Crohn Disease: Kruis W

Hoffmann JC, Preiss JC, Autschbach F, Buhr HJ, Häuser W, Herrlinger K, Höhne W, Koletzko S, Krieglstein CF, Kruis W, Matthes H, Moser G, Reinshagen M, Rogler G, Schreiber S, Schreyer AG, Sido B, Siegmund B, Stallmach A, Bokemeyer B, Stange EF, Zeitz M. · Medizinische Klinik I, St. Marienkrankenhaus, Ludwigshafen. · Z Gastroenterol. · Pubmed #18810679 No free full text.

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Hoffmann JC, Autschbach F, Bokemeyer B, Buhr HJ, Herrlinger K, Höhne W, Krieglstein C, Kruis W, Moser G, Preiss JC, Reinshagen M, Rogler G, Schreiber S, Schreyer AG, Siegmund B, Stallmach A, Stange EF, Zeitz M. · Medizinische Klinik I, St. Marienkrankenhaus Ludwigshafen. · Dtsch Med Wochenschr. · Pubmed #18788069 No free full text.

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Böhm SK, Kruis W. · Evangelisches Krankenhaus Kalk, Abteilung für Innere Medzin, Universität Zu Köln, Buchforststrasse 2, Köln, Germany. · Ann N Y Acad Sci. · Pubmed #17057214 No free full text.

Abstract: There is currently a growing appreciation for the role of the enteric flora in health and disease. In the past years overwhelming evidence has accumulated for the role of commensal gut bacteria in the inflammatory bowel diseases Crohn's disease and ulcerative colitis. Both entities are mainly located in areas with high bacterial concentrations. Reduction of the enteric bacterial concentration by antibiotics, lavage, or surgical bypass results in a mitigation of symptoms, while experimental colitis models depend on the presence of the bacterial flora and the NOD2/CARD15-mutation results in inefficient clearance of invasive bacteria. Those findings helped to bring the concept of probiotic therapy to the forefront, a therapy that had been known for millennia, but had been disregarded by the scientific world. Probiotics are meanwhile established in the maintenance therapy of ulcerative colitis and chronic recurrent or refractory pouchitis. Promising data exist for the primary prevention of pouchitis. Probiotic research at the intersection of gastroenterology, immunology and microbiology is highly dynamic in both the basic and the clinical field. Further understanding of the complex molecular mechanisms leading to the effectiveness of probiotics will also spur the development of more successful probiotic formulations.

Böhm S, Kruis W. · Evangelisches Krankenhaus Kalk, Köln. · MMW Fortschr Med. · Pubmed #16995360 No free full text.

Abstract: Current data show that probiotics are more effective in preventing the recrudescence of an inflammatory process than in suppressing active disease.This is reflected in the solid evidence for the effect of E. coli Nissle 1917 (Mutaflor) in the maintenance of remission of ulcerative colitis, and of VSL#3 in preventing the recurrence of pouchitis. These indications have since been incorporated in valid guidelines. Initial clinical studies have also provided promising results regarding the efficacy of VSL#3 in preventing pouchitis immediately following proctocolectomy.

Kruis W. · Evangelisches Krankenhaus Kalk, Akademisches Lehrkrankenhaus für die Universität zu Köln. · Praxis (Bern 1994). · Pubmed #16245637 No free full text.

Abstract: In Crohn's disease therapeutic concepts are according to distinct conditions. Course of the disease, the individual disease pattern and the aim of treatment are of particular significance. Care of patients with Crohn's disease requires interdisciplinary cooperation between gastroenterologists and surgeons. Primary therapy in mild to moderate disease comprises aminosalicylates and budesonide. Treatment of refractory or severe cases are corticosteroids. Immunosuppressive therapy is indicated in all kinds of complicated disease. First line immunosuppressants are Azathioprine and 6-Mercaptopurine while Methotrexate, Infliximab, Mycophenolatmofetil and other compounds represent alternative or rescue medications. Maintenance of remission should not be done on a regular basis but rather regarding the individual patients' situation. Risks have to be carefully balanced with possible benefits. The most important aim of treatment is quality of life.

Kruis W. · Evangelisches Krankenhaus Kalk, Teaching Hospital for the University of Cologne, Germany. · Aliment Pharmacol Ther. · Pubmed #15352898 links to  free full text

Abstract: Treatment with antibiotics in inflammatory bowel disease has a long tradition and is widely used. The indications for antibiotic therapy are wide ranging, from specific situations such as abscesses or fistulae, to patients with severe disease (as an unspecific 'protective' measure), and to address the hypothesis that the enteric flora as a whole, or specific microorganisms such as mycobacteria, are involved in the pathogenesis of inflammatory bowel disease. The best-studied single antibiotic compound is metronidazole. However, overall, the scientific basis for the use of antibiotics is limited, which may reflect a lack of interest from sponsors within the pharmaceutical industry. Despite this weak evidence base, antibiotics are a globally established therapeutic tool in inflammatory bowel disease. Growing evidence from human and animal studies points towards a pivotal pathogenetic role of intestinal bacteria in inflammatory bowel disease. In view of these experimental findings, clinical trials have been undertaken to elucidate the therapeutic effects of probiotics in inflammatory bowel disease. Probiotics are viable nonpathogenic microorganisms which confer health benefits to the host by improving the microbial balance of the indigenous microflora. So far, of the many candidates, one specific strain (Escherichia coli Nissle 1917) and a mixture of eight different bacteria have demonstrated convincing therapeutic efficacy in controlled studies. Maintenance therapy in ulcerative colitis and prevention therapy, as well as the treatment of pouchitis, have emerged as areas in which probiotic therapy offers a valid therapeutic alternative to current treatments. Further investigations may detect additional clinically effective probiotics and other clinical indications.

Hoffmann RM, Kruis W. · Innere Abteilung, Evangelisches Krankenhaus Kalk, Buchforststrasse 2, 51103 Köln. · Internist (Berl). · Pubmed #12524920 No free full text.

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Duchmann R, Lochs H, Kruis W. · Innere Medizin II, Universität des Saarlandes, Homburg/Saar. · MMW Fortschr Med. · Pubmed #10949626 No free full text.

Abstract: Crohn's disease (CD) and ulcerative colitis (UC) are clinical entities characterized by spontaneous relapses and are thought to be caused in large part by a dysregulated immune response to inflammatory stimuli. Specific infectious agents or antigens inducing or perpetuating inflammation, however, are not known. Recent results in contrast support the hypothesis, that the normal intestinal flora plays a central role in the pathogenesis of both diseases. Studies performed with E. coli Nissle 1917 demonstrated that this bacterium can positively affect the course of disease in UC and CD patients. The clinical efficacy of probiotics can yield valuable information about disease pathogenesis and, as a modification of current standard therapy, opens new and interesting therapeutic alternatives.

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.

Schreiber S, Nikolaus S, Malchow H, Kruis W, Lochs H, Raedler A, Hahn EG, Krummenerl T, Steinmann G, Anonymous00274. · First Medical Department, University Hospital Kiel, Germany. · Gastroenterology. · Pubmed #11313303 No free full text.

Abstract: BACKGROUND & AIMS: ISIS-2302, an antisense oligonucleotide directed against intercellular adhesion molecule 1, was effective in steroid refractory Crohn's disease in a pilot trial. The aim of this study was to investigate safety and efficacy of ISIS-2302 in chronic active Crohn's disease (CACD). METHODS: A dose-interval, multicenter, placebo-controlled trial was conducted in 75 patients with steroid-refractory CACD (Crohn's Disease Activity Index [CDAI], 200-400). The primary endpoint was steroid-free remission (CDAI <150) at week 14. RESULTS: Only 2 of 60 (3.3%) ISIS-2302-treated and no placebo patients reached the primary endpoint. Steroid-free remission at week 26 (secondary endpoint) was reached in 8 of 60 (13.3%) active treatment and 1 of 15 (6.7%) placebo patients. A greater proportion of ISIS-2302-treated than placebo patients achieved a steroid dose <10 mg/day at weeks 14 and 26 (48.3% vs. 33.3% and 55.0% vs. 40.0%, respectively, and a glucocorticoid dose of 0 mg [prednisone equivalent] at week 26 [23.3% vs. 6.7%, respectively]). Treatment with ISIS-2302 was safe. The most common side effects were injection site reactions in the active treatment group (23% in ISIS-2302-treated patients vs. none in placebo patients). No statistically significant differences in the frequency of side effects were detected between dose groups. CONCLUSIONS: The trial did not prove clinical efficacy of ISIS-2302 based on the primary endpoint. Positive trends were observed in some of the secondary endpoints.

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.

Allgayer H, Roisch U, Zehnter E, Ziegenhagen DJ, Dienes HP, Kruis W. · Department of Gastroenterology and Metabolism, Rehaklinik Ob der Tauber, Bad Mergentheim, Academic Teaching Hospital, University of Heidelberg, Heidelberg, Germany. · Dig Dis Sci. · Pubmed #17171446 No free full text.

Abstract: The role of colonic mucosal ornithine decarboxylase (ODC) in inflammatory bowel disease (IBD) remains controversial. This study assessed mucosal ODC activity in IBD patients segment by segment with regard to patient characteristics, disease activity/duration, medication, degree of mucosal inflammation, and presence/absence of epithelial regeneration and guanosine triphosphate (GTP) stimulation. Mucosal ODC activity was determined in biopsy specimens from the terminal ileum, cecum/ascending, transverse, and descending colon, and the sigmoid/rectum of 35 patients with IBD (18 with Crohn's disease, 17 with ulcerative colitis) and 29 controls, using the amount of 14CO2 liberated from (carboxyl-14C)ornithine hydrochloride. GTP-stimulatable activity was expressed as the ratio of ODC activity in the presence and absence of GTP (70 micromol/L). Mucosal inflammation was assessed endoscopically/microscopically with previously described criteria. Presence/absence of mucosal regeneration also was determined by predefined criteria. Mucosal ODC-activity did not significantly differ in IBD patients and controls. There was a 4.4-fold activity gradient from the ileum to the rectum. Mucosal ODC activity was significantly higher in areas with epithelial regeneration compared to those without regeneration, and was stimulated by GTP by a factor of 1.42 in Crohn's disease and 1.19 in ulcerative colitis patients compared to controls (p < 0.004). On the other hand, there was no significant association/relationship of mucosal ODC activity with disease activity/duration and the endoscopic/histologic degree of mucosal inflammation. The observation of unchanged mucosal ODC activity in patients with IBD and the absence of a significant relationship with clinical and endoscopic/histologic disease characteristics speaks against a major role of ODC in IBD as a major disease marker. The role of the ileorectal gradient, the enhanced activity in areas with epithelial regeneration, and the GTP-stimulatable form, however, need further investigation with regard to a possible involvement in carcinogenesis in IBD.

Holtmann MH, Krummenauer F, Claas C, Kremeyer K, Lorenz D, Rainer O, Vogel I, Böcker U, Böhm S, Büning C, Duchmann R, Gerken G, Herfarth H, Lügering N, Kruis W, Reinshagen M, Schmidt J, Stallmach A, Stein J, Sturm A, Galle PR, Hommes DW, D'Haens G, Rutgeerts P, Neurath MF. · First Department of Medicine, Johannes Gutenberg University, Mainz, Germany. · Dig Dis Sci. · Pubmed #16927148 No free full text.

Abstract: In Crohn's disease the optimal duration of azathioprine treatment is still controversial and for ulcerative colitis only limited data are available to support its efficacy. Charts of 1176 patients with IBD from 16 European centers were analyzed. Flare incidences and steroid dosages were assessed for the time before and during treatment and after discontinuation. Within the first 4 years, azathioprine suppressed flare incidence and steroid consumption in both diseases (P < 0.001). While in CD discontinuation after 3-4 years did not lead to reactivation, this was the case in UC. However, continuation beyond 4 years further improved clinical activity in CD and steroid requirement in both diseases (P < 0.001). Discontinuation of azathioprine may thus be considered after 3-4 years in CD patients in complete remission without steroid requirement. In all other CD patients and for UC patients in general, continuation seems beneficial. These results support a novel differential algorithm for long-term azathioprine therapy in IBD.

Lanyi B, Dienes HP, Kruis W. · Abteilung für Innere Medizin, Gastroenterologie, Evangelisches Krankenhaus Köln Kalk. · Dtsch Med Wochenschr. · Pubmed #16123897 No free full text.

Abstract: HISTORY: A 57-year-old woman complained about increasing pain and weakness in her hips and legs. 7 months earlier active (Crohn's) ileocolitis had been diagnosed. She had received several bouts of steroids and had been in clinical remission for 12 weeks under a dosage of 40 mg/d prednisone. INVESTIGATIONS: Clinical examination, laboratory work up, x-rays and MRI of the pelvis, bone scan, neurologic examination and muscle biopsy showed unspecific results. THERAPY AN COURSE: Steroides were tapered and replaced by weekly intramuscular methotrexate 20 mg which resulted in long lasting clinical remission. Pain and weakness persisted. 6 months later MRI revealed osteonecrosis of both femoral heads. 4 1/2 years after the initial diagnosis of Crohn's disease the patient complained about pain in her lower legs without evidence of osteonecrosis in MRI. Another 2 years later avascular osteonecrosis was diagnosed by tibial bone biopsy. Now MRI verified patchy osteonecrosis of the tibiae. Further osteonecrosis of the left foot were diagnosed by MRI ten years after initial diagnosis of Crohn's disease in the now 67-year-old patient. She is still in remission on weekly intramuscular 15 mg methotrexate. CONCLUSION: The long interval between steroid treatment and recurrent avascular bone necrosis as well as the unusual pattern of bone involvement indicate that osteonecrosis is an extraintestinal manifestation of Crohn's disease. More reports and comparative studies are necessary to give more evidence that avascular osteonecrosis is an extraintestinal manifestation of inflammatory bowel disease.

Kruis W. · Evangelisches Krankenhaus Kalk, Innere Abteilung. · Dtsch Med Wochenschr. · Pubmed #15368174 No free full text.

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