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Increased peripheral production of TNF-a and mucosal levels of activated NFkB predict relapse after treatment with infliximab in patients with Crohn's disease
AGAA567
April 2000
fractory CD. We also assessed the duration of response comparing children with early CD to children with longstanding (late) CD. Methods: Children age 6 - 18 with medically refractory CD were eligible for enrollment in a prospective, open-label trial of Infliximab, 5 mg/kg intravenous infusion. Primary endpoints included measurement of disease activity (pediatric Crohn's disease activity index; PCDAI), steroid use and duration of clinical response. Early CD was arbitrarily defined as disease duration of less than 2 years, while late CD required greater than 2 years of disease as measured from the time of diagnosis. Results: 15 consecutive children with medically refractory CD were enrolled (mean age 13.4 :!:3.3). 14/15 children (93%) improved following Infliximab infusion with a significant decrease of both PCDAI (p < 0.05) and daily steroid usage (p < 0.05) by four weeks. Eleven patients (74%) achieved complete remission by 10 weeks (PCDAI < 15). Four of six children (67%) with early CD maintained clinical response through the 12 month trial period, compared with 0/8 children with late disease. All late CD pts, relapsed by 8 months. There were no complications associated with Infliximab. Conclusions: Infliximab is safe and effective in the short-term treatment of medically refractory pediatric CD. More importantly, there is a remarkably prolonged duration of response following Infliximab therapy in children with early compared to late CD. Demographic data - Infliximab responders (14115)
CD duration (months) age (years) PCDAI entry
early CD (n = 6)
lateCD(n =8)
10.6 ± 6.2 12.7 ± 1.8
45.2 ± 16.6 13.7 ±45 52.9 ± 11
51.5± 18
2964 INHIBITION OF PARP-2 EXPRESSION BY AN ANTISENSE OLIGONUCLEOTIDE IMPROVES COLONIC PERMEABILITY IN IL10'\' MICE. Humberto B. Jijon, Ian J. Popoff, Michael Ma, Andreas Wessler, Howard G. Parsons, Lawrence D. Jewell, Karen L. Madsen, Univ of Calgary, Calgary, AB, Canada; ISIS Pharmaceuticals, San Diego, CA; Univ of Alberta, Edmonton, AB, Canada. Inflammatory bowel disease is characterized by high levels of reactive oxygen and nitrogen species, which indiscriminately attack DNA causing strand breakage. DNA damage subsequently activates a nuclear enzyme, poly-(ADP-ribose) polymerase (pARP) which can deplete cellular AIP and increase epithelial permeability. Recently, a new isoform of the PARP family, PARP-2, has been described in human and murine cDNA. However, to date, there has been no characterization of the role of PARP- 2 in intestinal inflammation. Previous studies have shown PARP-I to play a critical role in perpetuation of inflammation, and indeed, we have shown that pharmacological inhibition of the PARP family with 3-aminobenzamide (3-AB) improves colitis in IL-IO'\' mice. Aim: The aim of this study was to compare the results of 3-AB treatment in the IL-I 0'\' mouse with the specific inhibition of PARP-2 using an antisense oligonucleotide. Methods: Adult IL-IO'\' mice were administered either the PARP inhibitor, 3-AB (20 mg/kgld), a specific PARP-2 antisense oligonucleotide (25 mg/kgld), or a control mismatch nucleotide (25 mg/kg/d) for 14 days. In separate experiments, colonic permeability was assessed using a single pass perfusion technique in vivo and whole colons were removed for measurement of INFa and IFNy secretion and iNOS activity. Results: In comparison with control mice, IL-IO'\' mice displayed a 100% increase in INFa and IFNy secretion in conjunction with an 84% increase in colonic permeability and iNOS activity (p
2965 TREATMENT OF CROHN'S DISEASE WITH INFLIXIMAB· AN INITIAL COMMUNITY PRACTICE EXPERIENCE. Robert P. McCabe, Ronald M. Schwartz, Vicki Bebeau, Naomi Tatarek, David I. Weinberg, Minnesota Gastroenterology, P A, Minneapolis, MN. Aim: To assess the efficacy and safety of Crohn s disease treatment with infliximab in a community practice setting. Methods: Prospective data was collected on the first 52 infliximab treated patients from a 37-physician GI practice. COAl, medications, fistula drainage, seton status and subjective response were recorded at the time of infusion and at 4 weeks following the infusion(s). Duration of response.long term subjective response. seton status, surgeries, medications and adverse events were determined by a phone and chart survey conducted at 20 to 56 weeks. Response was measured in four ways: I)CDAI decrease ~ 70 at 4 weeks, 2)physician/ patient subjective impression at 4 weeks, 3) patient subjective impression at time of telephone survey and 4) discontinuation of steroids. Results: 43 patients were treated for active lumenal disease, 9 for fistulae. The average age and disease duration were 41 and II years. Average baseline COAl was 286. Chart and survey data were available on 43 (9 fistulous) of 52 patients. Both baseline and 4 week COAl results were available for 22. These averaged 263 and 174, respectively. Clinical response was as follows: COAl decrease ~ 70 = 50% (11/22); subjective response at 4 weeks = 72%(28/39); subjective response at follow up survey = 70% (28/40); steroids discontinued = 72% (18/25). Complete fistula closure was considered to have occurred in 44% (4/9) patients, partial closure in another 33% (3/9). A positive subjective response (4 weeks and follow up survey) occurred in 77% (7/9) of fistula patients. Four patients had setons, all were removed at approximately week two, none required replacement. Four fistula patients (44%) and 8 (18% )Iumenal disease patients required surgery during the follow up period. Initial COAl score, patient age and disease duration did not predict response. Average duration of response was 13 weeks (range I to 42). Four patients have maintained a response beyond 34 weeks. Patients on 6MP/azathioprine or methotrexate tended to have longer response duration (18 wks vs. 9 wks, p=.06) Adverse events occurred in 8/37 (21%)patients: most very mild except I serum sickness like reaction and I carcinoma in a rectovaginal fistula. One patient died of possible peritonitis 6 months post infusion. Conclusions: I) Infliximab is a generally safe and effective treatment for Crohn s disease in a community GI practice. 2) Convincing subjective improvement may occur without meeting objective response criteria. 3) Immunosuppressive therapy may prolong response to infliximab. 2966 INCREASED PERIPHERAL PRODUCTION OF TNF-A AND MUCOSAL LEVELS OF ACTIVATED NFKB PREDICT RELAPSE AFTER TREATMENT WITH INFLIXIMAB IN PATIENTS WITH CROHN'S DISEASE. Susanna Nikolaus, Tanja Kuhbacher, Ulrich R. Foelsch, Andreas Raedler, Stefan Schreiber, I Dept of Medicine, Christian-Albrechts-University, Kiel, Germany; Tabea Ctr for Inflammatory Bowel Diseases, Hamburg, Germany. Background: Secretion of TNF-a is increased in active CD. Mucosal NFKB, a major player in pro-inflammatory signal transduction, is activated in intestinal inflammation. Infliximab (Remicade'Y) binds to TNF-a and results in remission rates of up to 50% in chronic active CD (4 wks after single infusion). Intervals for (re)-infusion of infliximab which are necessary to avoid relapses are unknown. Aims: To find predictors of relapse in infliximab treated CD patients. Methods: 24 patients with active CD (CDAI>200, 18-50 yrs, rectosigmoidal lesions) were recruited from 35 consecutive patients treated by a single infusion with infliximab (5mg/kg). All patients had received steroidslimmunosupressives in the past without success. Rectal biopsies were taken before, 1,2,4,8 and 12 wks after infusion. Nuclear extracts were prepared from snap frozen biopsies for detection of activated NFKB-p65 (western blot). Blood was drawn for whole blood cytokine assay (LPS stimulated). After 24 hrs TNF-a was assessed in the cell-free phase by ELISA. Results: 21 of 24 patients were in remission (CDAI<150) at week I (88%). I day after infliximab therapy, LPS stimulated TNF-a secretion dropped from increased (1928 (interquart. range: 951-2510) pg/ml) to non-detectable levels «3,2 pglml) in all patients. Mucosal levels of activated nuclear NFKB-p65 markedly decreased within 2 wks after infusion, in some patients below detectable levels. Relapses (increase of COAl >50 points to > 150 in comparison with wkl values) were seen in 6/21 patients (29%) at wk 4, 13/21 patients (62%) at wk 8,17/21 patients (81%) at wk 12 and 19/21 patients (90%) at wk 16. Patients who relapsed, showed a statistically significant increase of stimulated TNF-a whole blood cytokine levels and increased levels of activated mucosal NFKB-p65 at least 2-4 wks prior to clinical and endoscopic relapse. Conclusions:Treatment with infliximab (Remicade'') reverts the pro-inflammatory immune regulatory imbalance. Short term remission (one week) is seen in 88% of treated patients although duration of response is highly variable. Immune activation in the mucosa (i.e. activation of NFKB-p65) as well as in the periphery (production of TNF-a) can predict clinical relapse.
April 2000
fractory CD. We also assessed the duration of response comparing children with early CD to children with longstanding (late) CD. Methods: Children age 6 - 18 with medically refractory CD were eligible for enrollment in a prospective, open-label trial of Infliximab, 5 mg/kg intravenous infusion. Primary endpoints included measurement of disease activity (pediatric Crohn's disease activity index; PCDAI), steroid use and duration of clinical response. Early CD was arbitrarily defined as disease duration of less than 2 years, while late CD required greater than 2 years of disease as measured from the time of diagnosis. Results: 15 consecutive children with medically refractory CD were enrolled (mean age 13.4 :!:3.3). 14/15 children (93%) improved following Infliximab infusion with a significant decrease of both PCDAI (p < 0.05) and daily steroid usage (p < 0.05) by four weeks. Eleven patients (74%) achieved complete remission by 10 weeks (PCDAI < 15). Four of six children (67%) with early CD maintained clinical response through the 12 month trial period, compared with 0/8 children with late disease. All late CD pts, relapsed by 8 months. There were no complications associated with Infliximab. Conclusions: Infliximab is safe and effective in the short-term treatment of medically refractory pediatric CD. More importantly, there is a remarkably prolonged duration of response following Infliximab therapy in children with early compared to late CD. Demographic data - Infliximab responders (14115)
CD duration (months) age (years) PCDAI entry
early CD (n = 6)
lateCD(n =8)
10.6 ± 6.2 12.7 ± 1.8
45.2 ± 16.6 13.7 ±45 52.9 ± 11
51.5± 18
2964 INHIBITION OF PARP-2 EXPRESSION BY AN ANTISENSE OLIGONUCLEOTIDE IMPROVES COLONIC PERMEABILITY IN IL10'\' MICE. Humberto B. Jijon, Ian J. Popoff, Michael Ma, Andreas Wessler, Howard G. Parsons, Lawrence D. Jewell, Karen L. Madsen, Univ of Calgary, Calgary, AB, Canada; ISIS Pharmaceuticals, San Diego, CA; Univ of Alberta, Edmonton, AB, Canada. Inflammatory bowel disease is characterized by high levels of reactive oxygen and nitrogen species, which indiscriminately attack DNA causing strand breakage. DNA damage subsequently activates a nuclear enzyme, poly-(ADP-ribose) polymerase (pARP) which can deplete cellular AIP and increase epithelial permeability. Recently, a new isoform of the PARP family, PARP-2, has been described in human and murine cDNA. However, to date, there has been no characterization of the role of PARP- 2 in intestinal inflammation. Previous studies have shown PARP-I to play a critical role in perpetuation of inflammation, and indeed, we have shown that pharmacological inhibition of the PARP family with 3-aminobenzamide (3-AB) improves colitis in IL-IO'\' mice. Aim: The aim of this study was to compare the results of 3-AB treatment in the IL-I 0'\' mouse with the specific inhibition of PARP-2 using an antisense oligonucleotide. Methods: Adult IL-IO'\' mice were administered either the PARP inhibitor, 3-AB (20 mg/kgld), a specific PARP-2 antisense oligonucleotide (25 mg/kgld), or a control mismatch nucleotide (25 mg/kg/d) for 14 days. In separate experiments, colonic permeability was assessed using a single pass perfusion technique in vivo and whole colons were removed for measurement of INFa and IFNy secretion and iNOS activity. Results: In comparison with control mice, IL-IO'\' mice displayed a 100% increase in INFa and IFNy secretion in conjunction with an 84% increase in colonic permeability and iNOS activity (p
2965 TREATMENT OF CROHN'S DISEASE WITH INFLIXIMAB· AN INITIAL COMMUNITY PRACTICE EXPERIENCE. Robert P. McCabe, Ronald M. Schwartz, Vicki Bebeau, Naomi Tatarek, David I. Weinberg, Minnesota Gastroenterology, P A, Minneapolis, MN. Aim: To assess the efficacy and safety of Crohn s disease treatment with infliximab in a community practice setting. Methods: Prospective data was collected on the first 52 infliximab treated patients from a 37-physician GI practice. COAl, medications, fistula drainage, seton status and subjective response were recorded at the time of infusion and at 4 weeks following the infusion(s). Duration of response.long term subjective response. seton status, surgeries, medications and adverse events were determined by a phone and chart survey conducted at 20 to 56 weeks. Response was measured in four ways: I)CDAI decrease ~ 70 at 4 weeks, 2)physician/ patient subjective impression at 4 weeks, 3) patient subjective impression at time of telephone survey and 4) discontinuation of steroids. Results: 43 patients were treated for active lumenal disease, 9 for fistulae. The average age and disease duration were 41 and II years. Average baseline COAl was 286. Chart and survey data were available on 43 (9 fistulous) of 52 patients. Both baseline and 4 week COAl results were available for 22. These averaged 263 and 174, respectively. Clinical response was as follows: COAl decrease ~ 70 = 50% (11/22); subjective response at 4 weeks = 72%(28/39); subjective response at follow up survey = 70% (28/40); steroids discontinued = 72% (18/25). Complete fistula closure was considered to have occurred in 44% (4/9) patients, partial closure in another 33% (3/9). A positive subjective response (4 weeks and follow up survey) occurred in 77% (7/9) of fistula patients. Four patients had setons, all were removed at approximately week two, none required replacement. Four fistula patients (44%) and 8 (18% )Iumenal disease patients required surgery during the follow up period. Initial COAl score, patient age and disease duration did not predict response. Average duration of response was 13 weeks (range I to 42). Four patients have maintained a response beyond 34 weeks. Patients on 6MP/azathioprine or methotrexate tended to have longer response duration (18 wks vs. 9 wks, p=.06) Adverse events occurred in 8/37 (21%)patients: most very mild except I serum sickness like reaction and I carcinoma in a rectovaginal fistula. One patient died of possible peritonitis 6 months post infusion. Conclusions: I) Infliximab is a generally safe and effective treatment for Crohn s disease in a community GI practice. 2) Convincing subjective improvement may occur without meeting objective response criteria. 3) Immunosuppressive therapy may prolong response to infliximab. 2966 INCREASED PERIPHERAL PRODUCTION OF TNF-A AND MUCOSAL LEVELS OF ACTIVATED NFKB PREDICT RELAPSE AFTER TREATMENT WITH INFLIXIMAB IN PATIENTS WITH CROHN'S DISEASE. Susanna Nikolaus, Tanja Kuhbacher, Ulrich R. Foelsch, Andreas Raedler, Stefan Schreiber, I Dept of Medicine, Christian-Albrechts-University, Kiel, Germany; Tabea Ctr for Inflammatory Bowel Diseases, Hamburg, Germany. Background: Secretion of TNF-a is increased in active CD. Mucosal NFKB, a major player in pro-inflammatory signal transduction, is activated in intestinal inflammation. Infliximab (Remicade'Y) binds to TNF-a and results in remission rates of up to 50% in chronic active CD (4 wks after single infusion). Intervals for (re)-infusion of infliximab which are necessary to avoid relapses are unknown. Aims: To find predictors of relapse in infliximab treated CD patients. Methods: 24 patients with active CD (CDAI>200, 18-50 yrs, rectosigmoidal lesions) were recruited from 35 consecutive patients treated by a single infusion with infliximab (5mg/kg). All patients had received steroidslimmunosupressives in the past without success. Rectal biopsies were taken before, 1,2,4,8 and 12 wks after infusion. Nuclear extracts were prepared from snap frozen biopsies for detection of activated NFKB-p65 (western blot). Blood was drawn for whole blood cytokine assay (LPS stimulated). After 24 hrs TNF-a was assessed in the cell-free phase by ELISA. Results: 21 of 24 patients were in remission (CDAI<150) at week I (88%). I day after infliximab therapy, LPS stimulated TNF-a secretion dropped from increased (1928 (interquart. range: 951-2510) pg/ml) to non-detectable levels «3,2 pglml) in all patients. Mucosal levels of activated nuclear NFKB-p65 markedly decreased within 2 wks after infusion, in some patients below detectable levels. Relapses (increase of COAl >50 points to > 150 in comparison with wkl values) were seen in 6/21 patients (29%) at wk 4, 13/21 patients (62%) at wk 8,17/21 patients (81%) at wk 12 and 19/21 patients (90%) at wk 16. Patients who relapsed, showed a statistically significant increase of stimulated TNF-a whole blood cytokine levels and increased levels of activated mucosal NFKB-p65 at least 2-4 wks prior to clinical and endoscopic relapse. Conclusions:Treatment with infliximab (Remicade'') reverts the pro-inflammatory immune regulatory imbalance. Short term remission (one week) is seen in 88% of treated patients although duration of response is highly variable. Immune activation in the mucosa (i.e. activation of NFKB-p65) as well as in the periphery (production of TNF-a) can predict clinical relapse.