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Sustained remission lowers the likelihood of hospitalization and surgery in patients with Crohn’s Disease
AJG – September, Suppl., 2002
Abstracts
or episodic treatment with 5 or 10mg/kg infliximab was associated with a sustained decrease in gelatinase B and a further reduction in subepithelial and lamina propria tenascin. The reduced expression of both gelatinase B and tenascin was not sustained in the single dose group that went onto episodic treatment at 5mg/kg infliximab. Conclusions: Infliximab downregulates gelatinase B and tenascin, molecules associated with the aberrant tissue remodeling, cell migration and angiogenesis observed in Crohn’s disease. 789 SUSTAINED REMISSION LOWERS THE LIKELIHOOD OF HOSPITALIZATION AND SURGERY IN PATIENTS WITH CROHN’S DISEASE Gary R. Lichtenstein*, Songkai Yan, Mohan Bala, Gregory Keenan and Stephen B. Hanauer. Hospital of University of Pennsylvania, Philadelphia, PA; Centocor, Inc., Malvern, PA and University of Chicago, Chicago, IL.
Purpose: Leukopenia resulting from 6 MP treatment accelerates remission of Crohn’s disease. We describe a dramatic febrile illness with a sustained leukopenia and a subsequent prolonged remission in 4 young women with severe fistulizing Crohn’s disease following treatment with 6 MP. Methods: We performed a retrospective review of hospital records. Patient # 1 was hospitalized for fever of 103F, hepatitis, liver, pancreatic abscesses and perforation of an ileocolic anastamosis. The patient was on 6 MP for 6 years prior. She was hospitalized for 3.5 mos. with a sustained leukopenia. Following recovery, all evidence of her Crohn’s disease disappeared for 8 yrs. Patient# 2 was on 6 MP for 4 years when she developed a febrile illness and leukopenia. She spiked fever to 105 F for 3 weeks. No etiology was found despite extensive work– up. After recovery she remitted for 4 yrs. Patient #3 was on 6 MP for 4 years. She was non compliant with blood testing. She developed a WBC 1100 with a febrile illness for which she was hospitalized for a month. No etiology was found. After recovery she remained in remission for 6 yrs. Patient #4 was hospitalized for total sloughing of her vulva and perineum. Treatment with 6MP caused leukopenia, fever, and hepatitis with jaundice. The leukopenia lasted for 2 weeks. Coincidentally she had reepithelization of her perineum and remained in remission for 3 yrs. Results: All 4 patients had 6 MP toxicity with high fever and a sustained leukopenia. Following recovery from the acute illness, they maintained a long remission. Conclusions: Severe and sustained leukopenia and febrile illness due to 6MP predisposes to a prolonged remission of Crohn’s disease. Work up for FUO with a sustained leukopnenia after 6MP yields no causative organism and may result in long term remission. A goal of future research should be to establish the immunological benefits without the toxicity of immunosuppression.
Purpose: Hospitalizations and surgeries/procedures comprise the major components of health care costs for patients (pts) with Crohn’s disease (CD). We examined the effect that maintenance of remission (REM) has on CD pts who used infliximab (INF), as assessed by duration of REM and number of hospitalizations and surgeries/procedures in a clinical trial comparing INF at two doses (5 mg/kg and 10 mg/kg) to placebo. Methods: In ACCENT I, 573 pts received an infusion of 5mg/kg INF at baseline. At week 2, pts were randomized to 1 of 3 infusion regimens: 1) placebo at wks 2 and 6 and then q8 wks, 2) 5mg/kg INF at wks 2 and 6 and then q8 wks, and 3) 5mg/kg INF at wks 2 and 6 and then 10mg/kg q8 wks. Regimens continued up to wk 46. For each regimen, beginning at wk 14 and on an episodic basis, pts who initially responded but later lost response were eligible to cross over to a dose 5mg/kg higher than their original assigned dose. Hospitalization and surgery/procedure data were collected up to wk 54. We grouped pts by percentage of time they spent in REM during the trial, based on their REM status at each visit, and examined if there is any association between this variable and number of CD–related hospitalizations and surgeries/procedures. This analysis was performed for wk 2 responders and all pts. Results: Number of hospitalizations/surgeries/procedures decreased as percentage of time in REM increased. Hospitalization rate for pts that spent ⬍⫽ 25% of time in REM was about 4 times that seen for pts that spent ⬎ 75%. Surgery/procedure rate on pts that spent ⬍⫽ 25% of time in REM was 5 to 10 times that on pts that spent ⬎ 75%.
* all 4 were female/caucasians with ileocolitis
Table 1 Percent Time in Remission (RPCT) and Average Number of Hospitalizations (HOSP) and Surgeries/Procedures (SURG) per 100 Patients, up to Week 54
791
HOSP HOSP SURG SURG
RPCT
0% to 25%
>25% to 50%
>50% to 75%
>75% to 100%
p– value*
Responders (N) All Patients (N) Responders (N) All Patients (N)
38 (108) 41 (272) 10 (108) 11 (272)
25 (56) 22 (88) 7 (56) 6 (88)
23 (70) 23 (96) 3 (70) 3 (96)
9 (101) 12 (117) 1 (101) 2 (117)
0.011 0.002 0.045 0.035
* Row mean scores differ test with Cochran–Mantel–Haenszel statistic
Conclusions: CD pts who spend longer duration in remission are less likely to be hospitalized or have surgeries/procedures. A treatment strategy that maintains pts in remission has the potential to offset costs by reducing the rate of hospitalizations and surgeries. 790 UNPLANNED SUSTAINED LEUKOPENIA WITH FEVER DUE TO 6 – MERCAPTOPURINE INDUCES LONG TERM REMISSION OF SEVERE CROHN’S DISEASE Efrat Z. Lobel, M.D., Burton I. Korelitz, M.D.*, Katherine Vakher, M.D. and Georgia Panagopoulos, Ph.D. Division of Gastroenterology, Lenox Hill Hospital and New York University School of Medicine, New York, NY.
S259
Patient Demographics Duration of Patient WBC Duration disease Age Lowest of 6 MP (years) 31 26 28 24
2000 2500 1100 2400
6 yrs 4 yrs 4 yrs 2 days
12 8 14 18
Surgeries prior to febrile illness
Duration Dose of of 6MP Remission
Right hemicolectomy 50 mg/day 10 years none 200 mg/day 3 years Right hemicolectomy 50 mg/day 6 years Total colectomy, 75 mg/day 3 years abdominoperineal resection
IN VITRO STUDY OF BUDESONIDE CAPSULES (ENTOCORT威 EC) 3 MG AFTER EXPOSURE OF THE GRANULES TO APPLESAUCE U. Espmarker, B.Sc.*, M. Kristensson, M.S. and F. Langkilde, Ph.D. R & D, AstraZeneca, Lund, Sweden. Purpose: Applesauce is often used to facilitate intake of oral doses of medication when given to children and adults with swallowing difficulties. Budesonide capsules 3 mg are a multiunit preparation of coated granules with both delayed– and modified–release properties contained within hard gelatin capsules. The enteric coating is soluble in media with a pH above 5.5. The purpose of this study is to test in an in vitro environment whether the granules in budesonide capsules 3 mg can be mixed with applesauce to facilitate intake without changing the properties of the product. Methods: The budesonide capsules 3 mg were opened, and the granules from each capsule were sprinkled into 15 g of applesauce (pH 3.6). After 30 minutes, the granules were washed with simulated gastric fluid (SGF) without enzymes (pH 1.2) and then transferred to 12 mm flow–through cells (USP 4). The release of budesonide, the active pharmaceutical ingredient, was analyzed in SGF for 2 hours using a media flow of 8 mL/min. Then the medium was changed to simulated intestinal fluid (SIF), 50 mM
Abstracts
or episodic treatment with 5 or 10mg/kg infliximab was associated with a sustained decrease in gelatinase B and a further reduction in subepithelial and lamina propria tenascin. The reduced expression of both gelatinase B and tenascin was not sustained in the single dose group that went onto episodic treatment at 5mg/kg infliximab. Conclusions: Infliximab downregulates gelatinase B and tenascin, molecules associated with the aberrant tissue remodeling, cell migration and angiogenesis observed in Crohn’s disease. 789 SUSTAINED REMISSION LOWERS THE LIKELIHOOD OF HOSPITALIZATION AND SURGERY IN PATIENTS WITH CROHN’S DISEASE Gary R. Lichtenstein*, Songkai Yan, Mohan Bala, Gregory Keenan and Stephen B. Hanauer. Hospital of University of Pennsylvania, Philadelphia, PA; Centocor, Inc., Malvern, PA and University of Chicago, Chicago, IL.
Purpose: Leukopenia resulting from 6 MP treatment accelerates remission of Crohn’s disease. We describe a dramatic febrile illness with a sustained leukopenia and a subsequent prolonged remission in 4 young women with severe fistulizing Crohn’s disease following treatment with 6 MP. Methods: We performed a retrospective review of hospital records. Patient # 1 was hospitalized for fever of 103F, hepatitis, liver, pancreatic abscesses and perforation of an ileocolic anastamosis. The patient was on 6 MP for 6 years prior. She was hospitalized for 3.5 mos. with a sustained leukopenia. Following recovery, all evidence of her Crohn’s disease disappeared for 8 yrs. Patient# 2 was on 6 MP for 4 years when she developed a febrile illness and leukopenia. She spiked fever to 105 F for 3 weeks. No etiology was found despite extensive work– up. After recovery she remitted for 4 yrs. Patient #3 was on 6 MP for 4 years. She was non compliant with blood testing. She developed a WBC 1100 with a febrile illness for which she was hospitalized for a month. No etiology was found. After recovery she remained in remission for 6 yrs. Patient #4 was hospitalized for total sloughing of her vulva and perineum. Treatment with 6MP caused leukopenia, fever, and hepatitis with jaundice. The leukopenia lasted for 2 weeks. Coincidentally she had reepithelization of her perineum and remained in remission for 3 yrs. Results: All 4 patients had 6 MP toxicity with high fever and a sustained leukopenia. Following recovery from the acute illness, they maintained a long remission. Conclusions: Severe and sustained leukopenia and febrile illness due to 6MP predisposes to a prolonged remission of Crohn’s disease. Work up for FUO with a sustained leukopnenia after 6MP yields no causative organism and may result in long term remission. A goal of future research should be to establish the immunological benefits without the toxicity of immunosuppression.
Purpose: Hospitalizations and surgeries/procedures comprise the major components of health care costs for patients (pts) with Crohn’s disease (CD). We examined the effect that maintenance of remission (REM) has on CD pts who used infliximab (INF), as assessed by duration of REM and number of hospitalizations and surgeries/procedures in a clinical trial comparing INF at two doses (5 mg/kg and 10 mg/kg) to placebo. Methods: In ACCENT I, 573 pts received an infusion of 5mg/kg INF at baseline. At week 2, pts were randomized to 1 of 3 infusion regimens: 1) placebo at wks 2 and 6 and then q8 wks, 2) 5mg/kg INF at wks 2 and 6 and then q8 wks, and 3) 5mg/kg INF at wks 2 and 6 and then 10mg/kg q8 wks. Regimens continued up to wk 46. For each regimen, beginning at wk 14 and on an episodic basis, pts who initially responded but later lost response were eligible to cross over to a dose 5mg/kg higher than their original assigned dose. Hospitalization and surgery/procedure data were collected up to wk 54. We grouped pts by percentage of time they spent in REM during the trial, based on their REM status at each visit, and examined if there is any association between this variable and number of CD–related hospitalizations and surgeries/procedures. This analysis was performed for wk 2 responders and all pts. Results: Number of hospitalizations/surgeries/procedures decreased as percentage of time in REM increased. Hospitalization rate for pts that spent ⬍⫽ 25% of time in REM was about 4 times that seen for pts that spent ⬎ 75%. Surgery/procedure rate on pts that spent ⬍⫽ 25% of time in REM was 5 to 10 times that on pts that spent ⬎ 75%.
* all 4 were female/caucasians with ileocolitis
Table 1 Percent Time in Remission (RPCT) and Average Number of Hospitalizations (HOSP) and Surgeries/Procedures (SURG) per 100 Patients, up to Week 54
791
HOSP HOSP SURG SURG
RPCT
0% to 25%
>25% to 50%
>50% to 75%
>75% to 100%
p– value*
Responders (N) All Patients (N) Responders (N) All Patients (N)
38 (108) 41 (272) 10 (108) 11 (272)
25 (56) 22 (88) 7 (56) 6 (88)
23 (70) 23 (96) 3 (70) 3 (96)
9 (101) 12 (117) 1 (101) 2 (117)
0.011 0.002 0.045 0.035
* Row mean scores differ test with Cochran–Mantel–Haenszel statistic
Conclusions: CD pts who spend longer duration in remission are less likely to be hospitalized or have surgeries/procedures. A treatment strategy that maintains pts in remission has the potential to offset costs by reducing the rate of hospitalizations and surgeries. 790 UNPLANNED SUSTAINED LEUKOPENIA WITH FEVER DUE TO 6 – MERCAPTOPURINE INDUCES LONG TERM REMISSION OF SEVERE CROHN’S DISEASE Efrat Z. Lobel, M.D., Burton I. Korelitz, M.D.*, Katherine Vakher, M.D. and Georgia Panagopoulos, Ph.D. Division of Gastroenterology, Lenox Hill Hospital and New York University School of Medicine, New York, NY.
S259
Patient Demographics Duration of Patient WBC Duration disease Age Lowest of 6 MP (years) 31 26 28 24
2000 2500 1100 2400
6 yrs 4 yrs 4 yrs 2 days
12 8 14 18
Surgeries prior to febrile illness
Duration Dose of of 6MP Remission
Right hemicolectomy 50 mg/day 10 years none 200 mg/day 3 years Right hemicolectomy 50 mg/day 6 years Total colectomy, 75 mg/day 3 years abdominoperineal resection
IN VITRO STUDY OF BUDESONIDE CAPSULES (ENTOCORT威 EC) 3 MG AFTER EXPOSURE OF THE GRANULES TO APPLESAUCE U. Espmarker, B.Sc.*, M. Kristensson, M.S. and F. Langkilde, Ph.D. R & D, AstraZeneca, Lund, Sweden. Purpose: Applesauce is often used to facilitate intake of oral doses of medication when given to children and adults with swallowing difficulties. Budesonide capsules 3 mg are a multiunit preparation of coated granules with both delayed– and modified–release properties contained within hard gelatin capsules. The enteric coating is soluble in media with a pH above 5.5. The purpose of this study is to test in an in vitro environment whether the granules in budesonide capsules 3 mg can be mixed with applesauce to facilitate intake without changing the properties of the product. Methods: The budesonide capsules 3 mg were opened, and the granules from each capsule were sprinkled into 15 g of applesauce (pH 3.6). After 30 minutes, the granules were washed with simulated gastric fluid (SGF) without enzymes (pH 1.2) and then transferred to 12 mm flow–through cells (USP 4). The release of budesonide, the active pharmaceutical ingredient, was analyzed in SGF for 2 hours using a media flow of 8 mL/min. Then the medium was changed to simulated intestinal fluid (SIF), 50 mM