- Email: [email protected]
Ileal mucosal response to bacterial toxin (FMLP) challenge
April 2000
AGAA1345
6124
6126
THE PREDICTORS OF SELF-REPORTED RELAPSE IN ULCERATIVE COLITIS: QUALITY OF LIFE AND NUMBER OF SYMPTOMS EXPERIENCED MAY BE MORE IMPORTANT THAN DISEASE EXTENT AND ACTIVITY. Seong-Won Han, Elaine McColl, 1. Nick Steen, John R. Barton, Mark R. Welfare, Peter James, Univ of Newcastle, Newcastle, United Kingdom; Ctr for Health Service Research, Newcastle, United Kingdom. Introduction: Previous studies have suggested that disease-related variables such as the number of previous relapses and the current level of symptoms are the best predictors of number of relapses in ulcerative colitis. Little attention has been paid to cognitive factors or the patients quality of life as determinants of relapse. Aims: To determine factors that predict relapse over I year in ulcerative colitis, including demographic, socio-economic, disease-related, quality of life and illness perception. Methods: 87 subjects completed the IBDQ, the SF-36, the illness perception questionnaire (IPQ), a symptom activity index (the CAl), and questions on socio-economic status, smoking and medication. Data on disease extent was extracted from the medical records. The subjects self-reported the number of relapses over the subsequent 12 months. Pearson correlations were calculated between the outcomes after I year and all baseline variables. Multiple regression modelling using stepwise analysis, identified those factors which best predicted the number of relapses after I year. Two models were used: model #1 included only the demographic, socio-economic and disease variables as independent factors; model #2 included all baseline variables as independent factors. Results: Individual correlations with the number of relapses were all weak (r
AN INVESTIGATION OF THE ASSOCIATION OF THE PROTHROMBIN GENE MUTATION AND INFLAMMATORY BOWEL DISEASE. Neil Haslam, Standen R. Graham, Jonathon L. Brown, Roland M. Valori, Christopher S. Probert, GIoucestershire Royal Hosp, Gloucester, United Kingdom; Bristol Royal Infirmary, Bristol, United Kingdom. Background: A thrombotic aetiology for inflammatory bowel disease (IBD) has been proposed as a result of its association with thromboembolic complications (l), smoking, the oral contraceptive pill (2) and the response of ulcerative colitis (UC) patients to heparin (3). We have previously demonstrated an increased incidence of the Factor V Leiden mutaion (4) in UC and wished to investigate the incidence of the recently discovered Pro-thrombin gene mutation in IBD. The Pro-thrombin gene mutation is the second commonest inherited risk factor for thromboembolism and is due to a single nucleotide change (Guanine to Adenine) at position 20210 of the 3' -untranslated region (5). The aim of the study was to investigate the hypothesis that the pro-thrombotic state associated with the pro-thrombin gene mutation is involved in the aetiology of IBD. Patients and Methods: A prospective cohort study of patients attending the Bristol Royal Infirmary and GIoucestershire Royal Hospital's IBD outpatient clinics was performed. Thirty nine patients with IBD (24 with Crohn's disease (CD) and 15 with UC) and 100 historical controls were screened for the presence of the pro-thrombin gene mutation using a heteroduplex-based polymerase chain reaction (PCR) technique. None of the patients with IBD had a personnel history of thrombo-embolism, whilst three of them had a family history. Results: No IBD patients had the pro-thrombin gene mutation compared to four (4%) controls (Allelic frequency 2%). Conclusion: There does not appear to be an association of the pro-thrombin gene mutaion with IBD and hence is unlikely to be involved in the aetiology of IBD. (1) Levine et ai. Gastroenterology clinics of North America 1995:24:633-46. (2) Logan et ai. Int J Epidemiol 1989;18:105107. (3) Gaffney et ai. AmI Gastroenterolo 1995;90:220-23. (4) Haslam et ai. Eur J Gastroenerol Hepatol 1999;11:1289-91. (5) Poort et ai. Blood 1996;88(10):3698-703.
6125 ILEAL MUCOSAL RESPONSE TO BACTERIAL TOXIN (FMLP) CHALLENGE. Yael Harari, Frank Moody, UT Med Sch, Houston, TX. Background and Aim: Disruption of the mucosal barrier of the intestinal tract is reflected in increased permeability to lumenal bacteria and/or their noxious byproducts. Lumenal perfusion of the ileum with FMLP results in increased mucosal permeability and an increment in appearance of myeloperoxidase (MPO) in the effluent. We hypothesized that mast cells and neutrophils within the gut wall are involved in this effect. Models and Measurements: a) Ileal permeability was measured 14 days following total abdominal irradiation (TAI;8Gy) which leads to the disappearance of mast cells for at least 30 days. Segments (15 ern) of the most distal ileum were perfused with Krebs buffer with or without FMLP (1O- 5M). Perfusate samples were collected every 15 min. Fluoresceinated marker (4000 kDa) was introduced systemically and its appearance as well as myeloperoxidase presence in intestinal effluent were measured. b) The release of 5-HT and histamine (mast cell mediators) with or without FMLP in different concentrations, into the serosal side of everted ileal sacs was measured. Results: Significant (P<.05) transient increases in intestinal permeability (7.3xlO-4::':7.lxlO-5 [n=5] vs.1.73xlO-2::':5.8xlO-3 [n=8] mllminlg) and MPO (0.64::':0.07 [n=4] vs.1.54::':0.04 [n=5] ng/mllg) were detected in control non-treated rats within 15 min after FMLP introduction. Irradiation resulted in ablation of the increase in permeability [n=5] as well as in the transient rise in MPO output into the perfusate [n=5]. Significant (p<0.05) increase in 5-HT release from ileal everted sac (28.5::':5.lvs 56.5::':1.5 [n=4] ng/g) was measured in the presence of FMLP. There was a nonsignificant rise (20.5::':3.8 vs 45.2::':9.9 [n=4] p..g/g) also in histamine output. Conclusions: Irradiation eliminates the rise in MPO in the effluent as well as the transient increase in ileal permeability caused by FMLP. These experiments reflect the involvement of mast cells and neutrophils in FMLP-induced mucosal inflammation and raise the possibility that in certain clinical situations proinflammatory mediators within the gut wall may be activated by toxic factors in the intestinal lumen.
6127 AUDIT OF CYCLOSPORIN USE IN INFLAMMATORY BOWEL DISEASE: LIMITED BENEFITS, NUMEROUS SIDE-EFFECTS. Neil Haslam, Stephen D. Hearing, Christopher S. Probert, Gloucestershire Royal Hosp, Gloucester, United Kingdom; Bristol Royal Infirmary, Bristol, United Kingdom. Background: The failure of standard treatments for inflammatory bowel disease (IBD) has led to the use of immuno-modulatory therapy, particularly cyclosporin and azathioprine. Most reports of the use of cyclosporin are from single specialist centres. We therefore undertook a survey of the use of cyclosporin in IBD in Bristol's three teaching hospitals. Patients and Methods: Over a four year period, all patients receiving cyclosporin for IBD were identified and the following data recorded; (i) diagnosis, (ii) duration of disease, (iii) initial treatment, (iv) date initiated, (v) dose of cyclosporin, (vi) side effects, (vii) initial clinical response and (viii) current patient status. Results: Thirty-three patients were identified (Table I); 26 had ulcerative colitis (UC), six Crohn s disease and one indeterminant colitis. The most frequent indication was as "rescue" therapy in acute severe UC. The overall initial response rate was 63%, but this was only maintained in 30% long-term with over half of the patients reporting side-effects. Four patients had life threatening side-effects. Conclusion: Although the initial response rates are encouraging, the long-term results are poor and at the expense of a high incidence of side-effects. We feel that the use of cyclosporin in lED should be reconsidered until more information from randomised controlled studies becomes available. Initial response and current status ofpatients bytreatment group Acute severe colitis Initial Current Good response noresponse colectomy Incomplete resp DiedofSAH Died of Carcinoma Stillsymptomatic Lostto FU
14(67%) 4(19%) 1(5%) 1(5%) 1(5%)
4(21%) 12(63%)
Refractory UC Initial Current 4(50%) 4(50%)
3(38%)
Crohn's Disease Initial Current 4(67%) 2(33%)
3(50%)
4(50%)
1(17%)
1(13%)
1(17%) 1(17%)
1(5%) 1(5%) 1(5%)
AGAA1345
6124
6126
THE PREDICTORS OF SELF-REPORTED RELAPSE IN ULCERATIVE COLITIS: QUALITY OF LIFE AND NUMBER OF SYMPTOMS EXPERIENCED MAY BE MORE IMPORTANT THAN DISEASE EXTENT AND ACTIVITY. Seong-Won Han, Elaine McColl, 1. Nick Steen, John R. Barton, Mark R. Welfare, Peter James, Univ of Newcastle, Newcastle, United Kingdom; Ctr for Health Service Research, Newcastle, United Kingdom. Introduction: Previous studies have suggested that disease-related variables such as the number of previous relapses and the current level of symptoms are the best predictors of number of relapses in ulcerative colitis. Little attention has been paid to cognitive factors or the patients quality of life as determinants of relapse. Aims: To determine factors that predict relapse over I year in ulcerative colitis, including demographic, socio-economic, disease-related, quality of life and illness perception. Methods: 87 subjects completed the IBDQ, the SF-36, the illness perception questionnaire (IPQ), a symptom activity index (the CAl), and questions on socio-economic status, smoking and medication. Data on disease extent was extracted from the medical records. The subjects self-reported the number of relapses over the subsequent 12 months. Pearson correlations were calculated between the outcomes after I year and all baseline variables. Multiple regression modelling using stepwise analysis, identified those factors which best predicted the number of relapses after I year. Two models were used: model #1 included only the demographic, socio-economic and disease variables as independent factors; model #2 included all baseline variables as independent factors. Results: Individual correlations with the number of relapses were all weak (r
AN INVESTIGATION OF THE ASSOCIATION OF THE PROTHROMBIN GENE MUTATION AND INFLAMMATORY BOWEL DISEASE. Neil Haslam, Standen R. Graham, Jonathon L. Brown, Roland M. Valori, Christopher S. Probert, GIoucestershire Royal Hosp, Gloucester, United Kingdom; Bristol Royal Infirmary, Bristol, United Kingdom. Background: A thrombotic aetiology for inflammatory bowel disease (IBD) has been proposed as a result of its association with thromboembolic complications (l), smoking, the oral contraceptive pill (2) and the response of ulcerative colitis (UC) patients to heparin (3). We have previously demonstrated an increased incidence of the Factor V Leiden mutaion (4) in UC and wished to investigate the incidence of the recently discovered Pro-thrombin gene mutation in IBD. The Pro-thrombin gene mutation is the second commonest inherited risk factor for thromboembolism and is due to a single nucleotide change (Guanine to Adenine) at position 20210 of the 3' -untranslated region (5). The aim of the study was to investigate the hypothesis that the pro-thrombotic state associated with the pro-thrombin gene mutation is involved in the aetiology of IBD. Patients and Methods: A prospective cohort study of patients attending the Bristol Royal Infirmary and GIoucestershire Royal Hospital's IBD outpatient clinics was performed. Thirty nine patients with IBD (24 with Crohn's disease (CD) and 15 with UC) and 100 historical controls were screened for the presence of the pro-thrombin gene mutation using a heteroduplex-based polymerase chain reaction (PCR) technique. None of the patients with IBD had a personnel history of thrombo-embolism, whilst three of them had a family history. Results: No IBD patients had the pro-thrombin gene mutation compared to four (4%) controls (Allelic frequency 2%). Conclusion: There does not appear to be an association of the pro-thrombin gene mutaion with IBD and hence is unlikely to be involved in the aetiology of IBD. (1) Levine et ai. Gastroenterology clinics of North America 1995:24:633-46. (2) Logan et ai. Int J Epidemiol 1989;18:105107. (3) Gaffney et ai. AmI Gastroenterolo 1995;90:220-23. (4) Haslam et ai. Eur J Gastroenerol Hepatol 1999;11:1289-91. (5) Poort et ai. Blood 1996;88(10):3698-703.
6125 ILEAL MUCOSAL RESPONSE TO BACTERIAL TOXIN (FMLP) CHALLENGE. Yael Harari, Frank Moody, UT Med Sch, Houston, TX. Background and Aim: Disruption of the mucosal barrier of the intestinal tract is reflected in increased permeability to lumenal bacteria and/or their noxious byproducts. Lumenal perfusion of the ileum with FMLP results in increased mucosal permeability and an increment in appearance of myeloperoxidase (MPO) in the effluent. We hypothesized that mast cells and neutrophils within the gut wall are involved in this effect. Models and Measurements: a) Ileal permeability was measured 14 days following total abdominal irradiation (TAI;8Gy) which leads to the disappearance of mast cells for at least 30 days. Segments (15 ern) of the most distal ileum were perfused with Krebs buffer with or without FMLP (1O- 5M). Perfusate samples were collected every 15 min. Fluoresceinated marker (4000 kDa) was introduced systemically and its appearance as well as myeloperoxidase presence in intestinal effluent were measured. b) The release of 5-HT and histamine (mast cell mediators) with or without FMLP in different concentrations, into the serosal side of everted ileal sacs was measured. Results: Significant (P<.05) transient increases in intestinal permeability (7.3xlO-4::':7.lxlO-5 [n=5] vs.1.73xlO-2::':5.8xlO-3 [n=8] mllminlg) and MPO (0.64::':0.07 [n=4] vs.1.54::':0.04 [n=5] ng/mllg) were detected in control non-treated rats within 15 min after FMLP introduction. Irradiation resulted in ablation of the increase in permeability [n=5] as well as in the transient rise in MPO output into the perfusate [n=5]. Significant (p<0.05) increase in 5-HT release from ileal everted sac (28.5::':5.lvs 56.5::':1.5 [n=4] ng/g) was measured in the presence of FMLP. There was a nonsignificant rise (20.5::':3.8 vs 45.2::':9.9 [n=4] p..g/g) also in histamine output. Conclusions: Irradiation eliminates the rise in MPO in the effluent as well as the transient increase in ileal permeability caused by FMLP. These experiments reflect the involvement of mast cells and neutrophils in FMLP-induced mucosal inflammation and raise the possibility that in certain clinical situations proinflammatory mediators within the gut wall may be activated by toxic factors in the intestinal lumen.
6127 AUDIT OF CYCLOSPORIN USE IN INFLAMMATORY BOWEL DISEASE: LIMITED BENEFITS, NUMEROUS SIDE-EFFECTS. Neil Haslam, Stephen D. Hearing, Christopher S. Probert, Gloucestershire Royal Hosp, Gloucester, United Kingdom; Bristol Royal Infirmary, Bristol, United Kingdom. Background: The failure of standard treatments for inflammatory bowel disease (IBD) has led to the use of immuno-modulatory therapy, particularly cyclosporin and azathioprine. Most reports of the use of cyclosporin are from single specialist centres. We therefore undertook a survey of the use of cyclosporin in IBD in Bristol's three teaching hospitals. Patients and Methods: Over a four year period, all patients receiving cyclosporin for IBD were identified and the following data recorded; (i) diagnosis, (ii) duration of disease, (iii) initial treatment, (iv) date initiated, (v) dose of cyclosporin, (vi) side effects, (vii) initial clinical response and (viii) current patient status. Results: Thirty-three patients were identified (Table I); 26 had ulcerative colitis (UC), six Crohn s disease and one indeterminant colitis. The most frequent indication was as "rescue" therapy in acute severe UC. The overall initial response rate was 63%, but this was only maintained in 30% long-term with over half of the patients reporting side-effects. Four patients had life threatening side-effects. Conclusion: Although the initial response rates are encouraging, the long-term results are poor and at the expense of a high incidence of side-effects. We feel that the use of cyclosporin in lED should be reconsidered until more information from randomised controlled studies becomes available. Initial response and current status ofpatients bytreatment group Acute severe colitis Initial Current Good response noresponse colectomy Incomplete resp DiedofSAH Died of Carcinoma Stillsymptomatic Lostto FU
14(67%) 4(19%) 1(5%) 1(5%) 1(5%)
4(21%) 12(63%)
Refractory UC Initial Current 4(50%) 4(50%)
3(38%)
Crohn's Disease Initial Current 4(67%) 2(33%)
3(50%)
4(50%)
1(17%)
1(13%)
1(17%) 1(17%)
1(5%) 1(5%) 1(5%)