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Evaluation of treatment response in active Crohn's disease by magnetic resonance imaging
A1030 AGA ABSTRACTS
• G4217 NORMAL BREAST MILK LIMITS THE DEVELOPMENT OF COLITIS IN IL-10 GENEDEFICIENT MICE. KL Madsen, JS Doyle, MM Tavernini, LD Jewell, D Gray, RN Fedorak. University of Alberta, Edmonton, Alberta, Canada. Background: We have previously shown that IL-10 gene deficient mice have a primary defect in secretion of secretory IgA (slgA) into breast milk. These mice also demonstrate increased levels of aerobic and anaerobic adherent bacteria in the colon and develop a colitis, histologically similar to Crohn's disease. Aim: The purpose of this study was to determine whether the breast milk, with its low levels of slgA, played a role in the increased levels of adherent bacteria seen at 2 wks of age, and the subsequent development of colitis at 4 wk of age in the IL-10 gene deficient mouse. Methods: IL-10 gene deficient (KO) and normal control (C) mice were raised under virus antibody-free conditions. Within 24 hours of birth, IL-10 genedeficient pups were cross-fostered to normal control mothers (XFKO), and normal control pups were cross-fostered to IL-10 gene-deficient mothers (XFC). Mice were weaned at 3 wk of age. Colon, harvested from 2, 4, and 8 wk old mice, was cultured for adherent bacteria and histologic injury scored (0 to 10). Results were compared with normal controls (C) and IL-10 genedeficient (KO) mice. Results: At 2 wks of age, normal control pups cross-fostered to an IL-10 gene-deficient mother (XFC) had significantly increased levels of aerobic and anaerobic colonic adherent bacteria compared with normal control pups raised with a normal control mothers (C) [Aerobic: XFC: 7.1 ± 0.2; C: 4.5 ± 0.3; Anaerobic: XFC: 7.5 ± 0.2; C: 5.6 -+ 0.7 logl0 cfa/gm; p<0.01]. In addition, XFC pups showed a significant increase in the ratio of adherent:total bacteria [XFC: 2.7 ± 0.2%; C: 0.003 ± 0.001% adherent; p<0.01] and 30% of the XFC pups had colonic neutrophilic infiltration, relative to C which had normal bacterial levels and no colonic histological injury. In contrast, IL-10 genedeficient pups cross-fostered to a normal control mother (XFKO) had reduced levels of aerobic and anaerobic colonic adherent bacteria, compared with IL-10 genedeficient pups raised with an IL-10 gene-deficient mother (KO) [Aerobic: XFKO: 5.6-+0.03; KO: 6.2-+0.2; Anaerobic: XFKO: 5.7 ±0.1; KO: 6.5-+ 0.2 log cfulgm; p<0.05] and a significantly reduced ratio of adherent:total bacteria [XFKO: 0.008 ± 0.001%; KO: 0.33 ± 0.1% adherent; p<0.01]. At 4 wks of age (1 wk after weaning) the XFKO pups continued to have reduced adherent colonic bacteria and demonstrated a markedly attenuated colonic histologic injury [Histological score: 1.0 ± 0.1] relative to KO pups [Histological score: 4.8 ± 0.8; p<0.01]. At 8 wk of age, 80% of XFKO pups remained free of colonic histological injury, while 100% of KO pups had severe colonic disease [Histological score = 10]. Conclusions: Breast milk from IL-10 gene-deficient mice alters bacterial colonization in the intestinal lumen of pups, which leads to the development of severe colonic inflammation and ulceration. Normal breast milk from control mice fed during the critical neonatal period, confers a protective effect to IL-10 gene-deficient pups by normalizing intestinal luminal bacteria levels and thus attenuating colonic injury in later life. • G4218 ACTIVE CROItN'S DISEASE AND ULCERATIVE COLITIS EVALUATED BY MAGNETIC RESONANCE IMAGING. SM Madsen, HS Thomsen, P Munkholm, S Dorph, P Schlichting. Herlev University Hospital, University of Copenhagen, Denmark. Background" Conventional bowel imaging in inflammatory bowel disease implies patient discomfort and hazards, the findings often being nonconsistent, correlating poorly to clinical disease activity assessment. Aim: To evaluate low-field Magnetic Resonance Imaging in the assessment of disease extension and activity in inflammatory bowel disease. Patients and methods: 19 patients with Crohn's disease, 8 with ulcerative colitis and 5 healthy controls were examined using low-field MRI (0,1 T) in transverse and coronal planes. MRI images were evaluated in a blinded fashion and the findings compared to findings of endoscopy, conventional radiography and surgery. Results: Comparisons between diseased versus both non-diseased bowel segments (in patients) and segments from the control group revealed significant differences for both diseases regarding signal intensity On T2-weighted images as well as increment of signal intensity on Tl-weighted images after contrast. Agreements between MRI, conventional radiography, endoscopy and surgery concerning disease extension in various bowel segments in Crohn's disease was 97 %. Extension was underestimated in two patients. For increased signal intensity on T2-weighted images (indicative of edema in bowel wall) and increment in signal intensity on Tl-weighted images after contrast (indicative of increased perfusion in bowel wall) predictive values of positive findings (PVvos) was 100 % and 87 % respectively (best fitted values). Corresponding predictive values of negative findings (PVneg) were 96 % and 92 %. For the disease extension in ulcerative colitis the agreement between MRI and conventional methods was 87.5 %. Extension was underestimated in 2 patients and overestimated in 2 patients as compared with barium enema. Values of PV_ s were 100 % (increased signal intensity on T2-weighted images) and 7~" % (increment in signal intensity on Tl-weighted images), with corresponding values of PVnegbeing 94 % and 93 %.
GASTROENTEROLOGYVol. 114, No. 4 Conclusion: Low-field MRI seems to be a promising, non-invasive, non-
radiating, patient-oriented imaging method with high predictive values of both positive and negative findings in the evaluation of patients with inflammatory bowel disease. 64219
EVALUATION OF TREATMENT RESPONSE IN ACTIVE CROHN'S DISEASE BY MAGNETIC RESONANCE IMAGING. SM Madsen. HS Thomsen, P Schlichting, S Dorph, P Munkholm Herlev University Hospital, University of Copenhagen, Denmark. Background: Conventional bowel imaging in the monitoring of disease activity during treatment with high-dose glucocorticoids in Crohn's disease is discomforting and potentially hazardous, the findings often being nonconsistent, correlating poorly to clinical disease activity assessment. Aim: To evaluate the ability of low-field Magnetic Resonance Imaging in detecting treatment response in active Crohn's disease during treatment with high-dose systemic glucocorticoids. Patients and methods: 8 patients with highly active Crohn's disease were examined before and during treatment with systemic glucocorticoids (1 mg/kg/day) using low-field MRI (0,1 T) pre- and post-intravenously bolus administered Gadodimide in transverse and coronal planes. 5 healthy controls were examined once. MRI images was evaluated in a blinded fashion and the findings compared to findings of endoscopy, conventional radiography and surgery. Results: Comparisons between diseased versus both non-diseased bowel segments and segments from the control group revealed significant differences regarding both level of signal intensity on T2-and increments of signal intensity on Tl-weighted images (indicative of grade of edema and perfusion respectively). Agreements between MRI, conventional radiology, endoscopy and surgery regarding disease extension in various bowel segments were 95 %. Extension was underestimated in two patients. Significant correlation was found between both signal intensity on T2-weighted images and increment in signal intensity on Tl-weighted images versus endoscopic activity gradings. Significant decrements during treatment of both signal intensity on T2-weighted images, increment in signal intensity on Tl-weighted images after contrast and bowel wall thickness was found. Conclusion: Low-field MRI seems to be a promising, non-invasive, nonradiating, patient-oriented method in the evaluation of disease extension and activity in Crohn's disease. The method provides new objective parameters for the evaluation of response during treatment with systemic glucocorticoids. G4220 EVALUATION OF ACTIVITY IN ULCERATIVE COLITIs (UC): WHO IS RIGHT: THE CLINICIAN, ENDOSCOPIST OR PATHOLOGIST? U. Mahadevan, PH Rubin, NA Harpaz, E. Goldstein, DH Present. Division of Gastroenterology, Depts. of Medicine and Pathology. Mount Sinai Medical Center, NY,NY. INTRODUCTION: In assessing patients with UC, gastroenterologists frequently rely on serial flexible sigmoidoscopies or colonoscopies, often with biopsies, to determine clinical activity and future therapy. The objective of this study is to determine the degree of concordance among the clinician, endoscopist and pathologist in ascertaining disease activity in UC. METHODS: 125 consecutive UC patients of one clinician (DHP) who required colonoscopy were referred to one endoscopist (PHR). 103 patients were referred for surveillance, 18 for a change in symptoms and 4 for follow up of a previous abnormal colonoscopy. There were 68 men and 57 women with a mean age of 46.9 years (range 18-80). The clinician assessed the degree of disease activity on a four point scale (quiescent, mild, moderate, severe) based upon history, physical exam, and the patient's own estimate of disease activity. The endoscopist, blinded to the clinician's evaluation, used the same four point scale to rate 9 different sites in the colon and gave an overall rating based on disease extent and severity. Biopsies obtained from these 9 sites were sent to one pathologist (NAH), blinded to the previous evaluations, who used the above scale to rate each site. The concordance among these 3 sets of ratings was analyzed utilizing standard statistical techniques. RESULTS: The correlation between the clinician's and endoscopist's overall ratings, by Spearman's correlation coefficient (r) was 0.589 (p~.001). The clinician's overall rating and the pathologist's mean score had less concordance with r = 0.454 (p<.001). The endoscopist's mean versus the pathologist's mean had an association of r = 0.539 (p<.001). On a site by site basis, the concordance was better for the distal five sites (r = 0.506 to 0.605) than for the proximal four sites (r = 0.269 to 0.461). The trend was for the clinician to give the lowest activity scores, followed by the endoscopist and then the pathologist. CONCLUSION: There is at best only moderate association among clinician, endoscopist and pathologist in assessing disease activity in UC. The endoscopist and pathologist tend to assess the activity of UC as being more severe than the clinical picture. Discordance has been found between the clinician and endoscopist in a similar study of Crohn's disease. 1 This raises the question of the relative utility of colonoscopy and histology in the evaluation of disease activity in UC and in the design of controlled clinical trials. [1] Cellier C, Sahmoud T, Froguel E, et al. Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn's disease. A prospective multicentre study of 121 cases. Gut 1994; 35:231-235.
• G4217 NORMAL BREAST MILK LIMITS THE DEVELOPMENT OF COLITIS IN IL-10 GENEDEFICIENT MICE. KL Madsen, JS Doyle, MM Tavernini, LD Jewell, D Gray, RN Fedorak. University of Alberta, Edmonton, Alberta, Canada. Background: We have previously shown that IL-10 gene deficient mice have a primary defect in secretion of secretory IgA (slgA) into breast milk. These mice also demonstrate increased levels of aerobic and anaerobic adherent bacteria in the colon and develop a colitis, histologically similar to Crohn's disease. Aim: The purpose of this study was to determine whether the breast milk, with its low levels of slgA, played a role in the increased levels of adherent bacteria seen at 2 wks of age, and the subsequent development of colitis at 4 wk of age in the IL-10 gene deficient mouse. Methods: IL-10 gene deficient (KO) and normal control (C) mice were raised under virus antibody-free conditions. Within 24 hours of birth, IL-10 genedeficient pups were cross-fostered to normal control mothers (XFKO), and normal control pups were cross-fostered to IL-10 gene-deficient mothers (XFC). Mice were weaned at 3 wk of age. Colon, harvested from 2, 4, and 8 wk old mice, was cultured for adherent bacteria and histologic injury scored (0 to 10). Results were compared with normal controls (C) and IL-10 genedeficient (KO) mice. Results: At 2 wks of age, normal control pups cross-fostered to an IL-10 gene-deficient mother (XFC) had significantly increased levels of aerobic and anaerobic colonic adherent bacteria compared with normal control pups raised with a normal control mothers (C) [Aerobic: XFC: 7.1 ± 0.2; C: 4.5 ± 0.3; Anaerobic: XFC: 7.5 ± 0.2; C: 5.6 -+ 0.7 logl0 cfa/gm; p<0.01]. In addition, XFC pups showed a significant increase in the ratio of adherent:total bacteria [XFC: 2.7 ± 0.2%; C: 0.003 ± 0.001% adherent; p<0.01] and 30% of the XFC pups had colonic neutrophilic infiltration, relative to C which had normal bacterial levels and no colonic histological injury. In contrast, IL-10 genedeficient pups cross-fostered to a normal control mother (XFKO) had reduced levels of aerobic and anaerobic colonic adherent bacteria, compared with IL-10 genedeficient pups raised with an IL-10 gene-deficient mother (KO) [Aerobic: XFKO: 5.6-+0.03; KO: 6.2-+0.2; Anaerobic: XFKO: 5.7 ±0.1; KO: 6.5-+ 0.2 log cfulgm; p<0.05] and a significantly reduced ratio of adherent:total bacteria [XFKO: 0.008 ± 0.001%; KO: 0.33 ± 0.1% adherent; p<0.01]. At 4 wks of age (1 wk after weaning) the XFKO pups continued to have reduced adherent colonic bacteria and demonstrated a markedly attenuated colonic histologic injury [Histological score: 1.0 ± 0.1] relative to KO pups [Histological score: 4.8 ± 0.8; p<0.01]. At 8 wk of age, 80% of XFKO pups remained free of colonic histological injury, while 100% of KO pups had severe colonic disease [Histological score = 10]. Conclusions: Breast milk from IL-10 gene-deficient mice alters bacterial colonization in the intestinal lumen of pups, which leads to the development of severe colonic inflammation and ulceration. Normal breast milk from control mice fed during the critical neonatal period, confers a protective effect to IL-10 gene-deficient pups by normalizing intestinal luminal bacteria levels and thus attenuating colonic injury in later life. • G4218 ACTIVE CROItN'S DISEASE AND ULCERATIVE COLITIS EVALUATED BY MAGNETIC RESONANCE IMAGING. SM Madsen, HS Thomsen, P Munkholm, S Dorph, P Schlichting. Herlev University Hospital, University of Copenhagen, Denmark. Background" Conventional bowel imaging in inflammatory bowel disease implies patient discomfort and hazards, the findings often being nonconsistent, correlating poorly to clinical disease activity assessment. Aim: To evaluate low-field Magnetic Resonance Imaging in the assessment of disease extension and activity in inflammatory bowel disease. Patients and methods: 19 patients with Crohn's disease, 8 with ulcerative colitis and 5 healthy controls were examined using low-field MRI (0,1 T) in transverse and coronal planes. MRI images were evaluated in a blinded fashion and the findings compared to findings of endoscopy, conventional radiography and surgery. Results: Comparisons between diseased versus both non-diseased bowel segments (in patients) and segments from the control group revealed significant differences for both diseases regarding signal intensity On T2-weighted images as well as increment of signal intensity on Tl-weighted images after contrast. Agreements between MRI, conventional radiography, endoscopy and surgery concerning disease extension in various bowel segments in Crohn's disease was 97 %. Extension was underestimated in two patients. For increased signal intensity on T2-weighted images (indicative of edema in bowel wall) and increment in signal intensity on Tl-weighted images after contrast (indicative of increased perfusion in bowel wall) predictive values of positive findings (PVvos) was 100 % and 87 % respectively (best fitted values). Corresponding predictive values of negative findings (PVneg) were 96 % and 92 %. For the disease extension in ulcerative colitis the agreement between MRI and conventional methods was 87.5 %. Extension was underestimated in 2 patients and overestimated in 2 patients as compared with barium enema. Values of PV_ s were 100 % (increased signal intensity on T2-weighted images) and 7~" % (increment in signal intensity on Tl-weighted images), with corresponding values of PVnegbeing 94 % and 93 %.
GASTROENTEROLOGYVol. 114, No. 4 Conclusion: Low-field MRI seems to be a promising, non-invasive, non-
radiating, patient-oriented imaging method with high predictive values of both positive and negative findings in the evaluation of patients with inflammatory bowel disease. 64219
EVALUATION OF TREATMENT RESPONSE IN ACTIVE CROHN'S DISEASE BY MAGNETIC RESONANCE IMAGING. SM Madsen. HS Thomsen, P Schlichting, S Dorph, P Munkholm Herlev University Hospital, University of Copenhagen, Denmark. Background: Conventional bowel imaging in the monitoring of disease activity during treatment with high-dose glucocorticoids in Crohn's disease is discomforting and potentially hazardous, the findings often being nonconsistent, correlating poorly to clinical disease activity assessment. Aim: To evaluate the ability of low-field Magnetic Resonance Imaging in detecting treatment response in active Crohn's disease during treatment with high-dose systemic glucocorticoids. Patients and methods: 8 patients with highly active Crohn's disease were examined before and during treatment with systemic glucocorticoids (1 mg/kg/day) using low-field MRI (0,1 T) pre- and post-intravenously bolus administered Gadodimide in transverse and coronal planes. 5 healthy controls were examined once. MRI images was evaluated in a blinded fashion and the findings compared to findings of endoscopy, conventional radiography and surgery. Results: Comparisons between diseased versus both non-diseased bowel segments and segments from the control group revealed significant differences regarding both level of signal intensity on T2-and increments of signal intensity on Tl-weighted images (indicative of grade of edema and perfusion respectively). Agreements between MRI, conventional radiology, endoscopy and surgery regarding disease extension in various bowel segments were 95 %. Extension was underestimated in two patients. Significant correlation was found between both signal intensity on T2-weighted images and increment in signal intensity on Tl-weighted images versus endoscopic activity gradings. Significant decrements during treatment of both signal intensity on T2-weighted images, increment in signal intensity on Tl-weighted images after contrast and bowel wall thickness was found. Conclusion: Low-field MRI seems to be a promising, non-invasive, nonradiating, patient-oriented method in the evaluation of disease extension and activity in Crohn's disease. The method provides new objective parameters for the evaluation of response during treatment with systemic glucocorticoids. G4220 EVALUATION OF ACTIVITY IN ULCERATIVE COLITIs (UC): WHO IS RIGHT: THE CLINICIAN, ENDOSCOPIST OR PATHOLOGIST? U. Mahadevan, PH Rubin, NA Harpaz, E. Goldstein, DH Present. Division of Gastroenterology, Depts. of Medicine and Pathology. Mount Sinai Medical Center, NY,NY. INTRODUCTION: In assessing patients with UC, gastroenterologists frequently rely on serial flexible sigmoidoscopies or colonoscopies, often with biopsies, to determine clinical activity and future therapy. The objective of this study is to determine the degree of concordance among the clinician, endoscopist and pathologist in ascertaining disease activity in UC. METHODS: 125 consecutive UC patients of one clinician (DHP) who required colonoscopy were referred to one endoscopist (PHR). 103 patients were referred for surveillance, 18 for a change in symptoms and 4 for follow up of a previous abnormal colonoscopy. There were 68 men and 57 women with a mean age of 46.9 years (range 18-80). The clinician assessed the degree of disease activity on a four point scale (quiescent, mild, moderate, severe) based upon history, physical exam, and the patient's own estimate of disease activity. The endoscopist, blinded to the clinician's evaluation, used the same four point scale to rate 9 different sites in the colon and gave an overall rating based on disease extent and severity. Biopsies obtained from these 9 sites were sent to one pathologist (NAH), blinded to the previous evaluations, who used the above scale to rate each site. The concordance among these 3 sets of ratings was analyzed utilizing standard statistical techniques. RESULTS: The correlation between the clinician's and endoscopist's overall ratings, by Spearman's correlation coefficient (r) was 0.589 (p~.001). The clinician's overall rating and the pathologist's mean score had less concordance with r = 0.454 (p<.001). The endoscopist's mean versus the pathologist's mean had an association of r = 0.539 (p<.001). On a site by site basis, the concordance was better for the distal five sites (r = 0.506 to 0.605) than for the proximal four sites (r = 0.269 to 0.461). The trend was for the clinician to give the lowest activity scores, followed by the endoscopist and then the pathologist. CONCLUSION: There is at best only moderate association among clinician, endoscopist and pathologist in assessing disease activity in UC. The endoscopist and pathologist tend to assess the activity of UC as being more severe than the clinical picture. Discordance has been found between the clinician and endoscopist in a similar study of Crohn's disease. 1 This raises the question of the relative utility of colonoscopy and histology in the evaluation of disease activity in UC and in the design of controlled clinical trials. [1] Cellier C, Sahmoud T, Froguel E, et al. Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn's disease. A prospective multicentre study of 121 cases. Gut 1994; 35:231-235.