Ulcerative Colitis: Valentine JF

Sandborn WJ, Sands BE, Wolf DC, Valentine JF, Safdi M, Katz S, Isaacs KL, Wruble LD, Katz J, Present DH, Loftus EV, Graeme-Cook F, Odenheimer DJ, Hanauer SB. · Mayo Clinic, Rochester, MN, USA. · Aliment Pharmacol Ther. · Pubmed #12786629 links to  free full text

Abstract: BACKGROUND: Repifermin (keratinocyte growth factor-2) has been shown to reduce inflammation in animal models of colitis. AIM: To evaluate repifermin for the treatment of active ulcerative colitis. METHODS: Eighty-eight patients with active ulcerative colitis were enrolled in a 6-week, double-blind trial. Patients were randomized to receive treatment for five consecutive days with intravenous repifermin at a dose of 1, 5, 10, 25 or 50 microg/kg, or placebo. The primary objective of the study was to evaluate the safety of repifermin. The primary efficacy outcome was clinical remission at week 4, defined as a score of zero on the endoscopic appearance and stool blood components of the Mayo score and a score of zero or unity on the stool frequency and physician's global assessment components. RESULTS: At week 4, the rates of clinical remission in the 1, 5, 10, 25 and 50 microg/kg repifermin groups were 19%, 9%, 0%, 0% and 0%, respectively, and 11% for the placebo group (P = 0.32 for repifermin vs. placebo). The frequencies of commonly occurring adverse events and severe adverse events were similar in both groups. CONCLUSIONS: Intravenous repifermin at a dose of 1-50 microg/kg was very well tolerated, but there was no evidence that repifermin was effective for the treatment of active ulcerative colitis at these doses. An additional study to determine the efficacy of repifermin at doses of > 50 microg/kg or for a longer treatment duration may be warranted, as the maximally tolerated dose was not reached in the present study.

Van Assche G, Sandborn WJ, Feagan BG, Salzberg BA, Silvers D, Monroe PS, Pandak WM, Anderson FH, Valentine JF, Wild GE, Geenen DJ, Sprague R, Targan SR, Rutgeerts P, Vexler V, Young D, Shames RS. · Universitaire Ziekenhuizen Leuven, Inwendige Geneeskunde, UZ Gasthuisberg, Herestraat 49-B-3000, Leuven, Belgium. · Gut. · Pubmed #16603634 No free full text.

Abstract: BACKGROUND: An uncontrolled pilot study demonstrated that daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), might be effective for the treatment of active ulcerative colitis. METHODS: A randomised, double blind, placebo controlled trial was conducted to evaluate the efficacy of daclizumab induction therapy in patients with active ulcerative colitis. A total of 159 patients with moderate ulcerative colitis were randomised to receive induction therapy with daclizumab 1 mg/kg intravenously at weeks 0 and 4, or 2 mg/kg intravenously at weeks 0, 2, 4, and 6, or placebo. The primary end point was induction of remission at week 8. Remission was defined as a Mayo score of 0 on both endoscopy and rectal bleeding components and a score of 0 or 1 on stool frequency and physician's global assessment components. Response was defined as a decrease from baseline in the Mayo score of at least 3 points. RESULTS: Two per cent of patients receiving daclizumab 1 mg/kg (p = 0.11 v placebo) and 7% of patients receiving 2 mg/kg (p = 0.73) were in remission at week 8, compared with 10% of those who received placebo. Response occurred at week 8 in 25% of patients receiving daclizumab 1 mg/kg (p = 0.04) and in 33% of patients receiving 2 mg/kg (p = 0.30) versus 44% of those receiving placebo. Daclizumab was well tolerated. The most frequently reported adverse events in daclizumab treated patients compared with placebo treated patients were nasopharyngitis (14.6%) and pyrexia (10.7%). CONCLUSION: Patients with moderate ulcerative colitis who are treated with daclizumab are not more likely to be in remission or response at eight weeks than patients treated with placebo.

Rumsey J, Valentine JF, Naser SA. · Department of Molecular Biology and Microbiology and Biomolecular Science Center, Burnett College of Biomedical Sciences. University of Central Florida, Orlando, FL 32816, USA. · Med Sci Monit. · Pubmed #16572045 No free full text.

Abstract: BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) is an intracellular pathogen that is known to parasitize macrophages. MAP is the known etiological agent of Johne's disease and implicated in the etiology of Crohn's disease. MATERIAL/METHODS: In this study, the survival of human-derived MAP isolate following phagocytosis was evaluated using murine macrophage cell line J774A.1 and polymorphonuclear cells (PMNC's) from six Crohn's disease patients. PMNC's from five healthy individuals and four ulcerative colitis patients, as well as Escherichia coli and Mycobacterium tuberculosis, were included as controls (MOI 10:1). Maturation of the phagosome was determined by evaluating the presence of stage specific markers on the surface of the phagosomal membrane. The endosomal protein, transferrin receptor, and the lysosomal protein, Lamp-1, were then immunostained with Cy-5 conjugated secondary antibodies, and colocalization of bacteria with each marker was evaluated separately using confocal scanning laser microscopy (CSLM). RESULTS: In both models, colocalization of viable MAP and M. tuberculosis with the early endosomal marker occurred with a higher frequency than did association with the late lysosomal marker, as compared to live E. coli, and all dead bacterial species. Using differential live/dead staining and fluorescent microscopy, survival of M. tuberculosis and MAP was calculated to be 85% and 79%, respectively compared to only 14% for E. coli. CONCLUSIONS: Overall, MAP survival in murine macrophages and human PMNCs appears to mimic M. tuberculosis, suggesting the ability of this microorganism to resist phagolysosome fusion, by maintaining association with the early endosomes. The data supports MAP virulence in humans.

Romero C, Hamdi A, Valentine JF, Naser SA. · Department of Molecular Biology and Microbiology and Biomolecular Science Center, The Burnett College of Biomedical Sciences, University of Central Florida, Orlando, Florida 32816, USA. · Inflamm Bowel Dis. · Pubmed #15677904 No free full text.

Abstract: Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) with tissue granuloma and histopathological alteration that resembles aspects in tuberculosis, leprosy, and paratuberculosis. Mycobacterium avium subsp paratuberculosis (MAP) is the causative agent of paratuberculosis, with a suspected role in the etiology of CD. We investigated the presence of MAP DNA in 31 surgical tissue samples from 20 subjects using fluorescence in situ hybridization (FISH) with the aid of confocal scanning laser microscopy and nested polymerase chain reaction (PCR) using the IS900 sequence unique to MAP. MAP DNA was detected by PCR in tissue from 10 of 12 (83%) patients with CD: 7/12 (58%) in inflamed, 6/11 (55%) in noninflamed and in 10 (83%) of either tissue and by FISH in 8 of 12 (67%) patients with CD: 7 of 12 (58%) in inflamed, 4 of 11 (36%) in noninflamed, and in 8(67%) of either tissue. In non-IBD subjects, MAP DNA was detected in the tissue of only 1 of 6 patients (17%) by PCR and 0 of 6 patients (0%) by FISH. MAP DNA was identified by PCR in inflamed tissue from 2 of 2 patients with ulcerative colitis. The detection of MAP DNA by either technique in tissue from subjects with CD is significant compared with non-IBD subjects (P < 0.005). Identification of MAP DNA in both inflamed and noninflamed tissue by both techniques suggests that MAP infection in patients with CD may be systemic. The data add more evidence toward a possible association of MAP in the pathogenesis of CD.

Naser SA, Ghobrial G, Romero C, Valentine JF. · Department of Molecular Biology and Microbiology and Biomolecular Science Center, Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32816, USA. · Lancet. · Pubmed #15380962 No free full text.

Abstract: BACKGROUND: Crohn's disease, a form of inflammatory bowel disease, resembles some aspects of tuberculosis, leprosy, and paratuberculosis. The role of Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn's disease is controversial. METHODS: We tested for MAP by PCR and culture in buffy coat preparations from 28 individuals with Crohn's disease, nine with ulcerative colitis, and 15 without inflammatory bowel disease. FINDINGS: MAP DNA in uncultured buffy coats was identified by PCR in 13 (46%) individuals with Crohn's disease, four (45%) with ulcerative colitis, and three (20%) without inflammatory bowel disease. Viable MAP was cultured from the blood of 14 (50%) patients with Crohn's disease, two (22%) with ulcerative colitis, and none of the individuals without inflammatory bowel disease. Current use of immunosuppressive medication did not correlate with a positive MAP culture. Sequencing of PCR products from MAP cultures confirmed the presence of the MAP-specific IS900 fragment. Among 11 MAP isolates assessed, we identified nine strains that were not identical. INTERPRETATION: We detected viable MAP in peripheral blood in a higher proportion of individuals with Crohn's disease than in controls. These data contribute to the evidence that MAP might be a cause of Crohn's disease.

Foster RA, Zander DS, Mergo PJ, Valentine JF. · Department of Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA. · Inflamm Bowel Dis. · Pubmed #14555914 No free full text.

Abstract: Lung injury related to mesalamine (5-aminosalicylic acid) has rarely been reported in patients with inflammatory bowel diseases. Patients present with progressive respiratory symptoms and radiographic abnormalities whose genesis may occur from days to years after initiation of therapy. Although pathologic features overlap with other pulmonary disorders, findings of chronic interstitial pneumonia and poorly formed nonnecrotizing granulomas should prompt consideration of mesalamine-related lung disease in a patient receiving this medication. The authors describe the clinical, radiographic, and pathologic manifestations of mesalamine-related lung disease in three patients and review the literature related to this topic.