Crohn Disease: Stein J

Stein J, Anonymous00113. · Med. Klinik II/Zentrum der Inneren Medizin, Universitätsklinikum. · Z Gastroenterol. · Pubmed #12541177 No free full text.

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Schröder O, Stein J. · Second Department of Internal Medicine, Division of Gastroenterology, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany. · Am J Gastroenterol. · Pubmed #12650783 No free full text.

Abstract: Despite many recent advances, some notable limitations exist in the medical management of patients with inflammatory bowel disease. Glucocorticoids suppress active inflammation very effectively, but their long term use is associated with high rates of relapse and unacceptable toxicity. 6-Mercaptopurine and its prodrug azathioprine are effective in inducing and maintaining remission; however, a significant number of patients are resistant or intolerant to thiopurines. Low dose methotrexate, an anti-inflammatory drug, is a well established medication for rheumatoid arthritis and psoriasis. After an initial report in 1989, several clinical trials and analyses of clinical notes have examined the role of methotrexate in patients with ulcerative colitis and Crohn's disease. This review was conducted to summarize the current knowledge about the underlying basic anti-inflammatory mechanisms of methotrexate as well as the pharmacology and toxicology of this drug with particular emphasis on inflammatory bowel disease. It also critically evaluates all existing trials not only in the induction of remission but also in maintenance therapy. We conclude that low dose methotrexate is an effective and safe treatment in glucocorticoid-dependent and thiopurine intolerant patients with Crohn's disease but not ulcerative colitis. It remains to be seen whether low dose methotrexate may also be useful in long term maintenance therapy in patients with inflammatory bowel disease.

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 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.

Fellermann K, Steffen M, Stein J, Raedler A, Hämling J, Ludwig D, Loeschke K, Stange EF. · Department of Internal Medicine I, Division of Gastroenterology, University of Lübeck, Lübeck, Germany. · Aliment Pharmacol Ther. · Pubmed #10651657 links to  free full text

Abstract: BACKGROUND: Mycophenolate mofetil (MMF) is a new immunosuppressant with pharmacodynamic properties comparable to azathioprine. Recent reports found MMF to be effective in inflammatory bowel disease (IBD). METHODS: An open-label prospective and uncontrolled multicentre 6 month trial of MMF in combination with steroids was conducted in 24 chronic active IBD patients. A daily steroid demand of >/= 10 mg prednisone in the preceding 2 months and a Crohn's disease activity index (CDAI) > 150, or moderate to severe activity according to Truelove, served as criteria for chronic activity. The treatment consisted of a steroid pulse and tapering protocol in combination with MMF 2 g/day. A prednisone dose of 5 mg/day was maintained during months 4-6. The primary end-point was induction and maintenance of remission. RESULTS: Only 10 of 24 patients had achieved remission after 3 months. All but one Crohn's disease patient had relapsed by the end of the study at 6 months. Depression and migraine necessitated drug withdrawal in two patients. CONCLUSION: In conclusion, MMF 2 g/day was unable to induce and maintain remission for a period of 6 months in 23 of 24 chronic active IBD patients. Further controlled investigations are required in view of recent conflicting reports.

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.

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.

Schröder O, Blumenstein I, Stein J. · First Department of Internal Medicine, ZAFES, Johann Wolfgang Goethe University, Frankfurt, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #16357613 No free full text.

Abstract: OBJECTIVES: Immunosuppression of chronic active Crohn's disease resistant or intolerant to purine antimetabolites still remains a clinical challenge. To obtain long-lasting effects with the anti-TNF-alpha antibody infliximab repeated infusions are often required. Methotrexate has been shown to be a moderately effective drug in maintaining remission in Crohn's disease. The aim of the present pilot study was to evaluate the combination of infliximab and methotrexate as therapy for refractory Crohn's disease. METHODS: Nineteen patients with chronic active Crohn's disease resistant or intolerant to azathioprine were enrolled. Patients received either two infusions of infliximab (5 mg/kg) alone (n=8) or in combination with long-term methotrexate at a dosage of 20 mg/week (n=11) over 48 weeks. RESULTS: Two out of eight patients receiving infliximab monotherapy and four out of 11 patients treated with infliximab and concomitant methotrexate had discontinued study treatment by week 48, solely because of lack of efficacy. Clinical remission at week 48 was observed in five out of seven patients treated with infliximab and methotrexate, but only in two out of six patients receiving infliximab monotherapy. In addition, patients treated with concomitant methotrexate achieved remission earlier (median time 2 versus 18 weeks) and needed fewer steroids (median prednisolone dose 0 versus 11.8 mg). Despite an increased mean number of adverse events per patient in the methotrexate group, the proportions of patients experiencing any adverse events and serious adverse events were similar across treatment groups. CONCLUSIONS: The combination of infliximab with long-term methotrexate may be a promising concept in refractory Crohn's disease. Our data prompt larger trials.

Schröder O, Naumann M, Stein J. · No affiliation provided · Aliment Pharmacol Ther. · Pubmed #15379845 links to  free full text

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Naumann M, Schaum B, Oremek GM, Hanisch E, Rösch W, Mössner J, Caspary WF, Stein J. · Medizinische Klinik II, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt. · Dtsch Med Wochenschr. · Pubmed #15314744 No free full text.

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Schröder O, Blumenstein I, Schulte-Bockholt A, Stein J. · IInd Department of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt, Germany. · Aliment Pharmacol Ther. · Pubmed #14984376 links to  free full text

Abstract: BACKGROUND: Crohn's disease is complicated by fistulas in 20-40% of patients at some time during the course of their illness. Azathioprine has been reported to heal fistulas in 30-40% of cases. Long-lasting effects by the anti-tumour necrosis factor-alpha antibody infliximab most often require repeated infusions. Methotrexate has been shown to be an effective drug in maintaining remission in Crohn's disease. AIM: To evaluate the combination of infliximab and methotrexate as therapy for fistulas in patients with Crohn's disease. METHODS: Twelve consecutive patients (mean age, 29.5 years) with fistulizing Crohn's disease resistant or intolerant to azathioprine were followed prospectively. Patients received three infusions of infliximab (5 mg/kg) and long-term methotrexate (20 mg/week). Therapy success was defined as sustained closure of fistulas > or = 6 months after fistula closure. RESULTS: In four of the 12 patients, complete closure of fistulas that persisted for > or = 6 months (median follow-up, 13.25 months) was observed. In three further patients, a partial response was noted. In five patients, persistent therapy success could not be achieved or therapy had to be stopped due to side-effects. CONCLUSIONS: A combination of infliximab with long-term methotrexate may be a promising concept in fistulizing Crohn's disease. Our data indicate the need for larger controlled trials.

Faust D, Menge F, Armbruster FP, Lembcke B, Stein J. · 2nd Department of Internal Medicine & Gastroenterology, Johann Wolfgang Goethe-University, Frankfurt, Germany. · Z Gastroenterol. · Pubmed #12664344 No free full text.

Abstract: INTRODUCTION: Impaired calcium homeostasis and/or the administration of corticosteroids are considered to be among the factors contributing to the pathogenesis of osteopenia in patients with inflammatory bowel disease. There is an increasing evidence suggesting that certain pro-inflammatory cytokines may also directly influence the bone metabolism in these patients. Routine measurement of bone mass and loss usually include dual energy X-ray absorptiometry as well as urinary and serum assessment of collagen crosslinks. More recent studies include likewise the detection of bone sialoprotein into a specific diagnostics of bone turnover. PATIENTS AND METHODS: We investigated 47 patients with inflammatory bowel disease (Crohn's disease N = 41, ulcerative colitis N = 6) and 17 healthy volunteers to assess and compare serum levels of bone sialoprotein and other routine parameters of bone turnover. Bone sialoprotein levels were measured by using a recently described radioimmunoassay. RESULTS: In comparison to the control group, bone sialoprotein and urinary crosslinks were significantly increased only in patients with Crohn's disease, while other markers of bone turnover (e. g. alkaline phosphatase, carboxylterminal propeptide of typ I procollagen, urinary deoxypyridinoline, vitamin D, phosphate and calcium) did not differ significantly between the patients' groups. CONCLUSION: According to these data, increased serum bone sialoprotein concentrations seem to be an additional valuable and sensitive marker of bone resorption in patients with Crohn's disease.

Schröder O, Stein J. · Medizinische Klinik II, Johann-Wolfgang-Goethe-Universität, Frankfurt. · Z Gastroenterol. · Pubmed #10413850 No free full text.

This publication has no abstract.