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April 1995 Immunology, Microbiology, and Inflammatory Disorders A829 • ULTRASONIC DIAGNOSIS OF INFLAMMATORY BOWEL DISORDERS - PRELIMINARY RESULTS OF A PROSPECTIVE STUDY E.Guenter, S.Ketterle, D.Becker, G.Nusko, EG.Hahn. Dep. of Medicine I, University of Erlangen-Nuernberg, FRG The diagnostic evaluation of patients with suspected inflammatory bowel disorders (IBD) relies on radiological, endoscopic and histological examinations. The role of ultrasound examination in these patients is not yet established. Methods: In a prospective study starting Dec. 1st. 1993, all patients referred to our hospital suspected of IBD undergo an ultrasound examination prior to other diagnostic procedures. A standard ultrasound equipment is used (Picker CS 192, 5Mhz curved array). The patients are examined in the fasting state, no other preparation is required. A bowel wall >lmm is considered pathological. Wall thickness and the extend of bowel involvement are established. Wall patterns are classified into 3 groups: A = accentuated wall layers, B = 3-layer-pattern, C = homogenous wall with few internal echoes. Results are compared to radiological (small intestine) and endoscopic (colon and term ileum) findings, with are considered as golden standard. Results: The results of 62 patients are available so far. 41 patients had Crohn's disease, 14 patients had ulcerative colitis, 5 patients had other inflammatory bowel disorders (2 pat. bact. colitis, 2 pat. ischemic colitis, 1 pat. CMV-colitis). 2 patients had no morphological alteration of the bowel wall in either examination. In 41 patients with Crohn's disease, 36 had active disease, All 14 patients with ulcerative colitis had active disease. The ultrasonic examination correctly detected inflammatory changes in 52 out 0f55 patients. There was one false-positive sonographic result. The sonographic wall pattern and -diameter correlated closely with the'degree of inflammatory changes. However, the different inflammatory bowel disorders showed a uniform sonographic picture and could not be distinguished. Conclusion: Inflammatory bowel disorders can be reliably identified by ultrasonography (sensitivity 94%, specifity 86%). Endoscopic and radiological examinations are important in the inital diagnostic procedure, most follow-up examinations however can be done by the sole means of ultrasonography. ASSESSEMENT OF 99mTc HMPAO LABELED GRANULOCYTES (99mTc-HMPAO PN) SCINT1GRAPHY FOR DETECTION OF SEVERE ATTACK OF ULCERATIVE COLITIS (UC). G_uimbauRR, Beades E*, Morelec I o, Gaudric M, Richard B*, Descos L °, Chaussade S. Couturier D H6pato-gastroent&ologie and m6decine nucl6,aire*, h6pital Cochin, Paris; Centre hospitalier Lyon Sud °, Pierre B6nite: France During a severe attack of UC. the presence of extensive deep ulcerations is associated with a high risk of major complications (colectasy, perforation...). Colonoscopy has been proposed to identif3 these mucosal damages but induces a risk of perforation or colonic dilatation. 99mTc- HMPAO PN scintigraphy is a non invasJve technique which identifies acute inflammation sites and has been proposed for the assessement of inflammatory bowel diseases attacks. The aim of this study was to describe 99mTc-HMPAO PN scintigraphy patterns Jn severe anatomical colitis during acute attacks of UC. Patients and method: 34 patients with a known UC have been evaluated during 47 acute attacks of moderate to severe intensity. A 99mTc- HMPAO PN scintigraphy was performed (as previously described*) and blindly analysed by a nuclear physician. Scintigraphic data were compared to endoscopic and/or pathologic data which assess the intensity of colitis damages Results: 11 pauents had a severe anatomical colitis according to histological findings (Buckell's classificatlon*'~,coleetom3 specimens: 10/I1) and/or endoscopyical findings /colonoscopy: 7/11). 99mTc- HMPAO scintigraphy displayed a "double track" aspect m ever 3, patient (ll/ll). This aspect was never seen in others patients without severe colonic damages at colonoscopy (36/36) all of them improved with medical treatment with no complication or need for surgery. Conclusion: In UC attacks, the 99mTc-HMPAO scintigraphic "double track aspect" was specific of severe anatomical colitis. 99mTc-HMPAO scintigraphy, as a safe. reliable and reproducible technique, could be usefull in the intensive medical management and evaluation of patients with severe attacks of UC. * Gut 1993, 34: 1364-9. ** Gastroenterology 1980, 79: 19-25. ULCERATIVE COLITIS IS AN OUTSTANDING DISEASE FOR THE NUMBER AND EXTENT OF INFLAMMATORY CYTOKINES LOCALLY PRODUCED. G u i ~ , Chauvelot-Moachon L °*, Giroud JP°*, Couturier D, Chaussade S, Hgpato-gastroentrrologie and pharmacologic°, CNRS 15- 34*; hrpital C<xzhin, 75014 Paris, France. The four major inflammatory cytokincs (lnf-cyt.) are tumor necrosis factor (TNF), interleukin-I (ILl), interleukin-6 (IL6) and interletikin-8 (ILS). Properties of inf-cyt can explain most of the local and systemic components of acute and chronic inflammatory diseases: induction of acute-phase protein synthesis (IL6, ILlg, TNF), stimulation of various effectors (PAF, eicosanoids, NO, collagenases...) (TNF, ILII3), chemotaxis and release of granule enzymes for neutrophils (IL8), thrombocytopoiesis (IL6)... The aim of the study was to quantify the four Inf-cyt. produced at the digestive mucosa level in patients with active ulcerative colitis (UC) and to determine which ones were associated with disease severity. Patients and method: Nineteen patients with mild and moderate attacks of UC and six healthy controls were studied with a technique of colonic peffusion. The study analysed with "blind" operators: 1) local parameters: perfusion liquid (Inf-cyt., PAF, myeloperoxydase or MPO (granule enzymes from neutrophils)), and endoscopic aspect, and 2) systemic parameters: haematological (ESR, serum APP levels, platelet number), clinical (Truelove score) and radiological (scintigraphy with neutrophils) criteria, lnf-cyt were measured by immunoassays (EASIA, Medgenix). Results: ~ ILIB (pg/min) IL6 (pg/min) II_8 (pg/min) ( n = 6 ) ~ Undetectable undetectable 29_+12 ~ " ~ 595_+136 [ 1753_+402 13255£-_747 (m±SEM) ~ <O.O0l p<0.001 p=O.00l Inf-cyt. concentrations were correlated two by two (Spearman rank order correlation, 0.76<r<0.91; p<0.O01, n=25). Each Inf-cyt. was highly correlated with endoscopic score (0.65<r<0.80; p<O.001, n=25), PAF and MPO values (0.70<r<0.93; p<O.003, n=16), scintigraphic score (0.69<r<0~77; p<0.001, n=24). ESR, serum APP levels and platelet number were also correlated with lnf-cyt. Conelusion: 1) The outstanding high levels of the four cyt. in the colonic perfusion liquid suggest that they play a major role in the pathology of UC tissular damage and are crucial target for therapeutic intervention (ex: anti- TNFa). 2) The high correlation between lnf-cyt altogether suggests that Inf- cyt induction involves a common pathway. 3) Colonic perfusion would be a preferential technique for exploring the inflammatory cytokine network and their pharmacological regulation. ALTERATION OF THE TCR REPERTOIRE IN THE INFLAMMED TISSUE OF CROHN'S DISEASE. B. Gulwani-Akolkar, P.N. Akolkar, M. McKinley and J. Silver, Dept. Medicine, North Shore University Hospital, Cornell Medical College, Manhasset, NY 11030. To identify disease-specific T cell changes that occur in Crohn's disease (CD), the T-cell receptor (TCR) V~ repertoires of lamina propria lymphocytes (LPL) isolated from the. diseased colon of CD patients were determined. As an internal control for the effects of HLA and other genes on the TCR repertoire, the V~ repertoires of peripheral blood lymphocytes (PBL) from the same individuals were used for comparison. It was observed that the VI3 repertoires of LPL and PBL of the same individual were very different in both the CD and a control group. However, the CD4+ repertoires of LPL and PBL differed to a much greater extent in the CD group than in the control group. Furthermore, Vl~-specific differences were observed primarily in CD4+ LPL when the V6 repertoires of LPL isolated from both the inflamed and uninflamed portions of the colon of three individuals with CD were compared. In addition, although some V~ segments were found to be increased uniquely in each patient, several V~ segments were found to be increased in common in the inflamed tissue of all three individuals. In contrast, no significant differences were observed when two inflamed portions of the colon of three individuals with CD were compared. These studies suggest that the inflammatery process in CD is directed against specific antigens and/or superantigens and is not merely a result of generalized dysregulation of the immune system.

Alteration of the TCR repertoire in the inflammed tissue of Crohn's disease

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April 1995 Immunology, Microbiology, and Inflammatory Disorders A829

• ULTRASONIC DIAGNOSIS OF INFLAMMATORY BOWEL DISORDERS - PRELIMINARY RESULTS OF A PROSPECTIVE STUDY E.Guenter, S.Ketterle, D.Becker, G.Nusko, EG.Hahn. Dep. of Medicine I, University of Erlangen-Nuernberg, FRG

The diagnostic evaluation of patients with suspected inflammatory bowel disorders (IBD) relies on radiological, endoscopic and histological examinations. The role of ultrasound examination in these patients is not yet established. Methods: In a prospective study starting Dec. 1 st. 1993, all patients referred to our hospital suspected of IBD undergo an ultrasound examination prior to other diagnostic procedures. A standard ultrasound equipment is used (Picker CS 192, 5Mhz curved array). The patients are examined in the fasting state, no other preparation is required. A bowel wall > lmm is considered pathological. Wall thickness and the extend of bowel involvement are established. Wall patterns are classified into 3 groups: A = accentuated wall layers, B = 3-layer-pattern, C = homogenous wall with few internal echoes. Results are compared to radiological (small intestine) and endoscopic (colon and term ileum) findings, with are considered as golden standard. Results: The results of 62 patients are available so far. 41 patients had Crohn's disease, 14 patients had ulcerative colitis, 5 patients had other inflammatory bowel disorders (2 pat. bact. colitis, 2 pat. ischemic colitis, 1 pat. CMV-colitis). 2 patients had no morphological alteration of the bowel wall in either examination. In 41 patients with Crohn's disease, 36 had active disease, All 14 patients with ulcerative colitis had active disease. The ultrasonic examination correctly detected inflammatory changes in 52 out 0f55 patients. There was one false-positive sonographic result. The sonographic wall pattern and -diameter correlated closely with the'degree of inflammatory changes. However, the different inflammatory bowel disorders showed a uniform sonographic picture and could not be distinguished. Conclusion: Inflammatory bowel disorders can be reliably identified by ultrasonography (sensitivity 94%, specifity 86%). Endoscopic and radiological examinations are important in the inital diagnostic procedure, most follow-up examinations however can be done by the sole means of ultrasonography.

ASSESSEMENT OF 99mTc HMPAO LABELED GRANULOCYTES (99mTc-HMPAO PN) SCINT1GRAPHY FOR DETECTION OF SEVERE ATTACK OF ULCERATIVE COLITIS (UC). G_uimbauRR, Beades E*, Morelec I o, Gaudric M, Richard B*, Descos L °, Chaussade S. Couturier D H6pato-gastroent&ologie and m6decine nucl6,aire*, h6pital Cochin, Paris; Centre hospitalier Lyon Sud °, Pierre B6nite: France

During a severe attack of UC. the presence of extensive deep ulcerations is associated with a high risk of major complications (colectasy, perforation...). Colonoscopy has been proposed to identif3 these mucosal damages but induces a risk of perforation or colonic dilatation. 99mTc- HMPAO PN scintigraphy is a non invasJve technique which identifies acute inflammation sites and has been proposed for the assessement of inflammatory bowel diseases attacks. The aim of this study was to describe 99mTc-HMPAO PN scintigraphy patterns Jn severe anatomical colitis during acute attacks of UC. Patients and method: 34 patients with a known UC have been evaluated during 47 acute attacks of moderate to severe intensity. A 99mTc- HMPAO PN scintigraphy was performed (as previously described*) and blindly analysed by a nuclear physician. Scintigraphic data were compared to endoscopic and/or pathologic data which assess the intensity of colitis damages Results: 11 pauents had a severe anatomical colitis according to histological findings (Buckell's classificatlon*'~,coleetom3 specimens: 10/I1) and/or endoscopyical findings /colonoscopy: 7/11). 99mTc- HMPAO scintigraphy displayed a "double track" aspect m ever 3, patient ( l l / l l ) . This aspect was never seen in others patients without severe colonic damages at colonoscopy (36/36) all of them improved with medical treatment with no complication or need for surgery. Conclusion: In UC attacks, the 99mTc-HMPAO scintigraphic "double track aspect" was specific of severe anatomical colitis. 99mTc-HMPAO scintigraphy, as a safe. reliable and reproducible technique, could be usefull in the intensive medical management and evaluation of patients with severe attacks of UC.

* Gut 1993, 34: 1364-9. ** Gastroenterology 1980, 79: 19-25.

ULCERATIVE COLITIS IS AN OUTSTANDING DISEASE FOR THE NUMBER AND EXTENT OF INFLAMMATORY CYTOKINES LOCALLY PRODUCED. G u i ~ , Chauvelot-Moachon L °*, Giroud JP°*, Couturier D, Chaussade S, Hgpato-gastroentrrologie and pharmacologic °, CNRS 15- 34*; hrpital C<xzhin, 75014 Paris, France.

The four major inflammatory cytokincs (lnf-cyt.) are tumor necrosis factor (TNF), interleukin-I (ILl), interleukin-6 (IL6) and interletikin-8 (ILS). Properties of inf-cyt can explain most of the local and systemic components of acute and chronic inflammatory diseases: induction of acute-phase protein synthesis (IL6, ILlg, TNF), stimulation of various effectors (PAF, eicosanoids, NO, collagenases...) (TNF, ILII3), chemotaxis and release of granule enzymes for neutrophils (IL8), thrombocytopoiesis (IL6)... The aim of the study was to quantify the four Inf-cyt. produced at the digestive mucosa level in patients with active ulcerative colitis (UC) and to determine which ones were associated with disease severity. Patients and method: Nineteen patients with mild and moderate attacks of UC and six healthy controls were studied with a technique of colonic peffusion. The study analysed with "blind" operators: 1) local parameters: perfusion liquid (Inf-cyt., PAF, myeloperoxydase or MPO (granule enzymes from neutrophils)), and endoscopic aspect, and 2) systemic parameters: haematological (ESR, serum APP levels, platelet number), clinical (Truelove score) and radiological (scintigraphy with neutrophils) criteria, lnf-cyt were measured by immunoassays (EASIA, Medgenix). Results: ~ ILIB (pg/min) IL6 (pg/min) II_8 (pg/min)

( n = 6 ) ~ Undetectable undetectable 29_+12 ~ " ~ 595_+136 [ 1753_+402 13255£-_747 (m±SEM) ~ <O.O0l p<0.001 p=O.00l Inf-cyt. concentrations were correlated two by two (Spearman rank order correlation, 0.76<r<0.91; p<0.O01, n=25). Each Inf-cyt. was highly correlated with endoscopic score (0.65<r<0.80; p<O.001, n=25), PAF and MPO values (0.70<r<0.93; p<O.003, n=16), scintigraphic score (0.69<r<0~77; p<0.001, n=24). ESR, serum APP levels and platelet number were also correlated with lnf-cyt. Conelusion: 1) The outstanding high levels of the four cyt. in the colonic perfusion liquid suggest that they play a major role in the pathology of UC tissular damage and are crucial target for therapeutic intervention (ex: anti- TNFa). 2) The high correlation between lnf-cyt altogether suggests that Inf- cyt induction involves a common pathway. 3) Colonic perfusion would be a preferential technique for exploring the inflammatory cytokine network and their pharmacological regulation.

ALTERATION OF THE TCR REPERTOIRE IN THE INFLAMMED TISSUE OF CROHN'S DISEASE. B. Gulwani-Akolkar, P.N. Akolkar, M. McKinley and J. Silver, Dept. Medicine, North Shore University Hospital, Cornell Medical College, Manhasset, NY 11030.

To identify disease-specific T cell changes that occur in Crohn's disease (CD), the T-cell receptor (TCR) V~ repertoires of lamina propria lymphocytes (LPL) isolated from the. diseased colon of CD patients were determined. As an internal control for the effects of HLA and other genes on the TCR repertoire, the V~ repertoires of peripheral blood lymphocytes (PBL) from the same individuals were used for comparison. It was observed that the VI3 repertoires of LPL and PBL of the same individual were very different in both the CD and a control group. However, the CD4+ repertoires of LPL and PBL differed to a much greater extent in the CD group than in the control group. Furthermore, Vl~-specific differences were observed primarily in CD4+ LPL when the V6 repertoires of LPL isolated from both the inflamed and uninflamed portions of the colon of three individuals with CD were compared. In addition, although some V~ segments were found to be increased uniquely in each patient, several V~ segments were found to be increased in common in the inflamed tissue of all three individuals. In contrast, no significant differences were observed when two inflamed portions of the colon of three individuals with CD were compared. These studies suggest that the inflammatery process in CD is directed against specific antigens and/or superantigens and is not merely a result of generalized dysregulation of the immune system.