. 105 outpatients with IBD of a University Hospital agreed to participate over a 4 week follow-up period. They were asked to report weekly their use of medical care and costs related to their illness. Visits to health care providers, hospitalizations, drug use, costs due to absence from paid and unpaid work, travel costs as well as out-of-pocket expenses were considered. RESULTS: The response rate was 90 %. Almost 70 % of the patients estimated the diary as easy to fill in. Compared with other data sources, the cost measurement using the cost diary showed good agreement regarding costs of drug therapy and outpatient hospital treatment.Mean costs due to illness were estimated to be 1,500 Euro per 4 weeks. This corresponds to total costs of about 20,000 Euro per year of care. 69 % of total costs were indirect costs due to illness-related absence from work, days of inactivity at home, and early retirement. Direct health care and direct non health care costs (e. g. travel costs) were responsible for 27 % and 4 % of costs, respectively. DISCUSSION AND CONCLUSION: The presented instrument offers a suitable and practical method of assessing IBD-related resource utilization. The prospectively obtained data for direct medical and non medical, as well as indirect costs allow a cost measurement from the societal perspective. The presented cost diary can be used for measuring costs for economic evaluations of medical interventions.

Rösch M, Leidl R, Thomas S, von Tirpitz C, Reinshagen M, Adler G, König HH. · Abteilung Gesundheitsökonomie, Medizinische Universitäts- und Poliklinik, Universität Ulm. · Med Klin (Munich). · Pubmed #11957787 No free full text.

Abstract: 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.

Kratzer W, von Tirpitz C, Mason R, Reinshagen M, Adler G, Möller P, Rieber A, Kächele V. · Department of Internal Medicine I, University of Ulm, Germany. · J Ultrasound Med. · Pubmed #11833871 No free full text.

Abstract: OBJECTIVE: To use power Doppler sonography to quantify the vascularization in the area of stenosed bowel segments in patients with Crohn's disease and to draw conclusions from these findings with regard to the development of these stenoses. METHODS: The study collective included 11 patients with confirmed Crohn's disease and sonographically visualized stenoses of the small bowel together with intermittent abdominal cramping as a clinical correlate. Power mode examination was repeated after application of a sonographic signal-enhancing agent. Semiquantitative evaluation based on the sonographically indicated degree of vascularization led to the presumptive diagnosis of either inflammatory or cicatricial intestinal obstruction. Sonographic diagnoses were compared with the findings of surgery and subsequent histologic examination or with patients' clinical responses to conservative therapy. RESULTS: Nine of 11 patients underwent surgery within 1 year of examination. All 3 cases in which sonography had facilitated the diagnosis of cicatricial stenosis were confirmed at postoperative histologic examination; similarly, the surgical and histologic findings in the other 6 patients confirmed the sonographic diagnosis of inflammatory stenosis. CONCLUSIONS: Power Doppler sonography in combination with the use of a signal-enhancing agent appears to be effective in the recognition of predominantly cicatricial stenoses in patients with Crohn's disease.

von Tirpitz C, Kohn C, Steinkamp M, Geerling I, Maier V, Möller P, Adler G, Reinshagen M. · Department of Medicine I, University of Ulm, Ulm, Germany. · J Clin Gastroenterol. · Pubmed #11743245 No free full text.

Abstract: 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.

Rieber A, Wruk D, Potthast S, Nüssle K, Reinshagen M, Adler G, Brambs HJ. · Department of Diagnostic Radiology, University of Ulm, Germany. · Int J Colorectal Dis. · Pubmed #10954191 No free full text.

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.